不斉ヘテロ
ディールス・アルダー反応に用いる新規有機分子触媒複合系の開発
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言語: English
出版者:
公開日: 2021-06-23
キーワード (Ja):
キーワード (En):作成者: ペルマルサミ, パラスラマン
メールアドレス:所属:

URL

https://doi.org/10.15118/00010397

Development of New Organocatalyst Component System for
Asymmetric Hetero Diels-Alder Reaction

Thesissubmitted in partial fulfillment of the requirements
for the degree of
DOCTOR OF PHILOSOPHY
by

Perumalsamy Parasuraman(18096013)
Research Supervisor
Professor. Hiroto Nakano

DEPARTMENT OF APPLIED SCIENCE, GRADUATE SCHOOL OF
ENGINEERING, MURORAN INSTITUTE OF TECHNOLOGY,
MURORAN, JAPAN2021

TITLE:
Development of New Organocatalyst Component System for Asymmetric Hetero Diels-Alder
Reaction(不斉ヘテロ ディールス・アルダー反応に用いる新規有機分子触媒複合系の開発)
NAME:
Perumalsamy Parasuraman（ペルマルサミー パラスラマン）
ABSTRACT
Many biologically active compounds, including pharmaceuticals, are optically active and often
only one of the enantiomer shows a high biologically activity. Therefore, it is important to develop
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 theoretically enables
infinite production of optically active compounds, is the most efficient in the synthetic organic
chemistry field. Moreover, this methodology is also important in terms of energy saving andenvironmental 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.
Spirooxindoles are considered to be promising scaffolds in drug discovery. The structure of
spirooxindoles is contained in many compounds having pharmacological activities such as
contraceptive, anti-HIV, anticancer, antituberculosis, antimalarial, and antiproliferative drugs.
Therefore, the development of an effective strategy for the preparation of highly optically purespirooxindoles is a significantly challenging task in research. The hetero Diels–Alder (HDA)
reaction is a versatile tool for effectively forming heterocyclic compounds. Especially, the catalytic
asymmetric version of this reaction is the most efficient and convenient method for constructing achiral heterocyclic skeleton, which acts as a precursor for many biologically active compounds
and drugs. In this class of HDA reactions, the reaction of isatins with enones is one of the superior
organic transformations for providing unique chiral spirooxindoles containing quaternary chiralcarbon center on the structure.
Author tried to explore new catalysts component system for this reaction using isatins as diene
and enones as dienophile. As a result, author developed a simple two catalysts component system
consisting of primary b-amino alcohol as a catalyst and N-protected amino acid as a co-catalyst
for the asymmetric HDA reaction of isatins with enones for the first time. This dual component
system showed efficient catalytic activity to afford the chiral spirooxindoles that are efficientsynthetic intermediates for many biologically active compounds and drug discovery, in good to
excellent chemical yields and with enough stereoselectivities.
In this study, author revealed that the new explored catalysts component system showed
excellent catalytic activity to the asymmetric HDA reaction of isatins with enones. It is expectedthat this results should be able to greatly contribute the development of new drug and its related
compounds.

TittleDevelopment of New Organocatalyst Component System for Asymmetric Hetero Diels-Alder
Reaction
Research Summary
Many biologically active compounds, including pharmaceuticals, are optically active. Often,
only one of the enantiomers is required because the enantiomers display different in vivo activities.
In pharmaceuticals in particular, differences in the absolute configuration can affect not only thepharmacological activity but also the toxicity. Catalytic asymmetric synthesis, in which a low
amount of a chiral molecular catalyst theoretically enables infinite production of an optically active
compounds, is among the most important current challenges in organic synthetic chemistry; it isalso important in terms of energy saving and environmental friendliness. Environmental effects
now have to be considered in chemical syntheses, and environmentally benign organic syntheses
have been receiving attention. The chiral catalysts used in catalytic asymmetric syntheses can bedivided into two categories: organometallic catalysts and metal-free chiral organocatalysts.
Particularly, organocatalysts are stable in air, easy to handle, and inexpensive, so they are being
focused on as next-generation, environmentally friendly catalysts.
On this background, Author developed the simple amino alcohol and simple amino silyl etherorganocatalyst. The both organocatalyst are synthesized from commercially available from aminoacids and amino alcohol. The catalytic activity of both organocatalyst were examined theasymmetric hetero Diels-Alder (hDA)reaction.
1.The asymmetric hetero Diels-Alder reaction was established with various isatins with enones
using simple b-amino alcohol organocatalysts. This protocol provided spirooxindole
tetrahydropyranones in good chemical yields and excellent diastereoselectives. The obtained chiralspirooxindole tetrahydropyanones are synthetic intermediate for preparing many biologically
active compounds.
2.The asymmetric hetero Diels-Alder reaction was further established with various isatins withenones using simple b-amino silyl ether organocatalysts. This protocol provided spirooxindole
tetrahydropyranones in excellent chemical yields and good diastereoselectives. The obtained chiralspirooxindole tetrahydropyanones are synthetic intermediate for preparing many biologically
active compounds.
In this study author revealed that the simple amino alcohol organocatalysts having both
covalent interaction (enamine formation site) and non-covalent interaction (hydrogen bond site) ina single molecule shows the good catalytic activity and simple amino silyl ether organocatalyst
having covalent interaction (enamine formation site) in i) Enantioselective hetero Diels-Alder(hDA) reaction. It is expected that this work might be able to development of pharmaceutically
active compounds.

Contents
Chapter 1
1. Introduction

1

1.1 Chirality

2

1.2 Asymmetric synthesis

3

1.3 Catalysis in asymmetric synthesis

3

1.4 Organocatalysis

3

1.5 Types of organocatalysis activation mode in enantioselective reactions

5

1.5.1 Covalent mode of organocatalysis activation

5

1.5.2 Non-covalent mode of organocatalysis activation

6

1.6 b-Amino alcohol organocatalysis importance in asymmetric synthesis

7

1.7 Spirooxindole importance in asymmetric synthesis

10

1.8 Author project

12
Chapter 2

Simple organocatalyst component system for asymmetric hetero Diels-Alder reaction of
isatins with enones
2.1

Author project

17

2.2

Diels Alder reaction

17

2.3

Mechanism of Diels Alder reaction

17

2.4

hetero Diels Alder reaction

18

2.4.1 Enantioselective oxa Diels-Alder reaction

19

2.5

Author strategy

21

2.6

Result and discussions

24

2.6.1 Synthesis of catalysts 2a-e

24

2.6.2 Synthesis of catalysts 4a-e

24

2.6.3 Various co-catalyst 5a-k to the asymmetric hetero Diels-Alder reaction of isatin withenones25

2.6.4 Optimized reaction condition for catalysts 2a-e and 4a-e in asymmetric hetero
Diels-Alder reaction25

2.6.5 Solvent screening for asymmetric hetero Diels-Alder reaction using catalyst 2c
and co-catalyst 5c

29

2.6.6 Substrate scope for asymmetric hetero Diels-Alder reaction using 6a-f and 7a-e

31

2.6.7 Plausible Reaction mechanism for hetero Diels-Alder reaction using 6a and 7a with 2c
2.7

and 5c34

Summary

36
Chapter 3

Simple amino silyl ether organocatalyst for asymmetric hetero Diels-Alder reaction of
isatins with enones
3.1

Author project

38

3.2

Author strategy

38

3.3

Result and discussions

41

3.3.1 Preparation of simple amino silyl ether organocatalysts 10a-o

41

3.3.2 Various co-catalysts 5b-c, 5h-j, 11a-n employed in asymmetric hetero Diels-Alderreaction
3.3.3 Screening of catalyst 10a-o in asymmetric hetero Diels-Alder reaction

42
43

3.3.4 Screening of co-catalyst 5b, 5h-j, 11a-n using catalyst 10e in asymmetric hetero
Diels-Alder reaction

45

3.3.5 Optimization of mole amount used for superior catalysts system and substrates

47

3.3.6 Solvent screening for catalyst 10e and co-catalyst 11j

49

3.3.7 Substrate scope for asymmetric hetero Diels Alder reaction using 6a-f and 7a-d

50

3.3.8 Plausible reaction mechanism for asymmetric hetero Diels Alder reaction of isatinwith enone using catalyst 10e and co-catalyst 11j

53

3.4

Summary

54

4.

Conclusion

55

5.

Experimental section

57

6.

Acknowledgements

62

7.

References

63

Chapter 1
Introduction

1. Introduction
Asymmetric organocatalysis has emerged as one of the most intensively investigated area insynthetic organic chemistry and one of the most powerful methods for the construct biologically
active compounds.1 Small organic molecules as catalysts can provide complex organic
transformations with high levels of stereoselectivity transformations in an environmentally andeconomically friendly manner. It has most effective and attractive one because it doesn’t involvethe use either of toxic metals or of expensive biocatalysts to carry out stereoselective
transformations. Particularly asymmetric organocatalysis have several advantages overorganometallic and enzymatic catalysis and some of the organocatalysts are showing
pharmaceutical activity also. Organocatalysts are usually in-expensive than metal based catalyst,
non-toxic. Which is huge benefits preparation of pharmaceutical intermediate when compared withother metal catalyst.
Author PhD objectives were to design and develope the simple b-amino alcohol organocatalysts
for asymmetric reactions. The simple b-amino alcohol oragnocatalysts were developed and usedin this thesis mainly concentrated on three sections (i) The development of simple amino alcoholand amino silyl ether organocatalysts, (ii) simple b- amino alcohol organocatalysts for asymmetrichetero Diels-Alder (hDA) reaction, (iii) simple b- amino silyl ether organocatalysts for asymmetrichDA reaction, The detail study and applications of these enantioselective reactions are discussed
in the following sections.

11.1 Chirality
Chirality is most important valuable function in biologically active compounds. Many researchrecent interest to the pharmaceutical industry and the U.S. Food and Drug Administration (FDA)
is the production and sale of “chiral drugs,” that is, drugs that contain a single enantiomer rather
than a racemate. Because all chiral compounds have both enantiomer such as R (D) and S (L) havedifferent nature of biologically activities. Generally the basic example of chirality is our humanbeing left and right hands mirror image of each other and but cannot superimposed on each other(Figure 1)

Figure 1. Two enantiomer of general amino acid
First synthesized in 1953, thalidomide was widely prescribed for morning sickness. The (R)thalidomide shows the activity towards for morning sickness, while the (S)-thalidomide shows thesedative morning sickness. (S)- ibuprofen showed the anti-inflammatory activity and (R)ibuprofen showing inactive even though (R)-isomer of ibuprofen is slowly converted into (S)isomer to the human body. (S)- methyldopa widely used as anti-hypertensive activity for primarychronic arthritis and (S)- methyldopa showing inactive. (S)- penicillamine commonly used astherapeutic activity and (S)- penicillamine showing inactive and also highly toxic (Figure 2).3

O

O

O
NH

N
O

O
NH

O

N

OH

OH

O
O

O

(S)-ibuprofen(R)-ibuprofen

anti inflmmatory activity

inactiveO(S)- thalidomide(R)- thalidomide

sedative morning
sicknesscauses fetal defects

2

HO
HO

O

O

O
OH
NH 2
(S)-methyldopa

HO

OH
NH 2

HO

(R)-methyldopa
inactiveantihypertensive activity

HS

O
OH

HS

OH

NH 2

NH 2

(S)-penicillamine(R)-penicillamine

therapeutic activity

inactive(highly toxic)

Figure 2. Biological activity of isomers
1.2 Asymmetric synthesis
Asymmetric synthesis is one of most significant area in synthetic organic chemistry.
Asymmetric synthesis as defined by Morrison and Mosher,2 is a chemical reaction in which anachiral molecule is converted into a chiral molecule the product unequal amounts of stereoisomers
are formed. Most of the biologically active compounds have different functionality in biologicalsystem such as R and S enantiomers. Moreover, biologically active compounds requisite tosynthesis the precise enantiomer using chiral catalyst through asymmetric synthesis.
1.3 Catalysis in asymmetric synthesis
The catalysis classified into three major parts, such as metal catalysis, enzyme or bio-catalysis
and organocatalysis. Enantioselective organocatalysis is known as an independent synthetic
research area in last two decades among enantioselective metallic catalysis and enzymatic catalysis
for the synthesis of optically active compounds. Many of the metal based reactions necessary forglove box . Among the metal and enzyme catalysis, the organocatalysis has some assets like nontoxic, commercially availability, easy to synthesis and environmentally friendly. They are mostly
stable under aerobic conditions, and the organocatalytic reactions do not require essentialconditions to proceed the reactions.
1.4 Organocatalysis
Organocatalysis is a chemical process that catalyzed by non-metallic compounds, and thisprocess has been attracting a great deal of attention to synthetic organic chemistry field for the lastfifteen years. Organocatalysts are less expensive, more stable and exhibit superior solubility inboth organic and aqueous solutions compared to organometallic and bioorganic counterparts andalso economically and environmentally friendly manner. Most importantly, organocatalysis
generally gives rise to outstanding stereoselectivity, which is significantly valuables of bioactive
compounds and pharmaceutical agents.
3

