エナンチオ選択的不斉反応に用いる新規アミノアミ
ド有機分子触媒の開発
メタデータ

言語: English
出版者:
公開日: 2019-06-25
キーワード (Ja):
キーワード (En):作成者: オウォラビ, イシアカ アラデ
メールアドレス:所属:

URL

https://doi.org/10.15118/00009910

THE DEVELOPMENT OF NEW AMINO AMIDEORGANOCATALYSTS FOR ENANTIOSELECTIVE
ASYMMETRIC REACTIONS
Thesissubmitted in partial fulfillment of the requirements
for the degree of
DOCTOR OF PHILOSOPHY
byIsiaka Alade Owolabi(16096010)
Supervisor
Professor Hiroto Nakano

DEPARTMENT OF APPLIED SCIENCESGRADUATE SCHOOL OF ENGINEERINGMURORAN INSTITUTE OF TECHNOLOGYMURORAN, JAPAN2019

TITLE:The Development of New Amino Amide Organocatalysts for Enantioselective Asymmetric
Reactions
(

	
 

NAME:
Isiaka Alade Owolabi)

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, easy to handle, and inexpensive, so they are being focused on as nextgeneration, environmentally friendly catalysts.
Author developed the new type amino amide organocatalyst. This catalyst is expected to work as
multipoint recognition catalyst having both covalent and non-covalent hydrogen bonding sites in the
single molecule. This catalyst was successfully derived from commercially available amino acids,
and the excellent catalytic activities were demonstrated in both (1) the aldol reaction and (2) the
Michael addition.
(1) The enantioselective asymmetric aldol reaction of ketones with aldehydes using amino
amide organocatalysts was carried out to provide chiral aldol products in excellent chemicalyields, diastereoselectivities and enantioselectivities. The obtained aldol products areimportant synthetic precursors of the synthesis of many biologically active compounds
including pharmaceuticals.
(2) The enantioselective asymmetric Michael reaction of β-keto esters with nitro olefins using
amino amide organocatalysts was carried out to provide chiral Michael adducts in excellent
chemical yields, diastereoselectivities and enantioselectivities. The obtained Michael
adducts with chiral quaternary carbon center are important synthetic precursors of thesynthesis of many biologically active compounds including pharmaceuticals such asplatencin (antibiotic).
In this study, author revealed that the new explored amino amide organocatalyst showedsatisfactory catalytic activities in both (1) the aldol reaction and (2) the Michael addition. It is
expected that this results should be able to greatly contribute the development of new drug and its
related compounds.

CONTENTS
Chapter 1 Introduction
1.1 Background
1.2 Catalysis
1.3 Organocatalysis field
1.3.1 Covalent organocatalyst
1.3.2 Non-covalent organocatalysis
1.4 Author approach

2
2
3
5
6
8

Chapter 2
A New Type Amino Amide Organocatalyzed Enantioselective Crossed Aldol Reaction of
Ketones with Aromatic Aldehydes
2.1. Background12
2.1.1 Mechanism
12
2.1.2 Enantioselective crossed Aldol reaction
13
2.1.3 Author approach
14
2.2 Results and discussions
16
2.2.1 Synthesis of new new type amino amide organocatalysts
162.2.2 Aldol reaction of cyclohexanone 63 with 4-nitrobenzaldehyde 64a using 62a-f
17
2.2.3 Optimization of Aldol reaction conditions using catalyst 62f
19
2.2.4 Generality of Aldol reaction of 63 with 64b-n catalyst 62c
212.2.5 Plausible transition model for enantioselective Aldol reaction
24
2.2.6 Summary28
Chapter 3
Amino Amide Organocatalysts for Asymmetric Michael Addition of β-Keto Esters with
β-Nitroolefin
3.1 Background3.1.1 Mechanism
3.1.2 Organocatalysis for Michael addition
3.1.3 Previous approaches on enantioselective Michael addition of β-keto esters with
β-nitroolefins
3.1.4 Author approach
3.2 Results and discussions
3.2.1 Asymmetric Michael reaction of β-keto esters 42 with β-nitroolefins 43 using
catalysts 62a-f and 70a-c
3.3 Summary

30
30
31
32
33
35
35
43

Conclusion

44

Experimental section

46

ACKNOWLEDGEMENT74

REFERENCES

75!

Chapter 1
Introduction

1Chapter 1
Introduction
1.1

Background

The importance of efficient enantioselective asymmetric reactions is one of the mostpromising and well-explored areas in synthetic organic chemistry. Because its discovery inenantiomerically catalyst can afford to achieve the high levels of stereocontrol for many
synthetic reactions. The organocatalysis does not involve any toxic metals or costly enzyme
catalysts to carry out the stereoselective organic reactions. From the last few years,
organocatalysis leading explored into one of the most attractive fields emerging in syntheticorganic chemistry.1 The enantioselective synthetic methods using organocatalysts provides apractical and cost-effective synthesis of chiral molecules but designing of simple and efficientorganocatalyst is interesting and often more challenging.
1.2

Catalysis

The study of the catalyst using an enantioselective asymmetric reaction is very importantfor our daily life. Because catalysts are needed in the production of therapeutic drugs. And, theworld is facing bigger crisis worsen to save humans from continually emerging of lifethreatening diseases. Hence, scientists are trying to find a new alternative gateway to treat,
reduce, and possibly finding a lasting solution to epidemic outbreaks of diseases and new drugs.
Therefore, there is a need to develop an enantioselective asymmetric synthesis for opticallybioactive compounds which can afford desirable optically active substances with highpharmaceutical values.
Catalysis can be classified as biocatalysis, transition-metal catalysis and organocatalysis.
Biocatalyst is natural catalysts such as enzymes and it performs chemical transformations onorganic compounds. Biocatalysis have complicated structures and can be difficult to separate
from the mass reactions. As a result, to predict its plausible mechanism might be a difficult
task. On the other hand, transition metal catalysis is a process of using metals as a catalyst.
However, there are general environmental concerns about the toxicity and disposal oforganometallic reagents, and toxicity of the residual metals in drugs which can creates a serious
health problem. So, there is a need to develop highly efficient environmentally friendly
catalysts and related catalytic reactions. As a catalyst, organocatalysis was first introduced by
Ostwald2-4 in 1900.
Over the last decade, organocatalysis has become one of the most promising, fascinating2

and rapid growth areas of study in organic chemistry.5,6 Because organocatalyst does notcontain a metal which in substoichiometric amounts accelerates the reaction.7 It usually has a
low molecular weight. The primary importance of organocatalyst is usually their lack ofsensitivity to moisture and oxygen, robust, inexpensive, readily available, non-toxic.8
Organocatalysts confer a huge key process for the chemical transformation of molecules forthe pharmaceutical intermediates, agrochemicals and exclusively chemical industries.
1.3

Organocatalysis field

Many different organocatalysts have been developed over the years and used fororganocatalysts and a variety of reactions.9 One of the simplest organocatalysts is L-proline,
which was introduced for asymmetric Aldol reactions by Eder and co-workers,10 and Hajos
and also Parrish.11 More recently List,12 MacMillan,13 Barbas14 and Jørgensen15 explored thecatalytic efficiency of proline and proline derivatives for asymmetric Friedel-Crafts
alkylation,16 Mannich reaction,17 Diels-Alder reaction,18 Alpha-halogenation19,20 and various
other transformations.
The Friedel-Crafts alkylation of N-methyl pyrrole 2 with methyl olefin 3 using MacMillan
catalyst afforded the corresponding pyrrolyl carbonyl product 4 in 83% yield and goodenantioselectivity in 91% ee (Scheme 1).16
O

Me
N Me
Me

N
Me
2

+

N
Bn
H
1
(20 mol%)
MeO
3

THF-H2O

O
N
H

Me
4
83% yield, 91% ee

Scheme 1. Organocatalyzed Friedel-Crafts alkylation reaction
The three-component system of the reaction between ketone 6 with aldehyde 7 and an amine
8 catalyzed by S-proline 5 was the first catalytic asymmetric and enantioselective Mannich
reaction. This reaction afforded the corresponding product 9 in moderate chemical yield but
excellent enantioselectively in (50% yield, 94% ee) (Scheme 2).17

3

CHO
O

NH2

+

OMe

5
(35 mol%)

+

6

CO2H

N
H

O

HN

DMSO

NO2
7

OMe
8

NO2
9
50% yield, 94% ee

Scheme 2. The first enantioselective asymmetric Mannich reaction
Macmillan and co-workers18 reported the first catalytic enantioselective Diels-Alder
cycloaddition of dienylamine 11 with ethyl vinyl ketone 12 using MacMillan catalyst andafforded the corresponding Diels-Alder product 13 in good yield and excellent
enantioselectivity (89%, 92% ee) (Scheme 3).
Me

NHCbz

O
+

N

Bn

N
H
10
(20 mol%)

Ph
H
COEt

HClO4, -30 0C

Et
11

O

NHCbz
13
89% yield, 92% ee

12Scheme 3. Organocatalyzed Diels-Alder cycloaddition of dienylaminewith ethyl vinyl ketone
Jørgensen and co-workers19 reported the first catalytic enantioselective a-chlorination ofaldehyde 15 with N-chlorosuccinimide (NCS) 16 using proline amide organocatalyst andafforded the corresponding product 17 with excellent yield and enantioselectivity (93%, 95%ee) (Scheme 4).
H O
N
H

O
H

+

NCS
16

15

NH2

14
(10 mol%)
CH2Cl2

O
H

*

Cl

17
93% yield, 95% ee

Scheme 4. The organocatalytic enantioselective a-chloronationof aldehyde

4Other examples of the catalytic efficiency of proline and derivatives A and B have also
reported (Figure 1).18,19

F3C
CF3
OTMS
N
H

CF3

N
H
F3C
A

B

MacMillans amine-catalyst

Hayashi-Jorgensen catalyst

Figure 1. The catalytic efficiency of proline
and derivatives
1.3.1

Covalent organocatalyst

Organocatalytic is classified into covalent and non-covalent catalysts. Covalentorganocatalysis forms a covalent bond between the catalysts and the substrate, leading to astrong interaction between the substrate and the reagent in the reaction. Covalent catalysis
enhances a higher level of stereocontrol. Because the catalyst is directly bonded with thesubstrate applying its chiral influence.
In covalent modes of activation iminium and enamine catalysis is well studied inenantioselective synthesis. The iminium catalysis involves the condensation of a secondaryamine catalyst with a carbonyl group containing substrate, which generates the electrophilic
iminium cation species which attacked by appropriate nucleophiles forms a chiral product(Scheme 5).21
N
R

N
R'

H
R
enamine species

iminium species

R

N

N

O

H
R'

O

N
R

R'

H

N

H

N

H
R

H
R

R

Nu

O
R
iminium catalysis

E

Nu
*

O
R'

H
enamine catalysis

*

E

R

Scheme 5. Covalent modes of activation in organocatalyst
5For examples, imidazolidone catalyst for Diels-Alder reactions using 2-methylfuran 19,
crotonaldehyde 20, and chlorinated quinone 21 and imidazolidinone catalyst 18 by MacMillans
and co-workers13 afforded the corresponding cascade product 22 with good yield andenantioselectivity (72% yield, 90% ee) (Scheme 6).
Me
N Me
Me
N
Ph
H
18
(20 mol%)
O

Me

O

O
Cl

19

Cl
Cl

+
Cl
Me

TFA, 40 oC

Cl

O

Me

O
O
Me

Cl

20

Cl

H

22
72% yield, 90% ee

21

Scheme 6. Organo-cascade type catalysis
Also, Ishimaru and co-workers22 developed L-valinamide with 2,6-difluorophenylamidegroup as an organocatalyst 23 for asymmetric crossed Aldol reaction of cyclohexanone 24 withisatin 25 and the catalyst afforded the corresponding Aldol product 26 with good yield andenantioselectivity (88% yield, 99% ee) (Scheme 7).

O F
H2N
O

O
+

24

O
N
H
25

NH
F
23
(25 mol%)
tBuOH

O
HO
O
N
H
26
88% yield, >99% ee

Scheme 7. Asymmetric cross-Aldol reaction of isatins with cyclohexanone
1.3.2

Non-covalent organocatalysis

Non-covalent organocatalysis formed hydrogen bond between a hydrogen atom and anelectronegative atom. The use of hydrogen bond in organic reaction has been widely
investigated, leading to the discovery of novel chiral organocatalysts for the enantioselective
transformations.23
Chiral hydrogen bonding catalysts act as a hydrogen bond donor toward an electronegativehydrogen bond acceptor (Scheme 8). The catalysts form a hydrogen bond complexes. The
hydrogen bonds are stronger than a van der Waals interaction but weaker than covalent or ionic6bonds. Generally, the combination of a neutral electrophile as an acceptor and a weak acidcatalyst as a donor leads to hydrogen bonding catalysis.24

R

O

H N

N R'

H

H
O

R
R'

R
H N

O

H

O

R

N R'

O

H N

H

H

R

O

N R'
Nu

H

R

O
R'

Nu *

R'

R
R'

Scheme 8. Non-Covalent modes of activation in organocatalyst
In 2004, Akiyama and co-workers25 reported Mannich reaction of 2-hydroxyphenyl imine
27 with silyl ketene acetal 28 using chiral Brønsted acid-catalyst 26 and afforded thecorresponding Mannich product 29 with excellent chemical yield and enantioselectivity (100%yield, 96% ee) (Scheme 9).

NO2

O

O
P

O

OH

HO

HO
OTMS

N

+
H

H

OEt

27
(10 mol%)

NO2
HN

toluene, -78 oC

CO2Et

Me
Me

28

29

30
100% yield, 96% ee

Scheme 9. Chiral Brønsted acid-catalyzed Mannich reaction of iminewith silyl ketene acetal

7

Shi and co-workers26 investigated the enantioselective cascade reaction of isocyanoacetate
31 with azodicarboxylate 32 catalyzed by Cinchona alkaloid squaramide catalyst 30 andafforded the corresponding optically active 1,2,4-triazoline products 34 in excellent yield andenantioselectivity (up to 98% yield, 97% ee) (Scheme 10).

F3C

O

O

N
H

HN

H

F3C
NC
N

+

CO2Me

t-BuO2C
32

N
OMe
N

CO2t-Bu31(3 mol%)N

N

CO2t-BuN CO t-Bu
2

N

CO2Me

CHCl3, 10 oC
33

34
98% yield, 97% ee

Scheme10. Cinchona alkaloid squaramide catalyzed enantioselective cascade reaction
Jacobsen and co-workers27 developed Thiourea-catalyst 34 for enantioselective Mannich
reaction of N-Boc imine 35 and silyl ketene acetal 36 and afforded the corresponding Mannich
product 37 in excellent yield and enantioselectivity (up to 99% yield, 98% ee) (Scheme 11).

S
Me

N
O

N
H

N
H

N
tBu

OH

N

Boc
OTBS
H

36

+
OiPr

35
(5 mol%)tBu

toluene, TFA, -30 oC

37

Boc

NH

O
OiPr

38
99% yield, 98% ee

Scheme 11. Thiourea-catalyst for enantioselective Mannich reaction

1.4

Author approach

Most recently, Ishimaru and co-workers22 developed a new type amino amideorganocatalyst 23 for crossed-Aldol reaction. The feature of this catalyst is to have two fluorine
atoms on the amide aromatic ring. One fluorine atom makes the hydrogen bonding with theamide hydrogen atom for fixing catalyst conformation. The second fluorine works as a stericinfluence site for controlling the stereoselective reaction course as indicated in the plausible8transition state D.

enamineformation
H

F

H

N

N

C

H2N

O

O

F
23

R1
O

CHO

O

F

H
electrostatic repulsion

X
R

O

D
Ishimaru's

O

OH

C

+
X
39
ketonesbiologically active
compounds

C

HN

HN R2

H2N

hydrogen bonding
site
F

R

R

enantioselective
crossed Aldol reaction

40
aldehydes

steric influencesite

enamineformation

R1

HN R2

H
O

N

X
polycyclicaromatic groups

41
Aldol products

O
H

X
R

hydrogenbonding siteE
Our approach

Scheme 12. Amino amide organocatalysts for enantioslective reactions
The author designed new type amino amide organocatalyst C based on a new simple concept
which is different from Ishimaru’s catalyst 23. This catalyst contains both an amino covalentsite and amide non-covalent binding site, influence site in the single molecule. Furthermore,
the substituent group at ß-position works as a steric influence site. The feature of this catalyst
is to have flexible bulky polycyclic aromatic ring on the amide nitrogen atom. This aromaticring might shield one side of enantiotopic face by only its steric factor according transition E(Scheme 12).
The catalytic ability of amino amide organocatalyst was examined in both i) Aldol reaction
and ii) Michael addition.
i) Enantioselctive Aldol reaction
The author initially tried and explored the catalytic activities of amino amide organocatalyst
62c in the enantioselective crossed Aldol reaction of various acyclic or cyclic ketones 39 witharomatic aldehydes 40 to affords the corresponding chiral anti-Aldol products 41 with good to
excellent chemical yields, diastereoselectivities and enantioselectivities (up to 99%, up to
syn:anti = 1:99, up to 97% ee) (Scheme 13).

9

HN
CHO

O
+

H2N

O

O
62c
(5 mol%)R

R

enantioselective
Aldol reaction

X
39

OH
+ syn isomerX
41
anti-Aldol isomer
up to 99%, syn/anti =1:99
up to 97% ee

40

Scheme 13. Amino amide organocatalyst for enantioselective Aldol reactionii) Enantioselective Michael addition
Furthermore, the author applied the newly developed amino amide oragnocatalyst 62b forenantioselective Michael addition of various β-keto esters 42 with trans-b-nitroolefins 43 toaffords the corresponding chiral Michael adducts 44 having quaternary chiral carbon centre
with good to excellent chemical yields (up to 99%), diastereoselectivities (up to dr. 99:1) andenantioselectivities (up to 98% ee). The detailed discovery of amino amide organocatalysts
preparations and its application for enantioselective asymmetric reactions will be discussed in
the following sections (Scheme 14).

