Organocatalytic stereoselective synthesis of acyclic γ- nitrothioesters with all-carbon quaternary stereogenic centers

Article abstract of DOI:10.1021/jo500403q

A method for the stereoselective synthesis of acyclic thioesters bearing adjacent quaternary and tertiary stereogenic centers under mild organocatalytic conditions was developed. α-Substituted monothiomalonates (MTMs) were used as thioester enolate equivalents. They reacted cleanly with nitroolefins in the presence of 1-6 mol % of cinchona alkaloid urea derivatives, and provided access to γ-nitrothioesters with quaternary stereocenters in high yields and diastereo- and enantioselectivities. Mechanistic investigations provided insight into the parameters that determine the stereoselectivity and showed that the diastereoselectivity can be controlled by the nature of the MTM substrate. The different reactivities of the three functional groups (oxoester, thioester, nitro moieties) within the conjugate addition products allowed for straightforward access to other compounds with quaternary stereogenic centers, such as γ-nitroaldehydes and γ-butyrolactams.

Full text of DOI:10.1021/jo500403q

Article
pubs.acs.org/joc
Organocatalytic Stereoselective Synthesis of Acyclic
γ‑Nitrothioesters with All-Carbon Quaternary Stereogenic Centers
Yukihiro Arakawa, Sven P. Fritz, and Helma Wennemers*
Laboratory of Organic Chemistry, D-CHAB, ETH Zurich, Vladimir-Prelog-Weg 3, 8093 Zurich, Switzerland
̈
̈
S
* Supporting Information
ABSTRACT: A method for the stereoselective synthesis of
acyclic thioesters bearing adjacent quaternary and tertiary
stereogenic centers under mild organocatalytic conditions was
developed. α-Substituted monothiomalonates (MTMs) were
used as thioester enolate equivalents. They reacted cleanly
with nitroolefins in the presence of 1−6 mol % of cinchona
alkaloid urea derivatives, and provided access to γ-nitrothioesters with quaternary stereocenters in high yields and diastereo- and
enantioselectivities. Mechanistic investigations provided insight into the parameters that determine the stereoselectivity and
showed that the diastereoselectivity can be controlled by the nature of the MTM substrate. The different reactivities of the three
functional groups (oxoester, thioester, nitro moieties) within the conjugate addition products allowed for straightforward access
to other compounds with quaternary stereogenic centers, such as γ-nitroaldehydes and γ-butyrolactams.
Previously we introduced monothiomalonates (MTMs) as
protected variants of MAHTs that react with electrophiles in a
significantly more controlled fashion than MAHTs.15,16 In
initial studies, unsubstituted MTMs were found to react cleanly
and stereoselectively with β-nitroolefins.15 More recently we
found that reactions of α-substituted MTMs with imines enable
the stereoselective formation of β-aminothioesters containing
adjacent quaternary and tertiary stereocenters.16 These results
inspired us to investigate whether α-substituted MTMs also
react with nitroolefins and allow access to acyclic γ-nitro-
thioesters with neighboring quaternary and tertiary stereo-
centers (Scheme 1).
INTRODUCTION
■
Stereoselective C−C bond forming reactions between enolates
and electrophiles that proceed under mild conditions and give
rise to acyclic compounds with an all-carbon quaternary
stereogenic center are among the most challenging reactions
in organic synthesis.1 Particularly useful are products of
reactions of thioester enolates, since the thioester moiety is a
versatile functional group. It is key in several biological
pathways, e.g., the biosynthesis of polyketides,2 and allows in
organic synthesis for numerous further transformations, e.g.,
into aldehydes, ketones, or amides.3 In comparison to
analogous oxoester moieties, thioesters are ∼100 fold more
reactive toward nucleophiles such as amines.4 Whereas
thioester enolates are convenient for introducing thioester
moieties, their formation under mild organocatalytic conditions
is not trivial because of the tendency of thioesters to react with
nucleophiles and the comparatively high pKa value of the
proton at the α-carbon.5,6 Barbas and Tan tackled this challenge
by using electron-poor thioesters and dithiomalonates,
respectively.7−9 Inspired by nature, Ricci, our group, and
others used malonic acid half thioesters (MAHTs) as thioester
enolate equivalents that serve as building blocks for the
biosynthesis of fatty acids and polyketides.2,10−12 With all of
these thioester enolate equivalents, stereoselective organo-
catalytic addition reactions to form chiral products bearing
tertiary stereogenic centers have been achieved.5−12 However,
reactions that provide acyclic thioesters with an all-carbon
quaternary stereogenic center adjacent to the thioester moiety
are difficult. Even with extensively investigated α-ketoesters and
α-cyanoacetates only a few examples for the stereoselective
synthesis of acyclic addition products with an all-carbon
quaternary stereocenter under metal-free conditions are
known, which highlights how challenging such syntheses
are.1,13,14
Scheme 1. Conjugate Addition Reactions between
Monothiomalonates (MTMs) and Nitroolefins
Herein we present reactions between α-substituted mono-
thiomalonates (MTMs) and nitroolefins that provide in the
presence of catalytic amounts of cinchona alkaloid derivatives γ-
nitrothioesters with an all-carbon quaternary stereogenic center
adjacent to a tertiary stereocenter in excellent yields and
stereoselectivities. We also show that the three functional
groups within the conjugate addition products are orthogonal
and can be used to access anti-configured α,β-disubstituted-γ-
nitrothioesters as well as other valuable compounds with an all-
carbon quaternary stereogenic center (e.g., chiral γ-nitro-
Received: February 19, 2014
Published: April 23, 2014
© 2014 American Chemical Society
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aldehydes and γ-butyrolactams) that are difficult to prepare by
other routes.
(Table 1, entry 8). Other common chiral bifunctional catalysts
such as unfunctionalized cinchona alkaloids or Takemoto’s
catalyst19 were found to be less stereoselective.20 Interestingly,
for reactions with α-unsubstituted MTMs epiquinidine thiourea
E and not H had been found to be the optimal catalyst.15 This
indicates that structural differences between substituted and
unsubstituted MTMs are easily accommodated by cinchona
alkaloid-urea catalysts.
Further optimization of the reaction parameters showed that
toluene is the best solvent in terms of both reactivity and
stereoselectivity.20 Variations in the temperature and the
amount of catalyst revealed that at −15 °C a catalyst loading
of 2 mol % sufficed to obtain a near quantitative conversion of
nitrostyrene to the conjugate addition product.20,21 Under
these optimized conditions MTM 1a reacted readily with
nitrostyrene to γ-nitrothioester 2a, which was obtained with a
diastereoselectivity of 11:1 and an enantiomeric excess of 99%
(Table 1, entry 13). These results were achieved both on a scale
of 0.1 mmol as well as on a 30 fold larger scale (Table 1, entry
14).