Importance of organocatalyst
It is stable in air and moisture.
Non-toxic and environmental friendly manner.
It is very cheaper than organic metal based catalyst.
Easy to handle.

o
o
o
o

In recent years organocatalyst (Figure 2) is most trending in the field of synthetic organic
chemistry. The advantages of organocatalyst as compared to metal based organometallic catalyst
is non-toxic, easy available from nature and commercially available and environmentally friendly
manner.4

N
H

O

Ar

OH

Ar

N
H

O

(S)-proline
organocatalyst

O
N

Bn

OSiMe3

N
Bn

N
H

N
H

Macmillian imidazolidinone
organoatalysts

proline silyl etherorganocatalyst

ipr

OMe
R

NH 2

R = alkyl, aryl
R ' = PhN
Cinchona
primary amine
organocatalyst

O

Bu

O

N

N
H

N
H

ipr

BINOL phosphoric acidphase transfer organocatalyst
H
N

F 3C

Bu
N

ipr

Primary β-amino alcoholorganocatalyst

Br

ipr

ipr
O
O
P
O
OR
ipr

R'
OH

NH 2

N

Ar

R'

tBu

H
N

N

S
N

CF 3

Ar
binapthylphase transfer organocatalyst

C2-symmetric squaramideorganocatalyst

thioureabifunctional organocatalyst

Figure 3. Commonly used organocatalysts

4

1.5 Types of organocatalysis activation mode in enantioselective reactions
Organocatalysts are approach by two ways in enantioselective reaction.
1) Covalent mode of activation- amine based organocatalysts
2) Non-covalent mode of activation- hydrogen bond based organocatalysts

1.5.1 Covalent mode of organocatalysis activation
Generally, enamine catalysis might be better described as bifunctional catalysis because theamine-containing catalyst typically interacts with a ketone substrate to form an enamineintermediate but simultaneously engages with an electrophilic reaction partner through eitherhydrogen bonding or electrostatic attraction. This mode of activation has now been used in a wide
range of enantioselective carbonyl α-functionalization processes.
Enamine activation
N
H

O
R2

R1

-H+

N
R2

R1

O

N

E
R2

+H+

R2
E

The concept was founded on the mechanistic hypothesis that the reversible formation ofiminium ions from α,β-unsaturated aldehydes and chiral amines might emulate the equilibrium
dynamics and π-orbital electronics that are inherent to Lewis acid catalysis (that is, lowestunoccupied molecular orbital (LUMO)-lowering activation). With its tailor-made family of
imidazolidinone catalysts, enamine, iminium catalysis is now used highly enantioselective
protocols.
Iminium activation
N
H

O
R1

N

R2

R1

Nu

O

R2

R1

Nu
R2

Enamine and iminium activation
N
H

O
R1

R2

N
R1

Nu

N

R2

R1

5

E

Nu
R2

N
H

O
R1

Nu
*
E

* R2

Example of covalent type organocatalyst such as (S)-proline, imidazolidinone and b-amino
alcohol (Figure 4) are widely used in asymmetric synthesis.5
O
OH
N
H

O

(S)-proline
organocatalyst

N

R

Bn

N
H
imidazolidinone
organocatalyst

R'

R'
OH

NH 2
β-amino alcoholorganocatalyst

Figure 4. covalent type organocatalysts
1.5.2 Non-covalent mode of organocatalysis activation
Hydrogen-bonding organocatalysts is called as non-covalent organocatalysts. It activate imine
electrophiles. In non-covalent modes of activation usually hydrogen bond-donor catalysis plays aprimitive role for activation of substrates, which is a well explored research area in enantioselective
catalysis. Among them, non-covalent modes of activation squaramide and thiourea basedorganocatalysts are well studied in last fifteen years. The squaramide catalyst usually forms a
multiple hydrogen bonding’s mode with the substrates (mainly electron deficient conjugatedketones) which allows an electrophilic site to attack an appropriate nucleophile on it to which
subsequently affords the chiral products.

R

R
X
X
H
H
chiral catalyst

O
R

R

X
H

X
H

R

O
Nu

O

R'

R
Nu

* R'

R
R'

Example of Non-covalent type organocatalyst such as thiourea , squaramide and phosphoric acidorganocatalysts (Figure 5) are widely used in asymmetric synthesis.6

6

O
Ph

S
N
H

Ph

CF 3 O

O

N
H

HN

CF 3

H

NH

F 3C

HN

O
O
P
O
OH

N

N

OMe
CF 3
N
squaramide organoacatalyst

Thiourea organoacatalyst

phosphoric acidorganocatlyst

Figure 5. examples of non-covalent type organocatalysts
1.6 b-Amino alcohol organocatalysis importance in asymmetric synthesis
Simple b-amino alcohol and derivatives are synthesized from the commercially available
corresponding amino acids by simple methods. The chiral of amino alcohol organocatalyst could
be used as enantioselective reactions. They have many assets such as easy to synthesis, stable inair and moisture. It has covalent site for making enamine and imine formation and non-covalentsite for making hydrogen bond in a single molecules (Scheme 1).
steric influence sites
R'R

covalent site
(enamine formation)

*

R'
OH

NH 2

non-covalent site
(hydrogen bonding)

Functionality of β-amino alcoholorganocatalysts

O
R

OH
NH 2
β-amino alcohol

OH

NH 2
amino acids

O
R

O
OH

NH 2
amino acids

R

O

Me

NH 2
amino acid esters

R

R'

R'
OH

NH 2
β-amino alcohol

Scheme 1. Functionality and preparation of b-amino alcohol

7

The b-amino alcohols can be easily prepared from corresponding amino acids and amino acid
ester salts.The simple primary b -amino alcohols can be easily derived in to a di amino alcohol,
squaramide fused amino alcohol. By introducing new functional groups on amino alcohol catalyst,
there might be increasing the catalyst activity. The primary b -amino alcohols and their derivatives
successfully showed the catalytic activity in important asymmetric reaction such as epoxidation,
Diels-Alder and 1,3-dipolar cycloadditions, aldol cross-aldol reactions, domino Michael reaction
and nitro aldol reaction to afford the chiral biological synthetic intermediates.
Alessandra lattanzi7 reported the enantioselective epoxidation of unsaturated enone using
diphenyl-L-prolinol as bifunctional organocatalyst to afforded the epoxides in good yield (up to87%) and good enantioselectivities (up to 80%, Scheme 2).

PhN
H

diphenyl-L-prolinolorganoacatalyst(30 mol%)

O

Ph
OH

R1

diphenyl-L-prolinolorganoacatalyst

TBHP
hexane, rtR2unsaturated
enones

O

O

R1

R2
epoxidesup to 87%, up to 80% ee

Scheme 2. Diphenyl-L-prolinol as bifunctional organocatalyst for epoxidation
Pavel Kocovsky8 and co-workers reported the enantioselective Cross Aldol reaction of isatinswith ketone using amino alcohol organocatalyst to afforded the chiral oxindole in excellent yield(up to 98%) and excellent enantioselectivities (up to 95%) amino alcohol (Scheme 3).
X

O

OH
NH 2
β-amino alcoholorganoacatalyst

O
X

+

O

O

X HO
O

DCM, rt, 36 hNR
isatins
X = alkyl
R = alkyl,

β-amino alcoholorganoacatalyst(20 mol%)XketonesN
Rchiral oxindole
up to 98%, up to 95% ee(R)-(+)-Convolutamydine A

Scheme 3. Amino alcohol organocatalyst for Cross-Aldol reaction
Author research group9 reported the chiral amino alcohol organocatalyst for enantioselective
Diels Alder reaction of 1,2-dihydropylidines with aldehydes to afforded the chiral isoquinuclidines
with excellent chemical yield (up to 98%) and excellent enantioselectivities (up to 98%, Scheme
4).

8

H 2N

.CF 3CO2H
β-amino alcoholorganocatalyst

β-amino alcoholorganocatalyst(10 mol%)

R1

Ph
Ph
OH

+

N
CO2R

N

MeCN-H 2O
0o C, 24-36 hO

1,2-dihydopyridines
R= Ph or Bn

R'O 2CR
CHO

chiralisoquinuclidines
up to 98%, up to 98% eealdehydes
R1 = H, CO2Me
or CN

Scheme 4. Amino alcohol organocatalyst for enantioselective Diels-Alder reaction
Author research group10 reported the optically active 2-azanorbornane amino alcoholorganocatalyst for enantioselective aldol reaction of isatins with ketone to afforded the chiraloxindole with excellent chemical yield (up to 95%) and moderate enantioselectivities (up to 64%,
Scheme 5).

Ph
Ph
OH

N
H
2-Azanorbornane
amino alcoholorganocatalyst

O

O
R2

+
O
N
R1
cyclohexanone
isatins
R1 = alkyl, aryl, allyl, Boc
R 2 = alkyl, halogens, NO 2

2-Azanorbornane
amino alcoholorganocatalyst(20 mol%)
TFA (10 mol%)toluene, rt, 24 h

O
HO
R1
O
N
R2
chiraloxindoles
up to 95%, up to 64% ee

Scheme 5. amino alcohol organocatalyst for aldol reaction
Author research group11 reported the diamino alcohol organocatalyst for enantioselective aldol
reaction of isatins with aldehyde to afforded the chiral 3-substituted-2-hydroxyindolin-2-one withexcellent chemical yield (up to 95%) and excellent enantioselectivities (up to 92%, Scheme 6).

O
R2
N
H 2N

Ph
Ph
OH

Di-amine amino
alcohol organocatalysts

O

+

O

Toluene, -10o C, 48 hNR1

isatins
R1 = alkyl, aryl, allyl, Boc
R 2 = alkyl, halogens, NO 2

Di-amine amino
alcohol organocatalyst(20 mol%)
PhCO 2H (30 mol%)aldehyde

HO
R2

O

O
N
R1
chiral3- substituted
3-hydroxyindolin-2-ones
up to 95, up to 92% ee

Scheme 6. Diamino alcohol organocatalyst for aldol reaction
Author research group12 reported the squaramide fused amino alcohol (SFAA) organocatalyst
for enantioselective nitro aldol reaction of isatins with nitro methane to afforded the chiral 3-

9substituted-3-hydroxy indoles with excellent chemical yield (up to 99%) and excellent
enantioselectivities (up to 95%, Scheme 7).
CF 3 O

O

O

R2
N

N
H

F 3C

N
H

+

O

CH 3NO 2

N
R1

Ph
HO Ph

squaramide fused amino
alcohol organocatalyst(10 %mol)
THF, 0o C, 60 h

isatins
nitro methane
R1 = alkyl, aryl, allyl, Boc
R 2 = alkyl, halogens, NO 2

squaramide fused amino
alcohol organocatalyst

R2

NO 2

HO

O
N
R1
chiral3-sustituted-3-hydroxy indoles
up to 99%, up to 95% ee

Scheme 7. Squaramide fused amino alcohol organocatalyst for enantioselective nitro aldol
reaction
Author research group13 reported the 2-azanorbornane based cage type amino alcoholorganocatalyst for enantioselective Michael reaction of b-keto ester with nitroolefins to afforded
the chiral Michael adducts with excellent chemical yield (up to 99%) and moderateenantioselectivities (up to 91%, Scheme 8).

