不斉反応に用いる新規ペプチド有機分子触媒の開発
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言語: English
出版者:
公開日: 2022-06-30
キーワード (Ja):
キーワード (En):作成者: シヤガラジャン, ラジクマー
メールアドレス:所属:

URL

https://doi.org/10.15118/00010860

Development of New Peptide Organocatalyst for Asymmetric
Reactions
ThesisSubmitted in partial fulfillment of the requirements for the degree of
DOCTOR OF PHILOSOPHY
byMr. THIYAGARAJAN RAJKUMAR

Supervisor Professor HIROTO Nakano

Course of Advanced Sustainable and Environmental Engineering
GRADUATE SCHOOL OF ENGINEERINGMURORAN INSTITUTE OF TECHNOLOGYMURORAN, JAPAN2022

博士論文題目
Development of New Peptide Organocatalyst for Asymmetric Reactions(不斉反応に用いる新規ペプチド有機分子触媒の開発)
氏名 Rajkumar Thiyagarajan (ラジクマー シャガラジャン)
論文内容の要旨
医薬品を含む多くの生物活性化合物は光学活性物質であり, その鏡像異性体は異なる生体 内活性を示すことが多く, 有効な一方の鏡像異性体を高立体選択的に合成する
ための不斉合 成反応，特に不斉触媒を用いる触媒的不斉合成反応の開発は医薬品や様々な光学活性機能性 分子を創製するために重要である。その不斉触媒の中で，金属を用いない有機分子触媒は空 気中で安定であり取り扱いやすく安価であるという利点などを有するため, 次世代の環境調 和型触媒として現在活発な研究開発が行なわれている。
著者は, 新規多点認識型有機分子触媒として，これまでその機能性の検討がなされていな かった γ—ターン型トリペプチドに着目し，その不斉触媒としての機能解明を
不斉アルドール 反応に適用することにより試みた。適用する不斉アルドール反応は炭素—炭素結合形成反応と して有用であり，各種医薬品や複雑な生物活性化合物を合成するための鍵反応として汎用さ れている。
新規有機分子触媒としての γ—ターン型トリペプチド有機分子触媒は，容易に入手可能な各 種アミノ酸から数工程を経て合成され, 得られたトリペプチド有機分子触媒の不斉触媒活性 をケトン類とアルデヒド類との不斉アルドール反応に適用し検討した。
その結果として, 創 製した γ—ターン型トリペプチド有機分子触媒が本反応において不斉触媒活性を示し，優れた 化学収率と良好な光学収率で光学活性アルドール生成物を与えることを見出した。得られた 生成物は，創薬のための様々な生物活性化合物の合成中間体として有用であり，この合成中 間体から新薬候補化合物を創製できることが期待される。
本研究において著者は，「分子構造が γ—ターン型分子内水素結合で固定化され，さらにそ の分子構造内に基質との共有結合部位と水素結合部位，さらには反応のエナ
ンチオ選択性の 制御に有効な立体制御部位を併せもつ新規多点認識機能を発現する γ—
ターン型トリペプチ ド有機分子触媒」を開発することに成功し, それらが創薬に有効な不斉アルドール反応にお いて良好な不斉触媒活性を示すことを明らかにした。開発した本ペプチド型有機分子触媒は， 他の有用な不斉触媒反応においても触媒機能を示すことが期待され，さらに，本反応によっ て得られる化合物は様々な医薬品をはじめとする生物活性化合物の合成中間体として有用で あることから，本研究の成果は, 新薬創製を指向した合成開発研究に大きく貢献できると期 待される。

TITLE: Development of New Peptide Organocatalyst for Asymmetric Reactions (不斉反応に用いる新規ペプチド有機分子触媒の開発)
NAME: Rajkumar Thiyagarajan (ラジクマー シャガラジャン)
ABSTRACT
Many biologically active compounds, including pharmaceuticals, are optically active andoften only one of the enantiomer shows a high biologically activity. Therefore, it is important todevelop the synthetic methodology for providing only necessary enantiomer. As the methodology,
catalytic asymmetric synthesis, in which the use of a low amount of a chiral catalyst theoreticallyenables infinite production of optically active compounds, is the most efficient in the syntheticorganic chemistry field. Moreover, this methodology is also important in terms of energy saving
and environmental friendliness. The chiral catalysts used in catalytic asymmetric syntheses can bedivided into two categories of organometallic catalyst and metal-free organocatalyst. Particularly,organocatalyst is stable in air, nontoxic, easy to handle, and inexpensive, so they are being focusedon as next-generation, environmentally friendly catalysts.
Author focused on a peptide as an organocatalyst. In organocatalyst, peptide catalyst has
been recognized as a powerful and useful tool in synthetic organic chemistry field, because
peptides are highly modular, structurally diverse and easily accessible from nature's chiral pool. In
the development of peptide organocatalyst, inspired by the efficient and stereospecific metal-free
enzymatic processes, synthetic chemists have devoted much effort in recent years towards thedevelopment of a broad range of short peptide-based asymmetric catalysts, which mimic various
qualities of enzymes. The structural diversity available with short peptide sequences and the factthat peptides offer a more strictly defined asymmetric environment to the reactants, compared tosingle amino acids, makes this class of molecules particularly promising towards the developmentof a wide range of organocatalysts with fine-tunable structural and electronic properties.
Author designed a new small g-turn type N-primary amino terminal tripeptide containing
the pyrrolidine ring as a backbone. This peptide has N-terminal side at nitrogen atom in pyrrolidine
backbone and C-terminal exists at 2-position on the pyrrolidine ring. As a reaction for providing
the utility of the peptide organocatalyst, asymmetric aldol reaction of ketones with aldehydes was
selected. The aldol products from this reaction work as an important synthetic precursor of thesynthesis of many biologically active compounds including pharmaceuticals.
Author tried the reaction of ketones with aldehydes using newly prepared g-turn type
tripeptide organocatalyst at first time. As a result, this tripeptide organocatalyst showed good
catalytic activity in this reaction and the desired chiral aldol products were obtained in goodchemical yields, diastereoselectivities and enantioselectivities.
In this study, author revealed that the new explored tripeptide organocatalysts were showedsatisfactory catalytic activities in the aldol reaction. It is expected that these results should be able
to greatly contribute the development of new drug and its related compounds.

Contents
Chapter 1
1.Introduction

1

1.1 Chirality

2

1.2 Catalysts for asymmetric reaction

3

1.3 Catalysis in asymmetric synthesis

4

1.4 Organocatalysis

4

1.5 Activation modes in organocatalysis

6

1.5.1 Mode activation of Covalent catalyst

6

1.5.2 Non-covalent modes of activation

9

1.6 Peptide as Organocatalysts for asymmetric reaction

12

1.7 Author project

17

Chapter 2
New small g-turn type N-primary amino terminal tripeptides organocatalyst
for solvent-free asymmetric aldol reaction of various ketones with aldehydes
2.1 Author approach21

2.2 Aldol reaction

23

2.3 Mechanism

23

2.4 Result and discussion

26

2.5 Evaluation of catalysts

29

2.6 Optimization of reaction condition31

2.7 Substrate scope33

2.7.1 Reaction of cyclohexanone 39a with various aldehydes 7a-l

33

2.7.2 Reaction of various ketones 39b-h with various aldehydes 7a35

2.8 Plausible reaction course

37

2.9 Summary40

Chapter 3
New small g-turn type N-primary amino terminal tripeptides organocatalyst
for solvent-free asymmetric cross aldol reaction of various cyclic andacyclic with isatins
3.1 Authors approach42

3.2 Result and discussion

46

3.3 Catalysts 61a-j, 65 and 69a,b screening in asymmetric cross aldol reaction

47

3.4 Optimization of reaction condition49

3.5 Asymmetric cross aldol reaction of various isatins 43b-m with cyclic and acyclicketones 39b-g, 6 using catalysts 61c

51

3.6 plausible reaction course

55

3.6 Summary

57

4. Conclusion

58

5. Experimental section

60

6. Acknowledgements

91

7. References

92Chapter 1
Introduction

1. Introduction
In recent years, the stereo-controlled organic molecule synthesis is highly desirable
technology, challenging, and easy to synthesis of various biologically active molecules. In viewof these, the development of new effective catalytic system in stochiometric quantity requires toregulate the stereoselectivity of products such as metals, bio-active molecules, organic
molecules.1 In asymmetric catalysis, organocatalysts is one of the leading research area as
intensively appealing and essential tools in synthetic chemistry for chiral induction of biologically
active molecules. When compared to other methods, this field stands out as a preferable option
for a variety of reasons, including the avoiding of hazardous metals and the use of expensive
enzyme catalysts to accomplish asymmetric organic reactions. Recently, significant progress has
been made in the development of efficient small chiral molecules to control the stereoselectivityof substrates. These molecules are appealing in biological and medicinal synthesis for a varietyof reasons, including their ease of handling, longstanding constancy, accessibility of bothenantiomers, and cost-effectiveness. In this regard, asymmetric reaction provides an easy
approach to important chiral molecule production, emerging synthetic methods for smaller andsuccessful organocatalysts are fascinating.
The author's Ph.D. purposes include the development of simple g-turn type N-primaryamino terminal peptide organocatalysts and their application to the asymmetric aldol reactions.
The establishment of new g-turn type N-primary amino terminal peptide organocatalysts and theirapplication were primarily focused on three parts in this thesis, (i) The development of New typeof g-turn type N-primary amino terminal peptide organocatalysts, (ii) Simple g-turn type Nprimary amino terminal peptide organocatalysts for asymmetric aldol reaction of various ketones
with aldehydes. (ii) Simple g-turn type N-primary amino terminal peptide organocatalysts forasymmetric cross aldol reaction of various ketones with substituted isatins. The following sections
go through the detailed results and applications of these organocatalysts in asymmetric Aldol
reactions.

11.1 Chirality
Chirality is the property of an object of being non- super imposable behavior on its mirror
image. A chiral molecule can then exist as two enantiomers which relate to the revealed mirror
imaginings. On a molecular scale, there are many ways to meet this definition and for a molecule
to be chiral it must possess a stereogenic center. The field of asymmetric synthesis progressing
totally based on that terminology which could be defined as follows, “organic molecule with sameattachments”.2 One of the classical examples to clarify the chirality term is our human both left
and right hands which are mirror images of each other and never be impose with each other across
any axis (Figure 1).

Figure 1. Two enantiomers of generic amino acids.
Amino acids are common chiral compounds that exist in enantiomer (D and L) forms andare broadly used in organic synthetic applications. For example, the amino acids have thefollowing properties in both D and L isomers. Generally, L-amino acids are naturally occurring(Figure 2).
O
R

O
O

O

R
NH3

NH3
L-Amino acids

D-Amino acids

Figure 2. Enantiomers of amino acids.
2

Optically active chiral centers are embedded in numerous bio-active compounds andpharmaceutical intermediate compounds administered to the human body. Surprisingly, one
enantiomer is an active one of two enantiomers, whereas the other enantiomer has no function or
extremely poisonings. In light of these deliberations, gram to bulk scale synthesis of that particular
active enantiomer is one of the most challenging tasks.

1.2 Catalysts for asymmetric reaction
In catalysis an addition of a small amount of a foreign material called “catalyst” speeds
up a chemical process by decreasing the transition state energy, thus increasing the rate of thereaction without being consumed itself during the transformation. This process seems ideal forthe preparation of chiral molecules since it only requires a very small amount of chiral catalyst totransform an achiral molecule into an enantioenriched chiral product. Asymmetric synthesis is
one of the most essential and straightforward method in organic synthesis to develop moleculeswith chiral centers from achiral molecules.3 During the course of this asymmetric reaction,
stereoisomers of products with imbalanced ratios were generated by experimenting with catalysts.
Many bioactive and natural chemicals are not found in nature in both isomeric forms,
necessitating laboratory synthesis for small- and large-scale productions. Generally, eachcompound which are obtain with different stereochemistry as an outcome might possess
distinctive biological applications. For instance, “Ibuprofen” preferred for non-steroidal antiinflammatory and “Omeprazole” recommended for gastric acid-related disorders (Figure 3).4
H

O

H

O

OH

OH

(R)-Ibuprofen(S)-Ibuprofen

Figure 3. Different stereoisomers of ibuprofen.

3

Based on this research background, (S)-Ibuprofen, the drug has the ability to inhibit
cyclooxygenase (COX), typically administered to the patients with heavy pain, fever andinflammation, but another stereoisomer (R)-Ibuprofen expresses no action at all. Based on thisexperience, synthesis of those bioactive compounds enantiomer in organic synthesis remains still
as a challenging task.

1.3 Catalysis in asymmetric synthesis
The investigation of the catalyst utilizes an asymmetric reaction is tremendously importantfor our everyday life. Because catalysts are needed in the production of therapeutic drugs.
Consequently, they are low toxicity, stability in air and moisture and easy preparation fromstarting materials. Commonly, catalysis field can predominantly categorize into three divisions
such as, i) Transition metal catalysis, ii) Enzyme catalysis, and iii) Organocatalysis.5 In transition
metal catalysis, catalysts merged with several metal atoms used for effective promotion of
optically active compounds, but it has numerous hindrances including, toxic metal usage, costeffective and extremely sensitive in air and moisture. To avoid metal usage, biological compounds
have demonstrated which also showed enhance performance on product formation in asymmetric
reactions. Furthermore, they also occupy certain disadvantages such as, high sensitivity, vast
compound structure and tedious synthesis method. From this knowledge, to rectify these problems
organic molecules alone supported chiral molecules were introduced in asymmetric synthesis forchiral induction.

1.4 Organocatalysis
Organocatalysis is now referred to as the third pillar of asymmetric synthesis, equal toorganometallic and enzymatic catalysis.6 Organocatalysts have several important advantages,
since they are usually robust, easily available, inexpensive and non-toxic. Because of theirinertness towards moisture and oxygen, demanding conditions such as inert atmosphere or
dry/degassed solvents are often not required. Due to the absence of transition metals,
organocatalytic methods are especially appealing for the synthesis of pharmaceuticals in which4hazardous metallic traces are unacceptable. Due to this reason, numerous chiral organic molecules
have been developed and demonstrated in asymmetric reactions as an organocatalysts. Still,
simple and effective organocatalysts development remains unsuccessful and highly demanded inasymmetric synthesis. There are numerous valid reasons behind this expansion such as, costeffective testing, the elevation of catalysts does not require tedious steps, it vanish toxic metal
involvement, resistance to moisture and air stability, commercial accessibility of ingredients,
environmentally benign, uncomplicated handling of catalysts and ambient reaction settings.
Ph
Ph
OH

O
N
H

N
H

OH

(S)-Proline
organocatalyst

O(S)-Proline silyl etherorganocatalyst

N

R
N
Bn
H
Macmillan imidazolidinone
organocatalyst

iPr

iPr

O
H 2N
H 3C

N
H
CH3

OMe

O

H
N

iPr
O
O
P
OR
O i
Pr

NH2

OH
R

O

N
iPr

Peptideorganocatalyst

Ph

iPr
BINOL phosphoric acidorganocatalyst

Cinchona
primary amine
organocatalyst
O

O
Br
Bu
Bu

Ph
Binaphthyl
phase transferorganocatalyst

N
H

N
H

N

H
N

F3C

N

S

N

N

H
N

CF3
Squaramideorganocatalyst

Thioureaorganocatalyst

Figure 4. Various chiral organocatalysts.
In interpretation of these advantages, researchers have documented enormous reliable catalysts
5for chiral induction of bio-active molecule synthesis. For example, various chiral organocatalysts
which delivers excellent results of stereochemical products that are shown in diagram below(Figure 4).7
The Friedel-Crafts alkylation of N-substituted pyrrole 2 with olefin 3 using MacMillanorganocatalyst 1 afforded corresponding pyrrolyl carbonyl products 4 in good chemical yield andstereoselectivities (up to 83% yield and 91% ee) (Scheme 1).8

O

Me
N Me

Bn

N
H

Me

1 (20 mol%)
+
N
Me

O
Me

O

THF-H2O

3

2

N
Me

Me

4
(83% yield, 91% ee)

Scheme 1. Macmillan catalyst for Friedel-Crafts alkylation reaction.

1.5 Activation modes in organocatalysis
The field of primary and secondary amine-based organocatalysts achieves satisfactory
development and extensively categorized into two divisions such as, covalent organocatalysts andnon-organocovalent catalysts. Generally, they classified on the basis of intermediate formation
by substrate and catalysts.

1.5.1 Mode activation of Covalent catalyst
Organocatalytic

isclassified

covalent

andnon-covalentcatalysts.

Covalent

organocatalysis forms a covalent bond between the catalysts and the substrate, leading to a strong
interaction between the substrate and the reagent in the reaction. Covalent catalysis enhances ahigher level of stereo control. Because the catalyst is directly bonded with the substrate applying
its chiral influence. Secondary amine catalysts mostly involve in characteristic mechanism such6

as, iminium and enamine intermediate formations based on substrates which is reacting withcatalysts.
In iminium catalysis, condensation of catalysts with substructures containing electrophiliccarbonyl carbons that make iminium unchanging intermediate cation during the course of reaction.
Subsequently, an effective nucleophile attack on the intermediate contributes to the formation of
products with chiral centers (Scheme 2).
N
HAmine catalyst

O
N

H

Nu

N

Nu

O

* R

H
R
R

R
iminiumintermediate

iminiumintermediateenonesScheme 2. Iminium mode of activation.
An essential class of Lewis base catalysis is asymmetric enamine, after iminium cationintermediate formation, electrophilic lacking carbonyl carbon involves in condensation with theamino group of organocatalysts to makes enamine intermediate. Followed by nucleophilic attacks
on enamine intermediate contribute to the formation of optically active products. In both cases,
catalysts are directly attached to substrates, catalysts often have high-level chiral dynamic
response (Scheme 3). The versatility of enamines in stochiometric reactions was demonstrated
for α-functionalisation of carbonyl compounds by Stork et al. in 1963.9

N

O
H

R

N
H
Amine catalyst

HRR

enamineintermediate

enamineintermediate

Scheme 3. Enamine mode of activation.
7

O

E

N

* R
E

In recent decades, huge progress on the development of numerous efficient covalentorganocatalysts which promotes chiral products with excellent optical purity in asymmetricorganic reactions. These are the examples of covalent organocatalysts which were reported byvarious research groups(Figure 5).10-12 The first catalytic application of enamines was recorded
by Hajos and Parrish and Eder, Sauer and Wiechert in the early 1970’s. L-Proline organocatalyst
for the asymmetric Robinson annulation of triketone to obtained corresponding precursor forsteroid in excellent chemical yield (up to 100 %) and enantioselectivity (up to 93 % ee).

O

N
N
H

N
H

Bn

Macmillan imidazolidinone
organocatalyst

O

O

R

OH

R NH

NH2

(S)-Proline
organocatalyst

H
N

H 2N

O

O

Amino amideorganocatalyst

N
H

R

Peptideorganocatalyst

Figure 5. Examples for covalent organocatalysts.
The three-component system of the asymmetric Mannich reaction between ketone 6 withaldehyde 7a and an amine 8 catalyzed by S-proline 5 was the first catalytic asymmetric Mannich
reaction. This reaction afforded the corresponding chiral Mannich products 9a in moderatechemical yield but excellent enantioselectivity (up to 50% yield and 94% ee) (Scheme 4).13

O
NH2

CHO
O

+

R

N
OH
H
5 (35 mol%)

+

7a

O

HN

DMSO
R

OMe
6

OMe

8

9a
50% yield, 94% ee

Scheme 3. Proline catalyst for asymmetric Michael addition.
In 2000, Macmillan and co-workers have reported that first imidazolidinone 10 catalyzed
extremely enantioselective organocatalytic Diels-Alder reaction of cyclopentadiene 11 with8

cinnamaldehyde 12. The chiral Diels-Alder adducts 13 were obtained in excellent chemical yield,
diastereoselectivity and enantioselectivity (99% yield, 2.7:1 = exo:endo, 93% ee) (Scheme 5).14
Me
N

O

N
H

+

Me
Me

Ph
10 (20 mol%)
Me

11

O

MeOH-H2O

12

CHO
Ph
13
99% yield,
2.7:1 exo:endo
93% eeScheme 5. Imidazolidinone catalyst for asymmetric Diels-Alder reaction.