Substrate Scope. With the optimized reaction conditions
in hand we evaluated the scope of the conjugate addition
reactions and reacted a range of different α-substituted MTMs
and nitroolefins in the presence of 2−6 mol % of the
epicinchonine urea H (Table 2). Various nitroolefins with both
electron-rich and electron-poor aromatic as well as hetero-
aromatic substituents reacted readily with the substituted MTM
1a. The γ-nitrothioesters 2a−2m with an all-carbon quaternary
stereogenic center adjacent to a tertiary stereocenter were
obtained in good yields, diastereoselectivities of 7:1−13:1, and
excellent enantioselectivities of 97−99% ee (Table 2, entries 1−
10).
RESULTS AND DISCUSSION
■
We started our investigations by exploring the reactivity of α-
methyl substituted MTM 1a with β-nitrostyrene under similar
conditions as those used before.16 Thus, we explored cinchona
alkaloid-(thio)urea derivatives (A−H) as catalysts17,18 and used
p-methoxyphenyl (PMP) thioester and p-methoxybenzyl
(PMB) oxoester moieties on the α-substituted MTM that
had in the previous studies been found to generate the products
with the highest stereoselectivities.16 The acid labile PMB
group was also expected to allow for facile removal followed by
decarboxylation of the resulting carboxylic acid moiety.
Remarkably, α-substituted MTM 1a reacted readily with β-
nitrostyrene in the presence of any of the tested cinchona
alkaloid derived (thio)ureas A−H, and the desired conjugate
addition product 2a with a quaternary stereogenic center was
generally obtained with good stereoselectivities (Table 1).
It is also notable that only a small excess of the MTM
sufficed to achieve quantitative conversion of the nitroolefin.
The best diastereo- and enantioselectivities were observed
when the epicinchonine urea derivative H was used as catalyst
Table 1. 1,4-Addition Reactions between MTM 1a and
Nitrostyrene Catalyzed by Cinchona Alkaloid Derivatives
a
A−H
MTMs 1b−1d bearing ethyl, allyl, or propargyl groups at
C(α) were also tolerated as substrates but required slightly
higher catalyst loadings (5 or 6 mol %) to provide the desired
addition products in good yields and enantioselectivities (Table
2, entries 11−13). Also the diastereoselectivities are in these
cases lower compared to all other examples, which illustrates
the challenge of forming a C−C bond in a sterically demanding
environment with high stereoselectivities and underlines how
remarkable the stereoselectivities that were obtained with
conjugate addition products 2a−2j are. Current limitations are
MTMs bearing an aromatic substituent at the α-carbon and
aliphatic nitroolefins, which did not react or only formed trace
amounts of the desired γ-nitrothioester.
Mechanistic Considerations. The conjugate additions of
the α-substituted MTMs proceed with a remarkably high
stereodifferentiation between the seemingly similar oxo- and
thioester moieties. A similarly high differentiation was
previously observed for addition reactions of these MTMs to
imines suggesting that it is general for this type of reactions.16
To understand this observation, we performed experiments
with MTMs bearing either two benzyl (-SBn, -OPMB) or two
phenyl groups (-SPMP, -OPMP) at the thio- and the oxoester
moieties. Conjugate additions with these MTMs provided the
products without or only with low diastereoselectivity
demonstrating that the combination of a rigid phenyl with a
flexible benzyl ester within the MTM is important for high
stereoselectivity (Figure 1a).20 This finding showed that the
directionality of the interaction between the MTM and the
catalyst is controlled by the groups that are attached to the oxo-
and thioester moieties. Taking this into account, it is plausible
that the MTM coordinates to the urea moiety of the
b
b
c
entry
catalyst
mol %
T (°C)
conv (%)
dr
ee (%)
d
1
A
10
10
10
10
10
10
10
10
1
rt
quant.
quant.
quant.
quant.
quant.
quant.
quant.
quant.
55
2:1
79
d
2
B
rt
2:1
81
d
3
C
D
E
rt
3:1
82
d
4
rt
3:1
91
5
rt
4:1
97
96
94
98
97
98
99
6
F
rt
4:1
7
G
H
H
H
H
H
H
H
rt
6:1
8
rt
7:1
9
rt
7:1
10
11
12
13
1
0
75
9:1
1
−15
−35
−15
−15
85
11:1
13:1
11:1
11:1
e
1
55
nd
2
≥95
99
99
f
g
14
2
87
a
Reactions were performed using 0.12 mmol of 1a and 0.10 mmol of
b
nitrostyrene in 200 μL of toluene. Determined by 1H NMR
c
spectroscopy of the crude reaction mixture. Enantiomeric excess of
the major stereoisomer determined by chiral stationary phase HPLC
d
e
analysis. The enantiomeric product was obtained. Not determined.
f
g
Reaction was performed on a gram scale. Isolated yield.
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a
Table 2. Scope of 1,4-Addition Reactions between Substituted MTMs and Nitroolefins
b
c
d
entry
product
R1
R2
mol %
yield (%)
dr
ee (%)
1
2
2a
2b
2c
2d
2e
2f
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
Ph
2
2
2
2
3
2
2
2
2
2
6
5
5
87
77
83
86
86
85
81
85
87
80
75
70
81
11:1
9:1
99
98
98
98
98
97
99
98
98
98
97
95
92
C6H4-4-F
C6H4-4-Cl
C6H4-4-Br
C6H4-4-OMe
C6H4-4-NO2
C6H4-2-Br
C6H3-2,4-Cl2
2-Naphthyl
2-Thienyl
Ph
3
10:1
11:1
9:1
4
5
6
7:1
7
2g
2h
2i
11:1
8:1
8
9
13:1
10:1
6:1
10
2j
e
11
2k
2l
12
13
CH2CHCH2
Ph
3:1
2m
CH2CCH
Ph
3:1
a
b
Reactions were performed using 0.24 mmol of 1 and 0.20 mmol of the nitroolefin in 400 μL of toluene. Isolated yields of the mixture of
stereoisomers of γ-nitrothioesters. Determined by H NMR spectroscopy of the isolated product. Determined by chiral stationary phase HPLC
analysis. 1.2 equiv of the nitroolefin was used.
c
d
1
e
agreement with the observed absolute and relative config-
uration of the major stereoisomer of the addition product that
was determined by X-ray crystal structure and NOE
spectroscopic analysis.24 An alternative Re−Re face approach
is less likely because of unfavorable steric interactions (Figure
1b, right).
