Memory of Chirality Concept in Asymmetric Intermolecular Michael Addition of α-Amino Ester Enolates to Enones and Nitroalkenes

Article abstract of DOI:10.1021/acs.joc.7b02315

A highly stereoselective asymmetric intermolecular conjugate addition of α-amino ester derivatives to cyclic enones via the memory of chirality (MOC) concept in high yields with excellent diastereo- and enantioselectivity (dr >99:1, up to 99% ee) is reported. The applicability and the generality of the strategy was demonstrated by its further exploration to acyclic α,β-unsaturated ketone and aromatic nitroalkenes, resulting in the formation of δ-keto-α-amino ester derivative and γ-nitro-α-amino ester derivatives, respectively, with excellent ee and dr.

Full text of DOI:10.1021/acs.joc.7b02315

Subscriber access provided by READING UNIV
Article
Memory of Chirality (MOC) Concept in Asymmetric Intermolecular
Michael Addition of #-Amino Ester Enolates to Enones and Nitroalkenes
Vadlamuri Veeraswamy, Gaurav Goswami, Satobhisha Mukherjee,
Koena Ghosh, Manik Lal Saha, Arunava Sengupta, and Manas K. Ghorai
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02315 • Publication Date (Web): 22 Dec 2017
Downloaded from http://pubs.acs.org on December 22, 2017
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Organic Chemistry is published by the American Chemical Society.
1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 38
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Memory of Chirality (MOC) Concept in Asymmetric
Intermolecular Michael Addition of αꢀAmino Ester Enolates
to Enones and Nitroalkenes
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Vadlamuri Veeraswamy, Gaurav Goswami, Satobhisha Mukherjee, Koena Ghosh, Manik Lal
Saha, Arunava Sengupta and Manas K. Ghorai*
Department of Chemistry, Indian Institute of Technology, Kanpur, 208016, India
Fax: (+91)ꢀ512ꢀ2596806; Phone: (+91)ꢀ512ꢀ2597518; email: mkghorai@iitk.ac.in
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if
required according to the journal that you are submitting your paper to)
Abstract
A highly stereoselective asymmetric intermolecular conjugate addition of αꢀamino ester
derivatives to cyclic enones via Memory of Chirality (MOC) concept in high yields with
excellent diastereoꢀ and enantioselectivity (dr >99:1, up to 99% ee) is reported. The applicability
and the generality of the strategy was demonstrated by its further exploration to acyclic α,βꢀ
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 38
1
2
3
4
5
6
unsaturated ketone and aromatic nitroalkenes resulting in the formation of δꢀketoꢀαꢀamino ester
derivative and γꢀnitroꢀαꢀamino ester derivatives, respectively, with excellent ee and dr.
7
8
9
Introduction
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The asymmetric intermolecular conjugate addition is one of the key reactions in organic
synthesis, especially, for accessing numerous biologically active natural products and other
important compounds.1 In most of the cases, the observed asymmetric induction is due to
external chiral sources, e. g. chiral auxiliary, chiral catalysts, chiral ligands, chiral electrophiles,
and chiral starting materials etc. The pioneering work by Alexakis2 and Feringa3 in asymmetric
conjugate addition of α,βꢀunsaturated carbonyl compounds utilizing copper catalysis, and by
Hayashi4 employing rhodium catalyzed reactions contributed significantly in the field.
Incidentally, the asymmetric intermolecular conjugate addition on nitroalkenes 5 has become an
useful tool as the adducts6 could easily be transformed into α,γꢀdiamino acid derivatives, an
useful building blocks for biologically active peptide and other substrates.7 Fuji and Kawabata
have introduced Memory of Chirality (MOC) concept and made seminal contribution in the field
of asymmetric synthesis for enantioselective construction of CꢀC bonds via MOC.8 This novel
concept has been explored in enolate and other chemistry for the synthesis of various
biologically significant chiral compounds.9 The MOC concept was successfully applied in
intramolecular conjugate addition reactions for the synthesis of pyrrolidine, piperidine,
tetrahydroisoquinoline, indoline and βꢀlactam derivatives with excellent enantioselectivity.10
Very recently Kim et. al. have reported total synthesis of lepadiformine C employing asymmetric
intramolecular conjugate addition via MOC concept.11 The implementation of the MOC concept
in asymmetric intermolecular conjugate addition remains largely unexplored till date except only
report by Kawabata et. al. who described the total synthesis of Manzacidin A.12 Earlier, we have
ACS Paragon Plus Environment

Page 3 of 38
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
demonstrated MOC concept in iminoꢀaldol reaction for the synthesis of nonracemic α,βꢀdiamino
ester derivatives and substituted aziridines.13 In continuation of our research activities in enolate
chemistry14 using MOC concept13, we have developed a simple protocol for intermolecular
conjugate addition of axially chiral enolate 1a′–b′ generated from enantiopure αꢀamino ester
derivatives 1a–b with Michael acceptors such as cyclic α,βꢀenones, acyclic (E)ꢀchalcone and
aromatic nitroalkenes (Scheme 1) to furnish the corresponding addition products with high yield
and excellent stereoselectivity (dr up to >99:1, up to 99% ee). Herein, we report our results in
detail as an article.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 1. Asymmetric Intermolecular Conjugate Addition via MOC Concept
Bn
N
O
Bn
O
Boc N CO2Me
n
Boc
OMe
ee >99%
O
∗
THF, − 78 °C, 6 h
R
R H
ee up to 99%
yield up to 71%
LDA, THF
−78 °C
dr up to >99:1
n
n = 0, 1
Li
O
O
MeO
Asymmetric Intermolecular
Michael addition via MOC
R
N
O
Bn
Bn
ee up to 95%
dr up to 97:3
NO2
Boc N CO2Me
R: Bn-, (CH3)2CHCH2-;
Ar: C6H5, 4-MeC6H4,
4-FC6H4, 2-furanyl
Ar
∗
−
THF, 78 °C, 3 h
R
NO2
yield up to 81%
Ar
Results and Discussion
Our study began with the intermolecular conjugate addition of the enolate generated from (S)ꢀNꢀ
benzylꢀNꢀBoc phenylalanine methyl ester 1a13b as the substrate with cyclohexꢀ2ꢀenone 2a as the
Michael acceptor. The enolate was generated from 1a by treatment with LDA in THF at −78 °C
in 1 h and reacted with cyclohexꢀ2ꢀenone 2a at the same temperature for 6 h to afford the
corresponding conjugate addition product 3a as a single diastereomer in moderate yield (42%)
and with good enantiomeric excess (77%) (Scheme 2, and Table 1, entry 1). Due to its existence
as a mixture of rotamers, the 1H NMR spectrum of the 3a displayed broad signals. To determine
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 38
1
2
3
4
1
the diastereoselectivity and to resolve H NMR spectrum, NꢀBoc group was deprotected with
5
6
1
4(N) HCl in ethyl acetate to give 4a as a single diastereomer (based on H NMR study of the
7
8
crude reaction mixture) in very high yield (Scheme 4).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 2. Asymmetric Intermolecular Conjugate Addition of 1a with 2a via MOC Concept
To find out the optimum reaction condition for better yield and enantioselectivity, different
bases, solvents, reaction time and amount of enolate were screened. The results are summarized
in Table 1. When the reaction was carried out with LDA in the presence of toluene, 3a was
obtained in trace amount with poor enantiomeric excess (18% ee) (Table 1, entry 2). We then
switched the base from LDA to KHMDS in different solvents. When KHMDS was employed in
THF, 3a was obtained with 31% yield and 23% ee as a single diastereomer (Table 1, entry 3).
Even on applying longer reaction time (20 h) and using KHMDS in toluene, 3a was obtained in
poor yield (26%) and with 20% ee (Table 1, entry 4). When KHMDS was used in THF/toluene
(1:4) solvent mixture, 3a was obtained in 28% yield and with 12% ee, whereas using
THF/toluene (4:1) mixture of solvent and KHMDS as base, yielded 3a in lower
enantioselectivity (14% ee) and poor yield (25%) (Table 1, entry 5 and 6). Other Na and Li based
nonꢀnucleophilic bases were also employed. When NaHMDS was used in THF, 3a was formed
in 22% yield and with 19% ee. Using LiHMDS instead of NaHMDS in THF furnished 3a with a
lower enantiomeric excess (23%) and yield (24%) (Table 1, entry 7 and 8). However, on using
LTMP in THF, 3a was obtained in 39% yield and with moderate enantioselectivity (65% ee)
(Table 1, entry 9). Based on the optimization studies LDA and THF were selected as the base
ACS Paragon Plus Environment