1.5.2 Non-covalent mode of activation
On alternative class, non-covalent organocatalysis formed hydrogen bond between ahetero atom attached hydrogen atom and an electronegative atom. The use of hydrogen bond inorganic reaction has been widely investigated, leading to the encounter of unique chiralorganocatalysts for the enantioselective transformations. Generally, thiourea and squaramidechiralscaffold

R
X
H

R

O

R
X
H
X = O, Nchiralcatalysts

R

R
X
H

chiralscaffold

X
H

Nu

Nu
R ∗

O

NO2

R
non-covalentinteraction

Scheme 6. Hydrogen bonding non-covalent interaction of catalysts.
based organocatalysts are often reported and delivers chiral products with considerably excellent
results on asymmetric reactions.15 Chiral non-covalent organocatalysts act as a hydrogen bond9

donor toward an electronegative hydrogen bond acceptor. The catalysts form a hydrogen bondintermediate. The hydrogen bonds are stronger than a van der Waals interaction but weaker thancovalent or ionic bonds. Commonly, the combination of a neutral electrophile as an acceptor anda weak acid catalyst as a donor leads to hydrogen bonding catalysis (Scheme 6). As an example
of non-covalent hydrogen bonding organocatalysts, chiral phosphoric acid, phase transfer catalyst,
thiourea, and cinchona based squaramide catalysts are widely used in asymmetric synthesis(Figure 6).16
H
Boc N

O

N
O

HOOC

Br

HN

F3C
HN

O

S

O

P
HO O

F3C
NH

NH

O

CF3

S

CF3

NH HN

N

O

HN

CF3
F3C

CF3

F3C

COOMe
Peptideorganocatalyst

Binaphthyl
phase transferorganocatalyst

BINOL phosphoric acidphase transfer organocatalyst

Thioureabifunctionalorganocatalyst

Figure 6. Example for non-covalent organocatalysts.
In 2004, Akiyama and co-workers reported asymmetric Mannich reaction of aldimine 15
and ketene silyl acetal 16 using chiral phosphoric acid catalyst 14 which promotes chiral Mannich
products 17 in excellent chemical yield, stereoselectivities (99% yield, dr. 99:1%, 96% ee)(Scheme 7).17
Ar
O
O
P
OH
O
HO
N

H

OTMS

R2

OR3

+

Ar
Phosphoric acid
14 organocatalyst
toluene, -78 °C

R1

HO
HN
CO2R3

R1
R2

15

16

17
up to 99% yield
up to 99:1 syn:anti dr
up to 96% ee

Scheme 7. Phosphoric acid catalyst for asymmetric Mannich reaction.

10

In 2017, Nakano and co-workers reported squaramide fused g-amino alcohol (SFAA) 18
organocatalyst for asymmetric domino Michael addition cyclization reaction of N-substituted 3dicyano-indanones 19 with ketones 20 in presence of THF solvent to afforded chiral spiroconjugated 2-aminopyrans 21 in both excellent chemical yield and stereoselectivities (up to 98%
yield and up to 95% ee) (Scheme 8).18
F3C

O

O
R

N
H

F3C

NC

CN
O

O

O

R’ R’’

19

20

Ph
Ph
HO

NC

R’
R’’

O

18 SFFA organocatalysts

+

N
R

N
H

THF, 0 °C, 48 h
N
R

OO

21
up to 98% yield
up to 95% ee

Scheme 8. Square amide fused amino alcohol catalyst for enantioselective domino Michael
addition cyclization reaction.
In 2005, Connon and co-workers reported chinchona alkaloid based thiourea 22organocatalyst for asymmetric Michael addition of dimethyl malonate 23 with nitroalkenes 24 inpresence of toluene solvent to afforded chiral Michael adduct 25 with excellent chemical yieldand stereoselectivities (98% yield, 99% ee) (Scheme 9).19
CF3
N

S

H
F3C

N
H

N
H
N
O

O

O

MeO

NO2

+

22 Thiourea based organocatalysts

OMe
23

MeO

toluene, 20 °C, 30 h

O
OMe
NO2

25
up to 98% yield
up to 90% ee

24

Scheme 9. Chinchona alkaloid catalyst for asymmetric Michael reaction.
111.6. Peptides as Organocatalysts for Asymmetric reactions
Peptides have been found to be effective organocatalysts for a variety of asymmetric
reactions,

includingasymmetricacylations,oxidations,brominations,

sulfonylations,

protonations, phosphorylations, and carbon-carbon bond forming reactions like hydrocyanations,conjugate addition reactions, mannich reactions, stetter reactions, and aldol reactions.20-22 Thesynthesis of peptides are achieved by standard peptide synthesis and their modular nature allows
for accessing a huge structural and functional diversity by various sequence of the amino acids.
Peptide catalysts are consequently fortunate suitable to contain the requirements of different
substrate arrangements. The simplicity of peptide synthesis combined with the modular nature
has also proven advantageous for the use of smart combinatorial screening for the design andoptimization of peptide organocatalysts.

23

The small peptides containing amide group act asbackbone and functional groups in the side chains of peptides provide plenty of active sites for
intramolecular and intermolecular interactions with the substrates. In addition, the conformational
space of short di- and tripeptides is large. These features have confirmed valuable for the
improvement of useful asymmetric catalysts and allow for properties, such as highchemoselectivity corresponding with substrate scope, site selectivity, easy to access, and stablein air and moisture environmental. Within this section the broad range of reactions that have beencatalyzed with peptides is summarized.
Generally, linear peptide organocatalysts can be classified in four main classes: Class IA, Class I-B, Class II-A and Class II-B. Therefore, Class I-A - if based on N-terminal primaryamino group and quaternary ammonium salt contained peptide organocatalysts, Class I-B - Nterminal primary amino group contained peptide organocatalysts, Class II-A -based on N-terminal
secondary amino group and free carboxyl group can be present as displaced in peptideorganocatalysts, Class II-B - N-terminal secondary amino group and C- terminal free carboxylgroup contained peptide organocatalysts (Figure 7).

12

R
R
N
R

O

O
R

PeptideNH2

Class I-A
-Primary amine-Quaternary ammonium salt

O
HO

PeptideNH2

Class I-B
-Primary amine

O

H
N

R

PeptideO

H
N

PeptideR

R

HOClass II-A
-Secondary amine-Free carboxyl

O

Class II-A
-N-terminal secondary amine-Cterminal free carboxyl

Figure 7. Classified peptide organocatalysts.
The first example of small peptides accomplished to provoke excellent enantioselectivities
into organic molecules via asymmetric organocatalysis were published in the late 1970s. The
inoue and co-workers was discovered cyclic dipeptide 26 organocatalyst for asymmetriccyanation reaction of benzaldehyde 7a with hydrogen cyanide to afforded correspondinghydrocyanation products with fairy good chemical yield and enantioselectivities (up to 97% yield,
up to 97% ee) (Scheme 10).

24

N
N
H
O
H

R

O

H
N

N
O
H
cyclic dipeptide
26 organocatalysts

HCN (2 eq), toluene, -20 °C

R

OH
CN
H
27a
up to 97% yield
up to 97% ee

7aScheme 10. Cyclic dipeptide catalyst for hydrocyanation of benzaldehyde.

13Julia and co-workers introduced polypeptide of alanine 28 were revealed asorganocatalysts for the asymmetric epoxidation reaction of chalcones 29 to afford thecorresponding chiral epoxide 30 with good chemical yield and excellent enantioselectivities (upto 85% yield and 93% ee)

25(Scheme 11). Consequently, the application and development of

N
H
O

28

H
N

O
n

O

polypeptide (poly-L-Ala)organocatalyst

OO

30% aq. H2O2, NaOH
rt, 24 h30
up to 85% yield
up to 93% ee

29Scheme 11. Poly-L-Ala catalyst for Julia-Colonna epoxidation.
peptide as organocatalysts remained undeveloped for some time until new concepts of catalyst
discovery were developed. It was recognized that general features such as facile synthesis andflexible, provide peptide organocatalysts attractive and replacements to metal-based catalysts andother organocatalysts. In recently, peptides have established progressively popular as asymmetricorganocatalysts for a sequence of significant asymmetric organic reactions, often affording thedesired chiral products in mild reaction conditions in excellent chemical yields andstereoselectivities. Important examples of some reactions contain the use of linear peptide-basedorganocatalysts for asymmetric reactions in below
Furthermore, Miller and co-workers introduced first linear tripeptide 31 organocatalyst
fixing by the hydrogen bonding based on b-turn concept for asymmetric acylation reaction of Nacetylamino-cyclohexan-1-ol 32 to afforded corresponding acetyloxy-cyclohexyl acetamide 33
in good chemical yield and excellent enantioselectivity (up to 80% yield, up to 94% ee) (Scheme
12).26

14

O
N
N
R N
HO

HN
O

N
NH H
Boc

NHAc

O
Me

Ph

Ac2O
CHCl3

32

NHAc

AcO

31

33
up to 94% ee

Scheme 12. Peptide catalyst for desymmetrization by selective acylation.
In recently, Du and co-workers reported tetrapeptide 34 organocatalyst for asymmetricMichael addition of 1-phenyl-pyrrole-2,5-dione 35 with aldehydes 36 in presence of toluene
solvent to afforded chiral Michael adduct 37 with excellent chemical yield and stereoselectivities(98% yield, dr 12:88, 99% ee) (Scheme 13). 27

O
N
H

N
R1
O

NH3

O

O

R2
O

O

O

34

+

N

O

O
HN

H

toluene

N

H
O

O
35

36

37
up to 98% yield
up to 99% ee

Scheme 13. Peptide catalyst for asymmetric Michael addition.
Considering enamine catalysis, a countless deal of consideration has been disbursed to
peptide catalysed asymmetric aldol reaction, one of the most significant carbon-carbon bondforming reactions. Although proline and proline and its derivatives can be applied as small and15

rigid organocatalysts for this transformation, nature uses to some extent the metal-free type I
aldolase for this task. In both cases, the mechanism is based on intermediate enamine formation.
With the aim to combine the best properties of the two systems, many research groups focused
their work on the development of linear peptide organocatalysts for asymmetric aldol reactions.
Numerous linear peptides were reported, including a secondary amine at the N-terminus (Scheme
14).28 Examples are also known for certain aldol reactions catalysed by peptides bearing primaryamines at the N-terminus (Scheme 15).29This work in general reveals that short peptides canindeed function as asymmetric catalysts, but the catalytic activity remains a major issue in mostexamples. Chen and co-workers reported N-terminal secondary amine-based dipeptide 38
organocatalyst for asymmetric aldol reaction of cyclic and acyclic ketones 39a with aldehydes 7ain presence of PhCOOH and CHCl3 solvent to afforded chiral anti-aldol products 40a withexcellent chemical yield and stereoselectivities (99% yield, syn:anti = 1:99 dr, 99% ee) (Scheme
14).30
O

O

CHO
+

39a

NH

R

H
N

N
H

O
38

PhCOOH
CHCl3

7a

O

OH
R

40a
up to 98% yield
up to 99:1 syn:anti dr
up to 99% ee

Scheme 14. N-Terminal secondary amine-based dipeptide catalyst for asymmetric Aldol
reaction.
Wu and co-workers reported N-terminal primary amine-based b-turn tetrapeptide 41
organocatalyst for asymmetric aldol reaction of cyclic and acyclic ketones 39a with aldehydes 7ain presence of PhCOOH and MeOH solvent to afforded chiral anti-aldol products 40a withexcellent chemical yield, good diastereoselectivity and excellent enantioselectivity (99% yield,
syn:anti = 76:24 dr, 96% ee) (Scheme 15).31

16

O
N
O
NH2
CHO

O
+
R

R

R
39a

N
H
H

O
N

HO

i-Bu
O

O

41
PhCOOH
MeOH

7a

R

OH

R

R

40a
up to 98% yield
up to 99:1 syn:anti dr
up to 99% ee

Scheme 15. N-Terminal primary amine-based tetrapeptide catalyst for asymmetric Aldol
Reaction.

1.7 Author approach
Author aimed to develop new g-turn type N-primary amino terminal tripeptidesorganocatalyst X by using commercially available amino acids as chiral precursors, the peptideorganocatalysts are remarkable system derived from amino acids. The g-turn type N-primaryamino terminal tripeptide A has the basic primary amino group for the enamine formation andhydrogen bonding sites, and also the amide group for hydrogen bonding site to the substrate. In
addition, the bulky flexible polycyclic aromatic group on the nitrogen atom of amide group in
catalyst might be shielded effectively the one enantiotopic face on the basis of a steric factor toenhance the selectivity.
The new developed new g-turn type N-primary amino terminal tripeptide organocatalysts
having primary amino group, amide group and bulky aromatic amine as an organocatalysts wasdemonstrated its catalytic activity for asymmetric aldol reaction of cyclic and acyclic ketones withaldehydes. Followed by new g-turn type N-primary amino terminal tripeptide organocatalysts
for asymmetric cross aldol reaction of cyclic and acyclic ketones with isatins.

17i) Asymmetric Aldol reaction
The author initially tried and explored the catalytic activities of peptide organocatalyst 42
in the asymmetric Aldol reaction of various acyclic or cyclic ketones 39a with aldehydes 7a toaffords the corresponding chiral anti-Aldol products 40a with good to excellent chemical yields,
diastereoselectivities and enantioselectivities (up to 99%, up to syn: anti = 13:87, up to 99% ee)(Scheme 16).
O
N

O
CHO

O
+
R

R

R
39

N
O H

N H
NH2

O

42
neat
0 °C, 24 h

7

R

OH

R

R

40
up to 99% yield
up to 13:87 syn:anti dr
up to 99% ee

Scheme 16. Peptide catalyst to asymmetric Aldol reaction.
ii) Asymmetric crossed Aldol reaction
Furthermore, the author has applied the newly prepared peptide organocatalyst 42 forasymmetric crossed Aldol reaction of various acyclic or cyclic ketones 39a with isatins 43a toaccesses the chiral3-substituted 3-hydroxy-indolines 44a in excellent chemical yield anddiastereoselectivity and moderate to good enantioselectivity (up to 99% yield, up to 1:99 dr, up
to 85% ee) (Scheme 17). The chiral 3-substituted-3-hydroxy-indolines are key synthetic
intermediates for many biologically active compounds such as 3-hydroxy-3-(2-oxocyclohexyl)2-indolinone, Convolutamydine A-E, Donaxaridine, dioxibrassinine, leptosin D, spiroisoxazolidinyl oxindole, witindolinone C, madindoline.

18

O
N

O

N
O H

N H
NH2

O
+
R

42
O

R
N
H

R
39

O
HO

O

Et2O
rt, 24 h

43

R
R
O

R
N
H
44

up to 99% yield
up to 1:99 syn:anti dr
up to 85% ee

Scheme 17. Peptide catalyst for asymmetric cross Aldol reaction.

19

Chapter 2
New small g-turn type N-primary amino terminal tripeptides organocatalyst
for solvent-free asymmetric aldol reaction of various ketones with aldehydes

202. New small g-turn type N-primary amino terminal tripeptides organocatalyst
for solvent-free asymmetric aldol reaction of various ketones with aldehydes
2.1 Authors approach
Conducting numerous organic transformations with assistance of small chiral moiety
derived from natural source to furnish desired chiral product have been grabbing the attention
widely over scientific community. Mainly, development of peptides based organocatalysts using
naturally and commercially existing amino acids for chiral induction of biologically active moiety
synthesis have been often reported. Peptide compounds are being considered as fascinating
moiety due to their exchangeable functional groups, easy way of preparations, remodify byaltering chiral amino acid sequences. Further, peptide-based catalysts are cheap chiral sources,
inert over moisture, evades the role of metals and comparatively less toxic than other type oforganocatalysts. Due to this reason, author have aimed to develop new class peptide throughcommercially accessible chiral amino acids and used as efficient organocatalysts in asymmetricorganic reactions to promote chiral induction (Scheme 18).

O
O
H 2N

OH

HN

NH

O

O

R1

Amino acid

R2

R1
N
H

1. Facile steps of synthesis
2. Less toxicity

H 2N
R3

Peptide organocatalyst

3. Stable to moisture and air
4. Metal free approach
5. Simply accessible of starting materials

Asymmetric reactions

Scheme 18. Peptide catalysts: approach and their properties.

21

The author's goal was to develop new g-turn type N-primary amino terminal tripeptides asorganocatalysts by condensation of various N-Boc amino acid sequences to investigate
asymmetric reactions. The catalyst X consisting of several steric hindrance sites, hydrogenbonding sites, enamine formation site to achieve chiral induction in asymmetric organic reactions(Scheme 19). Particularly, rigid aliphatic ring at C-terminus, substituents on various position inthat catalysts can act as stereocontrol site and steric influence sites, respectively. Further, thesecatalysts can be easily synthesised using condensation of various N-Boc amino acids withcorresponding primary aromatic amines, they are stable in moisture and air and cost effective.
Peptide catalyst X containing multiple functions and their role as an organocatalysts towards
asymmetric organic reactions remains unrevealed g-turn based linear peptide organocatalysts.
After the catalyst development of catalyst X, examined catalytic activity for asymmetric aldol
reaction of cyclic and acyclic ketones A with various substituted aldehydes B was selected to
discover the catalytic efficacy of developed catalyst (Scheme 19).

O

backbonesteric influence
site

O
H 2N

N
O

OH

enamine and hydrogen O
bond formation site

NH

H 2N

R''

R1

amino acids

steric influence
site

O
R

asymmetric
aldol reaction

B

Scheme 19. Concept of peptide catalysts X.

22steric influencesite

γ-turn

CHO
+

A

Ｈ

hydrogen bondingsite

tripeptide X
organocatalysts

O

Ar

N

R'

OH

*

*
C

R

2.2 Aldol reaction
The C-C bond formation can be achieved in organic synthesis which was discovered
independently by the Russian chemist Alexander Borodin in 1869 and by the French chemist
Charles-Adolphe Wurtz in 1872. This reaction can be defined as follows “The enolate ion
generated from ketone or aldehyde to electron deficient carbonyl carbon of another molecule topromote b-hydroxy carbonyl compound under basic or acidic condition”. The general aldol
reaction is mentioned as in below (Scheme 20).

O
R1

acid/
base

O

H
R3

R2
aldehyde/ketone

H

OH

O

β
✽

R1

solvent✽

R3

R2

aldehyde

β-hydroxy ketone

Scheme 20. General reaction of Aldol reaction.

2.3 Mechanism
Reaction initiated with base generating enolate anion by abstracting a-proton fromcarbonyl compound. Followed by nucleophilic addition to the electron deficient carbonyl carbon
of another molecule and abstraction of proton leads to formation of new b-hydroxy carbonylcompound with C-C bond (Scheme 21).

O

O

O
H
R

O

OCH3

O

H OCH
3

R’

O

OH
β

R

R

enolate

R’

R
R’
aldol

Scheme 21. Reaction mechanism of base promoted Aldol reaction.
23

In this case, reaction has initiated by acid which generates enol by protonation of carbonyl
oxygen and loss one hydrogen from a-carbon atom. Later, electron transfer from enol toelectrophilic carbon of carbonyl compound. Eventually, product delivered with loss of proton
from oxygen atom with new C-C bond formation (Scheme 22).

HO

O

H

OH

O

OH

O

OH

R’

H

β

R

R

R

enol
OH

R’

R
R’
aldol

H
H

OH2

R

Scheme 22. Reaction mechanism of acid promoted Aldol reaction.

In 1971, Hajos, Parrish, Eder, Sauer and Wiechert reported the first asymmetric direct
aldol reaction catalysed by proline amino acid with 3mol% catalyst loading in the presence of
DMF solvent for 20 h. That delivers enol-endo aldolization product with excellent results (100%)
chemical yield (93% ee) enantioselectivity (Scheme 23).32
O
O

O

N
OH
H
5 3 mol%
DMF

O

O

O

OH
46

45

100% yield
93% eeScheme 23. Proline catalyst for direct asymmetric Aldol reaction.

24

In 2003 List and co-workers have documented enol-endo aldolization using various
dialdehydes in presence of 3 mol% of proline catalyst in DCM solvent for 8-16 h. The six
membered cyclised products were obtained at excellent chemical yield (95%), excellent
diastereoselectivity (syn:anti = 1:10 dr), and enantioselectivity (99% ee) (Scheme 24).33
O

CHO

N
OH
H
5 3 mol%

CHO

OH
OHC

DCM
47

48
95% yield
1:10 syn:anti dr
99% eeScheme 24. Proline catalyst for asymmetric Aldolization of acyclic dialdehydes.
Z. Tang and research group have evaluated first small proline-based peptides 49 reactivity
in asymmetric aldol reaction of aldehydes 50 with hydroxy ketone 51. Surprisingly, peptide
catalysts worked effectively in water/THF solvent and delivered aldol products 52 with goodchemical yield (88%), excellent enantioselectivity (96% ee) (Scheme 25).34

N
H
O

O
R

+
H

50

OH
51

H
N
O

Ph
O
N
H

H
N
O

Ph
49 20 mol%

O
OMe
Ph

OH

R

THF/H2O

OH O

OH O

52
88% yield
96% ee+R
OH
53

Scheme 25. Proline-based peptide catalysts for asymmetric Aldol reaction.