O
H2N
O

O

O
R

42

N
H

+

NO2

R'
43

O

62b
enantioselective
Michael addition

R
R'

NO2

44
chiral Michael adducts
up to 99%, up to dr. 99:1
up to 98% ee

Scheme 14. Amino amide organocatalyst for enantioselective Aldol reaction

10Chapter 2
A New Type Amino Amide Organocatalyzed Enantioselective Crossed
Aldol Reaction of Ketones with Aromatic Aldehydes

11Chapter 2
A new type amino amide organocatalyzed enantioselective crossed Aldol
reaction of ketones with aromatic aldehydes

2.1 BackgroundThe crossed Aldol reaction is known as one of the basic reactions to the creation of the new
β-hydroxy carbonyl structural motif which is found in numerous biologically active natural
products and drug molecules (Scheme 15).28,29

OO

catalyst

HR'
aldehyde(electrophile)

Aldol reaction+RR
ketone(nucleophile)

O

OH

* R'
R
Aldol products

Scheme 15. General representation of aldol reaction
2.1.1

Mechanism

Aldol reaction proceeds via two basically different mechanisms (enol or enolate). These
species, being nucleophilic at the α-carbon, attack especially reactive protonated carbonyls
such as protonated aldehydes. This is the ‘enol mechanism’.29 Carbonyl compounds, being
carbon acids, is also deprotonated to form enolates, which are much more nucleophilic thanenols and attack electrophiles directly. The usual electrophile is an aldehyde since ketones aremuch less reactive. This is the ‘enolate mechanism’ (Scheme 16). Also, the condensation ofamine catalyst with carbonyl subtrate to gives the electrophilic iminium species anddeprotonate to genetate nuclophilic enamine species and attack appropriate electrophile to form
the desirable chiral Aldol products.

12

O
O
R

O

OH

H+
CH3

R

enol mechanism

R'

H

* R'
R
Aldol products

CH2
enol

O
R

OH

O
O

CH3

O

base

R'

H

* R'
R
Aldol products

enolate mechanism
Renolate mechanism

OH

CH2
enolateH3O
H

O
R'-NH2
R

CH3

N

O

R'

H

N

R'

H

H

R

R

H
R''

N

R

R'

OH
R''

Aldol
reaction

CH2

Scheme 16. Aldol reaction mechanism via enol and enolate
2.1.2

Enantioselective crossed-Aldol reaction

Over the last four decades, pioneering research by Evans,30 Heathcock,31 Masamune,32 andMukaiyama33 has established the Aldol reaction as the principal chemical reaction for thestereoselective construction of complex polyol compounds. Afterwards, the studies by
Barbas,34 List,35 Shibasaki,36 and Trost37 have outlined the first examples of enantioselective
direct Aldol reactions, using metal- or proline-catalyzed transformations.
Macmillan and co-workers38 reported the enantioselective Aldol dimerization of
propionaldehyde 45 and 46 to provide the desired Aldol product 47 with both anti-Aldol
selectivity and excellent levels of enantiocontrol (80% yield, 1:99 syn:anti, 99% ee) (Scheme
17).
CO2H
N
H
O

5
(10 mol%)

O
Me

H
45

+

Me

H
46

DMF, 4 oC

O
H

OH
Me

Me
47
80% yield, 99% ee

Scheme 17. Proline catalyzed aldehyde Aldol dimerization
Since List,35 Lerner, and Barbas34 initiated the reaction of acetone 47 with 4nitrobenzaldehyde 48 furnished Aldol product 49 with moderate to good yield andenantioselectivity (68%, 76% ee) (Scheme 18).

13

CO2H
N
H

O

O
+

O

OH

5
(30 mol%)

H

DMSO

48

NO2

50
(68%, 76% ee)

49

NO2

Scheme 18. Proline-catalyzed direct asymmetric Aldol reactions
Recently, our research group39 also reported that the enantioselective Aldol reaction of
isatins 51 with alkanones 52 using an easily prepared chiral amino amide organocatalyst 62a.
And the catalyst to provides chiral 3-substituted 3-hydroxy-2-oxindoles 53 in good to excellent
yields and with excellent stereoselectivities (up to 99%, up to 98% ee, syn:anti = 1:99) to 3hydroxy-3-(2-oxocyclohexyl)-2-indolinone that useful as a synthetic intermediate forpharmaceutically important compounds (Scheme 19).

O

NH2

O
N
H

R

+
52
alkanones

51
isatins62aamino amideorganocatalyst

amino amideorganocatalyst 62a(15 mol%)

O

O
N
H

THF, r.t.

O
HO

*

*

R

O
N
H
3-hydroxy-2-oxindoles[2S, 3R ]-53
up to 99%, 98% ee
syn:anti = 99:1

NH

O

O

Br HO

HO

56
3-hydroxy-3-(2-oxocyclohexyl)-2-indolinone(anticonvulsant activity)

O

O

O
N
H

HO

Br

N
H

55
convolutamydine A(leukemia inhibitory activity)NH
54
donaxaridine(anticancer activity)

Scheme 19. Amino amide organocatalyst catalyzed enantioselective Aldol reaction

2.1.3

Author approach

The author decided to explore a polycyclic aromatic substituted primary amino amide typeof organocatalyst C for an enantioselective crossed Aldol reaction of ketones 39 with various
aldehydes 40, based on the catalytic assumption that the primary amino group might work as
both the enamine formation site and the hydrogen bonding site. And also, the amide function

14

might work as the hydrogen bonding site to the substrate (Scheme 20).
Furthermore, the carbon-carbon bond at α-position and β-position in catalyst might berotated by the difference of the species of the bulky flexible polycyclic aromatic group on thenitrogen atom of amide carbonyl site to form efficient transition state for affording satisfactorystereoselectivity. The newly prepared amino amide organocatalysts existence of hydrogenbonding sites and sites of steric influence within one molecule, it can have a strong influenceon the stereoselectivity of the reaction of cyclohexanone and aldehydes.
As indicated in the plausible transition state E, where cyclohexanone and aldehydes can beconformationally fixed by two hydrogen bonding interaction, that is between the amines groupsof amino amide and the carbonyl group of aldehydes. The hydrogen bonding of the amino
nitrogen atom at the α-position with the amide hydrogen atom might strongly fix theconformation of this intermediate. Thus, the bulkier flexible polycyclic pyrenyl group on theamide nitrogen atom and substituent tert-butyl at the α-position might shield one face of thealdehydes from the incoming nucleophile. Their catalytic performance was examined inenantioselective crossed Aldol reaction of ketones with various aldehydes and afforded thecorresponding Aldol products 41 in high stereoselectivities.
O

CHO
+

X
39
ketonesR

steric influencesitehydrogenR1
O bondingsite

40
aldehydes
enantioselective
Aldol reaction

enamineformation
or
basic
sites

HN

N

R2

polycyclicaromatic groups

O

OH

H

H
hydrogenbonding
site
C

HN R2

R1
H

O N

H

O

R
X

X

R

41
Aldol productsE
plausible transition state

Scheme 20. Hypothesis of amino amide organocatalysts for Aldol reactions
15

2.2

Results and discussion

2.2.1

Synthesis of a new type amino amide organocatalysts

Initially, in this study, the author aimed to synthesise new type of amino amideorganocatalysts and their derivatives (Scheme 21,22). First, the author synthesized series of NBoc aromatic amines 59a-c by reaction with the corresponding amino acids 57a-c and di-tertbutyl dicarbonate 58 at 0 -100 0C conditions. The N-Boc aromatic amines were obtained withexcellent yields up to 99% (Scheme 21).
R1

O

O

O

O

+
H2N

OH
57

O

O
58

Et3N
dioxane
H2O
0 0C-100 0C
24 h
99%

R1

O

HN

OH
Boc
59a-c

57a: R1= tBu, 57b: R1= Ph
57c: R1= Bn

Scheme 21. Synthesis of N-Boc aromatic amino acids derivatives
from amino acids
The polyaromatic substituted amino amide organocatalysts 62a-f were prepared easily by
the condensation of the corresponding chiral N-Boc amino acid derivatives 59a-c withpolyaromatic amines derivatives 60a-d in the presence of 1-hydroxybenzotriazole (HOBt) and1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDC) followed by removal of the Bocgroup from crude N-protected amino amide compounds using CF3CO2H in dichloromethane
solvent 0 0C-r.t. to achieve desired chiral multifunctional amino amide organocatalysts 62a-f
in moderate yields up to 67% (Scheme 22). The newly synthesized amino amideorganocatalysts were characterized with 1H NMR, 13C NMR, HRMS and IR spectroscopy.

16

R1

O

HN

OH
Boc

R2-NH260a-dHOBt, EDC
CH2Cl2r.t., 20 h

R1

O

HN

H2N R2Boc

59a-c

CF3CO2H
CH2Cl2
rt., 3 h

R1

O

H2N

HN R2
62a-f

61

O
O
N
H

H2N

H2N

N
H

HN
H2N

62a: 54%

62b: 53%O
62c: 62%

HN
H2N

HN

O
H2N
62d: 52%O62e: 63%HN
H2N

O
62f: 67%

Scheme 22. Synthesis of a new type amino amide organocatalysts 62a-f
2.2.2

Aldol reaction of cyclohexanone 63 with 4-nitrobenzaldehyde 64a using 62a-f

Initially, the author carried out the Aldol reaction of cyclohexanone 63 as an Aldol donor
and 4- nitrobenzaldehyde 64a as an Aldol acceptor with organocatalyst (25 mol%) 62a with 2anthracenyl-amide, in the presence of water at room temperature (entry 1, Table 1). Although
the corresponding anti-Aldol product 65a as a major product was obtained with good chemicalyield and relatively high diastereoselectivity, but enantioselectivity was low (80 %, syn:anti =19:81, 43% ee). The absolute configuration and syn/anti diastereoselectivity of 65a wereidentified based on comparison with literature data.40

17

Table 1. Asymmetric crossed Aldol reaction of 63 and 64a using organocatalysts 62a-f

OO+

catalyst 62a-f(25 mol%)

H
NO2

63

O

OH
+

H2O
r.t., 48 h

NO2

65a

64a

yield (%)asyn isomer

anti ee (%)centrycatalyst 62

1

a

80

19:81

43

2

b

67

14:86

55

3

c

97

1:99

92

4

d

60

16:84

45

5

e

97

11:89

65

6

f

81

12:88

50

syn:antib

aIsolatedyields (a mixture of diastereomers). bDiastereoselectivity was determined by HPLC
analysis of the reaction mixture. cThe ee values were determined by HPLC analysis with a Daicel
Chiralpak AD-H column.

The author next examined the catalytic abilities of all prepared catalysts 62b-f for thisreaction and the results were shown in Table 1 (entries 2-6). The catalyst 62b with 1naphthylamide having tert-butyl group at a-position provided the corresponding anti-Aldol
adduct 65a in good chemical yield, but with slightly increased in enantioselectivity than the
result of catalyst 62b (entry 2). On the other hand, catalyst 62c with 1-pyrenylamide afforded
the corresponding anti-Aldol adduct 65a with excellent chemical yield, diastereoselectivity andfairly good enantioselectivity (97%, syn:anti = 1:99, 92% ee, entry 3). The case of catalyst 62dwith 4-pyrenylamide showed moderate catalytic activity (60%, syn:anti = 16:84, 45% ee, entry
4). Based on this result, the author also examined the catalytic activities of catalysts 62e and
62f with 1-pyrenylamide having various substitutions at a-position. Although the anti-Aldol
adduct 65a was obtained in good to excellent chemical yields, stereoselectivities weremoderate (entries 5,6). These results suggested that the combination of the tert-butyl group at18

β-position and 1-pyrenyl substituent on amide group is effective for affording sufficient
catalytic activity for achieving satisfactory stereoselectivity.
2.2.3

Optimization of Aldol reaction conditions using catalyst 62f

With these results in hand, the author examined to optimize the reaction conditions using
the superior catalyst 62c to further improve the enantioselectivity and results were shown in
Table 2. An extensive screening of the reaction was further carried out by varying different
parameters such as catalyst loading, solvent and reaction time period. First, the author
examined the effect of catalyst loading by varying from 25 mol% to 20 mol%, 10 mol%, 5mol%, 2.5 mol% and 1 mol%. As a result, 5 mol% of catalyst 62c showed the best catalytic
activity and afforded the corresponding anti-Aldol adduct 65a with fairly good chemical yield,
excellent diastereoselectivity, and enantioselectivity (90%, syn:anti = 1:99, 96% ee, entry 4).
Furthermore, we also carried out the reaction in distilled water and sea water using catalyst 62c(5 mol%) (entries 7,8).
Although the corresponding anti-Aldol adduct 65a was obtained in distilled water withfairly good chemical yield and stereoselectivities (92%, syn:anti = 1:99, 92% ee), the yield, as
well as selectivity, was also decreased in sea water (75%, syn:anti = 10:90, 78% ee). The
organic solvent screening was performed with different chlorinated (entries 9,10), non-polararomatic (entries 11,12), non-polar aliphatic (entry 13), ethereal (entries 14-16) and polar
solvents (entries 17-20) and the anti-Aldol adduct 65a was obtained in all cases with moderate
to good chemical yields and stereoselectivities.
Next, the author examined the effect of the reaction time period by reducing the time from48 h to 24 h and 12 h in water as the best solvent (entries 21,22). Although thediastereoselectivities and enantioselectivities were almost maintained, unfortunately, thechemical yields were reduced. From these results, it was shown that 5 mol% of catalyst loadingof water as a solvent and 48 h time period was the best reaction conditions to obtain the product65a in satisfactory chemical yield, diastereoselectivity and enantioselectivity as the optimized
conditions (entry 4, Table 2).

19

Table 2. Optimization conditions of asymmetric Aldol reactions of 63 with 64a
using catalyst 62c

63

64a

+

catalyst 62c(mol%)
solvent
temp., time

65a

syn isomer

+

entry

catalyst 62c (mol %)solvent

time (h)yield (%)a

syn:antib

anti ee (%)c

1

25

H2O

48

97

1:99

92

2

20

H2O

48

95

1:99

94

3

10

H2O

48

95

1:99

92

4

5

H2O

48

90

1:99

96

5

2.5

H2O

48

25

1:99

90

6

1

H2O

48

16

1:99

90

7

5

dist. Water

48

92

1:99

92

8

5

sea Water

48

75

10:90

78

9

5

DCM

48

33

4:96

88

10

5

CHCl3

48

62

6:94

75

11

5

toluene

48

74

10:90

72

12

5

benzene

48

79

10:90

78

13

5

hexane

48

77

1:99

93

14

5

Et2O

48

62

6:94

75

15

5

1,4-dioxane

48

64

4:96

89

16

5

THF

48

82

10:90

74

17

5

MeOH

48

52

5:95

81

18

5

DMF

48

47

7:93

74

19

5

DMSO

48

68

6:94

84

20

5

ACN

48

49

9:91

72

21

5

H2O

24

50

1:99

94

22

5

H2O

12

31

1:99

93

aIsolated yields (a mixture of diastereomers). bDiastereoselectivity was determined by
HPLC analysis of the reaction mixture. cThe ee values were determined by HPLC analysis
with a Daicel Chiralpak AD-H column.

In the best reaction condition, water was classified as a solvent. However, it might be work
as an additive for proceeding to the reaction from the ratio of cyclohexanone 63 and water inthe reaction.

20

2.2.4Generality of Aldol reaction of 63 with 64b-n using catalyst 62c

After optimization of the reaction conditions, the author examined the generality of the best
catalyst 62c in the reactions of cyclohexanone 63 with various aromatic aldehydes 64b-n(Table 3). The reaction of 63 with nitro-substituted aromatic aldehydes 64b,c afforded thecorresponding anti-Aldol adducts 65b,c as major products in good to moderate chemical yields,
diastereoselectivities and enantioselectivities (up to 79%, up to syn:anti = 5:95, up to 90% ee)(entries 1,2). All of the tried reaction proceeded to afford the corresponding products and withthe recovery of the corresponding starting materials. The reaction using o-nitrobenzaldehyde
64c afforded the product 65c in moderate chemical yield and it might be for the steric influenceof nitro group on 64c. The reactions using the halogenated benzaldehydes 64d-i were also
compatible with this protocol and the corresponding anti-Aldol adducts 65d-i as major
products were obtained with satisfactory results (up to 97%, up to syn:anti = 1:99, up to 93%
ee, entries 3-8). The simple benzaldehyde 64j also yielded the Aldol product 65j as a major
product with good chemical yield and selectivity (entry 9). The effect of electron-donatinggroups on benzaldehyde was also examined (entries 10-12). m-64k and o-64l
methoxybenzaldehydes and para- methylbenzaldehyde 64m afforded the corresponding antiAldol adducts 65k-m as major products in good to excellent chemical yields (65k: 96%, 65l:
73%, 65m: 86%) and fairly good to excellent enantioselectivities (65k: 96% ee, 65l: 92% ee,
65m: 94% ee) (entries 10-12). Also, 4-pyridinylcarboxyaldehyde provided the correspondinganti-Aldol adduct 65n as a major product in excellent chemical yield, fairly good
diastereoselectivity and enantioselectivity (98%, syn:anti = 9:91, 90% ee) (entry 13). These
results justified our finding that catalyst 62c enhance the generality application to the Aldol
reaction of different substituted aromatic aldehydes.

21

Table 3: Generality of Aldol reaction in 63 with 64b-n using
catalyst 62c
O

O
H
63

+

R

X

X

H2O
r.t.,48 h

64b-n

product 65
OR+

syn isomer

65b-nanti isomer(major)

X = CH, N
entry

OH

catalyst 62c(5 mol%)yield (%)a

syn:antib

anti ee (%)c

79

23:77

69

57

5:95

90

82

9:91

93

97

7:93

87

79

1:99

79

70

7:93

92

88

26:74

68

76

6:94

75

74

1:99

81

96

5:95

96

73

5:95

92

86

14:86

94

98

9:91

90

OH
NO2

1
65b
O

OH

NO2

2
65c
O

OH

3
Cl

65d
O

OH
Cl

4
65e
O

OH

Cl

5
65f
O

OH

6
Br

65g
O

OH
Br

7
65h
O

OH

Br

8
65i
O

OH

9
65j
O

OH
OCH3

10
65k
O

OH

OCH3

11
65l
O

OH

12
CH3

65m
O

OH

13
N
65n

aIsolated yields (a mixture of diastereomers). bDiastereoselectivity

was determined by HPLC of reaction mixture. cThe ee values were
determined by HPLC with a Diacel Chiralpak AD-H column.