Page 5 of 38
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
and the solvent, respectively, for the intermolecular conjugate addition. To improve the yield and
the enantioselectivity of 3a further, next the equivalent of enolate was varied. When the reaction
was carried out with 2.0 equiv. of enolate for 6 h, the yield and enantioselectivity of 3a enhanced
to 60% and 80%, respectively. Increasing the amount of the enolate further (2.5 equiv.), to our
pleasure, 3a was obtained with 71% yield and excellent ee (99%) (Scheme 3 and Table 2, entry
1). With longer reaction time (12 h), slightly improved yield (75%), but reduced ee (83%) was
observed.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 1. Effect of Bases and Solvents on Asymmetric Intermolecular Conjugate additiona
entry
base
LDA
solvent
THF
time (h)
6
yield 3a (%)b,c
ee (%)d of 3a
1
2
3
4
5
6
7
8
9
42
trace
31
77
18
23
20
12
14
19
23
65
LDA
Toluene
10
KHMDS
KHMDS
KHMDS
KHMDS
NaHMDS
LiHMDS
LTMP
THF
20
Toluene
20
26
THF/Toluene (1:4)
THF/Toluene (4:1)
THF
19
28
18
25
24
22
THF
24
24
THF
11
39
aAll the reactions were performed using 1.0 equiv of 1a, 1.1 equiv of base and 1.1 equiv of 2a.
c
bYields of isolated products (%) after column chromatographic separation. The product was
d
obtained as a single diastereomer. Determined by chiral HPLC analysis using chiralpak Lux 5µ
Celluloseꢀ2 column (95:5 Hexane/Isopropanol as mobile phase and 1.0 mL/min flow rate).
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 38
1
2
3
4
5
6
7
8
The methodology was generalized with cyclopentꢀ2ꢀenone 2b as a Michael acceptor and the
corresponding product 3b was obtained in good yield (67%) with excellent enantiomeric excess
(91%) (Scheme 3 and Table 2, entry 2).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 3. Asymmetric Intermolecular Conjugate Addition of 1a with 2a–b
Table 2. Asymmetric Synthesis of δꢀKetoꢀαꢀAmino Ester Derivatives 3a–ba
entry
conjugated adduct 3
yield 3 (%)b,c ee (%)d of 3
1
2
1
2a (n = 1)
71
67
99
91
1a
2
2a (n = 0)
1a
aAll the reactions were performed using 2.5 equiv of enolate of 1a and 1.0 equiv of 2a–b.
bYields of isolated products 3a–b (%) after column chromatographic separation. The products
c
d
3a–b was obtained as a single diastereomer. ee was determined from chiral HPLC analysis of
3a–b using Chiral pak Lux 5u Celluloseꢀ2 column (95:5 Hexane/Isopropanol as mobile phase
and 1.0 mL/min flow rate).
The NꢀBoc group of 3a–b was deprotected using 4(N) HCl in ethyl acetate at room temperature
overnight to afford 4a–b with free NH group (Scheme 4).
ACS Paragon Plus Environment

Page 7 of 38
The Journal of Organic Chemistry
1
2
3
4
Scheme 4. Boc Deprotection of Compounds 3a–b
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
To further demonstrate the scope of this methodology acyclic (E)ꢀchalcone 2c as the Michael
acceptor was explored (Scheme 5). When the chiral enolate of 1a was reacted with acyclic (E)ꢀ
chalcone 2c at −78 °C, the product 3c was obtained with high yield (74%) and ee (70%) as a
single diastereomer.
Scheme 5. Asymmetric Intermolecular Conjugate Addition of 1a with 2c
Next the scope of our protocol was further extended to transꢀβꢀaryl nitroalkenes 5a–d as the
Michael acceptor. The enolate generated from 1a by the treatment with LDA in THF at –78 °C
was reacted with transꢀβꢀnitrostyrene 5a at the same temperature for 6 h to afford the
corresponding addition product 6a in 74% yield as a mixture of diastereomers (Scheme 6a). The
1
broad peaks were observed in the H NMR spectrum of 6a at room temperature probably
because of coꢀexistence of both the rotamers as well as mixture of diastereomers. However, the
13
formation of the product was confirmed by IR, C{1H} NMR and mass spectral analysis. To
1
ascertain the diastereoꢀ and enantioselectivity and to get a simplified H NMR spectrum, the Boc
group of 6a was removed using 1:2 trifluoroacetic acid and dichloromethane to obtain the
corresponding product 7a in high yield (88%, dr 70:30) with good enantioselectivity (ee: 74%
for the major isomer and 78% for the minor isomer), as shown in scheme 6b and Table 3 (entry
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 38
1
2
3
4
5
6
7
8
9
1). To find out the optimum condition, reaction of enolate of 1a with 5a was studied employing
different solvents and bases, and the results are summarized in Table 3. The reaction was carried
out with LDA as a base and toluene as a solvent over 10 h and a trace amount of product 6a was
obtained (Table 3, entry 2). When the intermolecular conjugate addition was studied in KHMDS
as a base with different solvents (Table 3, entry 3, 4, 5 and 6), the product 6a was obtained with
the moderate yield and moderate to high diastereoselectivity but poor enantioselectivity (for both
diastereomers, based on chiral HPLC analysis of 7a) for all the cases. However, when LTMP
was used as a base and THF as a solvent for 11 h, 6a was obtained in 68% yield (Table 3, entry
7) but with moderate diastereoselectivity and enantioselectivity. Similarly, when other bases
such as NaHMDS and LiHMDS were employed in THF, the product 6a was obtained in trace
amount even after the reaction was carried out for a long time (16 h) (entry 8 and 9 in Table 3).
The best results were obtained with LDA in THF.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 6a. Asymmetric Intermolecular Conjugate Addition of 1a with 5a via MOC
Scheme 6b. Synthesis of Nonracemic γꢀNitroꢀαꢀAmino Ester Derivative
ACS Paragon Plus Environment