25

In 2005, Mruoka reported asymmetric aldol reaction of benzaldehyde with acetone
catalysed by other than proline catalysts. Aldol adduct was furnished with good chemical yield(85%), excellent enantioselectivity (95% ee) (Scheme 26).35
O
OH
NH
CHO
O

6

OH O
54

+

R

R
55a
82% yield
95% ee7aScheme 26. Binaphthyl catalyst for asymmetric Aldol reaction.

2.5 Results and discussion
Inspired by this background, author aimed to start the synthesis of new g-turn type peptide
catalysts 65a-j using condensation of chiral L-N-Boc-prolines 56 with amines 57a-d as shownin (Scheme 27). The first condensation of 56 with 57a-d in the presence of DCC followed
by, the deprotection of Boc group of the crude N-protected proline amides afforded thecorresponding proline amides 58a-d in 85-95% yields. Proline amide with phenyl group58a (90% yield), 1-naphthyl group 58b (95% yield), 1-anthryl group 58c (85% yield), 1pyrene group 58d (93% yield) was observed. Next, the condensation of the obtained 58ad with N-Boc amino acids 59a-e in the presence of DCC followed by the deprotection of
the crude N-protected dipeptides gave the corresponding dipeptides 60a-h in 60-92%
yields. As amino acids a-substituted amino acids that are effective towards a conformation
favourable to form g-turn intramolecular hydrogen bonding were used. Furthermore, final
condensation of the dipeptides 60a-h with N-protected 61’a-f, respectively, in the presence of

26

O
N
OH
Boc
56
+

1. DCCDCM
rt, 24h

R1NH2
57a-d

N

H 2N
O

O

N
HN R1
2. TFA
R2
HN R1
O
DCM
58a-d
NH2 60a-h
rt, 3ha: R1 - phenyl(90%)
1
b: R - 1-naphthyl (95%)
60a-h
c: R1 - 1-anthryl (85%)
1
2
d: R1 - 1-pyrenyl (93%) a: R 1 = 1-naphthyl, R2 = methyl (88%)
b: R = 1-naphthyl, R = i-propyl (91%)
1
c: R = 1-naphthyl, R2 = t-butyl (92%)
59a-e
d: R1 = 1-naphthyl, R2 = phenyl (78%)
a: Ala, b: Val, c: t-Leu,
e: R1 = 1-naphthyl, R2 = benzyl (60%)
d: ph-Gly, e: Ph-Ala
f: R1 = phenyl,
R2 = t-butyl (80%)
g: R1 = 1-anthryl, R2 = t-butyl (91%)
h: R1 = 1-pyrene, R2 = t-butyl (91%)

N

H 2N
O

HN

O

O

O

O
O

O

N

O

HN

H 2N

O

N

O
O

HN

O

O

N
H

N

HN

O

HN

61c

N
O

HN

H 2N

O

N
H

N
O

61g

61f

N
H

O
HN

H 2N

N
H

O

N
O

HN

O

H 2N

N
H

O

61h

61i

N
O

HN

O

61j

Scheme 27. Synthesis of di- 60a-h and tripeptide 61a-j organocatalysts.
27

O

O

O
N

N

N
H

H 2N

O

O
N
H

O

60f

61b

H 2N

HN

60e

HN

N

N

H 2N

O
N
H

O
H 2N

61a-j

61a-j
a: R1 = 1-naphthyl, R3 = (S)-methyl (87%)
1
b: R = 1-naphthyl, R3 = (S)-i-propyl (93%)
c: R1 = 1-naphthyl, R3 = (S)-t-butyl (90%)
d: R1 = 1-naphthyl, R3 = (S)-phenyl (75%)
e: R1 = 1-naphthyl, R3 = (S)-benzyl (72%)
f: R1 = 1-naphthyl, R3 = H(85%)
g: R1 = 1-phenyl, R3 = (S)-t-butyl (70%)
13
h: R = 1-anthryl, R = (S)-t-butyl (80%)
i: R1 = 1-pyrenyl, R3 = (S)-t-butyl (83%)
j: R1 = 1-naphthyl, R3 = (R)-t-butyl (80%)

O

61e

61d

NH2

O

H 2N

O
N

R3

O

HN

61a

O

NH

H 2N

O

60h

N
H

59’a-fa: Alab: Valc: t-Leu
d: ph-Glye: Ph-Ala
f: Gly

O

R1

O

N
H

H 2N

O

HN
O

2. TFADCM
rt, 3h

O

HN

O
N

60d

HN

60g

H 2N

HN

N

H 2N

HN

1. 59’a-f
DCC
DCM
rt, 24h

N

H 2N
O

60c

60b

N
O

N

H 2N

HN

60a

H 2N

O

N
H

2. TFADCM
rt, 3ha: R1 - phenyl
b: R1 - 1-naphthylc: R1 - 1-anthryld: R1 - 1-pyrenyl

1. 59a-e
DCC
DCM
rt, 24h

HN

OODCC followed by the deprotection afforded the corresponding tripeptides 61a-j in 70-93% yields.
Catalysts containing Ala 61a (87% yield), Val 61b (93% yield), t-Leu 61c (90% yield), Ph-Gly
Moreover, the diastereomer 65 of 61c, tripeptides 69a and 69b with azetidine and piperidine
backbones respectively, were also prepared using the same procedure used to prepare 61a-j.
Thus, the first condensation of D-N-Boc-62, L-N-Boc-66a,b with aromatic amine 57b
followed by the deprotection to yielded the corresponding amides 63, 67a,b in 79-91% yields.
Next the condensations of 63, 67a,b with N-Boc amino acid 59’c followed by the deprotection
gave the dipeptides 64, 68a,b in 70-89% yields. Then, the final condensation of 64, 68a,b with59’c followed by the deprotection to afford the corresponding tripeptides 65, 69a,b was 79-85%
yields (Scheme 28).

NH2

O
N
OH
Boc
62

+

1. DCCDCM
rt, 24hO
NH HN

2. TFADCM
rt, 3h

1. 59c
DCC
DCM
rt, 24h
2. TFADCM
rt, 3h

O
N

HN
O

63

57b

2. TFADCM
rt, 3hNH2O

1. 59’c
DCC
DCM
rt, 24h

N
HN
O
O

NH
NH2
65

64

O
N

HN
O

O
NH2

O
+

n

N
Boc

2. TFADCM
rt, 3hOH

66a: n-1
66b: n-3

1. DCCDCM
rt, 24h

57b

O
n

N
H

HN

1. 59c
DCC
DCM
rt, 24hN

2. TFADCM
rt, 3hNH2

67a: n-1
67b: n-3O
nHNO68a: n-1
68b: n-3

1. 59’c
DCC
DCM
rt, 24hNHNH2
69a: n-1

2. TFADCM
rt, 3h

O

N
HN
O
O

NH
NH2
69b: n-3

Scheme 28. Synthesis of tripeptide 65 and 69a,b organocatalysts.

28

2.6 Evaluation of catalysts
After the synthesis of the designed peptide organocatalysts, we were examined the crossed
aldol reaction of cyclohexanone 39a as an aldol donor and 4-nitrobenzaldehyde 7a as an aldol
acceptor using the precursor dipeptides 60a-h of tripeptides 61a-j as catalysts in Et2O at 25 °C(entries 1-8, Table 1). These dipeptide organocatalysts 60a-h showed catalytic activity in thisreaction to gave the desired chiral aldol product 40 was obtained. However, only low to moderatechemical yields, moderate diastereoselectivities (40a: anti or 40’a: syn forms), and low tomoderate enantioselectivities were obtained in this reaction condition. Dipeptide catalyst 61a
having Ala on N-terminus delivers chiral aldol adduct 40a’ at low chemical yield,
diastereoselectivity and enantioselectivity (18%, syn:anti = 33:67 dr, 34% ee) (entry 1).

The

catalysts 60b,c having Val and t-Leu were furnished aldol adducts but catalyst 60c showed goodresults in terms of enantioselectivity than catalyst 60b (52%, syn:anti = 67:33 dr, 63% ee) (entries2-3). Aromatic groups containing catalysts 60d,e to delivers the chiral product with moderate to
low results (entries 4-5). These results implies that t-Leu group performing better activity thanany other catalysts. Catalysts 60g with aromatic naphthyl amino substituent on amide group was
examined which promotes product 40a in low chemical yield, good diastereoselectivity, moderateenantioselectivity (20%, syn:anti = 72:28 dr, 54% ee) (entry 6). Pyrene attached catalyst 60h
affords 40a with reduced stereoselectivities (47%, syn:anti = 59:41 dr, 37% ee) (entry 8). The
absolute configurations of 40a and 40’a were identified based on comparison with literature data.
Next, we investigate this reaction using tripeptides 61a-j as catalysts (entries 9-18) under same
reaction condition wherein catalysts 61a-h were used as catalysts. Encouraged by the result of
dipeptide 60c, possessing t-butyl group at N-terminal side which showed better catalytic activity,
the substituent on the first amide part was fixed only to t-butyl group. Similarly, 60a-h and 61aj also showed catalytic activity in this reaction to afford the chiral aldol product anti-40a, with
low to moderate chemical yields. Interestingly, 61a-j used as catalyst for this reaction thediastereoselectivity increased and the main aldol product 40 was obtained in only anti form unlike
the catalysts 60a-h. Furthermore, enantioselectivity also quite increased with all the catalysts 61aj. Particularly, catalyst 61c with L-t-Leu-L-t-Leu moiety at N-terminal side and 1-naphthyl group29

on amide amino moiety at C-terminal side afforded 40a in good enantioselectivity (94% ee) anddiastereoselectivity (syn:anti = 22:78 dr), although chemical yield was low (25%)(entry 11).
Table 1. Evaluation of organocatalysts 60a-i, 61a-j, 65, 69a,b in asymmetric Aldol reaction.
CHO
O
+
NO2
39a

O

Cat. 60a-h, 61a-j,
65 and 68a,b

OH

O

OH

+

Et2O
rt, 24hNO2anti-[2S,3R]-40a7aNO2
syn-[2S,3S]-40a’

dr
syn:antibsynee (%)c
anti

18

33:67

18

34

60b

40

40:60

22

7

3

60c

52

67:33

63

10

4

60d

45

40:60

35

6

5

60e

33

47:53

35

8

6

60f

13

70:30

54

11

7

60g

20

72:28

54

13

8

60h

47

59:41

37

rac

9

61a

30

35:65

28

71

10

61b

19

40:60

28

74

11

61c

25

22:78

70

94

12

61d

16

23:77

25

50

13

61e

25

25:75

26

39

14

61f

58

25:75

1

30

15

61g

10

28:72

22

50

16

61h

26

25:75

30

80

17

61i

35

20:80

26

93

18

61j

20

25:65

7

-87

19

65

30

22:78

17

77

20

69a

20

30:70

44

86

21

69b

27

24:76

63

90

Entry

Cat.
(10 mol%)

Yield (%)a

1

60a

2

aIsolated yields. bDiastereoselectivity was determined by 1H NMR using crude reaction mixture.
cThe ee values were determined by HPLC witha Daicel Chiralpak AD-H column.

30

In addition, the catalyst 61i afforded 40a in fairly good enantioselectivity (93% ee) anddiastereoselectivity (syn:anti = 20:80 dr) (entry 17), but owing to the toxicity and costeffectiveness of pyrenes, 61c with 1-naphthyl group may be preferred for this reaction. Further,
we have tested the catalytic activity of catalysts 61j with D-t-Leu-L-t-Leu chains at N-terminal
side, 61 with D-pyrrolidine ring, 40a with four membered azetidine ring, and 69b with six
membered piperidine ring. As a result, the catalysts 61j, 65, 69a and 69b shows poor catalytic
activity than 61c due to their L- t-Leu-L-t-Leu moiety at N-terminal side and five membered
pyrrolidine ring. These results indicated that the chain length of N-terminal side, the size of
backbone ring for forming g-turn, the configuration, and types of substituents at N-terminal sideand the aromatic ring on amide amino group at C-terminal side are highly important for achieving
satisfactory stereoselectivities, by shielding one enantiotopic face to attack from the aldol
acceptor 41a in this reaction condition using ether solvent.

2.6 Optimization of reaction condition
Catalyst screening results has clearly revealed that catalysts 61c having t-Leu on Nterminus and naphthalene group on amide function might suitable catalysts to promote
asymmetric aldol reaction of 40a and 40a. Several screenings were required to determine
the optimal reaction condition of catalysts 61c for this reaction. First, the test reaction was
performed in various solvents including, ethereal (entries 1-4), non-polar aliphatic andaromatic solvents (entries 5-7), chlorinated (entries 8-9), polar protic and aprotic polar(entries 10-14), water and solvent free condition with 61c catalyst and results are depicted
in Table 2 (entries 15-16). Catalysts 61c have expressed better catalytic performance undersolvent free condition than other solvents in terms of chemical yield and stereoselectivities(45%, syn:anti = 22:78 dr, 87% ee) (entry 16). Consequently, reaction using various
catalysts loading such as 30, 20, 5 and 1 mole ratio in superior neat condition at room
temperature for 24 h (entries 17-20). After screening, we have observed that catalysts 61c
mole ratio might strongly affects the products outcome in terms of chemical andstereochemical yield rather than 30 mol%. Further, reaction of 39a with 7a have conducted31

with mole ratio 30% of catalyst in solvent free condition with multiple temperatures(entries 21-22). Finally, 1 gram scale up of reaction of 39a and 7a have
Table 2. Optimization of reaction condition using catalyst 61c for asymmetric Aldol
reaction.
CHO

O

O

NO2
39a

OH

O

cat. 61c

+

OH

N

+

Et2O
rt, 24h

O

NO2

HN

O

NO2
NH2
cat. 61c

syn-[2S,3S]-40a’

anti-[2S,3R]-40a

7a

NH

O

Yield (%)adr
syn:antibsynee (%)c
anti

Et2O

25

22:78

70

94

25

i-Pr2O

25

47:53

30

81

18

45:55

47

83

Entry

Cat. 61c(mol%)

Temp

Solvent

1

10

25

2

10

3

10

25

tBuOMe

4

10

25

THF

11

45:55

37

70

5

10

25

pentane

20

40:60

53

79

6

10

25

hexane

15

38:62

14

76

7

10

25

toluene

15

38:62

70

80

8

10

25

CH2Cl2

13

28:72

40

67

9

10

25

CHCl3

10

38:62

45

93

10

10

25

CH3CN

18

35:65

23

51

11

10

25

DMSO

10

30:70

02

30

12

10

25

DMF

10

31:69

07

51

13

10

25

i-PrOH

10

41:59

08

55

14

10

25

MeOH

13

44:56

69

24

15

10

25

H 2O

16

28:72

10

65

16

10

25

neat

45

22:78

64

87

17

30

25

neat

85

23:77

60

96

18

20

25

neat

79

22:78

64

90

19

5

25

neat

20

24:76

60

87

20

1

25

neat

4

23:77

48

65

21

30

0

neat

96

20:80

64

98

22

30

-25

neat

40

21:79

43

93

23

30

0

neat

98

24:76

55

93

aIsolated yields. bDiastereoselectivity was determined by 1H NMR using crude reaction mixture. cThe ee values were determined by HPLC witha Daicel Chiralpak AD-H column.

32conducted with superior neat reaction condition (entry 23). Surprisingly, aldol adduct 40a’
was delivered excellent chemical yield, enantioselectivity when reaction performed at 0o

C for 24 h. However, the reaction was performed in different temperature

diastereoselectivity remains unchanged. Based on the outcomes, the best optimal reaction
condition for this reaction using superior catalyst 61c under solvent neat condition at 0 oC
for 24 h.

2.7 Substrate scope
2.7.1 Reaction of cyclohexanone 39a with various aldehydes 7a-j
After the optimization, substrate scope of aldol reactions were conducted between
various cyclic ketones 39a-h and aromatic substituted aldehydes 7a-j with catalyst 61c inneat condition for 24h at room temperature and are documented in Table 3 & 4. All thereactions afforded the corresponding chiral aldol products 40b-i with low to moderatechemical yields, good diastereoselectivities, moderate to excellent enantioselectivities.
Initially, reaction using cyclohexanone 39a with various benzaldehydes 7a-j in presenceof 30 mol % catalyst under optimal condition and findings are showed Table 3. Initially,
o-nitro benzaldehyde 7b reacts under optimal condition to delivered 40b in excellent
enantioselectivity with good chemical yield and diastereoselectivity (78%, syn:anti =22:78 dr, 99% ee) (entry 1). Similarly, reaction of m-nitro benzaldehyde 7c with cyclicketone to yielded the desired product 40c delivered with excellent chemical yield andenantioselectivity but diastereoselectivity maintained as good (99%, syn:anti = 20:80 dr,
99% ee) (entry 2). Further, benzaldehyde 7d possess electron withdrawing bromo
substituent at ortho position promotes product 40d excellent chemical yield, good
diastereoselectivity but its strongly affects chemical yield (30%, syn:anti 25:75, 93% ee)(entry 3). In addition, benzaldehyde having bromo substitution at meta 7e with 39a also
provides product 40e with almost similar results as like previous case (48%, syn:anti =25:75 dr, 93% ee) (entry 4). In the case of bromo substituent at para position slightly
enhance the chemical yield though it shows no effect on stereoselectivities (63%, syn:anti
33

Table 3. Reaction of cyclohexanone 39a with various aldehydes 7b-j using catalysts 61c.

O

Cat. 61c(30 mol%)

CHO
+
R

39a

Entry

O

O

OH

NH

O

O
HN

NH2
Cat. 61c

Yield (%)

syn:antiee (%)

40b

78

22:78

99

40c

99

20:80

99

40d

30

25:75

93

40e

48

25:75

93

40f

63

23:77

94

40g

57

14:86

98

40h

85h

33:67

94

40i

72

25:75

60

40j

13

30:70

32

NO2

7b

O

R
syn-40’

40b-j

CHO

OH
NO2

7c

2

O

+

anti-40b-j

CHO

N

OH

R

7b-j

NO2

O

neat
0 °C, 24 h

7b-j

1

OH

NO2
CHO

O
Br

3

OH

CHO

O

OH
Br

7e

4

Br

7d

Br
CHO
5

O

OH

7f
Br

Br
CHO

O

OH

7g

6

Cl

Cl
CHO
7

O

OH

7h
CN

CN
CHO
8

O

OH

7i

CHO

O

OH

7j

9
OMe

OMe

aIsolated yields. bDiastereoselectivity was determined by 1H NMR using crude reaction mixture. cThe ee values were determined by HPLC

with a Daicel Chiralpak AD-H, AS-H, OD-H columns.

34

= 26:74 dr, 94% ee) (entry 5). Consequently chloro group effect was examined after thebromine, which promotes the product 40g at moderate chemical yield, improved
stereoselectivity was realised (57%, syn:anti = 14:86 dr, 98% ee) (entry 6). Based on this,reaction has caused by halogen substituents might be mainly because of bulkiness of thatgroups during the course of the reaction. When reaction of aldehyde containing cyanogroup at para positioned with 39a elevates chemical yield and enantioselectivity but
decreases the diastereoselectivity (72%, syn:anti = 33:67 dr, 94% ee) (entry 7). Eventually,
simple benzaldehyde 7i also examined which affects the stereoselectivity and chemicalyield in considerable manner (30%, syn:anti = 25:75 dr, 60% ee) (entry 8). Finally, Paramethoxy benzaldehyde 7j with 39a also provides corresponding aldol product 40j withlow chemical yield and stereoselectivities (13%, syn:anti = 30:70 dr, 32% ee) (entry 9).
These results justified that peptide catalyst 61c enhances the generality of application
toward the aldol reaction of cyclohexanone 39a with different substituted benzaldehydes
7b-j.