22

The enantioselective Aldol reaction of other carbocyclic 66a,b,e, heterocyclic 66c,d,f andacyclic 66g ketones with 64a were examined under best reaction conditions (r.t., H2O, 48 h,
Table 4). The reaction of cyclopentanone 66a with 64a reacted smoothly and provided thecorresponding anti-Aldol adduct 67a as a major product in fairly good chemical yield andstereoselectivity (92%, syn:anti = 2:98, 91% ee, entry 1).
Table 4: The scope of Aldol reaction of 64a with different types of ketones 66a-g
using catalyst 62c
O

O

OH

catalyst 62c (5 mol%)
+

R1

R2
X
66a-g

64a

R1

r.t., H2O, 48 h

X

X = CH2, O, S, (CH)CH3, N-Boc
entry

66

R1

R2

product 67

a
67a

b

O

4

5

c

d

O
O

67c

O

OH

92

2:98

91

84

16:84

86

99

3:97

91

98

5:95

96

63

45:55

97

94

5:95

90

90

--

90

NO2

S
S

67d

O

OH

O

NO2

NO2

OH

N
Boc

anti ee (%)c

NO2

e

f

syn : antib

OH

67e

6

yield (%)a

NO2

67b

3

67a-g
anti isomer(major)OH

O
2

syn isomer

NO2

OH

O
1

+

R2

67f

N

NO2

Boc
O
7

g

OH

H
67g

NO2

aIsolated yields (a mixture of diastereomers). bDiastereoselectivity was determined by HPC

HPLC of reaction mixture. cThe ee values were determined by HPLC with a Diacel Chiralpak
AD-H column.

23

The bulkier cycloheptanone 66b also gave the corresponding anti-Aldol adduct 67b as amajor product with good chemical yield and stereoselectivity (entry 2). The uses of bothheterocyclic tetrahydropyran-4-one 66c and tetrahydrothiopyran-4-one 66d afforded the Aldol
products 67c and 67d, respectively, as major products in excellent chemical yields (67c: 99%,
67d: 98%) with good to excellent enantioselectivities (67c: 91% ee, 67d: 96% ee, entries 3,4).
Although 4-methylcyclohexanone 66e gave the corresponding anti-Aldol adduct bothmoderate chemical yield (67%) and diastereoselectivity (45:55 dr), the major anti-Aldol adduct67e as a major product was obtained in excellent enantioselectivity (97% ee, entry 5).
In addition, N-Boc-piperidine-4-one 66f provide the corresponding anti-Aldol adduct 67f
as a major product in a high level of chemical yield and stereoselectivities (94%, syn:anti =
5:95, 90% ee, entry 6). The obtained heterocyclic anti-Aldol adducts 67c-f as major products
might be useful as synthetic intermediates for the synthesis of some biologically active
compounds including drug. Finally, the reaction of acyclic acetophenone 66g with 64a also
gave the corresponding anti-Aldol adduct 67g as a major product in good chemical yield andenantioselectivity (90%, 90% ee, entry 7). The anti-Aldol adducts 65a-n and 67a-g havecharacterized in accordance with full spectroscopic data originated from the previous report.40
And also, absolute stereochemistry of all anti-Aldol adducts 65a-n and 67a-g were resolved tobe equivalent to specific optical rotation values in literature.40

2.2.5

Plausible transition model for enantioselective Aldol reaction

Considering to both the excellent enantioselectivity (96% ee) of the anti-Aldol adduct(2S,3R)-65a that was obtained in the reaction of cyclohexanone 63 with 4-nitrobenzaldehyde

HNN

A Scan of total energies of theintermediate (I) generated by varying
two torsion angles

H

O

I-2

DFT optimized structures of
1-2

Figure 2. A scan of total energies of the intermediate I generated by varying two torsion
angles (the dihedral scans showed with u-shaped arrows, as shown in the right structure).
The arrow at the bottom represents the global energy minimum conformer (in the left
Figure).

24

64a and the results of its conformational calculation studies (Figure 2), an enantioselective
reaction course is proposed as follows (Scheme 23).

HN
63

catalyst
62c

N

H

HN

HN

O

N

H

H

N

O
I-2

I-1

H

O
I-3

64a

HN
N

H

HN

NO2

HN

O

N

NO2

O
H H

H O N

O

H

O

N
H

Ts-1
H

Ts-2

H

O

O

H N

H

O

O

Ts-3

Ts-4

Ts-5

O2N

O2N

O2N

O

HN

HN

96 % ee

O

OH

O

OH

NO2

O

OH

2

3

NO2

O

anti isomer

anti isomer(2R,3S)-65a(2R,3S)-65a(2S,3R)-65a

OH

NO2

NO2

NO2

anti isomerOOH

anti isomer(2S,3R)-65a

syn isomer(2S,3S)-65a

Scheme 23. Plausible reaction course for Aldol reaction
The condensation of organocatalyst 62c with 63 gives the enamine intermediate I, that isfixed by the hydrogen bonding interaction between the hydrogen atom on the nitrogen atom of
enamine segment and the amide carbonyl group in organocatalyst species. It might exist as I1 or I-2, which are having less steric interaction between the amide carbonyl group and 1pyrenyl substituent group on the amide nitrogen atom in catalyst species than that ofintermediate I-3. Furthermore, I-2 forming trans-configuration between the tert-butyl group at
α-position and the enamine olefin site might have the highest stability order is compared with
I-1 that possesses a predominantly cis-configuration arrangement between the tert-butyl groupat α-position and the enamine olefin site. For that reason, I-1 might have more steric and/or
electric interactions than that of the relationship of trans-configuration.
Subsequently, 4-nitrobenzaldehyde 64a might approach the stable enamine intermediate I2 in five possible ways to form different transition states Ts-1-Ts-5 as shown in Scheme 3.
Among Ts-1-T-4 which afford (2S,3R)-64a as a major product, Ts-1, Ts-2, and Ts-4
experience the strong steric interaction between intermediate I-2 and 63a than that of Ts-3.
Therefore, this reaction might proceed preferentially through Ts-3 to afford (2S,3R)-65a. On
the other, Ts-5 also might have the strong steric interaction between intermediate I-2 and 64a,
to afford diastereomer (2S,3S)-65a.
25

According to the construction of catalyst 62c, the conformational analyses for the enamineintermediates I was also carried out and it was indicated that the conformation of I-2 was moststable, as presented in Figure 2. The scan of total energies of 64a and intermediate I generated
by varying two torsion angles (see the Figure S1 in the experimental section for details).
Interestingly, enamine intermediate F with the 2-anthracenyl group, that was generated fromthe reaction of catalyst 62a with 63, forms the hydrogen bonding between the enamine nitrogen
atom and amide hydrogen atom (Figure 3).39,41 On the other hand, enamine intermediate G withthe 1-pyrenyl group, that was generated from the reaction of catalyst 62c with 63, forms thehydrogen bonding between an enamine hydrogen atom and amide nitrogen atom (Figure 3).

O
HN

N

HN

H
N

O
H

F

G

Figure 3. Enamine intermediates F and G
This difference of intramolecular hydrogen bonding site might be for the steric and/or
electric influences of each aromatic ring substituents.
To predict the regioselectivity of the reaction between 64a and I-2 more precisely,
calculation of the energies and coefficients of their frontier orbitals was conducted. The energy
levels of the orbitals clearly showed the dominant interaction between the LUMO of 64a andthe HOMO of I-2, and their orbital phase clearly demonstrated a matching in favour ofoverlapping to product Ts-3 (Figure 4).

26

HN
HN
N

H

H

O N

O

H

O

O

O2N

H

E-hartree

NO2

LUMO
LUMO
-0.1146-0.2784-0. 0591

OO

O-0.1911

HOMO

O
64a

HOMO
I-2
“favor"

The red and blue dotted lines:
the matching of orbital phasebetween 64a and I-2.

64a
I-2

Figure 4. The frontier orbitals between 64a and I-2 obtained by DFT calculations at theB3LYP/6-31G(d) level using a B3LYP exchange-correction functional [the dotted lines (blueand red) in the red square indicated an interaction between the molecular orbitals of 64a and I2.

27

2.2.6

Summary

In summary, the author developed the new type of simple amino amide organocatalysts 62af and was explored based on a new catalyst design concept. Their catalytic activities were
examined in the enantioselective crossed aldol reaction of various acyclic or cyclic ketones
with aromatic aldehydes. As a result, catalyst 62c with a bulky 1-pyrenyl group showed best
catalytic performance and afforded the corresponding chiral anti-Aldol products with good to
excellent chemical yields, diastereoselectivities and enantioselectivities (up to 99%, up to
syn:anti. 1:99, up to 97% ee). Furthermore, the plausible stereoselective reaction course ofcrossed Aldol reaction was predicted with the support of DFT calculation.

28

Chapter 3
Amino Amide Organocatalysts for Asymmetric Michael Additionof β-Keto Esters with β-Nitroolefins29Chapter 3
Amino Amide Organocatalysts for Asymmetric Michael Additionof β-Keto Esters with β-Nitroolefins
3.1 Background
The Michael addition generally accepted as one of the most popular and useful methods forthe creation of carbon-carbon bonds in the field of synthetic organic chemistry.42 The Michael
reactions (Michael additions) is the nucleophilic addition of carbanion or another nucleophile
to an a-b-carbon carbonyl compound (EWG such as nitro group).43,44 This is one of the mostuseful methods for the mild formation of carbon-carbon bonds (Scheme 24). Also, the reaction
using trisubstituted carbon nucleophiles as a cyclic or acyclic b-ketoesters with electrondeficient olefins to form the chiral Michael adducts containing adjacent quaternary and tertiary
stereocenters, that significantly recognised as chiral building blocks for many synthetic
intermediates and biologically active natural products.45 Hence various effective chiralorganocatalysts and organometallic catalysts have been investigated in recent years for thisreaction.46 For instances, using both thioureas- and squaramide type of organocatalyst andchiral bifunctional carbon dioxide catalyzed by binaphthyl Schiff bases type of organometallic
catalyst have been reported to achieve high levels of stereoselectivities.47,48 For these reasons,
there are still needed to design and develop even more efficient, effective and environmentallyfriendly catalysts, especially, organocatalysts that will enhance high stereoselectivities for thisreaction.
O

O
+

R

OR'

Michael donor
R = alkyl, aryl, R' = Me, Et

R"

EWG

O
Base
Michaeladdition

Michael acceptor
R" = alkyl, aryl
EWG = NO2, CO2R

R

O
*

OR'

EWG
R'' *
Michael adduct

Scheme 24. General representation of Michael addition
3.1.1

Mechanism

The general mechanism approach for the Michael reaction involves the combination of a
nucleophile with an electron-deficient alkene in the presence of a chiral, non-racemic catalyst(either a metal complex or organocatalyst). Addition of the nucleophile to the b-carbon of theelectrophilic olefin generates at least one new stereogenic centre. The Michael reaction consistsof the addition of a stabilized carbon nucleophile (i.e. an enolate or enolate equivalent) to the30b-carbon of an electron-deficient alkene. Protonation or treatment with an electrophile converts
the resulting stabilized anion into a product in which the alkenic carbons bear two new bonds(Scheme 25).

O

O

R

OR'
Base

O
R

O

O
OR'

O

R

OR'

EWG

Michaeladdition R"

O
R

O
*

OR'

EWG
R'' *
Michael adduct

Scheme 25. Mechanistic pathway for the Michael addition

3.1.2

Organocatalysis for Michael addition

Iminium ions formed from a,b-unsaturated aldehydes and chiral amines are more
electrophilic than the starting aldehydes. Thus, amines can be used as electrophile-activating
catalysts in certain types of Michael reactions. Nucleophilic addition at the b-position of the
conjugated iminium ion affords an enamine, which undergoes hydrolysis to form the productand regenerate the amine catalyst (Scheme 26).

31

N
H
N
H

H2O

(cat.)
A-H (co-cat.)

O

NuH

N

A-H

N

H

O

H2O

A
H

H

R
R

R

Nu

R

Nu

The bulky group provide p-facial
discrimination and favors (E) geometry

Scheme 26. Mechanism pathway of Michael addition
3.1.3

Previous approaches on enantioselective Michael addition of β-keto esters with βnitroolefins

An efficient approach for the enantioselective Michael additions of β-keto esters to βsubstituted nitroolefins had been developed.
Pedrosa and co-workers49 developed a chiral thiourea 68 prepared from natural L-valine
which is an excellent catalyst for the construction of adjacent tertiary and quaternarystereocenters by enantioselective Michael addition of β-keto esters 42 with β-nitroolefins 43.
The corresponding Michael adduct 44 occur with very good yields and excellent
stereoselectivities (up to 99%, dr up to >98:2 and 99% ee) (Scheme 27).

F3C
S

F3C
O

O

+
OR

42

NO2

R'

N
H

N
H

NMe2

thiourea organocatalyst 68(10 mol%)O*

toluene, -18 oC
43

O
OR
NO2

*
44
Michael adducts
up to 99%, dr > 98:2
up to >99% ee
R'Scheme 27. Organocatalyzed asymmetric Michael additions using thiourea

Cavallo and co-workers50 reported that the Michael addition of β-keto esters 42 with βnitroolefins 43 catalysed L-prolinol 69 in C6F6 as a solvent. Catalyst afforded the corresponding
Michael adduct 44 in good yields and excellent stereoselectivities (up to 98%, dr up to >99:1
and 95% ee) (Scheme 28).

32

OH
N
H

42

L-prolinol organocatalyst 69(15 mol%)

43

+

44
up to 98%, dr > 99:1
up to 95% ee

C6F6, r.t.

Scheme 28. Organocatalyzed asymmetric Michael additions using prolinol
3.1.4

Author approach

The organocatalyst D enhances the basic primary amino group for the formation of basic
sites, hydrogen sites and the amide derivatives for hydrogen bonding site to the substrate. In
addition, the bulky flexible polycyclic aromatic group on the nitrogen atom of amide group in
catalyst might be shielded effectively the one enantiotopic face on the basis of a steric factor
to enhance the selectivity (Scheme 29).39,41

enamineformation
or
basic
sites

O

steric influencesitehydrogenRbonding
O
site
HN

N

H

H

hydrogenbondingsiteR'polycyclicaromatic groupsamino amideorganocatalysts

C

O
O
R

*

42

β-keto esters
+
NO2

R'
43

nitroolefinsOR'

asymmetricMichael addition

*

R
NO2

44

chiralMichael adducts
up to 99%, up to dr. 99:1
up to 98% ee

Scheme 29. Catalyst’s concept and its use in Michael addition
To further expand the efficiency of amino amide as an organocatalyst D, the author
examined the Michael reaction of β-keto esters with various nitroolefins using chiral amino
33

amide organocatalyst. As a concept of the expression of enantioselectivity in this reaction using
amino amide catalyst, the reaction might be proceeding through a transition state H, in which
the hydrogen bonding interactions between the hydrogen atom and the amide oxygen might befixed by amide site on the catalyst. Furthermore, the ammonium hydrogen atom on theammonium catalyst species with β-keto esters and nitroolefin might be fixed by the hydrogenbonding interactions from the less steric interaction site of the fixed tert-butyl substituent andsubstituent of an amide group (Scheme 30).

OO

steric influencehydrogenbonding
R
site

OR
R1

42

H2N

NO2

43

O
HN

R2

O

enantioselective
Michael addition

H

N

O

H

C

+
R'

basic
site

O
R

N
H

N
H

O

*
R2

hydrogenbonding

H

R
NO2

*
44
chiralMichael adducts
R'

O
O

O

hydrogenbondingtransition state H

Scheme 30. Hypothesis of amino amide organocatalysts for Michael reaction
The obtained Michael adducts could be used as synthetic precursors for the several natural
products that have a broad spectrum of fascinating biological activities.

34

3.2 Results and discussions
3.2.1 Asymmetric Michael reaction of β-keto esters 42 with β-nitroolefins 43 using
catalysts 62a-f and 70a-c.
The catalysts 62a-f and 70a-c were developed by the condensations of the correspondingchiral N-Boc amino acids 59a-d with polycyclic aromatic amines 60a-d, according to ourprevious methods.39,41
For an amino amide with polycyclic aromatic ring organocatalysts for Michael reaction,amino amides having1-anthracenyl 62a, 1- or 4-pyrenyl 62c-f, and 1-naphthyl 62b and 70a-c
groups were selected (Scheme 31). The catalysts 62a-f and 70a showed good catalytic activities
in the Aldol reactions using isatins and general ketones such as cyclohexanone, respectively,in our previous reports.39,41
R1

O

HN

OH

R2-NH2R1

60a-d
HOBt, EDC

HN

O
HN

CH2Cl2

Boc

R1

O

H2N

HN

CF3CO2H
R2rt., 3 hBocr.t., 20 h

59a-d

CH2Cl2

R2

62a-f

61

O
O
H2N

N
H

N
H

H2N

62a: 54%

HN

62b: 53%

H2N

O

62c: 62%

HN
HN

HN
H2N

O
H2N

H2N

O

62d: 52%NH

70a: 66%

62f: 67%

62e: 63%

O

H2N

O

O

O

H2N

N
H

70b: 74%

H2N

N
H

70c: 59%

Scheme 31. Synthesis of a new type amino amide organocatalysts 62a-f and 70a-c
First, the author carried out the Michael addition of methyl 2-oxo-cyclopentanecarboxylate
42a and trans-β-nitroolefin 43a with 10 mol% of our explored bulkiest organocatalysts 62c-f
35

having pyrenyl groups in the presence of H2O at room temperature (Table 1), according to ourprevious reported Aldol reaction conditions.41 All catalysts 62c-f showed catalytic activities in
Michael reaction and afforded the chiral Michael adduct 44a as the main product with moderate
to good chemical yields and stereoselectivities, (up to 89%, up to dr. 90:10, 77% ee). Especially,
tert-butyl-catalyst 62c with 1-pyrenyl group afforded the corresponding Michael adduct 44a ingood chemical yield and stereoselectivities (83%, dr. 90:10, 77% ee, entry 3). Furthermore, thesame reaction using bulkier catalyst 62a with the 1-anthracenyl group also gave the adduct 44ain good chemical yield and moderate stereoselectivities (74%, dr. 90:10, 59% ee, entry 1).
Moreover, the reaction using less bulky tert-butyl-catalyst 62b with 1-naphthyl group was also
examined and the best result (91%, dr. 92:8, 84% ee, entry 2) was obtained by using thiscatalyst.
Table 1. Asymmetric Michael additions of β-keto esters 42a withtrans-β-nitroolefin 43a using organocatalyst 62a-f and 70a-c.
R1

O

NH2

NHR2

62a-f, 70a-c

O

NO2

O
OMe

42a (2.0 equiv.)