Page 9 of 38
The Journal of Organic Chemistry
1
2
3
4
Table 3. Effect of Bases and Solvents on transꢀβꢀNitrostyrene Asymmetric Intermolecular
5
6
Conjugate Additiona
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ee (%)e of
ee (%)e of
6a
(%)b
74
ꢀ
7a
drc,d
70:30
ꢀ
entry
base
solvent
time (h)
7a (major) 7a (minor)
1
2f
3
LDA
LDA
THF
toluene
THF
6
10
3
74
ꢀ
78
ꢀ
KHMDS
KHMDS
68
65
66
62
68
ꢀ
74:36
78:22
81:19
79:21
64:36
ꢀ
54
20
42
40
68
ꢀ
8
4
toluene
10
5
18
17
05
70
ꢀ
5
KHMDS THF/toluene (1:4)
KHMDS THF/toluene (4:1)
6
5
7
LTMP
THF
THF
THF
12
16
16
8f
9f
NaHMDS
LiHMDS
ꢀ
ꢀ
ꢀ
ꢀ
aAll the reactions were performed using 1.0 equiv of 1a, 1.1 equiv of base and 1.1 equiv of 5a.
bYields of isolated product 6a (%) after column chromatographic separation. cCombined yield of
both the inseparable diastereomers 7a after column chromatographic purification and were
obtained in the range of 83ꢀ88%. ddr based on crude 1H NMR analysis of 7a. eee was determined
from chiral HPLC analysis of 7a using chiral ODꢀH column (95:5 hexane/isopropanol as mobile
phase and 1.0 mL/min flow rate). fTrace amount of 6a was obtained.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 38
1
2
3
4
5
6
7
8
9
Based on the above observations, we anticipated that enhancing the amount of the enolate and
reducing the enolate generation time, both the yield and the stereoselectivity could be improved.
To our great pleasure, 7a was obtained with high dr (80:20) and excellent enantioselectivity (ee:
88% for the major and 90% for the minor diastereomers), employing 3.0 equivalents of enolate
generated in 30 min at −78 °C (Table 4, entry 1). The relative stereochemistry of the major
diastereomer of 7a was confirmed by Xꢀray crystallographic analysis wherein the aryl and Nꢀ
benzyl groups were found to be anti to each other (the crystal was obtained as racemate based on
centrosymmetric point group) (Figure 2).15 However, the absolute stereochemistry of the two
stereocenters in the major diastereomer of 7a was ascertained by an indirect approach. Firstly,
the chiral HPLC analysis of the unreacted substrate 1a, isolated after intermolecular conjugate
addition between 1a and 4a, revealed the retention of original stereochemical information with
only partial racemization. Secondly, the enolate generated from enantiopure 1a on quenching
with water at −78 °C resulted in recovery of the starting substrate 1a with retention of
configuration with 95% ee, whereas, the complete racemization was noticed on quenching the
enolate with water at room temperature.16 These results suggest that the base would abstract
proton from the bottom face of substrate 1a to form chiral enolate 1a' (supported by
computational studies) which on intermolecular conjugate addition with 5a would proceed
through the same face leading to the formation of the product 6a with complete retention of
configuration at the quaternary stereogenic center (C2) as R. Following the anti relative
stereochemistry of aryl and Nꢀbenzyl groups as revealed in the Xꢀray crystal structure of 7a
(Figure 2), the absolute configuration of the other stereocenter will become S. Thus, the absolute
configuration of the major diastereomer 7a is tentatively assigned as (2R,3S) which is further
supported by the computational studies.17 The generalization of our strategy was made by
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment

Page 11 of 38
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
studying the intermolecular Michael addition between chiral enolate of 1a'–b' and various
aromatic or heteroaromatic nitroalkenes 5b–d. The corresponding addition products 6a–e were
obtained as a mixture of diastereomers (Scheme 7, Table 4). When the axial chiral enolate of 1a'
was reacted with transꢀ4ꢀmethylꢀβꢀnitrostyrene 5b, the product 6b was obtained in good yield
(76%) as a mixture of diastereomers (Table 4, entry 2). Notably, fluoroꢀsubstituted product 6c
was synthesized in good yield (75%) from the reaction of axial chiral enolate of 1a and 4ꢀfluoroꢀ
βꢀnitrostyrene 5c following our protocol (Table 4, entry 3). Similarly, hetero aryl transꢀβꢀ
nitrostyrene 5d i.e., 2ꢀ(2ꢀnitrovinyl)furan was treated with axial chiral enolate of 1a to furnish 6d
as a mixture of diastereomers in good yield (76%) (Table 4, entry 4). After successful
demonstration of the intermolecular addition with 1a' and various aromatic transꢀβꢀnitrostyrenes
5a–d, the scope of our strategy was further extended by employing (S)ꢀNꢀbenzylꢀNꢀBoc leucine
methyl ester as the axial chiral source. When axial chiral enolate of 1b was reacted with 5c the
corresponding intermolecular adduct, 6e was obtained in good yield (Table 4, entry 5) as a
mixture of diastereomers.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 7. Asymmetric Intermolecular Conjugate Addition of 1a–b with 5a–d
5a d
-
Bn
Bn
N
O
Li
O
O
NO2
MeO
R
Boc N CO2Me
LDA, THF
Ar
Boc
OMe
∗
−78 °C, 30 min
R
NO2
6a-e
−78 °C, 3 h
R
1a-b
H
N
O
1a′-b′
Ar
Bn
1a':
5a:
1b':
5b:
R = Bn,
Ar = Ph,
R = (CH3)2CHCH2;
5c:
5d:
Ar = 2-furanyl
Ar = 4-MeC6H4,
Ar = 4-FC6H4,
Table 4. Asymmetric synthesis of Intermolecular Conjugated Adducts 6a
substrate
Michael acceptor
product
yield 6
entry
(1)
(5)
(6)
(%)b
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 38
1
2
3
4
5
6
7
8
1
2
81
76
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3
4
5
75
76
75
Bn
Boc N CO2Me
Bn
N
O
∗
NO2
Boc
OMe
H
1b
6e
F
aAll the reactions were performed using 3.0 equiv enolates of 1a–b and 1.0 equiv of 5a–d.
bCombined yield of both the diastereomers after column chromatographic purification.
The NꢀBoc groups of 6a–e were deprotected with trifluoroacetic acid and dichloromethane (1:2)
to afford the corresponding products 7a–e again as a mixture of diastereomers (Scheme 8 and
Table 5). The major diastereomer could be obtained in pure form by fractional crystallization.19
All the results are shown in Table 5.
Scheme 8. Boc Deprotection of Intermolecular Conjugated Adducts 6a–e
ACS Paragon Plus Environment

Page 13 of 38
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 5. Synthesis of Nonracemic γꢀNitroꢀαꢀAmino Ester Derivatives 7a–e
ee (%)c of 7
ee (%)c of 7
entry
product (7)
yield 7 (%)a
7 drb
major (anti)
minor (syn)
1
88
80:20
88
90
70
2
87
85:15
81
3
4
86
83
86
75:25
81:19
97:3
95
85
88
95
70
ꢀ
5d
aCombined yield of 7a–e (%) both the diastereomers after column chromatographic purification.
1
c
bdr determined by H NMR of the crude reaction mixture. ee was determined by chiral HPLC
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 38
1
2
3
4
analysis of 7a–e using chiral ODꢀH column (95:5 hexane/isopropanol as mobile phase and 1.0
5
6
mL/min flow rate). dMinor diastereomer could not be isolated in column chromatography.
7
8
9
It is noteworthy that we observed high chiral induction in the present investigation and our
earlier report on asymmetric iminoꢀaldol reaction employing LDA as the base starting from our
substrate (S)ꢀNꢀbenzylꢀNꢀBoc phenylalanine methyl ester 1a. On the contrary, Kawabata et. al.
showed that KHMDS as an effective base for achieving excellent asymmetric induction using
(S)ꢀNꢀBocꢀNꢀMOMꢀαꢀamino ester derivatives as the substrate via MOC concept.9a,12 Hence, we
were curious to see the outcome of the intermolecular conjugate addition reaction between (S)ꢀNꢀ
BocꢀNꢀMOM phenylalanine methyl ester derivative 8 and transꢀβꢀnitrostyrene 5a by using our
optimized condition. Accordingly, substrate 89a was treated with LDA in THF at –78 °C for 30
min followed by reaction with transꢀβꢀnitrostyrene 5a at –78 °C for 3 h to furnish the
corresponding intermolecular conjugated adduct 9 in moderate yield (56%). To established the
stereoselectivity of this reaction the BOC group was deprotected with 1:2 trifluoroacetic acid in
dichloromethane at room temperature to afford 10 with good yield (Scheme 9) as a single
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
diastereomer (determined by H NMR spectrum of the crude reaction mixture) with negligible
enantiomeric excess (ee 2%). It is worth further mentioning that the observation is in consistent
with the Kawabata’s reports9a,12 of using KHMDS as a base in obtaining good to excellent level
of asymmetric induction starting from their designed substrate (S)ꢀNꢀBocꢀNꢀMOMꢀαꢀamino ester
derivatives.
Scheme 9. Asymmetric Intermolecular Conjugate Addition of 8 with 5a via MOC
ACS Paragon Plus Environment