N
Ph

OH
H
Ph

2-azanorbornane based
cage type amino alcoholorganocatalyst

O

O
O R1

β-keto esters
R1 = alkyl

+

NO 2

R2

2-azanorbornane based
cage type amino alcoholorganocatalyst(10 mol%)
toluene, rt, 24 h

nitroolefins
R 2 = aryl

O

R2

O
O R1
NO 2

chiralMichael adducts
up to 99%
up to dr 91:9, up to 91% ee

Scheme 8. 2-Azanorbornane based cage type amino alcohol organocatalyst for enantioselective
Michael reaction10

1.7 Spirooxindole importance in asymmetric synthesis
The spirooxindole framework bear spirocyclic ring fused at the 3-position and it has
tetrasubstituted carbon. Synthesis of spirooxindoles core moieties still challenging task inasymmetric synthesis field. Chiral spiro oxindole core structure are one of the most important
heterocyclic property and its showing biologically active (Figure 6) activities14 such as antimalarial activity,15 MDM2 inhibitor, anti-tubercular activity, anti-proliferative activity. Synthetic
spirooxindole also showed biological activity such as antimalarial, anti-HIV,16 anticancer,17
antituberculosis,18 antiproliferative.19

3

*

O
N
H
Spirooxindole

O

HO

OH

O

CH 3

O

N
O

Me
N

HO

N
Me

O

N

O

OMe

N

NH

O

OH

CO2Me

N
H

O
N
H
anti-mitotic activity

MeO
kidney diseases activity

anti-tumor activity

Cl

Me

O Ar

NH O

F
N
H

Cl

NH

NH
Cl

Cl
anti-malarial activity

anti- inflammatory activity

N
H

F

S

N

Cl

O

O

O

O
O

O

NH

anti-tubercular activity

MDM2 inhibitor

NH
anti-proliferative activity

Figure 6. Spiro oxindoles containing biologically active compounds

111.8 Author project
Functionality of spirooxindoles widely present in many an biologically active compounds andpharmaceiticals . Author decide to develop the simple amino alcohol and simple amino silyl etherorganocatalyst to explored the hDA reaction of isatins with enones to afford the chiralspirooxindole tetrahydropyranones.
In order to develop the asymmetric hDA reaction of isatin with enones using two component
catalyst system of simple b-amino alcohol organocatalyst D and N- protected amino acids as cocatalyst E. The functionality of amino alcohol has covalent site (enamine formation) and noncovalent site (hydrogen bond formation) in single molecule. Moreover, the bulky substitution at a
substituent b-position works as a steric influence sites.
The asymmetric hDA reaction of isatin with enones using two component catalyst system ofsimple b-amino silyl organocatalyst F and N- protected amino acids as co-catalyst E. The
functionality of amino silyl ether has covalent site (enamine formation). Moreover, the bulky
substitution at a substituent b-position works as a steric influence sites.
In firstly Tanaka and co-workers developed three component catalyst system including,chinchona primary amine A (catalyst), N-Boc-amino acid B (co-catalyst) and thiourea C (cocatalyst) for asymmetric hetero Diels-Alder reaction of isatin with enones to afford the chiralspirooxindole

tetrahydropyraones

in

good

chemical

yield

(up

to

87%),

excellent

diastereoselectivity and enantioselectivities (up to dr 95:5, up to 94% ee). The feature of cinchona
alkaloid primary amine organocatalyst has aromatic quinoline act as steric influence site and bulky
bicyclic quinuclidine is making hydrogen bond formation with N-Boc amino acid.Thiourea
containing hydrogen is making hydrogen bond with isatin substrate. The advantage of threecomponent catalyst system to furnish the good chemical yields and excellent stereoselectivities
and disadvantage of that catalytic system using two chiral co-catalyst in situ (Scheme 9). As
comparatively previous report amino alcohol having all functionality in a single molecule such ascovalent site, non-covalent site and steric influence sites.

12

O

O
O

R'

+

N
H
isatins X

R"enones Y

Tanaka three component
catalyst system

Author two component
catalyst system 1
R'

R
N

N
A
catalyst
CF 3

B
co-catalyst

*

N
H

N
H

OH
NHR
E
amino acidco-catalysts

CF 3C
co-catalyst

R'
OSiR"

NH 2
F
catalyst
O

R'

S

COOH
F 3C

R'

R

O

CF 3

NHBoc

R'
OH

NH 2
D
catalyst

NH 2

O tBu

*

Author two component
catalyst system 2

R'

*

OH
NHR
E
amino acidco-catalysts

R''
O

O

R'

O
N
R
Z
chiralspirooxindoletetrhydropyranones

Scheme 9. Component system of hDA reaction
The author designed the simple two component catalyst system using simple b-amino alcoholorganocatalyst D and N-protected-amino acid E act as co-catalyst and simple b-amino silyl etherorganocatalyst F and N-protected-amino acid E The simple two component catalyst is altered fromthe Tanaka three component catalyst system.
The catalytic activity of simple two component catalyst system was examined in asymmetrichetero Diels-Alder reaction.

13

Author developed simple amino alcohol organocatalysts from amino acids. It has stability in
air and moisture, covalent site for enamine formation , non-covalent site for hydrogen bondformation and remaining substitution act as steric influence site (Figure 7).

steric influence sites
O
R

R'

OH

R

NH 2

R'
OH

NH 2

covalent site
(enamine formation)amino acids
R = alkyl, aryl*

non-covalent site
(hydrogen bonding)

Functionality of β-amino alcoholorganocatalysts

Figure 7. Functionality of b-amino alcohol organocatalyst
The author first examined the catalytic activities of simple two component catalyst of amino
alcohols 2a-e, 4a-e and N-Boc amino acids in the asymmetric hetero Diels-Alder reaction of isatinwith enones to afforded the chiral Spiro oxindole tetrahydropyaranones good to excellent chemicalyields, diastereoselectivities and enantioselectivities (up to 86%, up to dr = 85:15, up to 95% ee,
Scheme 10).
O
OH

OH
NH 2
catalyst(20 mol%)

O

O

R'

O
N
R
isatins X

+

HN

Boc
co-catalyst(40 mol%)R''catalyst system

asymmetric HDA reaction
R''enones Y

*
O

O

*

O
N
R
Z
chiralspirooxindoletetrahydropyranones
up to 86%, up to dr 85:15
up to 95% ee
R'Scheme 10. Amino alcohol organocatalyst for asymmetric hetero Diels-Alder reaction
Modified of that work the author developed simple amino silyl ether organocatalysts fromamino alcohols organocatalyst. It has similar assets an amino alcohol like stability in air and14

moisture, covalent for enamine formation and remaining substitution act as steric influence site
(Figure 8).
steric influence sites

R'

R

R'
OH

R

R'

R'

*

O SiR''

NH 2

NH 2

β−amino alcohol
R = alkyl, aryl
R' = Phcovalent site
(enamine formation)
Functionality of amino silyl
ether organocatalysts

Figure 8. Functionality of amino silyl ether organocatalyst
In extension of previous work the author developed simple amino silyl ether oragnocatalyst
10a-o and N-protected amino acid as a co-catalyst for enantioselective asymmetric hetero DielsAlder reaction of isatin with enones to afforded the chiral spiro oxindole tetrahydropyaranones
good to excellent chemical yields, diastereoselectivities and enantioselectivities (up to 94%, up to
dr 78:22, up to 86% ee, Scheme 11). The detail of simple amino alcohol and amino silyl etherorganocatalysts preparations and its application for enantioselective asymmetric reactions will be
discussed in the following sections.
OTMS
NH 2
catalyst(20 mol%)

O

O

R'

O
N
R
isatins X

+

O
N
OH
Boc
co-catalyst(40 mol%)R''catalyst system

asymmetric HDA reaction
R''enones Y

*
O

O

*

O
N
R
Z
chiralspirooxindoletetrahydropyranones
up to 94%, up to dr 78:22
up to 86% ee
R'Scheme 11. Amino silyl ether organocatalyst for asymmetric hetero Diels-Alder reaction

15

Chapter 2
Simple organocatalyst component system for asymmetric hetero Diels-Alderreaction of isatins with enones

16

2. Simple organocatalyst component system for asymmetric hetero DielsAlder reaction of isatins with enones
2.1 Author project
Author aimed to develop the simple b-amino alcohol organocatalyst component system forasymmetric hDA reaction of isatins with enones to afford the chiral spirooxindole
tetrahydropyranones. The utility of amino alcohol has covalent site (enamine formation) and noncovalent site (hydrogen bond formation) in single molecule. Moreover, the bulky substitution at a
substituent b-position works as a steric influence sites (Figure 9).
steric influence sites
R'R

covalent site
(enamine formation)

*

NH 2

R'
OH

non-covalent site
(hydrogen bonding)Figure 9. Functionality of b- amino alcohol organocatalyst
2.2 Diels-Alder reaction
The Diels-Alder (DA) reaction is a useful classical organic reaction using with conjugated dieneand dienophile to form a cyclohexene system, it’s also refered as a [4+2] cycloaddition reaction(Scheme 12). The DA reaction discovered by Otto Diels and Kurt Alder in 1928 for theirtremendous contribution they received Nobel prize in chemistry in the year of 1950. The DielsAlder reaction is also reliable practical method for constructing the six membered bicyclic
compounds in synthetic organic chemistry.20
DA reaction
diene

dienophile

DA adduct

Scheme 11. General Diels-Alder reaction
2.3 Mechanism of Diels-Alder reaction
Diels-Alder reaction is also called as [4+2] cycloaddition reaction. In generally Diels-Alderreaction (Figure 10) proceed via two ways such as i) Normal electron demand Diels-Alder reaction,17ii) Inverse electron demand Diels-Alder reaction. Usually, normal electron demand Diels-Alderreaction is diene contain electron donating group and dienophile have electron withdrawing group.
In the same way for Inverse electron demand Diels-Alder reaction is diene contain electron
withdrawing group and dienophile have electron donating group to provide the six memberedring.21
Normal electron demand DA reaction
EWG

Inverse electron demand DA reaction
EDG

EWG

EDG

+

+
EWG

EDG

Normal electron DA reaction

Inverse electron DA reaction

Normal electron DA reaction

Inverse electron DA reaction

Diene

Dienophile

Diene
LUMO

LUMO

Dienophile

HOMO

Figure 10. Pictorial representation of Diels-Alder reaction
2.4 hetero Diels-Alder reaction
The hetero Diels-Alder (hDA) reaction (Scheme 12) is one of the most powerfultransformations in the chemistry for the synthesis of heterocycles embodying multiple stereogenic
centers. However, as compared to other cycloadditions, in particular the dipolar cyclo additions
reaction, the hetero Diels-Alder reaction has been much less explored in organic synthesis.
Nevertheless, this powerful transformation has opened up efficient and creative routes tobiologically relevant small molecules and different natural products which contain six-membered
oxygen or nitrogen ring systems.22

18

X

+

X

hDA reaction

heterodienophile
X = O, N

diene

hDA adduct

Scheme 12. General reaction for hetero Diels-Alder reaction
First hetero Diels-Alder reaction was reported by Thomas R. Steadman23 in 1948 using
methylpentadiene act as a diene and formaldehyde act as dienophile in the presence of 185 oC in
6.5 h to provide the 2,4-dimethyl-5,6-dihydro-1,2-pyran with yield (61%, Scheme 13).
hetero Diels-AlderreactionO+O

185 oC, 6.5 h,methylpentadiene

formadehyde

2,4-dimethyl-5,6dihyo-1,2-pyran
61%

Scheme 13. hetero Diels-Alder reaction
2.4.1 Enantioselective oxa Diels-Alder reaction
Xiao and co-workers24 reported the first organocatalytic oxa Diels-Alder reaction of a, bunsaturated ketones with aldehydes to afforded the tethahydropyran-4-ones with good chemicalyield up to 80% and diastereoselectivity up to 95:5 (scheme 14). Followed by they explored using
amine organocatalyst for enantioselective reaction of a, b-unsaturated ketone with nitro
benzaldehyde to afforded the tethahydropyran-4-ones (up to 45%, up to dr 77:23, up to 40% ee,
Scheme 15).
O+R1unsaturated
ketones
R1 = alkyl, aryl

R 2CHOO

pyrrolidine (30 mol%)
AcOH (30 mol%)
CH2Cl2 (1.0 M), rt, 24 h
R1aldehydesOR2

tetrahydropyran-4-one
up to 80%
chemoselectivity up to 85:15
dr up to 90:10 to

R 2 = aryl

Scheme 14. Pyrrolidine organocatalyzed oxa Diels-Alder reaction

19

O

O
N
H

O

HN

amine
organocatalyst(20 mol%)
AcOH (20 mol%)CHO+

THF (1.0 M), rt, 72 h

NH

Ph

amine
organocatalyst

O

Ph

O

NO 2

α,β-unsaturated
ketoneNO 2

nitro
benzaldehyde

tetrahydropyran-4-one
up to 45%
dr 77:23, up to 40% ee

Scheme 15. Amine organocatalyst for enantioselective oxa Diels-Alder reaction
Wang and co-workers25 developed the oxa Diels-Alder reaction of isatins with enones in thepresence of dienamine and metal Lewis acid to afforded the spirooxindole tetrahydropyaranones
with good chemical yield and stereoselectivities (up to 86%, up to dr 85:15, up to 81% ee, Scheme
16).

N
HN
N
H
dienamineorganocatalyst
O

R1

O
N
H

isatins
R1 = alkyl, aryl

R2

dienamineorganocatalyst(20 mol%)Yb(OTf)3 (10 mol%)O

O+

CH2Cl2 (1.0 M), rt, 4 d

R2enonesR 2 = alkyl, aryl

O

O
R1

O
N
H

up to 86%
up to dr 85:15, up to 81% ee

Scheme 16. Dienamine and metal Lewis acid organocatalyst for enantioselective oxa DielsAlder reaction
Tanaka and co-workers19 developed the oxa Diels-Alder reaction of isatins with enones using
three component catalyst system to afforded the chiral spiro oxindole tetrahydropyaranones withexcellent chemical yield (up to 92%) and excellent stereoselectivities (up to dr 95:5, up to 94% ee,
Scheme 17). The provided chiral spiro oxindole tetrahydropyaranones is synthetic precursor for
making many biological active compounds.