2.7.2 Reaction of various ketones 39a-h with 4-nitro benzaldehyde 7a
Encouraged by the aldol products, next were examined the present approach was
extended to various ketones 39a-h with 4-nitro benzaldehyde 7a. In all the cases reactions
have proceeded in pleasant manner and products 40j-p were furnished in Table 4 (entries
1-7). At first, ring effect was examined for that 5-membered cyclopentanone 39b used andreaction was performed which promotes product 40j at good chemical yield,
diastereoselectivity and almost excellent enantioselectivity (81%, syn:anti = 15:85 dr,
92% ee) (entry 1). Reaction between 7-membered cycloheptanone 39c with 7a to afforded
corresponding 40k excellent chemical yield, enantioselectivity and diastereoselectivity
was unchanged (95%, syn:anti = 15:85 dr, 90% ee) (entry 2). After that, reaction with 3methyl cyclohexanone 39d affected the chemical yield and diastereoselectivity but
excellent enantioselectivity was noticed (70%, syn:anti = 21:79 dr, 90% ee) (entry 3).
Variation in ring size has some effect on stereoselectivities, but it does35

Table 4. Reaction of various ketones 39b-h with 7a using catalyst 61c.
CHO

OCat. 61c(30 mol%)

O
+

O

NO2
anti-40m-s

39b-h,6

O

NO2

NH

O

O
HN

NH2
Cat. 61csyn-40’

Yield (%)

syn:antiee (%)

40m

81

15:85

92

40n

90

15:85

95

40o

70

21:79

90

40p

66

30:70

68

40q

72

13:87

94

40r

67

-

90

68

-

59

40m-s

OH

O
1

N

OH

+

7a

Entry

O

neat
0 °C, 24 h

NO2
39b-h

OH

39b
NO2
O HO

O
39c

2

NO2

O

O

3

OH

39d
NO2

O

O

OH

39e

4
O

O

O

O

O

O
5

NO2

OH

39f
O

O

NO2
O

O

6

OH

39h

NO2
O

O
7

OH
40s

6
NO2

aIsolated yields. bDiastereoselectivity was determined by 1H NMR using crude reaction mixture. cThe ee values were determined by HPLC

with a Daicel Chiralpak AD-H, AS-H, OD-H columns.

36

affect chemical yield. Diol protected cyclic ketone 39e reaction unfortunately considerably
affected the chemical yield, stereoselectivity (66%, syn:anti = 30:70 dr, 68% ee) (entry 4).
Tetrahydropyran based ketone 39f promotes corresponding product 40n with excellent
enantioselectivity, good diastereoselectivity, chemical yield was remains as good (72%,
syn:anti = 13:87 dr, 94% ee) (entry 5). In the case of simple acetophenone 39g have
employed which delivers product with moderate chemical yield, enantioselectivity (68%,
59% ee) (entry 6). Simple aliphatic ketones can enable non-rigidity while transition state
if compared with cyclic aliphatic ketones thus might affect the results in this case.
Eventually, aromatic acetophenone 39h with 7a with catalysts 61c shows excellent
catalytic activity in terms of enantioselectivity though chemical yield was not satisfactory(67%, 90% ee) (entry 7). This effect on results might be arose by the electronic influencesof aromatic ring over the reaction which can implies on the product results.

2.8 Plausible reaction course
Based on the excellent enantiopurity (98% ee) of the obtained optically active aldol
product (2R,3S)- 40a from the asymmetric aldol reaction of cyclohexanone 39a with 4nitrobenzaldehyde 41a using our superior catalyst 61c, a model of the asymmetric reaction
course is proposed (Scheme 29). Initially, the condensation of N-terminal primary amine
peptide organocatalyst 61c with aldol donor 39a forms the enamine as intermediate I. The
conformation of intermediate I is fixed by g-turned intramolecular hydrogen bonding
interactions between the amide carbonyl group at N-terminal side and the amide aminogroup at C-terminal side on pyrrolidine ring and also the amino hydrogen atom and thenext amide amino group of organocatalyst species. Intermediate I might exist as I-1 which

37

I
I-2

I-1

Figure 8. Scan of total Energy of peptide catalysts intermediate.

is having less steric interaction between dipeptide chain on N-terminal side and theenamine part than that of intermediate I-2. This expectation was supported by the
conformational analyses using scan of total energies and DFT calculations for the enamineintermediates I-1 and I-2 and the result indicated that the conformation of I-1 is most stable(Figure 8). Subsequently, more stable enamine intermediate I-1 might attack 4nitrobenzaldehyde 7a through possible transition states TS-1 to TS-4 as shown in Scheme
29. In the TS, the reaction might procced through TS-1 to afford [2S,3R]- 40a as a major
product than those of TS-2, TS-3, and TS-4, wherein the substrate 7a has stericinteractions from N-terminal side and C-terminal side fixed by g-turn intramolecularhydrogen bonding. On the other hand, aldol acceptor 7a might coordinate with amidehydrogen atom through hydrogen bonding at N-terminal side on I-1 species in TS-1.
38

O
N

O

O

HN

N

O

39a

NH

O

NH2

O

N

H

N
H

61c

H

O
N

N
O H
O

H

H

N

H

N
O H

H
H
N H
H

I-1

I-2

O2N

CHO
7a

O
N

N

O

H

O
N

N
O H

H O

O

N
H
H

N

H

O
N

N
O H
O

H

O
N
H
H
H

H

N

N
O H
O

H
H

N
H
H
TS-2

TS-1

H

O
N

N

N
O H

H
H

H

N
H
H

O

TS-3

O

TS-4

98% ee
O

O

OH

OH

OH

NO2

NO2
[2S,3R]-40a
anti-isomer

O

O

NO2
[2S,3S]-40’asyn-isomer[2R,3S]-40a’
anti-isomerOH

NO2[2R,3R]-40’a’
syn-isomer

Scheme 29. Plausible reaction course.
Subsequently, the enamine moiety attacks the enantiotopic face of 40a resulting 40a as the
major isomer.

39

2.9 Summary
In summary, the author developed new small g-turn type N-primary amino terminal
tripeptides organocatalysts 61a-j and was explored based on a new catalyst design concept.
Their functionality as organocatalyst were examined in the asymmetric aldol reaction ofvarious acyclic or cyclic ketones 39a-h with different aromatic aldehydes 7b-i to afford thedesired chiral aldol products 40a-p. All the catalysts showed catalytic activity in thisreaction. As a result, catalyst 61c showed best catalytic performance and afford thecorresponding chiral anti-aldol products with good to excellent chemical yields,
diastereoselectivities and enantioselectivities (up to 99%, up to syn: anti = 13:87 dr, up to
99% ee) under eco-friendly solvent-free condition.

40

Chapter 3
New small g-turn type N-primary amino terminal tripeptides organocatalyst
for solvent-free asymmetric cross aldol reaction of various cyclic andacyclic ketones with isatins41

3. New small g-turn type N-primary amino terminal tripeptidesorganocatalyst for solvent-free asymmetric cross aldol reaction of various
cyclic and acyclic ketones with isatins
3.1 Author approach
The author aim was to develop new g-turn type N-primary amino terminal tripeptidesorganocatalyst A by synthesis from simple commercially available amino acids. The g-turn typeN-primary amino terminal tripeptide A has the basic primary amino group for the enamine
formation and hydrogen bonding sites, and also the amide group for hydrogen bonding site to thesubstrate. In addition, the bulky flexible polycyclic aromatic group on the nitrogen atom of amidegroup in catalyst might be shielded effectively the one enantiotopic face on the basis of a stericfactor to enhance the selectivity. To further develop the efficiency of g-turn type N-primaryamino terminal tripeptides as an organocatalyst A, the author examined the asymmetric crossed
aldol reaction of cyclic and acyclic ketones with isatins using chiral tripeptide organocatalyst.
Asymmetric crossed aldol reaction has widely recommended for chiral carbon-carbon bondformation tool in the field of organic synthesis. Specifically, asymmetric cross aldol reaction of
ketones B and isatins C to deliver the chiral aldol products D is preferred predominantly toconstruct contagious chiral centers. The chiral aldol products D affords from that reaction possess
quaternary chiral center which is existing as highly challenging task to construct in the field of
natural and bio-active molecule synthesis. Hence, author has decided to study their catalytic
activity in asymmetric aldol reaction of ketones B and isatins C to deliver the chiral aldol products
D. To the best of our knowledge, this is the first report on g-turn type N-primary amino terminal
peptide organocatalyst A exhibiting an extremely efficient catalytic activity in asymmetricintermolecular cross-aldol reaction of several cyclic and acyclic ketones B with substituted isatins
C to afford the corresponding 3-substituted 3-hydroxy-2-oxindolinones D in good to excellent
chemical yields and stereoselectivities (Scheme 30). The synthesis of carbon-carbon, carbonheteroatom bonds is an important technique for the construction of biologically relevant key
motifs and includes pharmaceutical intermediates in the rapidly growing field of synthetic organic42

backboneOsteric influencesite

enamine and hydrogenbond formation sitesteric influence
site
N Ar
O H
γ-turn

N
R’
O

NH

H 2N

R’’

hydrogen bondingsite
steric influence
site

O
HO

O

O
+R

O
N
H

39

asymmetric
aldol reaction

R

O
N
H
44

43

Scheme 30. Catalyst’s concept and its use in asymmetric cross Aldol reaction.
chemistry. Asymmetric aldol reaction have been providing effortless approach for carbon-carbon
bond construction especially, The asymmetric cross aldol reaction of cyclic or acyclic ketones
with oxoindolines to provide the synthetically advantageous chiral carbo-hetero atom
Br

R OH

O
HO

NH
HO

O

O

N
H

Br

O

N
H

convolutamydin A-E

N
H

3-hydroxy-3-(2-oxocyclohexyl)2-indolinone

donaxaridine
O

HO

HO
O

N

N H
R

N H
Me

madindoline A-B

CPC-1

OH
OH
N

Me
N

O
Cephalanthrin A

Figure 9. 3-substituted 3-hydroxyindolin-2-ones containing bioactive compounds.
containing 3-hydroxyindolin-2-ones which are structural motifs with quaternary stereogenic
centers and are present in various natural and artificial bioactive compounds and also they act asprecursors in the total synthesis of natural products and pharmaceutically active compounds, such43

asConvolutamydines

A-E,

3-hydroxy-3-(2-oxocyclohexyl)-2-indolinone,Donaxaridine,

dioxibrassinine, leptosin D, spiro-isoxazolidinyl oxindole, witindolinone C, madindoline,
Donaxaridine and some new biologically active motifs in the field of synthetic organic
36

chemistry. In recent years, a variety of catalytic asymmetric methods have been devoted for theconstruction of 3-substituted 3-hydroxyindolin-2-ones containing an asymmetric quaternarystereogenic center carbon atom at the 3-position.

37

However, Nakano and co-workers have reported for primary aminoamide basedorganocatalysts for enantioselective aldol reaction of various isatins with different ketones toafforded chiral aldol products with excellent chemical yield and stereoselectivities (up to 99%
yield, dr 99:1, 99% ee) (Scheme 31).

38

O

O
+ R

NH2
O

N
H
39

N
H

O

45

THF,
rt, 6-168 h

43

O
HO
R

O
N
H

44
99% yield
99:1 syn:anti dr
98% eeScheme 31. Amino amide catalyst for asymmetric cross Aldol reaction.
There are only three reports wherein N-terminal secondary amine-based peptides wereused as catalysts for the asymmetric aldol reaction of isatins to give 3-substituted 3-hydroxy-2oxindoles which is a partial structure in various biologically active compounds. First, theTomasini and co-workers have explored the dipeptide as an organocatalysts for the asymmetric
aldol reaction of isatins with ketones to afforded corresponding chiral aldol products with
39

moderate to good chemical yield and stereoselectivities (up to 77% ee).

44

Ph

O
O
O

+

R

N
H
46

NH
O

O
HO

OBn

-15 °C

N
H
6

O

O

R
N
H

43

47
96% yield
77% eeScheme 32. Dipeptide catalyst for asymmetric cross Aldol reaction.
Panda and co-workers described the unnatural tripeptide as an organocatalysts for theasymmetric aldol reaction of isatins with simple ketones to afford the chiral aldol products withgood chemical yield and enantioselectivities (up to 84% ee).40

O

NH

NH
O
O

+

NH

R

O

O
HO

O

DMSO, H2O
TFA

N
H
6

O
HO
48

O

R
N
H
47
85% yield
84% ee43

Scheme 33. Unnatural tripeptide catalyst for asymmetric cross Aldol reaction.
Murata and co-workers have reported the third tripeptide organocatalyzed asymmetric
aldol reaction of isatins with acyclic ketones to obtained chiral aldol products with good to41

excellent chemical yield and enantioselectivities (up to 97% ee).
O
O
NH HN
O
O

+ R

O
N
H

6

NH

O
HO

O
49
H 2O

HO
R

O
N
H
47
99% yield
97% ee43a

Scheme 34. Tripeptide catalyst for asymmetric cross Aldol reaction.
45

3.2 Results and Discussion
For an g-turn tripeptide with N-terminal of several amino acids and C-terminal of various
aromatic ring organocatalysts for this reaction, g-turn tripeptides having glycine - L-phenyl
alanine 61a-f, and C-terminal amine like 1-phenyl, 1-anthacene, 1-pyrene 61g-i groups wereselected moreover, 61j (D-tert leucine) and 65 (D-proline) are diastereomers of catalysts 61c.
Additionally we change the ring size 4 and 6 membered 69a and 69b were selected (Figure 10).
O

NH2

O
N
H

N
O

NH2

O

HN

O
N
H

61a

N
O

NH2

O

HN

O
N
H

O

NH2

H

N
O

O

HN

H

O

NH2

N
H

N
O

HN

O

61d
O

O

HN

O

NH2

N

N
H

O

HN

O

61g

61f
O

O
N
H

N
H

H 2N

N

O
HN

HN

O

N

65

HN

N

N
H

O

O

O

O

N
N
H

HN

61j

61i

O

O

O

NH2

O

61h

N
H

O

N

O

NH2

HN

NH2

O

N

N
H

61e

H 2N

O

61c

61b

N
H

N

O

NH2

69a

O
HN

NH2

N
H

N
O
HN

O

69b

Figure 10. N-Terminal primary tripeptide organocatalysts.
The catalysts 61a-j, 65 and 69a,b showed good catalytic activities in the aldol reactions
using general ketones as cyclohexanone, and aldehydes such respectively, in our previous reports.
The catalysts 61a-j, 65 and 69a,b were easily prepared by the condensations of the correspondingchiral N-Boc amino acids with polycyclic aromatic amines, according to our previous methods.
46

3.3 Catalysts 61a-j, 65 and 69a,b screening in asymmetric cross aldol reaction
Initially, we examined the cross aldol reaction of cyclohexanone 39a with isatin 43a using
N-terminal primary amino peptide organocatalysts 61a-j, 65 and 69a,b (10 mol%) in the presenceof Et2O at room temperature (Table 5). All catalysts showed effective, and the correspondingchiral-aldol product (2S,3R)-44 was produced in excellent syn:anti selectivities (syn:anti = 1:99
dr). The absolute configurations of 44 were identified based on comparison with literature data.
The use of g-turn N-terminal primary amino tripeptide catalyst 61a-j with poly aromatic amine
afforded the desired chiral aldol products 44 in good to excellent chemical yield (up to 99 %),diastereoselectivity (up to syn:anti = 1:99 dr) and good enantioselectivity (up to 85 % ee) (entries
1-10, Table 5). Tripeptide catalyst 61a having Ala on N-terminus delivers chiral aldol adduct 44
at excellent chemical yield, diastereoselectivity and low enantioselectivity (95%, syn:anti = 5:95
dr, 11% ee) (entry 1). The catalysts 61b,c having Val and t-Leu were furnished aldol adducts
but catalyst 61c showed good results in terms of enantioselectivity than catalyst 61b (99%,
syn:anti = 1:99 dr, 85% ee) (entries 2-3). Aromatic groups containing catalysts 61d,e to delivers
the chiral aldol product with excellent chemical yield, diastereoselectivity and low
enantioselectivity (80-85%, syn:anti = 10:90-7:93 dr, 20-35% ee)(entries 4-5). The catalysts 61f
having Gly were furnished aldol product with moderate chemical yield and diastereoselectivity
and low enantioselectivity (70%, syn:anti = 15:85 dr, rac ee) (entry 6).These results implies thatt-Leu group performing better activity than any other catalysts. Catalysts 61g with aromatic
naphthyl amino substituent on amide group was examined which promotes chiral aldol product44 in excellent chemical yield, diastereoselectivity and moderate enantioselectivity (98%, syn:anti= 3:97 dr, 35% ee) (entry 7). Bulkier catalyst 61h-i gave 44 in excellent chemical yield (99 %),diastereoselectivity (syn:anti = 1:99 dr) and with moderate to good enantioselectivity (50-76 %ee) (entry 8-9, Table 5), Similarly, the use of diastereomer of 61c tripeptide catalyst 61j with (Dtert-Leucine) 1-naphthyl also gave good chemical yield and moderate enantioselectivity (93 %,70 % ee) (entry 10, Table 5). Similarly, the use of another diastereomer of 61c tripeptide catalyst
65 with (D-proline) 1-naphthyl also gave excellent chemical yield and moderateenantioselectivity (99 %, 40 % ee) (entry 11,Table 5). We have also examined different ring size
47

Table 5. Asymmetric aldol reaction of 39a with 43a using organocatalysts 61a-j, 65, and 69a,b.

+

O
N
H

O
HO

cat. 61a-j, 65
and 69a,b(10 mol%)

O

O

Et2O
rt, 24h

O
N
H
44a

39a

43a

Entry

Cat.
(10 mol%)

Yield (%)adr
syn:antibee (%)c
anti

1

61a

95

5:95

11

2

61b

96

5:95

56

3

61c

99

1:99

85

4

61d

80

10:90

20

5

61e

85

7:93

35

6

61f

70

15:85

rac

7

61g

98

3:97

35

8

61h

99

1:99

50

9

61i

99

1:99

72

10

61j

93

10:90

70

11

65

99

10:90

40

12

69a

95

1:99

63

13

69b

97

1:99

58

aIsolated yields. bDiastereoselectivity was determined by 1H NMR using crude

reaction mixture. cThe ee values were determined by HPLC with a Daicel
Chiralpak OJ-H column.

69a with four membered azetidine ring, and 69b with six membered piperidine ring,
respectively in this reaction. As a result, the catalysts 69a and 69b did show catalytic
activity similar to 61c having L-t-Leu-L-t-Leu moiety at N-terminal side and fivemembered pyrrolidine ring (95-97%, 1:99 dr, 58-63 ee). These results indicated that the
chain length of N-terminal side, the size of backbone ring for forming g-turn, theconfiguration and types of substituents at N-terminal side and the aromatic ring on amide
48

amino group at C-terminal side are highly important for achieving satisfactorystereoselectivities, by shielding one enantiotopic face to attack from the aldol acceptor 43ain this reaction condition using ether solvent.

3.4 Optimization of reaction condition
To optimize the reaction conditions using superior catalyst 61c having t-Leu on Nterminus and naphthalene group on amide function might suitable catalysts to promote
asymmetric cross aldol reaction, we next examined the effects of solvent, the molar ratioof catalyst, co-catalyst, reaction temperature (entries 1-25, Table 6). First, the test reaction
was performed in various solvents including, ethereal, non-polar, aromatic solvents,
chlorinated, polar protic, aprotic, polar, water and solvent free condition with 61c catalyst
and results are depicted (entries 1-11, Table 6). Consequently, reaction using various
catalysts loading such as 10, 7.5, 5, 2.5 and 1 mole ratio in superior Et2O reaction condition
at room temperature for 24 h (entries 12-15, Table 6). After screening, we have observedthat catalysts 61c mole ratio might strongly affects the products outcome in terms ofchemical and stereochemical yield rather than 10 mol %. Asymmetric cross aldol product44 was obtained in 99% yield with 85% ee when the reaction was carried out in Et2O using
10 mol% of 61c at room temperature for 24 h (entry 1, Table 6). In contrast to aldol
reaction conditions using an acidic co-catalyst, our reaction system using organocatalyst
61c did not afford satisfactory enantioselectivity, although the reasons for this are not yet
clear (entries 16-23, Table 6). Further, reaction of 39a and 43a have conducted with moleratio 10% of catalyst in presence of Et2O condition with multiple temperatures (entries 2425, Table 6). Surprisingly, aldol adduct 44a was delivered excellent chemical yield,
enantioselectivity when reaction performed at room temperature for 24 h. However, thereaction was performed in different temperature diastereoselectivity remains unchanged.
Based on the outcomes, the best optimal reaction condition for this reaction using superior
catalyst 61c in presence of Et2O at room temperature for 24 h.

49Table 6. Optimization of catalyst 61c for asymmetric cross Aldol reaction.