43a (1.0 equiv.)

catalyst 62a-f
70a-c(10 mol%)

O O

2 3

OMe
NO2

H2O
rt., 48 h[2R,3S]-44a

entryacatalyst 62,70

yield (%)bdrcee (%)d

1

62c

83

90:10

77

2

62d

76

83:17

69

3

62e

89

90:10

64

4

62f

78

87:13

72

5

62a

74

90:10

59

6

62b

91

92:8

84

7

70a

82

90:10

69

8

70b

78

87:13

72

9

70c

69

83:17

65

aThe reaction was carried out under suppersion. bIsolated yields. cThe

diastereomeric ratio (dr) was determined by 1H NMR spectroscopy ofthe crude reaction mixture. dThe ee values were determined by HPLC
with a Daicel Chiralpak OD-H column.

The determination of stereoselectivity and absolute configuration of Michael adduct 44a were
established on comparison with the previous report.51
36

Exclusively, the reaction condition was changed and optimized using the most highly
reactive catalyst 62b, by examined the molar ratio of the catalyst, effects of solvents, and thereaction time (Table 2).
Table 2. Optimization conditions of asymmetric Michael additions of β-ketoesters 42a,b with trans-β-nitroolefin 43a using organocatalysts 62b.

42a,b(2.0 equiv.)+

43a(1.0 equiv.)

catalyst 62b(mol%)[2R,3S]-44a,b

solventr.t., 48 h

entryacatalyst 62bf
(mol%)

solventyield (%)bdrcee (%)d

1

20

H2O

90

90:10

80

2

10

H2O

91

98:2

84

3

5

H2O

92

99:1

96

4

2.5

H2O

46

90:10

91

5

1

H2O

23

99:1

90

6e

5

H2O

74

96:4

92

7

5

toluene

92

90:10

88

8

5

benzene

64

81:19

62

9

5

hexane

88

86:14

68

10

5

CH2Cl2

99

88:12

43

11

5

CHCl3

34

84:16

83

12

5

Et2O

37

89:11

76

13

5

THF

68

88:12

49

14

5

1,4-dioxane

89

80:20

51

15

5

EtOAC

74

84:16

69

16

5

MeOH

17

80:20

64

17

5

DMF

37

77:23

90

18

5

DMSO

89

80:20

51

19

5

CH3CN

24

82:18

88

20f

5

H2O

64

99:1

90

21f

5

H2O

57

99:1

90

aIsolated yields. bThe diastereomeric ratio (dr) was determined by
1H NMR spectroscopy of the crude reaction mixture. cThe cThe eevalues were determined by HPLC with a Diacel Chiralpak OD-H
column. eThe use of ethyl ester 42b in entry 5. fThe reactions werecarried out at 24h and 12h, respectively.

Firstly, the effect of catalyst loading was examined (entries 1-4). Subsequently, 5 mol% oforganocatalyst 62b shown the best catalytic activity and afforded the corresponding chiralMichael adduct 44a with good chemical yield with both excellent diastereoselectivity and37

enantioselectivity (92%, dr. 99:1, 98% ee, entry 2). Furthermore, the use of ethyl ester 42b also
afforded the corresponding adduct 44b in good chemical yield and selectivities (74%, dr. 96:4,
94% ee). Next, the Michael addition was examined in various solvents (entries 6-18) in thepresence of 5 mol % of 62b for 48 h. Although all reactions proceeded in these solvents, better
results than the use of water were not obtained. Considering that, the reaction using H2O was
carried out under suspension, H2O might be works as an additive but a solvent, although thereasons are not clear. We also examined the effect of the reaction time period (24 h and 12 h)in the presence of best H2O (24 h: entry 19, 12h: entry 20). However, the chemical yields andthe enantioselectivities decreased than the result of 48 h, although the reasons are not clear.
Based on these results, it was proved that 5 mol% of catalyst loading in the presence of H2O at
48 h was the best reaction conditions to obtain the chiral Michael adduct 44a in satisfactory
chemical yield and stereoselectivities (entry 2).
After optimization of the reaction conditions, the author examined the generality of superior
catalyst 62b in the reactions of β-keto esters 42a,c-e with various trans-β-nitroolefins 42a-h(Scheme 32). All the reactions proceeded to afford the corresponding chiral Michael adducts
44c-l. The reactions of substrate 42a with o- or p-methylated nitrostyrenes 43b,c afforded thecorresponding chiral Michael adducts 44c,d in good to moderate chemical yields,
diastereoselectivities and good enantioselectivities (44c: 74%, dr. 98:2, 98% ee, 44d: 91%, dr.
93:7, 90% ee). The use of p-methoxynitrostyrene 44d afforded the corresponding adduct 44e
in good chemical yield (86%) and stereoselectivities (dr. 97:3, 90% ee). Also, the reaction
mixtures using the p-halogenated nitrostyrenes 44f,g was also in accordance with this condition
and resulted in corresponding adducts 44f,g were obtained with satisfactory results (44f: 81%,dr. 94:6, 97% ee, 44g: 91%, dr. 99:1, 92% ee). The uses of both heterocyclic 2-furylnitroethylene 43g and nitrovinyl-thiophene 43h afforded the adducts 44h and 44i, respectively,
in good chemical yields (44h: 86%, 44i: 79%) with good stereoselectivities (44h: dr. 93:7, 93%ee, 44i: dr. 83:17, 91% ee). Furthermore, 1-oxo-2-indanecarboxylate 42c with 43a also
afforded the corresponding adduct 44j in good chemical yield and enantioselectivity (82%,
88% ee) with good diastereoselectivity (dr. 85:15). Also, the uses of methyl 2-oxo-1cyclohexanecarboxylate 42d and 2-oxo-1-cycloheptanecarboxylate 42e also provided thecorresponding adducts 44k,l in good chemical yields and high level of stereoselectivities (44k:
76%, dr. 90:10, 91% ee, 44l: 84%, dr. 86:14, 88% ee).

38

O

O
R

+

O

43a-h
(1.0 equiv.)

42a,c-e(2.0 equiv.)
O

O

OMe

O

O

catalyst 62b(5 mol%)H2Ort., 48 h

NO2

R'

O

O

[2R,3S]-44c-l

O

O

OMe
NO2

NO2

[2R,3S]-44d
91%, dr. 93:7,
90% eeO

OMe

O[2R,3S]-44h
86%, dr. 93:7,
93% eeCl[2R,3S]-44e
86%, dr. 97:3,
90% ee
O

OMe

NO2
O

NO2

NO2

[2R,3S]-44c
74%, dr. 98:2,
98% ee
O

OMe

NO2

OMe

O

O

O

OMe

OMe

O

[2R,3S]-44f
81%, dr. 94:6,
97% ee
O

OMe
NO2

NO2

F

O

[2R,3S]-44g
91%, dr. 99:1,
92% ee
O

OMe

O

OMe

NO2

NO2

S

[2R,3S]-44i
79%, dr. 83:17,
91% ee[2R,3S]-44j
82%, dr. 85:15,
88% ee[2R,3S]-44k
76%, dr. 90:10,
91% ee[2R,3S]-44l
84%, dr. 86:14,
88% eeScheme 32. Generality of catalyst 62b in asymmetric Michael additions of β-ketoesters 42a,c-e with trans-nitroolefins 43a-h

In view of the excellent enantioselectivity (98% ee) of the Michael adduct [2R,3S]-44a thatwas obtained in the reaction of 42a with 43a using catalyst 62b, the results of its calculation
studies (Figure 18-20), and based on the structure of catalyst 62c by our previous study,41 an
enantioselective reaction course is proposed as follows (Scheme 33). For the estimation ofenantioselective reaction course, the conformational analysis by using the scan of total energies
for 62b was firstly carried out and the result was indicated that the conformation of C-1 wasmost stable as the conformation of 62b (Figure 5).

39

Figure 5. The scan of total energies for 62 (conformations C-1
to C-4 generated)
Furthermore, to examine the regioselectivity of the reaction between 42a and 43a moreaccurately, the calculation of the energies and coefficients of their frontier orbitals was
conducted. The energy levels of the orbitals clearly showed the dominate the interaction
between the LUMO of 43a and the HOMO of 42a, and their orbital phase and the coefficientof the orbital clearly demonstrated a matching in favour of overlapping to afford the observed
configuration of major adduct 44a (Figure 6).

40

NO 2

O

O
OMe

6a

5a

43 a

42 a

O
H

N

O
O

MeO

O

H

!0.*0238

LUMO

( ))

!0.0967!0.2553!0.2232

HOMO

43 a
43 a

HOMO

LUMO

42 a
“favor"42 a

Theredandandblue
bluedotted
dottedlines:
lines:
The
red
thematchingofoforbital
orbitalphase
phase
the
matching
between 5a and 6a
between 42a and 43a.

Figure 6: The frontier orbitals between 42a and 43a obtained by DFT
calculations at the 6-31 G(d) level using a B3LYP exchange correction
functional [the dotted lines (blue and red)] in the red square indicated aninteractions between the molecular orbitals of 42a and 43a.
In addition, the positive charge was on the nitrogen atom of the amino moiety in the catalyst
62b (C-1), and the negative charges were both on the oxygen atoms of the nitro group in
nitrostyrene 43a and on the oxygen atoms of the β-keto ester 42a (Figure 7).

C-1
I-1

2143a6a2142a

5a

Figure 7. The electrostatic potential maps of 62b (C-1),
42a and 43a
Moreover, the author examined the reaction of amino amide 62b, that acts as the best
catalyst, with β-keto methyl ester under the same reaction condition in Table 1. However, the41formation of enamine species was not observed in this reaction condition. This result indicatesthat amino amide 62b may act as a basic catalyst in this reaction.
Based on the calculation results of the scan total energy, the structure of catalyst 62b might
be fixed by the intramolecular hydrogen bonding interaction between the amino hydrogen atomand the amide oxygen atom, and thereby catalyst 62b might have the conformation shape C-1
of which are having less steric interaction between the tert-butyl substituent at the α-position
and the 1-naphthy substituent on amide group. Furthermore, when the reaction proceeds, 62b
acts as a base and then it might be formed Ts-1-4 in which both substrates 42a and 43a fixedwith the ammonium hydrogen atom on the ammonium catalyst species by the hydrogenbonding interactions. In the proposed Ts-1-4, the reaction might be proceeding through Ts-1,
based on the frontier and the electrostatic potential map, that has a smaller steric interaction
both between substrates 42a and 43a and between 62b and the 1-naphthyl substituent at amidegroup on the ammonium catalyst species than those of Ts-2-4 that have a larger stericinteraction between substrates 42a, 43a and the 1-naphthyl substituent ammonium catalyst
species (Scheme 33).
O

O

NO2

+

OMe

O
HN

42a

N
H

43a

HN

NH2

O

H

N

N

H
O

H

H

O

MeO

O

H

N

O H

H
O

O

H

O

H

N

N

N

O

O

N
H

O

N

O
OMe

OMe

H

C-2

O
O

H

H

H

H

O
H

C-1

O

N

HN

H

catalyst 62b

O

HN

O

H
O

N

N
H

H
O O

N

O

H

OMe

H

Ts-2

Ts-1

Ts-3

Ts-4

98% ee

O

O
R

MeO

O

O
S

Ph

[2R,3S]-44a

Ph

NO2

[2S,3R]-44a,b

O

O
R
R

R

S
O2N

O
OMe

Ph

OMe
NO2

[2R,3R]-44a,c

O
S
S
Ph

OMe
NO2

[2S,3S]-44a,dScheme 33. Plausible reaction course using catalyst 62b (the blue dotted lines
indicated the hydrogen bonds among the N+H moiety of 62b, 43a and 42a.The red
dotted lines indicated the interactions between the molecular orbitals of 43a and 42a).

423.3 Summary
In summary, the new simple amino amide organocatalysts 62a-f and 70a-c were developedand examined based on a new catalyst design concept in the asymmetric Michael addition ofvarious β-keto esters 42a-e with trans-b-nitroolefins 43a-h. Among the optimized catalysts
62a-f and 70a-c, the catalyst 62b possessing with 1-naphthyl group have showed a best
catalytic activity in this reaction and afforded the corresponding chiral Michael adducts 44a-l
having quaternary chiral carbon centre with good to excellent chemical yields (up to 99%),
diastereoselectivities (up to 99:1) and enantioselectivities (up to 98% ee).

43Conclusion
The world is facing bigger crisis worsen to save humans from continually emerging of lifethreatening diseases. Hence, scientists are trying to find a new alternative gateway to treat,
reduce, and possibly finding a lasting solution to epidemic outbreaks of diseases and new drugs.
Most of the bioactive compounds, including medicines, are optically active substanceswhereby a pair of enantiomers exhibits different biological activities. Particularly, in
pharmaceuticals, 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 optically
active compounds, is among the most important current challenges in organic synthetic
chemistry. Environmental implications evade as a result of chemical syntheses, andenvironmentally benign organic syntheses have been receiving attention. The chiral catalysts
used in catalytic asymmetric syntheses can be divided 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. Therefore, there is a need to develop an enantioselective
synthesis for optically bioactive compounds which can afford desirable optically active
substances with high pharmaceutical values.
On these backgrounds, the author developed a new set of simple amino amideorganocatalysts and was explored based on a new catalyst design concept. These amino amideorganocatalysts were successfully prepared from commercially available amino acids by using
simple organic transformations and the catalytic activity was demonstrated in theenantioselective Aldol reactions (chapter 1) and Michael additions (chapter 2).
In chapter 1, the author discussed the detailed application of new type amino amideorganocatalysts 62a-f based on a new catalyst design concept. Their catalytic activities were
examined in the enantioselective crossed Aldol reaction of various acyclic or cyclic ketones 63
and 65a-g with aromatic aldehydes 64a-n. As a result, catalyst 62c with a bulky 1-pyrenyl
group showed best catalytic performance and afforded the corresponding chiral anti-Aldol
products 44 with good to excellent chemical yields, diastereoselectivities andenantioselectivities (up to 99%, up to syn:anti = 1:99, up to 97% ee).
In chapter 2, the enantioselective Michael addition was established with various β-ketoesters 42a-e and trans-b-nitroolefins 43a-h using amino amide organocatalysts 70a-c. This
protocol provides the corresponding chiral Michael adducts having quaternary chiral carbon
centre. In this study, the author revealed that the new explored amino amide organocatalyst
44having both hydrogen-bonding sites and enamine formation with 1-naphthyl group the catalyst
62b shows high catalytic activity in the enantioselective to afford the corresponding chiralMichael adducts 44a-l having quaternary chiral carbon centre with good to excellent chemicalyields (up to 99%), diastereoselectivities (up to 99:1) and enantioselectivities (up to 98% ee).
In conclusion, the author developed new type amino amide organocatalysts. Their catalytic
activities were examined in enantioselective Aldol reactions and Michael additions which
afforded the corresponding products. It’s expected that these findings might be able tocontribute greatly to the development of new synthetic drugs in the field of synthetic organic
chemistry.

45

Experimental section
General information: All glassware used were firstly flame drying and cool in a desiccator
before been used for an experiment. All reactions were performed in an argon atmosphere,
examined with thin layer chromatography (TLC) and under ultraviolet light (UV, 254 nm). The
products were visualized using ninhydrin staining, anisaldehyde staining and/or iodine vapour
developed. The reaction mixtures were monitored with TLC incorporated with silica plate gel
60F254 on Merck. Also, the purifications of products were confirmed using flash
chromatography system in silica gel 60 N (40-50 μm) purchased from Kanto Chemical
Company. Expect preconditioned stated, all purchased reagents were used without any further
purifications. A JEOL JNM-ECA500 instrument was used for the NMR Spectra determination.
The spectra for 1H NMR (500 MHz) and 13C NMR (125 MHz) were measured in CDCl3,
DMSO-d6 or MeO-d4 for solvents and named ppm obtained in tetramethylsilane (δ = 0.00 ppm)
or sometime residual solvents system suitability used for internal standard DMSO-d6 (δ = 2.50ppm), CDCl3 (δ = 7.26 ppm) for 1H NMR; CDCl3: δ = 77.16 ppm for 13C NMR). Report datafor 1H NMR spectroscopy are reported as follows: chemical shift (d ppm), multiplicity (s =singlet, d = doublet, t. triplet, q = quadruplet, dd = doublet of doublets, td = triplet of doublets,
m = multiplet and br. = broad, coupling constants (J) and integration were measured in Hz. A
JASCO FT/IR-4100 instrument was used to determined infrared (IR) spectral data. Also, a
JASCO DIP-360 incorporated in ethanol were measured for optical rotation. The melting point
for was determined using a Yanaco micro melting point apparatus. By using EI mode in Hitachi
RMG-6MG and JEOL-JNM-DX303 spectrometers, HRMS spectra were recorded. The result
values were determined for diastereomeric ratio diastereomeric excess using HPLC principle
by DAICEL CHIRALPAK AD-H columns. HRMS spectra were performed by EI using sector
instruments.