20Three component catalyst system
CF 3

CF 3

O tBu

N

S
COOH

NH 2

NHBoc

N
chinchonaorganocatalyst

F 3C

N
H

N-boc amino acidco-catalyst

N
H

CF 3

thiourea
co-catalyst

R2
O

O

R1

O
N
H

isatins
R1 = alkyl, halogen

+

CH 3

three component
catalyst system

O

toluene, 48 h, rt

O

O
N
H
chiralspirooxindoletetrahydropyranones
up to 92%
up to dr 95:5, up to 94% ee
R1

R2

enonesR 2 = alkyl, aryl

Scheme 17. Three component catalyst system for enantioselective oxa Diels-Alder reaction
2.5 Author strategy
Author aimed to develop the simple b-amino alcohol and derivatives organocatalysts (Figure11). It has easy to synthesis from the commercially available amino acids, inexpensive than others
like cinchona derived primary organocatalyst and stability towards the air and moisture. simple bamino alcohol possess covalent site for enamine formation, non-covalent site for hydrogen bondformation and a, b-substitution act as steric influence sites in single molecules. Most recently,
author developed the simple b-amino alcohol organocatalysts and the utility of this organocatalyst
explored the asymmetric hetero Diels-Alder reaction of isatins with enones to afforded the chiralspiro oxindole tetrahydropyaranones. The obtained product is used in synthetic precursor for
preparing many biologically active compounds.
steric influence sites
O
R

R'

OH

R

NH 2
amino acids
R = alkyl, aryl

covalent site
(enamine formation)

*
NH 2

R'
OH

non-covalent site
(hydrogen bonding)

Functionality of β-amino alcoholorganocatalysts

Figure 11. Functionality of b-amino alcohol organocatalysts

21

To further activity of simple b-amino alcohol organocatalysts, author examined the asymmetrichetero Diels-Alder reaction of isatin with enones using b-amino alcohol organocatalysts. As aconcept of the enantioselectivity in this reaction using b-amino alcohol organocatalysts, thereaction might be proceeding via transition state I, the first amino alcohol react with enones toform diene (Scheme 18).
O

O
+

O

R'
N
H
isatins X

R"enones Y

R'

O tBu

N

R

COOH
NH 2
N

A
catalyst

NHBoc
B
co-catalyst

CF 3

CF 3

*

R'
OH

NH 2
D
catalyst
O
R'

S
F 3C

N
H

OH
NHR

N
H

E
amino acidco-catalysts

CF 3C
co-catalyst
two component
catalytic systemthree component
catalytic systemco-cat. OtBu
N H

cat.
A'

O

N

R'

X

O
H

H

N

N

C
Ar

S co-cat.

cat.
O
H
D'

R''

R''

O

R

R

OtBu

RN

Ar

H
R

O B
CH 3

O

H
N
H

HN

O

H
R''

RN

O

R'

O
N
R
Z
chiralspirooxindoletetrhydropyranones

N

O

R'

H

X

O
H

O

NR

O
R'

E
co-cat.

transition state I

transition state II

Tanaka's

our approach

Scheme 18. Concept of b-amino alcohol organocatalysts for asymmetric hetero Diels-Alderreaction.

22

then isatin second oxygen atom make hydrogen bond interaction with acid group for N-protectedamino acid and third oxygen make hydrogen bond interaction nitrogen atom of protected aminoacid. The dienophile attack from the less steric hinderance side of diene intermediate to furnish thechiral spirooxindoles tetrahydropyranones. The simple b -amino alcohol organocatalysts has both
covalent site for making enamine formation and non-covalent site for making hydrogen bond in asingle molecule showed the catalytic activity in asymmetric hetero Diels-Alder reaction of isatinwith enones to afforded the chiral spirooxindole tetrahydropyaranones.

23

2.7 Result and discussions
2.7.1 Synthesis of catalysts 2a-e
Author synthesized the simple b -amino alcohol organocatalysts 2a-e26 having no substitution
at primary alcohol a-position for freely react with substrate were prepared from the commerciallyavailable corresponding amino acids 1a-e by reduction of using lithium aluminium hydride(LiAlH4) or sodium borohydride (NaBH4)/iodine to afford the organocatalysts 2a-e (Scheme 19).
LiAlH 4or
NaBH 4/ I 2

O
R

OH
NH 2

0 °C to reflux
over night

2a-eamino acids

β-amino alcoholOH

2a: 85%

OH
NH 2

1a-e

OH
NH 2

R

THF

OH

NH 2

NH 2

2b: 90%2c: 91%

OH
OH

NH 2
NH 2

2e: 92%

2d: 92%

Scheme 19. Synthesis of b-amino alcohol organocatalysts 2a-e
2.7.2 Synthesis of catalysts 4a-e
Author synthesized the diphenyl b-amino alcohol organocatalysts 4a-e26 having diphenyl
substitution at primary a-position for steric factor were synthesized from corresponding aminoacid esters followed by Grignard reaction of using phenyl magnesium bromide to giveorganocatalysts 4a-e (Scheme 20).
O
R

O
OH

NH 2

SOCl2
MeOH
0 oC to rt
overnight

1a-eamino acids

Ph Ph

R

OMe
NH 2
.HCl

0 °C to rt
ether
overnight

OH

Ph Ph

OH
NH 2

NH 2

4a: 60%4b: 65%4c: 40%

Ph
OH

NH 2

Ph Ph

Ph Ph

OH

OH

NH 2

Ph

4a-e
β-amino alcohol

3a-eamino acid esters

Ph Ph

R

PhMgBr

OH

NH 2

NH 2

4d: 55%4e: 70%Scheme 20. Synthesis of b-amino alcohol organocatalysts 4a-e

24

2.7.3 Various co-catalyst 5a-k to the asymmetric hetero Diels-Alder reaction of isatin withenones
The co-catalysts are playing crucial role in this asymmetric hetero Diels Alder reaction toincrease the yield moreover with substrate to make more steric and hydrogen bond formation toprovide results. Here author examined the listed of co-catalyst such as achiral 5a-b, chiral of NBoc and N-Cbz amino acids 5c-g, organic acids 5h-j and thiourea 5k (Figure 12).

O

O

OH

OH
HN

NH 2

5a

HN

O
OH

OH

Cbz
5b

HN

O
OH

OH

HN

Boc
5c

Cbz
5d

O

O

HN

Boc
5e

O
OH

H 3C

OH

Ph

F 3C

OH

5g

5h

5j

5i

CF 3
S

OH

Boc

Cbz

5f

CF 3

O

HN

O

O

F 3C

N
H

N
H

CF 3

5k

Figure 12. Various co-catalyst 5a-k to the asymmetric hDA reaction
2.7.4 Optimized reaction condition for catalysts 2a-e and 4a-e in asymmetric hetero DielsAlder reaction
In first author examined simple amino alcohol organocatalyst 2a-e in asymmetric hetero DielsAlder reaction model substrate is isatin with 3-hepten-2-one 7a and N-Boc glycine 5c as a model
co-catalyst in the presence toluene at room temperature for 48 h in this reaction (entries 1-5) toafford the desired chiral spirooxindole tetrahydropyranones. All simple amino alcoholorganocatalyst 2a-e affords the desired chiral spirooxindole tetrahydropyranones with moderate togood chemical yield (16-86%), moderate to good diastereoselectivities (dr 50:50-80:20) andmoderate to excellent enantioselectivities (72-92% ee). Catalyst 2b having isopropyl group afford
the less chemical yield (16%, entry 2). In extension with using simple amino alcohol diphenylgroup contain at alpha position organocatalyst 4a-e at same reaction condition instead oforganocatalyst 2a-e to afford the desired product with less chemical yield (14-28%, entries 6-10),
moderate to good diastereoselectivities (dr 74:26-83:17) and less enantioselectivities (6-41% ee).
In contrast amino alcohol organocatalyst 4c having diphenyl group at a-position did not affords
the desired product because steric interaction between tert-butyl and diphenyl group. Concept ofin this reaction amino alcohol as organocatalyst and acid as co-catalyst in the same way to continue
25

tertiary leucine amino acid 1a has covalent site for enamine formation and acid group for making
hydrogen bond formation for expect in this reaction but did not afford the desired product. The
catalytic activity of amino acid 1a (L-tert-leucine) with the primary amino group for generating
diene species was also examined under the same reaction condition (entry 11). However, its
catalytic activity was not confirmed at all, for a reason that neutral amino acids exist in betaine
form which might not work for the generation of the diene species. Thus, amino alcohol alone
worked as a catalyst for almost completely shielding one side of the enantiotopic face when dieneattack to dienophile. These results indicated the necessity of our two catalysts component systemcomprising of amino alcohol catalyst for generating diene species and for controllingstereoselective reaction course and amino acid co-catalyst for activating isatin dienophile. These
results indicated the necessity of our two catalysts component system comprising of amino alcohol
catalyst for generating diene species and for controlling stereoselective reaction course and aminoacid co-catalyst for activating isatin dienophile. The best organocatalyst is 2c, from 2a-e, 4a-e.
Author examined the one catalyst system using 2c for in this reaction to furnish the desired the
product with less chemical yield (14%, entry12), good diastereoselectivities (dr 85:15) andexcellent enantioselectivity (92% ee).
Next, author tried the co-catalyst screening for in this reaction using best organocatalyst 2c withco-catalysts 5a-b, 5d-k. Catalyst 2c with unprotected glycine to afford the desired product withless chemical yield (14%, entry 13), moderate diastereoselectivity (dr 75:25) and excellent
diastereoselectivity (95% ee). This system also same like one catalyst system. Next, tried with cocatalyst N-Cbz glycine 5b to affords the desired product with god chemical yield (80%, entry 14)
with good diastereoselectivity (dr 79:21) and excellent diastereoselectivity (91% ee). And also
examine with chiral N-protected amino acid as co-catalyst 5d-g to affords the desired product withgood to excellent chemical yield (61-97%, entries 15-18), good diastereoselectivities (dr 72:2882:18) and good enantioselectivities (84-88% ee). Next, tried with simple acid like acetic acid 5h,
benzoic acid 5i to affords the desired product with good chemical yield (68%, entry 19-20), good
diastereoselectivities (dr 75:25-84:16) and good enantioselectivities (86-87% ee). strong trifluoro
acetic acid 5j did not furnish the desired product. Next tried with thiourea 5k to afford the desired
product with less chemical yield (19%, entry 22), good diastereoselectivity (dr 73:27) and goodenantioselectivity (75% ee). Moreover, three catalysts component system of catalyst 2c and cocatalysts of both amino acid 5c and thiourea 5k also to affords the product (85%), good26

diastereoselectivity (dr 75:25) and good enantioselectivity (82% ee). This three component catalyst
showed less activity than two component system.
Furthermore, the best catalyst 2c and co-catalyst 5c conducted different reaction condition at 0
°C to afford low chemical yield 56% (entry 25) as compared with room temperature condition.
Next, examined the molar ratio of catalyst 2c and co-catalyst 5c in this reaction of 6a with 7a (4equiv) at room temperature (entries 26-30) to furnish the good chemical yield (52-60%), good
diastereoselectivities (dr 78:22-81:19) and good enantioselectivities (87-89% ee). However,chemical yields comparatively decreased when the reaction was carried out under the molar ratioof 20 mol% of catalyst 2c and 40 mol% of co-catalyst 5c (entry 3).
Table 1. Asymmetric hetero Diels-Alder reaction of catalysts 2a-e, 4a-e and co-catalysts 5a-k
O

O
O
N
H

+

catalyst
2a-e or 4a-e
co-catalyst
5a-ktoluene
48 h

O

2'

O
N
H
[2'S ,6'R]-8a

7a

6a

O

6'

entry

enone 7a(eq.)

catalyst
2a-f, 4a-e
(20 mol%)co-catalyst
5a-k(40 mol%)

temp.

yield
(%) a

drb

ee
(%) c

1

4

2a

c

rt

66

55:45

72

2

4

2b

c

rt

16

75:25

86

3

4

2c

c

rt

86

80:20

92

4

4

2d

c

rt

78

64:36

81

5

4

2e

c

rt

61

50:50

88

6

4

4a

c

rt

18

74:26

41

7

4

4b

c

rt

14

75:25

24

8

4

4c

-----

rt

trace

-----

-----

9

4

4d

c

rt

28

83:17

14

10

4

4e

c

rt

24

78:22

6

11

4

1c

-----

rt

trace

-----

-----

12

4

2c

-----

rt

15

85:15

92

continue to next page

27

13

4

2c

a

rt

14

75:25

95

14

4

2c

b

rt

80

79:21

91

15

4

2c

d

rt

61

82:18

88

16

4

2c

e

rt

87

81:19

87

17

4

2c

f

rt

90

82:18

88

18

4

2c

g

rt

97

75:25

84

19

4

2c

h

rt

68

75:25

86

20

4

2c

i

rt

68

84:16

87

21

4

2c

j

rt

trace

-----

-----

22

4

2c

k

rt

19

73:27

75

23

2

2c

c

rt

47

77:23

90

24

1

2c

c

rt

17

73:27

89

25

4

2c

c

0 °C

56

81:19

93

26

4

2c
(20 mol %)c(20 mol %)

rt

54

78:22

89

27

4

2c
(20 mol %)c(10 mol %)

rt

52

79:21

87

28

4

2c
(10 mol %)c(10 mol %)

rt

54

78:22

89

29

4

2c
(10 mol %)c(20 mol %)

rt

60

81:19

89

30

4

2c
(10 mol %)c(5 mol %)

rt

52

79:21

87

aIsolated yields. bDiastereoselectivity (dr) was determined by 1HNMR of the crude reaction mixture (major diastereomer: 8a).cTheee value were determined by HPLC using Daicel chiralpak IB column.

