Memory of chirality (MOC) concept in imino-aldol reaction: Enantioselective synthesis of α,β-diamino esters and aziridines

Article abstract of DOI:10.1021/jo302018a

A simple strategy for the synthesis of chiral α,β-diamino- and α-amino,β-hydroxy ester derivatives in high yields with moderate to high ee has been developed via asymmetric imino-aldol and aldol reactions, respectively, starting from protected aminoesters employing memory of chirality concept for chiral induction. This strategy has been extended for the enantioselective synthesis of aziridines (ee up to 92%). The absolute configuration of the imino-aldol adducts has been determined. The stereochemical outcome of the products has been explained by a suitable mechanism and supported by computational studies.

Full text of DOI:10.1021/jo302018a

Article
pubs.acs.org/joc
Memory of Chirality (MOC) Concept in Imino-Aldol Reaction:
Enantioselective Synthesis of α,β-Diamino Esters and Aziridines
Manas K. Ghorai,* Koena Ghosh, A. K. Yadav, Y. Nanaji, Sandipan Halder, and Masthanvali Sayyad
Department of Chemistry, Indian Institute of Technology, Kanpur 208 016, India
S
* Supporting Information
ABSTRACT: A simple strategy for the synthesis of chiral α,β-
diamino- and α-amino,β-hydroxy ester derivatives in high yields
with moderate to high ee has been developed via asymmetric
imino-aldol and aldol reactions, respectively, starting from
protected aminoesters employing memory of chirality concept
for chiral induction. This strategy has been extended for the enantioselective synthesis of aziridines (ee up to 92%). The absolute
configuration of the imino-aldol adducts has been determined. The stereochemical outcome of the products has been explained by a
suitable mechanism and supported by computational studies.
article, we report our detailed study for the synthesis of chiral α,β-
diamino ester derivatives via the imino-aldol protocol following
MOC concept. This methodology was further explored for aldol
reaction.
INTRODUCTION
■
The asymmetric aldol and imino aldol reactions of enolates
with aldehydes (or equivalents) and imines, respectively, are
synthetically very important for the construction of β-amino
esters,1 α,β-diamino ester derivatives,2 nonproteogenic β-amino
acids,3 different polyfunctionalized chiral building blocks,4 and
β-lactam antibiotics,3,5 etc. The enantioselective synthesis of
many of these bioactive compounds were achieved by the
addition of chiral enolates with imines where a chiral auxiliary
or an untouched stereogenic center of the ester enolate controls
the stereoselectivity.3,6 Other approaches for asymmetric imino-
aldol reactions either involve achiral enolates and chiral imines
along with achiral Lewis acids7 or chiral enolate complexes
generated from achiral enolates with chiral Lewis acids.8,9
However, there is no report other than ours for asymmetric
imino-aldol reaction without using any external chiral source,
for example, chiral auxiliary or a catalyst. To induce asymmetry
in imino-aldol reaction without the aid of an external chiral
source, we anticipated that a conformationally chiral enolate could
be added to an imine following Memory of Chirality (MOC)
concept. The phenomenon of MOC was first demonstrated in the
field of enolate chemistry by Fuji and Kawabata where enantio-
selective alkylation of chiral ketones, amides and amino acid esters
were achieved through enolate carbanions with a high degree of
selectivity.10−15 A number of synthetically and biologically im-
portant compounds including substituted α-amino acids,11 quater-
nary amino acids,3b,c cyclic amino acids,12,13 N-heterocycles,14,15 etc.
were synthesized utilizing this concept. Recently, we have explored
MOC in an asymmetric imino-aldol reaction to obtain α,β-diamino
esters with consecutive quaternary and tertiary stereogenic centers in
high yields and streoselectivities.16
RESULTS AND DISCUSSION
■
To begin our study, the enolate was generated from N-benzyl-
N-tert-butoxycarbonylphenylalanine ethyl ester 1a16 by the
treatment of KHMDS at −78 °C and was reacted with N-
benzylidene-4-methylbenzenesulfonamide at the same temper-
ature to afford the corresponding α,β-diamino ester derivative
4a following the imino-aldol protocol (Scheme 1).16 The
imino-aldol adduct 4a was isolated as an inseparable mixture of
diastereomers. However, 3 did not cyclize to produce the
corresponding β-lactam 5 since the negative charge developed
on nitrogen was highly delocalized over the sulfonyl group. The
1H NMR spectrum of the imino-aldol adduct 4a showed broad
signals at room temperature possibly because of its existence as a
mixture of rotamers. However, the formation of the product 4a was
confirmed by 13C NMR, DEPT NMR and mass spectral analysis.
To restrict the interconversion of possible rotamers of the imino-
aldol adduct 4a at room temperature, extensive low temperature
NMR study was carried out at −25, −40 and −55 °C (in CDCl3)
with an idea that one of the rotamers might be frozen at lower
temperature (see Supporting Information). Resolution of the
1H NMR spectrum was improved to some extent upon lowering
the temperature, although it was not completely resolved even at
−55 °C (in CDCl3). 1H NMR spectrum of 4a recorded at higher
temperature (60 °C in DMSO-d6) showed similar broad spectrum
1
as discussed earlier. To simplify the H NMR spectrum, N-Boc
group of 4a was removed using 1:2 trifluoroacetic acid and
dichloromethane to give 6a as a mixture of diastereomers in 88%
Optically active α,β-diamino acids are found in a variety of
antibiotics and natural products.2a,17 A number of synthetic routes
are available in the literature2,18 for the synthesis of α,β-diamino
acids and their derivatives including direct catalytic asymmetric
Mannich reaction,18a−c opening of aziridine rings,18d−f imino-aldol
reaction,2 catalytic asymmetric aza-Henry reaction,18g etc. In this
1
yield with dr 75:25 (based on H NMR study of the crude
reaction mixture) (Scheme 2). The diastereomers were separated
Received: October 27, 2012
© XXXX American Chemical Society
A
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Scheme 1. Addition of N-Benzyl-N-tert-butoxycarbonylphenylalanine Ethyl Ester Enolate to 2-Phenyl-N-tosyl Aldimines
Scheme 2. Boc Deprotection of α,β-Diamino Ester
Derivatives 4a
corresponding acid 7 was produced by the hydrolysis of the
ester group of 1a (Scheme 3).
Scheme 3. Addition of 1a to 2-Phenyl-N-tosyl Aldimines at
Ambient Temperature
by flash column chromatography. Compound 6a was charac-
terized by spectroscopic and analytical data.
The reaction of 1a with N-tosylphenylaldimine was studied in
different solvents using KHMDS as the base (Table 1, entries 1−4).
In all cases, compound 4a was obtained in moderate yield but with
low enantioselectivity (up to 28% for the major diastereomer, based
on chiral HPLC analysis of 6a). The reaction was studied with
other bases such as LDA, LiHMDS, NaHMDS and LTMP etc. as
shown in Table 1 (entries 5−8). When NaHMDS or LiHMDS was
used, the reaction did not proceed (Table 1, entry 5) at all. The best
result was obtained using LDA as the base and THF as the solvent
where 4a was obtained with dr 83:17 (ee 92% for the major
diastereomer) (Table 1, entry 6). When toluene was used as the
solvent, only a trace amount of 4a was formed (Table 1, entry 7).
However, using LTMP, 4a was obtained with high yield (80%) and
selectivity (based on ee 80% for the major diastereomer of 6a)
(Table 1, entry 8). In all the cases, stereoselectivity was determined
only after removal of the Boc group from 4a.
On the basis of the above results, further studies were carried
out using LDA as the base. Although the reaction proceeded
smoothly with 1.2 equivalent of enolate, for obtaining better
yield and selectivity the use of 2.2 equivalents of enolate was
found to be the best. This optimized condition was used in all
the subsequent reactions. The reaction was nearly completed
within 2 h; however, for further improvement in yield and ee,
the reaction was continued for 10 h. To extend the scope of this
reaction, a variety of N-activated imines with electron donating
as well as electron withdrawing aryl substitutents were reacted
with amino acid ester 1a to afford the substituted nonracemic
α,β-diamino ester derivatives 4b−j (based on optical rotation)
as a mixture of diastereomers in 62−81% yields (Scheme 4).
1
Although H NMR signals of imino-aldol adducts 4b−j were
found to be wavy as discussed earlier (low temperature
1H NMR spectra are provided in the Supporting Information),
the formation of all the compounds 4b−j were fully confirmed
by 13C NMR, DEPT NMR and HRMS data. The stereoisomers
of the imino-aldol products 4b−j could not be separated at this
stage.
Recently Kawabata et al.13a have reported enantioselective
cyclization of α-amino acid derivatives at ambient temperature
using powdered KOH in DMSO or DMF. Encouraged by this
report, we carried out the imino-aldol reaction using KOH in
DMSO or DMF at ambient temperature. The addition reaction
(imino-aldol) did not proceed under this condition; instead, the
To confirm the diastereoselectivity as well as the
enantioselectivity, the imino-aldol adducts 4b−j were subjected
Table 1. Effect of Bases and Solvents on Imino-aldol Reaction
a
a
bc
,
d
entry
base
KHMDS
solvent
time (h)
yield 4a (%)
yield 6a (%)
ee (%)
dr (%)
1
2
3
4
5
6
7
8
THF
6.0
2.0
55
89
94
92
87
4
16
26
28
75:25
58:42
64:36
74:26
KHMDS
KHMDS
KHMDS
LiHMDS/NaHMDS
LDA
THF/Toluene 4:1
THF/Toluene 1:4
Toluene
71
2.5
70
2.5
56
THF
14.0
10.0
10.0
2.0
Trace
84
THF
88
80
92
80
83:17
64:36
LDA
Toluene
Trace
80
LTMP
THF
a
b
Combined yield of both the diastereomers after purification. HPLC separation was done using Chiral AD-H column (95:5 Hexane/Isopropanol as
c
d
1
mobile phase and 1.0 mL/min flow rate). ee was determined from HPLC analysis of 6a. dr based on crude H NMR analysis of 6a.
B
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Scheme 4. Synthesis of α,β-Diamino Acid Derivatives 4a−j
Scheme 5. Boc Deprotection of Compounds 4a−j
to BOC-group deprotection following the aforementioned
condition to afford 6b−j as a mixture of diastereomers with
70−91% yields (Scheme 5, Table 2). Diastereoselectivity was
determined by 1H NMR spectrum of the crude reaction
mixture and the maximum dr (83:17) was achieved in the cases
of compounds 6a and 6c (Table 2, entries 1, 4). At this stage,
the major diastereomers of the α,β-diamino ester derivatives
6a−j could be separated by flash column chromatography on
silica gel (Table 2). The minor diastereomers of 6b, 6d and 6h
could not be obtained in pure forms; their ees were determined
by chiral HPLC analysis comparing the peaks of the mixture
with that of the pure major diastereomer. All of the compounds
(6a−j) were fully characterized by spectral and analytical data.
The substrate scope of the reaction was studied by replacing
the benzyl group of 1a with a less sterically demanding methyl
group. When the ester enolate generated from the alanine
derivative 1b was reacted with 2-phenyl-N-tosylaldimine, the
corresponding addition product 4k was obtained with 72%
yield. Its Boc group was removed to produce the compound 6k
as a mixture of diastereomers in 79% yield (Scheme 6). In this
case, lower stereocontrol was observed (major/minor = 55:45
and ee 33% for the major diastereomer) probably due to the
rapid racemization of the chiral enolate during the course of the
reaction. This result is consistent with the work reported by
Kawabata et al. where such type of chirality loss was overruled
by rapid cyclization in the case of intramolecular reaction,
however, in the case of intermolecular reaction lower ee
(∼33%) of the product was observed.12a
To provide evidence in support of the MOC concept in
imino-aldol reaction, ester enolate generated from (S)-methyl
2-[bis(tert-butoxycarbonyl) amino]-3-phenylpropanoate (1c)
was treated with 2-phenyl-N-tosylaldimine to produce the
corresponding addition product 4l.16 In this case, the enolate
having no axial chirality along C−N axis was expected not to
induce any chirality into the product (Scheme 7). Although the
corresponding addition product 4l could not be separated in
chiral HPLC column (Chiralcel OD-H or AD-H), the Boc
deprotected derivative 6l was well separated in chiracel AD-H
column and obtained as a racemate.20 This interesting result
unambiguously supports that the MOC is operating in our
imino-aldol reaction with substrates 1a−b.
After successful demonstration of the memory of chirality in
imino-aldol reaction we intended to explore the concept in
aldol reaction. Although in recent years memory of chirality
concept has become a conceptually new strategy in the field of
asymmetric synthesis, surprisingly, MOC based aldol reaction
C
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Table 2. Imino-aldol Adducts 6 Generated after Boc Removal from 4a−h
a
b
Corresponding imino-aldol adducts (a mixture of major and minor isomers of 6) obtained after 10 h. Combined yield of both the diastereomers
c
d
1
after purification. dr based on crude H NMR analysis. Minor diastereomer could not be separated in available chiral HPLC columns.
remained unexplored. Stoodley and co-workers demonstrated
the memory of chirality effect in intramolecular aldol cyclization
of 1-(3-oxabutyryl) derivatives of L-4-oxaproline and proline
isopropyl esters via the involvement of an axially chiral enolate
intermediate.19a,b Very recently Kawabata and co-workers
demonstrated the application of MOC concept in asymmetric
D
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electrophilicity of the carbonyl carbon. All of the compounds
were characterized by spectroscopic and analytical data. These
results are summarized in Table 3.19d
Scheme 6. Addition of N-Benzyl-N-tert-
butoxycarbonylalanine Methyl Ester Enolate 1b
to 2-Phenyl-N-tosylaldimines
The major and the minor diastereomers of the products
8a−d were produced with syn and anti relative stereochemistry,
respectively, as determined by the NOE experiments of both
the diastereomers of 8b.20
The N-Boc group of 8a (as a mixture of diastereomers) was
deprotected using TFA/DCM (1:2) to give the corresponding
NH-free aldol product 9 (Scheme 9). Both the isomers of
compound 9 were separated by column chromatography. The
major isomer was obtained with very poor ee (9%), although
the minor isomer was obtained with good ee (67%) based on
chiral HPLC analysis. In the same fashion, other α-amino,β-
hydroxy ester derivatives 8c−d were subjected to Boc group
removal step as discussed earlier but even after the Boc group
deprotection the diastereomers could not be separated in
column chromatography and the enantiomers remained
inseparable in available chiral HPLC columns.
The formation of the nonracemic aldol products 8 suggests
that memory of chirality concept is operating in the aldol
reaction. Unfortunately, in most of the cases, the pure diaster-
eomer could not be isolated by column chromatography and
the ee also could not be determined. At this stage, the
stereocontrol in aldol reaction was further investigated using
KHMDS as a base.