To probe this transition state model we prepared MTM 1a′
within which the benzyl and phenyl groups have exchanged
places compared to 1a and are now on the thioester and
oxoester moieties, respectively (Figure 1c). On the basis of our
proposed transition state model, this MTM derivative was,
upon reaction with nitroolefins in the presence of catalyst H,
expected to provide the epimer of 2 in which the thio- and
oxoester moieties have exchanged their places at the quaternary
stereogenic center. This was found to be the case, and the
conjugate addition product 2a′ was obtained as the major
diastereoisomer (dr 18:1) with an enantiomeric excess of 93%.
These results, which are similar to those previously obtained
with imines as electrophiles,16 not only support the proposed
transition state model, but also show that diastereomeric
products are easily accessible with the same catalyst by a simple
variation of the functional groups within the substrate MTM.25
Derivatives of the γ-Nitrothioesters. Next, we explored
the synthetic versatility of the conjugate addition products. The
γ-nitrothioesters have a high density of orthogonal, functional
Figure 1. (a) Reactions with MTMs bearing two phenyl or two benzyl
groups at the quaternary stereogenic center that should allow
esters (i: R1 = Bn, R2 = PMB, ii: R1 = R2 = PMP), (b) proposed
access to other synthetically valuable chiral compounds by
transition state model, and (c) substrate controlled formation of the
selective functionalization of the nitro (a), thioester (b), and
quaternary stereogenic center. See Supporting Information for the
determination of the absolute and relative stereochemistry.
oxoester (c) moieties.
(a). Reduction of the Nitro Group. The distinctly different
reactivities of oxo- and thioesters toward nucleophilic amines4
were envisioned to allow for a controlled lactamization upon
reduction of the nitro group with the thioester group. Such γ-
lactams are widespread in natural products with biological
activity.26 Indeed, reaction of γ-nitrothioester 2a with Zn/
AcOH provided γ-lactam 3a without a detectable trace of the
lactam derived from cyclization at the oxoester (Scheme 2a,
top). Noteworthy, related conjugate addition products derived
catalyst18,22 with the benzyl moiety on the same side as the 3,5-
di(trifluoromethyl)phenyl group of the catalyst (Figure 1b, left)
followed by addition of the MTM enolate from the Si face to
the Re face of the nitroolefin. The depicted orientation of the
nitroolefin will likely be favored by a H-bond between the
quinuclidine moiety of the catalyst and the nitronate that is
generated upon C−C bond formation.23 This model is in
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from symmetric malonates only allow access to the
diastereoisomeric (3S,4S)-configured lactams (Scheme 2a,
bottom).27
Table 3. anti-Selective Decarboxylation of γ-Nitrothioesters
2
Scheme 2. Synthesis of Lactam 3a and γ-Nitroaldehyde 4a
a
b
dr
yield (%)
entry product
R1
R2
anti:syn
anti-5
1
2
3
4
5
5a
5b
5c
5d
5e
Me
Me
Me
Me
Me
Ph
5:1
5:1
5:1
5:1
5:1
80
78
71
66
80
C6H4-4-F
C6H4-4-Cl
C6H4-4-Br
c
C6H4-4-
OMe
6
7
5f
CH2CHCH2
CH2CCH
Ph
Ph
5:1
5:1
51
70
5g
a
Determined by 1H NMR spectroscopy of the crude reaction mixture.
Isolated yield of the anti-stereoisomers of the γ-nitrothioesters. 5c
b
c
was formed with an enantioselectivity of 95% ee as determined by
comparison with a racemic sample.31
compounds are typically the major stereoisomers formed in
addition reactions of carbonyl compounds to nitroolefins that
are catalyzed by chiral amines.29 Thus, this anti-selective
decarboxylation of the γ-nitrothioesters provides an attractive
complementary approach to organocatalytic reactions relying
on an enamine-based mechanism.
(b). Reduction of the Thioester Moiety. Reaction of 2a
under Fukuyama’s conditions28 yielded γ-nitroaldehyde 4a,
without affecting the integrity of the stereogenic centers
(Scheme 2b, bottom). Related γ-nitroaldehydes are readily
available by 1,4-addition reactions between aldehydes and
nitroolefins utilizing chiral amines as catalysts.29 However,
despite the numerous chiral amines that have been developed
for such Michael additions, reactions of α,α-disubstituted
aldehydes bearing an alkyl and an ester moiety at the α-carbon
have so far not been achieved. The presented 1,4-addition
reaction of MTMs with nitroolefins therefore provides not only
a convenient entry to these synthetically valuable γ-nitro-
aldehydes with an all-carbon quaternary stereogenic center but
is also an attractive alternative to the synthesis of γ-
nitroaldehydes via a route that relies on an enamine-based
mechanism.
(c). Decarboxylation of the Oxoester Moiety. Finally we
explored the reactivity of the oxoester moiety and reacted
several of the γ-nitrothioesters 2 with trifluoroacetic acid to
remove the acid-sensitive PMB protecting group.30 Treatment
with base induced then decarboxylation of the resulting
carboxylic acid moiety and yielded γ-nitrothioesters 5a−g
(Table 3).
CONCLUSIONS
■
In conclusion we have introduced a route to access synthetically
versatile acyclic γ-nitrothioesters with an all-carbon quaternary
stereogenic center in high yields and stereoselectivities. The
method relies on reactions between α-substituted monothio-
malonates and nitroolefins that proceed under mild organo-
catalytic conditions and require only low catalyst loadings. The
functional groups within the γ-nitrothioesters are orthogonal
and can be selectively modified to provide access to many other
valuable compounds with all-carbon quaternary stereogenic
centers as well as anti-configured γ-nitroaldehydes. In addition,
the stereochemistry of the quaternary stereocenter can be
controlled by the choice of the substituents on the thio- and
oxoester moieties of the MTMs. The results also show that
substituted MTMs are valuable thioester enolate equivalents for
asymmetric addition reactions in general and suggest that they
will enable the synthesis of numerous other synthetically
valuable chiral thioesters bearing quaternary stereogenic centers
under mild conditions.