28

2.7.5 Solvent screening for asymmetric hetero Diels-Alder reaction using catalyst 2c and cocatalyst 5c.
Next, examined the effects of various solvents and the reaction times to this reaction with an
optimized catalyst combination of 2c (20 mol%) and 5c (40 mol%) at room temperature (Table 2).
As a result, aromatic solvents toluene, benzene, xylene (entries 1-3) performed better giving goodchemical yields (60-86%) Particularly, toluene was found to be effective in this reaction (entry 1).
Also examined the non-polar such as cyclohexane affords the moderate chemical yield (66%,entries 4), and hexane did not afford (entry 5). Next tried with etherate solvent diethyl ether anddiisopropylether and tetrahydrofuran to giving moderate chemical yields and stereoselectivities(40-68%, dr 77:23- 79:21, 82-90% ee). Furthermore, tried with and chlorinated solvent
dichloromethane, chloroform and dichloroethane to furnish chemical yields and stereoselectivities(entries 9-11, 34-75%, dr 77:23-84:16, 88-90% ee). In addition that tried with polar solventacetonitrile and methanol to giving less chemical yield (38-70%, entries 12,13) and satisfactorystereoselectivities (dr 68:32-75:25, 83-88% ee). Furthermore, no significant improvement inchemical yields and stereoselectivities was observed when the reaction times were shortened for
24 h and prolonged for 72 h and 96 h, respectively (entries 14-16). From these results, it was
revealed that the catalyst combination of simple catalyst 2c (20 mol %) and simple non-chiral NBoc-glycine 5c (40 mol %), toluene as solvent, room temperature and 48 h reaction time was best
reaction condition for this reaction. While this reaction also slightly afforded aldol product 9 which
is obtained by aldol reaction as a by-product. Similarly, This catalysts component system alsoslightly afforded similar aldol product 9 in low chemical yield (12%) and stereoselectivities (72:28
dr, 16% ee).

29

Table 2. Solvent screening for catalyst 2c and co-catalyst 5c

6a +

7a

catalyst 2c (20 mol%)co-catalyst 5c (40 mol%)[2'S,6'R]-8a
Major

entry

solvent

time (h)yield (%) adrbee (%) c

1

toluene

48

86

80:20

92

2

benzene

48

60

78:22

90

3

xylene

48

73

77:23

88

4

cyclohexane

48

66

74:26

89

5

hexane

48

trace

----

----

6

Et 2O

48

55

78:22

90

7

iPr 2O

48

68

77:23

89

8

THF

48

40

79:21

82

9

CH2Cl2

48

74

79:21

90

10

CHCl 3

48

34

84:16

92

11

C2H 4Cl2

48

75

77:23

88

12

CH 3CN

48

70

75:25

88

13

MeOH

48

38

68:32

83

14

toluene

24

73

79:21

90

15

toluene

72

86

78:22

86

16

toluene

96

76

78:22

86

17

neat

24

87

71:29

86

18

neat

48

75

68:32

82

aIsolated yields. bDiastereoselectivity (dr) was determined by 1HNMR of the crude reaction
mixture (major diastereomer: 8a). cThe ee value were determined by HPLC using Daicel
chiralpak IB column.

30

2.7.6 Substrate scope for asymmetric hetero Diels-Alder reaction using 6a-f and 7a-e.
After optimizing the reaction conditions, Next tried with application of using different isatin
substrate 6b-f and different enones 7a-e. First tried with electron donating group contain 5-Me
isatin 6b with 3-hepten-2-one 7a to furnish the desired chiral 5-Methyl spirooxindole
tetrahydropyranone with good chemical yield (71%), good diastereoselectivity dr 78:22 and goodenantioselectivity 86% ee. After that examined with isatin contain electron withdrawing groupbromine and chlorine at fourth position to affords the desired chiral 4-bromo and 4-chloro
spirooxindole tetrahydropyranone with moderate chemical yields (68-70%), did not afford thediastereoselectivities in this application and moderate enantioselectivities (56-66% ee) because it
make with steric repulse between the isatin. Next tried with isatin contain electron withdrawing
group bromine and chlorine at fifth and sixth position with moderate chemical yields (62-71%),
good diastereoselectivity (dr 78:22 )and good enantioselectivity 86-88% ee.
Furthermore, examined with long chain enone 3-decan-2-one 7b with isatin 6a to afford thedesired chiral product with good chemical yield 68%, good diastereoselectivity dr 81:19 and goodenantioselectivity 78% ee. In addition that examined with olefin contain enone 7c with isatin 6a
to afford the desired chiral product with low chemical yield 25%, good diastereoselectivity dr
70:30 and excellent enantioselectivity 93% ee. Moreover that examined with 5-methyl-3-hexen2-one 7d with isatin 6a to afford the desired chiral product with good chemical yield 66%,
moderate diastereoselectivity dr 52:48 and good enantioselectivity 88% ee. Next, tried withbenzalacetone 7e with isatin 6a did not afford the desired product.
Moreover, author examined the gram scale reaction of isatin 6a with 3-hepten-2-one 7a using
optimized two component catalytic system catalyst 2c and co-catalyst 5c. As a result, the HDA
adduct 8a was successfully obtained with 87% chemical yield with good s good enantioselectivity(dr 80:20) and good enantioselectivity (85% ee). In overall the reaction carried out small scale togram scale the desired product was formation slightly decrease was observed.

31

Table 3. Substrate scope for asymmetric HDA reaction

OR

catalyst 2c(20 mol %)co-catalyst 5c(40 mol %)

O
O

+

R1

N
H

7a-e
R1

6b-f
R

1

toluene
rt
48 h

R

8b-j

yield (%) adrbee (%) c

71

78:22

86

70

-----

56

68

-----

66

71

78:22

88

62

78:22

86

68

81:19

78

O

O

O
O

N
H

N
H
8b

7a

6b

O

O

Br

2

O

O

O

O

N
H

N
H

7a

6c

Cl

8c
O

O

Cl

3

O

O

O

O

N
H

N
H

7a

6c

8d
O

O
Br
4

Br

O

O

O
O

N
H

N
H

7a

6d

8e

O

O

O

O

5

O
O

N
H

Cl

O
N
H
8b-j

O

O

Br

O

O

7a-e

6a-f

entry

R2

N
H

Cl
7a

6e

8f
O

O

O

O

6

O
O

N
H
6a

N
H

8g

7b

continue to next page

32

O
O

O

O

7

O

70:30

93

66

52:48

88

-----

-----

-----

N
H
8h

7c

6a

O

O
8

25
O

N
H

O

O

O
N
H

O
N
H

6a

7d

8i
Ph

O

O

O

O

9

O
N
H
6a

O

Ph

N
H

7e

8j

aIsolated yields. bDiastereoselectivity (dr) was determined by 1HNMR of the crude reaction mixture (major diastereomer:8a).cThe ee value were determined by HPLC using Daicel chiralpak IB column.

33

2.7.7 Plausible Reaction mechanism for hetero Diels-Alder reaction using 6a and 7a with 2cand 5cBased on the observed highly highly enantiopurity of the obtained HDA adduct [2S,6R]-8a (rt:92% ee, 0°C: 93% ee, entries 6 and 25, Table1), the model of the enantioselective reaction course
was proposed as shown in Scheme 4. First, the reaction of b-amino alcohol catalyst 2c with enone
7a forms the diene intermediate I-1 that has less steric interaction of between amino alcohol thatis fixed by intramolecular hydrogen bonding and substituted diene parts on generated diene I-1
than that of intermediate I-2. Furthermore, isatin 6a is activated by the two points of hydrogenbonding interactions with N-Boc amino acid co-catalyst 5c. Then, the reaction might proceed
through TS-1 to afford 8a that has a less steric interaction between I-1 and dienophile 6a thanthose of TS-2-4 to afford 8a’-8a’’ that have more steric interaction between I-1 and 6a. Thus,
diene I-1 might attack stereoselectively from less sterically hindered site of the incoming activatedisatin dienophile 6a to afford [2S,6R]-8a with excellent optically purity (92% ee). On the other
hand, it is also expected that the formation of adduct 8a via aldol reaction followed by oxa-Michael
addition may be minor pathway based on the chemical yield and enantioselectivity of the obtained
aldol product 9 and 8a was quite low (9: 12%, dr 72:28., 16% ee, 8a: 8%, dr 80:20., 86% ee,
Scheme 21).

34

O
H
OH

+
H

2c

6a, 5c

N

O

NH 2

H

N

O

H

asymmetric
HDA reaction

O

major
pathway

N
H

N
H

9
12%, dr = 72:28
11% eeminor
pathway

I-2

I-1
favor

O

aldol
reaction

H

7a

O

HO

H

oxa-Michael
reaction

2c, 5cO
O

BocHN[2'S,6'R]-8a

OH

8%, dr = 80:20
86% ee

5c

6a

H

O
H

N

HN

H
HN

H

O

O

H

H

O

N

O
H

O

N
H

H

O

O

H

H O
N
O

O
H

O
O H

H
N
N
H
HN

O

O

H

O

O

O

O

H

H N
O
H

O

H N

N
H

O

TS-1 favor

TS-2

TS-3

TS-4

92% ee

O

6'

O 2'

O

O

O

O

O

O
N
H

[2'S,6'R]-8a

O

O
O

O

N
H

N
H

N
H

[2'R,6'S]-8a'[2'R,6'R]-8a''[2'S,6'S]-8a'''Scheme 21. Plausible reaction course for asymmetric hDA reaction

35

O2.5 Summary
In summary, author developed a simple two catalysts component system consisting of primaryb-amino alcohol 2c as a catalyst and N-protected amino acid 5c as a co-catalyst for the asymmetrichDA reaction of isatins with enones for the first time. This two component catalytic system showed
excellent catalytic activity to afford the chiral spirooxindole-tetrahydropyranones 8a-j. The
obtained chiral spirooxindole-tetrahydropyranones are efficient synthetic intermediates for
preparing many biologically active compounds and drug discovery, in good chemical yields (upto 86%), good diastereoselectivities (up to dr 85:15 ) and excellent enantioselectivities (up to 95%
ee). Moreover, the single simple b-amino alcohol catalyst 2c has tert-butyl also showed good
catalytic activity for affording 8a with an excellent enantioselectivity (92% ee) and chemical yield
was very low.
R1
O

O

R

O
N
H
6a-f
isatins+
R1

catalyst
2a-e or 4a-e
co-catalyst
5a-k

7a-e
enones

O

O

R

O
N
H
8a-j
chiral spirooxindoletetrhydrapyranones

up to 86%
up to dr 85:15, up to 95% ee

36Chapter 3
Simple amino silyl ether organocatalyst for asymmetric hetero Diels-Alderreaction of isatins with enones

37

3. Simple amino silyl ether organocatalyst for asymmetric hetero Diels-Alderreaction of isatins with enones
3.1 Author project
Author aimed to develop the further expand study of simple b-amino alcohol organocatalyst to
simple b-amino silyl ether organocatalyst component system for asymmetric hDA reaction of
isatins with enones to afford the chiral spirooxindole tetrahydropyranones. The function of amino
silyl ether organocatalyst having covalent site (enamine formation), a, b and alcohol protected
like silyl group act as steric influence site in a single molecule (Figure 13).

steric influence sites

R

R'

R'

*

O SiR''

NH 2
covalent site
(enamine formation)
Functionality of β-amino silyl
ether organocatalysts

Figure 13. Functionality of b-amino silyl ether organocatalysts
3.2 Author strategy
Author aimed to develop the simple b-amino silyl ether and derivatives organocatalyst (Figure14). It is synthesis from the b-amino alcohol and stability towards the air and moisture. simple bamino silyl ether possess covalent site for enamine formation and remaining substitution act assteric influence site in single molecule. Most recently, author developed the simple b-amino silyl
ether organocatalysts and the utility of this organocatalyst explored the asymmetric hetero DielsAlder reaction of isatins with enones to afforded the chiral spirooxindole tetrahydropyaranones.

38

steric influence sites

R'

R

R'
OH

R

R'

R'

*

O SiR''

NH 2

NH 2

β-amino alcohol
R = alkyl, aryl
R' = Phcovalent site
(enamine formation)
Functionality of β-amino silyl
ether organocatalysts

Figure 14. Functionality of b-amino silyl ether organocatalysts
To further activity of b-amino silyl ether organocatalysts, author tried to compare asymmetrichDA reaction of isatin with enones using b-amino alcohol and b-amino silyl ether organocatalysts(Scheme 22). As a concept of the enantioselectivity in this reaction using b-amino alcohol proceed
via transition state I and b-amino silyl organocatalysts might be proceeding via transition state II,
the first amino silyl ether react with enones to make act as diene. The second oxygen atom on
isatin make hydrogen bond interaction with acid group for N-protected amino acid. The dienophileattack from the less sterichinderance side of diene intermediate to furnish the chiral spirooxindoles
tetrahydropyranones.