O

O
+

O
N
H

39a

O

Cat. 61c(10 mol%)
Co-cat(10 mol%)O
HO

Solvent

N
O

HN

O

O
N
H
44a

Temp
24h

43a

NH2

N
H

cat. 61c

Entry

Cat. 61c
mol%

Temp

Co-catSolvent

Yield (%)adrbee (%)c
anti

1

10

25

-

Et2O

99

1:99

85

2

10

25

-

iPr2O

93

1:99

77

3

10

25

-

THF

80

1:99

83

4

10

25

-

pentane

95

5:95

68

5

10

25

-

CH2Cl2

95

10:90

36

6

10

25

-

CHCl3

85

9:91

21

7

10

25

-

CH3CN

70

10:90

18

8

10

25

-

toluene

99

5:95

80

9

10

25

-

MeOH

65

1:99

50

10

10

25

-

H 2O

80

9:91

10

11

10

25

-

neat

99

8:92

61

12

1

25

-

Et2O

55

5:95

70

13

2.5

25

-

Et2O

60

3:97

77

14

5

25

-

Et2O

83

3:97

78

15

7.5

25

-

Et2O

90

1:99

79

16

10

25

N-Boc proline

Et2O

55

1:99

70

17

10

25

PhCOOH

Et2O

30

1:99

76

18

10

25

AcOH

Et2O

99

1:99

42

19

10

25

TFA

Et2O

99

1:99

14

20

10

25

4-NO2PhCOOH

Et2O

99

1:99

10

21

10

25

3-NO2PhCOOH

Et2O

99

1:99

25

1,3,5-Ph(COOH)3

Et2O

99

1:99

67

22

10

25

23

10

25

Thiourea

Et2O

97

1:99

2

24

10

0

-

Et2O

90

10:90

75

25

10

-25

-

Et2O

99

10:90

62

aIsolated yields. bDiastereoselectivity was determined by 1H NMR using crude reaction mixture. cThe ee values were

determined by HPLC with a Daicel Chiralpak OJ-H column.

503.5 Asymmetric aldol reaction of various isatin with ketones using
catalyst 61c
After the optimization, substrate scope of aldol reactions were conducted between various
ketones 39a-g, 6 and aromatic substituted isatins 43a-m with catalyst 61c in presence of Et2O for
24h at room temperature and are documented in Table 7 & 8. All the reactions afforded thecorresponding chiral aldol products 44b-t with low to moderate chemical yields, good
diastereoselectivities, moderate to excellent enantioselectivities. Initially, we investigated thegenerality of the reaction of cyclohexanone 39a with isatins 43b-m using catalyst 61c (entries 112, Table 7). Isatins 43b-m with different substitution patterns and electronic properties were
evaluated, and all were readily converted into their corresponding chiral-aldol products (2R,3R)44b-m with high stereoselectivities (syn:anti = 1:99), high chemical yields (83-99%), and withmoderate to good enantioselectivities (37-99% ee) (entries 1-12, Table 7). In the attempted
reactions, N-methylisatin 43b afforded aldol product 44b in excellent

chemical yield,

diastereoselectivity and with good enantioselectivity (99%, syn:anti = 1:99, 85% ee) (entry 1,
Table 7). Aldol reactions of both N-allylisatin 43c and N-benzyl isatin 43d, afforded products 44c
and 44d in fairly good chemical yields, diastereoselectivity and good enantioselectivities (44c:98%, syn:anti = 1:99, 73% ee; 44d: 83%, syn:anti = 5:95, 84% ee) (entries 2-3, Table 7). Isatin
43e, bearing an electron-donating methyl group on the aromatic ring, also gave rise in excellent
chemical yield, diastereoselectivity and low enantioselectivity to product 44e (93%, syn:anti =10:90, rac) (entry 4, Table 7). isatins 43f-l, bearing halogen atoms on their aromatic rings, also
afforded the corresponding indolinones 44f-l with god to excellent chemical yield,
diastereoselectivities and low to moderate enantioselectivities (90-99%, syn:anti = 15:85 – 10:90,
47-63% ee) (entries 5-11, Table 7). Additionally, good results of chemical yield,
diastereoselectivity and low enantioselectivity (99%, syn:anti = 10:90, 37% ee) were obtained
from the reaction of isatin 43m, bearing a strong electron-withdrawing NO2 group on its aromaticring, with ketone 39a using 10 mol% of 61c at room temperature for 24 h (entry 12, Table 7).
These results indicate that catalyst 61c is generally applicable to the aldol reaction of differently
substituted isatins.
51

Table 7. Aldol reaction of cyclohexanone 39a with various isatins 43b-m using catalyst 61c.
O
O

O

R2

+

O
N
R1

39a

Cat. 61c(10 mol%)

R2

Et2O
rt, 24hIsatinNR1
44a-m

Product

43b-l

O
43b

O

O

N

O

O

43c

43d

O

O

N
Bn

44a-m

Yield (%)a

syn:antibee (%)c

44b

99

1:99

99

44c

98

1:99

73

44d

83

5:95

84

44e

99

10:90

rac

44f

93

15:85

47

44g

95

15:85

52

44h

96

13:87

60

44i

99

10:90

47

44j

99

10:90

63

44k

90

14:86

52

44l

92

15:85

59

44m

99

10:90

37

N
Bn
O

H 3C
O

43e

H 3C

O
I
5

O

43f

I

O
Br
O

43g

N
H
O
HO
O

N
H

6

O
HO
O

N
H

Br

N
H
O
HO
O

N
H

N
H

O
F
7

O

43h

F

O
HO
O

N
H

N
H
O
HO

O
8

O

43i

N
H

O
N
H

Br

O
HO

O
9

O

43j

N
H

O
N
H

Cl
O
Br HO

O

10

43k

O

O

N
H

N
H
O
Cl HO

O

11

43l

O

O

N
H

N
H
O

12

Cat. 61c

O
HO

3

Cl

O

N

O

Br

HN

O
HO

N

Cl

N
O

N

O

Br

N
H

O
HO

1

2

NH2
O

43b-m

Entry

4

O
HO

O2N
O
N
H

43m

O2N

O
HO
O
N
H

aIsolated yields. bDiastereoselectivity was determined by 1H NMR using crude reaction mixture. cThe ee values were determinedby HPLC with a Daicel Chiralpak OJ-H, OD-H, AD-H, IC columns.

52

We next examined the asymmetric cross aldol reaction of isatin 43a with several acyclic
or cyclic ketones 39b-g, 6 using the optimal catalyst 61c under the same reaction conditions used
Table 8. Aldol reaction of various ketones 39b-g, 6 with 43a using catalysts 61c.
O
O

O
+

O

Et2O
rt, 24hNH39b-g,6

Entry

O
HO

Cat. 61c(10 mol%)

N
O

HN

O

O
N
H
44n-t

43a

Ketones
39b-f,6NH2

N
H

Product
44n-tCat. 61c

Yield (%)a

syn:antibee (%)c

95

5:95

35

93

5:95

43

83

10:90

51

40

13:87

35

O

O

HO
1

O
39b
O

N
H
44n
O
HO

2

O
39c

N
H
44o
O

O

HO

O

3

O

O
39d

N
H
44p
O

O

HO
4

N
Boc
39e
O

5

Boc

O
N
H
44q
O

HO

Ph

Ph
N
H
44r

39f

6

N

O

HO

39g

N
H
44s

O

HO

6

N
H
44t

63

—:—

55

60

—:—

10

70

—:—

10

O
Naph

Naph

7

O

O

O

O

aIsolated yields. bDiastereoselectivity was determined by 1H NMR using crude reaction mixture. cThe ee values were

determined by HPLC with a Daicel Chiralpak OJ-H, OD-H, AD-H, IC columns.

53

to generate earlier chiral aldol products 44 (Table 8). The reaction of cyclopentanone 39b withisatin 43a proceed and afforded the corresponding chiral aldol product 44n in good chemical yield,
diastereoselectivity and low enantioselectivity (95%, syn:anti = 5:95, 35% ee) (entry1, Table 8).
Although bulkier cycloheptanone 39c gave rise to product 44o in good chemical yield,
diastereoselectivity and low enantioselectivity (93%, syn:anti = 5:95, 43% ee) (entry 2, Table 8).
Tetrahydropyran based ketone 39d promotes corresponding aldol product 44p with goodchemical yield, good diastereoselectivity and moderate enantioselectivity (83%, syn:anti = 10:90
dr, 51% ee) (entry 3, Table 8). N-Boc piperidone 39e with 43a to afforded corresponding 44q
moderate chemical yield, low diastereoselectivity and enantioselectivity (40%, syn:anti = 13:87
dr, 35% ee) (entry 4, Table 8). Additionally, acetophenone 39f gave rise to product 44q inmoderate chemical yield, enantioselectivity (63%, 55% ee) (entry 5, Table 8). In the case of
simple acetonaphthone 39g have employed which delivers chiral aldol product with moderatechemical yield, low enantioselectivity (60%, 10% ee) (entry 6). The reaction of isatin 43a withsimple acetone 6 proceeded smoothly to give the corresponding aldol product 44t in goodchemical yield (70%), although the enantioselectivity for this conversion was low (10% ee) (entry
7, Table 8). were characterize on the basis of full spectroscopic data analyses and were found to
be consistent with previously reported data. Absolute configurations of all aldol products were
determined by comparing specific optical rotation values obtained herein with literature values.4254

3.6 Plausible reaction course
Based on the good enantiopurity (85% ee) of the obtained optically active aldol
product (2R,3R)- 44a from the asymmetric aldol reaction of cyclohexanone 39a with isatin
43a using our superior catalyst 61c, a model of the asymmetric reaction course is proposed(Scheme 29). Initially, the condensation of N-terminal primary amine peptideorganocatalyst 61c with aldol donor 39a forms the enamine as intermediate I. The
O
O
O

N
HN

N

O

39a

NH

O

N

O
NH2

61c
H

H

O
N

N
O

H
N

O

H

N

H

H

N

H

N
O

H

H
H

H

H

I-1

I-2

O
O
N
H

43a
N

O

N

H

H

N

O

H
O
O

N H

N

N

N
O

H

O

O

O

N
H

H

N
O

H
N

O

H

N H
HO

H

H

O

N
N
O H
O

H

N H

N
O
H
N

O

H

N

O

H

H
H N H
O
O

O

NH

N
H

TS-2

TS-1

TS-3

TS-4

85% ee
O

O

O

O

HO

HO

HO

HO

O

O

O

O

N
H

N
H

N
H

N
H

[2R,3R]-44a
anti-isomer[2S,3S]-44a’anti-isomer[2R,3S]-44’a
syn-isomer[2S,3R]-44’a’
syn-isomer

Scheme 29. Plausible reaction course.

55

conformation of intermediate I is fixed by g-turned intramolecular hydrogen bonding
interactions between the amide carbonyl group at N-terminal side and the amide aminogroup at C-terminal side on pyrrolidine ring and also the amino hydrogen atom and thenext amide amino group of organocatalyst species. Intermediate I might exist as I-1 whichis having less steric interaction between dipeptide chain on N-terminal side and theenamine part than that of intermediate I-2. This expectation was supported by the
conformational analyses using scan of total energies and DFT calculations for the enamineintermediates I-1 and I-2 and the result indicated that the conformation of I-1 is moststable. Subsequently, more stable enamine intermediate I-1 might attack isatin 43a throughpossible transition states TS-1 to TS-4 as shown in Scheme 29. In the TS, the reaction
might procced through TS-1 to afford [2R,3R]- 44a as a major product than those of TS2, TS-3, and TS-4, wherein the substrate 43a has steric interactions from N-terminal side
and C-terminal side fixed by g-turn intramolecular hydrogen bonding. On the other hand,aldol acceptor 43a might coordinate with amide hydrogen atom through hydrogen bondingat N-terminal side on I-1 species in TS-1. Subsequently, the enamine moiety attacks theenantiotopic face of 44a resulting 44a as the major isomer.

56

3.7 Summary
We have developed a simple new new small g-turn type N-primary amino terminal
tripeptides organocatalysts 61a-j based on a new catalyst design concept. This catalyst is stable
when exposed to air and has the two significant features of easy preparation and desirable
structural characteristics. Thus, it can be derived easily from the corresponding amino acid by
few steps, and it contains primary amino group for transient enamine generation and a modifiableamide group that enables non-covalent conformational locking of the enamine intermediate
within a single molecule. Furthermore, the bulkier 1-naphthyl substituent on the amide N-atom inthe catalyst makes possible high levels of enantioselectivity during asymmetric cross aldol
reaction. Thus, when 61c was used in the asymmetric aldol reaction of several isatins with cyclic
and acyclic ketones, one enantiotopic face of the enamine intermediate was effectively shieldedby the amide-linked naphthyl substituent; the corresponding chiral aldol products wereconsequently generated in excellent chemical yields (up to 99%) diastereoselectivity (syn:anti =1:99 dr) and moderate to excellent enantioselectivity (up to 99% ee,) under mild andenvironmentally friendly conditions. Further studies, including alterations to the catalyst designand detailed mechanistic investigations using calculation methods, are currently in progress.

57

4. Conclusion
The world is in a growing crisis in terms of saving humanity from the continuous
emergence of life-threatening diseases. As a result, scientists are attempting to find a newalternative pathway for treating, reducing, and possibly eliminating pandemic outbreaks of
diseases and new medicines. The majority of bioactive molecules, including drugs, are optically
active compounds, which means that a pair of enantiomers has different biological functions.
Notably, in pharmaceuticals, differences in the absolute configuration may affect including not
only the pharmacological activity but also toxicity. Asymmetric catalysis, in which a small
quantity of chiral molecular catalyst theoretically allows for the indefinite creation of optically
active molecules, is one of the most demanding problems in organic synthetic chemistry.
Environmental implications evade as a result of chemical syntheses, and environmentally benignorganic syntheses have been receiving lot of attention in recent years. Organometallic catalysts
and metal-free chiral organocatalysts are the two types of chiral catalysts utilized in catalytic
asymmetric syntheses. Especially, organocatalysts are stable in air, easy to handle, andinexpensive, so they are being focused on as next-generation, environmentally friendly catalysts.
As a result, an enantioselective synthesis for optically bioactive compounds is required in orderto produce attractive optically active molecules with high medicinal properties.
On these backgrounds, the author developed a new g-turn type N-primary amino
terminal tripeptides organocatalysts and was explored based on a new catalyst design concept.
These peptide organocatalysts were successfully prepared from commercially available aminoacids by using simple organic transformations and the catalytic activity was demonstrated in theasymmetric Aldol reactions various ketones with aldehydes (chapter 2) and asymmetric crossaldol reaction of cyclic and acyclic ketones with several substituted isatins (chapter 3).
In chapter 2, the author discussed about the detailed application of new g-turn type Nprimary amino terminal tripeptide organocatalysts 61a-j based on a new catalyst designconcept. The primary amine-based peptide organocatalysts 61a-j were prepared fromcommercially available amino acids. Their catalytic activities were examined in the asymmetric
Aldol reaction of various acyclic or cyclic ketones 39a-h and 7a-g with aldehydes 40a-s. As a58

result, catalyst 61c with a 1-naphthyl group showed best catalytic performance and afforded thecorresponding chiral anti-Aldol products 40 with good to excellent chemical yields,
diastereoselectivities and enantioselectivities (up to 99%, up to syn:anti = 13:87 dr, up to 99%ee).
In chapter 3, the asymmetric cross aldol reaction was established with various acyclic or
cyclic ketones 39a-g, 6 and isatins 43a-m using N-primary amino terminal tripeptideorganocatalysts 61a-j, 65 and 69a,b. This protocol provides the corresponding chiral aldol
products having quaternary chiral carbon centre. In this study, the author revealed that the new
explored peptide organocatalyst 61c shows good catalytic activity in the enantioselective to afford
the corresponding chiral aldol products 44a-t having quaternary chiral carbon centre with good
to excellent chemical yields (up to 99%), diastereoselectivities (up to syn:anti = 1:99 dr) andmoderate to good enantioselectivities (up to 99% ee).
In conclusion, the author developed g-turn type N-primary amino terminal tripeptideorganocatalysts from commercially amino acids and corresponding amine as a synthetic precursor.
Their catalytic activities were examined in asymmetric Aldol reactions which afforded thebiological active chiral synthetic intermediates in excellent chemical yield, diastereoselectivity
and moderate to excellent enantioselectivities. It’s expected that these findings might be able tocontribute greatly to the development of new synthetic drugs in the field of synthetic organic
chemistry.

59

5. Experimental section
New small g-turn type N-primary amino terminal tripeptides organocatalyst
forsolvent-free asymmetric aldol reaction of various ketones withaldehydes

General procedure for the synthesis of peptide organocatalysts 58a-d, 60a-h, 61a-j, 63, 64,
65, 67a,b, 68a,b and 69a,b
To a solution of N-Boc-L-Proline 56 (0.5mmol), N,N'-Dicyclohexylcarbodiimide (DCC)(0.6 mmol) was suspended in dry CH2Cl2 (5 ml) and stirred at 0 °C for 1 hour. The corresponding
primary aromatic amines 57a-d (0.55 mmol) were added slowly, and the reaction mixture was
gradually allowed to stir from 0 °C to 30 °C until the reaction completion. After the reaction wascompleted, as monitored by TLC, the insoluble by-product Dicyclohexyl urea (DCU) was filtered
off and the filtrate was evaporated to dryness. The obtained oily residue was dissolved in CHCl3
and washed consecutively with saturated aqueous NaHCO3 solution, aqueous HCl (1.0 M) andbrine. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated under areduced pressure to afford the obtained crude products that were used for next step without further
purification. To the solution of the crude products in dry CH2Cl2, TFA was added dropwise overa period of times (v/v) at 0 °C and successively stirred at room temperature (r.t.) for 4 h. After thereaction completion, DCM and TFA were removed under a reduced pressure, the residue wasbasified by drop-wise addition of saturated NaHCO3 solution at 0 °C and stirred for 1 hour at r.t.
The crude products were extracted with CHCl3, dried over Na2SO4 and concentrated under
reduced pressure. The residue was purified by flash column chromatography on SiO2 (CHCl3:
MeOH = 99:1 to 95: 5) to afford the corresponding amino amides 58a-d, 63 and 67a,b.

60

2.1.1

L-Pro-Ph (58a)Colorless solid. 90% yield. m p 73 °C. [a]D20 = -71.87 (c = 0.64, CHCl3).
O

N
H

HN

1

H NMR (500 MHz, CDCl3, ppm): δ 9.73 (s, 1H), 7.60 (m, 2H), 7.30-

7.34 (m, 2H), 7.09 (t, J = 7.2 Hz, 1H), 3.86 (dd, J = 9.0, 5.3 Hz, 1H),
3.06-3.11 (m, 1H), 2.96-3.00 (m, 1H), 2.18-2.25 (m, 1H), 2.01-2.08 (m,1H), 1.70-1.82 (m, 2H). 13C NMR (125 MHz, CDCl3, ppm): δ 173.5,

58a

137.8, 128.9, 123.8, 119.2, 61.0, 47.3, 30.77, 26.3. MS (EI): m/z = 190[M]+, HRMS calculated for C11H14N2O1 [M]+: 190.2460; found 190.1114.
2.1.2. L-Pro-1-Naph (58b)Colorless solid. 95% yield. mp 63 °C. [a]D20 = -11.11 (c = 0.81, CHCl3).
O
N
H

HN

1

H NMR (500 MHz, CDCl3, ppm): δ 10.59 (s, 1H), 8.24-8.32 (m, 1H),

7.83-7.90 (m, 2H), 7.63-7.68 (m, 1H), 7.47-7.55 (m, 3H), 4.02 (q, J =4.8 Hz, 1H), 3.10-3.21 (m, 2H), 2.25-2.35 (m, 1H), 2.15 (m, 1H), 1.771.91 (m, 2H). 13C NMR (125 MHz, CDCl3, ppm): δ 173.5, 134.0, 132.5,
128.8, 126.1, 126.0, 125.7, 124.4, 120.2, 117.7, 61.5, 47.6, 30.9, 26.5.