Remarkably, these two steps proceeded not only smoothly
but provided all of the desired γ-nitrothioesters anti-selectively
in an anti:syn ratio of ∼5:1.31 The diastereoisomers were easily
separable by silica gel column chromatography so that
diastereomerically pure anti-α-alkyl-β-aryl-γ-nitrothioesters
5a−5g were isolated in good yields. The anti configuration of
5a−5g was determined by crystal structure analysis (5a and
5c), derivatization to the corresponding lactams followed by
NOE spectroscopic analysis (5f and 5g), or by analogy of the
NMR spectra (see Supporting Information). A plausible
rationale for the anti-selectivity involves coordination of the
thioester enolate to the nitromethane moiety followed by
protonation from the less hindered site (Scheme 3).
EXPERIMENTAL SECTION
■
General Aspects. Materials and reagents were of the highest
commercially available grade and used without further purification.
Reactions were monitored by thin layer chromatography using silica
gel 60 F254 plates. Compounds were visualized by UV and KMnO4.
Flash chromatography was performed using silica gel, high-purity
grade, pore size 60 Å, particle size 230−400 mesh. H and 13C NMR
1
spectra were recorded on 300, 400, and 600 MHz NMR
spectrometers. Chemical shifts are reported in ppm using TMS or
the residual solvent peak as a reference. HPLC analyses were
performed on an analytical HPLC with a diode array detector. IR
spectra were recorded on a FT-IR spectrometer. High resolution mass
spectra were recorded on a ESI-Q-TOF instrument.
The enantioselective formation of such anti-configured
stereoisomers under mild organocatalytic conditions has proven
to be difficult32 since syn-configured α,β-disubstituted carbonyl
4-Methoxybenzyl-3-((4-methoxyphenyl)thio)-2-methyl-3-oxopro-
panoate (1a), 4-methoxybenzyl-2-ethyl-3-((4-methoxyphenyl)thio)-3-
oxopropanoate (1b), 4-methoxybenzyl-2-allyl-3-((4-methoxyphenyl)-
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Scheme 3. Model for the anti-Selectivity of the Decarboxylation of Products 2
thio)-3-oxopropanoate (1c), 4-methoxybenzyl-3-((4-methoxyphenyl)-
thio)-3-oxo-2-propargylpropanoate (1d), 4-methoxyphenyl-3-(ben-
zylthio)-2-methyl-3-oxopropanoate (1a′), 4-methoxybenzyl-3-(ben-
zylthio)-2-methyl-3-oxopropanoate (1e), 4-methoxyphenyl-3-((4-
methoxyphenyl)thio)-2-methyl-3-oxopropanoate (1f) were synthe-
sized according to the previously published procedure.16
General Procedure for Conjugate Addition Reactions of
MTMs 1a−1f to Nitroolefins. The MTM 1a-1f (1.2 equiv) and the
nitroolefin (1 equiv) were dissolved in toluene (0.5 M), and the
resulting mixture was cooled to −15 °C. The catalyst (2 mol %) was
added to the mixture, which was then stirred for 24 h at −15 °C. The
reaction mixture was then washed with saturated aqueous NH4Cl (3 ×
5 mL per mmol of nitroolefin) and extracted with EtOAc (3 × 5 mL
per mmol of nitroolefin). The combined organic layers were dried over
MgSO4, concentrated at reduced pressure, and the crude product was
purified by flash column chromatography on silica gel using a gradient
of hexane:EtOAc from 15:1 to 5:1 to afford the γ-nitrothioesters 2a−
2m. Reactions were typically performed on a 0.2 mmol scale, in a
screw top vial, unless otherwise stated.
131.0, 127.2, 116.9, 115.8 (d, J = 21 Hz), 115.4, 114.4, 77.6, 68.0, 64.2,
54.9, 54.8, 48.7, 20.4; IR (neat) νmax/cm−1 3012, 2942, 2837, 1734,
1681, 1551, 1494, 1245; HRMS (ESI) m/z calculated for
C27H26FNO7S [M + Na]+ 550.1306, found 550.1307. The
enantiomeric excess was determined by HPLC using a Chiracel AD-
H column (n-hexane/i-PrOH 90:10, 25 °C) at 1.0 mL/min, UV
detection at 254 nm, tR = 25.0 min (minor enantiomer), 33.0 min
(major enantiomer).
(2S,3S)-4-Methoxybenzyl-3-(4-chlorophenyl)-2-(((4-methoxy-
phenyl)thio)carbonyl)-2-methyl-4-nitrobutanoate (2c). Colorless
1
viscous oil (90 mg, 83%, dr = 10:1, 98% ee): H NMR (400 MHz,
C6D6, 25 °C) 7.16−7.09 (m, 4H), 6.95−6.88 (m, 2H), 6.74−6.68 (m,
4H), 6.67−6.61 (m, 2H), 4.98 (d, J = 11.9 Hz, 1H), 4.92 (d, J = 11.9
Hz, 1H), 4.86−4.82 (m, 2H), 4.39 (dd, J = 8.5, 5.7 Hz, 1H), 3.24 (s,
3H), 3.15 (s, 3H), 1.30 (s, 3H); 13C NMR (100 MHz, C6D6, 25 °C)
197.0, 169.8, 161.5, 160.6, 136.8, 134.5, 134.0, 131.2, 131.1, 129.1,
127.2, 116.9, 115.4, 114.4, 77.4, 68.0, 64.1, 54.9, 54.8, 48.8, 20.5; IR
(neat) νmax/cm−1 3011, 2971, 1730, 1686, 1549, 1514, 1243; HRMS
(ESI) m/z calculated for C27H26ClNO7S [M + NH4]+ 561.1457, found
561.1458. The enantiomeric excess was determined by HPLC using a
Chiracel AD-H column (n-hexane/i-PrOH 90:10, 25 °C) at 1.0 mL/
min, UV detection at 254 nm, tR = 25.0 min (minor enantiomer), 31.3
min (major enantiomer).