Scheme 7. Synthesis of Compound 6I
aldol reaction followed by cylization to form cyclic 2-
oxooxazolidine derivatives in high ee starting from amino acid
ester enolate and aldehyde using KHMDS as the base.19c
To begin our study in aldol reaction, the ester enolate was
generated from N-benzyl-N-tert-butoxycarbonylphenylalanine
ethyl ester 1a using LDA as the base at −78 °C and was reacted
with an electron withdrawing aldehyde (4-nitrobenzaldehyde)
at the same temperature to afford the corresponding α-amino,
β-hydroxy ester derivative 8a as a mixture of diastereomers
(dr 3:2.4) in 65% yield (Scheme 8). The formation of the aldol
When ester enolate generated from 1a was generated by
using KHMDS at −78 °C and reacted with benzaldehyde at the
same temperature (Scheme 10), ethyl 3,4-dibenzyl-2-oxo-5-
phenyloxazolidine-4-carboxylate (10a) was obtained in 55%
yield. The intermediate aldolate anion, instead of giving the
corresponding aldol product, underwent intramolecular cycliza-
tion with the carbamate group to produce 10a as a single
diastereomer with low ee (16%).19d Very recently similar aldol
reaction followed by cylization has been reported by Kawabata
et al.19c with excellent enantioselectivities (ee up to 94%).
This finding was generalized with a variety of aromatic
aldehydes having electron donating (e.g., 3,4-dimethoxybenzal-
dehyde) and electron withdrawing (2-chlorobenzaldehyde, 3-
nitrobenzaldehyde) substituents (Scheme 10). In the case of
electron withdrawing aldehydes, compound 10 was obtained in
higher yield (up to 59%) as compared to the electron donating
ones. However, all of the compounds 10b−d were obtained as
single diastereomers but with very poor ees (4−16%).19d
Formation of 10 with poor ees from our substrate 1a using
KHMDS as the base is consistent with our earlier observation
in imino-aldol reaction. It is interesting to note that using LDA
as the base, the substrate 1a undergoes intermolecular aldol
reaction to produce the free aldol products 8, whereas ethyl 3,4-
dibenzyl-5-aryloxooxazolidine-4-carboxylates 10 were obtained
via aldol followed by intramolecular cylization with N-Boc
group when KHMDS was used as the base.
Different reactivity patterns of the enolates generated from
1a using LDA or KHMDS as the base could be explained by
considering the chelating ability of the counterion Li+ or K+ as
shown in Scheme 11. In the case of LDA, the counterion Li+ is
strongly coordinating and hence the intermediate aldolate
anion remained in chelated form as shown in 12a−b, whereas
K+, being a less coordinating metal ion, makes the alkoxy anion
15 more available for further attack to carbamate to form the
cyclized product 10. Possible retroaldol reaction from the
aldolate anion 15 would regenerate the K-enolate 14. Probably
because of faster racemization of K-enolate 14 being in
Scheme 8. Synthesis of α-Amino,β-hydroxy Ester Derivatives
8a−d
1
product was confirmed by H NMR, 13C NMR, DEPT NMR
and HRMS analysis. The diastereoselectivity of 8a was
1
confirmed by H NMR of the crude reaction mixture after
removal of the unreacted starting material by flash column
chromatography. Although the major diastereomer could be
isolated in pure form in small amount, the minor isomer could
not be obtained in pure form. The ee of the minor diastereomer
was found to be 68%, however, the major isomer was produced
with low ee (16%). The generalization of the methodology was
made by studying the aldol reaction of the ester enolate of 1a
with a variety of aldehydes to afford the corresponding α-
amino,β-hydroxy ester derivatives 8a−d in 51−66% yields
(Scheme 8, Table 3).
In the case of another electron withdrawing aromatic
aldehyde (3-nitrobenzaldehyde), the corresponding addition
product 8b was obtained in 66% yield as a mixture of
diastereomers (Table 3, entries 2). Both of the isomers of 8b
could be isolated in pure forms by column chromatography.
The ee of the major and the minor isomers were found to be 30
and 76%, respectively. On increasing the reaction temperature
to −70 °C, the diastereomeric ratio of 8b changed to ∼3:2. The
major and the minor diastereomers of 8b were obtained with
reduced ee (14 and 67%, respectively). Using electron rich
aromatic aldehydes (e.g., 4-methoxybenzaldehyde and 3,4-
dimethoxybenzaldehyde), the corresponding addition products
(8c and 8d, respectively) were obtained with reduced yields
(51−52%) (Table 3, entries 3−4) probably due to the reduced
E
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Table 3. Synthesis of α-Amino,β-hydroxy Ester Derivatives 8a−d
a
b
dr based on 1H NMR of the crude reaction mixture after removal of the unreacted ester 1a. ee (%) for the minor and the major diastereomers of 8
c
d
based on chiral HPLC analysis. ee (%) for 8a: 68 (minor isomer), 16 (major isomer). ee (%) for 8b: 76 (minor isomer), 30 (major isomer).
be syn with relative configuration (2S,3S).20 Unfortunately, in
Scheme 9. Boc Deprotection of α-Amino,β-hydroxy Ester
Derivative 8a
both the cases the crystals were obtained as a racemate (based
on centrosymmetric point group and HPLC analysis) and the
mother liquor contained the pure enantiomer. Unfortunately,
the pure enantiomer of 6a (obtained from the mother liquor)
in combination of various solvents could not be crystallized and
hence we were unable to determine its absolute configuration.
However, using our imino-aldol protocol α,β-diamino ester
derivatives (e.g., 6a) could be obtained in enantiomerically pure
forms.
Other α,β-diamino ester derivatives 6b, 6e, 6g and 6j after
crystallization from their diastereomeric mixtures resulted the
crystals of pure major diastereomers as racemates with anti
relative stereochemistry (see Supporting Information). In
general, the major diastereomer of α,β-diamino ester derivatives
were obtained with anti geometry following our imino-aldol
protocol. Recently, anti/syn selectivity of α,β-diamino ester
derivatives has been nicely explained independently by Davis21
and de Kimpe et al.18c
Scheme 10. Synthesis of Ethyl 3,4-Dibenzyl-5-
aryloxooxazolidine-4-carboxylates 10a−e
Next, different derivatization processes were attempted with
enantiopure 6a (major diastereomer). Initially, the ester moiety
of 6a was reduced with lithium borohydride in tetrahydrofuran
at room temperature22 to give the corresponding alcohol 16a
without loss of enantioselectivity (Scheme 12).23 In this case,
the enantiomerically pure alcohol 16a could not be crystallized
from different combination of solvents.
In another attempt, when compound 4a was subjected to
acid group hydrolysis using LiOH in THF or THF/MeOH or
THF/MeOH/H2O or dioxane/H2O, the racemic amino acid 7
was formed via the C−C bond breaking followed by hydrolysis
of the ester group (Scheme 13).
nonchelated form compared to chelated Li-enolate 11a−b, the
aldolate anion intermediate 15 gets racemized easily and further
cyclizes to produce 10 with poor ees.
After successful demonstration of the memory of chirality
concept in imino-aldol reaction, we attempted to determine the
absolute configuration of α,β-diamino ester derivatives. For this
purpose the pure major and minor diastereomers of 6a were
separately crystallized out using 9:1 CHCl3 in hexane. On the
basis of X-ray crystallographic analysis, the major diastereomer
of 6a was assigned to be anti having relative configuration
(2S,3R) and that of the minor diastereomer of 6a was found to
F
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Scheme 11. Comparison between LDA and KHMDS Mediated Aldol Reactions
Scheme 12. Reduction of α,β-Diamino Ester Derivative 6a
(Major Diastereomer)
Scheme 13. Attempted Hydrolysis of Imino-aldol Adduct 4a
Figure 1. HPLC chromatogram of 1a (enolate was quenched at
−78 °C).
Furthermore, when enantiopure alcohol 16a was treated with
various alcohol protecting groups in basic medium (TBDMSCl
or TBDPSCl in imidazole or p-nitrobenzylchloride in the
presence of triethylamine in dichloromethane), the reaction did
not proceed. Next, the diphenyl acetate ester of enantiopure
16a was prepared using diphenylacetic acid and DCC in
dichloromethane24 to give the corresponding coupling product,
which could not be crystallized.25
As discussed earlier, the absolute configuration of α,β-diamino
ester derivatives could not be assigned on the basis of X-ray
crystallographic data of 6 or its derivatives; hence, other indirect
methods were employed to determine the absolute stereo-
chemistry of both stereogenic centers.20 First, the recovered
starting material 1a after imino-aldol reaction (Table 1, entry 6) at
−78 °C showed retention in configuration with partial
racemization (based on chiral HPLC analysis). Second, the
enolate generated from 1a using LDA at −78 °C was quenched
with water at the same temperature where the regenerated starting
material was obtained with retention in configuration along with
partial racemization (based on chiral HPLC analysis, Figure 1).
These experiments revealed that the stereogenic center of the
starting ester (S)-1a remained unchanged during the course of the
reaction. Third, the enolate of 1a was formed using LDA as the
base at −78 °C and was quenched with water at 0 °C, which
showed complete racemization of the starting amino acid ester
(based on chiral HPLC analysis, Figure 2). This result evidenced
that the enolization was completed at −78 °C.
Figure 2. HPLC chromatogram of 1a (enolate was quenched at 0 °C).
configurationally stable carbanion stabilized by N-Boc group
and intermediate 19 was a chiral enolate in which the chiral
nitrogen was strongly coordinated with the lithium ion.
Formation of anti isomer as the major diastereomer in imino-
aldol reaction with retention of configuration was rationalized
by the abstraction of proton from the bottom face of the N-
benzyl-N-tert-butoxycarbonylphenylalanine ethyl ester 1a to
give intermediate 18 or 19. The anionic species thus generated
had a chance to react with the imines from the same face (in
the intermediate 18) to produce the major diastereomer of the
imino-aldol adduct 4 with retention in configuration (Figure 3).
Removal of the Boc group from 4 produced 6 where the
stereogenic centers remained unaltered. However, the absolute
configuration at the quaternary stereogenic center (C2)
becomes R as priority order at this center being changed in 4
or 6 compared to 1a (H of 1a was replaced by PhCHNHTs).
On the basis of these observations, plausible intermediates 18
and 19 were proposed where intermediate 18 was a
G
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adduct was obtained in good to excellent yield with moderate to
high ee (up to 96%). Enantiopure α,β-diamino ester derivatives
could be obtained using our imino-aldol protocol. Similar results
were observed in the case of aldol reaction where α-amino,β-
hydroxyl ester derivatives were formed in moderate yield with up
to76% ee using LDA as the base. Thus, utilizing MOC concept
higher stereocontrol was achieved from our substrate when LDA
was used as the base. The absolute configuration of the major
isomer of the imino-aldol product was assigned to be (2R,3S).
This methodology was further extended for the asymmetric
synthesis of substituted aziridines.
Figure 3. Proposed intermediates for imino-aldol reaction.
The stereochemistry of both the stereogenic centers in 4 or 6
was compared with the crystal structures of 6 and the absolute
stereochemistry was assigned.
From the above discussion it is evident that absolute
configuration of quaternary stereogenic center in the imino
aldol product 4 is R. The X-ray crystallographic analysis
revealed that the relative configuration of the major
diastereomer of 6a was (2R,3S) and hence the absolute
configuration of its tertiary stereocenter is S. Thus, the absolute
configuration of the major diastereomer of the addition product
4 is (2R,3S).
The stereochemical assignment of the product 6 was further
supported by computational studies20 taking 6a as an example.
For this purpose all the possible structures of the enolate 19
(obtained from the starting material 1a) with different
geometry of the double bond (E and Z) and the orientation
of the protecting groups (Boc and benzyl) attached with
nitrogen were modeled and optimized using Gaussian 03
program. The Z-enolate was found to be more stable in
comparison with E-enolate. In the presence of the counter-
cation (Li+) in THF solvent, the possible geometries of the
enolate 19 Z with different orientation of the protecting groups
attached with nitrogen were also modeled and optimized, and
we found that enolate 19 Z-1 is more stable in comparison to
the enolate 19 Z-2 by 8.08 kcal mol−1.20
EXPERIMENTAL SECTION
■
General Procedures. Unless otherwise noted, all reactions were
carried out in oven-dried glassware under nitrogen atmosphere using
anhydrous solvents. Wherever appropriate, all reagents were purified
prior to use following Vogel’s or Perrin and Armarego guidelines.26
1H NMR spectra were recorded on 400 or 500 MHz in CDCl3 as the
solvent and TMS as an internal standard. 13C NMR spectra were
recorded on 100 or 125 MHz. Melting points were measured using hot
stage apparatus and were uncorrected. Infrared spectra were recorded
in dichloromethane for liquid compounds and KBr for solid compounds.
HRMS were obtained using (ESI) mass spectrometer (TOF). Optical
rotations were measured using a 2.0 mL cell with a 1.0 dm path length
25
and are reported as [α]D (c in g per 100 mL solvent) at 25 °C.
Enantiomeric excess (ee) was determined using chiralcel OD-H, AD-H or
cellulose-2 analytical column (detection at 254 nm). Analytical thin layer
chromatography (TLC) was carried out using silica gel 60 F254 precoated
plates, (0.25 mm thickness). Visualization was performed using UV lamp
or I2 stain. Silica gel 230−400 mesh size was used for flash column
chromatography using the combination of ethyl acetate and petroleum
ether as eluent. Relative stereochemistry of the major diastereomer was
assigned on the basis of X-ray crystallography.
All the N-sulfonylaldimines were prepared in the laboratory from
the corresponding sulfonamide and aldehyde in the presence of Lewis
acid catalyst following a reported procedure.27
Next, the imino aldol strategy has been utilized for the
enantioselective synthesis of substituted aziridines. The ester
group of 6a was reduced to the corresponding alcohol 16a as
mentioned earlier. 16a on cyclization in the presence of mesyl
chloride and triethyl amine produced the substituted aziridine
20a in good yield with high enantioselectivity (ee 92%)
(Scheme 14). This strategy was successful in the case of 6d as
General Procedure for the Synthesis of N-Benzylated Amino Acid
Ester.28 To a solution of amino acid ester hydrochloride (20.0 mmol)
in MeOH (30 mL) were added triethylamine (20.0 mmol) and
benzaldehyde (30.0 mmol). The reaction mixture was stirred at room
temperature for 1.5 h, cooled to 0 °C and NaBH4 (40.0 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 (3 × 50.0 mL) and washed with H2O and brine. The
organic layer was dried over Na2SO4 and the solvent was evaporated.
The residue was purified by flash column chromatography on silica gel
(230−400 mesh) using 4% ethyl acetate in petroleum ether as the
eluent.
Scheme 14. Synthesis of Nonracemic Aziridines 20
General procedure described above was followed to obtain (S)-
Ethyl 2-(N-benzylamino)-3-phenylpropanoate as a colorless liquid
in 92% (5.2 g) yield; IR νmax (CH2Cl2, cm−1): 3332, 3062, 3028,
2980, 2929, 2851, 1731, 1603, 1494, 1454, 1372, 1337, 1185, 1130,
1
well and the reaction went smoothly to afford the corresponding
aziridine 20b in 71% yield with 80% ee (Scheme 14). 20a−b were
1027; H NMR (400 MHz, CDCl3): δ (ppm) 1.09 (t, J = 7.1 Hz,
3H), 2.92 (d, J = 6.6 Hz, 2H), 3.46−3.49 (m, 1H), 3.61 (d, J = 13.2
Hz, 1H), 3.76 (d, J = 13.2 Hz, 1H), 4.02 (q, J = 7.1 Hz, 2H), 7.17−
7.30 (m, 10H); 13C NMR (100 MHz, CDCl3): δ (ppm) 13.9, 39.4,
53.1, 60.1, 61.7, 126.2, 126.6, 127.8, 128.0, 129.0, 137,1, 139.4,
174.0.