Page 15 of 38
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
The stereochemical assignment of 3a–b and 7a were further supported by computational
studies.17 For this purpose, the structure of enolate (generated from 1a by the treatment with
LDA in THF at –78 °C) was optimized with respect to different geometry of the double bond (E
and Z) and the orientation of the protecting groups (Boc and benzyl) attached to nitrogen and
1a'Z1 was found to be the most stable enolate. Next, to establish the most stable product and the
stereochemical assignment of 3a–b, all the possible geometries of 3a–b both in THF and in
vacuum were modelled and optimized. For the case of 3a, the structure 3aA was found to be
most stable whereas in the case of 3b the structure 3bE was found to be most stable (Figure 1).
Similarly, all the different geometries possible in the case of 7a were optimized in vacuum and in
THF condition and 7aC was found to be more stable than other geometries which is reaffirmed
by the crystal structure of 7a. Based on Xꢀray crystallographic analysis, experimental
observation and computational studies, the absolute configuration of the major diastereomer of
7a was tentatively confirmed (2R,3S).15,17
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 1. B3LYP/6ꢀ311+G(d) Minimized structure of 1a′, 3a, 3b and 7a
1a′ꢀZ1
3aA
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 38
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3bE
7ac
Figure 2. Xꢀray crystal structure of 7a and 7e (major diastereomer)
7a
7e
Conclusion
In conclusion, we have developed a new strategy for the intermolecular conjugate addition of
(S)ꢀNꢀbenzylꢀNꢀBoc phenylalanine methyl ester with cyclic α,βꢀenones and acyclic (E)ꢀchalcone
in good to excellent enantioselectivity and excellent diastereoselectivity via Memory of Chirality
concept. The MOC concept was further extended for the synthesis of nonracemic γꢀnitroꢀαꢀ
ACS Paragon Plus Environment

Page 17 of 38
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
amino ester derivatives containing adjacent quaternary and tertiary carbon stereocenters starting
from (S)ꢀNꢀbenzylꢀNꢀBocꢀαꢀamino ester derivatives employing aromatic nitroalkenes as the
Michael acceptors. We have demonstrated that maximum chiral induction in the conjugate
addition products via MOC could be made possible employing LDA as the base. The observed
stereoselectivity of the products are supported by computational studies. The absolute
configuration of the major diastereomer of 7a could be tentatively ascertained as (2R,3S). Further
work is in progress.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Experimental Section
General Procedures. The analytical thin layer chromatography (TLC) was carried out for
monitoring the progress of the reactions using silica gel 60 F254 precoated plates. Visualizations
of the spots were accomplished with a UV lamp or I2 stain. Silica gel 230–400 mesh size was
used for flash column chromatographic purification using a combination of ethyl acetate and
petroleum ether as the eluent. Unless otherwise mentioned, all of the reactions were carried out
in ovenꢀdried glassware under an atmosphere of nitrogen or argon using anhydrous solvents.
Where appropriate, the solvents and all of the reagents were purified prior to use following the
guidelines of Armarego and Chai.19 (S)ꢀNꢀbenzylꢀNꢀBocꢀαꢀamino methyl esters13 and (S)ꢀNꢀ
MOMꢀNꢀBoc phenylalanine methyl ester9a were prepared by following the earlier reports. All of
the commercial reagents were used as received without further purification unless otherwise
mentioned. Proton nuclear magnetic resonance (1H NMR) were recorded at 400 MHz and 500
MHz. The chemical shifts were recorded in parts per million (ppm, δ) using tetramethylsilane (δ
1
0.00) as the internal standard. Splitting patterns of the H NMR are mentioned as singlet (s),
doublet (d), doublet of doublet (dd), triplet (t), triplet of doublets (td), multiplet (m) etc. Carbon
nuclear magnetic resonance (13C{1H} NMR) spectra were recorded at 100 MHz and 125 MHz.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 38
1
2
3
4
5
6
7
8
9
HRMS were obtained using (ESI) mass spectrometer (TOF). KBr pellets were used for IR
spectra of solid compounds and dichloromethane for liquied . The melting point measurements
were made using a hot stage apparatus and are reported as uncorrected. The enantiomeric excess
(ee) was determined by chiral HPLC using a Chiralcel ODꢀH, ADꢀH and Celluloseꢀ2 column
(detection at 254 nm) using hexane and isopropanol as the mobile phase and an UV/VIS
detector. Optical rotations were measured using a 6.0 mL cell with a 1.0 dm path length and are
reported as [α]25D (c in g per 100 mL solvent) at 25 °C.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
General experimental procedure for preparation of (S)ꢀNꢀbenzylated amino acid methyl
ester.13 Method A. To a solution of (S)ꢀamino acid methyl ester hydrochloride (5.00 g, 23.18
mmol (for (S)ꢀMethyl 2ꢀ(benzylamino)ꢀ3ꢀphenylpropanoate S1)) in dry MeOH (40.0 mL),
triethylamine (3.24 mL, 23.18 mmol) and benzaldehyde (3.53 mL, 34.77 mmol) were added. The
reaction mixture was stirred at room temperature for 1.5 h, cooled to 0 °C and NaBH4 (1.75 g,
46.36 mmol) was added in portions. After stirring at room temperature for additional 2 h, the
solvent was evaporated to dryness and the residue was extracted with ethyl acetate and washed
with H2O and brine. The organic layer was dried over Na2SO4 and solvent was evaporated. The
residue was purified by flash column chromatography on silica gel (230ꢀ400 mesh) using ethyl
acetate in petroleum ether as eluent.
General experimental procedure for preparation of (S)ꢀNꢀbenzylꢀNꢀBoc amino acid methyl
esters (1a–b).13 Method B. To a solution of (S)ꢀNꢀbenzylated amino acid methyl esters (5.00 g,
18.56 mmol (for 1a)) in dry CH2Cl2, diꢀtertꢀbutyl dicarbonate (5.12 mL, 22.27 mmol) and
triethylamine (2.85 mL, 20.42 mmol) were added at 0 °C and the mixture was stirred at room
temperature for 24 h. After completion of the reaction (monitored with TLC), the reaction
mixture was quenched with 0.5 M aqueous HCl and the aqueous layer was extracted with
ACS Paragon Plus Environment

Page 19 of 38
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
CH2Cl2. The combined organic extract was washed with brine and dried over anhydrous Na2SO4
and the solvent was evaporated under reduced pressure. The residue was purified by flash
column chromatography over silica gel (230ꢀ400 mesh) using ethyl acetate in petroleum ether as
eluent to afford the pure products (1a–b).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
General procedure for the intermolecular conjugate addition of (S)ꢀNꢀbenzylꢀNꢀBocꢀαꢀ
amino methyl ester (1a) with various cyclicꢀ and acyclic enones (2a–c). Method C. To a
solution of diisopropylamine (0.15 mL, 1.04 mmol) in 2.0 mL dry THF was added nꢀBuLi (1.6
M in hexane, 0.66 mL, 1.05 mmol) at 0 °C and stirred for 30 min. It was cooled to −78 °C and a
solution of (S)ꢀNꢀbenzylꢀNꢀtertꢀbutoxycarbonyl phenylalanine methyl ester (1a, 387.9 mg, 1.05
mmol) in 3.0 mL dry THF was added to it and allowed to stir for 1 h. Cyclicꢀ and acyclic enone
(2a–c) (40 mg, 0.42 mmol (for 2a)) dissolved in 0.5 mL dry THF was slowly added into the
reaction mixture and stirring was continued at the same temperature for 6 h. After completion of
the reaction (monitored with TLC), it was quenched with aqueous saturated ammonium chloride
solution and extracted with ethyl acetate (3 × 5.0 mL). The combined organic extract was
washed with brine and dried over anhydrous Na2SO4. After removal of the solvent under reduced
pressure, the crude reaction mixture was purified by flash column chromatography on silica gel
(230−400 mesh) using ethyl acetate in petroleum ether as the eluent to afford the pure products
(3a–c).
General method for removal of Boc group from intermolecular conjugate adduct (3a–b).
Method D. 4(N) HCl in ethyl acetate (3.1 mL) was added to the intermolecular conjugate adduct
(3a–b) (100.0 mg, 0.21 mmol (for 3a)) at 0 °C. The reaction mixture was stirred at room
temperature overnight. After completion of the reaction (monitored with TLC), it was neutralized
with aqueous saturated NaHCO3 solution and extracted with ethyl acetate (3 × 4.0 mL). The
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 38
1
2
3
4
5
6
7
8
9
combined organic extract was washed with brine and dried over anhydrous Na2SO4. After
removal of the solvent under reduced pressure, the crude reaction mixture was purified by flash
column chromatography on silica gel (230−400 mesh) using ethyl acetate in petroleum ether as
the eluent to afford the pure products (4a–b).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
General procedure for the intermolecular conjugate addition of (S)ꢀNꢀbenzylꢀNꢀBocꢀαꢀ
amino methyl ester derivatives (1a–b) with various transꢀβꢀaromatic nitroalkenes (5a–d).
Method E. To a solution of diisopropylamine (0.15 mL, 0.81 mmol) in 2.0 mL dry THF was
added nꢀBuLi (1.6 M in hexane, 0.50 mL, 0.81 mmol) at 0 °C and stirred for 30 min. It was
cooled to −78 °C and a solution of (S)ꢀNꢀbenylꢀNꢀtertꢀbutoxycarbonylꢀαꢀamino methyl ester
derivatives (1a–b) (299.3 mg, 0.81 mmol) in 3.0 mL dry THF was added to it and allowed to stir
for 30 min. Transꢀβꢀaromatic nitroalkenes (5a–d) (40.0 mg, 0.27 mmol (for 5a)) dissolved in 1.0
mL dry THF was slowly added into the reaction mixture and stirring was continued at the same
temperature for 3 h. After completion of the reaction (monitored with TLC), it was quenched
with saturated aqueous ammonium chloride solution and extracted with ethyl acetate (3 × 5.0
mL). The combined organic extract was washed with brine and dried over anhydrous Na2SO4.
After removal of the solvent under reduced pressure, the crude reaction mixture was purified by
flash column chromatography on silica gel (230−400 mesh) using ethyl acetate in petroleum
ether as the eluent to afford the pure products (6a–e).
General method for removal of Boc group from intermolecular conjugate adduct (6a–e).
Method F. To a solution of intermolecular conjugate adduct (6a–e) (90.0 mg, 0.17 mmol (for
6a)) in dry CH2Cl2 (2.0 mL), trifluoroacetic acid (0.9 mL) was added at 0 °C and the mixture was
stirred at room temperature overnight. After completion of the reaction (monitored with TLC), it
was neutralized with aqueous saturated NaHCO3 solution and extracted with of CH2Cl2 (3 × 3.0
ACS Paragon Plus Environment