39

O

O
O

R1

+

N
H

R2
enonesisatins

R'

R

*

R'
OH

R'

O
R'

R
OH

NH 2

NHR

NH 2

catalyst

amino acidco-catalysts

catalyst

*

OH

NHR
amino acidco-catalysts

R

R'

cat.R

R'

cat.

O
R'

β-amino silyl etherorganocatalyst

β-amino alcoholorganocatalyst

H

*

R'
OSiR"

N
O

H

H
RN
O

H

O
NR

O
R'

co-cat.

R1

R'
SiR"

H

R"'
O

O

X

H

O

R2

R'

R'
O

N

O

R''

H

O
N
H
chiralspirooxindoletetrhydropyranones

transition state I

N
H

O

R"H
H
O
RN
O
R'

transition state II

Scheme 22. Concept of amino silyl ether in asymmetric hDA reaction

40

co-cat.

3.3 Result and discussions
3.3.1 Preparation of simple amino silyl ether organocatalysts 10a-o
The desired amino silyl ethers 10a-o27 having several silyl groups on oxygen atom at a-position
were easily prepared by the reactions of the corresponding b-amino alcohols 9a-o with XCl [X=TMS(trimethylsilyl),

TES(triethylsilyl),

TIPS(triisopropylsilyl),

TBDMS(tert-

butyldimethylsilyl)], respectively, in good yields (Scheme 2). Furthermore, the bulkiest b-amino
silyl ether catalyst 2o having a super silyl [tris(trimethylsilyl)silyl: TTMSS] group on oxygen atom
was also easily prepared from the reaction of the corresponding amino alcohols with TTMSSCl inmoderate to good yields. Furthermore, several N-Cbz- and N-Boc-amino acids 11a-s as cocatalysts were also easily derived from the corresponding commercially available non-protected
acyclic and cyclic amino acids, respectively (Scheme 23).

R1

R2

R 3OTf
or
R 3Cl
Et 3N

R2
OH

-30 oC to rt
0 oC to rt
CH2Cl2, 24 h

NH 2

9a-o
R1 = alkyl, aryl
R 2= H, aryl

O Si

R1

R2

R2

O SiR 3
NH 2

10a-o

R 3 = TMS, TES, TIPS,TPDMS,TTMSSO

O Si

O Si

O Si

Ph

O Si

NH 2

NH 2

NH 2

NH 2

NH 2

10a: 88%

10b: 90%

10c: 80%

10d: 85%

10e: 89%

Ph

Ph

Ph

Ph

O Si

Ph
O Si

Ph

Ph
O Si

O Si

Ph
Ph

Ph
O Si

NH 2

NH 2

NH 2

NH 2

NH 2

10f: 84%

10g: 80%

10h: 76%

10i: 80%

10j: 68%

Ph

Ph

NH 2

NH 2

NH 2

NH 2

Si
O Si Si
NH 2
Si

10k: 46%

10l: 89%

10m: 90%

10n: 89%

10o: 90%

Ph

O Si

Ph

O Si

Ph

O Si

Ph

O Si

Scheme 23. Preparation of organocatalysts 10a-o

41Ph3.3.2 Various co-catalysts 5b-c, 5h-j, 11a-n employed in asymmetric hetero Diels-Alderreaction
The co-catalysts are participating essential role in asymmetric hetero Diels-Alder reaction toincrease the yields and stereoselectivities. Additionally, interact with substrate to make more stericand hydrogen bond formation to afford them products. Here author listed the achiral 5b-c,
carboxylic acid 5i, 11a-g, organic acids 5h, 5j, chiral of N-Boc and N-Cbz amino acids 11h-n(Figure 15).
O

O
OH

HN

OH
HN

Boc

O

O

OH

OH
O2N

Cbz

5c

OH

11b

11a

O
O

OH
F

5i

5b

O

O

OH

O

O

OH

OH

OH

H 3C

11d

11c

O
H 3C

11e

O

O
OH

F 3C

5h

NH

O
N
Boc

11k

NH

Boc
11h

5j

OH

OH

N
Boc

O

Boc

11i

O
N
Cbz

11g

O
OH

OH

11f

O
N
Cbz

OH

11l

11m

OH

OH

11j

O
N
Boc OH

11n

Figure 15. Various co-catalysts 5b-c, 5h-j, 11a-n employed in asymmetric hDA reaction

42

3.3.3 Screening of catalyst 10a-o in asymmetric hetero Diels-Alder reaction
Author first examined the hDA reaction of isatin 6a as a dienophile with heptene-2-one 7a as adiene using the combinations of simple b-amino silyl ether organocatalysts 10a-f with primary
trimethylsiloxy (TMS) methyl or 10g-o with bulkier TMS diphenylmethyl groups (20 mol %) withthe simplest N-Boc-amino acid 5c as a previous work best co-catalyst (40 mol %) at room
temperature for 48 h (Table 4). As a result, every amino silyl ethers 10a-f showed catalytic
activities in this reaction and the corresponding HDA adduct [2’S,6’R]-8a was obtained in goodenantioselectivities (72-85% ee) and with moderate diastereoselectivities (dr 53:47-67:33),
although the chemical yield was the range of extremely low to good (2-77%, entries 1-6). In
contrast catalyst 10d contain tert-butyl bulky substituent and Trimethyl silyloxy (TMS) act as moresteric hinderance because of that to afford the very low chemical yield (2%). Among these catalysts,
the uses of catalysts 10e, and 10f having Bn and Ph bulkier substituents at b-position provides
better catalytic activity (entries 5 and 6).

43

Table 4. Asymmetric hetero Diels-Alder reaction of catalyst 10a-o and co-catalyst 5c

O

O
O
N
H

catalyst 10a-ococatalyst 5c+

Otoluenert, 48 h

6a

N
H

7a
catalyst
10a-o(20 mol%)O

O[2S' 6R']-8a

co-catalyst(40 mol%)

yield
(%) a

drb

ee
(%) c

10a

5c

11

54:46

72

4

10b

5c

9

64:36

79

3

4

10c

5c

44

67:33

85

4

4

10d

5c

2

63:37

76

5

4

10e

5c

74

67:33

81

6

4

10f

5c

77

53:47

72

7

4

10e

----

31

56:44

59

8

4

10g

5c

2

65:35

40

9

4

10h

5c

trace

-----

-----

10

4

10i

5c

trace

-----

-----

11

4

10j

5c

trace

-----

-----

12

4

10k

5c

9

74:26

14

13

4

10l

5c

64

61:39

75

14

4

10m

5c

46

69:31

15

15

4

10n

5c

65

66:34

18

16

4

10o

5c

84

51:49

51

entry

enone 7a
(eq)

1

4

2

aIsolated yields. bDiastereoselectivity (dr) was determined by 1HNMR of the crude reaction mixture. cThe eevalue were determined by HPLC using Daicel chiralpak IB column.

Catalyst 10e having bulkier benzyl group provided the adduct 8a in good chemical yield (74%)
and enantioselectivity (81% ee) with moderate diastereoselectivity (67:33)(entry 5). It might befor a steric factor. In addition that, examined with single catalyst 10e at same reaction condition
without co-catalyst to furnish the desired product 8a with less chemical yield (31%), moderate
diastereoselectivity (dr 56:44) and moderate enantioselectivity (59% ee). On the other hand, the44

reactions using 10g-k with bulkier TMSO diphenyl groups hardly proceeded. Catalyst 10g and
10k affords the product 8a with very less chemical yields (2-9%) and enantioselectivity also
considerably decreased (14-40% ee, entries 8-12). Moreover, catalyst 10h-j did not afforded the
product 8a. Next, based on these best catalyst 10e results, the reaction using different catalysts 2lo having different silyl groups on oxygen atom and co-catalyst 11a were carried out under same
reaction condition. However, these catalysts 10l-o furnish the moderate to good chemical yield(46-84%, entry 13-16), moderate stereoselectivities (dr 51:49-61:39, 15-75% ee) bulkiest
protecting having catalyst 10l-o did not show better catalytic activity than 10e. From these results,
it was revealed that the best catalyst was b-amino silyl ether 10e with primary TMSO siloxy group.
This reaction using two catalysts component system by our group mainly afforded HDA
adducts 8a, which was obtained by concerted HDA cycloaddition, while this reaction also slightly
afforded aldol product 9, which is obtained by aldol reaction as a by-product. Similarly, thiscatalysts component system also slightly afforded similar aldol product 9 in low chemical yield(10%) and enantioselectivity (9% ee) than previous two-component system using b-amino alcoholorganocatalyst.

3.3.4 Screening of co-catalyst 5b, 5h-I, 11a-n using catalyst 10e in asymmetric hetero DielsAlder reaction.
Next examined this reaction using the combinations of superior catalyst 10e (20 mol%) withseveral acids 5b, 5h-j, 11a-n as co-catalysts (40 mol%) at room temperature for 48 h (Table 5).
First, the reactions using N-Cbz-amino acids 5b and also common aromatic or aliphatic acids 5hj, 11a-g as co-catalysts were carried out (entries 4–11). All co-catalysts 5b, 5h-j, 11a-g assisted
the progress of the reaction for affording chiral 8a with moderate to good chemical yields andstereoselectivities. However, bulkier aromatic acid 11f only afforded 8a in low chemical yields,
although moderate to good stereoselectivities was observed. Furthermore, strongest trifluoro acetic
acid (TFA) 5j did not work as a co-catalyst in this reaction condition (entry 13). Unfortunately,
these co-catalysts did not show better co-catalytic activity than the result of the combination of
catalyst 10e and co-catalyst 5c. Next, the reactions using chiral N-Boc- or N-Cbz-amino acids 11h,i as co-catalysts (40 mol%) were examined (entries 12,13). However, these co-catalysts 11h, i also
did not show better co-catalytic activity compared to the combination of catalyst 10e and cocatalyst 5c. Moreover, the utilities of combination of bulkier chiral N-Boc- or N-Cbz-prolines.

45

Table 5. asymmetric hetero Diels-Alder reaction of catalyst 10e and co-catalyst 5b, 5h-j, 11a-n
6a+catalyst 10e
cocatalyst 5b, 5h-j, 11a-n

7a[2S' 6R']-8a

solvent
temp, hentry

enone 7a(eq)

catalyst(20 mol%)co-catalyst
5b, 5h-j,
11b-s(40 mol%)

temp

yield
(%) a

drb

ee
(%) c

1

4

10e

5b

rt

69

65:35

82

2

4

10e

5i

rt

85

69:31

79

3

4

10e

11a

rt

76

68:22

79

4

4

10e

11b

rt

94

69:21

80

5

4

10e

11c

rt

85

70:30

78

6

4

10e

11d

rt

91

65:35

78

7

4

10e

11e

rt

90

68:32

80

8

4

10e

11f

rt

53

65:35

81

9

4

10e

11g

rt

80

67:33

80

10

4

10e

5h

rt

82

65:35

80

11

4

10e

5j

rt

trace

-----

-----

12

4

10e

11h

rt

79

76:24

80

13

4

10e

11i

rt

78

68:22

81

14

4

10e

11j

rt

85

77:23

82

15

4

10e

11k

rt

76

77:23

80

16

4

10e

11l

rt

79

67:33

81

17

4

10e

11m

rt

87

68:32

78

18

4

10e

11n

rt

75

57:43

78

19

4

10e

11j

0 oC

35

82:18

84

20

4

10e

11j

40 oC

79

77:23

76

aIsolated yields. bDiastereoselectivity (dr) was determined by 1HNMR of the crude reaction mixture.
cThe ee value were determined by HPLC using Daicel chiralpak IB column.

Co-catalyst 11j-m and N-Boc-piperidine 11n as a cyclic amino acid were also examined in thisreaction condition (entries 19–22). Similarly to the results of general amino acids 5b-c, 11h-i, andcommon organic acids 5i, 5j, 11a-g, these cyclic amino acids 11j-n also showed moderate to good46

catalytic activities for affording 8a in good chemical yields and stereoselectivities. Particular, NBoc-L-proline 11j showed best co-catalytic activity and afforded 8a in good chemical yield (85%,entry 14) and stereoselectivities( dr 77:23, 82% ee). However, the reaction of this combination of
10e with 11j at 0 °C brought about a large decrease in chemical yield up to 35% (entry 19),
although good stereoselectivity (dr 82:18 , 84% ee) were kept. On the other hand, the reaction at
40 °C afforded 8a in good chemical yield (79%, entry 20) and with stereoselectivity (dr 77:23,
76% ee). From these results, It was revealed that the combination of 10e with 11j was best
combination in this reaction.
3.3.5 Optimization of mole amount used for superior catalysts system and substrates.
Next, examined the molar ratio of catalyst 10e and co-catalyst 11j in this reaction of 6a (1equiv) with 7a (4 equiv.) at room temperature (entries 1-5, Table X) to afford the product 8a with
low to good chemical yield (17-85%) Satisfactory enantioselectivities (79-83% ee) and good
diastereoselectivities( dr 69:31-75:25%) were confirmed under all of the molar ratios of 10e and11j. However, chemical yields comparatively decreased when the reaction was carried out under
the use of 10 mol% of catalyst 10e (entry 6). Next, the ratio of substrate amounts 6a and 7a were
examined in the presence of optimized 10e (20 mol%) and co-catalyst 11j (40 mol%) under same
reaction condition (Table 6). Good chemical yield (48-92%) and stereoselectivity (dr 70:30-78:22,
76-81% ee) were observed under the uses of all of ratios, but the use of 1 equiv. of 7a to 10ebrought about the decrease of chemical yield (48%).