1
characterized by H NMR, 13C NMR, IR and mass spectral
analysis. Following our methodology, aziridines 20a−b could be
synthesized in almost enantiopure form with contiguous
quaternary and tertiary stereogenic centers.
General procedure described above was followed to obtain (S)-
Methyl 2-(N-benzylamino)-3-propanoate as a colorless liquid in 87%
(3.36 g) yield; IR νmax (CH2Cl2, cm−1): 3324, 3086, 3063, 3028, 2977,
2950, 2850, 1736, 1603, 1494, 1453, 1374, 1334, 1200, 1152, 1065,
CONCLUSION
■
The memory of chirality concept has been successfully
demonstrated in imino-aldol and aldol reactions. Using KHMDS
as the base imino-aldol reaction produced α,β-amino ester
derivatives with poor ee whereas in aldol reaction 2-oxazolidinone
derivatives were obtained as a single diastereomer with low ee.
Interestingly, when LDA was used as a base, the imino-aldol
1
1044, 1026; H NMR (400 MHz, CDCl3): δ (ppm) 1.30 (d, J = 7.1
Hz, 3H), 3.37 (q, J = 7.1 Hz, 1H), 3.64 (d, J = 12.9 Hz, 1H), 3.71 (s,
3H), 3.77 (d, J = 12.9 Hz, 1H), 4.70 (s, 1H), 7.21−7.35 (m, 5H); 13C
NMR (100 MHz, CDCl3): δ 19.0, 52.0, 55.9, 65.3, 127.1, 128.2, 128.4,
139.7, 176.2.
H
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Article
General Procedure for the Synthesis of (1a−b).29 To a solution of
N-benzylated amino acid ester (7.06 mmol) in dry dichloromethane
(15.0 mL) were added di-tert-butylpyrocarbonate (8.75 mmol) and
triethylamine (7.9 mmol) and the mixture was stirred at room
temperature for 24 h. The reaction mixture was quenched with 0.5 M
aqueous HCl and the aqueous layer was extracted with CH2Cl2 (3 ×
20.0 mL). 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 (230−400 mesh) using 4% ethyl
acetate in petroleum ether as eluent to provide 1a−b.
diastereomers (100 MHz, CDCl3): δ 13.4, 21.0, 21.3, 27.9, 29.6, 37.1,
40.6, 49.5, 61.2, 61.4, 61.9, 71.0, 80.9, 81.1, 81.5, 125.5, 125.8, 126.2,
127.0, 127.2, 127.80, 127.86, 128.0, 128.1, 128.5,128.7, 128.8, 129.4,
129.9, 130.8, 131.2, 134.6, 135.7, 136.8, 138.1, 139.6, 139.9, 141.9,
142.3, 156.1, 157.1, 169.5; HRMS (ESI) m/z Calcd. for C37H43N2O6S
(M+ + H): 643.2842, Found: 643.2834.
Ethyl 2-Benzyl-2-[(N-benzyl)-(N-t-butoxycarbonyl)amino]-3-phe-
nyl-3-phenylsulf- onamidopropanoate (4b). General procedure
described above was followed to afford 4b as a white solid in 62%
(0.15 g) yield; Eluent: EtOAc/petroleum ether 10/90; Rf 0.32 (ethyl
25
acetate/petroleum ether: 15/85); Optical rotation: [α]D = +3.70
(c 0.415, CHCl3); IR νmax (KBr, cm−1) 3380, 2976, 2926, 1739, 1697,
1451, 1388, 1330, 1253, 1160, 1090, 1021; 13C NMR for mixture of
diastereomers (100 MHz, CDCl3): δ (ppm) 13.4, 27.9, 37.2, 40.5,
49.5, 61.2, 61.4, 61.9, 71.2, 80.9, 81.5, 125.5, 125.7, 126.2, 126.8, 127.3,
127.9, 128.0, 129.4, 129.8, 130.7, 131.1, 131.4, 131.6, 134.5, 135.6,
136.6, 139.5, 139.8, 141.2, 156.0, 157.2, 169.4; HRMS (ESI) m/z:
Calcd. for C36H41N2O6S (M+ + H): 629.2685, Found: 629.2687.
Ethyl 2-Benzyl-2-[(N-benzyl)-(N-t-butoxycarbonyl)amino]-3-(4-
nitrophenylsulfonamido)-3-phenylpropanoate (4c). General proce-
dure described above was followed to afford 4c as a light yellow solid
in 80% (0.21 g) yield; Eluent: EtOAc/petroleum ether 10/90; Rf 0.37
(S)-Ethyl 2-[(N-Benzyl)-(N-t-butoxycarbonyl)amino]-3-phenylpro-
panoate (1a). General procedure described above was followed to
obtain 1a as a colorless liquid in 75% (2.03 g) yield as a mixture of two
25
conformers major M and minor m in a ∼5:3 ratio; [α]D = −91.0
(c 1.30, CHCl3); IR νmax (CH2Cl2, cm−1): 3087, 3063, 3029, 2977,
2932, 1740, 1698, 1494, 1453, 1425, 1392, 1366, 1250, 1164, 1079,
1048, 1030, 982; For mixture of rotamers: 1H NMR (500 MHz,
CDCl3): δ (ppm) 1.17 (bs, 3H, M+m), 1.40 (s, 9H, m), 1.50 (s, 9H,
M), 3.06−3.11(m, 1H, M), 3.17−3.22(m, 1H, m), 3.30 (d, J = 5.50
Hz, 1H, M), 3.32 (d, J = 5.50 Hz, 1H, m), 3.51 (d, J = 15.3 Hz, 1H,
M), 3.78 (d, J = 15.6 Hz, 1H, m), 3.88−3.90 (m, 1H, m), 3.98−4.08
(m, 2H, M+m), 4.21−4.27 (m, 1H, M), 4.40 (d, J = 15.58 Hz, 1H, m);
4.62 (d, J = 15.3 Hz, 1H, M), 7.02−7.14 (m, 10H, m), 7.21−7.28 (m,
10H, M); 13C NMR (125 MHz, CDCl3): δ (ppm) 14.1 (m+M), 28.4
(m), 28.5 (M), 35.7 (m), 36.6 (M), 51.9 (m+M), 61.2 (m), 61.3 (M),
80.5 (m), 80.9 (M), 126.5 (m), 126.7 (M), 127.1 (m), 127.4 (M),
127.8 (m), 128.2 (m), 128.3 (M), 128.5 (m), 128.7 (M), 128.9 (m),
129.4 (M), 137.3 (M), 138.1 (m), 138.3 (M+m), 155.2 (M+m), 171.0
(M), 171.1 (m); HRMS (ESI) m/z: Calcd. for C23H29NNaO4 (M+ +
Na): 406.1994, Found: 406.1994.
25
(ethyl acetate/petroleum ether: 15/85); [α]D = +40.0 (c 0.30,
CHCl3); IR νmax (KBr, cm−1): 3302, 2978, 2930, 1743, 1671, 1529,
1454, 1391, 1349, 1165, 1089; 13C NMR for mixture of diastereomers
(100 MHz, CDCl3): δ 13.6, 27.9, 40. 1, 49.2, 61.4, 61.5, 70.7, 82.1,
123.3, 125.5, 126.0, 126.4, 127.6, 127.9, 128.1, 128.2, 129.7, 130.6,
130.9, 134.0, 136.5, 139.2, 146.8, 149.1, 157.8, 169.0; HRMS (ESI)
m/z Calcd. for C36H39N3NaO8S (M+ + Na): 696.2356, Found: 696.2350.
Ethyl 2-benzyl-2-[(N-benzyl)-(N-t-butoxycarbonyl)amino]-3-(3-
bromophenyl)-3-(4-methylphenylsulfonamido)propanoate (4d).
General procedure described above was followed to afford 4d as a
white solid in 68% (0.21 g) yield; Eluent: EtOAc/petroleum ether 10/
90; Rf 0.33 (ethyl acetate/petroleum ether: 15/85); Optical rotation:
[α]D25 +4.05 (C 0.37, CHCl3); IR νmax (KBr, cm−1) 3353, 3063, 3031,
2978, 2930, 1740, 1701, 1598, 1495, 1453, 1389, 1368, 1342, 1252,
1160, 1091, 1033; 13C NMR for mixture of diastereomers (100 MHz,
CDCl3): δ (ppm) 13.4, 21.3, 27.9, 38.0, 40.9, 49.4, 60.4, 61.3, 61.6, 71.1,
81.2, 81.7, 122.1, 125.5, 125.8, 126.1, 126.3, 126.7, 127.3, 128.0, 128.2,
128.9, 129.0, 129.2, 130.7, 130.9, 131.0, 131.9, 133.1, 134.4, 135.3, 137.9,
138.9, 139.3, 139.6, 142.4, 142.8, 156.8, 169.3; HRMS (ESI) m/z: Calcd.
for C37H42BrN2O6S (M+ + H) 721.1947, Found: 721.1946.
(S)-Methyl 2-[(N-Benzyl)-(N-t-butoxycarbonyl)amino]propanoate
(1b). General procedure described above was followed to obtain 1b as
25
a viscous liquid in 60% (1.24 g) yield. [α]D = −36.21 (c 1.86,
CHCl3); IR νmax (CH2Cl2, cm−1): 3064, 3029, 2977, 1747, 1697, 1605,
1496, 1453, 1424, 1366, 1314, 1252, 1219, 1166, 1101, 1068, 1017;
For mixture of rotamers: 1H NMR (400 MHz, CDCl3): δ (ppm) 1.28
(bs, 9H), 1.39 (bs, 3H), 3.59 (s, 3H), 3.85 (bs, 1/2H), 4.26 (bs, 1/
2H), 4.47 (bs, 2H), 7.17−7.24 (m, 5H); 13C NMR (100 MHz,
CDCl3): δ 15.5, 15.9, 28.4, 49.6, 50.9, 52.1, 54.6, 55.4, 80.6, 80.7,
126.9, 127.3, 128.0, 128.4, 128.5, 138.2, 139.2, 155.4, 155.7, 172.7,
172.9.
Ethyl 2-Benzyl-2-[(N-benzyl)-(N-t-butoxycarbonyl)amino]-3-(2-
chlorophenyl)-3-(4-methylphenylsulfonamido)propanoate (4e).
General procedure described above was followed to afford 4e as a
white solid in 74% (0.19 g) yield; Eluent: EtOAc/petroleum ether 10/
General Procedure for the Imino-aldol Reaction of N-Benzyl-N-t-
butoxycarbonylamino Acid Esters (1a−b) with Various Imines. To a
solution of diisopropylamine (0.12 mL, 0.848 mmol) in 2.0 mL dry
THF was added n-BuLi (1.6 M in hexane, 0.53 mL, 0.848 mmol) at
0 °C and stirred for 20 min. It was cooled to −78 °C and a solution of
N-benzyl-N-tert-butoxycarbonyl amino acid esters 1a−b (0.848 mmol)
in 1.0 mL dry THF was added to it and allowed to stir for 1 h. N-
sulfonylimine (0.385 mmol) dissolved in 1.0 mL dry THF was slowly
added into the reaction mixture and stirring was continued at the same
temperature for 10 h. After completion of the reaction (monitored with
TLC), it was quenched with saturated aqueous ammonium chloride
solution and extracted with 5.0 mL of ethyl acetate in two portions. The
combined organic extract was dried over anhydrous Na2SO4 and the
solvent was evaporated under reduced pressure. The residue was purified
by flash column chromatography on silica gel using ethyl acetate in
petroleum ether as the eluent to afford the pure products 4a−k.
Imino-aldol Reaction of N-Benzyl-N-tert-butoxycarbonyl Amino
Acid Esters (1a−b) with Various Imines. The reaction is highly
dependent on temperature, solvent, bases and most importantly on
time and the corresponding de/ee of the products may change with
slight change in any of these conditions.
25
90; Rf 0.45 (ethyl acetate/petroleum ether: 20/80); [α]D = +3.45
(c 0.26, CHCl3); IR νmax (KBr, cm−1): 3351, 3030, 2925, 1739, 1701,
1368, 1304, 1161, 1088; 13C NMR for mixture of diastereomers (100
MHz, CDCl3): δ 13.5, 21.3, 27.7, 27.9, 38.1, 42.6, 49.4, 57.2, 60.6, 61.5,
71.1, 80.6, 125.6, 126.2, 126.4, 126.8, 126.9, 127.5, 127.7, 127.9, 128.1,
128.2, 128.8, 128.9, 129.4, 131.1, 131.5, 132.4, 133.8, 134.8, 135.0, 135.2,
137.3, 139.8, 142.3, 145.1, 157.1, 169.9; HRMS (ESI) m/z Calcd. for
C37H41ClN2NaO6S (M+ + Na): 699.2272, Found: 699.2278.
Ethyl 2-Benzyl-2-[(N-benzyl)-(N-t-butoxycarbonyl)amino]-3-(4-
methylphenylsulfonamido)-3-(4-nitrophenyl)propanoate (4f). Gen-
eral procedure described above was followed to afford 4g as a mixture
of diastereomers in the form of white solid in 75% (0.20 g) yield;
Eluent: EtOAc/petroleum ether 10/90; Rf 0.30 (ethyl acetate/petroleum
25
ether: 15/85); [α]D = +20.0 (c 0.40, CHCl3), IR νmax (KBr, cm−1):
3431, 2927, 1741, 1697, 1523, 1452, 1388, 1347, 1254, 1160, 1088; 13C
NMR for mixture of diastereomers (100 MHz, CDCl3): δ 13.4, 21.2, 27.8,
38.5, 41.6, 49.0, 60.4, 61.3, 62.6, 70.5, 81.8, 122.6, 125.5, 125.8, 126.6,
126.9, 127.4, 128.0, 128.2, 128.9, 129.1, 130.6, 131.0, 134.2, 137.5, 138.9,
139.3, 143.0, 143.4, 143.9, 144.5, 147.2, 156.2, 169.4; HRMS (ESI) m/z
Calcd. for C37H41N3NaO8S (M+ + Na): 710.2512, Found: 710.2511.
Ethyl 2-Benzyl-2-[(N-benzyl)-(N-t-butoxycarbonyl)amino]-3-(4-
methoxyphenyl)-3-(4-methylphenylsulfonamido)propanoate (4g).