(2S,3S)-4-Methoxybenzyl-2-(((4-methoxyphenyl)thio)carbonyl)-
2-methyl-4-nitro-3-phenylbutanoate (2a). Colorless viscous oil (89
1
mg, 87%, dr = 11:1, 99% ee): H NMR (400 MHz, C6D6, 25 °C)
7.18−7.07 (m, 4H), 7.05−6.94 (m, 5H), 6.74−6.69 (m, 2H), 6.67−
6.62 (m, 2H), 5.07−4.91 (m, 4H), 4.52 (dd, J = 10.0, 4.2 Hz, 1H),
3.24 (s, 3H), 3.17 (s, 3H), 1.39 (s, 3H); 13C NMR (100 MHz, C6D6,
25 °C) 197.2, 170.0, 161.5, 160.5, 136.9, 135.5, 131.0, 129.8, 128.9,
128.6, 128.4, 127.4, 115.3, 114.3, 77.8, 68.0, 64.3, 54.9, 54.8, 49.5, 20.6;
IR (neat) νmax/cm−1 3021, 2961, 1734, 1685, 1592, 1551, 1249;
HRMS (ESI) m/z calculated for C27H27NO7S [M + NH4]+ 527.1846,
found 527.1850. The enantiomeric excess was determined by HPLC
using a Chiracel AD-H column (n-hexane/i-PrOH 90:10, 25 °C) at 1.0
mL/min, UV detection at 254 nm, tR = 28.0 min (minor enantiomer),
33.4 min (major enantiomer).
Gram-Scale Synthesis of Conjugate Addition Product 2a
(Table 1, entry 14). MTM 1a (1.00 g, 2.8 mmol) and trans-β-
nitrostyrene (0.50 g, 3.4 mmol) were dissolved in toluene (5.6 mL),
and the resulting mixture was cooled to −15 °C. The catalyst (31 mg,
56 μmol, 2 mol %) was added to the mixture, which was then stirred
for 22 h at −15 °C. The reaction mixture was then washed with
saturated aqueous NH4Cl (5 mL) and extracted with EtOAc (3 × 15
mL). The combined organic layers were dried over MgSO4 and
concentrated at reduced pressure. The resulting crude product was
purified by flash column chromatography on silica gel using a gradient
of n-hexane:EtOAc from 15:1 to 5:1 to afford the γ-nitrothioester
(2S,3S)-2a as a colorless viscous oil (1.30 g, 87%, dr = 11:1, 99% ee).
The characterization data was identical to the one described above for
2a.
(2S,3S)-4-Methoxybenzyl-3-(4-bromophenyl)-2-(((4-methoxy-
phenyl)thio)carbonyl)-2-methyl-4-nitrobutanoate (2d). Colorless
1
viscous oil (101 mg, 86%, dr = 11:1, 98% ee): H NMR (400 MHz,
C6D6, 25 °C) 7.15−7.04 (m, 6H), 6.74−6.67 (m, 2H), 6.67−6.60 (m,
4H), 4.96 (d, J = 11.9 Hz, 1H), 4.94 (d, J = 11.9 Hz, 1H), 4.85−4.82
(m, 2H), 4.36 (dd, J = 8.6, 5.6 Hz, 1H), 3.24 (s, 3H), 3.15 (s, 3H),
1.29 (s, 3H); 13C NMR (100 MHz, C6D6, 25 °C) 197.0, 169.8, 161.5,
160.6, 136.8, 134.5, 132.1, 131.5, 131.1, 127.2, 122.8, 116.9, 115.4,
114.4, 77.3, 68.0, 64.0, 54.85, 54.84, 48.8, 20.5; IR (neat) νmax/cm−1
3005, 2980, 1731, 1692, 1589, 1528; HRMS (ESI) m/z calculated for
C27H26BrNO7S [M + NH4]+ 605.0952, found 605.0951. The
enantiomeric excess was determined by HPLC using a Chiracel AD-
H column (n-hexane/i-PrOH 95:5, 40 °C) at 1.0 mL/min, UV
detection at 210 nm, tR = 42.4 min (minor enantiomer), 47.6 min
(major enantiomer).
(2S,3S)-4-Methoxybenzyl-3-(4-methoxyphenyl)-2-(((4-methoxy-
phenyl)thio)carbonyl)-2-methyl-4-nitrobutanoate (2e). Light yellow
1
viscous oil (93 mg, 86%, dr = 9:1, 98% ee): H NMR (400 MHz,
C6D6, 25 °C) 7.20−7.10 (m, 4H), 6.99−6.90 (m, 2H), 6.73−6.68 (m,
2H), 6.67−6.61 (m, 2H), 6.61−6.55 (m, 2H), 5.08−4.90 (m, 4H),
4.51 (dd, J = 10.9, 3.6 Hz, 1H), 3.23 (s, 3H), 3.22 (s, 3H), 3.15 (s,
3H), 1.44 (s, 3H); 13C NMR (100 MHz, C6D6, 25 °C) 197.3, 170.1,
161.5, 160.5, 159.9, 136.9, 131.0, 130.9, 127.4, 127.1, 117.2, 115.3,
114.4, 114.3, 78.0, 67.9, 64.5, 54.83, 54.80, 54.6, 49.0, 20.7; IR (neat)
νmax/cm−1 3018, 2969, 1739, 1690, 1568, 1516, 1247; HRMS (ESI)
m/z calculated for C28H29NO8S [M + NH4]+ 557.1952, found
557.1948. The enantiomeric excess was determined by HPLC using a
Chiracel AD-H column (n-hexane/i-PrOH 90:10, 25 °C) at 1.0 mL/
min, UV detection at 254 nm, tR = 34.4 min (minor enantiomer), 49.5
min (major enantiomer).
(2S,3S)-4-Methoxybenzyl-3-(4-fluorophenyl)-2-(((4-methoxy-
phenyl)thio)carbonyl)-2-methyl-4-nitrobutanoate (2b). Colorless
1
viscous oil (81 mg, 77%, dr = 9:1, 98% ee): H NMR (400 MHz,
C6D6, 25 °C) 7.18−7.09 (m, 4H), 6.80−6.76 (m, 2H), 6.73−6.67 (m,
2H), 6.67−6.56 (m, 4H), 5.06−4.92 (m, 2H), 4.91−4.77 (m, 2H),
4.43 (dd, J = 8.1, 6.3 Hz, 1H), 3.23 (s, 3H), 3.15 (s, 3H), 1.32 (s, 3H);
13C NMR (100 MHz, C6D6, 25 °C) 197.1, 169.9, 162.9 (d, J = 270
Hz), 161.5, 160.6, 136.8, 131.5 (d, J = 8 Hz), 131.2 (d, J = 3 Hz),
(2S,3S)-4-Methoxybenzyl-2-(((4-methoxyphenyl)thio)carbonyl)-
2-methyl-4-nitro-3-(4-nitrophenyl)butanoate (2f). Colorless viscous
3941
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1
oil (94 mg, 85%, dr = 7:1, 97% ee): H NMR (400 MHz, C6D6, 25
H column (n-hexane/i-PrOH 90:10, 25 °C) at 1.0 mL/min, UV
detection at 254 nm, tR = 29.4 min (minor enantiomer), 38.2 min
(major enantiomer).