47

Table 6. Optimization of asymmetric hetero Diels-Alder reaction of catalyst 10e and co-catalyst
11j

6a

+

7a

catalyst 10e
cocatalyst 11j
toluenert, 48 h[2S' 6'R]- 8aentry

enone 7a(eq)

catalyst
10e

co-catalyst
11j

yield
(%) a

drb

ee
(%) c

1

4

20 mol%20 mol%

85

75:25

80

2

4

20 mol%10 mol%

82

72:28

79

3

4

10 mol%10 mol%

30

71:29

82

4

4

10 mol%20 mol%

50

69:31

82

5

4

10 mol%5 mol%

17

72:28

83

6

1

20 mol%40 mol%

48

70:30

81

7

2

20 mol%40 mol%

78

78:22

79

8

3

20 mol%40 mol%

84

78:22

78

9

5

20 mol%40 mol%

92

76:24

76

aIsolated yields. bDiastereoselectivity (dr) was determined by 1HNMR of the crude reaction mixture .
cThe ee value were determined by HPLC using Daicel chiralpak IB column.

48

3.3.6 Solvent screening for catalyst 10e and co-catalyst 11j
Examined the effects of various solvents to this reaction with an optimized catalyst combinationof 10e (20 mol%) and 11j (40 mol%) at room temperature (Table 7). As a result, aromatic solvents
toluene, benzene, xylene performed better giving good to excellent chemical yields (85-92%) andstereoselectivities (dr 77:23, 77-82% ee ,entries 1-3). Also examined the non-polar like
cyclohexane and hexane to affords the good chemical yield (75-86%, entries 4-5), satisfactorystereoselectivities (dr 51:49-67:33, 64-74% ee), Next tried with etherate solvent diethyl ether anddiisopropylether to giving adequate yields and stereoselectivities (62-82%, dr 55:45, 71-75% ee).
Furthermore, tried with polar aprotic and chlorinated solvent tetrahydrofuran, dichloromethane,chloroform and dichloroethane to furnish chemical yields and stereoselectivities (entries 9-11, 7482%, dr 61:39-65:35, 78-70% ee). In addition that tried with polar solvent acetonitrile andmethanol to giving less chemical yield (25-30%, entries 12,13) and satisfactory stereoselectivities(
dr 53:47, 67-79% ee). Finally, examined the neat condition to affords the good chemical yield(82%, entry 13) and satisfactory stereoselectivity (dr 63:37, 73% ee). Particularly, toluene wasfound to be effective in this reaction (entry 1) for affording highly enantioselectivity. From theseresults, it was revealed that the catalyst combination of catalyst 10e having TMS protection andBn substituent at b-position (20 mol %) and simple chiral N-Boc-L-proline 11j (40 mol %) intoluene at room temperature for 48 h was found as best reaction condition to obtain chiral DA
adduct 8a (entry 1).

49

Table 7. Solvent screening for catalyst 10e and co-catalyst 11j
6a

+

7a

catalyst 10e
cocatalyst 11j
toluenert, 48 h[2S' 6R']-8a

entry

solvent

yield
(%) a

drb

ee
(%) c

1

toluene

85

77:23

82

2

benzene

92

77:23

77

3

Xylene

92

77:23

79

4

cyclohexane

86

51:49

74

5

hexane

75

67:33

64

6

Et 2O

62

67:33

75

7

iPr 2O

82

55:46

71

8

THF

35

70:30

74

9

CH2Cl2

82

61:39

78

10

CHCl 3

86

61:39

80

11

C2H 4Cl2

74

65:35

80

12

CH 3CN

30

53:47

79

13

MeOH

25

79:21

67

14

neat

82

63:37

73

aIsolated yields. bDiastereoselectivity (dr) was determined by 1HNMR of thecrude reaction mixture. cThe ee value were determined by HPLC using Daicel

chiralpak IB column.

3.3.7 Substrate scope for asymmetric hetero Diels-Alder reaction using 6b-f and 7b-e.
After optimizing the reaction conditions, examined the generality of the developed superior two
catalysts component system of 10e and 11j in the reactions of different isatins 6b-f with enones
7a-d (Table 8). This component system also showed catalytic activity in the reactions and afforded
the corresponding chiral spirooxindole-tetrahydropyranones 8b–i in moderate to good chemicalyields and stereoselectivities. However, the reactions of 6a with enones 7e having bulky phenylgroup hardly proceeded in this reaction condition to afford the corresponding adducts 8j
respectively.

50

Table 8. Substrates scope for asymmetric hetero Diels-Alder reaction
OR

catalyst 10e(20 mol %)co-catalyst 11j(40 mol %)

O
O

+

R1

8b-i

O

drb

ee (%) c

81

73:27

83

82

>99:1

40

57

77:23

43

92

77:23

77

90

63:37

84

76

78:22

78

O

N
H

N
H
8b

7a

6b

O

O

Br

2

O

O

O

O

N
H

N
H

7a

6c

8c
O

O

Cl

3

O

O

O

O

N
H

N
H

7a

6d

8d
O

O
Br
4

Br

O

O

O
O

N
H

N
H

7a

6d

8e

O

O

O

O

5

O
O

N
H

Cl

yield (%) a

O

O

Cl

N
H

O

O

Br

O

8b-j

7a-e
R1

6b-f
R

1

R

7a-e

6a-f

O

O

toluene
rt
48 h

N
H

entry

R2

N
H

Cl
7a

6e

8f
O

O

O

O

6

O
O

N
H
6f

N
H

8g

7b

continue to next page

51

O
O

O

O

7

O

91

64:36

85

77

55:45

81

trace

-----

-----

O

N
H

N
H
8h

7c

6a

O

O
8

O

O

O
N
H

O
N
H

6a

7d

8i
Ph

O

O

O

O

9

O
N
H
6a

O

Ph

N
H

7e

8j

aIsolated yields. bDiastereoselectivity (dr) was determined by 1HNMR of the crude reaction mixture . cThe ee value were

determined by HPLC using Daicel chiralpak IB column.

523.3.8 Plausible reaction mechanism for asymmetric hetero Diels-Alder reaction of isatin withenone using catalyst 10e and co-catalyst 11j
Based on the observed highly enantiopurity of the obtained hDA adduct [2S,6R]-8a (82% ee,
Table 4), the model of the enantioselective reaction course was proposed. First, the reaction of bamino silyl ether catalyst 10e with enone 7a forms the diene intermediate I-1 that has less stericinteraction of between amino silyl ether and substituted diene parts on generated diene I-1 thanthat of intermediate I-2. Furthermore, isatin 6a is activated by the two points of hydrogen bonding
interactions with N-Boc proline co-catalyst 11j. Then, the reaction might proceed through TS-1 toafford 6a that has a less steric interaction between I-1 and dienophile 7a than those of TS-2-TS-4
to afford 8a’-8a’’’ that have more steric interaction between I-1 and 6a. Thus, diene I-1 might
attack stereoselectively from less sterically hindered site of the incoming activated isatin
dienophile 7a to afford [2S,6R]- 8a with excellent optically purity (82% ee). On the other hand, it
is also expected that the formation of adduct 8a via aldol reaction followed by oxa-Michael
addition may be minor pathway based on the chemical yield and enantioselectivity of the obtained
aldol product 9 and 8a was quite low (9: 10%, 9% ee, 8a: 7%, dr 77:23, 77% ee, Scheme 24).

O
O
NH 2

Si

H

+

N
O H

10e, 11j
N
H

O

O

aldol
reaction

Si

Si

10e

O

HO

H

minor
pathway

7a
I-1
favor

I-2

asymmetrichDA reaction

O

major
pathway

N
H

N
Boc

6a

11j

N
H

9
10%, 9% ee
oxa-Michael
reaction[2'S,6'R]-8aOHO

10e, 11j

7%, dr 77:23, 77% ee

O

H

O

O

Si

N
O

Si

O
H

O

O

O

O

HN
O

H

H

O

HN

N
H

H

N
O H

O
O

H

O

TS-2

O

N
H

TS-4

TS-3

82% ee

O

6'

O 2'
O
N
H

[2'S,6'R]-8a

O

O

O

O

O

O

O
O

O

N
H

N
H

N
H

[2'R,6'S]-8a'[2'R,6'R]-8a''[2'S,6'S]-8a'''Scheme 24. Plausible reaction course for asymmetric hetero Diels Alder reaction.
53

N

O

H

O
Si

O

TS-1 favor

O

H

O
HN

O

O

O

Si
O

O

O

N

N
O H

N

H
N

O

3.4 Summary
In summary author developed a simple two catalysts component system consisting of primaryb-amino silyl ether 10e as a catalyst and N-Boc-proline 11j as a co-catalyst for the asymmetrichDA reaction of isatins with enones for the first time. This dual component system showed
efficient catalytic activity to afford the chiral spirooxindole-tetrahydropyranones 8a-i that are
efficient synthetic intermediates for many biologically active compounds and drug discovery, ingood chemical yields (up to 94%) and with enough stereoselectivities (up to dr 78: 22, 85% ee).
In addition, the independent use of simple b-amino silyl ether catalyst 10e also showed good
catalytic activity for affording 8a with an moderate enantioselectivity (59% ee), although chemicalyield was low.

R1
O

O

R

O
N
H
6a-f
isatins+

catalyst
10a-oco-catalyst
5b-c, 5h-j, 11a-n

R1
7a-d
enones

O

O

R

O
N
H
8a-i
chiral spirooxindoletetrhydrapyranones

up to 94%
up to dr 78:22, up to 85% ee

54

4. Conclusion
Many of the biologically active compounds are optically active. The way of biological systemsof human beings only one form of enantiomers plays key role in treatment of particular diseases.
Therefore, synthesis of optically active molecules is often more challenging task in the field ofsynthetic organic chemistry. The catalytic asymmetric synthesis is useful for the preparation of
biologically active molecules including a drugs. The enantioselective synthesis usingorganocatalysts is recognized as an independent synthetic tool besides asymmetric metal catalysis
and enzyme catalysis, and the catalysts are easy to handle even on large scale and relatively lesstoxic compared to transition metals. In the present thesis, author aimed to develop an efficient
simple b-amino alcohol and simple b-amino silyl ether organocatalysts for asymmetric reactions.
The simple amino alcohol organocatalysts were prepared by using with commercially available
corresponding amino acids. Simple b-amino silyl ether organocatalysts were prepared fromcorresponding amino alcohol. The simple amino alcohol catalysts possess with multiple activationsites in the molecule such as, covalent site for making enamine formation and non-covalent site
for making hydrogen bonding in single molecule. Simple b-amino silyl ether organocatalysts
having covalent site for making enamine formation. By these properties of simple b-amino alcoholand amino silyl ether organocatalysts enables the formation of covalent and non-covalentintermediates with wide-variety of the substrates and allows for enantioselective reactions. The
prepared amino alcohol and amino silyl ether organocatalysts successfully applied for asymmetrichetero Diels-Alder reaction (chapter 2 and 3).
In chapter 2, author discussed about the detailed application of simple b-amino alcoholorganocatalyst for asymmetric hetero Diels-Alder reaction. The simple organocatalysts 2a-e, 4a-e
were prepared and examined in asymmetric hetero Diels-Alder reaction of isatins 6a-f with enone
7. Among the prepared simple amino alcohol organocatalysts, the catalysts 2c has showed the best
catalytic activity to afford the chiral spirooxindole tetrahydropyaranones in good chemical yields
and stereoselectivities (up to 86%, up to dr 85:15, 95% ee). The obtained chiral spirooxindole
tetrahydropyaranones 8a-j are prominent synthetic intermediates for preparing many biologically
active compounds.