General procedure described above was followed to afford 4g as
a white solid in 65% (0.17 g) yield; Eluent: EtOAc/petroleum ether
Characterization Data. Ethyl 2-Benzyl-2-[(N-benzyl)-(N-t-
butoxycarbonyl)amino]-3-(4-methylphenylsulfon-amido)-3-phenyl-
propanoate (4a).16 General procedure described above was followed
to afford 4a as a white solid in 84% (0.21 g) yield; Eluent: EtOAc/
petroleum ether 10/90; Rf 0.45 (ethyl acetate/petroleum ether: 20/
25
80); [α]D = +10.76 (c 0.415, CHCl3); IR νmax (KBr, cm−1): 3334,
2978, 2927, 1738, 1696, 1389, 1160, 1090; 13C NMR for mixture of
I
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25
10/90; Rf 0.21 (ethyl acetate/petroleum ether: 15/85); [α]D = +8.0
(c 0.75, CHCl3); IR νmax (KBr, cm−1): 3432, 3032, 2927, 2855, 1738,
1692, 1609, 1510, 1448, 1388, 1329, 1252, 1159, 1087, 1027; 13C
NMR for mixture of diastereomers (100 MHz, CDCl3): δ (ppm) 13.4,
21.3, 21.4, 27.9, 28.3, 40.5, 46.7, 49.4, 55.2, 61.2, 61.4, 71.2, 80.0, 81.1,
81.4, 113.2, 113.9, 125.5, 125.7, 126.2, 126.6, 127.1, 127.2, 127.5,
127.7, 127.9, 128.0, 128.2, 128.3, 128.7, 129.1, 129.4, 129.6, 130.7,
130.9, 131.1, 134.6, 135.9, 138.4, 139.6, 139.9, 141.9, 142.2, 143.3,
157.1, 159.2, 169.6; HRMS (ES+) m/z Calcd. for C38H45N2O7S (M+ + H):
673.2947, Found: 673.2947.
Ethyl 2-Benzyl-2-(N-benzylamino)-3-(4-methylphenylsulfonami-
do)-3-phenylpropanoate 6a.16 General procedure described above
was followed to afford 6a (major) and 6a (minor) as a white solid in
88% (0.048 g) overall yield (combined yield of both the
diastereomers). It was obtained as a mixture of diastereomers with
dr 83:17 (based on 1H NMR analysis of crude reaction mixture) where
the diastereomers were separated through flash column chromatog-
raphy (eluent: EtOAc/petroleum ether 10/90).
For the Major Diastereomer 6a. Rf 0.45 (ethyl acetate/petroleum
25
ether: 20/80); mp: 158−160 °C; Optical rotation: [α]D = +10.25
(c 0.335, CHCl3) for a 92% ee sample; Optical purity was determined
by chiral HPLC analysis (Chiralcel AD-H column) using 95/5
hexane/isopropanol, flow rate = 1.0 mL/min, TR 1: 72.6 min (major),
TR 2: 97.3 min (minor); IR νmax (KBr, cm−1): 3344, 3281, 2925, 2854,
2354, 1732, 1600, 1454, 1263, 1161, 1091, 1019; 1H NMR (400 MHz,
CDCl3): δ (ppm) 1.03 (t, J = 7.2 Hz, 3H), 2.20 (s, 3H), 3.04 (d, J =
14.8 Hz, 1H), 3.33 (d, J = 14.8 Hz, 1H), 3.51 (d, J = 12.4 Hz, 1H),
3.66 (d, J = 12.4 Hz, 1H), 3.95 (q, J = 7.2 Hz, 2H), 4.83 (d, J = 6.6 Hz,
1H), 6.2 (brs, 1H), 6.88 (d, J = 8.0 Hz, 2H), 6.97−7.06 (m, 4H),
7.08−7.23 (m, 11H), 7.31 (d, J = 8.0 Hz, 2H); 13C NMR (100 MHz,
CDCl3): δ (ppm) 13.7, 21.2, 38.7, 46.9, 61.6, 61.7, 68.8, 126.8, 127.0,
127.6, 127.7, 128.26, 128.28, 128.3, 128.4, 128.9, 129.8, 130.4, 135.9,
136.3, 137.9, 139.5, 142.5, 173.1; HRMS (ES+) m/z: Calcd. for
C32H34N2O4S (M+ + H): 543.2329, Found: 543.2337.
Ethyl 2-[(N-Benzyl)-(N-t-butoxycarbonyl)amino]-3-(2-furanyl)-3-
(4-methylphenylsulfonamido)propanoate (4h). General procedure
described above was followed to afford 4h as a white solid in 74%
(0.18 g) yield; Eluent: EtOAc/petroleum ether 15/85; Rf 0.30 (ethyl
25
acetate/petroleum ether: 15/85); [α]D = +18.0 (c 1.0, CHCl3), IR
νmax (KBr, cm−1): 3292, 2977, 2925, 1739, 1673, 1601, 1453, 1390,
1304, 1160, 1088, 1017; 13C NMR for mixture of diastereomers (100
MHz, CDCl3): δ (ppm) 13.4, 13.8, 21.4, 27.8, 27.9, 40.1, 41.6, 47.1,
48.8, 55.7, 61.2, 61.6, 71.0, 81.6, 94.7, 110.6, 110.9, 125.5, 125.7, 126.0,
126.2, 126.6, 126.9, 127.3, 127.9, 128.0, 128.1, 128.3, 128.4, 128.9,
129.0, 130.7, 133.1, 134.2, 137.8, 139.4, 139.8, 141.9, 142.2, 150.5,
151.2, 155.6, 168.3, 169.0; HRMS (ESI) m/z Calcd. for C35H41N2O7S
(M+ + H): 633.2634, Found: 633.2634.
Ethyl 2-Benzyl-2-[(N-benzyl)-(N-t-butoxycarbonyl)amino]-3-(4-
chlorophenyl)-3-(4-methylphenylsulfonamido)propanoate (4i).
General procedure described above was followed to afford 4i as
white solid in 72% (0.19 g) yield; Eluent: EtOAc/petroleum ether 10/
For the Minor Diastereomer 6a. Rf 0.44 (ethyl acetate/petroleum
25
ether: 20/80); mp: 118−120 °C; Optical rotation [α]D −10.77
(c 0.65, CHCl3) for a 80% ee sample; Optical purity was determined by
chiral HPLC analysis (Chiralcel AD-H column) using 95/5 hexane/
isopropanol, flow rate = 1.0 mL/min, TR 1: 35.1 min (major), TR 2:
43.2 min (minor); IR νmax (KBr, cm−1): 3347, 3296, 2959, 2924, 2853,
1730, 1661, 1600, 1454, 1264, 1161, 1090, 1019; 1H NMR (500 MHz,
CDCl3): δ (ppm) 1.08 (t, J = 7.1 Hz, 3H), 2.25 (s, 3H), 3.02 (d, J =
15.2 Hz, 1H), 3.34 (d, J = 15.2 Hz, 1H), 3.74 (d, J = 11.8 Hz, 1H),
3.81 (d, J = 11.8 Hz, 1H), 3.98 (q, J = 7.1 Hz, 2H), 4.73 (d, J = 7.7 Hz,
1H), 6.10 (d, J = 7.7 Hz, 1H), 6.85−6.88 (m, 2H), 6.98−7.09 (m,
4H), 7.22−7.33 (m, 11H), 7.70 (d, J = 8.3 Hz, 2H); 13C NMR (125
MHz, CDCl3): δ (ppm) 13.9, 21.5, 38.7, 48.9, 61.7, 62.4, 71.1, 127.0,
127.5, 128.19, 128.2, 128.3, 128.7, 128.8, 128.9, 129.2, 130.3, 130.4,
135.0, 135.3, 136.8, 137.2, 143.0, 171.1; HRMS (ES+) m/z: Calcd. for
C32H34N2O4S (M+ + H): 543.2329, Found: 543.2328.
25
90; Rf 0.45 (ethyl acetate/petroleum ether: 20/80); [α]D = +5.92
(c 1.35, CHCl3); IR νmax (KBr, cm−1): 3351, 2977, 2927, 1740, 1701,
1389, 1160, 1089; 13C NMR for mixture of diastereomers (100 MHz,
CDCl3): δ (ppm) 13.4, 21.3, 27.9, 37.7, 41.1, 49.4, 60.4, 61.2, 61.5,
61.9, 81.2, 81.6, 125.6, 125.8, 126.1, 126.4, 126.9, 127.3, 127.9, 128.0,
128.2, 128.8, 128.9, 130.9, 131.1, 131.2, 133.8, 134.5, 135.4, 137.9,
139.3, 139.7, 142.5, 142.8, 156.7, 169.5; HRMS (ESI) m/z Calcd. for
C37H41ClN2O6S (M+ + Na): 699.2271, Found: 699.2229.
Ethyl 2-Benzyl-2-[(N-benzyl)-(N-t-butoxycarbonyl)amino]-3-(4-
methylphenylsulfonamido)-3-(3-nitrophenyl)propanoate (4j). Gen-
eral procedure described above was followed to afford 4j as a white
solid in 81% (0.21 g) yield; Eluent: EtOAc/petroleum ether 10/90; Rf
25
0.28 (ethyl acetate/petroleum ether: 15/85); [α]D = +8.0 (c 0.80,
CHCl3), IR νmax (KBr, cm−1): 3433, 2926, 1741, 1697, 1532, 1449,
1388, 1349, 1254, 1160, 1090, 1020; 13C NMR for mixture of
diastereomers (100 MHz, CDCl3): δ (ppm) 13.4, 21.1, 27.7, 28.1,
38.6, 41.1, 49.1, 60.0, 61.4, 62.0, 70.7, 81.6, 81.9, 122.4, 125.0, 125.5,
126.6, 126.7, 126.9, 127.5, 128.1, 128.3, 128.5, 128.9, 129.0, 129.2,
129.3, 130.9, 134.1, 134.5, 135.7, 136.4, 137.8, 138.3, 138.9, 139.3,
142.6, 142.9, 147.5, 147.7, 156.5, 169.2; HRMS (ES+) m/z Calcd. for
C37H42N3O8S (M+ + H): 688.2693, Found: 688.2691.
E t h y l 2 - B e n z y l - 2 - ( N - b e n z y l a m i n o ) - 3 - p h e n y l - 3 -
(phenylsulfonamido)propanoate 6b. General procedure described
above was followed to afford 6b (major) and 6b (minor) as a white
solid in 70% (0.037 g) overall yield (combined yield of both the
diastereomers). The compound was isolated as a mixture of
1
diastereomers with dr 71:29 (based on H NMR analysis of crude
reaction mixture) where the major and minor diastereomers could not
be separated through flash column chromatography (eluent: EtOAc/
petroleum ether 10/90), Rf 0.30 (ethyl acetate/petroleum ether: 15/85);
Methyl 2-[(N-Benzyl)-(N-t-butoxycarbonyl)amino]-2-methyl-3-(4-
methylphenylsulfonamido)-3-phenylpropanoate (4k). General pro-
cedure described above was followed to afford 4k as a white solid in
72% (0.15 g) yield; Eluent: EtOAc/petroleum ether 10/90; Rf 0.23
25
Optical rotation: [α]D +7.29 (c 0.415, CHCl3).
For the Major Diastereomer 6b. ee 80%; Optical purity was
determined by chiral HPLC analysis of the mixture (Chiralcel OD-H
column) using 99/1 hexane/isopropanol, flow rate = 0.8 mL/min, TR
1: 38.1 min (major), TR 2: 53.4 min (minor). Major diastereomer was
obtained in pure form after recrystallization and it was injected in
HPLC to identify the pair of peaks for each diastereomers; IR νmax
(CH2Cl2, cm−1): 3303, 3062, 3029, 2925, 2853, 1731, 1602, 1495,
25
(ethyl acetate/petroleum ether: 15/85); [α]D = −10.0 (c 0.30,
CHCl3); IR νmax (KBr, cm−1): 3396, 2927, 1742, 1695, 1453, 1391,
1254, 1162, 1046; 13C NMR for the major diastereomer (125 MHz,
CDCl3): δ 15.5, 15.9, 28.4, 49.6, 51.0, 52.0, 54.6, 55.4, 80.6, 80.7,
126.9, 127.3, 128.0, 128.4, 128.5, 138.2, 139.2, 155.4, 155.7, 172.7,
172.9; HRMS (ESI) m/z Calcd. for C30H36N2NaO6S (M+ + Na):
575.2192, Found: 575.2192.
1
1451, 1325, 1209, 1163, 1090, 1064, 1029, 912; H NMR (400 MHz,
CDCl3): δ (ppm) 1.03 (t, J = 7.1 Hz, 3H), 3.07 (brs, 1H), 3.34 (d, J =
14.9 Hz, 1H), 3.51 (d, J = 12.5 Hz, 1H), 3.68 (d, J = 12.5 Hz, 1H),
3.96 (q, J = 7.0 Hz, 2H), 4.86 (brs, 1H), 6.30 (brs, 1H), 6.90−7.32 (m,
18H), 7.44 (d, J = 7.3 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ
(ppm) 13.8, 38.8, 47.0, 61.7, 61.9, 68.9, 126.8, 126.9, 127.2, 127.8,
127.9, 128.2, 128.3, 128.4, 128.7, 129.8, 130.4, 131.9, 135.7, 135.8,
135.9, 140.8, 172.9; HRMS (ES+) m/z: Calcd. for C31H32N2O4S
(M+ + H): 529.2161, Found: 529.2161.
For the Minor Diastereomer 6b. ee 80%; Optical purity was
determined by chiral HPLC analysis (Chiralcel OD-H column) using
99/1 hexane/isopropanol, flow rate = 0.8 mL/min, TR 1: 47.7 min
(major), TR 2: 67.5 min (minor).
General Method for Removal of Boc Group from Imino-
aldol Products (6a−k). To a stirring solution of substrate 4a−k
(0.10 mmol) in dry dichloromethane (1.0 mL) was added trifluoro-
acetic acid (0.5 mL) at 0 °C. The reaction mixture was stirred at room
temperature for 2 h. It was neutralized with aq. saturated NaHCO3
solution and the aqueous layer was extracted with CH2Cl2 (3 × 5.0 mL).
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 on
silica gel (230−400 mesh) using ethyl acetate in petroleum ether as the
eluent to provide 6a−k.
J
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The Journal of Organic Chemistry
Article
Ethyl 2-Benzyl-2-(N-benzylamino)-3-(4-nitrophenylsulfonamido)-
3-phenylpropanoate 6c. General procedure described above was
followed to afford 6c (major) and 6c (minor) as a pale yellow solid in
84% (0.48 g) overall yield (combined yield of both the diastereomers).
It was obtained as a mixture of diastereomers with dr 83:17 (based on
1H NMR analysis of crude reaction mixture) where the major
7.1 Hz, 3H), 2.19 (s, 3H), 2.96 (d, J = 14.4 Hz, 1H), 3.44 (d, J = 14.6
Hz, 1H), 3.52−3.59 (m, 2H), 3.91−4.06 (m, 2H), 5.39 (d, J = 6.8 Hz,
1H), 6.32 (brs, 1H), 6.85−6.94 (m, 3H), 6.99−7.24 (m, 13H), 7.39
(d, J = 8.0 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ (ppm) 13.7,
21.3, 38.2, 47.5, 56.9, 62.3, 69.4, 126.5, 127.1, 127.3, 127.8, 128.5,
128.8, 129.1, 129.2, 129.6, 130.4, 134.6, 134.8, 135.3, 137.2, 142.8,
172.4; HRMS (ES+) m/z: Calcd. for C32H34ClN2O4S (M+ + H):
577.1928, Found: 577.1929.
diastereomer 6c was separated through flash column chromatography
(eluent: EtOAc/petroleum ether 10/90).