°C) 7.64−7.54 (m, 2H), 7.17−7.03 (m, 4H), 6.74−6.62 (m, 6H), 4.97
(d, J = 11.8 Hz, 1H), 4.93 (d, J = 11.8 Hz, 1H), 4.91−4.75 (m, 2H),
4.36 (dd, J = 9.7, 4.5 Hz, 1H), 3.28 (s, 3H), 3.15 (s, 3H), 1.23 (s, 3H);
13C NMR (100 MHz, C6D6, 25 °C) 196.8, 169.5, 161.7, 160.8, 147.9,
142.1, 136.8, 131.2, 130.4, 127.0, 123.7, 116.5, 115.5, 114.4, 77.0, 68.2,
63.8, 54.90, 54.89, 48.8, 20.6; IR (neat) νmax/cm−1 3008, 2973, 1742,
1678, 1592; HRMS (ESI) m/z calculated for C27H26N2O9S [M + Na]+
577.1251, found 577.1254. The enantiomeric excess was determined
by HPLC using a Chiracel AD-H column (n-hexane/i-PrOH 90:10, 25
°C) at 1.0 mL/min, UV detection at 254 nm, tR = 62.8 min (minor
enantiomer), 87.5 min (major enantiomer).
(2S,3S)-4-Methoxybenzyl-2-ethyl-2-(((4-methoxyphenyl)thio)-
carbonyl)-4-nitro-3-phenylbutanoate (2k). Colorless viscous oil (79
1
mg, 75%, dr = 6:1, 97% ee): H NMR (400 MHz, CDCl3, 25 °C)
7.41−7.35 (m, 2H), 7.33−7.15 (m, 5H), 7.01−6.87 (m, 6H), 5.30 (d, J
= 11.8 Hz, 1H), 5.24 (d, J = 11.8 Hz, 1H), 5.01 (dd, J = 13.8, 3.0 Hz,
1H), 4.89 (dd, J = 13.8, 10.9 Hz, 1H), 4.22 (dd, J = 10.9, 3.0 Hz, 1H),
3.84 (s, 3H), 3.83 (s, 3H), 2.02 (dq, J = 14.7, 7.3 Hz, 1H), 1.65 (dq, J
= 14.7, 7.3 Hz, 1H), 0.93 (apt. t, J = 7.3 Hz, 3H); 13C NMR (100
MHz, CDCl3, 25 °C) 197.4, 169.8, 161.3, 160.3, 136.7, 136.4, 135.3,
131.2, 129.0, 128.9, 128.5, 126.7, 115.3, 114.3, 78.7, 68.2, 67.7, 55.6,
55.5, 46.4, 28.1, 8.5; IR (neat) νmax/cm−1 3011, 2973, 1735, 1681,
1551, 1514, 1249; HRMS (ESI) m/z calculated for C28H29NO7S [M +
NH4]+ 541.2003, found 541.1997. The enantiomeric excess was
determined by HPLC using a Chiracel AD-H column (n-hexane/i-
PrOH 90:10, 25 °C) at 1.0 mL/min, UV detection at 254 nm, tR =
19.9 min (minor enantiomer), 22.4 min (major enantiomer).
(2S,3R)-4-Methoxybenzyl-3-(2-bromophenyl)-2-(((4-methoxy-
phenyl)thio)carbonyl)-2-methyl-4-nitrobutanoate (2g). Brownish
viscous oil (95 mg, 81%, dr = 11:1, 99% ee): H NMR (400 MHz,
1
C6D6, 25 °C) 7.28−7.20 (m, 3H), 7.14−7.07 (m, 2H), 7.01 (dd, J =
7.9, 1.6 Hz, 1H), 6.78−6.63 (m, 5H), 6.59−6.48 (m, 1H), 5.46 (dd, J
= 9.8, 4.0 Hz, 1H), 5.18−5.08 (m, 2H), 5.03−4.90 (m, 2H), 3.23 (s,
3H), 3.16 (s, 3H), 1.58 (s, 3H). 13C NMR (100 MHz, C6D6, 25 °C)
197.8, 169.9, 161.6, 160.5, 137.0, 136.2, 133.9, 131.1, 129.7, 128.7,
127.3, 116.9, 115.4, 114.3, 78.4, 67.9, 65.2, 54.9, 54.8, 46.8, 21.2; [2 ×
arom. C underneath C6D6 peaks] IR (neat) νmax/cm−1 3013, 2943,
1735, 1689, 1549, 1514, 1244; HRMS (ESI) m/z calculated for
C27H26BrNO7S [M + NH4]+ 605.0952, found 605.0955. The
enantiomeric excess was determined by HPLC using a Chiracel AD-
H column (n-hexane/i-PrOH 90:10, 25 °C) at 1.0 mL/min, UV
detection at 254 nm, tR = 23.9 min (minor enantiomer), 44.0 min
(major enantiomer).
(2S,3S)-4-Methoxybenzyl-2-allyl-2-(((4-methoxyphenyl)thio)-
carbonyl)-4-nitro-3-phenylbutanoate (2l). Colorless viscous oil (75
1
mg, 70%, dr = 3:1, 95% ee): H NMR (400 MHz, CDCl3, 25 °C)
7.40−7.35 (m, 2H), 7.34−7.16 (m, 5H), 7.01−6.88 (m, 6H), 5.78−
5.67 (m, 1H), 5.31 (d, J = 11.7 Hz, 1H), 5.25 (d, J = 11.7 Hz, 1H),
5.22−5.05 (m, 4H), 5.03−4.86 (m, 2H), 4.21 (dd, J = 10.9, 3.1 Hz,
1H), 3.84 (s, 3H), 3.83 (s, 3H), 2.75 (ddt, J = 14.9, 6.4, 1.5, 1H),
2.42−2.34 (m, 1H); 13C NMR (100 MHz, CDCl3, 25 °C) 196.8,
169.5, 161.3, 160.3, 136.6, 135.0, 131.2, 130.4, 129.1, 129.0, 128.6,
126.6, 120.6, 116.5, 115.3, 114.3, 78.5, 68.4, 67.1, 55.6, 55.5, 47.0, 39.3;
IR (neat) νmax/cm−1 3003, 2981, 1731, 1687, 1548, 1510; HRMS
(ESI) m/z calculated for C29H29NO7S [M + NH4]+ 553.2003, found
553.1998. The enantiomeric excess was determined by HPLC using
two Chiracel columns connected to each other (1st column; OD-H,
second column; AS-H), (n-hexane/EtOH 97.5:2.5, 40 °C) at 0.8 mL/
min, UV detection at 254 nm, tR 58.8 min (minor enantiomer), 69.3
min (major enantiomer).