Chapter 2: A new type amino amide organocatalyzed enantioselective crossed Aldol
reaction of ketones with aromatic aldehydes

General procedure for the synthesis of amino amide organocatalysts catalysts 62a-f: To asolution of amines 60a-d (0.36 mmol) in anhydrous DCM (3 mL) was added N-Boc aminoacids 59a-c (0.3 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbondiimide (EDC) (64 mL,
0.36 mmol) (EDC) and 1-hydroxybenzotriazole (HOBt) (49 mg, 0.36 mmol) at 0 oC and the
mixture was stirred for 1 h. Afterwards, the reaction was allowed to room temperature the46reaction was carried out for 24 h. After the reaction was completed, which was monitored by
TLC, the solution was diluted with EtOAc and then washed with 0.1 N HCl, saturated NaHCO3
solution, and brine. The combined organic layer was dried over Na2SO4 and concentrated undera reduced pressure to afford the crude products that were used for the next step without further
purification. To the solution of the crude products in dry DCM, TFA was added in dropwise
over a period of times (0.4 mL) at 0 oC and subsequently stirred at room temperature (r.t.) for
3 h. After DCM and TFA were removed under reduced pressure, the residue was neutralized
by drop-wise addition of saturated NaHCO3 solution at 0 oC and stirred for 1 h at r.t. The crude
products were extracted with DCM, dried over Na2SO4 and concentrated under reducedpressure. The residue was purified by flash column chromatography on SiO2 (n-hexane:
EtOAc. 3:1 to 1: 1) to afford the amino amide organocatalysts 62a-f.

(S)-2-Amino-N-(anthracene-2-yl)-3,3-dimethylbutanamide (62a):39 Brown solid (EtOAc),
54% yield. M.p. 201-202 oC. [α]D29 = -31.37 (c = 0.51, CH2Cl2).
H2N

O

IR (neat) ν˜ = 4313, 3879, 2361, 1669, 890, 754 cm–1. 1H NMR

N
H(500 MHz, CDCl3): δ = 9.26 (br s, 1H, NH), 8.50 (s, 1H), 8.358.34 (d, 2H, J = 4.0 Hz), 7.99-7.94 (m, 3H), 7.45-7.40 (m, 3H),

62a

3.34 (s, 1H), 1.66 (br s, 2H, NH2), 1.11 (s, 9 H). 13C NMR (125MHz, CDCl3): δ = 172.14, 134.48, 132.26, 132,13, 131.13,

129.29, 129.30, 128.27, 128.06, 126.12, 125.75, 125.60, 125.06, 120.76, 115.18, 64.98. 34.64,
26.99. MS (EI): m/z = 306 [M+H]+. HRMS (EI): calculated for C20H22N2O [M+H]+ 306.1732,
found 306.1725.

(S)-2-Amino-N-(naphthalene-1-yl)-3,3-dimethylbutan-amide (62b): White solid (EtOAc),
53% yield. M.p. 88-89 oC. [α]D20 = -104 (c = 0.24, CH2Cl2). IR

H2N

13

O

(neat) ν˜ = 3360, 2954, 1681, 1540, 970, 774 cm-1. 1H NMR (500N
H

MHz, CDCl3): δ = 9.88 (br s, 1H, NH), 8.24-8.22 (dd, J = 7.562b

7.54-7.48 (m, 3H), 3.42 (s, 1H), 1.73 (br s, 2H, NH2), 1.14 (s, 9H).

Hz,1.0 Hz, 1H), 7.90-7.85 (m, 2H), 7.65-7.63 (d, J = 8.5 Hz, 1H),C NMR (125 MHz, CDCl3): δ = 171.90,134.15, 132.56, 128,92, 126.24, 126.18, 126.10,

125.91, 124.60, 120.34, 118.30, 65.21, 34.56, 27.08, 14.30. MS (EI): m/z = 256 [M+H]+.
HRMS (EI): calcd. for C16H20N2O [M+H]+ 256.1576, found 256.1568.

47

(S)-2-Amino-N-(pyrene-1-yl)-3,3 dimethylbutanamide (62c): Green solid (EtOAc), 62%
yield. M.p. 130–131 °C. [α]D27 = -45.00 (c = 0.200, CH2Cl2). IR(neat) ν˜ = 3253, 2958, 1654, 1515, 1263, 710 cm–1. 1H NMR (500
MHz, CDCl3): δ = 10.08 (br. s, 1H, NH), 8.67-8.65 (d, 1H, J = 8.0

HN
H2NHz), 8.13-8.08 (m, 3H), 8.01 (s, 2H), 7.97-7.95 (m, 3H), 3.49 (s,O 62c1H), 2.19 (br. s, 2H, NH2), 1.84 (s, 9H). 13C NMR (125 MHz,CDCl3): δ = 172.18, 131.49, 130.88, 128.34, 127.72, 127.47,

126.39, 126.12, 125.42, 125.32, 125.20, 124.90, 124.81, 122.12, 120.30, 119.96, 65.19, 34.67,
27.14. MS (EI): m/z = 330 [M+H]+. HRMS (EI): calcd. for C22H22N2O [M+H]+ 330.1732,
found 330.1736.

(S)-2-Amino-N-(pyrene-4-yl)-3,3-dimethylbutanamide (62d): Brown solid (EtOAc), 52%
yield. M.p. 174-175 °C. [α]D20 = -60.00 (c = 0.100, CH2Cl2). IR(neat) ν˜ = 3281, 2957, 1651, 1519, 826, 719 cm–1. 1H NMR (500

HN

MHz, CDCl3): δ = 10.23 (br s, 1H, NH), 8.97 (s, 1H), 8.20-8.19
H2N

O(m, 3H), 8.12-7.99 (m, 5H), 3.52 (s, 1H), 1.83 (br s, 2H, NH2),
1.20 (s, 9H). 13C NMR (125 MHz, CDCl3): δ = 172.21,131.76,

62d

131.25, 130,83, 127.90, 127.21, 126.45, 125.80, 125.72, 125.57,
125.48, 125.21, 124.46, 122.30, 117.37, 65.39, 34.65, 27.15. MS (EI): m/z = 306 [M+H]+.
HRMS (EI): calcd. for C22H22N2O [M+H]+ 330.1732, found 330.1733.

(S)-2-Amino-N-(pyrene-1-yl)-2-phenylethanamide (62e): Brown solid (EtOAc), 63% yield.
M.p. 65-66 °C. [α]D30 = -12.66 (c = 0.24, CH2Cl2). IR (neat) ν˜= 1668, 1599, 1555, 1267, 531, cm–1. 1H NMR (500 MHz,CDCl3): δ = 10.40 (br s, 1H, NH), 8.67-8.66 (d, 1H J = 8.16
HN
H2NHz), 8.15-8.09 (m, 3H), 8.05 (s, 2H), 8.02-7.96 (m, 3H), 7.597.56 (m, 2H), 7.41-7.34 (m, 3H), 4.85 (s, 1H), 2.23 (br s, 2H).

O
62e

13

C NMR (125 MHz, CDCl3): δ = 172.83,137.77, 131.49,

130,88, 130.73, 129.53, 129.01, 128.48, 127.71, 127.50, 125.75, 127.14, 126.49, 126.17,
125.49, 125.37. 125.37, 125.17, 124.88, 122.12, 120.15, 119.95, 77.44, 77.19, 76.94, 57.27,
40.94. MS (EI): m/z = 350 [M H]+. HRMS (EI): calcd. for C24H18N2O [M+H]+ 350.1419, found350.1409.

48

(S)-2-Amino-N-(pyrene-1-yl)-3-phenylpropanamide (62f): Brown soild (EtOAc), 67%
yield. M.p. 98-100 °C. [α]D26 = -20.00 (c = 0.200, CH2Cl2). IR(neat) ν˜ = 3262, 2360, 1655, 1519, 1267, 838, 772, 696 cm–1.
1
HN

H NMR (500 MHz, CDCl3): δ = 10.38 (br s, 1H, NH), 8.73-

8.72 (d, 1H, J = 8.16 Hz), 8.16-8.11 (m, 3H), 7.99-7.95 (m,
H2N

O
62f

4H), 7.89-7.88 (d, 1H, J = 9.0 Hz), 7.34-7.29 (m, 5H), 3.943.92 (m, 1H), 3.49-3.46 (dd, 1H, J = 14.02 Hz, 4.00 Hz), 3.01–

2.96 (dd, 1H, = 13.50 = 9.50 Hz), 1.75 (br s, 2H, NH2). 13C NMR (125 MHz, CDCl3): δ =172.83, 137.77, 131.49, 130,88, 130.73, 129.53, 129.01, 128.48, 127.71, 127.50, 125.75,
127.14, 126.49, 126.17, 125.49, 125.37. 125.37, 125.17, 124.88, 122.12, 120.15, 119.95, 77.44,
77.19, 76.94, 57.27, 40.94. MS (EI): m/z = 364 [M+H]+. HRMS (EI): calcd. for C25H20N2O[M+H]+ 364.1576, found 364.1579.

General procedure for the synthesis of compounds Aldol products (65 and 67): To asolution of catalysts 62a-f (0.125 mmol, 25 mol%) in H2O (0.5 mL) was added cyclohexanones(5.0 mmol) and the aldehydes (0.5 mmol) at room temperature under argon. The reaction
mixture was stirred at room temperature for an appropriate time until the reaction wascompleted, as monitored by TLC. Afterward, the mixture was extracted with DCM (3x5 mL),and the organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under areduced pressure. The residue was purified by flash column chromatography on SiO2 (nhexane/CH3CO2Et = 4:1) to afford the corresponding Aldol products.40

49

Spectroscopic data for compounds 65 and 67(S)-2-((R)-hydroxy(4-nitrophenyl)methyl)cyclohexanone (65a):40 Yield: 90%, dr (syn/anti)O= 1:99, 96 ee anti. 1H NMR (500 MHz, CDCl3) δ = 8.22-8.20 (d,OH

2H, J = 8.5Hz), 7.51-7.49 (d, 2H, J = 8.4Hz), 4.90-4.88 (d, 1H, J= 8.2Hz), 4.08 (s, 1H), 2.63-2.55 (m, 1H), 2.51-2.49 (d, 1H, J =

65a

NO2

13.6Hz), 2.42-32 (m, 1H), 2.12-2.09 (t, 1H, J = 6.5Hz), 1.84-1.81(d, 1H, J = 13.1Hz ), 1.71-1.38 (m, 5H) ppm. 13C NMR (125 MHz,CDCl3) δ = 214.8, 148.4, 147.5, 127.8, 123.4, 73.9, 57.1, 42.6, 30.7, 27.6, 24.6 ppm; HPLC
(Chiralpak AD-H column, n-hexane/iso-propanol = 80/20, flow rate = 0.5 mL/min, λ=220 nm.
Retention time: tr (major) = 32.02 min, tr (minor) = 25.02 min.
(S)-2-((R)-hydroxy(3-nitrophenyl)methyl)cyclohexanone (65b):40 Yield: 79%, dr (syn/anti)O= 23:77, 69 ee anti. 1H NMR (500 MHz, CDCl3) δ = 8.22-8.18

OHNO2(t, 2H, J = 11.9Hz), 7.68-7.67 (d, 1H, J = 7.2Hz), 7.55-7.52 (t,1H, J = 7.7Hz), 4.92-4.88 (d, 1H, J = 8.3Hz), 4.13 (s, 1H),
2.16-2.09 (t, 1H, J = 6.1Hz), 2.54-2.48 (d, 1H, J = 13.8Hz),

65b

2.40-2.34 (m, 1H), 2.11 (s, 1H), 1.84-1.39 (m, 5H) ppm. 13C
NMR (125 MHz, CDCl3) δ = 214.9, 148.2, 143.2, 133.2, 129.3, 122.8, 122.0, 74.0, 57.1, 42.6,
30.7, 27.6, 24.6 ppm; HPLC (Chiralpak AD-H column, n-hexane/iso propanol = 95/5, flowrate = 0.8 mL/min, λ=220 nm. Retention time: tr (major) = 17.18 min, tr (minor) = 12.18 min.
(S)-2-((R)-hydroxy(2-nitrophenyl)methyl)cyclohexanone (65c):40 Yield: 57%, dr (syn/anti)
O

OH

NO2

= 5:95, 90 ee anti. 1H NMR (500 MHz, CDCl3) δH (500.1 MHz,CDCl3): 7.84-7.82 (1H, d, J = 8.0 Hz), 7.76-7.75 (1H, d, J = 7.5 Hz),7.64-7.61 (1 H, t, J = 8.0 Hz), 7.43-7.39 (1 H, t, J = 7.5 Hz), 5.46-

65c

5.44 (d, 1H, J = 8.5 Hz), 4.11 (s, 1 H, s, OH), 2.76- 2.72 (1 H, q, J =6.5 Hz), 2.45–2.30 (2 H, m), 2.09–2.07 (1 H, m), 1.85–1.83 (1 H, m),

1.76-1.57 (4 H, m) ppm. 13C NMR (125 MHz, CDCl3) δ = 214.9, 148.7, 136.6, 133.1, 129.0,
128.4, 124.0, 69.7, 57.3, 42.8, 31.1, 27.7, 24.9 ppm; HPLC (Chiralpak AD-H column, nhexane/iso-propanol: 95/5, flow rate = 1.0 mL/min, λ=220 nm, Retention time: tr (major) =13.65 min, tr (minor) = 22.10 min.

50

(S)-2-((R)-(4-chlorophenyl)(hydroxy)methyl)cyclohexanone (65d):40 Yield: 82%, drO(syn/anti) = 9:91, 93 ee anti. 1H NMR (500 MHz, CDCl3), δ =OH

7.34-7.32 (d, 2H, J = 6.8Hz), 7.26-7.25 (d, 2H, J = 6.7Hz), 4.774.75 (d, 1H, J = 8.6Hz), 3.98 (s, 1H), 2.55-2.46 (m, 2H), 2.38-2.35(t, 1H, J = 6.7Hz), 2.12-2.09 (d, 1H, J = 10.0Hz), 1.83-1.54 (m,

Cl

65d

5H) ppm. 13C NMR (125 MHz, CDCl3) δ = 215.1, 139.3, 133.4,
128.3, 128.2, 74.1, 57.4, 42.7, 30.8, 27.6, 24.6 ppm; HPLC (Chiralpak AD-H column, nhexane/isopropanol = 90/10, flow rate = 0.5 mL/min, λ=220 nm. Retention time: tr (major) =42.29 min, tr (minor) = 53.65 min.
(S)-2-((R)-(3-chlorophenyl)(hydroxy)methyl)cyclohexanone (65e):40 Yield: 97%, drO(syn/anti) = 7:93, 87% ee anti. 1H NMR (500 MHz, CDCl3): δOHCl

7.35-7.19 (m, 4H), 4.77 (dd, J = 2.8, 8.4, 1H), 4.03 (d, J = 2.9,
1H), 2.63-2.61 (m, 1H), 2.60-2.33 (m, 2H), 2.14-2.06 (m, 1H),
1.84-1.81 (m, 1H), 1.73-1.52 (m, 3H), 1.38-1.27 (m, 2H) ppm.

65e

13

C NMR (125 MHz, CDCl3): δ = 215.3, 143.1, 134.3, 129.6,

128.0, 127.1, 125.3, 74.3, 57.3, 42.7, 30.8, 27.7, 24.7; HPLC (Chiralpak AD-H column, nhexane/iso-propanol = 90/10, flow rate = 0.5 mL/min, λ=220 nm. Retention time: tr (major) =47.08 min, tr (minor) = 30.42 min.
(S)-2-((R)-(2-chlorophenyl)(hydroxy)methyl)cyclohexanone (65f):40 Yield: 79%, dr(syn/anti) = 1:99, 79% ee anti. 1H NMR (500 MHz, CDCl3), δ = 7.54O

OHCl

7.51 (1H, dd, J = 7.8 and 1.9 Hz), 7.36-7.16 (3H, m), 5.34 (1H, d, J
= 8.2 Hz), 3.86 (1H, br s), 2.77-2.61 (1H, m), 2.54-2.22 (2H, m),
2.17-2.02 (1H, m), 1.86-1.42 (5H, m) ppm. 13C NMR (125 MHz,

65f

CDCl3) δ = 215.3, 139.1, 132.9, 129.2, 128.7, 128.3, 127.3, 70.5, 57.6,
42.7, 30.4, 27.8, 24.9; HPLC (Chiralpak AD-H column, n-hexane/iso-propanol = 95/5, flowrate = 1 mL/min, λ=220 nm. Retention time: tr (major) = 45.72 min, tr (minor) = 24.01 min.
(S)-2-((R)-(4-bromophenyl)(hydroxy)methyl)cyclohexanone (65g):40 Yield: 70%, drO(syn/anti) = 7:93, 92 ee anti. 1H NMR (500 MHz, CDCl3) δ =OH

7.48-7.46 (d, 2H, J = 8.0Hz), 7.22-7.20 (d, 2H, J = 8.0Hz), 4.764.74 (d, 1H, J = 8.6Hz), 3.99 (s, 1H), 2.56-2.47 (m, 2H), 2.31-

65g

Br

2.38 (m, 1H), 2.11-2.08 (t, 1H, J = 6.5Hz), 1.82-1.24 (m, 5H)
ppm. 13CNMR (125 MHz, CDCl3) δ 215.2, 143.3, 130.9, 130.0,

129.8, 125.7, 122.5, 74.2, 57.2, 42.6, 30.7, 27 ppm; HPLC (Chiralpak AD-H column, n51

hexane/iso-propanol = 90/10, 0.5 mL/min, λ=220 nm, Retention time: tr (major) = 43.51 min,tr (minor) = 26.77 min.
(S)-2-((R)-(3-bromophenyl)(hydroxy)methyl)cyclohexanone (65h):40 Yield: 88%,O

dr(syn/anti) = 26:74, 68% ee anti. 1H-NMR (500 MHz, CDCl3) δ =OH
Br

7.49-7.47 (1H, m, Ar-H), 7.40 (1H, dt, J = 7.3 Hz, J = 1.9 Hz, ArH), 7.24-7.17 (2H, m, Ar-H), 4.75 (1H, d, J = 8.7 Hz, CH-OH),
4.00 (1H, d, J = 2.7 Hz), 2.60-2.52 (1H, m), 2.51-2.42 (1H, m),

65h

2.40-2.30 (1H, m), 2.13-2.06 (1H, m), 1.85-1.73 (1H, m), 1.731.48 (3H, m), 1.34-1.22 (1H, m) ppm. 13CNMR (125 MHz, CDCl3) δ = 215.2, 143.3, 130.9,
130.0, 129.8, 125.7, 122.5, 74.2, 57.2, 42.6, 30.7, 27.7, 24.6 ppm. HPLC testing conditions:(Chiralpak AD-H column, n-hexane/iso-propanol = 90/10, flow rate = 0.5 mL/min, λ=220 nm,
Retention time: tr (major) = 23.42 min, tr (minor) = 21.48 min.
(S)-2-((R)-(2-bromophenyl)(hydroxy)methyl)cyclohexanone (65i):40 Yield: 76%, dr
O

OH

Br

(syn/anti) = 6:94, 75% ee anti. 1H NMR (500 MHz, CDCl3) δ = 7.547.53 (d, 2H, J = 3.5Hz), 7.37-7.34 (t, 1H, J = 7.4Hz), 7.17-7.13 (t, 1H,
J = 7.5Hz), 5.32-5.30 (t, 1H, J = 3.9Hz), 4.04 (s, 1H), 2.71-2.67 (m,65i1H), 2.49-2.45 (d, 1H, J = 13.4Hz), 2.39-2.31 (m, 1H), 2.11-2.08 (d,1H, J = 10.5Hz), 1.85-1.57 (m, 5H) ppm; 13C NMR (125 MHz, CDCl3): d = 215.3, 139.9, 131.4,
128.7, 121.6, 74.1, 57.2, 42.6, 30.7, 27.7, 24.6 ppm. HPLC testing conditions: (Chiralpak ADH column, n-hexane/iso-propanol = 90/10, flow rate = 1.0 mL/min, λ=220 nm, Retention time:tr (major) = 17.97 min, tr (minor) = 24.26 min.
(S)-2-((R)-hydroxy(phenyl)methyl)cyclohexanone (65j):40 Yield 74%, dr (syn/anti) = 9: 91,OOH

81% ee anti. 1H NMR (500 MHz, CDCl3) δ = 7.35-7.33 (d, 5H, J =8.7Hz), 4.80-4.77 (d, 1H, J = 8.7Hz), 3.98 (s, 1H), 2.63-2.59 (d, 1H, J= 7.2Hz), 2.50-2.47 (d, 1H, J = 13.2Hz), 2.39-2.32 (m, 1H), 2.10-2.07

65j(t, 1H, J = 6.3Hz), 1.80-1.25 (m, 5H) ppm. 13C NMR (125 MHz,CDCl3) δ = 215.6, 140.9, 128.3, 127.9, 127.0, 74.7, 57.4, 42.6, 30.8,

27.8, 24.7 ppm; HPLC testing conditions: DAICEL Chiralpak AD-H column, n-hexane/isopropanol = 90/10, flow rate = 0.5 mL/min, λ=220 nm, Retention time: tr (major) = 19.49 min,tr (minor) = 21.7 min.