For the Major Diastereomer 6c. Rf 0.37 (ethyl acetate/petroleum
ether: 15/85); mp: 112−114 °C; Optical rotation: [α]D = +20.00
For the Minor Diastereomer 6e. Rf 0.48 (ethyl acetate/petroleum
ether: 20/80); Optical purity could not be determined as it was
inseparable in chiral HPLC columns (Chiralcel AD-H, OD-H); mp:
169−170 °C; IR νmax (KBr, cm−1): 3348, 3279, 2980, 2924, 1736,
1597, 1495, 1444, 1371, 1219, 1162, 1064, 1033; 1H NMR (400 MHz,
CDCl3): δ (ppm) 0.93 (t, J = 7.1 Hz, 3H), 2.18 (s, 3H), 2.97 (d, J =
14.9 Hz, 1H), 3.31 (d, J = 14.9 Hz, 1H), 3.67 (d, J = 11.9 Hz, 1H),
3.77 (d, J = 11.9 Hz, 1H), 3.92−3.97 (m, 2H), 5.36 (s, 1H), 6.00 (brs,
1H), 6.87 (d, J = 8.1 Hz, 2H), 6.97−7.05 (m, 2H), 7.09−7.27 (m,
12H), 7.37 (d, J = 8.1 Hz, 2H); 13C NMR (125 MHz, CDCl3): δ
(ppm) 13.6, 21.4, 36.6, 46.0, 56.6, 61.7, 69.7, 126.1, 126.7, 127.0,
127.3, 128.1, 128.3, 128.5, 128.8, 129.1, 129.3, 130.1, 134.2, 134.3,
136.0, 136.5, 139.0, 142.9, 171.7; HRMS (ES+) m/z: Calcd. for
C32H34ClN2O4S (M+ + H): 577.1928, Found: 577.1922.
25
(c 0.25, CHCl3) for a 88% ee sample; Optical purity was determined by
chiral HPLC analysis (Chiralcel AD-H column) using 95/5 hexane/
isopropanol, flow rate = 1.0 mL/min, TR 1: 14.2 min (minor); TR 2:
17.0 min (major); IR νmax (KBr, cm−1): 3430, 3334, 2926, 1729, 1604,
1529, 1456, 1408, 1347, 1252, 1205, 1164, 1092, 1022; 1H NMR (500
MHz, CDCl3): δ (ppm) 1.05 (t, J = 7.0 Hz, 3H), 3.08 (d, J = 14.5 Hz,
1H), 3.35 (d, J = 14.5 Hz, 1H), 3.51 (d, J = 12.5 Hz, 1H), 3.71 (d, J =
12.5 Hz, 1H), 3.97−4.05 (m, 2H), 4.88 (s, 1H), 6.49 (brs, 1H), 6.95
(m, 4H), 7.03−7.08 (m, 3H), 7.13−7.23 (m, 8H), 7.52 (d, J = 9.0 Hz,
2H), 7.88 (d, J = 9.0 Hz, 2H); 13C NMR (125 MHz, CDCl3): δ (ppm)
13.8, 38.7, 47.0, 61.6, 62.1, 68.8, 123.4, 127.0, 127.2, 127.6, 127.9,
128.0, 128.2, 128.3, 128.4, 129.7, 130.5, 135.4, 139.2, 146.0, 146.4,
149.2, 173.2; HRMS (ES+) m/z: Calcd. for C31H31N3O6S (M+ + H):
574.2011, Found: 574.2014.
Ethyl 2-Benzyl-2-(N-benzylamino)-3-(4-methylphenylsulfonami-
do)-3-(4-nitrophenyl)propanoate 6f. General procedure described
above was followed to afford 6f (major) and 6f (minor) as a white
solid in 86% (0.051 g) overall yield (combined yield of both the
diastereomers). The compound was isolated (eluent: EtOAc/
petroleum ether 10/90) as a mixture of diastereomers with dr 73:27
(based on 1H NMR analysis of crude reaction mixture); Rf 0.30 (ethyl
For the Minor Diastereomer 6c. Minor diastereomer could not be
isolated in pure form. Optical purity of this isomer could not be
determined as it was inseparable in chiral HPLC columns (Chiralcel
AD-H, OD-H).
Ethyl 2-Benzyl-2-(N-benzylamino)-3-(3-bromophenyl)-3-(4-
methylphenylsulfonamido)propanoate 6d (Table 2, entry 4).
General procedure described above was followed to afford 6d
(major) and 6d (minor) as a white solid in 87% (0.054 g) overall
yield (combined yield of both the diastereomers). It was obtained as a
mixture of diastereomers with dr 71:29 (based on 1H NMR analysis of
crude reaction mixture) where the major diastereomer was separated
through flash column chromatography (eluent: EtOAc/petroleum
ether 10/90), Rf 0.30 (ethyl acetate/petroleum ether: 15/85).
25
acetate/petroleum ether: 15/85); Optical rotation: [α]D = +17.80
(c 1.3, CHCl3); IR νmax (KBr, cm−1): 3343, 3290, 3030, 2925, 1733,
1601, 1522, 1495, 1453, 1346, 1162.
For the Major Diastereomer 6f. mp: 84−86 °C; H NMR (500
1
MHz, CDCl3): δ (ppm) 1.0 (t, J = 7.3 Hz, 3H), 2.21 (s, 3H), 3.03 (d,
J = 14.3 Hz, 1H), 3.22 (d, J = 14.3 Hz, 1H), 3.50 (d, J = 12.8 Hz, 1H),
3.65 (d, J = 12.8 Hz, 1H), 3.89−3.96 (m, 2H), 4.90 (d, J = 6.5 Hz,
1H), 6.40 (brs, 1H), 6.92 (d, J = 8.0 Hz, 2H), 7.06−7.29 (m, 12H),
7.34 (d, J = 8.5 Hz, 2H), 7.85 (d, J = 9.0 Hz, 2H); 13C NMR (125
MHz, CDCl3): δ (ppm) 13.8, 21.3, 38.7, 46.7, 60.4, 62.1, 68.6, 122.7,
126.8, 127.2, 127.5, 128.5, 128.6, 129.2, 129.7, 129.8, 130.1, 134.9,
137.2, 138.7, 143.5, 144.2, 147.2, 172.4; HRMS (ES+) m/z: Calcd. for
C32H33N3O6S (M+ + H): 588.2168, Found: 588.2168; [α]D25 = +54.0
(c 0.2, CH2Cl2) for a 75% ee sample. Optical purity was determined by
chiral HPLC analysis (Lux 5u Cellulose-2 column) using 95/5
hexane/isopropanol, flow rate = 1.0 mL/min, TR 1: 106.4 min (major),
TR 2: 122.6 min (minor)
25
For the Major Diastereomer 6d. Optical rotation: [α]D = +3.03
(c 0.66, CHCl3) for a 84% ee sample; Optical purity was determined by
chiral HPLC analysis (Chiralcel AD-H column) using 90/10 hexane/
isopropanol, flow rate = 1.0 mL/min, TR 1: 20.3 min. (major), TR 2:
28.5 min. (minor); IR νmax (CH2Cl2, cm−1): 3291, 3062, 3029, 2925,
2854, 1732, 1597, 1494, 1452, 1336, 1209, 1161, 1093, 1030; 1H NMR
(400 MHz, CDCl3): δ (ppm) 1.05 (t, J = 7.1 Hz, 3H), 2.24 (s, 3H), 3.04
(d, J = 14.9 Hz, 1H), 3.29 (d, J = 14.9 Hz, 1H), 3.51 (d, J = 12.4 Hz, 1H),
3.69 (d, J = 12.4 Hz, 1H), 3.98 (q, J = 7.1 Hz, 2H), 4.77 (d, J = 7.1 Hz),
6.22 (brs, 1H), 6.83−7.05 (m, 4H), 7.09−7.32 (m, 14H); 13C NMR (100
MHz, CDCl3): δ (ppm) 13.8, 21.4, 38.6, 46.9, 60.9, 62.0, 68.7, 122.1,
126.7, 127.0, 127.3, 127.5, 127.8, 128.4, 128.5, 129.3, 129.9, 130.3, 130.7,
131.5, 135.5, 137.5, 138.4, 139.2, 143.0, 172.8. HRMS (ES+) m/z: Calcd.
for C32H33BrN2O4S (M+ + H): 621.1426, Found 621.1429.
For the Minor Diastereomer 6f. ee 43%, Optical purity was
determined by chiral HPLC analysis (Lux 5u Cellulose-2 column)
using 95/5 hexane/isopropanol, flow rate = 1.0 mL/min, TR 1: 120.6
min. (major), TR 2: 153.2 min. (minor)
Ethyl 2-Benzyl-2-(N-benzylamino)-3-(4-methoxyphenyl)-3-(4-
methylphenylsulfonamido)propanoate 6g (Table 2, entry 7).
General procedure described above was followed to afford 6g (major)
and 6g (minor) as a white solid in 91% (0.052 g) yield. The compound
was isolated (eluant: EtOAc/petroleum ether 8/92) as a mixture of
diastereomers with dr 75:25 (based on 1H NMR analysis); Rf 0.18 (ethyl
acetate/petroleum ether: 15/85); Optical rotation: [α]D25 = +11.70 (c 0.85,
CHCl3); IR νmax (CH2Cl2, cm−1): 3328, 3292, 3062, 3029, 2955, 2925,
2853, 1732, 1610, 1513, 1495, 1454, 1326, 1250, 1160, 1093, 1032, 916.
For the Minor Diastereomer 6d. It could not be isolated in pure
form; ee 62%; Optical purity was determined by chiral HPLC analysis
(Chiracel OD-H column) using 97/3 hexane/isopropanol, flow rate =
0.8 mL/min, TR 1: 21.8 min (major), TR 2: 26.5 min (minor).
Ethyl 2-Benzyl-2-(N-benzylamino)-3-(2-chlorophenyl)-3-(4-
methylphenylsulfonamido)propanoate 6e. General procedure de-
scribed above was followed to afford 6e (major) and 6e (minor) as a
white solid in 80% (0.046 g) overall yield (combined yield of both the
diastereomers). It was obtained as a mixture of diastereomers with dr
1
For the Major Diastereomer 6g. mp: 115−117 °C H NMR (400
1
79:21 (based on H NMR of the crude reaction mixture) where the
MHz, CDCl3): δ (ppm) 1.05 (t, J = 6.8 Hz, 3H), 2.2 (s, 3H), 3.06
(brs, 1H), 3.30 (d, J = 14.6 Hz, 1H), 3.52 (d, J = 12.7 Hz, 1H), 3.64−
3.70 (m, 4H), 3.98 (q, J = 6.8 Hz, 2H), 4.78 (brs, 1H), 6.14 (brs, 1H),
6.52 (d, J = 8.6 Hz, 2H), 6.90−7.23 (m, 14H), 7.32 (d, J = 8.04 Hz,
2H); 13C NMR (100 MHz, CDCl3): δ (ppm) 13.8, 21.3, 38.7, 46.9,
55.2, 61.1, 61.8, 68.8, 113.2, 126.8, 126.9, 127.1, 127.7, 128.3, 128.4,
128.9, 129.6, 129.8, 130.4, 135.9, 137.9, 139.6, 142.5, 159.2, 173.2;
HRMS (ES+) m/z: Calcd. for C33H36N2O5S (M+ + H): 573.2423,
diastereomers were separated through flash column chromatography
(eluent: EtOAc/petroleum ether 10/90).
For the Major Diastereomer 6e. mp: 160−162 °C; Rf 0.50 (ethyl
acetate/petroleum ether: 20/80); [α]D25 = +12.45 (c 1.36, CHCl3) for
a 56% ee sample; Optical purity was determined by chiral HPLC
analysis (Chiralcel OD-H column), 97/3 hexane/isopropanol, flow
rate = 0.8 mL/min, TR 1: 19.19 min (minor), TR 2: 23.93 min (major);
IR νmax (KBr, cm−1): 3344, 3282, 3029, 2962, 2885, 1729, 1305, 1261,
1160, 1093, 1021; 1H NMR (400 MHz, CDCl3): δ (ppm) 1.05 (t, J =
25
Found: 573.2421; [α]D = +13.94 (c 0.416, CH2Cl2) for a 96% ee
sample, Optical purity was determined by chiral HPLC analysis
K
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The Journal of Organic Chemistry
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(Lux 5u Cellulose-2 column) using 95/5 hexane/isopropanol, flow
rate = 1.0 mL/min, TR 1: 75.9 min (major), TR 2: 64.3 min (minor).
For the Minor Diastereomer 6g. ee 70%; Optical purity was
determined by chiral HPLC analysis (Lux 5u Cellulose-2 column)
using 95/5 hexane/isopropanol, flow rate = 1.0 mL/min, TR 1: 120.9
min (major), TR 2: 90.5 min (minor).
(c 0.50, CHCl3); IR νmax (CH2Cl2, cm−1): 3343, 3294, 3063, 3030,
2924, 2853, 1732, 1599, 1530, 1494, 1451, 1412, 1348, 1267, 1210,
1161, 1091, 1029.
1
For the Major Diastereomer 6j. mp 64−66 °C; H NMR (400
MHz, CDCl3): δ (ppm) 1.04 (t, J = 7.1 Hz, 3H), 2.20 (s, 3H), 3.06
(d, J = 14.4 Hz, 1H), 3.24 (d, J = 14.4 Hz, 1H), 3.55 (d, J = 12.4 Hz,
1H), 3.69 (d, J = 12.4 Hz, 1H), 3.97 (q, J = 7.1 Hz, 2H), 4.90 (d, J =
6.8 Hz, 1H), 6.36 (brs, 1H), 6.89 (d, J = 8.1 Hz, 2H), 7.09−7.33 (m,
12H), 7.48 (d, J = 7.6 Hz, 1H), 7.77 (s, 1H), 7.88−7.92 (m, 2H); 13C
NMR (100 MHz, CDCl3): δ (ppm) 13.8, 21.2, 38.7, 46.9, 60.3, 62.1,
68.6, 122.5, 122.7, 123.6, 126.8, 127.2, 127.4, 127.7, 128.6, 128.8,
129.2, 129.9, 130.1, 134.9, 135.2, 137.4, 138.6, 143.3, 147.7, 172.4;
HRMS (ES+) m/z: Calcd. for C32H33N3O6S (M+ + H): 588.2168,
Ethyl 2-Benzyl-2-(N-benzylamino)-3-(2-furanyl)-3-(4-methylphenyl-
sulfonamido)propanoate 6h (Table 2, entry 8). General procedure
described above was followed to afford 6h (0.046 g) as a white solid in
87% overall yield (combined yield of both the diastereomers). The
compound was isolated as a mixture of diastereomers with dr 67:33
1
(based on H NMR analysis of the crude reaction mixture) where a
little amount of pure major diastereomer was isolated through flash
column chromatography (eluent: EtOAc/petroleum ether 10/90)
which was injected in chiral HPLC condition (see below) to identify
pair of peaks for each diastereomer; Rf 0.30 (ethyl acetate/petroleum
ether: 15/85).
25
Found: 588.2166; [α]D = +25.15 (c 0.33, CH2Cl2) for a 60% ee
sample, Optical purity was determined by chiral HPLC analysis (Lux
5u Cellulose2 column) using 95/5 hexane/isopropanol, flow rate = 1.0
mL/min, TR 1: 113.8 min (major), TR 2: 78.2 min (minor).
For the Minor Diastereomer 6j. ee 33%, Optical purity was
determined by chiral HPLC analysis (Lux 5u Cellulose2 column)
using 95/5 hexane/isopropanol, flow rate = 1.0 mL/min, TR 1: 63.0
min (major), TR 2: 95.7 min (minor).