(2S,3R)-4-Methoxybenzyl-3-(2,4-dichlorophenyl)-2-(((4-methoxy-
phenyl)thio)carbonyl)-2-methyl-4-nitrobutanoate (2h). Colorless
viscous oil (98 mg, 85%, dr = 8:1, 98% ee): H NMR (400 MHz,
1
C6D6, 25 °C) 7.24−7.19 (m, 2H), 7.14−7.05 (m, 3H), 7.03 (d, J = 2.2
Hz, 1H), 6.80−6.63 (m, 5H), 5.30 (dd, J = 10.6, 3.4 1H), 5.11−4.73
(m, 4H), 3.24 (s, 3H), 3.16 (s, 3H), 1.46 (s, 3H). 13C NMR (100
MHz, C6D6, 25 °C) 197.6, 169.7, 161.6, 160.6, 136.9, 136.6, 134.7,
133.0, 131.6, 131.2, 130.3, 129.5, 127.1, 116.7, 115.4, 114.4, 77.8, 68.0,
64.9, 54.87, 54.85, 43.7, 21.0; IR (neat) νmax/cm−1 3022, 2958, 1734,
1689, 1554, 1514, 1244; HRMS (ESI) m/z calculated for
C27H25Cl2NO7S [M + NH4]+ 595.1067, found 595.1066. The
enantiomeric excess was determined by HPLC using a Chiracel AD-
H column (n-hexane/i-PrOH 80:20, 40 °C) at 0.7 mL/min, UV
detection at 210 nm, tR = 12.1 min (minor enantiomer), 16.7 min
(major enantiomer).
(2S,3S)-4-Methoxylbenzyl-2-(((4-methoxyphenyl)thio)carbonyl)-
2-methyl-3-(naphthalene-2-yl)-4-nitrobutanoate (2i). Light brown
solid (97 mg, 87%, dr = 13:1, 98% ee): 1H NMR (400 MHz, C6D6, 25
°C) 7.60−7.42 (m, 4H), 7.24−7.18 (m, 2H), 7.14−7.10 (m, 5H),
6.73−6.66 (m, 2H), 6.65−6.59 (m, 2H), 5.20−4.98 (m, 4H), 4.71 (dd,
J = 10.8, 3.3 Hz, 1H), 3.24 (s, 3H), 3.14 (s, 3H), 1.43 (s, 3H); 13C
NMR (100 MHz, C6D6, 25 °C) 197.3, 170.1, 161.5, 160.5, 136.9,
133.7, 133.5, 133.1, 131.0, 129.7, 128.9, 128.5, 127.4, 126.8, 126.6,
126.5, 117.1, 115.3, 114.4, 77.8, 68.0, 64.5, 54.83, 54.81, 49.7, 20.8 [1
× C arom. underneath C6D6 peaks]; IR (neat) νmax/cm−1 3001, 2879,
1720, 1673, 1545, 1254; HRMS (ESI) m/z calculated for C31H29NO7S
[M + NH4]+ 577.2003, found 577.2001. The enantiomeric excess was
determined by HPLC using a Chiracel AD-H column (n-hexane/i-
PrOH 90:10, 25 °C) at 1.0 mL/min, UV detection at 254 nm, tR =
47.0 min (minor enantiomer), 56.3 min (major enantiomer).
(2S,3S)-4-Methoxybenzyl-2-(((4-methoxyphenyl)thio)carbonyl)-
2-methyl-4-nitro-3-(thiophen-2-yl)butanoate (2j). Light yellow
(2S,3S)-4-Methoxybenzyl-2-(((4-methoxyphenyl)thio)carbonyl)-
4-nitro-3-phenyl-2-propargylbutanoate (2m). Colorless viscous oil
1
(86 mg, 81%, dr = 3:1, 92% ee): peaks of major diastereoisomer, H
NMR (400 MHz, CDCl3, 25 °C) 7.41−7.36 (m, 2H), 7.34−7.14 (m,
5H), 7.09−7.04 (m, 2H), 6.98−6.88 (m, 4H), 5.31 (d, J = 11.8, 1H),
5.26 (d, J = 11.8, 1H), 5.15 (d, J = 13.8, 2.9 Hz, 1H), 4.92 (dd, J =
13.8, 11.2 Hz, 1H), 4.52 (dd, J = 11.2, 2.9 Hz, 1H), 3.84 (s, 3H), 3.83
(s, 3H), 2.98 (dd, J = 17.6, 2.7 Hz, 1H), 2.46 (dd, J = 17.6, 2.7 Hz,
1H), 2.24 (apt. t., J = 2.7 Hz, 1H); 13C NMR (100 MHz, CDCl3, 25
°C) 195.0, 168.3, 161.3, 160.4, 136.6, 134.8, 131.3, 130.5, 129.0, 128.7,
126.4, 116.2, 115.3, 114.3, 77.8, 74.0, 68.7, 68.3, 66.2, 55.6, 55.5, 45.7,
25.5; IR (neat) νmax/cm−1 3290, 3020, 2956, 1729, 1683, 1554, 1517;
HRMS (ESI) m/z calculated for C29H27NO7S [M + NH4]+ 551.1846,
found 551.1842. The enantiomeric excess was determined by HPLC
using a Chiracel AS-H column (n-hexane/i-PrOH 90:10, 40 °C) at 0.8
mL/min, UV detection at 210 nm, tR = 28.6 min (minor enantiomer),
43.1 min (major enantiomer).
(2R,3S)-4-Methoxyphenyl-2-((benzylthio)carbonyl)-2-methyl-4-
nitro-3-phenylbutanoate (2a′). Colorless viscous oil (85 mg, 89%, dr
= 18:1, 93% ee): νmax (neat)/cm−1 3010, 2951, 1740, 1681, 1552,
1
1503, 1248, 1175; H NMR (400 MHz, C6D6, 25 °C) 7.15−7.10 (m,
2H), 7.08−6.92 (m, 8H), 6.74−6.69 (m, 2H), 6.62−6.55 (m, 2H),
4.82 (dd, J = 11.4, 2.0, 1H), 4.78−4.64 (m, 2H), 3.94 (d, J = 13.8 Hz,
1H), 3.85 (d, J = 13.8 Hz, 1H), 3.18 (s, 3H), 1.39 (s, 3H); 13C NMR
(100 MHz, C6D6, 25 °C) 197.4, 168.5, 157.7, 144.0, 136.9, 134.7,
129.6, 128.9, 128.5, 128.5, 128.2, 127.4, 121.8, 114.3, 76.8, 63.0, 54.7,
48.3, 33.5, 18.2; HRMS (ESI) m/z calculated for C26H25NO6S [M +
Na]+ 502.1295, found 502.1294; The enantiomeric excess was
determined by HPLC using a Chiracel AD-H column (n-hexane/i-
PrOH 90:10, 25 °C) at 0.8 mL/min, UV detection at 254 nm, tR =
(minor enantiomer) = 25.5 min, (major enantiomer) = 38.0 min.