58b

MS (EI): m/z = 240 [M]+, HRMS calculated for C15H16N2O [M]+:240.3060; found 240.1255.
2.1.3. L-Pro-1-Anth (58c)
Yellow solid. 85% yield. mp 91 °C. [a]D20 = -134.95 (c = 0.45, CHCl3).
O
N
H

HN

1

H NMR (500 MHz, CDCl3, ppm): δ 10.75 (s, 1H), 8.42 (d, J = 17.2 Hz,2H), 8.27 (d, J = 6.9 Hz, 1H), 7.97-8.05 (m, 2H), 7.80 (d, J = 8.6 Hz,
1H), 7.45-7.54 (m, 3H), 4.08 (q, J = 4.8 Hz, 1H), 3.17-3.28 (m, 2H),
2.28-2.36 (m, 1H), 2.20 (m, 1H), 1.88 (m, 2H). 13C NMR (125 MHz,CDCl3, ppm): δ 173.6, 132.2, 132.1, 131.4, 128.4, 128.0, 127.2, 125.7,

58c

125.4, 125.3, 124.6, 118.8, 116.4, 77.3, 77.0, 76.8, 61.6, 47.6, 30.9, 26.5.
MS (EI): m/z = 290 [M]+, HRMS calculated for C19H18N2O [M]+:290.3660, found 290.1414.
61

2.1.4. L-Pro-1-Pyr (58d)Colorless solid. 93% yield. mp 141 °C. [a]D20 = -75.55 (c = 0.45,

N
H

O

CHCl3). 1H NMR (500 MHz, CDCl3, ppm): δ 10.85 (s, 1H), 8.79

HN(d, J = 8.0 Hz, 1H), 8.17 (q, J = 7.4 Hz, 3H), 8.09 (dd, J = 17.2, 9.7
Hz, 2H), 8.03-7.98 (m, 3H), 4.15-4.09 (m, 1H), 3.28-3.17 (m, 2H),
2.38-2.31 (m, 1H), 2.22 (m, 1H), 1.97-1.82 (m, 2H). 13C NMR (125MHz, CDCl3, ppm): δ 173.7, 131.6, 131.0, 130.9, 128.3, 127.8,
127.6, 126.3, 126.2, 125.6, 125.3, 125.3, 124.9, 124.8, 121.8, 119.9,

58d

119.7, 77.4, 77.1, 76.9, 61.7, 47.7, 31.1, 26.6. MS (EI): m/z = 314[M]+, HRMS calculated for C21H18N2O [M]+: 314.3880; found 314.1419.
2.1.5. D-Pro-1-Naph (63)Colorless solid. 90% yield. mp 75 °C. [a]D20 = 38.11 (c = 0.45, CHCl3).
O
N
H

1

H NMR (500 MHz, CDCl3, ppm): δ 10.57 (s, 1H), 8.27 (dd, J = 7.4,

1.1 Hz, 1H), 7.88-7.81 (m, 2H), 7.62 (d, J = 8.6 Hz, 1H), 7.54-7.46 (m,HN3H), 3.98 (q, J = 4.8 Hz, 1H), 3.17-3.06 (m, 2H), 2.29-2.22 (m, 2H),
2.13 (m, 1H), 1.87-1.74 (m, 2H). 13C NMR (125 MHz, CDCl3, ppm): δ
173.6, 134.1, 132.7, 128.9, 126.2, 126.1, 126.1, 125.9, 124.5, 120.3,
63

117.8, 61.6, 47.6, 31.0, 29.8, 26.6. MS (EI): m/z = 314 [M]+, HRMS

calculated for C21H18N2O [M]+: 240.3060; found 240.1267.
2.1.6. L-Aze-1-Naph (67a)O

Colorless solid. 60% yield. mp 110 °C. [a]D20 = -40.62 (c = 0.45, CHCl3).
1

N
H

HN

HNMR (500 MHz, CDCl3, ppm): δ 10.41 (s, 1H), 8.28 (d, J = 7.4 Hz,

1H), 7.98 (d, J = 8.6 Hz, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.67 (d, J = 8.0
Hz, 1H), 7.57-7.48 (m, 3H), 4.60 (dd, J = 9.2, 8.0 Hz, 1H), 3.96-3.88 (m,1H), 3.50 (m, 1H), 2.84-2.77 (m, 1H), 2.61-2.53 (m, 1H). 13C NMR (12567aMHz, CDCl3, ppm): δ 172.2, 134.1, 132.3, 128.8, 126.1, 126.0, 125.9,

62124.7, 120.2, 117.9, 60.0, 43.6, 26.7. MS (EI): m/z = 226 [M]+, HRMS calculated for C21H18N2O[M]+: 226.2790; found 226.1103.
2.1.7. L-Pip-1-Naph (67b)Colorless solid. 70% yield. mp 99 °C. [a]D20 = -28.96 (c = 0.45, CHCl3).
1

O
N
H

HN

H NMR (500 MHz, CDCl3, ppm): δ 9.61 (s, 1H), 8.17 (d, J = 6.9 Hz, 1H),

7.88-7.85 (m, 2H), 7.65 (d, J = 8.6 Hz, 1H), 7.55-7.46 (m, 3H), 3.51 (q, J= 4.6 Hz, 1H), 3.16 (m, 1H), 2.87-2.81 (m, 1H), 2.13-2.08 (m, 1H), 1.871.81 (m, 1H), 1.74-1.69 (m, 1H), 1.68-1.61 (m, 1H), 1.57-1.50 (m, 2H).
1367b

C NMR (125 MHz, CDCl3, ppm): δ 172.5, 134.1, 132.5, 128.9, 126.3,

126.2, 126.0, 126.0, 124.9, 120.4, 118.8, 60.7, 45.7, 29.8, 26.1, 23.8. MS(EI): m/z = 254 [M]+, HRMS calculated for C21H18N2O [M]+: 254.3330;

found 254.1423.
2.2. General procedure for the synthesis of peptide organocatalysts 60a-h, 64 and 68a,b
N-Boc-

amino

acids

59a-e

(4.135

mmol)

were

stirred

with

N,

N

'-

Dicyclohexylcarbodiimide DCC (4.55 mmol) in CH2Cl2 (15 mL) at 0 °C for 1 h. Corresponding
amino amides 58a-d, 63 and 67a,b (4.135 mmol) were added slowly, and the reaction was stirred
at 30 °C. After the reaction completion, as monitored by thin layer chromatography, insoluble byproduct DCU was filtered off and the filtrate was evaporated to dryness. The obtained oily residue
was dissolved in CH2Cl2, and washed sequentially with saturated aqueous NaHCO3 solution,
aqueous HCl (1.0 M), and brine. The organic phase was dried over anhydrous Na2SO4, filtered,and concentrated under a reduced pressure to afford the crude products that were used for next
step without further purification. To the solution of the obtained crude products in dry CH2Cl2,
TFA was added in dropwise over a period of times (2 mL) at 0 °C and successively stirred at room
temperature (r.t.) for 4 h. After the reaction completion DCM and TFA were removed under areduced pressure, the residue was basified by drop-wise addition of saturated NaHCO3 solution
at 0 °C and stirred for 1 h at r.t. The crude products were extracted with CHCl3, dried over Na2SO4
63

and concentrated under reduced pressure. The residue was purified by flash column
chromatography on SiO2 (CHCl3: MeOH = 99:1 to 95: 5) to obtain the corresponding dipeptide
catalysts 60a-h, 64 and 68a,b.
2.2.1. L-Ala- L-Pro-1-Naph (60a)Colorless solid. 88% yield. mp 96 °C. [a]D20 = -115.6 (c = 0.50, CHCl3).
1

N

H 2N
O

H NMR (500 MHz, CDCl3, ppm): δ 9.93 (s, 1H), 8.15 (d, J = 8.6 Hz,

1H), 8.04 (d, J = 8.6 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.64 (d, J = 8.0
HNO

Hz, 1H), 7.53-7.56 (m, 1H), 7.44-7.51 (m, 2H), 5.01 (d, J = 6.9 Hz, 1H),
3.77 (q, J = 6.7 Hz, 1H), 3.55-3.63 (m, 2H), 2.70-2.74 (m, 1H), 2.18-2.28(m, 1H), 2.06-2.14 (m, 1H), 1.83-1.90 (m, 1H), 1.70 (s, 2H), 1.32 (d, J =6.9 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 177.4, 169.2, 133.98, 133.2,

60a

128.6, 126.2, 126.1, 125.9, 125.7, 124.8, 120.9, 118.7, 60.7, 48.6, 47.1,
25.9, 25.3, 21.6. MS (EI): m/z = 311 [M]+, HRMS calculated for C18H21N3O2 [M]+: 311.3850;
found 311.1638.
2.2.2. L-Val- L-Pro-1-Naph (60b)Colorless solid. 91% yield. mp 111 °C. [a]D20 = -84.13 (c = 0.57, CHCl3).
1

N

H 2N
O

HN

H NMR (500 MHz, CDCl3, ppm): δ 10.02 (s, 1H), 8.19-8.21 (m, 1H),

8.11 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 7.4 Hz, 1H), 7.63 (d, J = 8.0 Hz,
O1H), 7.51-7.55 (m, 1H), 7.43-7.51 (m, 2H), 5.03 (d, J = 6.9 Hz, 1H),
3.58-3.64 (m, 2H), 3.40 (d, J = 6.3 Hz, 1H), 2.69-2.73 (m, 1H), 2.202.29 (m, 1H), 2.06-2.13 (m, 1H), 1.84-1.98 (m, 2H), 1.57 (s, 2H), 0.91
(q, J = 3.4 Hz, 6H). 13C NMR (125 MHz, CDCl3) δ 176.5, 169.2, 133.9,

60b133.3, 128.5, 126.1, 125.8, 125.7, 124.7, 121.0, 118.2, 60.6, 58.5, 47.5,

32.6, 25.9, 25.3, 19.9, 17.1. MS (EI): m/z = 339 [M]+, HRMS calculated for C20H25N3O2 [M]+:339.4390; found 339.1942.

64

2.2.3. L-Tle- L-Pro-1-Naph (60c)
Colorless solid. 92% yield. mp 121 °C. [a]D20 = -110 (c = 0.63, CHCl3).
11H), 8.16 (d, J = 8.6 Hz, 1H), 7.85-7.83 (m, 1H), 7.63 (d, J = 8.0 Hz, 1H),

N

H 2N
O

HN

H NMR (500 MHz, CDCl3, ppm): δ 10.02 (s, 1H), 8.22 (d, J = 6.9 Hz,O

7.54-7.47 (m, 2H), 7.44 (t, J = 7.7 Hz, 1H), 5.03 (dd, J = 8.0, 1.1 Hz, 1H),
3.69-3.65 (m, 2H), 3.41 (s, 1H), 2.73-2.68 (m, 1H), 2.30-2.20 (m, 1H),
2.12-2.05 (m, 1H), 1.93-1.86 (m, 1H), 1.66 (s, 2H), 0.97 (s, 9H). 13C
NMR (125 MHz, CDCl3, ppm): δ 175.6, 169.2, 133.9, 133.3, 128.5,

60c

126.1, 126.0, 125.8, 125.7, 124.6, 121.1, 118.1, 60.5, 60.4, 48.5, 35.5,

26.1, 25.3. MS (EI): m/z = 353 [M]+, HRMS calculated for C21H27N3O2 [M]+: 353.4660; found353.2097.
2.2.4. L-Phg- L-Pro-1-Naph (60d)Colorless solid. 78% yield. mp 101 °C. [a]D20 = -29.60 (c = 0.42, CHCl3).
1

H NMR (500 MHz, CDCl3, ppm): δ 9.77 (s, 1H), 8.03 (t, J = 8.9 Hz,

2H), 7.85-7.86 (m, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.49-7.56 (m, 2H), 7.43
N

H 2N
O

HN

(t, J = 8.0 Hz, 1H), 7.32-7.33 (m, 2H), 7.14-7.20 (m, 3H), 5.06 (d, J =O

6.9 Hz, 1H), 4.70 (s, 1H), 3.58 (dd, J = 17.2, 9.7 Hz, 1H), 3.27-3.31 (m,1H), 2.62-2.66 (m, 1H), 2.01-2.12 (m, 5H), 1.83-1.91 (m, 1H). 13C NMR(125 MHz, CDCl3) δ 174.2, 169.0, 140.4, 133.9, 133.0, 129.3, 128.5,60d

128.2, 126.9, 126.3, 126.2, 125.8, 125.6, 125.0, 121.1, 119.0, 61.0, 58.1,
46.9, 26.2, 25.1. MS (EI): m/z = 373 [M]+, HRMS calculated for

C23H23N3O2 [M]+: 373.4560; found 373.1794.

65

2.2.5. L-Phe- L-Pro-1-Naph (60e)Colorless solid. 60% yield. mp 99 °C. [a]D20 = -88.00 (c = 0.40, CHCl3). 1H NMR (500 MHz,CDCl3, ppm): δ 9.99 (s, 1H), 8.24 (d, J = 8.6 Hz, 1H), 8.16 (d, J = 8.6
Hz, 1H), 7.87 (d, J = 8.6 Hz, 1H), 7.67 (d, J = 8.6 Hz, 1H), 7.58-7.62(m, 1H), 7.44-7.53 (m, 2H), 7.02-7.05 (m, 3H), 6.96-6.98 (m, 2H), 4.99

N

H 2N
O

HN

(d, J = 6.9 Hz, 1H), 3.85 (t, J = 7.2 Hz, 1H), 3.48 (m, 1H), 3.02-3.08 (m,O

1H), 2.96 (q, J = 6.9 Hz, 1H), 2.85 (q, J = 6.5 Hz, 1H), 2.64 (q, J = 5.9
Hz, 1H), 1.95-2.07 (m, 2H), 1.76-1.84 (m, 1H), 1.66 (s, 2H). 13C NMR(125 MHz, CDCl3) δ 175.7, 168.6, 136.7, 134.0, 133.3, 129.1, 128.6,

60e

128.5, 126.8, 126.3, 125.9, 125.9, 125.7, 124.7, 120.9, 118.2, 60.6, 55.0,
47.1, 43.1, 25.9, 25.1. MS (EI): m/z = 387 [M]+, HRMS calculated for C24H25N3O2 [M]+:387.4830; found 387.1950.
2.2.6. L-Tle- L-Pro-1-Ph (60f)
Colorless solid. 80% yield. mp 153 °C. [a]D20 = -42.50 (c = 0.40, CHCl3).
1

N

H 2N
O

HN

H NMR (500 MHz, CDCl3, ppm): δ 9.56 (s, 1H), 7.48 (d, J = 8.0 Hz,2H), 7.29 (m, 2H), 7.05 (t, J = 7.2 Hz, 1H), 4.86 (dd, J = 8.0, 1.7 Hz, 1H),O

3.60-3.63 (m, 2H), 3.37 (s, 1H), 2.55-2.59 (m, 1H), 2.11-2.21 (m, 1H),
1.98-2.05 (m, 1H), 1.80-1.88 (m, 1H), 1.71 (s, 2H), 0.98 (s, 9H). 13C
NMR (125 MHz, CDCl3, ppm): δ 175.4, 168.9, 138.3, 129.0, 124.0,

60f

119.7, 60.5, 60.5, 48.5, 35.6, 26.2, 26.0, 25.3. MS (EI): m/z = 303 [M]+,HRMS calculated for C17H25N3O2 [M]+: 303.4060; found 303.1949.

66

2.2.7. L-Tle- L-Pro-1-Anth (60g)
Yellow solid. 91% yield. mp 91 °C. [a]D20 = -134.95 (c = 0.45, CHCl3).
11H), 8.29 (d, J = 7.4 Hz, 1H), 8.11 (dd, J = 5.4, 3.7 Hz, 1H), 7.99 (dd, J

N

H 2N
O

HN

H NMR (500 MHz, CDCl3, ppm): δ 10.23 (s, 1H), 8.77 (s, 1H), 8.42 (s,O= 5.7, 4.0 Hz, 1H), 7.78 (d, J = 8.6 Hz, 1H), 7.41-7.50 (m, 3H), 5.09 (d,J = 6.9 Hz, 1H), 3.66-3.71 (m, 2H), 3.42 (s, 1H), 2.74 (m, 1H), 2.23-2.33(m, 1H), 2.09-2.13 (m, 1H), 1.89-1.97 (m, 1H), 1.69 (s, 2H), 0.96 (s, 9H).
1360g

C NMR (125 MHz, CDCl3, ppm): δ 175.8, 169.3, 133.3, 132.1, 131.6,

131.4, 128.7, 127.7, 126.9, 125.7, 125.4, 125.2, 124.7, 124.7, 119.7,

116.3, 60.6, 60.4, 48.5, 35.5, 26.2, 26.1, 25.4. MS (EI): m/z = 403 [M]+, HRMS calculated for
C25H29N3O2 [M]+: 403.5260; found 403.2269.
2.2.8. L-Tle- L-Pro-1-Pyr (60h)Green solid. 91% yield. mp 95 °C. [a]D20 = -151.78 (c = 0.56, CHCl3).
1

N

H 2N
O

HN

H NMR (500 MHz, CDCl3, ppm): δ 10.35 (s, 1H), 8.75 (d, J = 8.6 Hz,

1H), 8.37 (d, J = 9.2 Hz, 1H), 8.14-8.18 (m, 3H), 8.11 (t, J = 4.6 Hz, 1H),O

7.95-8.02 (m, 3H), 5.12-5.14 (m, 1H), 3.67-3.74 (m, 2H), 3.44 (s, 1H),
2.74-2.79 (m, 1H), 2.26-2.35 (m, 1H), 2.13 (m, 1H), 1.91-1.99 (m, 1H),
1.63 (s, 2H), 1.00 (s, 9H). 13C NMR (125 MHz, CDCl3, ppm): δ 175.9,
169.2, 131.6, 131.4, 130.9, 128.2, 127.7, 127.3, 126.3, 126.0, 125.2,

60h

125.1, 124.8, 124.7, 121.6, 120.6, 119.7, 60.6, 60.5, 48.5, 35.6, 26.2,
26.1, 25.4. MS (EI): m/z = 427 [M]+, HRMS calculated for C27H29N3O2[M]+: 427.5480; found 427.2254.

672.2.9. L-Tle-D-Pro-1-Naph (64)
Colorless solid. 85% yield. mp 153 °C. [a]D20 = 10.96 (c = 0.40, CHCl3).
1

7.83 (d, J = 8.0 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.54-7.43 (m, 3H), 5.01

N

H 2N
O

H NMR (500 MHz, CDCl3, ppm): δ 10.07 (s, 1H), 8.16-8.10 (m, 2H),

HN

O(d, J = 8.0 Hz, 1H), 3.73-3.59 (m, 2H), 3.40 (d, J = 11.5 Hz, 1H), 2.71 (q,J = 6.1 Hz, 1H), 2.26-2.16 (m, 1H), 2.08 (s, 1H), 1.90-1.82 (m, 1H), 1.63(s, 2H), 1.08 (s, 9H). 13C NMR (125 MHz, CDCl3, ppm): δ 175.6, 169.2,
133.9, 133.3, 128.5, 126.1, 126.0, 125.8, 125.7, 124.6, 121.1, 118.1, 60.5,

64

60.4, 48.5, 35.5, 26.1, 25.3. MS (EI): m/z = 353 [M]+, HRMS calculated

for C27H29N3O2 [M]+: 353.4660; found 353.2097.
2.2.10. L-Tle- L-Aze-1-Naph (68a)Colorless solid. 70% yield. mp 153 °C. [a]D20 = -121.06 (c = 0.40,
O

N
H 2N

O

HN

CHCl3). 1H NMR (500 MHz, CDCl3, ppm): δ 10.32 (s, 1H), 8.28 (d,J = 7.4 Hz, 1H), 8.15 (d, J = 8.6 Hz, 1H), 7.86-7.84 (m, 1H), 7.65 (d,J = 8.0 Hz, 1H), 7.53-7.46 (m, 3H), 5.21 (dd, J = 9.2, 6.3 Hz, 1H),
4.29 (m, 1H), 4.17 (m, 1H), 3.12 (s, 1H), 2.97-2.91 (m, 1H), 2.58-

68a

2.51 (m, 1H), 1.60 (s, 2H), 1.00 (s, 9H). 13C NMR (125 MHz, CDCl3,ppm): δ 177.0, 169.1, 134.0, 133.2, 128.5, 126.2, 125.9, 125.7, 124.8,

121.1, 118.3, 62.9, 58.5, 49.5, 35.2, 26.1, 18.0. MS (EI): m/z = 339 [M]+, HRMS calculated for
C27H29N3O2 [M]+: 339.4390; found 339.1951.