Page 21 of 38
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
mL). The combined organic extract was washed with brine and dried over anhydrous Na2SO4.
After removal of the solvent under reduced pressure, the crude reaction mixture was purified by
flash column chromatography on silica gel (230−400 mesh) using ethyl acetate in petroleum
ether as the eluent to afford the pure products as a mixture of diastereomers (7a–e).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
Diastereoselectivity was determined by H NMR spectrum of the crude reaction mixture. In the
case of substrates 7a, 7b, 7d, the diastereomeric mixtures were not separated by column
chromatography and their ee was determined by chiral HPLC analysis of diastereomeric
mixtures. However, when the mixture of diastereomers obtained after column chromatography
was dissolved in minimum amount of HPLC grade ethanol followed by sonication and allowed
to cool at low temperature (−20 °C) to obtain the major diastereomer in pure form. The mother
liquor mostly contained the minor diastereomer along with some amount of the major isomer and
hence the minor isomer could not be obtained in pure form. In the case of 7c, diastereomers were
not separated and it was obtained only as the mixture of diastereomers. In the case of 7e, the
major diastereomer was separated by column chromatography. However, the minor diastereomer
was not isolated in pure form.
(S)ꢀMethyl 2ꢀ(benzylamino)ꢀ3ꢀphenylpropanoate20 (S2). The general method A described
above was followed when the (S)ꢀmethyl 2ꢀaminoꢀ3ꢀphenylpropanoate hydrochloride (S1, 5.00
g, 23.18 mmol) was reacted with triethylamine (3.24 mL, 23.18 mmol), benzaldehyde (3.53 mL,
34.77 mmol) followed by sodium borohydride (1.75 g, 46.36 mmol to afford (S)ꢀmethyl 2ꢀ
(benzylamino)ꢀ3ꢀphenylpropanoate20 (S2) as a colorless liquid in 90% (5.61 g, 20.86 mmol)
yield; Rf: 0.40 (20% ethyl acetate in petroleum ether); IR νmax
̃
(CH2Cl2, cm−1) 3321, 3062, 3027,
1
2949, 2845, 1735, 1603, 1495, 1453, 1343, 1198, 1170, 1129, 1076, 1027; H NMR (400 MHz,
CDCl3) δ 1.72 (s, 1H), 2.96 (dd, J = 6.4, 1.4 Hz, 2H), 3.54 (t, J = 6.6 Hz, 1H), 3.61–3.64 (m,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 38
1
2
3
4
5
6
7
8
4H), 3.81 (d, J = 13.2 Hz, 1H), 7.15–7.17 (m, 2H), 7.20–7.29 (m, 8H); 13C{1H} NMR (125 MHz,
CDCl3) δ 39.9, 51.8, 52.1, 62.2, 126.8, 127.2, 128.3, 128.54, 128.59, 129.4, 137.4, 139.7, 175.2;
HRMS (ESI) for C17H20NO2, (M+H)+ found 270.1490, calcd 270.1494.
9
(S)ꢀMethyl 2ꢀ(benzylamino)ꢀ4ꢀmethylpentanoate21 (S4). The general method A described
above was followed when the (S)ꢀmethyl 2ꢀaminoꢀ4ꢀmethylpentanoate hydrochloride (S3, 2.50
g, 13.76 mmol) was reacted with triethylamine (1.92 mL, 13.76 mmol), benzaldehyde (2.10 mL,
20.64 mmol) followed by sodium borohydride (1.04 g, 27.42 mmol) to afford (S)ꢀmethyl 2ꢀ
(benzylamino)ꢀ4ꢀmethylpentanoate21 (S4) as a colorless liquid in 78% (2.52 g, 10.73 mmol)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
yield; Rf: 0.56 (20% ethyl acetate in petroleum ether); IR νmax
(CH2Cl2, cm−1) 3337, 3063, 3028,
̃
2961, 2874, 1732, 1604, 1495, 1454, 1434, 1386, 1367, 1333, 1236, 1196, 1178, 1149, 1075,
1
1027; H NMR (500 MHz, CDCl3) δ 0.84 (d, J = 6.5, 3H), 0.91 (d, J = 6.6 Hz, 3H), 1.44–1.49
(m, 2H), 1.71 (s, 1H), 1.74–1.80 (m, 1H), 3.30 (t, J = 6.8 Hz, 1H), 3.60 (d, J = 12.9 Hz, 1H),
3.71 (s, 3H), 3.80 (d, J = 12.9 Hz, 1H), 7.22– 7.33 (m, 5H); 13C{1H} NMR (125 MHz, CDCl3) δ
22.3, 22.9, 25.0, 43.0, 51.8, 52.3, 59.4, 127.2, 128.4, 128.5, 140.1, 176.7; HRMS (ESI) for
C14H22NO2, (M+H)+ found 236.1655, calcd 236.1651.
(S)ꢀMethyl 2ꢀ(benzyl(tertꢀbutoxycarbonyl)amino)ꢀ3ꢀphenylpropanoate20 (1a). The general
method B described above was followed when the (S)ꢀmethyl 2ꢀ(benzylamino)ꢀ3ꢀ
phenylpropanoate (S2, 5.00 g, 18.56 mmol) was reacted with diꢀtertꢀbutyl dicarbonate (5.12 mL,
22.27 mmol) and triethylamine (2.85 mL, 20.42 mmol) at 0 °C and the mixture was stirred at
room temperature for 24 h to afford 1a20 as a colorless liquid in 78% (5.34 g, 14.48 mmol) yield;
Rf: 0.61 (15% ethyl acetate in petroleum ether); [α]25 = −112.67 (c 0.450, CH2Cl2); IR νmax
̃
D
(CH2Cl2, cm−1) 3064, 3029, 2950, 2977, 1744, 1698, 1605, 1496, 1454, 1427, 1392, 1366, 1314,
1278, 1278, 1250, 1164, 1129, 1079, 1046, 1030, 1002; 13C{1H} NMR (125 MHz, CDCl3) for
ACS Paragon Plus Environment