55

In chapter 2, author discussed about the detailed application of simple amino silyl etherorganocatalyst for asymmetric hetero Diels-Alder reaction. The simple organocatalysts 10a-o wereprepared and examined in asymmetric hetero Diels-Alder reaction of isatins 6a-f with enone 7.
Among the prepared simple amino alcohol organocatalysts, the catalysts 10e has showed the best
catalytic activity to afford the chiral spirooxindole tetrahydropyaranones in excellent chemicalyields and stereoselectivities (up to 94%, up to

dr 78:22, 85% ee). The obtained chiralspirooxindole tetrahydropyaranones 8a-i are prominent synthetic intermediates for preparing
many biologically active compounds.
In conclusion, author developed simple b-amino alcohol and b-amino silyl etherorganocatalysts. The prepared simple b-amino alcohol and b-amino silyl ether organocatalysts
successfully applied in asymmetric hetero Diels-Alder reaction which afforded the biologicalactive chiral synthetic intermediates in excellent chemical yields and enantioselectivities. It’s
expected that these results might be able to contribute greatly in the development of pharmaceuticaldrugs in the field of synthetic organic chemistry.
O

O

R

O

+

N
H
6a-f
isatins

R1
7a-e
enones

O

NH 2
2c

OTMS

OH

OH
HN

Boc
5c

two component system1

O

NH 2

N
Boc

10e

11j

OH

two component system 2

R1

R1
O

O

O

R

O

R

O
N
H
8a-j
chiral spirooxindoletetrhydrapyranones

O
N
H
8a-i
chiral spirooxindoletetrhydrapyranones

up to 86%
up to dr 85:15, up to 95% ee

up to 94%
up to dr 78:22, up to 85% ee

56

5. Experimental section
General information
All reagents and dry solvents were purchased from commercial vendors and used directly
without further purification. All reactions were placed in dried sample vials inserted with magnetic
beads. Thin-layer chromatography (TLC) was performed on Merck silica gel 60 F254 plates andthe analytes were identified under UV light. Flash column chromatography was performed using
silica gel pore size 60N (40-100 µm). Melting points were recorded with a micro-melting point
apparatus. IR spectra were recorded with a JASCO-4100 Fourier transform infrared
spectrophotometer. 1H and 13C NMR spectroscopic data were recorded using a JEOL JNMECA500 instrument with tetramethyl silane as the internal standard. HPLC data were collectedusing the TOSOH instrument equipped with (UV-8020, DP-8020, and SD-8022) detectors using
CHIRALPAK IB column. Optical rotations were recorded using a JASCO DIP-360 digitalpolarimeter. High-resolution mass spectrometry (HRMS) data were collected by electron impact(EI) modes using Hitachi RMG-GMG and JEOL JNX-DX303 sector instruments.

Chapter 2
Simple organocatalyst component system for asymmetric hetero Diels-Alder reaction of
isatins with enones
General procedure for the hetero Diels-Alder reaction of isatins (6a-f) with enones (7a-e)
R1
O

O

R

O
N
H
6a-f
isatins+
R1

catalyst
2a-e or 4a-e
co-catalyst
5a-k

7a-e
enones

O

O

R

O
N
H
8a-j
chiral spirooxindoletetrhydrapyranones

To a solution of the corresponding isatins 6a-f (0.2 mmol, 1 eq) and enones 7a-d (0.8 mmol,
4 eq.) in anhydrous toluene (0.3 mL) were added catalysts 2a-e, 4a-e (0.04 mmol, 20 mol%) andco-catalysts 5a-k (0.08 mmol, 40 mol%) at room temperature and the mixture were stirred at thattemperature for 48 h. The mixture was purified by flash column chromatography (SiO2,
hexane:ethyl acetate= 7:3) to afford the corresponding major hDA adducts 8a-i. The
57

diastereoselectivity of the obtained hDA adducts were determined by the crude reaction mixtureby 1H-NMR. The enantiomeric excess of 8a-i were determined by HPLC (CHIRALPAK-IB,
hexane/i-PrOH = 90:10, 70:30 and 0.6ml/min, 1.0ml/min, λ = 245 nm).19

Large scale synthesis of 8a using hetero Diels-Alder reaction of isatins (6a) with enones
(7a)
O
OH

OH
NH 2
2c
(20 mol %)

O
O

HN

Boc
5c
(40 mol %)catalyst system

O

O
O

+

O

N
H
6a
isatintolune, 48 h, rtNH
8a
87% yield,
dr = 80:20, 85% ee

7a
enone

To a solution of the corresponding isatins 6a (6.79 mmol, 1 eq) and enones 7a (27.1 mmol, 4eq) in anhydrous toluene (15 mL) were added catalysts 2c and (1.35 mmol, 20 mol%) and cocatalysts 5c (2.71 mmol, 40 mol%) at room temperature and the mixture were stirred at thattemperature for 48 h. The mixture was purified by column chromatography (SiO2, hexane:ethyl
acetate= 7:3) to afford the corresponding major hDA adducts 8a as a pale yellow amorphous solid(1.52g, 87% yield, dr 80:20 and major diastereomer 85% ee). The diastereoselectivity of theobtained hDA adducts were determined by the crude reaction mixture by 1H NMR. The
enantiomeric excess of 8a were determined by HPLC (CHIRALPAK-IB, hexane/i-PrOH = 90:10
1.0mL /min, λ = 245 nm).19

58

Chapter 3
Simple amino silyl ether organocatalyst for asymmetric hetero Diels-Alder reaction of
isatins with enones
General procedure for the hetero Diels-Alder reaction of isatins (6a-f) with enones (7a-d)
R1
O

O

R

O
N
H
6a-f
isatins+R

co-catalyst
5b-c, 5h-j, 11a-n

R1

O

O

catalyst
10a-o

7a-d
enonesONH
8a-ichiral spirooxindoletetrhydrapyranones

To a solution of the corresponding isatins 6a-f (0.2 mmol, 1 eq) and enones 7a-d (0.8 mmol,
4 eq) in anhydrous toluene (0.3 mL) were added catalysts 10a-o (0.04 mmol, 20 mol%) and cocatalysts 5b-c, 5h-j, 11a-n (0.08 mmol, 40 mol%) at room temperature and the mixture werestirred at that temperature for 48 h. The mixture was purified by flash column chromatography(SiO2, hexane:ethyl acetate= 7:3) to afford the corresponding major hDA adducts 8a-i. The
diastereoselectivity of the obtained hDA adducts were determined by the crude reaction mixtureby 1H-NMR. The enantiomeric excess of 8a-i were determined by HPLC (CHIRALPAK-IB,
hexane/i-PrOH = 90:10, 95:5 and 0.6mL, 1.0ml/min, λ = 245 nm).19

Large scale synthesis of 8a using hetero Diels-Alder reaction of isatins (6a) with enones
(7a)
OTMS
NH 2

O
O

OH

10e
11j
(20 mol %)(40 mol %)catalyst system

O

O
O

+

O

N
H
6a
isatinON
Boc

tolune, 48 h, rt
7a
enone

N
H
8a
88% yield,
dr = 78:22, 79% ee

59To a solution of the corresponding isatins 6a (6.79 mmol, 1 eq) and enones 7a (27.1 mmol, 4eq) in anhydrous toluene (15 mL) were added catalysts 10e and (1.35 mmol, 20 mol%) and cocatalysts 11j (2.71 mmol, 40 mol%) at room temperature and the mixture were stirred at thattemperature for 48 h. The mixture was diluted with ethyl acetate and washed with water. Separate
the organic layer dried with sodium sulphate. The mixture was purified by column chromatography(SiO2, hexane:ethyl acetate= 7:3) to afford the corresponding major hDA adducts 8a as a paleyellow amorphous solid (1.52g, 87% yield, dr 78:22 and major diastereomer 79% ee). The
diastereoselectivity of the obtained HDA adducts were determined by the crude reaction mixtureby 1H NMR. The enantiomeric excess of 8a were determined by HPLC (CHIRALPAK-IB,
hexane/i-PrOH = 90:10 and 0.6ml/min, λ = 254 nm).19

General procedure for synthesis of catalysts 10a-o:
To a solution of the corresponding amino alcohol 2a-e, 4a-e (6.79 mmol, 1 eq) in dry CH2Cl2 andcooled in 0 oC or -30 oC were added corresponding trialkyl silyl chloride or trifluoromethane
sulfonate (1.2 eq) and triethylamine (1.2 eq) for 10 mins under argon atmosphere. The solution
was stirred for 24 h at room temperature. Then reaction mixture was diluted with water andextracted with dichloromethane. Separate the organic layer dried with sodium sulphate. The
mixture was purified by flash column chromatography (SiO2, hexane:ethyl acetate= 7:3 andMeOH/CH2Cl2, 9:1) to give the corresponding amino silyl ether catalysts 10a-o.
(S)-1-phenyl-3-((triethylsilyl)oxy)propane-2-amine (10l): light yellow oil. 89% yield. [a]D24 =+6.24 (c = 0.48, DCM solvent). IR (neat): cm-1 = 3027, 2875, 1602, 1495,
Ph

OTES
NH 2

10l

1097, 794, 699.1H-NMR (500 MHz, CDCl3) δ 7.25-7.30 (m, 2H), 7.20 (td,J = 5.0, 2.1 Hz, 3H), 4.11 (s, 2H), 3.62 (q, J = 4.6 Hz, 1H), 3.49 (dd, J =9.7, 6.3 Hz, 1H), 3.21 (qd, J = 6.8, 4.3 Hz, 1H), 2.81 (dq, J = 46.5, 6.9 Hz,

2H), 0.87-0.99 (m, 9H), 0.56-0.63 (m, 6H). 13C-NMR (125 MHz, CDCl3) δ 138.31, 129.37, 128.61,
126.56, 77.41, 77.17, 76.91, 65.35, 54.62, 38.90, 6.90, 4.42. MS (FAB): m/z : 265 [M]+, HRMS
(FAB): calcd for C15H27NOSi m/z 265.47; found: 265.69.

60

(S)-1-phenyl-3-((triisopropylsilyl)oxy)propane-2-amine (10m): light yellow oil. 90% yield.
[a]D24 = +1.84 (c = 0.55, DCM solvent). IR (neat): cm-1 = 2941, 2864,
Ph

OTIPS
NH 2
10m

1558, 1105, 782, 700. 1H-NMR (500 MHz, CDCl3) δ 7.27-7.30 (m, 2H),
7.19-7.22 (m, 3H), 3.67 (q, J = 4.6 Hz, 1H), 3.56 (dd, J = 10.0, 6.0 Hz,
1H), 3.31 (s, 2H), 3.12-3.18 (m, 1H), 2.83 (q, J = 6.7 Hz, 1H), 2.66 (dd,J = 13.5, 7.7 Hz, 1H), 1.04-1.06 (m, 21H).13C-NMR (125 MHz,CDCl3) δ 138.26, 129.38, 128.68,
126.66, 77.39, 77.15, 76.89, 66.24, 54.89, 38.94, 18.06, 11.96. MS (FAB): m/z : 307 [M]+, HRMS
(FAB): calcd. for C18H33NOSi m/z 307.55; found: 307.64.
(S)-1-((1,1,1,1,3,3,3-heptamethyl-2-(trimethylsilyl)-1-trissilan-2-yl)oxy)3-phenylpropane-2amine- propane-2-amine (10o): Colourless liquid. 88% yield. [a]D24 = -17.24 (c = 0.58, DCM
solvent). IR (neat): cm-1 = 2947, 2892,1558,1540, 1070, 769, 699. 1HPh

OTTMSSNH 2

10o

NMR (500 MHz, CDCl3) δ 7.27-7.29 (m, 2H), 7.17-7.20 (m, 3H), 3.37
(q, J = 4.6 Hz, 1H), 3.31 (dd, J = 9.5, 6.6 Hz, 1H), 2.99-3.04 (m, 1H), 2.72
(q, J = 6.3 Hz, 1H), 2.54 (q, J = 6.9 Hz, 1H), 1.45 (d, J = 22.3 Hz, 2H),

0.17 (s, 27H).13C-NMR (125 MHz, CDCl3) δ 139.16, 129.38, 128.53, 126.31, 77.39, 77.15, 76.89,
71.98, 54.82, 40.47, 0.39. MS (FAB): m/z : 397 [M]+, HRMS (FAB): calcd. for C18H39NOSi4 m/z
397.86; found: 397.91.

61

6. Acknowledgements
Formost, I would like to express my gratitude to my supervisor Professor. Hiroto Nakano forgiving me opportunity and continuous support of my Ph. D study and research, for his patience,motivation, enthusiasm and immense knowledge. His guidance helped me in all the time ofresearch and writing thesis. I could not have imagined having advisor and mentor for my Ph. D
study.
I express my sincere thanks to Professor. Satomi Niwayama and Professor. Koji Uwai forsupporting me during my Ph. D study and thesis examination. I also, extend my acknowledgements
to all faculty members in the chemistry department for their kindness and timely help. I am grateful
thanks 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 scientificprograms and conferences. I would like to thank Eunsang Kwon and Yuko Okuyama for theircontinuous analytical support to my research work. I sincerely thanks to Chigusa Seki for her
kindness and timely help.
I would like to express my deepest gratitude to my beloved my mother and father and family
members supporting me spiritually throughout my life. Last but not least my words are insufficientto thank god almighty without whom anything is impossible by this little man as his ubiquitouspresence and omniscient role is gargantuan indeed.

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