68

2.2.11. L-Tle- L-Pip-1-Naph (68b)Colorless solid. 70% yield. mp 153 °C. [a]D20 = -109.72 (c = 0.40,
CHCl3). 1H NMR (500 MHz, CDCl3, ppm): δ 9.10 (s, 1H), 8.21 (d, J
O

N
HN
O
NH2

= 7.4 Hz, 1H), 7.98-7.95 (m, 1H), 7.85 (dd, J = 7.2, 2.6 Hz, 1H), 7.64
(d, J = 8.0 Hz, 1H), 7.53-7.48 (m, 3H), 7.47-7.44 (m, 1H), 5.50 (d, J= 5.2 Hz, 1H), 4.06 (d, J = 13.7 Hz, 1H), 3.66 (s, 1H), 3.21 (m, 1H),
2.36 (d, J = 13.7 Hz, 1H), 2.18-2.08 (m, 1H), 1.83-1.76 (m, 3H), 1.67

68b(s, 3H), 1.59 (m, 1H), 0.95 (s, 9H). 13C NMR (125 MHz, CDCl3,ppm): δ 177.0, 169.7, 134.1, 132.9, 128.8, 126.3, 126.0, 125.9, 125.6, 124.8, 120.6, 118.2, 57.8,
52.9, 45.1, 36.0, 26.5, 25.7, 25.1, 20.3. MS (EI): m/z = 367 [M]+, HRMS calculated for
C27H29N3O2 [M]+: 367.4930; found 367.2268.
2.3. General procedure for the synthesis of peptide organocatalysts 61a-j, 65 and 69a-b
To a solution of N, N'-Dicyclohexylcarbodiimide (DCC) (1.29 mmol) in dry CH2Cl2 (10mL) were added N-Boc-L-amino acids 59’a-f (0.86 mmol) at 0 °C and the reaction mixture wasstirred for 1 hour. After 1 hour, corresponding dipeptides 60a-h, 64 and 68a-b (0.95 mmol) wereadded, and the reaction was stirred for another 24 hour at rt. The insoluble by-product DCU was
filtered off and the filtrate evaporated to dryness. The obtained oily residue was dissolved in
CH2Cl2 and extracted sequentially with saturated aqueous NaHCO3 solution, aqueous HCl (1.0M), and brine. The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated
under a reduced pressure to afford the crude products that were used for next step without further
purification. To the solution of the crude products in dry CH2Cl2, TFA was added in dropwise
over a period of times (0.4 mL) at 0 °C and successively stirred at room temperature (r.t.) for 4 h.
After the reaction completion, DCM and TFA were removed under a reduced pressure, the residue
was basified by drop-wise addition of saturated NaHCO3 solution at 0 °C and stirred for 1 h at r.t.
The crude products were extracted with CHCl3, dried over Na2SO4 and concentrated under69

reduced pressure. The residue was purified by flash column chromatography on SiO2 (CHCl3:
MeOH = 99:1 to 95: 5) to obtain the corresponding tripeptide catalysts 61a-j, 65 and 69a,b.
2.3.1. L-Ala- L-Tle- L-Pro-1-Naph (61a)White solid. 93% yield. mp 102 °C. [a]D20 = -46.59 (c = 0.58,
CHCl3). 1H NMR (500 MHz, CDCl3, ppm): δ 9.83 (s, 1H), 8.20 (d,

O
H 2N

N
H

J = 6.9 Hz, 1H), 8.15 (q, J = 4.6 Hz, 2H), 7.84-7.86 (m, 1H), 7.64 (d,N

J = 8.0 Hz, 1H), 7.44-7.54 (m, 3H), 4.98 (dd, J = 7.4, 1.7 Hz, 1H),

O
HN

O

4.65 (d, J = 9.2 Hz, 1H), 3.97 (m, 1H), 3.71-3.76 (m, 1H), 3.56 (q, J= 6.9 Hz, 1H), 2.65-2.69 (m, 1H), 2.20-2.30 (m, 1H), 2.05-2.13 (m,1H), 1.87-1.95 (m, 1H), 1.57 (s, 3H), 1.39 (d, J = 6.9 Hz, 3H), 1.01

61a(s, 9H). 13C NMR (125 MHz, CDCl3, ppm): δ 175.7, 172.8, 169.1,

133.9, 133.2, 128.5, 126.1, 125.8, 125.8, 125.7, 124.7, 121.0, 118.2, 60.6, 56.5, 50.8, 48.8, 35.2,
26.3, 26.1, 25.3, 21.9. MS (EI): m/z = 424 [M]+, HRMS calculated for C24H32N4O3 [M]+:424.5450; found 424.2467.
2.3.2. L-Val- L-Tle- L-Pro-1-Naph (61b)White solid. 90% yield. mp 83 °C. [a]D20 = -62.50 (c = 0.58,
O
H 2N

CHCl3). 1H NMR (500 MHz, CDCl3, ppm): δ 9.85 (s, 1H), 8.24 (d,NH

J = 9.2 Hz, 1H), 8.20 (d, J = 8.0 Hz, 1H), 8.15 (d, J = 8.0 Hz, 1H),N

7.83-7.87 (m, 1H), 7.64 (t, J = 8.3 Hz, 1H), 7.47-7.54 (m, 2H), 7.45

O
HN

O

(t, J = 7.7 Hz, 1H), 4.98 (dd, J = 7.7, 1.4 Hz, 1H), 4.67 (d, J = 9.2
Hz, 1H), 4.00 (m, 1H), 3.71-3.75 (m, 1H), 3.31 (d, J = 4.0 Hz, 1H),

61b

2.66 (m, 1H), 2.33-2.42 (m, 1H), 2.20-2.29 (m, 1H), 2.07-2.12 (m,1H), 1.86-1.94 (m, 1H), 1.03 (d, J = 6.9 Hz, 4H), 1.01 (s, 9H), 0.87

(d, J = 6.9 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 174.4, 172.9, 169.1, 133.9, 133.2, 128.5,
126.1, 125.8, 125.8, 125.7, 124.7, 121.1, 118.2, 60.6, 60.2, 56.6, 48.8, 34.9, 30.6, 26.4, 26.1, 25.3,
19.7, 16.1. MS (EI): m/z = 452 [M]+, HRMS calculated for C26H36N4O3 [M]+: 452.5990; found452.2781.
70

2.3.3. L-Tle- L-Tle- L-Pro-1-Naph (61c)White solid. 96% yield. mp 177 °C. [a]D20 = -70.31 (c = 0.40,
CHCl3). 1H NMR (500 MHz, CDCl3, ppm): δ 1.02 (s, 9H), 1.05 (s,O
H 2N9H), 1.57 (s, 2H), 1.84-1.98 (m, 1H), 2.04-2.15 (m, 1H), 2.17-2.32

N

N
H

O

(m, 1H), 2.66 (m, 1H), 3.20 (s, 1H), 3.68-3.77 (m, 1H), 3.99 (m,O

HN1H), 4.67 (d, J = 9.2 Hz, 1H), 4.97 (d, J = 8.0 Hz, 1H), 7.41-7.56(m, 3H), 7.63 (d, J = 8.6 Hz, 1H), 7.78-7.90 (m, 2H), 8.14 (d, J =8.0 Hz, 1H), 8.20 (d, J = 7.4 Hz, 1H), 9.83 (s, 1H). 13C NMR (12561cMHz, CDCl3, ppm): δ 173.8, 173.0, 169.1, 133.9, 133.2, 128.5,

126.1, 125.8, 125.7, 124.7, 121.1, 118.2, 64.4, 60.5, 56.6, 48.8, 34.9, 34.2, 26.9, 26.5, 26.1, 25.3.
MS (EI): m/z = 466 [M]+, HRMS calculated for C27H38N4O3 [M]+: 466.6260; found 466.2949.
2.3.4. L-Phg- L-Tle- L-Pro-1-Naph (61d)White solid. 72% yield. mp 106 °C. [a]D20 = +46.59 (c = 0.58,
CHCl3). 1H NMR (500 MHz, CDCl3, ppm): δ 9.75 (s, 1H), 8.14

O
H 2N

N
H

(dd, J = 23.8, 7.7 Hz, 2H), 7.83-7.85 (m, 1H), 7.64 (d, J = 8.6

N
O

HN

O

Hz, 1H), 7.49-7.54 (m, 3H), 7.43-7.47 (m, 1H), 7.36-7.42 (m,4H), 7.30-7.34 (m, 1H), 4.93 (dd, J = 7.7, 2.0 Hz, 1H), 4.68 (d,J = 9.7 Hz, 1H), 4.57 (s, 1H), 3.86 (m, 1H), 3.66-3.70 (m, 1H),61d

2.60-2.66 (m, 1H), 2.15-2.25 (m, 1H), 1.99-2.06 (m, 1H), 1.831.87 (m, 2H), 0.94 (s, 9H). 13C NMR (125 MHz, CDCl3, ppm):

δ 172.8, 172.4, 169.1, 141.1, 134.0, 133.1, 129.0, 128.5, 128.2, 126.9, 126.1, 125.9, 125.8, 125.7,
124.8, 121.0, 118.4, 60.6, 59.9, 56.8, 48.7, 35.4, 26.3, 26.2, 25.2. MS (EI): m/z = 486 [M]+, HRMS
calculated for C29H34N4O3 [M]+: 486.6160; found 486.2638.

712.3.5. L-Phe- L-Tle- L-Pro-1-Naph (61e)White solid. 85% yield. mp 93 °C. [a]D20 = +84.63 (c = 0.58,
CHCl3). 1H NMR (500 MHz, CDCl3, ppm): δ 9.79 (s, 1H),

O
N
H

H 2N

8.12-8.19 (m, 3H), 7.82 (dd, J = 9.5, 8.3 Hz, 1H), 7.63 (d, J

N
O

O

HN

= 8.6 Hz, 1H), 7.42-7.53 (m, 3H), 7.32 (t, J = 7.4 Hz, 2H),
7.24 (dd, J = 16.3, 7.2 Hz, 3H), 4.96 (dd, J = 8.0, 1.7 Hz, 1H),
4.61-4.67 (m, 1H), 3.99 (m, 1H), 3.71-3.76 (m, 1H), 3.67 (q,J = 4.4 Hz, 1H), 3.28 (dd, J = 13.7, 3.4 Hz, 1H), 2.75 (dd, J

61e= 13.7, 9.2 Hz, 1H), 2.63-2.67 (m, 1H), 2.20-2.33 (m, 1H),

2.07-2.16 (m, 1H), 1.88-1.95 (m, 1H), 1.56 (d, J = 8.0 Hz, 2H), 0.93-1.02 (m, 9H). 13C NMR (125MHz, CDCl3, ppm): δ 174.3, 172.6, 169.1, 137.6, 133.9, 133.2, 129.3, 128.7, 128.5, 126.9, 126.1,
125.8, 125.7, 124.7, 121.1, 118.3, 60.6, 56.7, 56.5, 48.8, 40.9, 35.2, 26.3, 26.2, 25.3. MS (EI):m/z = 500 [M]+, HRMS calculated for C30H36N4O3 [M]+: 500.6430; found 500.2792.
2.3.6. Gly- L-Tle- L-Pro-1-Naph (61f)
White solid. 87% yield. mp 99 °C. [a]D20 = -55.00 (c = 0.4, CHCl3).
1

O

H 2N

N
H

7.7 Hz, 2H), 8.01 (d, J = 9.2 Hz, 1H), 7.84-7.85 (m, 1H), 7.64 (d, J

N
O

HN

H NMR (500 MHz, CDCl3, ppm): δ 9.81 (s, 1H), 8.17 (dd, J = 26.6,

O= 8.0 Hz, 1H), 7.43-7.54 (m, 3H), 4.97 (dd, J = 8.0, 1.7 Hz, 1H),
4.72 (d, J = 9.2 Hz, 1H), 3.95 (m, 1H), 3.72-3.76 (m, 1H), 3.43 (dd,J = 21.8, 17.2 Hz, 2H), 2.66 (m, 1H), 2.20-2.30 (m, 1H), 2.04-2.12

61f(m, 1H), 1.88-1.95 (m, 1H), 1.60 (s, 2H), 1.01 (s, 9H). 13C NMR(125 MHz, CDCl3, ppm): δ 172.6, 169.1, 133.9, 133.2, 128.5, 126.1,

125.8, 125.7, 124.7, 121.0, 118.3, 60.6, 56.5, 48.8, 44.6, 35.3, 26.3, 26.2, 25.3. MS (EI): m/z =410 [M]+, HRMS calculated for C23H30N4O3 [M]+: 410.5180; found 410.2319.

72

2.3.7. L-Tle- L-Tle- L-Pro-Ph (61g)
White solid. 70% yield. mp 233 °C. [a]D20 = -71.42 (c = 0.55,
CHCl3). 1H NMR (500 MHz, CDCl3, ppm): δ 9.38 (s, 1H), 7.55

O
N
H

H 2N

(d, J = 8.0 Hz, 2H), 7.31 (t, J = 8.0 Hz, 2H), 7.09 (t, J = 7.4 Hz,

N
O

HN

O

1H), 4.62-4.70 (m, 2H), 3.88 (q, J = 8.4 Hz, 1H), 3.71 (m, 1H),
3.37 (s, 1H), 2.40 (q, J = 3.6 Hz, 1H), 2.12-2.21 (m, 1H), 1.922.05 (m, 2H), 1.04 (s, 9H), 0.99 (s, 9H). 13C NMR (125 MHz,CDCl3, ppm): δ 171.8, 168.9, 138.2, 129.0, 124.1, 119.5, 64.1,

61g

60.7, 57.3, 48.8, 35.1, 33.6, 27.1, 26.6, 26.5, 25.1. MS (EI): m/z =416 [M]+, HRMS calculated for C23H36N4O3 [M]+: 416.5660; found 416.2853.
2.3.8. L-Tle- L-Tle- L-Pro-1-Anth (61h)Brown solid. 80% yield. mp 105 °C. [a]D20 = -23.45 (c = 0.60,
CHCl3). 1H NMR (500 MHz, CDCl3, ppm): δ 10.04 (s, 1H), 8.74

O
H 2N

N
H

(s, 1H), 8.43 (s, 1H), 8.27 (d, J = 7.4 Hz, 1H), 8.09-8.11 (m, 1H),

N
O
HN

O

8.00 (dd, J = 5.9, 3.9 Hz, 1H), 7.90 (d, J = 9.2 Hz, 1H), 7.79 (d, J= 8.6 Hz, 1H), 7.48 (m, 2H), 7.43 (dd, J = 8.6, 7.4 Hz, 1H), 5.05
(dd, J = 7.7, 1.4 Hz, 1H), 4.69 (d, J = 9.7 Hz, 1H), 4.02 (m, 1H),
3.74-3.78 (m, 1H), 3.24 (s, 1H), 2.69-2.72 (m, 1H), 2.23-2.33 (m,61h1H), 2.12 (m, 1H), 1.91-1.99 (m, 1H), 1.60 (s, 2H), 1.08 (s, 9H),

1.00 (s, 9H). 13C NMR (125 MHz, CDCl3, ppm): δ 173.9, 173.0, 169.2, 133.1, 132.1, 131.5, 131.4,
128.6, 127.8, 127.0, 125.7, 125.5, 125.2, 124.8, 124.7, 119.6, 116.6, 77.2, 77.0, 76.7, 64.5, 60.6,
56.7, 48.8, 34.8, 34.2, 26.9, 26.5, 26.1, 25.3. MS (EI): m/z = 516 [M]+, HRMS calculated for
C31H40N4O3 [M]+: 516.6860; found 516.3094.

73

2.3.9. L-Tle- L-Tle- L-Pro-1-Pyr (61i)
Green solid. 83% yield. mp 115 °C. [a]D20 = -8.0 (c = 0.50,
CHCl3). 1H NMR (500 MHz, CDCl3, ppm): δ 10.16 (s, 1H), 8.72

O
N
H

H 2N

(d, J = 8.6 Hz, 1H), 8.34 (d, J = 9.2 Hz, 1H), 8.14-8.16 (m, 3H),

N
O

HN

O

8.10 (d, J = 9.2 Hz, 1H), 7.97-8.02 (m, 3H), 7.90 (d, J = 9.2 Hz,
1H), 5.07 (d, J = 8.0 Hz, 1H), 4.70 (d, J = 9.2 Hz, 1H), 4.02 (m,1H), 3.74-3.79 (m, 1H), 3.22 (s, 1H), 2.72 (m, 1H), 2.24-2.34 (m,1H), 2.09-2.17 (m, 1H), 1.92-2.00 (m, 1H), 1.58 (s, 4H), 1.06 (s,9H), 1.04 (s, 9H). 13C NMR (125 MHz, CDCl3, ppm): δ 174.0,

61i

173.2, 169.3, 131.6, 131.5, 131.0, 128.4, 127.7, 127.4, 126.5,

126.1, 125.3, 125.2, 125.2, 124.9, 124.8, 121.8, 120.7, 120.0, 64.5, 60.7, 56.8, 48.9, 35.0, 34.3,
27.0, 26.6, 26.3, 25.5. MS (EI): m/z = 540 [M]+, HRMS calculated for C33H40N4O3 [M]+:540.7080; found 540.3094.
2.3.10. D-Tle- L-Tle- L-Pro-1-Naph (61j)White solid. 70% yield. mp 233 °C. [a]D20 = 56.13 (c = 0.45,
CHCl3). 1H NMR (500 MHz, CDCl3, ppm): δ 9.82 (s, 1H), 8.20 (d,

O
H 2N

N
H

J = 7.4 Hz, 1H), 8.13 (d, J = 8.0 Hz, 1H), 7.85-7.84 (m, 1H), 7.64

N
O

HN

O

(d, J = 8.6 Hz, 1H), 7.51 (m, 2H), 7.47-7.43 (m, 1H), 7.11 (d, J =9.2 Hz, 1H), 4.96 (dd, J = 8.0, 1.7 Hz, 1H), 4.70 (d, J = 9.2 Hz,
1H), 3.96 (m, 1H), 3.74-3.70 (m, 1H), 3.12 (s, 1H), 2.69-2.66 (m,1H), 2.29-2.20 (m, 1H), 2.10 (m, 1H), 1.94-1.87 (m, 1H), 1.55 (s,61j2H), 1.03 (s, 9H), 1.01 (s, 9H). 13C NMR (125 MHz, CDCl3, ppm):
δ 173.8, 172.9, 169.2, 134.1, 133.3, 128.7, 126.2, 126.0, 125.9,

124.8, 121.2, 118.3, 64.8, 60.7, 56.8, 48.8, 35.2, 34.5, 26.8, 26.6, 26.3, 25.4. MS (EI): m/z = 466[M]+, HRMS calculated for C33H40N4O3 [M]+: 466.6260; found 466.3142.
74

2.3.11. L-Tle- L-Tle-D-Pro-1-Naph (65)White solid. 85% yield. mp 225 °C. [a]D20 = 73.22 (c = 0.51,
CHCl3). 1H NMR (500 MHz, CDCl3, ppm): δ 9.66 (s, 1H), 8.05 (d,

O
N
H

H 2N

J = 8.6 Hz, 1H), 7.98 (d, J = 7.4 Hz, 1H), 7.82 (d, J = 8.6 Hz, 1H),

N
O

O

HN

7.65 (d, J = 8.6 Hz, 1H), 7.53-7.42 (m, 3H), 4.93 (d, J = 8.0 Hz,
1H), 4.58 (d, J = 8.0 Hz, 1H), 4.15-4.11 (m, 1H), 3.74-3.65 (m,1H), 2.77 (s, 1H), 2.64 (q, J = 6.3 Hz, 1H), 2.29-2.19 (m, 1H),
2.13-2.08 (m, 1H), 2.01-1.93 (m, 1H), 1.12 (s, 9H), 0.80 (s, 9H).

65

13

C NMR (125 MHz, CDCl3, ppm): δ 174.4, 172.3, 169.7, 134.2,

133.3, 128.5, 127.2, 126.0, 125.8, 125.4, 122.0, 120.4, 64.3, 61.1, 57.6, 48.4, 34.6, 34.0, 28.1,
26.8, 26.7, 24.8. MS (EI): m/z = 466 [M]+, HRMS calculated for C33H40N4O3 [M]+: 466.6260;
found 466.4930.
2.3.12. L-Tle- L-Tle- L-Aze-1-Naph (69a)White solid. 90% yield. mp 168 °C. [a]D20 = -89.70 (c = 0.55,
O

N
O
NH

O

NH2

HN

CHCl3). 1H NMR (500 MHz, CDCl3, ppm): δ 10.15 (s, 1H),
8.25 (d, J = 6.9 Hz, 1H), 8.13-8.11 (m, 1H), 7.86-7.83 (m,2H), 7.65 (d, J = 8.0 Hz, 1H), 7.52-7.46 (m, 3H), 5.19 (dd, J= 9.7, 6.3 Hz, 1H), 4.60 (dd, J = 15.8, 8.9 Hz, 1H), 4.30 (d, J69a= 9.2 Hz, 1H), 4.21 (td, J = 8.6, 5.7 Hz, 1H), 3.21 (d, J = 16.0
Hz, 1H), 2.97-2.90 (m, 1H), 2.59-2.51 (m, 1H), 1.58 (s, 2H),

1.06 (s, 10H), 1.05 (s, 9H). 13C NMR (125 MHz, CDCl3, ppm): δ 174.7, 174.1, 169.2, 134.1,
133.2, 128.7, 126.2, 126.0, 126.0, 125.9, 125.0, 121.2, 118.6, 64.5, 63.0, 55.0, 50.0, 34.4, 34.3,
27.0, 26.6, 18.1. MS (EI): m/z = 466 [M]+, HRMS calculated for C33H40N4O3 [M]+: 452.5990;
found 452.2785.