Page 23 of 38
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
mixture of rotamers δ 28.5, 35.8, 36.7, 51.4, 51.7 52.0, 60.9, 61.2, 76.9, 81.0, 126.6, 126.7,
127.1, 127.4, 127.7, 128.3, 128.5, 128.6, 128.8, 129.4, 137.3, 138.1, 138.2, 155.2, 155.4, 171.5,
171.6; HRMS (ESI) for C22H27NNaO4, (M+Na)+ found 392.1834, calcd 392.1838.
9
(S)ꢀMethylꢀ2ꢀ(benzyl(tertꢀbutoxycarbonyl)amino)ꢀ4ꢀmethylpentanoate21 (1b). The general
method B described above was followed when the (S)ꢀmethyl 2ꢀ(benzylamino)ꢀ4ꢀ
methylpentanoate (S3, 2.40 g, 10.21 mmol) was reacted with diꢀtertꢀbutyl dicarbonate (2.81 mL,
12.25 mmol) and triethylamine (1.57 mL, 11.23 mmol) at 0 °C and the mixture was stirred at
room temperature for 24 h to afford 1b21 as a colorless liquid in 72% (2.46 g, 10.21 mmol) yield;
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Rf: 0.50 (15% ethyl acetate in petroleum ether); [α]25 = −54.711 (c 2.25, CH2Cl2); IR νmax
̃
D
(CH2Cl2, cm−1) 3065, 3030, 2957, 2870, 1744, 1697, 1605, 1496, 1454, 1434, 1406, 1392, 1366,
1318, 1247, 1202, 1165, 1075, 1048, 1030; 13C{1H} NMR (100 MHz, CDCl3) for mixture of
rotamers δ 22.1, 22.8, 24.9, 25.0, 28.4, 38.6, 39.4, 49.4, 50.4, 52.0, 57.0, 57.7, 80.7, 127.0, 127.4,
128.3, 128.5, 138.3, 139.2, 156.0, 156.1, 172.6, 172.9; HRMS (ESI) for C19H29NNaO4, (M+Na)+
found 358.1991, calcd 358.1994.
(2R)ꢀMethyl
2ꢀ(benzyl(tertꢀbutoxycarbonyl)amino)ꢀ2ꢀ(3ꢀoxocyclohexyl)ꢀ3ꢀ
phenylpropanoate (3a). The general method C described above was followed when the enolate
of (S)ꢀmethyl 2ꢀ(benzyl(tertꢀbutoxycarbonyl)amino)ꢀ3ꢀphenylpropanoate (1a, 387.9 mg, 1.05
mmol) was reacted with cyclohexꢀ2ꢀenone (2a, 40.0 mg, 0.42 mmol) at −78 °C for 6 h to afford
3a (138.0 mg, 0.30 mmol) in 71% yield as a thick liquid; Rf: 0.48 (30% ethyl acetate in
petroleum ether); [α]25 = +5.085 (c 0.236, CH2Cl2); Optical purity was determined by Chiral
D
HPLC analysis (Chiralpak Lux 5u Celluloseꢀ2 column), hexane−isopropanol 95:5, flow rate =
1.0 mL/min; ee 99%; TR 1: 24.3 min (major), TR 2: 33.3 min (minor); IR νmax
̃
(CH2Cl2, cm−1)
1
3030, 2975, 1736, 1696, 1604, 1496, 1453, 1389, 1366, 1253, 1159, 1086, 1030; H NMR (500
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 38
1
2
3
4
5
6
7
8
9
MHz, CDCl3) δ 1.25–1.50 (m, 11H), 1.94 (bs, 1H), 2.064–2.11 (m, 2H), 2.18–2.25 (m, 2H),
2.35–2.38 (m, 2H), 2.95 (d, J = 13.1 Hz, 1H ), 3.18 (d, J = 13.7 Hz, 1H), 3.58 (d, J = 13.7 Hz,
1H), 3.72 (s, 3H), 3.96 (bs, 1H), 7.08–7.10 (m, 2H), 7.15–7.18 (m, 1H), 7.26–7.27 (m, 7H);
13C{1H} NMR (125 MHz, CDCl3) δ 24.7, 27.3, 28.1, 37.8, 41.2, 42.2, 45.6, 49.7, 51.8, 71.2,
80.9, 125.8, 126.3, 127.4, 128.2, 128.4, 128.6, 130.7, 135.9, 140.2, 155.9, 171.5, 210.6; HRMS
(ESIꢀTOF) for C28H39N2O5, (M+NH4)+ found 483.2850, calcd 483. 2859.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(2R)ꢀMethyl
2ꢀ(benzyl(tertꢀbutoxycarbonyl)amino)ꢀ2ꢀ(3ꢀoxocyclopentyl)ꢀ3ꢀ
phenylpropanoate (3b). The general method C described above was followed when the enolate
of (S)ꢀmethyl 2ꢀ(benzyl(tertꢀbutoxycarbonyl)amino)ꢀ3ꢀphenylpropanoate (1a, 454.4 mg, 1.23
mmol) was reacted with cyclopentꢀ2ꢀenone (2b, 40.0 mg, 0.49 mmol) at −78 °C for 6 h to afford
3b (150.0 mg, 0.33 mmol) in 67% yield as a thick liquid; Rf: 0.47 (30% ethyl acetate in
petroleum ether); [α]25D = +22.356 (c 0.416, CH2Cl2); Optical purity was determined by chiral
HPLC analysis (Chiralpak Lux 5u Celluloseꢀ2 column), hexaneꢀisopropanol 95:5, flow rate 1.0
mL/min; ee 91%; TR 1: 40.8 min (major), ), TR 2: 62.0 min (minor). IR νmax
̃
(CH2Cl2, cm−1) 3029,
1
2975, 1742, 1693, 1604, 1496, 1453, 1384, 1366, 1254, 1216, 1159, 1088, 1031; H NMR (500
MHz, CDCl3) δ 1.24 (s, 9H), 1.94–2.09 (m, 4H), 2.21–2.28 (m, 2H), 2.64–2.69 (m, 1H), 2.78–
2.80 (m, 1H), 3.07 (d, J = 13.7 Hz, 1H), 3.63–3.65 (m, 1H), 3.78 (s, 3H), 4.07 (bs, 1H), 7.09–
13
7.11 (m, 2H), 7.17–7.19 (m, 1H), 7.26–7.30 (m, 7H); C{1H} NMR (125 MHz, CDCl3) δ 24.7,
28.0, 38.6, 39.1, 40.9, 42.5, 49.2, 52.1, 69.9, 81.0, 125.7, 126.3, 127.4, 128.2, 128.6, 130.5,
135.8, 140.2, 155.9, 172.0, 217.1; HRMS (ESIꢀTOF) for C27H34NO5, (M+H)+ found 452.2438,
calcd 452.2437.
(R)ꢀMethyl 2ꢀbenzylꢀ2ꢀ(benzyl(tertꢀbutoxycarbonyl)amino)ꢀ5ꢀoxoꢀ3,5ꢀdiphenylpentanoate
(3c). The general procedure described above was followed when the enolate of (S)ꢀmethyl 2ꢀ
ACS Paragon Plus Environment