52

(S)-2-((R)-(3-methoxyphenyl)(hydroxy)methyl)cyclohexanone (65k):40 Yield 96%,O

dr(syn/anti) = 5:95, 96% ee anti. 1H NMR (500 MHz, CDCl3):

OH
OCH3

δ = 7.28–7.33 (m, 1H, ArH), 6.80–7.00 (m, 3H, ArH), 4.80
(d, J = 8.7 Hz, 1H), 3.85 (s, 3H), 2.30–2.75 (m, 3H), 2.00–
2.15 (m, 1H), 1.55–1.90 (m, 4H), 1.20–1.40 (m, 1H) ppm.

65k

13

C NMR (125 MHz, CDCl3): d = 215.5, 159.6, 142.5, 129.3,

119.4, 113.3, 112.4, 74.6, 57.3, 55.2, 42.6, 30.8, 27.8, 24.6 ppm. HPLC testing conditions:
DAICEL Chiralpak AD-H column, n-hexane/iso-propanol = 95/5, flow rate = 1.0 mL/min,
λ=220 nm. Retention time: tr (major) = 6.68 min, tr (minor) = 12.24 min.
(S)-2-((R)-(2-methoxyphenyl)(hydroxy)methyl)cyclohexanone
OOH(65l):40

Yield

73%,

dr(syn/anti) = 5:95, 92% ee anti. 1H NMR (500 MHz, CDCl3): δ =OCH3

7.42 (d, J = 8.0, 1H), 7.40 (t, J = 7.6, 2H), 7.28 (t, J = 8.0, 1H), 6.88
(d, J = 8.4, 1H), 5.28 (dd, J = 2.8, J = 8.4, 1H), 3.85 (d, J = 4.8, 1H),
3.83 (s, 3H), 2.78-2.71 (m, 1H), 2.51-2.32 (m, 2H), 2.08-2.04 (m,65l

1H), 1.85-1.27 (m, 5H) ppm. 13C NMR (125 MHz, CDCl3): δ =215.6, 156.7, 129.6, 128.6, 127.8, 120.9, 110.5, 68.6, 57.3, 55.4, 42.6, 30.5, 28.0, 24.7 ppm;
HPLC testing conditions: DAICEL Chiralpak AD-H column, n-hexane/iso-propanol = 98/2,
flow rate = 0.8 mL/min, λ=220 nm, Retention time: tr (major) = 12.85 min, tr (minor) = 23.96
min.
(2S,R)-2-[Hydroxy(4-tolyl)methyl]cyclohexan-1-one (65m):40 Yield 86%, dr (syn/anti) =O

14:86, 94% ee anti. 1H NMR (500 MHz, CDCl3) δ = 7.22-7.20

OH(d, 2H, J = 8.1Hz), 7.16-7.14 (d, 2H, J = 8.0Hz), 4.77-4.44 (dd,
1H, J = 2.6Hz, J = 8.9Hz), 3.92-3.91 (d, 1H, J = 2.8Hz), 2.64-

65m

CH3

2.57 (m, 1H), 2.51-2.45 (m, 1H), 2.40-2.32 (m, 4H), 2.11-2.05(m, 1H), 1.81-1.49 (m, 5H) ppm. 13C NMR (125 MHz, CDCl3):

δ = 199.1, 161.1, 138.9, 137.9, 129.0, 128.9, 128.3, 128.0, 124.3, 80.1, 42.1, 41.5, 37.1, 29.5,
22.5, 21.4 ppm. HPLC testing conditions: DAICEL Chiralpak AD-H column, n-hexane/isopropanol = 90/10, flow rate = 0.5 mL/min, λ=220 nm, Retention time: tr (major) = 17.41 min,tr (minor) = 06.56 min.

53

(S)-2-((R)-(pyridin-4-yl)(hydroxy)methyl)cyclohexanone (65n):40 Yield: 98%, dr (syn/anti)= 9:91, 90% ee anti. 1H NMR (500 MHz, CDCl3) δ = 8.60-8.59 (t,OOH

2H, J = 1.7Hz), 7.27-7.25 (d, 2H, J = 4.5Hz), 4.79-4.77 (d, 1H, J =7.9Hz), 4.05 (s, 1H), 2.62-2.56 (m, 1H), 2.50-2.47 (d, 1H, J =N

65n

13.6Hz), 2.40-2.35 (m, 1H), 2.13-2.10 (t, 1H, J = 6.4Hz), 1.86-1.52(m, 5H) ppm; 13C NMR (50 MHz, CDCl3) d 214.6, 142.6, 131.5,

130.6, 129.1, 129.0, 118.7, 112.4, 73.9, 57.1, 42.6, 30.6, 27.6, 24.6; HPLC testing conditions:
DAICEL Chiralpak AD-H column, n-hexane/iso-propanol = 98/2, flow rate = 0.5 mL/min,
λ=220 nm, Retention time: tr (major) = 43.55 min, tr(minor) = 33.13 min.
(S)-2-[(R)-Hydroxy-(4-(nitrophenyl)methyl)-cyclopentan-1-one (67a):40 Yield 92%,

(syn/anti) = 2:98, 91% ee anti. 1H NMR (500 MHz, CDCl3) δ =

OH

O

dr

8.20 (2H, d, J = 7.0 Hz, ArH), 7.52 (2H, d, J = 7.0 Hz, ArH),
5.25 (1H, m,), 3.56 (1H, br s), 3.01-2.71 (2H, m), 2.21 (3H, s);
67a

NO2

13

C NMR (125 MHz, CDCl3), δ = 208.6, 149.9, 147.4, 126.4,

123.8, 68.9, 51.5, 30.7 ppm. HPLC testing conditions: DAICEL
Chiralpak AD-H column, n-hexane/iso-propanol = 95/5, flow rate = 1.0 mL/min, λ=220 nm.
Retention time: tr (major) = 22.38 min, tr (minor) = 30.49 min.
(2S)-[(R)-2-[Hydroxy(4-nitrophenyl)methyl]cycloheptan-1-one (67b):40 Yield 84%,Odr(syn/anti) = 16:84, 86% ee anti. 1H NMR (500 MHz, CDCl3):

OHδ = 8.22 (d, J = 8.7 Hz, 2H, Ar), 7.53 (d, J = 8.6 Hz, 2H, Ar),
4.92 (dd, J = 6.4, 5.0 Hz, CH), 3.72–3.74 (s, 1H, OH), 2.96–
67b

NO2

3.00 (m, 1H, CH), 2.44–2.60 (m, 2H, CH2), 1.26–1.90 (m, 8H,
CH2) ppm. 13C NMR (125 MHz, CDCl3): δ = 209.7, 138.6,

134.1, 128.8, 127.9, 71.4, 69.7, 68.3, 57.9, 42.7 ppm. HPLC testing conditions: DAICEL
Chiralpak AD-H column, n-hexane/iso-propanol = 90/10, flow rate = 1.0 mL/min, λ=220 nm.
Retention time: tr (major) = 18.31 min, tr (minor) = 12.04 min.
(S)-3-[(R)-Hydroxy-[4-(nitrophenyl)methyl]dihydro-2H-pyran-4(3H)-one (67c):40 Yield
O

99%, dr (syn/anti) = 3:97, 91% ee anti. 1H NMR (500 MHz,OH

CDCl3) δ = 8.21 (2H, d, J = 8.8 Hz, ArH), 7.50 (2H, d, J = 8.8
Hz, ArH), 4.97 (1H, d, J = 8.2 Hz), 4.28-4.09 (1H, m), 3.90-

O

67c

NO2

3.64 (3H, m), 3.44 (1H, dd, J = 11.4, 9.8 Hz), 3.02-2.41 (3H,m) ppm; 13C NMR (125 MHz, CDCl3) δ = 209.2, 147.7, 147.4,
54127.4, 123.8, 71.2, 69.7, 68.2, 57.5, 42.7 ppm. HPLC testing conditions: DAICEL Chiralpak
AD-H column, n-hexane/iso-propanol = 90/10, flow rate = 1.0 mL/min, λ=220 nm. Retention
time: tr (major) = 54.78 min, tr (minor) = 46.24 min.
(S)-3-[(R)-Hydroxy-[4-(nitrophenyl)methyl]dihydro-2H-thiopyran-4(3H)-oneO(67d):40

Yield 98%, dr (syn/anti) = 5:95, 96% ee anti. 1H NMR (500OH

MHz, CDCl3): δ = 8.24 (d, J = 8.7 Hz, 2 H, Ar), 7.54 (d, J =8.6 Hz, 2H, Ar), 5.05 (dd, J = 8.0, 3.6 Hz, CH), 3.64 (d, J = 3.8

S

67d

NO2

Hz, 1H, OH), 2.65–3.05 (m, 6 H, CH, CH2), 2.51–2.53 (m, 1H,CH) ppm. 13C NMR (125 MHz, CDCl3): d = 211.4, 147.8,

147.6, 127.8, 123.9, 73.2, 59.5, 44.8, 32.87, 30.9 ppm. HPLC testing conditions: DAICEL
Chiralpak AD-H column, n-hexane/iso-propanol: 90/10, flow Rate = 1.0 mL/min, λ=220 nm.
Retention time: tr (major) = 76.59 min, tr (minor) = 33.26 min.
(2S,4R)-2-[(R)-Hydroxy-(4-(nitrophenyl)methyl)-4-methylcyclohexanone (67e):40 Yield
O

63%, dr (syn/anti) =45:55, 97% ee anti. 1H NMR (500 MHz,OH

CDCl3) δ = 8.22 (2H, d, J = 8.8 Hz, ArH), 7.51 (2H, d, J = 8.8
Hz, ArH), 4.92 (1H, d, J = 8.6 Hz), 3.99-3.87 (1H, br s), 2.81-

67e

NO2

2.29 (3H, m), 2.15-1.29 (5H, m); 1.07 (3H, d, J = 7.1 Hz,
CH3); 13C NMR (125 MHz, CDCl3) δ = 214.8, 148.4, 147.5,

127.8, 123.7, 73.9, 52.9, 38.3, 36.1, 33.0, 26.5, 18.2 ppm. HPLC testing conditions: DAICEL
Chiralpak AD-H column, n-hexane/iso-propanol: 90/10, flow Rate = 1.0 mL/min, λ=220 nm.
Retention time: tr (major) = 48.27 min, tr (minor) = 27.75 min.
(S)-tert-butyl-3-[(RO)-hydroxy(4-nitrophenyl)

methyl]-4-oxopiperidine-1-carboxylate(67f):40 Yield 94%, dr (syn/anti) = 5:95, 90% ee anti. 1H NMR

OH(500 MHz, CDCl3): d = 8.25 (d, J = 6.5 Hz, 2H), 7.57–7.54 (m,2H), 4.96 (d, J = 6.1 Hz, 1H), 4.19 (m, 1H), 3.81–3.71 (m, 2H),

N
Boc

67f

NO2

3.25 (br s, 1H), 2.91 (t, J = 8.7 Hz, 1H), 2.77 (br s, 1H), 2.59–
2.52 (m, 2H), 1.41 (s, 9H) ppm. 13C NMR (75 MHz, CDCl3):
d = 210.4, 154.2, 147.7, 147.6, 127.1, 124.0, 80.8, 72.1, 56.4,

45.4, 43.5, 41.6, 28.0 ppm. HPLC testing conditions: DAICEL Chiralpak AD-H column, nhexane/iso-propanol: 80/20, flow Rate = 1.0 mL/min, λ=220 nm. Retention time: tr (major) =7.67 min, tr (minor) = 12.58 min.

55

(R)-3-Hydroxy-3-(4-nitrophenyl)-1-phenylpropan-1-one (67g):40 Yield 90%, dr (syn/anti)= n.d, 90% ee anti. δ = 8.53–8.55 (m, 2H, Ar), 7.68–
OOH

7.72 (m, 2H, Ar), 7.17–7.21 (m, 5H, Ar), 4.79 (s, 1H),
2.66–1.77–1.97 (m, 2H) ppm. 13C NMR (125 MHz,

67g

NO2

CDCl3): δ = 209.9, 164.2, 160.9, 135.9, 135.9, 128.2,
115.7, 115.4, 71.3, 69.8, 68.3, 58.0, 42.6 ppm. HPLC

testing conditions: DAICEL Chiralpak (AD-H column, n-hexane/iso-propanol: 80/20, flow
Rate = 0.6 mL/min, λ=220 nm. Retention time: tr (major) = 18.14 min, tr (minor) = 12.58 min.
Theoretical calculations1)
The semiempirical molecular-orbital method (PM6) was used to perform theconformational analysis with Gaussian 16 program package. The gas phase geometry
optimization of the molecules leading to energy minima was achieved using the B3LYP hybrid
functional with the 6-31G (d) basis set as implemented in the Gaussian 16. For the optimized
structures of the states, vibrational normal mode analysis was carried out to ensure that theobtained structures were corresponding to minimum energy state.
1) Gaussian 16, Revision A.03,
M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb, J. R. Cheeseman, G.
Scalmani, V. Barone, G. A. Petersson, H. Nakatsuji, X. Li, M. Caricato, A. V. Marenich, J.
Bloino, B. G. Janesko, R. Gomperts, B. Mennucci, H. P. Hratchian, J. V. Ortiz, A. F. Izmaylov,
J. L. Sonnenberg, D. Williams-Young, F. Ding, F. Lipparini, F. Egidi, J. Goings, B. Peng, A.
Petrone, T. Henderson, D. Ranasinghe, V. G. Zakrzewski, J. Gao, N. Rega, G. Zheng, W. Liang,
M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda,
O. Kitao, H. Nakai, T. Vreven, K. Throssell, J. A. Montgomery, Jr., J. E. Peralta, F. Ogliaro,
M. J. Bearpark, J. J. Heyd, E. N. Brothers, K. N. Kudin, V. N. Staroverov, T. A. Keith, R.
Kobayashi, J. Normand, K. Raghavachari, A. P. Rendell, J. C. Burant, S. S. Iyengar, J. Tomasi,
M. Cossi, J. M. Millam, M. Klene, C. Adamo, R. Cammi, J. W. Ochterski, R. L. Martin, K.
Morokuma, O. Farkas, J. B. Foresman, and D. J. Fox, Gaussian, Inc., Wallingford CT, 2016.

56

Scan

Scan

Figure S1. Scan of total energies of 64a and intermediate I generated by varying two
torsion angles (the dihedral scans showed with u-shaped arrows, as shown in the below
structure). The arrow at the bottom represents the global energy minimum conformer(in the above figure).