For the Major Diastereomer 6h. mp: 110−112 °C; Optical
25
rotation: [α]D = +9.23 (c 1.3, CHCl3) for a 80% ee sample; Optical
purity was determined by chiral HPLC analysis (Chiralcel OD-H
column) using 97/3 hexane/isopropanol, flow rate = 0.8 mL/min, TR
1: 19.5 min (minor), TR 2: 25.5 min (major); IR νmax (KBr, cm−1):
3359, 3294, 3030, 2923, 1735, 1600, 1495, 1453, 1336, 1162, 1091,
1016; 1H NMR (400 MHz, CDCl3): δ (ppm) 1.05 (t, J = 7.2 Hz, 3H),
2.27 (s, 3H), 3.12 (d, J = 15.2 Hz, 1H), 3.34 (d, J = 15.2 Hz, 1H), 3.50
(d, J = 12.2 Hz, 1H), 3.70 (d, J = 12.2 Hz, 1H), 3.91−3.98 (m, 2H),
4.93 (d, J = 7.3 Hz, 1H), 5.97 (d, J = 3.3 Hz, 1H), 6.02−6.04 (m, 1H),
6.08 (brs, 1H), 7.04 (d, J = 8.1 Hz, 2H), 7.10−7.23 (m, 11H), 7.45 (d,
J = 8.1 Hz, 2H); 13C NMR (125 MHz, CDCl3): δ (ppm): 13.9, 21.5,
38.4, 46.4, 55.9, 62.0, 68.8, 109.5, 110.4, 126.9, 127.0, 128.2, 128.45,
128.53, 128.7, 129.3, 129.9, 130.7, 135.8, 137.8, 141.9, 142.8, 149.9,
172.9; HRMS (ES+) m/z: Calcd. for C30H32N2O5S (M+ + H):
533.2110, Found: 533.2110.
Methyl 2-[(N-Benzylamino]-2-methyl-3-(4-methylphenylsulfona-
mido)-3-phenylpropanoate 6k (Scheme 6). General procedure
described above was followed to afford 6k (major) and 6k (minor)
as a white solid in 71% (0.32 g) overall yield (combined yield of both
the diastereomers). The compound was isolated as a mixture of
diastereomers with dr 55:45 (based on 1H NMR analysis of the crude
reaction mixture) where the major diastereomer was separated
through flash column chromatography (eluent: EtOAc/petroleum
ether 10/90); Rf 0.17 (ethyl acetate/petroleum ether: 15/85).
For the Major Diastereomer 6k. mp: 134−136 °C; Optical purity
(ee 33%) was determined by chiral HPLC analysis (Chiralcel OD-H
column) using 95/5 hexane/isopropanol, flow rate = 1.0 mL/min, TR
1: 14.9 min (major), TR 2: 18.4 min (minor); IR νmax (KBr, cm−1):
3340, 3279, 2923, 1707, 1496, 1378, 1309, 1257, 1168; 1H NMR (500
MHz, CDCl3): δ (ppm) 1.28 (s, 3H), 2.28 (s, 3H), 3.51−3.59 (s, 2H),
3.62 (s, 3H), 4.53 (s, 1H), 6.09 (bs, 1H), 6.98 (d, J = 8.2 Hz, 2H),
7.09−7.12 (m, 5H), 7.25−7.33 (m, 5H), 7.43 (d, J = 8.1 Hz, 2H); 13C
NMR (100 MHz, CDCl3): δ (ppm) 17.8, 21.5, 48.2, 52.4, 63.1, 65.9,
127.3, 127.9, 128.2, 128.6, 129.2, 136.1, 136.7, 139.6, 143.1, 174.6;
HRMS (ES+) m/z: Calcd. for C25H28N2O4S (M+ + H): 453.1848,
Found: 453.1848.
For the Minor Diastereomer 6h. It could not be isolated in pure
form; ee 88%; Optical purity was determined by chiral HPLC analysis
(Chiralcel OD-H column) using 97/3 hexane/isopropanol, flow rate =
0.8 mL/min, TR 1: 16.2 min (minor), TR 2: 22.2 min (major).
Ethyl 2-Benzyl-2-(N-benzylamino)-3-(4-chlorophenyl)-3-(4-
methylphenylsulfonamido)propanoate 6i (Scheme 4). General
procedure described above was followed to afford 6i (major) and 6i
(minor) as a white solid in 88% (0.051 g) yield. It was obtained as a
1
mixture of diastereomers with dr 75:25 (based on H NMR); Rf 0.45
25
For the Minor Diastereomer 6k. IR νmax (KBr, cm−1): 3431, 3287,
2998, 1727, 1597, 1478, 1413, 1326, 1288, 1160, 1091, 1066, 982; 1H
NMR (500 MHz, CDCl3): δ (ppm) 1.25 (s, 3H), 2.25 (s, 3H), 3.57
(s, 3H), 3.62−3.68 (m, 2H), 4.66 (d, J = 9.2 Hz, 1H), 6.0 (d, J = 9.45
Hz, 1H), 6.84 (d, J = 7.35 Hz, 2H), 6.93 (d J = 7.95 Hz, 2H), 7.012−
7.04 (m, 2H), 7.06−7.08 (m, 1H), 7.28−7.33 (m, 4H), 7.39 (d, J = 8.3
Hz, 2H); 13C NMR (100 MHz, CDCl3): δ (ppm) 20.3, 21.4, 48.2,
52.1, 66.3, 126.8, 127.2, 127.8, 128.3, 128.6, 129.1, 136.4, 140.0, 174.4;
HRMS (ES+) m/z: Calcd. for C25H28N2O4S (M+ + H): 453.1848,
Found: 453.1847. Optical purity of this isomer could not be
determined as it was inseparable in chiral HPLC columns (Chiralcel
AD-H, OD-H, AS-H).
Methyl 2-Amino-2-benzyl-3-(4-methylphenylsulfonamido)-3-
phenylpropanoate (6l). Compound 6l was obtained by Boc
deprotection of the corresponding addition product 4l in 89% (38.9
mg) yield as a white solid; IR νmax (KBr, cm−1): 3378, 3170, 2953,
1748, 1597, 1443, 1329, 1158, 1090, 1059; 1H NMR (400 MHz,
CDCl3): δ (ppm) 2.14 (d, J = 13.4 Hz, 1H), 2.21 (s, 3H), 3.20 (d, J =
13.4 Hz, 1H), 3.59 (s, 3H), 4.77 (d, J = 9.1 Hz, 1H), 6.19 (d, J = 9.5
Hz, 1H), 6.86−7.21 (m, 12H), 7.34 (d, J = 7.6 Hz, 2H); HRMS (ESI)
m/z Calcd. for C24H26N2O4S (M+ + H): 439.1692, Found: 439.1692.
2-(Benzyl(tert-butoxycarbonyl)amino)-3-phenylpropanoic acid
(7). To a suspension of KOH (0.047 g, 0.848 mmol) in 2.0 mL dry
THF was added a solution of N-benzyl-N-tert-butoxycarbonyl amino
acid ester 1a (0.848 mmol) in 1.0 mL dry THF and allowed to stir for
1 h. 2-Phenyl-N-tosylimine (0.385 mmol) dissolved in 1.0 mL dry
THF was slowly added into the reaction mixture and the stirring was
continued at the same temperature for 2 h. After completion of the
(ethyl acetate/petroleum ether: 20/80); [α]D = +9.33 (c 0.965,
CHCl3); IR νmax (KBr, cm−1): 3344, 3279, 3029, 2925, 2853, 1735,
1333, 1161, 1092, 1075 cm−1.
For the Major Diastereomer 6i. mp: 131−133 °C; H NMR (400
1
MHz, CDCl3): δ (ppm) 1.03 (t, J = 7.1 Hz, 3H), 2.26 (s, 3H), 3.02 (d,
J = 14.7 Hz, 1H), 3.26 (d, J = 14.7 Hz, 1H), 3.50 (d, J = 12.5 Hz, 1H),
3.66 (d, J = 12.4 Hz, 1H), 3.94 (q, J = 7.1 Hz, 2H), 4.77 (d, J = 7.8 Hz,
1H), 6.18 (brs, 1H), 6.86−6.95 (m, 6H), 7.08−7.26 (m, 10H), 7.30
(d, J = 8.3 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ (ppm) 13.8,
21.3, 38.7, 46.9, 60.9, 61.9, 68.7, 126.9, 127.0, 127.2, 127.6, 127.9,
128.4, 128.5, 129.1, 129.9, 130.0, 130.3, 133.7, 134.9, 135.5, 137.7,
143.0, 172.8; HRMS (ES+) m/z: Calcd. for C32H34ClN2O4S (M+ + H):
25
577.1928, Found: 577.1923; [α]D = +12.01 (c 0.33, CH2Cl2) for a
57% ee sample, Optical purity was determined by chiral HPLC analysis
(Lux 5u Cellulose-2 column) using 95/5 hexane/isopropanol, flow
rate = 1.0 mL/min, TR 1: 41.2 min (major), TR 2: 57.7 min (minor).
For the Minor Diastereomer 6i. ee 67%; Optical purity was deter-
mined by chiral HPLC analysis (Lux 5u Cellulose-2 column) using
95/5 hexane/isopropanol, flow rate = 1.0 mL/min, TR 1: 59.9 min
(major), TR 2: 48.6 min (minor).
Ethyl 2-Benzyl-2-(N-benzylamino)-3-(4-methylphenylsulfonami-
do)-3-(3-nitrophenyl)propanoate 6j (Scheme 4). General procedure
described above was followed to afford 6j (major) and 6j (minor) as a
white solid in 85% (0.05 g) overall yield (combined yield of both the
diastereomers). The compound was isolated (eluent: EtOAc/
petroleum ether 6/94) as a mixture of diastereomers with dr 62:38
(based on 1H NMR analysis of crude reaction mixture); Rf 205.21 (ethyl
acetate/petroleum ether: 15/85); Optical rotation: [α]D = +24.0
L
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reaction (monitored with TLC), it was quenched with saturated
aqueous ammonium chloride solution and extracted with 2 × 5.0 mL
of ethyl acetate. The combined organic extract was dried over
anhydrous Na2SO4 and the solvent was evaporated under reduced
pressure. The residue was purified by flash column chromatography on
a silica gel using ethyl acetate in petroleum ether as the eluent to afford
7 as a colorless liquid in 66% (0.2 g) yield as a 1:1 mixture of rotamers
(R and r); IR νmax (CH2Cl2, cm−1): 2977, 2928, 2853, 1744, 1699,
1454, 1367, 1250, 1161; For mixture of rotamers: 1H NMR (500
MHz, CDCl3): δ (ppm) 1.43 (s, 9H, R), 1.51 (s, 9H, r), 3.08−3.12
(m, 1H, r), 3.27−3.28 (m, 3H, 2R+r), 3.48 (d, J = 15.0 Hz, 1H, R),
3.71 (d, J = 16.0 Hz, 1H, r), 3.88−3.89 (m, 1H, R), 4.13−4.15 (m, 1H,
r), 4.37 (d, J = 16.0 Hz, 1H, r), 4.61 (d, J = 15.0 Hz, 1H, R), 7.04−7.09
(m, 7H, r), 7.21−7.28 (m, 13H, 10R+3r); 13C NMR (125 MHz,
CDCl3): δ (ppm) 28.4, 28.5, 35.4, 36.5, 52.1, 52.9, 61.0, 62.6, 81.54,
81.55, 126.8, 127.3, 127.5, 127.8, 128.4, 128.7, 128.8, 129.4, 136.9,
137.4, 137.7, 138.0, 155.2, 156.1, 175.6, 176.9; HRMS (ES+) m/z:
Calcd. for C21H25NaNO4 (M+ + Na): 378.1681, Found: 378.1654.
Attempted Hydrolysis of Compound 4a. To a suspension of LiOH
(0.047 g, 0.848 mmol) in 2 mL dry THF (MeOH or THF/MeOH/
H2O or dioxane/H2O etc.) was added a solution of N-benzyl-N-tert-
butoxycarbonyl amino acid esters 4a (0.848 mmol) in 1.0 mL dry
THF at 0 °C. The reaction was monitored by TLC. The reaction was
acidified with 2(N) HCl up to pH 2 and was extracted with 3 × 5.0
mL of diethyl ether. The combined organic extract was washed with
water, dried over anhydrous Na2SO4 and the solvent was evaporated
under reduced pressure. The residue was purified on a silica gel
column by flash column chromatography using ethyl acetate in
petroleum ether as the eluent to afford 7 as a colorless liquid in 66%
(0.2 g) yield. Spectrum was same as above.
General Procedure for the Aldol Reaction of N-Benzyl-N-
tert-butoxycarbonyl Phenylalanine Ethyl Ester 1a with a
Variety of Aldehydes in the Presence of LDA. To a solution of
diisopropylamine (0.10 mL, 0.75 mmol) in 2 mL dry THF was added
n-BuLi (1.6 M in hexane, 0.50 mL, 0.75 mmol) at 0 °C and stirred for
20 min. It was cooled to −78 °C and a solution of N-benzyl-N-tert-
butoxycarbonyl phenylalanine ethyl ester 1a (0.75 mmol) in 1.0 mL
dry THF was added to it and allowed to stir for 1 h. Aldehydes (0.50
mmol) dissolved in 1.0 mL dry THF was slowly added into the
reaction mixture and stirring was continued at the same temperature
for 10 h. The reaction (monitored with TLC) was quenched with
saturated aqueous ammonium chloride solution and extracted with 5.0 mL
of ethyl acetate in two portions. The combined organic extract was dried
over anhydrous Na2SO4 and the solvent was evaporated under reduced
pressure. The residue was purified by flash column chromatography on a
silica gel column using ethyl acetate in petroleum ether as the eluent to
afford the pure products 8a−d.