Page 25 of 38
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
(benzyl(tertꢀbutoxycarbonyl)amino)ꢀ3ꢀphenylpropanoate (1a, 177.3 mg, 0.48 mmol) was reacted
with (E)ꢀchalcone (2c, 40.0 mg, 0.19 mmol) at −78 °C for 3h to afford 3c (80.0 mg, 0.14 mmol)
in 74% yield as a semi solid; Rf: 0.53 (30% ethyl acetate in petroleum ether); [α]25D = +5.085 (c
0.236, CH2Cl2); Optical purity was determined by Chiral HPLC analysis (Chiralpak ADꢀH
column), hexane−isopropanol 95:5, flow rate = 1.0 mL/min; ee 70%; TR 1: 24.3 min (major), TR
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2: 33.3 min (minor); IR νmax
̃
(CH2Cl2, cm−1) 2953, 2924, 2853, 1735, 1700, 1604, 1510, 1496,
1
1453, 1387, 1367, 1345, 1304, 1249, 1208, 1162, 1123, 1093, 1046, 1018; H NMR (500 MHz,
CDCl3) δ 1.25–1.45 (m, 9H), 3.00 (bs, 1H), 3.53–3.83 (m, 8H), 4.49 (bs, 1H), 6.86 (bs, 1H),
7.05–7.13 (m, 4H), 7.22–7.46 (m, 15H); 13C{1H} NMR (125 MHz, CDCl3) δ 28.2, 39.0, 42.2,
44.4, 48.0, 51.9, 71.2, 80.9, 125.9, 126.0, 127.1, 127.5, 127.8, 127.9, 128.1, 128.4, 128.5, 130.33,
130.37, 131.1, 132.6, 136.6, 137.1, 139.8, 140.3, 156.3, 172.6, 197.8; HRMS (ESIꢀTOF) for
C37H43N2O5, (M+NH4)+ found 595.3173, calcd 595.3172.
(2R)ꢀMethyl 2ꢀ(benzylamino)ꢀ2ꢀ(3ꢀoxocyclohexyl)ꢀ3ꢀphenylpropanoate (4a). The general
method D described above was followed when intermolecular conjugate adduct 3a (100 mg, 0.21
mmol) was reacted with 4(N) HCl in ethyl acetate (3.1 mL) to afford 4a (64.0 mg, 0.18 mmol) in
86% yield as a thick liquid; Rf: 0.48 (30% ethyl acetate in petroleum ether); IR νmax
̃
(CH2Cl2,
1
cm−1) 3361, 3061, 3028, 2949, 2862, 1712, 1602, 1495, 1453, 1346, 1316, 1079, 1029; H NMR
(500 MHz, CDCl3) δ 1.39–1.51 (m, 2H), 1.90 (bs, 1H), 2.05–2.08 (m, 1H), 2.12–2.15 (m, 1H),
2.18–2.26 (m, 2H), 2.35–2.41 (m, 2H), 2.57 (d, J = 14.3 Hz, 1H), 3.08 (d, J = 14.3 Hz, 1H), 3.24
(d, J = 14.3 Hz, 1H), 3.716–3.718 (m, 3H), 3.75–3.83 (m, 2H), 7.21–7.28 (m, 6H), 7.30–7.31 (m,
13
4H); C{1H} NMR (125 MHz, CDCl3) δ 25.1, 26.3, 37.8, 41.4, 43.91, 43.95, 47.5, 52.0, 68.4,
126.9, 127.2, 128.1, 128.4, 128.6, 130.2, 136.6, 140.2, 174.4, 211.4; HRMS (ESIꢀTOF) for
C23H28NO3, (M+H)+ found 366.2063, calcd 366.2069.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 38
1
2
3
4
5
6
7
8
(2R)ꢀMethyl 2ꢀ(benzylamino)ꢀ2ꢀ(3ꢀoxocyclopentyl)ꢀ3ꢀphenylpropanoate (4b). The general
method D described above was followed when intermolecular conjugate adduct 3b (100.0 mg,
0.22 mmol) was reacted with 4(N) HCl in ethyl acetate (3.2 mL) to afford 4b (65.0 mg, 0.18
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
mmol) in 82 % yield as a thick liquid; Rf: 0.47 (30% ethyl acetate in petroleum ether); IR νmax
̃
(CH2Cl2, cm−1) 3354, 3086, 3061, 3028, 2951, 2924, 2852, 1740, 1603, 1495, 1454, 1404, 1365,
1255, 1211, 1162, 1080, 1029; 1H NMR (500 M Hz, CDCl3) δ 1.72 (bs, 1H), 1.82–1.88 (m, 1H),
2.07–2.18 (m, 2H), 2.28–2.42 (m, 3H), 2.63 (bs, 1H), 3.07 (d, J = 14.9 Hz, 1H), 3.24–3.32 (m,
1H), 3.73 (s, 3H), 3.73–3.82 (m, 1H), 3.92 (d, J = 12.0 Hz, 1H), 7.23–7.30 (m, 6H), 7.31–7.36
(m, 4H); 13C{1H} NMR (125 MHz, CDCl3) δ 24.3, 38.8, 39.0, 41.0, 42.5, 48.1, 52.0, 68.1, 127.1,
127.4, 128.3, 128.5, 128.7, 130.3, 136.4, 140.2, 174.5, 218.0; HRMS (ESIꢀTOF) for C22H26NO3,
(M+H)+ found 352.1913, calcd 352.1911.
(R)ꢀMethyl 2ꢀbenzylꢀ2ꢀ(benzyl(tertꢀbutoxycarbonyl)amino)ꢀ4ꢀnitroꢀ3ꢀphenylbutanoate (6a).
The general method E described above was followed when the enolate of (S)ꢀmethyl 2ꢀ
(benzyl(tertꢀbutoxycarbonyl)amino)ꢀ3ꢀphenylpropanoate (1a, 299.30 mg, 0.81 mmol) was
reacted with transꢀβꢀnitrostyrene (5a, 40.0 mg, 0.27 mmol) at −78 °C for 3 h to afford 6a as a
mixture of diastereomers (115.0 mg, 0.22 mmol) in 81% yield as thick liquid where the
diastereomers were not separated through flash column chromatography; Rf: 0.40 (20% ethyl
acetate in petroleum ether); IR νmax
̃
(CH2Cl2, cm−1) 3031, 2977, 1818, 1745, 1692, 1603, 1554,
13
1496, 1454, 1380, 1367, 1251, 1156, 1086, 1031; C{1H} NMR (125 MHz, CDCl3) for mixture
of diastereomers δ 28.2, 38.5, 48.6, 49.9, 51.9, 52.2, 70.0, 81.6, 81.7, 125.80, 125.88, 126.6,
127.7, 127.9, 128.3, 128.6, 128.7, 128.9, 129.0, 129.74, 129.79, 130.7, 131.0, 134.4, 135.3,
135.6, 136.0, 139.5, 156.1, 170.7; HRMS (ESIꢀTOF) for C30H34N2NaO6, (M+Na)+ found
541.2313, calcd 541.2315.
ACS Paragon Plus Environment