Table S1. Cartesian coordinates (Angstroms) for 64a.
Point Group: C1
Total energy = -550.071364 hartree
SymbolX

Y

Z

C

1.705149 0.219998-1E-06

C

0.914926 1.376766-4E-06

C-0.47395 1.280288-8E-06C-1.04621

0.01012-1.2E-05

C-0.28329 -1.15932-7E-06C

1.101122 -1.04681-2E-06H

1.389721 2.354922-1E-06H-1.1119

2.155208-7E-06

H-0.7811-2.12107-7E-06H

1.735755 -1.92714 0.000001

N-2.51874 -0.10278

O-3.1691-5E-060.940918 0.000016

57

O-3.00178 -1.23336 0.000005

C

3.187041 0.336802

H

3.572913 1.379312 0.000007

O3.945508 -0.61117 0.000011

0

Table S2. Cartesian coordinates (Angstroms) for I-2.
Point Group: C1
Total energy = -1269.836923 hartree
SymbolX

Y

Z

C

3.080707 -2.70593 0.201605

C

1.753159 -3.46438 0.005064

H

1.010276 -3.20897 0.768147

H

1.313573

H

1.928439 -4.54461 0.063988

C

3.624421 -2.99904 1.614184

H

3.719554

H

4.621139 -2.56657 1.756441

H

2.965381-2.606C

4.09592-3.19637 -0.84908

H

3.703808 -3.07716 -1.86726

H

5.031534 -2.63496 -0.77909

H

4.314973 -4.26029 -0.69908

C

2.853975 -1.16678 -0.02593

H

2.596968 -1.04655 -1.08479

C

1.715739 -0.60057

O

1.916913 -0.32128 2.032091

N

0.504324 -0.45205 0.218257

H

0.504072C-0.72748 0.010896 0.731105

C-1.90747 -0.21485 -0.02746

C-0.79158 0.704617 1.947846

C-3.14459

C-1.93287 -0.96262 -1.25633

C-2.00298-3.2612-4.0819-0.6955

0.32185
1.19939-0.98089

1.756722
2.393599

0.85593-0.76062

0.451544
2.411685

58

H

0.116563 0.845001 2.516231

C-4.34693 0.143055 -0.30066

C-3.19131 1.037978 1.685911

C-3.07988

H-1.03017 -1.44302 -1.62318

H-2.02834 1.737905 3.355828

C-4.32692 -0.58045 -1.53115

C-5.58116 0.686597

C-4.44522 1.567234 2.141579

H-3.06564 -1.71077

C-5.51798 -0.74083 -2.25801

C-6.74659 0.501944

C-5.58775 1.403438 1.420407

H-4.46093 2.109569 3.083945

C-6.71351 -0.20236 -1.78821

H-5.49677 -1.29337 -3.19417

H-7.68396

0.91688-0.22345

H-6.52986

1.81277

1.77662H-7.62721 -0.33386-2.3615C

4.264327-0.3297

C

5.532736 1.526495 0.180532

C

3.481654 1.458499 -1.25377

C

5.622231 3.013562 -0.18536

H

6.399734 0.981967 -0.22216

H

5.587738 1.406602 1.273031

H

2.555305

C

5.250544 3.227625 -1.65599

H

6.632726

H

4.934611 3.588982 0.449636

H

5.377933 4.279312 -1.94069

H

5.932865

2.64144N

4.07833-0.41912 0.210818

H

4.312075 -0.43867 1.199515

C

3.804803 2.779498-1.9119

H

3.623203 2.710268-2.9943-1.13350.87067

0.98551
3.38594-1.971150.17555-2.8924-0.5859-1.5698
0.022698-2.28762

59

H

3.110439 3.555627 -1.54963

Chapter 3: Amino amide organocatalysts for asymmetric Michael addition of β-ketoesters with β-nitroolefins
General procedure for the synthesis of catalysts (70a-c): To a vial contain amine 60d (0.36mmol) and N-Boc amino acids 59b,c (0.30 mmol) were added 1-hydroxybenzotriazole (HOBt)(49 mg, 0.36 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbondiimide (EDC) (64 μL, 0.36mmol) (EDC) in CH2Cl2 (3 mL) and the mixtures was stirred at 0 oC for 1 h. Subsequently, thereaction mixture was stirred for 20 h. The crude reaction mixture was washed with EtOAc, 0.1
N HCl, saturated NaHCO3 solution and brine. The organic layer was dried over anhydrous
Na2SO4 and evaporated under a reduced pressure. The residue was dissolved in dry CH2Cl2 (1mL) and CF3CO2H (0.4 mL) was added at 0 oC. The reaction temperature was increased to r.t.
and stirred for 3 h. Upon the completion of the reaction (monitored by TLC) in detail follow(Scheme 2). The residue 70a-c were purified by flash column chromatography on SiO2
(EtOAc/hexane = 3/1).39,41
The synthesis of the catalysts 70a-c(S)-2-Amino-N-(naphthalen-1-yl)-3-methylbutanamide (70a):39 White crystals (EtOAc),
66 % yield. M.p. 77–78 °C. [α]D25 = –29.99 (c = 0.12, EtOH). IR
O
N
H

H2N
70a

(neat): ν˜ = 3246, 2958, 1649, 1530, 1499, 795 cm–1. 1H NMR(500 MHz, CDCl3): δ = 10.34 (br. s, 1H, NH), 8.28–8.26 (dd, J =7.73, 0.86 Hz, 1H, ArH), 7.93–7.91 (d, J = 8.31Hz, 1H, ArH),
7.87–7.86 (m, 1H, ArH), 7.65–7.64 (d, J = 8.31 Hz, 1H, ArH),

7.55– 7.47 (m, 3 H, ArH), 3.54–3.53 (d, J = 3.44 Hz, 1 H, CH), 2.59–2.50 (m, 1 H, CH), 1.63
(br. s, 2 H, NH2), 1.11–1.10 (d, J = 6.87 Hz, 3H, CH3), 0.95–0.94 (d, J = 6.87 Hz, 3 H, CH3)
ppm. 13C NMR (125 MHz, CDCl3): δ = 172.85, 134.17, 132.61, 128.93, 126.23, 126.20, 126.16,
126.14, 125.94, 124.66, 120.39, 118.14, 60.89, 30.89, 20.03, 16.09 ppm. MS (EI): m/z = 242[M + H]+. HRMS (EI): calcd. for C15H18N2O [M + H]+ 242.1419, found 242.1410.

60

(S)-2-Amino-N-(naphthalene-1-yl)-2-phenylethanamide (70b): Brown oil, 74% yield.
[α]D22 = -36.00 (c = 0.200, CH2Cl2). IR (neat): ν˜ = 3288, 1681,
1526, 947, 858, 770,696, cm-1. 1H NMR (500 MHz, CDCl3): δO= 10.20 (br s, 1H, NH), 8.23-8.22 (d, J = 7.0 Hz,1H), 7.91-7.86(m, 2H), 7.66-7.64 (d, J = 8.0 Hz, 1H), 7.56-7.25 (m, 8H), 2.05

N
H

H2N

(br s, 2H, NH2), 1.14-1.13 (d, J = 6.0 Hz, 1H). 13C NMR (12570bMHz, CDCl3): δ = 171.83,141.02, 134.16, 132,48, 129.02,

128.92, 128.26, 127.12, 126.37, 126.09, 126.03, 125.14, 120.57, 118.81, 77.69, 77.43, 77.18,
60.67. MS (EI): m/z = 276 [M+H]+. HRMS (EI): calcd. for C18H16N2O [M+H]+ 276.1263,
found 276.1263.
(S)-2-Amino-N-(naphthalene-1-yl)-3-phenylpropan-amide (70c): Brown oil, 59% yield.
[α]D20 = -17.34 (c = 0.64, CH2Cl2). IR (neat): ν˜ = 3295,
O
N
H

H2N
70c

2920, 1677, 1524, 1250, 771, 699 cm-1. 1H NMR (500
MHz, CDCl3): δ = 10.21 (br s, 1H, NH), 8.26-8.25 (d, J= 7.0 Hz,1H), 7.87-7.85 (m, 1H), 7.66-7.64 (t, J = 9.5 Hz,
J = 5.0 Hz 1H), 7.67-7.65 (d, J = 8.5 Hz, 1H), 7.52-7.25(m, 8H), 3.91 (m, 1H), 3.47-3.43 (dd, J = 13.5 Hz, J =10.0 Hz 1H), 2.94-2.89 (m, 1H), 1.65 (br s, 2H, NH2). 13C NMR (125 MHz, CDCl3): δ =172.96,137.81, 134.19, 132.60, 129.53, 128.98, 128.87, 127.09, 126.47, 126.27, 126.09,
125.04, 120.65, 118.69, 77.69, 77.45, 77.19, 57.21, 40.89. MS (EI): m/z = 290 [M+H]+. HRMS
(EI): calcd. for C19H18N2O [M+H]+ 290.1419, found 290.1418.
General procedure for the compound 44a-l: To a stirred solution of trans-β-nitroolefins 43ah (0.34 mmol, 50.00 mg) and organocatalysts 70a-c (0.03 mmol, 10 mol%) in H2O (0.5 mL)
were added β-keto esters 42a-e (0.67 mmol, 0.08 mL) at room temperature (r.t.). The crude
reaction mixture was stirred at r.t. until the reaction completed been monitored by TLC.
Afterwards, the mixture was extracted with CH2Cl2 (3x5 mL), and the organic layer was driedover anhydrous Na2SO4, filtered, and concentrated under a reduced pressure. The residue waspurified by flash column chromatography on SiO2 (EtOAc/hexane = 10/1) to afford thecorresponding chiral Michael adducts 44a-l. The diastereomeric ratio was determined by the1

H NMR analysis of the crude product. The compounds44-l were known compounds and wereidentified in accordance with the previously reported methods.51

61

Spectroscopic data for compounds 44(2R,3S)-Methyl-1-(2-nitro-1-phenylethyl)-2-oxocyclopentanecarboxylate (44a):51 Yield
O O

92%, dr = 1:99, 98% ee. 1H NMR (500 MHz, CDCl3): d = 7.32-7.22 (m,OMeNO25H), 5.20-5.14 (dd, J = 13.8, 4.2 Hz, 1H), 5.07-4.98 (dd, J = 13.5, 10.8
Hz, 1H), 4.08 (dd, J = 10.8, 3.9 Hz, 1H), 3.76 (m, 3H), 2.30–2.43 (m, 2H),
1.77–2.09 (m, 4H) ppm.13C NMR (125 MHz, CDCl3): d = 212.2, 169.8,
135.2, 129.3, 128.8, 128.3, 76.4, 62.4, 53.1, 46.2, 37.9, 31.1, 19.3 ppm.

44a

HPLC testing conditions: DAICEL Chiralpak OD-H column, nhexane/iso-propanol: 90/10, flow Rate = 1.0 mL/min, λ=220 nm. Retention time: tr (major) =18.10 min, tr (minor) = 14.40 min.
(2R,3S)-Ethyl-1-(2-nitro-1-phenylethyl)-2-oxocyclopentanecarboxylate
O O(44b):51

Yield

74%, dr = 4:96, 94% ee. 1H NMR (500 MHz, CDCl3): d 7.33-7.24 (m,OEt
NO25H), 5.18 (dd, J = 13.6, 4.0 Hz, 1H), 5.01 (dd, J = 13.6, 10.8 Hz, 1H),
4.21 (q, J = 7.2 Hz, 2H), 4.08 (dd, J = 10.8, 4.0 Hz, 1H), 2.41-2.31 (m,2H), 2.08-1.79 (m, 4H), 1.27 (t, J = 7.2 Hz, 3H) ppm. 13C NMR (CDCl3,
125 MHz): d 212.4, 169.3, 135.3, 129.3, 128.8, 128.3, 76.5, 62.4, 62.2,

44b

46.2, 37.9, 31.2, 19.4, 14.0 ppm. HPLC testing conditions: DAICEL Chiralpak OD-H column,n-hexane/iso-propanol: 90/10, flow Rate = 1.0 mL/min, λ=220 nm. Retention time: tr (major)= 18.10 min, tr (minor) = 14.40 min.
(2R,3S)-Methyl-1-[1-(4-methylphenyl)-2-nitroethyl]-2-oxocyclopentanecarboxylate
O O

OMe
NO2

(44c):51 Yield 74%, dr = 2:98, 98% ee. 1H NMR (500 MHz, CDCl3) d= 7.14-7.08 (m, 4H) , 5.13 (dd, J = 13.2, 4.5 Hz, 1H), 4.99 (dd, J =13.2, 11.1 Hz, 1H), 4.07 (dd, J = 10.8, 3.6 Hz, 1H), 3.76 (s, 3H), 2.522.34 (m, 2H), 2.30 (s, 3H), 2.07-1.77 (m, 4H) ppm. 13C NMR (12544cMHz, CDCl3) d 212.64, 170.07, 138.36, 132.20, 129.78, 129.35, 76.68,
62.74, 53.31, 46.03, 38.26, 31.18, 21.29, 19.61 ppm. HPLC testing

conditions: DAICEL Chiralpak OD-H column, n-hexane/iso-propanol: 90/10, flow Rate = 1.0
mL/min, λ=220 nm. Retention time: tr (major) = 27.63 min, tr (minor) = 16.49 min.

62

(2R,3S)-Methyl-1-[1-(2-methylphenyl)-2-nitroethyl]-2-oxocyclopentanecarboxylate
O O(44d):51 Yield 91%, dr = 7:93, 90% ee. 1H NMR (500 MHz, CDCl3):
OMe
NO2

d = 7.13-7.07 (m, 4H) , 5.14 (dd, J = 13.2, 4.5 Hz, 1H), 4.99 (dd, J =13.2, 11.1 Hz, 1H), 4.07 (dd, J = 10.8, 3.6 Hz, 1H), 3.77 (s, 3H), 2.522.34 (m, 2H), 2.30 (s, 3H), 2.07-1.77 (m, 4H) ppm. 13C NMR (125MHz, CDCl3) d 212.64, 170.07, 138.36, 132.20, 129.78, 129.35, 76.68,

44d62.74, 53.31, 46.03, 38.26, 31.18, 21.29, 19.61 ppm. HPLC testing
conditions: DAICEL Chiralpak OD-H column, n-hexane/iso-propanol: 90/10, flow Rate = 1.0
mL/min, λ=220 nm. Retention time: tr (major) = 21.73 min, tr (minor) = 14.60 min.
(2S,3R)-Methyl-1-[1-(4-methoxyphenyl)-2-nitroethyl]-2-oxocyclopentanecarboxylate
O O

OMe
NO2

(44e):51 Yield 86%, dr = 3:97, 90% ee. 1H NMR (500 MHz, CDCl3): d= 7.18-7.15 (m, 2H), 6.84-6.82 (m, 2H), 5.11 (dd, J = 13.3, 4.1 Hz, 1H), 4.89-5.01 (dd, J = 13.3, 11 Hz, 1H), 4.04 (dd, J = 11.0, 4.1 Hz, 1H),
3.78 (s, 3H), 3.75(s, 3H), 2.44-2.30 (m, 2H), 2.06-1.80 (m, 4H) ppm.
13

44e
OMe

C NMR (125 MHz, CDCl3) d = 212.3, 169.8, 159.3, 130.4, 126.9,

114.1, 76.5, 62.6, 55.1, 53.0, 45.4, 37.9, 30.9, 19.3 ppm. HPLC testing

conditions: DAICEL Chiralpak OD-H column, n-hexane/iso-propanol: 90/10, flow Rate = 1.0
mL/min, λ=220 nm. Retention time: tr (major) = 29.14 min, tr (minor) = 17.93 min.
(2R,3S)-Methyl-1-[1-(4-chlorophenyl)-2-nitroethyl]-2-oxocyclopentanecarboxylate (44f):
O O

51

OMe
NO2

Yield 81%, dr = 6:94, 97% ee. 1H NMR (500 MHz, CDCl3) d = 7.58-

7.55 (m, 1H), 7.40-7.37 (m, 1H), 7.26-7.22 (m, 2H), 5.48 (dd, J = 14.1,
3.6 Hz, 1H), 5.10 (dd, J = 13.8, 10.5 Hz, 1H), 4.52 (dd, J = 10.8, 3.6
Hz, 1H), 4.20 (q, J = 7.2 Hz, 2H), 2.49 (t, J = 7.5 Hz, 2H), 2.27-1.88(m, 4H), 1.27 (t, J = 7.2 Hz, 3H); 13C NMR (125 MHz,) d = 212.6,

44f

Cl

169.3, 135.5, 134.7, 130.1, 129.3, 129.0, 127.6, 76.8, 62.1, 37.8, 33.0,
29.7, 19.3, 14.0 ppm. HPLC testing conditions: DAICEL Chiralpak

OD-H column, n-hexane/iso-propanol: 90/10, flow Rate = 1.0 mL/min, λ=220 nm. Retention
time: tr (major) = 21.18 min, tr (minor) = 14.18 min.

63

(2R,3S)-Methyl-1-[1-(4-fluoro-phenyl)-2-nitroethyl]-2-oxocyclopentanecarboxylate
O O

OMe
NO2

(44g):51 Yield 91%, dr = 1:99, 92% ee. 1H NMR (500 MHz, CDCl3) d= 7.29-7.27 (m, 2H), 7.03-6.98 (m, 2H), 5.15 (dd, J = 13.5, 3.8 Hz, 1H),
4.97 (dd, J = 13.5, 11.1 Hz, 1H), 4.20 (q, J = 7.2 Hz, 2H), 4.05 (dd , J= 11.1, 3.6 Hz, 1H), 2.43–2.32 (m, 2H), 2.08-1.82 (m, 4H), 1.27 (t, J =7.2 Hz, 3H) ppm. 13C NMR (125 MHz, CDCl3) d = 212.3, 169.3, 162.4

44g
F(d, J = 46.5 Hz), 131.2, 131.1, 115.9, 115.7, 77.2, 76.5, 62.4, 62.3, 45.5,

37.9, 31.4, 19.4, 14.0 ppm. HPLC testing conditions: DAICEL Chiralpak OD-H column, nhexane/iso-propanol: 90/10, flow Rate = 1.0 mL/min, λ=220 nm. Retention time: tr (major) =22.71 min, tr (minor) = 15.06 min.
(2R,3S)-Methyl-1-[1-(furan-2-yl)-2-nitroethyl]-2-oxocyclopentanecarboxylate
O O

OMe
NO2

(44h):51

Yield 86%, dr = 7:93, 93% ee. 1H NMR (500 MHz, CDCl3) d = 7.33
(d, J = 1.2 Hz, 1H), 6.30 (dd, J = 3.3, 1.8 Hz, 1H), 6.18 (d, J = 3.2 Hz,
1H), 4.95-4.91 (m, 2H), 4.44 (dd, J = 9.8, 4.6 Hz, 1H), 4.21 (q, J = 7.2
Hz, 2H), 2.51-2.30 (m, 2H), 2.15-1.95 (m, 3H), 1.80-1.72 (m, 1H), 1.28

O(t, J = 7.2 Hz, 3H); 13C NMR (125 MHz, CDCl3): d = 212.1, 168.9,

44h

149.1, 142.7, 110.8, 110.1, 74.5, 62.3, 61.9, 40.4, 37.9, 30.2, 19.5, 14.0

ppm.HPLC testing conditions: DAICEL Chiralpak OD-H column, n-hexane/iso-propanol:
90/10, flow Rate = 1.0 mL/min, λ=220 nm. Retention time: tr (major) = 22.00 min, tr (minor)= 15.17 min.
(2R,3S)-Methyl-1-(1-(2-thienyl)-2-nitroethyl)-2-oxocyclopentanecarboxylate
O O

OMe
NO2
S

44i

(44i):51

Yield 79%, dr = 17:83, 91% ee. 1H NMR (CDCl3, 500 MHz) d = 7.247.23 (m, 1H), 6.96- 6.92 (m, 2H), 5.12 (dd, J = 13.8, 3.7 Hz, 1H), 4.92
(dd, J = 13.8, 10.1 Hz, 1H), 4.41 (dd, J = 10.1, 3.7 Hz, 1H), 3.77 (s,3H), 2.45-2.37 (m, 2H), 2.16-1.91 ppm (m, 4H) ppm.13C NMR (CDCl3,
125 MHz) d 212.3, 169.8, 137.4, 128.6, 126.8, 126.1, 77.5, 62.4, 53.1,
42.1, 38.0, 31.5, 19.4 ppm. HPLC testing conditions: DAICEL

Chiralpak OD-H column, n-hexane/iso-propanol: 90/10, flow Rate = 1.0 mL/min, λ=220 nm.
Retention time: tr (major) = 17.76 min, tr (minor) = 11.53 min.