(ES+) m/z: Calcd. for C30H34N2O7 (M+ + Na): 557.2263, Found:
557.2263. The minor diastereomer could not be isolated in pure form.
Ethyl 2-Benzyl-2-(benzyl(tert-butoxycarbonyl)amino)-3-hydroxy-
3-(3-nitrophenyl)propanoate 8b. General procedure described above
was followed to afford 8b as a pale yellow solid in 66% (0.18 g) overall
yield as a mixture of diastereomers (dr 3:1). Both the isomers could be
obtained in pure forms after purification through flash column
chromatography (eluent: EtOAc/petroleum ether 10/90); Optical
purity of 8b (obtained at −78 °C) was determined by chiral HPLC
analysis (Cellulose-2 column); 98/2 hexane/isopropanol, flow rate =
1.0 mL/min; for the major diastereomer ee 30% (TR 1: 18.6 min, TR 2:
22.3 min) and for the minor diastereomer ee 76% (TR 1: 41.1 min, TR
2: 55.9 min); Optical purity of 8b (obtained at −70 °C): for the major
diastereomer ee 14% (TR 1: 20.74 min, TR 2: 25.31 min) and for the
minor diastereomer ee 67% (TR 1: 45.1 min, TR 2: 62.5 min); mp: 62−
63 °C; Rf 0.20 (ethyl acetate/petroleum ether: 15/85); IR νmax (KBr,
cm−1): 3440, 2955, 2925, 2854, 1741, 1697, 1531, 1453, 1391, 1350,
1267, 1158. For the major diastereomer: 1H NMR (400 MHz,
CDCl3): δ (ppm) 1.20 (bs, 9H), 1.27 (bs, 3H), 2.75 (d, J = 12.8 Hz,
1H), 3.44 (d, J = 12.8 Hz, 1H), 3.64 (d, J = 18.6 Hz, 1H), 3.82−3.98
(m, 1H), 4.12−4.18 (m, 1H), 4.39 (d, J = 18.6 Hz, 1H), 5.69 (s, 1H),
7.11−7.23 (m, 10H), 7.49−7.51 (m, 1H), 7.83−7.96 (m, 1H), 8.11−
8.16 (m, 1H,), 8.27 (s, 1H); 13C NMR (100 MHz, CDCl3): δ (ppm)
13.7, 27.9, 36.8, 48.9, 61.1, 70.6, 73.5, 81.9, 122.8, 123.3, 125.9, 126.5,
127.1, 127.9, 128.1, 128.8, 131.0, 134.5, 135.4, 139.5, 142.2, 148.2,
155.5, 170.6; HRMS (ES+) m/z: Calcd. for C30H34N2O7 (M+ + Na):
1
557.2256, Found: 557.2256. For the Minor Diastereomer. H NMR
(500 MHz, CDCl3): δ (ppm) 1.20 (m, 3H), 1.28 (bs, 9H), 3.0 (d, J =
13.4 Hz, 1H), 3.09 (d, J = 13.4 Hz, 1H), 3.24 (d, J = 18.0 Hz, 1H),
3.96−3.98 (m, 1H), 4.01−4.06 (m, 1H), 4.28 (d, J = 18.0 Hz, 1H),
5.52 (s, 1H), 7.60−7.63 (m, 10H), 7.60−7.63 (m, 1H), 7.91−7.93 (m,
1H), 8.25−8.27 (m, 1H,), 8.44 (s, 1H); HRMS (ES+) m/z: Calcd. for
C30H34N2O7 (M+ + Na): 557.2264, Found: 557.2264.
Ethyl 2-Benzyl-2-(benzyl(tert-butoxycarbonyl)amino)-3-hydroxy-
3-(4-methoxyphenyl)propanoate 8c. General procedure described
above was followed to afford 8c as a thick liquid in 52% (0.13 g) overall
yield. It was obtained as an inseparable mixture of diastereomers with dr
3:1 (based on 1H NMR analysis of crude reaction mixture) after
purification through flash column chromatography (eluent: EtOAc/
petroleum ether 10/90). Rf 0.26 (ethyl acetate/petroleum ether: 15/85);
IR νmax (CH2Cl2, cm−1) 3489, 2977, 2928, 1742, 1692, 1513, 1453, 1386,
1
1366, 1252, 1159; For the major diastereomer: H NMR (500 MHz,
CDCl3): δ (ppm) 1.25 (brs, 12H), 2.63 (d, J = 13.2 Hz, 1H), 3.24 (d, J =
18.3 Hz, 1H), 3.42 (d, J = 13.2 Hz, 1H), 3.79 (s, 3H), 3.79−3.83
(m, 1H), 4.06−4.15 (m, 2H), 5.63 (s, 1H), 6.89 (d, J = 8.0 Hz, 2H), 7.05−
7.14 (m, 6H), 7.17−7.23 (m, 4H), 7.36 (d, J = 8.0 Hz, 2H); 13C NMR
(125 MHz, CDCl3): δ (ppm) 13.9, 28.3, 35.8, 48.7, 55.4, 61.1, 70.0, 73.8,
80.9, 113.6, 125.9, 126.4, 126.9, 127.7, 128.1, 129.3, 131.3, 131.4, 136.2,
140.2, 155.9, 159.5, 172.0; HRMS (ES+) m/z: Calcd. for C31H37NO6
(M+ + H): 520.2699, Found: 520.2695.
Ethyl 2-Benzyl-2-(benzyl(tert-butoxycarbonyl)amino)-3-(3,4-di-
methoxyphenyl)-3-hydroxypropanoate 8d. General procedure
described above was followed to afford 8d as a thick liquid in 51%
(0.14 g) overall yield; It was obtained as an inseparable mixture of
diastereomers with dr 4:1 (based on 1H NMR analysis of crude
reaction mixture) after purification through flash column chromatog-
raphy (eluent: EtOAc/petroleum ether 10/90). Rf 0.29 (ethyl acetate/
petroleum ether: 30/70); IR νmax (CH2Cl2, cm−1) 3456, 2926, 2854,
1741, 1693, 1516, 1453, 1388, 1367, 1262, 1157, 1029. For the major
diastereomer: 1H NMR (400 MHz, CDCl3): δ (ppm) 1.25 (brs, 12H),
2.65 (d, J = 13.4 Hz, 1H), 3.26 (d, J = 18.3 Hz, 1H), 3.45 (d, J = 13.4
Hz, 1H), 3.80−3.94 (m, 1H), 3.88 (brs, 6H), 4.09−4.13 (m, 1H), 4.16
(d, J = 18.3 Hz, 1H), 5.63 (s, 1H), 6.85−6.91 (m, 2H), 6.96 (s, 1H),
7.04−7.13 (m, 6H), 7.18−7.22 (m, 4H); 13C NMR (100 MHz,
CDCl3): δ (ppm) 13.7, 28.1, 35.7, 48.7, 55.9, 56.0, 60.9, 70.2, 73.8,
80.9, 110.9, 111.5, 120.6, 125.8, 126.3, 126.8, 127.6, 128.0, 131.3,
131.6, 136.1, 140.0, 148.6, 148.8, 155.7, 173.6; HRMS (ES+) m/z:
Calcd. for C32H39NO7 (M+ + H): 550.2804, Found: 550.2803.
Ethyl 2-Benzyl-2-(benzylamino)-3-hydroxy-3-(4-nitrophenyl)-
propanoate 9. To a stirring solution of substrate 8a (0.10 mmol)
Ethyl 2-Benzyl-2-(benzyl(tert-butoxycarbonyl)amino)-3-hydroxy-
3-(4-nitrophenyl)propanoate 8a. General procedure described above
was followed to afford 8a as a white solid in 65% (0.17 g) overall yield.
It was obtained as a mixture of diastereomers with dr 3:2.4 (based on
1H NMR analysis of crude reaction mixture) where little amount of
pure major diastereomer was separated by flash column chromatog-
raphy (eluent: EtOAc/petroleum ether 10/90) and was injected in
chiral HPLC to identify pair of peaks. Optical purity was determined
by chiral HPLC analysis (Chiralcel AD-H column); 95/5 hexane/
isopropanol, flow rate = 1.0 mL/min; for the minor diastereomers ee
68% (TR 1: 17.4 min, TR 2: 34.4 min) and for the major diastereomer
ee 16% (TR 1: 23.1 min, TR 2: 44.8 min); Rf 0.20 (ethyl acetate/
petroleum ether: 15/85). The pure major diastereomer was injected in
aforesaid HPLC condition to identify pair of peaks; mp: 105−112 °C;
IR νmax (KBr, cm−1): 3481, 2926, 2855, 1743, 1677, 1521, 1388, 1349,
1
1269, 1159, 1036; For the major diastereomer H NMR (500 MHz,
CDCl3): δ (ppm) 1.19 (brs, 3H), 1.23 (brs, 9H), 2.75 (d, J = 13.2 Hz,
1H), 3.48 (d, J = 13.2 Hz, 1H), 3.68 (d, J = 17.7 Hz, 1H), 3.85−3.92
(m, 1H), 4.25−4.12 (m, 1H), 4.36 (d, J = 17.7 Hz, 1H), 5.68 (s, 1H),
7.03−7.19 (m, 6H), 7.21−7.28 (m, 4H), 7.64 (d, J = 8.6 Hz, 2H), 8.18
(d, J = 8.6 Hz, 2H); 13C NMR (125 MHz, CDCl3): δ (ppm) 13.9,
28.1, 36.8, 48.0, 61.2, 70.5, 73.7, 81.3, 123.2, 125.8, 126.6, 127.3, 128.0,
128.2, 129.2, 131.1, 135.4, 139.7, 147.5, 147.7, 155.6, 172.2; HRMS
M
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in dry dichloromethane (1.0 mL) was added trifluoroacetic acid
(0.5 mL) at 0 °C. The reaction mixture was stirred at room temperature
for 2 h. It was neutralized with aq. saturated NaHCO3 solution and the
aqueous layer was extracted with CH2Cl2 (3 × 5.0 mL). 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 on silica gel
(230−400 mesh) using ethyl acetate in petroleum ether (20:80) as
eluent to provide 9 as a pale yellow paste in 85% (0.04 g) yield;
Optical purity was determined by chiral HPLC analysis (Cellulose-2
column), 95/5 hexane/isopropanol, flow rate = 1.0 mL/min, for the
minor diastereomer ee 67% (TR 1: 32.40 min, TR 2: 37.82 min); for the
major diastereomers ee 9% (TR 1: 30.8 min, TR 2: 41.48 min); Rf 0.25
(ethyl acetate/petroleum ether: 25/75); IR νmax (CH2Cl2, cm−1):
3438, 3340, 2960, 2925, 2854, 1728, 1602, 1520, 1346, 1019; For the
major diastereomer: 1H NMR (400 MHz, CDCl3): δ (ppm) 1.11
(t, J = 7.2 Hz, 3H), 2.92 (d, J = 14.2 Hz, 1H), 3.01 (d, J = 14.2 Hz,
1H),3.66 (d, J = 12.8 Hz, 1H), 3.86 (d, J = 12.8 Hz, 1H), 4.09 (q, J =
7.2 Hz, 2H), 5.14 (s, 1H), 7.07−7.28 (m 10H), 7.60 (d, J = 8.3 Hz,
2H), 8.12 (d, J = 8.3 Hz, 2H); 13C NMR (125 MHz, CDCl3): δ (ppm)
13.9, 38.3, 47.9, 61.7, 69.2, 74.2, 122.9, 127.8, 128.6, 128.8, 128.9,
129.2, 130.1, 130.3, 135.2, 139.4, 147.2, 147.6, 173.2; HRMS (ES+) m/
z: Calcd. for C25H26N2O5 (M+ + H): 435.1920, Found: 435.1923. For
column chromatography (eluent: EtOAc/petroleum ether 20/80). Rf
0.24 (ethyl acetate/petroleum ether: 20/80); 10% ee; Optical purity
was determined by chiral HPLC analysis (Chiralcel AD-H column)
using 95/5 hexane/isopropanol, flow rate = 1.0 mL/min, TR 1: 35.5
min (major), TR 2: 42.5 min (minor); IR νmax (KBr, cm−1): 3065,
3032, 2925, 2853, 1765, 1719, 1533, 1451, 1390, 1353, 1276, 1202,
1
1095, 1048; H NMR (500 MHz, CDCl3): δ (ppm) 0.77 (t, J = 7.2
Hz, 3H), 3.23−3.29 (m, 1H), 3.41−3.54 (m, 3H), 4.54 (AB quartet,
Jgem = 15.1 Hz, 2H), 5.42 (s, 1H), 7.18−7.20 (m, 2H), 7.27−7.35 (m,
6H), 7.42−7.49 (m, 4H), 8.05 (s, 1H), 8.14 (dd, J = 7.9, 2.1 Hz, 1H);
13C NMR (125 MHz, CDCl3): δ (ppm) 13.4, 37.1, 47.6, 62.3, 72.8,
77.8, 121.5, 123.9, 128.2, 128.3, 128.7, 129.3, 129.5, 130.8, 132.2,
133.5, 135.8, 136.6, 148.1, 157.8, 169.0; HRMS (ES+) m/z: Calcd. for
C26H24N2O6 (M+ + H): 461.1713, Found: 461.1714.
Ethyl 3,4-Dibenzyl-5-(2-chlorophenyl)-2-oxooxazolidine-4-car-
boxylate 10c. General procedure described above was followed
when 1a reacted with 2-chlorobenzaldehyde to afford 10c as a thick
liquid in 57% (0.13 g) yield as a single diastereomer (based on
1H NMR analysis of crude reaction mixture). The compound was
purified through flash column chromatography (eluent: EtOAc/
petroleum ether 20/80). Rf 0.30 (ethyl acetate/petroleum ether: 20/
80); 4% ee; Optical purity was determined by chiral HPLC analysis
(Chiralcel OD-H column) using 95/5 hexane/isopropanol, flow rate =
1.0 mL/min, TR 1: 18.3 min (minor), TR 2: 27.4 min (major); IR νmax
(KBr, cm−1): 3065, 3032, 2924, 2854, 1764, 1749, 1444, 1395, 1355,
1279, 1208, 1024; 1H NMR (500 MHz, CDCl3): δ (ppm) 0.75 (t, J =
7.2 Hz, 3H), 3.24 (dq, J = 7.2, 7.3 Hz, 1H), 3.44 (dq, J = 6.9, 7.3 Hz,
1H, 1H), 3.61 (AB quartet, Jgem = 15.5 Hz, 2H), 4.50 (AB quartet,
Jgem = 15.5 Hz, 2H), 5.36 (s, 1H), 7.12−7.15 (m, 2H), 7.21−7.23 (m,
2H), 7.26−7.36 (m, 8H), 7.40−7.42 (m, 2H); 13C NMR (125 MHz,
CDCl3): δ (ppm) 13.1, 38.9, 47.6, 61.9, 73.2, 76.6, 126.9, 127.7, 127.9,
128.5, 128.7, 128.8, 128.9, 129.4, 130.2, 130.3, 132.5, 133.8, 133.9,
136.6, 157.9, 168.8; HRMS (ES+) m/z: Calcd. for C26H24ClNO4
(M+ + H): 450.1472, Found: 450.1474.
1
the minor diastereomer: H NMR (500 MHz, CDCl3): δ 1.18 (t, J =
7.33, 3H), 2.98 (d, J = 14.05 Hz, 1H), 3.07 (d, J = 14.05 Hz, 1H), 3.72
(d, J = 12.83 Hz, 1H), 3.92 (d, J = 12.83 Hz, 1H), 4.13−4.17 (m, 2H),
4.24 (bs, 1H), 7.14 (d, J = 7.64 Hz, 2H), 7.25−7.34 (m, 8H), 7.67
(d, J = 8.55 Hz, 2H), 8.18 (d, J = 7.94 Hz, 2H); 13C NMR (125 MHz,
CDCl3): δ 14.1, 38.3, 61.7, 69.2, 74.2, 76.9, 123.0, 127.3, 127.5, 127.8,
128.6, 128.8, 129.3, 13.3, 135.3, 139.5, 147.2, 147.7.; HRMS (ESI)
calcd for C25H27N2O5 (M + H)+ 435.1914, found 435.1921.
General Procedure for the Aldol Reaction of N-Benzyl-N-
tert-butoxycarbonyl Phenylalanine Ethyl Ester 1a with Various
Aldehydes using KHMDS. A KHMDS solution in THF (0.5 M in
Toluene, 1.5 mL, 0.75 mmol) was diluted with dry THF and cooled to
−78 °C. A solution of compound 1a (0.75 mmol) in dry THF (1.0
mL) was added dropwise to the KHMDS solution. After 1 h, the
corresponding aldehyde (0.5 mmol), dissolved in 1.0 mL dry THF was
added dropwise into the reaction mixture and stirring was continued
for 6 h. The reaction was monitored with TLC. After 6 h, it was
quenched with saturated aqueous ammonium chloride solution and
extracted with 5 mL of ethyl acetate in two portions. The combined
organic extract was dried over anhydrous Na2SO4 and the solvent was
evaporated under reduced pressure. The residue was purified on a
silica gel column by flash column chromatography using ethyl acetate
in petroleum ether as the eluent to afford the pure products 10a−e.