75

2.3.13. L-Tle- L-Tle- L-Pip-1-Naph (69b)White solid. 75% yield. mp 220 °C. [a]D20 = -93.81 (c = 0.50,
CHCl3). 1H NMR (500 MHz, CDCl3, ppm): δ 8.83 (s, 1H), 8.15 (d,
O

N
HN
O
O

J = 8.0 Hz, 1H), 7.93-7.88 (m, 1H), 7.85-7.78 (m, 2H), 7.73-7.67(m, 2H), 7.52-7.48 (m, 2H), 5.46 (d, J = 4.0 Hz, 1H), 5.04 (d, J =NH

9.7 Hz, 1H), 4.63 (d, J = 7.4 Hz, 1H), 4.21 (d, J = 14.9 Hz, 1H),

NH2

3.27 (m, 1H), 3.18 (s, 1H), 2.33 (d, J = 13.7 Hz, 1H), 2.09-1.62 (m,69b2H), 1.56 (s, 2H), 1.04 (s, 9H), 0.97 (s, 9H). 13C NMR (125 MHz,CDCl3, ppm): δ 174.7, 174.1, 169.2, 134.1, 133.2, 128.7, 126.2,

126.0, 126.0, 125.9, 125.0, 121.2, 118.6, 64.5, 63.0, 55.0, 50.0, 34.4, 34.3, 27.0, 26.6, 18.1. MS(EI): m/z = 480.6530 [M]+, HRMS calculated for C33H40N4O3 [M]+: 480.6530; found 480.3100.

76

General procedure for the asymmetric aldol reaction of various ketones with aromatic
aldehydes
The peptide catalyst 61c (30 mol%) was added to a solution of ketones 39a-h (0.4 mmol)
and the aldehydes 7a-i (0.1 mmol) under the neat reaction condition. The reaction mixture wasstirred at 0 °C for appropriate time until the reaction completion, monitored by thin layer
chromatography (TLC). The diastereomeric ratio was determined by 1H NMR spectroscopic
analysis of the crude reaction mixture. Consequently, the reaction mixture was purified by flash
column chromatography on SiO2 (n-hexane/CH3CO2Et) to afford the corresponding aldol
products 40a-s. (6a-j)
Gram scale for the asymmetric aldol reaction of cyclohexanone (39a) with 4nitrobenzaldehyde (7a)The peptide catalyst 61c (30 mol%) was added to a solution of cyclohexanone 39a (2.06
ml, 19.851 mmol) and the 4-nitrobenzaldehyde 7a (1g, 6.617 mmol) under neat reaction condition.
The reaction mixture was stirred at 0 °C for appropriate time until the reaction completion,
monitored by thin layer chromatography (TLC). The diastereomeric ratio was determined by 1H
NMR spectroscopic analysis of the crude reaction mixture. Consequently, the reaction mixture
was purified by flash column chromatography on SiO2 (n-hexane/CH3CO2Et) to afford the 2[Hydroxy-(4-nitrophenyl)-methyl]-cyclohexan-1-one 40a. The enantiomeric excess (ee) of 40a
was determined by HPLC (CHIRALPAK-AD-H hexane/i-PrOH = 90:10 1.0mL /min, λ = 254
nm) (1.65g, 98% yield, dr= 24:76 and enantiomeric excess 93 %ee).

77

Theoretical Calculations
The DFT method (at the B3LYP/6-31G(d) level of theory) was used to perform theconformational analysis with Gaussian 16 program package. The Gas phase geometry
optimizations were performed using the B3LYP hybrid density functional and the 6-31G(d) basis
set as implemented in the Gaussian 16. Vibrational mode analysis was performed for all structures
to ensure that they have zero (for a ground state) or one (for a transition state) imaginary frequency.
1) Gaussian 16, Revision A.03,
M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb, J. R. Cheeseman, G.
Scalmani, V. Barone, G. A. Petersson, H. Nakatsuji, X. Li, M. Caricato, A. V. Marenich, J. Bloino,
B. G. Janesko, R. Gomperts, B. Mennucci, H. P. Hratchian, J. V. Ortiz, A. F. Izmaylov, J. L.
Sonnenberg, D. Williams-Young, F. Ding, F. Lipparini, F. Egidi, J. Goings, B. Peng, A. Petrone,
T. Henderson, D. Ranasinghe, V. G. Zakrzewski, J. Gao, N. Rega, G. Zheng, W. Liang, M. Hada,
M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H.
Nakai, T. Vreven, K. Throssell, J. A. Montgomery, Jr., J. E. Peralta, F. Ogliaro, M. J. Bearpark,
J. J. Heyd, E. N. Brothers, K. N. Kudin, V. N. Staroverov, T. A. Keith, R. Kobayashi, J. Normand,
K. Raghavachari, A. P. Rendell, J. C. Burant, S. S. Iyengar, J. Tomasi, M. Cossi, J. M. Millam,
M. Klene, C. Adamo, R. Cammi, J. W. Ochterski, R. L. Martin, K. Morokuma, O. Farkas, J. B.
Foresman, and D. J. Fox, Gaussian, Inc., Wallingford CT, 2016.

78

I-2

I-1
Ratio I-1 : I-2 = 96.14 : 3.86

Figure S1. The coordinate scan calculations (at the B3LYP/6-31G(d) level of theory) and total energies(in hartree, calculated at the B3LYP/6-31G(d) level of theory in gas phase) of 6c generated by varying two
torsion angles (the dihedral scans showed with u-shaped arrows, as shown in the bottom structures).
Table S1. Cartesian coordinates (Angstroms) for I-1 in gas phase.
Point Group: C1
Imaginary Freq: 0
Total energy = -1729.297620 hartree
SymbolX

Y

Z

C-4.49757-0.46142 1.037219

C-3.41505-0.88272 1.860457

C-3.61771-1.73187 2.927445

C-4.91203-2.20898 3.233678

C-5.98055-1.8197 2.460511

C-5.81235-0.94465 1.353602

C-6.92297-0.54508 0.565208

C-6.74187 0.303832-0.49938

79

C-5.46032 0.791319-0.83497

C-4.34993 0.422096-0.09184

N-3.05418 0.889281-0.39962

C-2.66623 1.751865-1.39003

O-3.40928 2.298002-2.19775C-1.1338 2.008465-1.39628C-0.73191 3.060562-2.43486C-0.50229 2.233577-3.7091C

0.155118 0.943637-3.19688N-0.37235 0.806185-1.81639

C-0.01448-0.12661-0.90364

C

0.978817-1.22341-1.32241O-0.44021-0.08936 0.265267

C

0.36532-2.66443

C

0.070519-3.16401 0.120565

C

1.376213-3.61478-1.97768

C-0.93965-2.65885-2.1278N

2.149876-1.08598-0.46259

C

3.273934-0.43955-0.89222

O

3.474703-0.12178-2.06289

C

4.320738-0.14619 0.207987

N

3.654384 0.083426 1.486207

C

3.081032 1.341093 1.770359

C

2.714845 1.510583 3.231157

C

1.714723 2.651951 3.457827

C

2.135781 3.901499 2.677294

C

2.169967 3.608428-1.30656

1.17064

C

2.8321 2.289543 0.847939

C

5.43236-1.24934 0.314325

C

6.543652-0.74213 1.260567

C

4.873876-2.58406 0.846418

C

6.062742-1.48112H-2.4022-0.54559 1.667771-1.07398

80

H-2.77172-2.03523 3.538323

H-5.05899-2.87835 4.077033

H-6.98288-2.17685 2.685536

H-7.91082-0.9201 0.820488

H-7.59076 0.612848-1.10349

H-5.33245 1.458681-1.67475

H-2.27553 0.510829 0.137428

H-0.81917 2.266964-0.3798H

0.196225 3.548387-2.1159

H-1.50872 3.816293-2.5587H

0.125779 2.741375-4.44651

H-1.468 2.011993-4.17334

H

1.24761 1.021582-3.169H-0.11375

0.07321-3.80281

H

1.343051-1.03492-2.33211

H-0.34853-4.17632 0.077202

H-0.64318-2.51811 0.636879

H

0.985889-3.21613 0.721453

H

0.988921-4.64036-1.98068

H

2.333306-3.61827-1.44579

H

1.5699-3.32558-3.0178H-1.34404-3.67488-2.19854

H-0.77056-2.30164-3.15163H-1.71062-2.03037-1.66887

H

1.998529-1.06114

0.54121

H

4.822879 0.770719-0.13436

H

4.155623

H

3.631359 1.695372 3.815079

H

2.299461 0.565286 3.606574

H

1.633507

H

0.720207 2.330421

H

3.135167 4.214879 3.010734

H

1.455321 4.735992 2.886177-0.29597 2.280363

2.86791 4.529957
3.1201481

H

2.691152 4.420873 0.645036

H

1.140331

H

3.089748 2.121073

H

7.365438-1.46643 1.294361

H

6.199094-0.60264 2.292336

H

6.952249

0.21381 0.912904

H

5.680161-3.32292 0.920909

H

4.106245-2.99047 0.180664

H

4.429431-2.48393 1.843608

H

6.892355-2.19247-0.98651

H

6.456516-0.54894-1.49345

H

5.342439-1.88199-1.79134

3.61859 0.773863-0.1944

Table S2. Cartesian coordinates (Angstroms) for TS-1 in gas phase.
Point Group: C1
Imaginary Freq: 1
Total energy = -1729.287407 hartree
SymbolX

Y

C-0.00399-0.00636 0.005573

C-0.00781-0.00926

C

1.169509-0.01472 2.146598

C

2.417601-0.01743 1.484094

C

2.457533-0.01665 0.109509

C

1.266011-0.01241-0.66477C

1.318721-0.01598-2.0832C

0.156552-0.01447-2.81542

C-1.10528-0.00603-2.1827

C-1.19929 0.000285-0.7997N-2.44391 0.007678-0.1342C-3.70351-0.01238-0.67117

O-3.97383-0.05627-1.86609

C-4.81809 0.007488 0.411421

C-6.21547-0.13097

Z
1.42932-0.201282

C-6.61464 1.320414-0.50823

C-6.04929 2.116858 0.677151

N-4.88324 1.310144 1.117923

C-4.09983 1.540797 2.198007

C-4.3668 2.800531 3.041448

O-3.2045 0.743699 2.531851

C-3.1759 3.817824 3.036681

C-1.95314

C-3.6696 5.129292 3.678367

C-2.7682 4.098161 1.576117

N-4.74163 2.362394 4.380832

C-6.0486 2.229016 4.750077

O-6.99472 2.614513 4.063936

C-6.27656 1.562508 6.126232

N-5.18585 0.630115 6.413547

C-5.14507-0.63911 5.732577

C-6.44784-1.28514 5.295012

C-6.27349-2.77247 4.946704

C-5.01932-3.0022 4.096909

C-3.764-2.55873 4.860248

C-3.95486-1.22302 5.531392

C-6.47009 2.601661 7.288813

C-6.90722 1.844771 8.563655

C-5.17716 3.388181 7.579138

C-7.59589 3.589107 6.920364

H-0.93899-0.00567 1.985729

H

1.13464-0.0174H

3.338793-0.02132 2.060545

H

3.410688-0.02058-0.41426

H

2.289088-0.02154-2.57309

H

0.194015-0.01879-3.90153

H-2.01126-0.00559-2.77102H-2.43687 0.089447 0.881374

3.30016 3.818365

3.2327383

H-4.59555-0.76746 1.152596

H-6.89368-0.57167 0.538441

H-6.20057-0.76051-1.09191

H-7.69485 1.458908-0.6087

H-6.13888 1.634389-1.44214H-6.76828 2.202595 1.498894

H-5.73466 3.123396 0.385016

H-5.24299 3.323002 2.658237

H-1.14798 4.043265 3.776217

H-1.57754

H-2.19176 3.141804 4.876686

H-2.86085 5.869071 3.699901

H-4.00488 4.967957 4.708023

H-4.50533 5.562023 3.114924

H-1.99409 4.873129 1.544307

H-3.61769 4.458868 0.982219

H-2.36095 3.207529

H-4.08392

1.80578 4.917137

H-7.24647

1.0574 6.014455

H-5.03137 0.518512

H-6.86378-0.74588 4.430151

H-7.19501-1.18062 6.094116

H-7.16865-3.13969 4.430076

H-6.18629-3.35207 5.876392

H-5.10051-2.41946 3.168369

H-4.93687-4.05605

H-2.90806-2.4973 4.175156

H-3.49076-3.3211 5.608069

H-3.0609-0.70025 5.868119

H-7.13915 2.560291 9.360733

H-6.13208 1.175802 8.956837

H-7.80722

H-5.33687 4.075445 8.418254

2.36129 3.405599

1.08566

7.408643.80494

1.24572 8.380206

84

H-4.86985 3.983202 6.713424

H-4.34319 2.728519 7.842031

H-7.77597 4.271026 7.759853

H-8.53248

H-7.34684 4.186745 6.040322

3.06359 6.703072

Table S3. Cartesian coordinates (Angstroms) for I-2 in gas phase.
Point Group: C1
Imaginary Freq: 0
Total energy = -1729.294587 hartree
SymbolX

Y

Z

C-4.49281 1.137375 0.376766

C-3.3592 1.921935 0.732478

C-3.48268 3.027202 1.547174

C-4.74453 3.412478 2.053158

C-5.86085 2.678786 1.726615

C-5.77443 1.534527 0.888494

C-6.93387 0.787645 0.552845

C-6.83175-0.31389-0.26141

C-5.58419-0.72921-0.775C-4.42825-0.02874-0.4676

N-3.16415-0.41685-0.96125C-2.85194-1.4527-1.80108

O-3.65001-2.23931-2.29779

C-1.33009-1.54391-2.10088

C-1.01121-2.62796-3.13538C-0.8186-3.89047-2.28167

C-0.0988-3.37834-1.02571

N-0.55734-1.9709-0.90768

C-0.12623-1.05346-0.01268

C

0.854866-1.49911 1.088282

O-0.48732 0.137221

C

0.241624-0.0794-1.43612 2.528278

85

C-0.00228 0.009066 3.005741

C

1.222906-2.12953 3.494006

C-1.095-2.20514 2.534514

N

2.069371-0.70517 0.961448

C

3.079873-1.07875 0.127608

O

3.113702-2.15965-0.46105

C

4.219468-0.04356-0.018N

3.744635 1.309513

0.32777

C

3.376391 2.217244-0.70188

C

2.376693 1.705218-1.71662

C

2.205221 2.670375-2.89953

C

2.06252 4.115402-2.41037

C

3.324399

4.55316-1.6521

C

3.812741 3.488878-0.70053

C

5.506093

C

6.623469 0.583081 0.497098

C

5.228496-0.48125 2.310962

C

6.009382-1.82698 0.338777

H-2.36845 1.669451 0.369981

H-2.59923 3.607226 1.799971

H-4.82909 4.285446 2.694757

H-6.83902 2.965004 2.106223

H-7.89565 1.104173 0.948348

H-7.71824-0.88608-0.52173

H-5.51832-1.59752-1.41429

H-2.34929 0.092487-0.62361

H-0.97356-0.55181-2.39599

H-0.08377-2.36853-3.65821

H-1.81583-2.73216-3.86454

H-0.24115-4.66922-2.78783

H-1.79822-4.30228-2.02086

H

0.990577-3.39418-1.13666

H-0.37019-3.94991-0.13313-0.44169 0.794647

86

H

1.16187-2.52939 0.907542

H-0.44987-0.00649 4.006437

H-0.67471 0.549788 2.336244

H

0.934556 0.573827

H

0.827117-2.10851 4.516083

H

2.196789-1.62953 3.499596

H

1.382339-3.17926 3.218232

H-1.50168-2.24146

H-0.96632-3.24088 2.195781

H-1.84719-1.72759 1.897447

H

2.047681 0.285957 1.181402

H

4.50593H

4.357597 1.764399 0.994687

H

1.412958 1.539792-1.21356

H

2.68549

0.71976-2.09122

H

1.332305 2.371749-3.49242

H

3.078592 2.597751-3.56268

H

1.193134 4.183161-1.74188

H

1.871164

4.79302-3.25132

H

3.126367 5.483519-1.10085

H

4.120833 4.804528-2.3718

H

4.546948 3.794878 0.046514

H

7.555968 0.263535 0.976006

H

6.39977 1.588647

0.87074H

6.809484-0.58025

H

6.150901-0.71665 2.854338

H

4.488086-1.2477 2.562021

H

4.859685 0.476761 2.697293

H

6.931686-2.07576 0.877345

H

6.233567-1.83316-0.73403

H

5.275211-2.61321

0.52349-0.08848

0.66323.08299

3.55134-1.07611

Table S4. Cartesian coordinates (Angstroms) for TS-2 in gas phase.

87

Point Group: C1
Imaginary Freq: 1
Total energy = -1729.285376 hartree
SymbolX

Y

Z

C-4.53233 1.041345 0.406089

C-3.42473 1.821816 0.843175

C-3.58989 2.859493

C-4.86993 3.177425 2.242724

C-5.96206 2.445736 1.838985

C-5.83255 1.370096 0.919471

C-6.96725 0.624912 0.504919

C-6.82323-0.40955-0.38727

C-5.55664-0.75687-0.90472

C-4.42363-0.05592-0.52198

N-3.1417-0.37726-1.01704C-2.78934-1.33883-1.92679

O-3.55977-2.10175-2.49844

C-1.26038-1.37385-2.20038

C-0.89591-2.37096-3.30477C-0.6946-3.68941-2.54259

C-0.01327-3.25818-1.23565N-0.50046-1.87081-1.02625C-0.10237-1.01092-0.0618

C

0.873322-1.51368 1.019951

O-0.49434

0.17211

C

0.244371-1.54342 2.454006

C-0.01319-0.13309 3.020298

C

1.21615-2.29359 3.386446

C-1.08842-2.31722 2.395034

N

2.087751-0.71271 0.954462

C

3.09529-1.01607 0.089926

O

3.116666-2.0367C

4.252332 0.007607 0.047571

1.73566-0.04975-0.5987388

N

3.770251

1.3423 0.459673

C

3.325126 2.243728-0.59488

C

1.913054 2.762043-0.43889

C

1.400877 3.478277-1.69839

C

2.472126 4.400704-2.29152

C

3.722751 3.597705-2.67874

C

4.124034 2.617053-1.60327

C

5.496908

C

6.66612 0.519911 0.642289

C

5.176915-0.50915 2.395965

C

5.956988-1.85689 0.423343

H-2.421711.61903H-2.72542 3.438141 2.049867

H-4.98746 3.997386 2.946111

H-6.9538 2.680657 2.218603

H-7.94366 0.889058 0.903028

H-7.69066-0.9803-0.70803

H-5.45798-1.57266-1.60594

H-2.34527 0.123138-0.62614

H-0.92157-0.35488-2.4135H

0.037081-2.05458-3.78448

H-1.68185-2.43653-4.05843

H-0.08905-4.41612-3.09154

H-1.67047-4.13944-2.33659

H

1.078158-3.24577-1.32057

H-0.29535-3.89774-0.3938H

1.184084-2.53085 0.779884

H-0.47339-0.21533 4.012021

H-0.68011

0.44557 2.377769

H

0.918978 0.430601 3.146883

H

0.804371-2.3435 4.401201

H

2.18631-1.78957 3.441774

H

1.387431-3.32149 3.043741-0.45984 0.888644

0.4833389

H-1.50504-2.42346

3.4029H-0.95063-3.32718 1.988778

H-1.83652-1.80147 1.783609

H

2.095189 0.244213 1.293928

H

4.571632

0.01232H

4.481972

1.80987 1.011819

H

1.881927 3.443695 0.426963

H

1.243817 1.931491-0.18512H

0.489362

4.04075-1.46369

H

1.119876 2.725682-2.44844

H

2.747 5.161372-1.54737H

2.083209 4.938256-3.16487

H

4.561881 4.276393-2.88529

H

3.546008 3.055895-3.62172H

5.129483 2.201318-1.66795

H

7.562409 0.168886 1.166257

H

6.465467 1.535921 1.002745

H

6.908408 0.585213

H

6.071461-0.7965 2.960892

H

4.394675-1.24348 2.613066

H

4.840141 0.459782 2.782269

H

6.863531-2.14419 0.969515

H

6.190277-1.86259

H

5.19458-2.61955 0.593736-1.00247-0.42521-0.64725

90

6. Acknowledgments
With an immense pleasure, first I would like to express my sincere thanks to my supervisor
Prof. Hiroto Nakano for his invaluable encouragement and guidance in my research career. The
research work presented here would have not been possible without his suggestions and everwillingness to teach. I have greatly benefited from several stimulating and constructive criticism
during my initial learning period. I consider myself luckiest person to be part of his research group.
I sincerely, thank to Prof. Niwayama Satomi and Prof. Koji Uwai for their valuable time andsuggestions in my thesis examination. I also, extend my acknowledgements to all faculty
members in the chemistry department for their kindness and timely help. I am grateful to the
President, Muroran Institute of Technology for giving me an opportunity to use infrastructure,necessary facilities and granting me necessary funds for attending the scientific programs andconferences. I would like to thank Eunsang Kwon and Yuko Okuyama for their continuous
analytical support to my research work. I sincerely thanks to Chigusa Seki for her kindness andtimely help.
My acknowledgement would be incomplete without expressing my gratitude to myparents and family members. I am greatly indebted to my parents for their unconditional love andaffection. Without their encouragement, it would be impossible for me to achieve the present
stage in my life.

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