64

(2R,3S)-2-(1-Naphthalen-1-yl-2-Nitro-ethyl)-2-phenyl-cyclopentanone (44j):51 Yield 82%,
O O

dr = 15:85, 88% ee. 1H NMR (500 MHz, CDCl3) δ = 7.35-7.25

OMe
NO2

(m, 3H), 7.21-7.10 (m, 2H), 5.12 (dd, J = 13.6, 11.1 Hz, 0.17H),
5.00-4.89 (m, 1.66H), 4.81 (dd, J = 13.7, 3.1 Hz, 0.17H), 4.07 (dd,J = 10.1, 4.3 Hz, 1H), 3.783 (s, 0.51H), 3.776 (s, 2.49H), 2.61
(ddd, J = 12.7, 8.4, 4.0 Hz, 0.83H), 2.53 (ddd, J = 12.7, 8.9, 4.3

44jHz, 1H), 2.16-1.23 (m, 8.17H) ppm. 13C NMR (125 MHz, CDCl3)
δ = 208.3, 171.3, 135.5, 129.36, 128.7, 128.3, 77.8, 65.4, 52.4, 48.4, 41.3, 32.8, 28.9, 24.99,
210.7, 172.4, 135.0, 129.41, 128.8, 128.5, 77.9, 65.6, 52.7, 50.7, 45.2, 34.0, 30.0, 25.03, 24.2
ppm. HPLC testing conditions: DAICEL Chiralpak OD-H column, n-hexane/iso-propanol:
90/10, flow Rate = 1.0 mL/min, λ=220 nm. Retention time: tr (major) = 21.41 min, tr (minor)= 14.83 min.
(2R,3S)-Methyl-1-(1-(2-nitro-1-phenylethyl)-2-oxocycloheptanecarboxylateOO(44k):51

Yield 76%, dr = 10:90, 91% ee. 1H NMR (500 MHz, CDCl3) δ =

OMe
NO2

7.36-7.15 (m, 5H), 5.26 (dd, J = 13.4, 11.0 Hz, 0.07H), 5.16 (dd, J =13.7, 4.0 Hz, 0.93H), 5.01 (dd, J = 13.3, 11.1 Hz, 0.93H), 4.83 (dd, J= 13.4, 3.7 Hz, 0.07H), 4.21 (dd, J = 11.0, 3.1 Hz, 0.07H), 4.07 (dd,J = 13.3, 3.8 Hz, 0.93H), 3.76 (s, 3H), 2.45-2.25 (m, 2H), 2.10-1.76

44k(m, 4H) ppm; 13C NMR (125 MHz, CDCl3) δ 212.3, 169.9, 135.3,

129.3, 128.9, 128.4, 76.4, 62.4, 53.0, 46.1, 37.9, 31.1, 19.2 ppm. HPLC testing conditions:
DAICEL Chiralpak OD-H column, n-hexane/iso-propanol: 90/10, flow Rate = 1.0 mL/min,
λ=220 nm. Retention time: tr (major) = 21.41 min, tr (minor) = 14.83 min.
(2R,3S)-Methyl-1-(1-(2-nitro-1-phenylethyl)-2-oxocyclohexanecarboxylate (44l):51 Yield
O O

OMe
NO2

84%, dr = 14:86, 88% ee. 1H NMR (500 MHz, CDCl3): d = 7.357.25 (m, 3H), 7.21-7.10 (m, 2H), 5.00-4.89 (m, 2H), 4.07 (dd, J =10.1, 4.3 Hz, 1H), 3.78 (s, 3H), 2.66-2.49 (m, 2H), 2.53 (ddd, J =12.7, 8.9, 4.3 Hz, 1H), 1.94-1.40 (m, 8H) ppm. 13C NMR (125 MHz,CDCl3) d = 208.3, 171.3, 135.5, 129.4, 128.7, 128.3, 77.8, 65.4, 52.4,

44l

48.4, 41.3, 32.8, 28.9, 25.0, 24.4 ppm. HPLC testing conditions:

DAICEL Chiralpak OD-H column, n-hexane/iso-propanol: 90/10, flow Rate = 1.0 mL/min,
λ=220 nm. Retention time: tr (major) = 30.03 min, tr (minor) = 18.80 min.

65

Computational Methods1
The semiempirical molecular-orbital method (PM6) was used to perform the conformational
analysis with Gaussian 09 program package. The gas phase geometry optimization of themolecules leading to energy minima was achieved using the B3LYP hybrid functional with the
6-31G(d) basis set as implemented in the Gaussian 09. For the optimized structures of the states,
vibrational normal mode analysis was carried out to ensure that the obtained structures werecorresponding to minimum energy state.
––––––––––––––––––––––––––
1.

Gaussian 09, Revision D.01, M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria,
M. A. Robb, J. R. Cheeseman, G. Scalmani, V. Barone, B. Mennucci, G. A. Petersson,
H. Nakatsuji, M. Caricato, X. Li, H. P. Hratchian, A. F. Izmaylov, J. Bloino, G. Zheng,
J. L. Sonnenberg, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T.
Nakajima, Y. Honda, O. Kitao, H. Nakai, T. Vreven, J. A. Montgomery, Jr., J. E. Peralta,
F. Ogliaro, M. Bearpark, J. J. Heyd, E. Brothers, K. N. Kudin, V. N. Staroverov, T. Keith,
R. Kobayashi, J. Normand, K. Raghavachari, A. Rendell, J. C. Burant, S. S. Iyengar, J.
Tomasi, M. Cossi, N. Rega, J. M. Millam, M. Klene, J. E. Knox, J. B. Cross, V. Bakken,
C. Adamo, J. Jaramillo, R. Gomperts, R. E. Stratmann, O. Yazyev, A. J. Austin, R.
Cammi, C. Pomelli, J. W. Ochterski, R. L. Martin, K. Morokuma, V. G. Zakrzewski, G.
A. Voth, P. Salvador, J. J. Dannenberg, S. Dapprich, A. D. Daniels, O. Farkas, J. B.
Foresman, J. V. Ortiz, J. Cioslowski, and D. J. Fox, Gaussian, Inc., Wallingford CT, 2013.

66

SC1 SC2

Figure S1. Dihedral angle changes for theconformational analysis of compound 62b
Table S1. Cartesian coordinates (Angstroms) for C-1.
Point Group: C1
Total energy = -806.502991 hartree
SymbolX

Y

Z

C

3.458314 -0.50287 0.585083

C

4.485289 -1.6336

H

5.137172 -1.71906 1.260193

H

3.986891 -2.60206 0.243075

H

5.103543 -1.43922 -0.49753

C

2.544736 -0.86244 1.772912

H

3.149412 -1.04284 2.669114

H

1.835477 -0.0622

H

1.971963 -1.78026 1.580811

C4.200157 0.812744 0.891047

H

4.915457 1.053302 0.097721

H

3.50894H

4.764482 0.713813 1.825938

C

2.616455 -0.37806 -0.7347

H

2.229272 -1.38238 -0.95728

N

3.469132 0.022743 -1.85881

H

2.986883 -0.18173 -2.73348

H

3.549875 1.039979 -1.82886

C

1.428167 0.598966 -0.59311

N

0.215668 0.00738

0.382454

2.011285

1.654668 0.995672-0.3216967

H

0.248993 -0.99165 -0.18416

C-1.04436 0.610315 -0.10396

C-2.20338 -0.24196 -0.0994

C-1.17783 1.970919 0.114594

C-2.16096 -1.63668 -0.376

C-3.47929 0.347223 0.192535

C-2.44835 2.530688 0.372428

H-0.29855 2.598296 0.084158

C-3.29892 -2.41273 -0.3355

H-1.22858 -2.11554 -0.66229

C-4.63097 -0.48397 0.231455

C-3.57374 1.744205 0.425768

H-2.52077 3.601364 0.542489

C-4.54881 -1.83401 -0.01901

H-3.23535 -3.4744

H-5.58941 -0.02447 0.461046

H-4.54792 2.176582 0.638646

H-5.4402

O

1.584965 1.806082 -0.74744-0.55749-2.45415 0.014309

Table S2. Cartesian coordinates (Angstroms) for C-2.
Point Group: C1
Total energy = -806.497917 hartree
SymbolX

Y

Z

C-2.71425 -0.66603 0.868314

C-3.04792 -0.17343 2.290042

H-3.47233 -0.98951 2.887361

H-2.14872 0.185344 2.807618

H-3.77165 0.645437 2.253046

C-1.60823 -1.73533 0.950887

H-1.91987 -2.54624 1.619709

H-1.39729 -2.18092 -0.02798

H-0.67156 -1.3224

C-3.9766H-4.80378 -0.56404 0.233195

1.345071-1.28171 0.235351

68

H-3.79622 -1.60243 -0.79446

H-4.29695 -2.15339 0.818958

C-2.20523 0.575935 0.05068

H-1.43938 1.055825 0.664335

N-3.29086 1.546945 -0.14853

H-2.89693 2.452179 -0.40304

H-3.83337 1.243404 -0.95757

C-1.60517 0.16631

N-0.23385 0.172267 -1.48214

H

0.029596 -0.20606 -2.38732

C

0.805747 0.728229 -0.68758

C

1.936458 -0.08669 -0.35561

C

0.762627 2.050257 -0.28704

C

2.036625 -1.45318 -0.73149

C

3.011495 0.504192 0.388027

C

1.808471 2.611207 0.480369

H-0.07809 2.668328 -0.58764

C

3.152461 -2.19424 -0.40993

H

1.212154 -1.9175

C

4.147072 -0.29048 0.700367

C

2.913686 1.859171 0.802811

H

1.741067 3.650066 0.790341

C

4.22148

H

3.209986 -3.23909 -0.70218

H

4.960594 0.164275 1.26046

H

3.729437 2.292282 1.375988

H

5.096786 -2.20207 0.553493

O-2.32662 -0.18869 -2.23256-1.6073-1.30469-1.262560.307526

Table S3. Cartesian coordinates (Angstroms) for C-3.
Point Group: C1
Total energy = -806.498254 hartree69

Symbol

X

Y

Z

C

3.610433 -0.21562 -0.43172

C

4.827579 -1.12909 -0.17745

H

5.534233 -1.04992 -1.01229

H

5.354279 -0.83157 0.737059

H

4.538287 -2.17686 -0.06508

C

4.118062 1.229218 -0.61034

H

4.843859 1.261618 -1.43182

H

3.310671 1.929332 -0.83514

H

4.618749 1.586909 0.296378

C

2.897946 -0.6576

H

2.563413 -1.70259 -1.6902

H

2.028767 -0.02872 -1.95095

H

3.586953 -0.581

C

2.649119 -0.31046 0.808697

H

3.212529 0.075205 1.667049

N

2.325958 -1.7074

H

1.682343 -1.80146 1.886248

H

1.964459 -2.22137 0.307234

C

1.446182 0.663761 0.702076

N

0.246273 0.071673 0.379012

H

0.296654 -0.9293

C-1.02095 0.659679 0.186159

C-2.15765 -0.21452 0.059818

C-1.18566 2.032575 0.102986

C-2.08625 -1.63046 0.177705

C-3.44263 0.372862 -0.19511

C-2.46379 2.585727 -0.12809

H-0.32284 2.672429 0.219787

C-3.20357 -2.42345 0.031161

H-1.14689 -2.12208 0.41656

C-4.57273 -0.47519 -0.34563

C-3.56838 1.783748 -0.28493

H-2.55952 3.666303 -0.18982

C-4.4625-1.72753-2.5763

1.105781

0.26891-1.84215 -0.2412
70

H-3.11645 -3.50176 0.132143

H-5.53781 -0.01484 -0.54357

H-4.54901 2.212927 -0.47318

H-5.33779 -2.47489 -0.35849

O

1.589772 1.863439 0.905297

Table S4. Cartesian coordinates (Angstroms) for C-4.
Point Group: C1
Total energy = -806.486682 hartree
SymbolX

Y

Z

C-3.10349 0.604772 0.447751

C-3.52462 0.942386 1.893496

H-4.27373 1.743543 1.879973

H-3.97449 0.070566 2.383706

H-2.67829 1.261099 2.504764

C-4.37845 0.254208 -0.34526

H-5.08031 1.096135 -0.29676

H-4.16799 0.031683 -1.3917

H-4.87909 -0.62139 0.085965

C-2.43453 1.839375 -0.19017

H-1.52642 2.143085 0.345208

H-2.17079 1.658381 -1.23874

H-3.12184 2.69321

C-2.09912 -0.61577 0.496902

H-2.69351 -1.4818

N-1.08873 -0.39235 1.527027

H-0.51169 -1.21622 1.661394

H-0.45828 0.363749 1.273381

C-1.60682 -0.99178 -0.92444

N-0.27045 -0.82323 -1.29031

H-0.17626 -1.04635 -2.27844

C

0.936404 -0.99876 -0.53246

C

1.836637 0.103313 -0.38524

C

1.270807 -2.24182 -0.02959

C

1.553164 1.396601 -0.90118-0.16691
0.814956

71

C

3.070501 -0.10779 0.316391

C

2.483009 -2.43878 0.671764

H

0.588797 -3.07408 -0.18211

C

2.447481 2.431167 -0.73584

H

0.617539 1.551371 -1.42768

C

3.967941 0.983546 0.467252

C

3.363458 -1.39495 0.840681

H

2.716684 -3.42361 1.066135

C

3.666532 2.224228 -0.04648

H

2.217106 3.414595 -1.13632

H

4.902027 0.819138 0.998993

H

4.299307 -1.54297 1.373669

H

4.362565 3.04935

O-2.3963

0.076686-1.36503 -1.78308

Table S5. Cartesian coordinates (Angstroms) for 42a.
Point Group: C1
Total energy = -498.444622 hartree
SymbolX

Y

Z

O

0.598809 2.2028

C

1.011872 1.073995 -0.03776

C

2.315864 0.517237 0.535118

C0.286633 -0.0704-0.81506C

2.186135 -1.0076

0.416122H

2.482405 0.898511 1.547

H

3.134596 0.900429 -0.09182

C

1.311159 -1.21908 -0.84121

H

0.003916 0.314179 -1.79871

H

3.152786 -1.51439 0.34095

H

1.661721 -1.40916 1.28905

H

1.923626 -1.13161 -1.74693

H

0.833319 -2.20174 -0.85082

C-0.98256 -0.43322 -0.06077

O-2.01764 0.326316 -0.46247

O-1.05581 -1.27604 0.809927

0.074969

72

C-3.24995 0.119631 0.250149

H-3.96365 0.811211 -0.19762

H-3.58927 -0.91335 0.137087

H-3.1173

0.33795

1.312882

Table S6. Cartesian coordinates (Angstroms) for 42a.
Point Group: C1
Total energy = -514.151813 hartree
SymbolX

Y

Z

C-3.60377 -0.22512 0.000027

C-2.73676 -1.32353 0.000105

C-1.36044 -1.12978 0.000096

C-0.81994 0.171516 0.000005

C-1.70504 1.26521

C-3.08429 1.069964 -0.0001

H-4.67886 -0.3815

H-3.13838 -2.33286 0.00019

H-0.70064 -1.99226 0.000116

H-1.30015 2.27406

H-3.75167 1.926968 -0.00019

C

0.614477 0.442246 0.000069

H

0.917091 1.486885 0.000389

C

1.607036 -0.45922 -0.00018

H

1.521632 -1.53646 -0.00037

N

2.99326

O

3.833533 -0.93591 -0.00011

O3.255269 1.174088 0.000217-0.00012
0.000064-0.00024-0.03114 -3.1E-05

73

ACKNOWLEDGEMENTS
I wish to express my profound gratitude to my supervisor Professor Hiroto Nakano for yourguidance, motivation, encouragement, advice and kind support. You helped me shape mycareer and showed me how to transform my mistakes into skills during the entire journey ofthis program. It was real golden privilege, opportunity and honour to share your knowledge
and also of your extraordinary human qualities.
To my fellow laboratory members, thank you all for your companionship and providing avery pleasurable and friendly working environment.
I am also indebted to the Dr. Chigusa Seki, Prof. Eusang Kwon, Prof. Koji Uwai and Prof.
Niwayama Satomi for their collective supports.
Special thanks to my darling wife, Mrs Rasheedat Owolabi, you were always there for me,even whenever seems like giving up, you always brought me back on track in the candle ofdifficulties. Thank you for bringing balance into my life and your unconditional love. And to
my precious gift’s children (Olaromola and Ololade), I love you. May God give me strength,
ability and capacity to elicit you best parental cares.
I wish to express my sincere gratitude to my parents, Mr and Mrs Owolabi for theirunconditional love, moral and parental support.
Lastly, all glory to the God of the universe, may I continue to enjoy your everlasting graceand blessing in my entire life.

74

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