Ethyl 3,4-Dibenzyl-2-oxo-5-phenyloxazolidine-4-carboxylate
10a. General procedure described above was followed when 1a
reacted with benzaldehyde to afford 10a as a thick liquid in 55%
(0.11 g) yield as a single diastereomer (based on 1H NMR analysis of
crude reaction mixture). The compound was purified through flash
column chromatography (eluent: EtOAc/petroleum ether 20/80). Rf
0.30 (ethyl acetate/petroleum ether: 20/80); 16% ee; Optical purity
was determined by chiral HPLC analysis (Chiralcel OD-H column)
using 97/3 hexane/isopropanol, flow rate = 0.8 mL/min, TR 1: 36.7
min (major), TR 2: 41.4 min (minor); IR νmax (KBr, cm−1): 3064,
3032, 2924, 2853, 1763, 1738, 1496, 1454, 1391, 1356, 1202, 1092,
1049; 1H NMR (500 MHz, CDCl3): δ (ppm) 0.75 (t, J = 7.2 Hz, 3H),
3.23−3.29 (m, 1H), 3.41−3.53 (m, 3H), 4.50 (AB quartet, Jgem = 15.5
Hz, 2H), 5.36 (s, 1H), 7.12−7.15 (m, 2H), 7.21−7.23 (m, 2H), 7.26−
7.36 (m, 9H), 7.40−7.42 (m, 2H); 13C NMR (125 MHz, CDCl3): δ
(ppm) 13.2, 37.1, 47.6, 61.8, 73.2, 78.9, 125.9, 127.6, 127.8, 128.2,
128.4, 128.7, 128.9, 129.1, 130.6, 133.8, 134.2, 136.2, 158.4, 169.2;
HRMS (ES+) m/z: Calcd. for C26H25NO4 (M+ + H): 416.1861,
Found: 416.1860.
Ethyl 3,4-Dibenzyl-2-oxo-5-(4-methoxyphenyl)-oxazolidine-4-
carboxylate 10d. General procedure described above was followed
when 1a reacted with 4-methoxybenzaldehyde to afford 10d as a white
1
solid in 49% (0.11 g) yield as a single diastereomer (based on H
NMR analysis of crude reaction mixture). The compound was purified
through flash column chromatography (eluent: EtOAc/petroleum
ether 20/80). Rf 0.20 (ethyl acetate/petroleum ether: 20/80); 4% ee;
Optical purity was determined by chiral HPLC analysis (Chiralcel OD-
H column) using 95/5 hexane/isopropanol, flow rate = 1.0 mL/min,
TR 1: 21.9 min (minor), TR 2: 34.5 min (major); IR νmax (KBr, cm−1):
3062, 3031, 2922, 2852, 1763, 1737, 1612, 1515, 1454, 1391, 1355,
1253, 1177, 1028; 1H NMR (500 MHz, CDCl3): δ (ppm) 0.83 (t, J =
7.2 Hz, 3H), 3.33−3.37 (m, 1H), 3.42−3.54 (m, 3H), 3.76 (s, 3H),
4.48 (AB quartet, Jgem = 15.5 Hz, 2H), 5.31 (s, 1H), 6.81 (d, J = 7.2
Hz, 2H), 7.12 (d, J = 7.2 Hz, 4H), 7.25−7.33 (m, 6H), 7.40 (d, J = 7.5
Hz, 2H); 13C NMR (125 MHz, CDCl3): δ (ppm) 13.5, 37.3, 47.8,
53.4, 61.9, 73.4, 79.1, 113.7, 126.1, 127.5, 127.7, 127.9, 128.6, 129.0,
129.2, 130.8, 134.1, 136.4, 158.6, 160.0, 169.4; HRMS (ES+) m/z:
Calcd. for C27H27NO5 (M+ + H): 446.1968, Found: 446.1970.
Ethyl 3,4-Dibenzyl-5-(3,4-dimethoxyphenyl)-2-oxooxazolidine-4-
carboxylate 10e. General procedure described above was followed
when 1a reacted with 3,4-dimethoxybenzaldehyde to afford 10e as a
white solid in 49% (0.12 g) yield as a single diastereomer (based on
1H NMR analysis of crude reaction mixture). The compound was purified
through flash column chromatography (eluent: EtOAc/petroleum
ether 20/80). Rf 0.20 (ethyl acetate/petroleum ether: 30/70); 10% ee;
Optical purity was determined by chiral HPLC analysis (Chiralcel OD-
H column) using 95/5 hexane/isopropanol, flow rate = 1.0 mL/min,
TR 1: 40.2 min (minor), TR 2: 53.7 min (major); IR νmax (KBr, cm−1):
2923, 2851, 1762, 1748, 1517, 1453, 1390, 1356, 1266, 1242, 1142,
1024; 1H NMR (500 MHz, CDCl3): δ (ppm) 0.81 (t, J = 7.2 Hz, 3H),
3.37−3.50 (m, 3H), 3.52−3.57 (m, 1H), 3.79 (s, 3H), 3.84 (s, 3H),
4.46 (AB quartet, Jgem = 15.2 Hz, 2H), 5.32 (s, 1H), 6.72−6.78
(m, 3H), 7.12−7.14 (m, 2H), 7.25−7.32 (m, 6H), 7.41 (d, J = 7.2 Hz,
2H); 13C NMR (125 MHz, CDCl3): δ (ppm) 13.6, 37.8, 47.8, 55.9,
56.0, 61.9, 73.5, 79.3, 109.1, 110.7, 118.8, 126.6, 127.8, 127.9, 128.6,
Ethyl 3,4-Dibenzyl-5-(3-nitrophenyl)-2-oxooxazolidine-4-carbox-
ylate 10b. General procedure described above was followed when 1a
reacted with 3-nitrobenzaldehyde to afford 10b as a sticky solid in 59%
(0.13 g) yield as a single diastereomer (based on 1H NMR analysis of
crude reaction mixture). The compound was purified through flash
N
dx.doi.org/10.1021/jo302018a | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
129.0, 129.1, 130.7, 134.1, 136.5, 148.9, 149.4, 158.5, 169.4; HRMS
(ES+) m/z: Calcd. for C28H29NO6 (M+ + H): 476.2073, Found:
476.2076.
1163, 1089, 1062, 1044, 1030; 1H NMR (400 MHz, CDCl3): δ (ppm)
2.21 (s, 3H), 2.27 (s, 2H), 2.47 (d, J = 14.9 Hz, 1H), 2.67 (d, J = 14.9
Hz, 1H), 3.46 (d, J = 13.4 Hz, 1H), 3.85 (d, J = 13.4 Hz, 1H), 4.23 (d,
J = 7.6 Hz, 1H), 5.52 (d, J = 7.8 Hz, 1H), 6.72 (d, J = 7.8 Hz, 2H),
6.87−7.04 (m, 6H), 7.18−7.34 (m, 11H); 13C NMR (100 MHz,
CDCl3): δ (ppm) 21.3, 29.7, 34.0, 35.7, 44.1, 56.5, 126.7, 126.8, 127.3,
127.4, 127.9, 128.1, 128.4, 128.5, 128.6, 129.0, 129.2, 137.2, 139.2,
139.3, 142.3, 142.4; HRMS (ES+) m/z: Calcd. for C30H30N2O2S (M+
+ H): 483.2106, Found: 483.2106.
[2-Benzyl-(3-bromophenyl)(N-benzylaziridin-2-yl)methyl]-4-
methylbenzenesulfonamide 20b. General procedure described above
was followed to provide 20b as a white solid in 71% (0.020 g) yield. Rf
0.26 (ethyl acetate/petroleum ether: 20/80); ee 80%; Optical purity
was determined by chiral HPLC analysis (Chiralcel OD-H column);
97/3 hexane/isopropanol, flow rate = 0.8 mL/min. TR 1: 24.3 min
(minor), TR 2: 32.1 min (major); IR νmax (KBr, cm−1): 3278, 3061,
3028, 2922, 2852, 1596, 1494, 1452, 1332, 1160, 1093, 1075; 1H NMR
(500 MHz, CDCl3): δ (ppm) 2.30 (s, 3H), 2.31 (d, J = 14.4 Hz, 1H),
2.37 (bs, 1H), 2.51 (d, J = 14.8 Hz, 1H), 2.77 (d, J = 14.8 Hz, 1H),
3.56 (d, J = 13.4 Hz, 1H), 3.88 (d, J = 13.4 Hz, 1H), 4.22 (d, J = 7.6
Hz, 1H), 5.62 (bs, 1H), 6.76 (bs, 1H), 6.84 (t, J = 7.9 Hz, 1H), 6.97
(d, J = 8.3 Hz, 2H), 7.01 (d, J = 6.9 Hz, 2H), 7.19 (d, J = 8.3 Hz, 1H),
7.24−7.36 (m, 8H), 7.39−7.40 (m, 3H); 13C NMR (125 MHz,
CDCl3): δ (ppm) 21.5, 34.2, 35.9, 43.9, 56.0, 56.7, 122.2, 126.5, 126.7,
127.1, 127.6, 128.4, 128.7, 128.8, 129.18, 128.19, 129.7, 130.5, 131.2,
136.7, 137.7, 139.0, 141.1, 142.8; HRMS (ES+) m/z: Calcd. for
C30H29BrN2O2S (M+ + H): 561.1211, Found: 561.1210.
General Procedure for Reduction of Ethyl Ester using LiBH4.23
To a stirring solution of ester 6a, 6d (50 mg, 0.10 mmol) in dry THF
(1.0 mL) were added LiBH4 (2 M in THF) (3 mmol) and methanol
(0.10 mL) at 0 °C. The reaction mixture was stirred at room
temperature for 12 h. The reaction was quenched with water. Most of
the methanol was evaporated under reduced pressure. The mixture
was extracted with ethyl acetate (3 × 5.0 mL), the combined organic
layer was dried over anhydrous Na2SO4 and solvent was evaporated
under reduced pressure. The residue was purified by flash column
chromatography over silica gel (230−400 mesh) using ethyl acetate in
petroleum ether to give 16a, 16b.
[2-Benzyl-2-(N-benzylamino)-3-hydroxy-1-phenylpropyl]-4-
methylbenzenesulfonamide 16a. General procedure described above
was followed for the reduction of 6a (major diastereomer) to provide
16a as a white solid in 75% (0.04 g) yield. Rf 0.10 (ethyl acetate/
25
petroleum ether: 15/85); mp: 205−207 °C; Optical rotation: [α]D
=
+52.0 (c 0.50, CHCl3) for a 92% ee sample. Optical purity was
determined by chiral HPLC analysis (Chiralcel AD-H column) using
95/5 hexane/isopropanol, flow rate = 1.0 mL/min, TR 1: 51.9 min
(major), TR 2: 88.7 min (minor); IR νmax (KBr, cm−1): 3453, 3328,
3061, 3028, 2924, 2854, 1600, 1494, 1453, 1324, 1158, 1090, 1027; 1H
NMR (400 MHz, CDCl3): δ (ppm) 2.21 (s, 3H), 2.40 (d, J = 13.7 Hz,
1H), 2.97 (d, J = 13.7 Hz, 1H), 3.32 (d, J = 12.2 Hz, 1H), 3.41 (d, J =
12.2 Hz, 1H), 3.57 (d, J = 11.6 Hz, 1H), 3.71 (d, J = 11.5 Hz, 1H), 4.5
(s, 1H), 6.22 (brs, 1H), 6.89 (d, J = 8.3 Hz, 2H), 7.00−7.25 (m, 15H),
7.35 (d, J = 8.3 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ (ppm) 21.3,
29.7, 38.7, 46.2, 60.5, 62.4, 126.9, 127.0, 127.1, 127.6, 128.0, 128.6,
128.8, 129.0, 129.08, 129.12, 130.5, 134.9, 136.50, 136.80, 136.83,
142.9; HRMS (ES+) m/z: Calcd. for C30H33N2O3S (M+ + H):
501.2211, Found: 501.2210.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, characterization, X-ray crystallo-
graphic data of some of the compounds, computational results
1
and related data, copies of H NMR, 13C NMR spectra of all
[(2-Benzyl-2-(N-benzylamino)-1-(3-bromophenyl)-3-hydroxy-
propyl]-4-methylbenzenesulfonamide 16b. General method de-
scribed above was followed for the reduction of 6d (major
diastereomer) to afford 16b as a white solid in 73% (0.034 g) yield.
Rf 0.13 (ethyl acetate/petroleum ether: 20/80); ee 80%; Optical purity
was determined by chiral HPLC analysis (Chiralcel OD-H column),
95/5 hexane/isopropanol, flow rate = 1.0 mL/min, TR 1: 26.3 min
(minor), TR 2: 31.5 min (major); IR νmax (KBr, cm−1): 3490, 3328,
2923, 2854, 1596, 1451, 1332, 1159, 1092; 1H NMR (500 MHz,
CDCl3): δ (ppm) 2.30 (s, 3H), 2.54 (d, J = 13.7 Hz, 1H), 2.99 (d, J =
14.0 Hz, 1H), 3.48 (d, J = 12.4 Hz, 1H), 3.56 (d, J = 12.4 Hz, 1H),
3.59 (d, J = 11.4 Hz, 1H), 3.71 (d, J = 11.0 Hz, 1H), 4.58 (s, 1H), 7.00
(d, J = 8.2 Hz, 2H), 7.14−7.31 (m, 14H), 7.41 (d, J = 8.2 Hz, 2H); 13C
NMR (125 MHz, CDCl3): δ (ppm) 21.4, 39.1, 45.9, 60.1, 61.6, 62.9,
122.1, 126.90, 126.94, 127.2, 127.3, 127.7, 128.5, 128.6, 129.2, 129.4,
130.3, 130.4, 131.8, 136.4, 136.6, 139.2, 139.8, 143.2; HRMS (ES+)
m/z: Calcd. for C30H31BrN2O3S (M+ + H): 579.1317, Found: 579.1317.
General Procedure for the Synthesis of Aziridine. To a
solution of alcohol 16a, 16b (30 mg, 0.059 mmol) (single
diastereomer) in dry CH2Cl2 (0.5 mL) were added mesyl chloride
(2 mmol) and triethylamine (2.5 mmol). The reaction mixture was
stirred at room temperature for 5 h. It was poured into water and the
aqueous layer was extracted with CH2Cl2 (2 × 10 mL). 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
(230−400 mesh) using 10% ethyl acetate in petroleum ether as eluent
to provide 20a, 20b.
new compounds and HPLC chromatograms for ee determi-
nation. This material is available free of charge via the Internet
at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: mkghorai@iitk.ac.in.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
M.K.G. is grateful to IIT-Kanpur and DST, India. K.G., A.K.Y.,
Y.N., and M.S. thank CSIR, India and S.H. thanks UGC, India
for research fellowships.
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