Page 27 of 38
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
(R)ꢀMethyl 2ꢀbenzylꢀ2ꢀ(benzyl(tertꢀbutoxycarbonyl)amino)ꢀ4ꢀnitroꢀ3ꢀpꢀtolylbutanoate (6b).
The general method E described above was followed when the enolate of (S)ꢀmethyl 2ꢀ
(benzyl(tertꢀbutoxycarbonyl)amino)ꢀ3ꢀphenylpropanoate (1a, 277.1 mg, 0.75 mmol) was reacted
with transꢀ4ꢀmethylꢀβꢀnitrostyrene (5b, 40.0 mg, 0.25 mmol) at −78 °C for 3 h to afford 6b as a
mixture of diastereomers (101.0 mg, 0.19 mmol) in 76% yield as thick liquid where the
diastereomers were not separated through flash column chromatography; Rf: 0.41 (20% ethyl
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
acetate in petroleum ether); IR νmax
̃
(CH2Cl2, cm−1) 3031, 2978, 1800, 1745, 1693, 1604, 1554,
13
1515, 1496, 1454, 1381, 1368, 1307, 1252, 1210, 1157, 1085, 1030; C{1H} NMR (125 MHz,
CDCl3) for mixture of diastereomers δ 21.3, 28.3, 28.4, 38.7, 48.1, 49.9, 51.9, 52.2, 81.6, 125.8,
125.9, 126.0, 126.6, 127.6, 127.9, 128.3, 128.6, 128.7, 128.9, 129.7, 130.1, 130.7, 131.0, 132.8,
134.5, 138.4, 138.5, 139.5, 139.9, 156.2, 156.5, 170.8; HRMS (ESIꢀTOF) for C31H36N2NaO6,
(M+Na)+ found 555.2471, calcd 555.2477.
(R)ꢀMethyl
2ꢀbenzylꢀ2ꢀ(benzyl(tertꢀbutoxycarbonyl)amino)ꢀ3ꢀ(4ꢀfluorophenyl)ꢀ4ꢀ
nitrobutanoate (6c). The general method E described above was followed when the enolate of
(S)ꢀmethyl 2ꢀ(benzyl(tertꢀbutoxycarbonyl)amino)ꢀ3ꢀphenylpropanoate (1a, 266.0 mg, 0.72
mmol) was reacted with transꢀ4ꢀfluoroꢀβꢀnitrostyrene (5c, 40.0 mg, 0.24 mmol) at −78 °C for 3 h
to afford 6c as a mixture of diastereomers (98.0 mg, 0.18 mmol) in 75% yield as thick liquid
where the diastereomers were not separated through flash column chromatography; Rf: 0.39
(20% ethyl acetate in petroleum ether); IR νmax
(CH2Cl2, cm−1) 3064, 3032, 2977, 2928, 1798,
̃
1745, 1693, 1605, 1554, 1511, 1496, 1454, 1382, 1368, 1250, 1229, 1108, 1085, 1030, 1007;
13C{1H} NMR (125 MHz, CDCl3) for mixture of diastereomers δ 28.2, 28.4, 38.7, 47.9, 49.9,
52.0, 52.3, 81.7, 81.9, 115.9, 116.2, 125.80, 125.88, 126.7, 127.7, 128.0, 128.4, 128.6, 128.7,
1
128.8, 128.9, 130.6, 130.9, 131.3, 131.8, 134.2, 135.3, 139.3, 139.5, 156.1, 156.5, 162.8 (d, JC–F
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 38
1
2
3
4
5
= 240.0 Hz), 170.6; HRMS (ESIꢀTOF) for C30H37FN3O6, (M+NH4)+ found 554.2666, calcd
554.2664.
6
7
8
9
(R)ꢀMethyl 2ꢀbenzylꢀ2ꢀ(benzyl(tertꢀbutoxycarbonyl)amino)ꢀ3ꢀ(furanꢀ2ꢀyl)ꢀ4ꢀnitrobutanoate
(6d). The general method E described above was followed when the enolate of (S)ꢀmethyl 2ꢀ
(benzyl(tertꢀbutoxycarbonyl)amino)ꢀ3ꢀphenylpropanoate (1a, 321.4 mg, 0.87 mmol) was reacted
with 2ꢀ(2ꢀnitrovinyl)furan (5d, 40.0 mg, 0.29 mmol) at −78 °C for 3 h to afford 6d as a mixture
of diastereomers (111.9 mg, 0.22 mmol) in 76% yield as thick liquid where the diastereomers
were not separated through flash column chromatography; Rf: 0.38 (20% ethyl acetate in
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
petroleum ether); IR ν
̃
max (CH2Cl2, cm−1) 3063, 3032, 2977, 1798, 1744, 1690, 1604, 1554, 1497,
13
1454, 1391, 1368, 1272, 1253, 1199, 1158, 1086, 1031, 1015; C{1H} NMR (125 MHz, CDCl3)
for mixture of diastereomers δ 28.2, 40.7, 42.5, 48.5, 52.0, 52.3, 69.1, 75.8, 81.5, 82.4, 111.11,
111.17, 125.7, 125.8, 126.61, 126.69, 127.9, 128.4, 128.6, 128.83, 128.89, 130.7, 131.0, 134.2,
139.5, 140.1, 143.1, 150.2, 156.4, 170.3; HRMS (ESIꢀTOF) for C28H36N3O7, (M+NH4)+ found
526.2551, calcd 526.2553.
(S)ꢀMethyl
2ꢀ(benzyl(tertꢀbutoxycarbonyl)amino)ꢀ2ꢀ(1ꢀ(4ꢀfluorophenyl)ꢀ2ꢀnitroethyl)ꢀ4ꢀ
methylpentanoate (6e). The general method E described above was followed when the enolate
of (S)ꢀmethylꢀ2ꢀ(benzyl(tertꢀbutoxycarbonyl)amino)ꢀ4ꢀmethylpentanoate (1b, 241.5 mg, 0.72
mmol) was reacted with transꢀ4ꢀfluoroꢀβꢀnitrostyrene (5c, 40.0 mg, 0.24 mmol) at −78 °C for 3 h
to afford 6e as a mixture of diastereomers (90.5 mg, 0.18 mmol) in 75% yield as thick liquid
where the diastereomers were not separated through flash column chromatography; Rf: 0.40
(20% ethyl acetate in petroleum ether); IR νmax
(CH2Cl2, cm−1) 2967, 2930, 2872, 1737, 1691,
̃
1605, 1556, 1511, 1497, 1466, 1453, 1384, 1368, 1349, 1274, 1253, 1229, 1162, 1128, 1108,
13
1073, 1031; C{1H} NMR (125 MHz, CDCl3) for mixture of diastereomers δ 23.2, 24.3, 24.9,
ACS Paragon Plus Environment

Page 29 of 38
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
28.0, 28.4, 41.2, 42.0, 47.2, 47.9, 52.2, 68.1, 81.3, 115.8, 116.0, 125.7, 126.5, 128.2, 132.1,
139.6, 156.0, 162.7 (d, 1JC–F = 246.8 Hz), 173.0; HRMS (ESIꢀTOF) for C27H39FN3O6, (M+NH4)+
found 520.2823, calcd 520.2820.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Methyl 2ꢀbenzylꢀ2ꢀ(tertꢀbutoxycarbonyl(methoxymethyl)amino)ꢀ4ꢀnitroꢀ3ꢀphenylbutanoate
(9). The general method E described above was followed when the enolate of (S)ꢀmethyl 2ꢀ(tertꢀ
butoxycarbonyl(methoxymethyl)amino)ꢀ3ꢀphenylpropanoate (8, 261.94 mg, 0.81 mmol) was
reacted with transꢀβꢀnitrostyrene (5a, 40.0 mg, 0.27 mmol) at −78 °C for 3 h to afford 9 (70.0
mg, 0.15 mmol) in 56 % yield as thick liquid. Rf: 0.44 (30% ethyl acetate in petroleum ether); IR
νmax
(CH2Cl2, cm−1) 3064, 3032, 2954, 2924, 2853, 1745, 1709, 1603, 1584, 1554, 1495, 1455,
̃
1434, 1409, 1392, 1369, 1296, 1255, 1208, 1179, 1081, 1033; 1H NMR (500 MHz, CDCl3) for
mixture of rotamers δ 1.25–1.47 (m, 12H), 3.23–3.30 (m, 5H), 3.60 (s, 1H), 3.84 (s, 3H),4.33
(bs, 2H), 4.76 (bs, 1H), 5.50 (bs, 1H), 7.17–7.38 (m, 11H); 13C{1H} NMR (125 MHz, CDCl3) δ
28.2, 28.4, 38.7, 48.7, 52.0, 52.3, 55.8, 70.0, 78.1, 82.1, 127.3, 127.9, 128.6, 128.7, 128.9, 129.4,
129.9, 130.8, 130.9, 134.9, 136.0, 155.5, 171.0; HRMS (ESIꢀTOF) for C25H32N2NaO7, (M+Na)+
found 495.2103, calcd 495.2107.
(2R,3S)ꢀMethyl
2ꢀbenzylꢀ2ꢀ(benzylamino)ꢀ4ꢀnitroꢀ3ꢀphenylbutanoate
(7a
major
diastereomer). The general method F described above was followed when intermolecular
conjugate adduct 6a (90.0 mg, 0.17 mmol) was reacted with trifluoroacetic acid (0.9 mL) in dry
CH2Cl2 (2.0 mL) at 0 °C and mixture was stirred at room temperature overnight to afford 7a as a
mixture of inseparable diastereomers in semiꢀsolid form with 88% overall yield (64.0 mg, 0.15
1
mmol) with dr 80:20 (based on H NMR analysis of crude reaction mixture). Optical purity was
determined by Chiral HPLC analysis (Chiralpak ODꢀH column), hexane−isopropanol 95:5, flow
rate = 1.0 mL/min; for the major diastereomer, ee 88%, TR 1: 15.46 min (major), TR 2: 35.15 min
ACS Paragon Plus Environment