(2S,3S)-4-Methoxybenzyl-2-(((4-chlorophenyl)thio)carbonyl)-2-
methyl-4-nitro-3-phenylbutanoate (2a-Cl). Colorless viscous oil that
slowly crystallized (28 mg, 55%, dr = 7:1, 98% ee): νmax (neat)/cm−1
1
viscous oil (83 mg, 80%, dr = 10:1, 98% ee): H NMR (400 MHz,
C6D6, 25 °C) 7.20−7.10 (m, 4H), 6.74−6.60 (m, 6H), 6.54 (dd, J =
5.2, 3.5 Hz, 1H), 5.05 (d, J = 11.8 Hz, 1H), 5.02 (d, J = 11.8 Hz, 1H),
4.99−4.75 (m, 3H), 3.23 (s, 3H), 3.14 (s, 3H), 1.48 (s, 3H); 13C NMR
(100 MHz, C6D6, 25 °C) 196.8, 169.8, 161.5, 160.5, 137.6, 136.8,
130.9, 129.1, 127.3, 126.9, 126.3, 116.9, 115.3, 114.3, 79.0, 68.1, 64.6,
54.82, 54.80, 45.6, 20.2; IR (neat) νmax/cm−1 3031, 2962, 1728, 1689,
1595, 1555, 1514, 1244; HRMS (ESI) m/z calculated for
C25H25NO7S2 [M + NH4]+ 533.1411, found 533.1408. The
enantiomeric excess was determined by HPLC using a Chiracel AD-
3942
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1
3008, 2971, 1745, 1677, 1548, 1250; H NMR (400 MHz, C6D6, 25
(3R,4R)-4-Phenyl-3-(prop-2-yn-1-yl)pyrrolidin-2-one (3d). From
pure anti-5g. White, gummy solid (9 mg, 47%): νmax (neat)/cm−1
3280, 2987, 2972, 2865, 1681; 1H NMR (600 MHz, DMSO-d6, 25 °C)
7.96 (s, 1H), 7.35−7.30 (m, 2H), 7.28−7.21 (m, 3H), 3.73−3.69 (m,
1H), 3.67−3.60 (m, 1H), 3.37 (dtd, J = 10.0, 2.0, 1.0 Hz, 1H), 2.84
(ddd, J = 10.0, 8.5, 4.0 Hz, 1H), 2.72 (t, J = 2.7 Hz, 1H), 2.28−2.21
(m, 1H), 1.57 (dddd, J = 17.0, 10.0, 2.7, 1.0 Hz, 1H); 13C NMR (150
MHz, DMSO-d6, 25 °C) 175.6, 140.0, 128.3, 127.8, 126.8, 82.4, 71.7,
46.1, 45.1, 42.6, 15.5; HRMS (ESI) m/z calculated for C13H13NONa
[M + Na]+ 222.0889, found 222.0892.
°C) 7.14−7.08 (m, 2H), 6.99−6.90 (m, 7H), 6.87−6.81 (m, 2H),
6.73−6.66 (m, 2H), 5.00 (d, J = 11.8, 1H), 4.94 (d, J = 11.8, 1H),
4.91−4.76 (m, 2H), 4.48 (dd, J = 10.2, 4.0 Hz, 1H), 3.23 (s, 3H), 1.33
(s, 3H); 13C NMR (100 MHz, C6D6, 25 °C) 195.8, 169.7, 160.6,
136.4, 136.3, 135.3, 131.0, 129.8, 129.7, 128.9, 128.5, 127.2, 125.1,
114.3, 77.6, 76.9, 68.1, 64.3, 54.8, 49.3, 20.2; HRMS (ESI) m/z
calculated for C26H24ClNO6S [M + K]+ 552.0644, found 552.0643;
The enantiomeric excess was determined by HPLC using a Chiracel
AD-H column (n-hexane/i-PrOH 90:10, 25 °C) at 1.0 mL/min, UV
detection at 254 nm, tR = (minor enantiomer) = 23.9 min, (major
enantiomer) = 30.8 min. The absolute configuration was determined
by X-ray crystallographic analysis.
General Procedure for the Synthesis of Lactams 3a−3d. To a
solution of the thioester 2 (1 equiv) and acetic acid (12 equiv) in
EtOAc (0.05 M) was added freshly activated (washed with 2 M HCl,
H2O, EtOH and Et2O and then dried in vacuo) zinc powder (10
equiv). The resulting mixture was stirred at room temperature for 4 h
and filtered through Celite, which was carefully rinsed with EtOAc.
The combined filtrates were concentrated under reduced pressure, and
the resulting crude material was purified by flash column
chromatography on silica gel, eluting with CH2Cl2/MeOH.
(2R,3S)-4-Methoxybenzyl-2-formyl-2-methyl-4-nitro-3-phenylbu-
tanoate (4a). To a mixture of the thioester 2a (51 mg, 0.1 mmol) and
Pd/C (10% Pd, 5 mg, 5 μmol, 5 mol %) in acetone (250 μL) was
added triethylsilane (48 μL, 0.3 mmol). The resulting mixture was
stirred at room temperature for 4 h and filtered through Celite, which
was flushed with EtOAc. The combined filtrates were concentrated
under reduced pressure. The resulting crude mixture was characterized
by 1H NMR spectroscopy, and if the starting material 2a was not fully
consumed, it was again subjected to the reduction under the above
conditions. After full conversion of 2a was obtained, the crude product
was purified by flash column chromatography on silica gel by eluting
with EtOAc/hexane (1:5) to give 25 mg of the product 4a as colorless
1
oil (67%): νmax (neat)/cm−1 2953, 1743, 1715, 1555, 1514, 1246; H
(3R,4S)-4-Methoxybenzyl-3-methyl-2-oxo-4-phenylpyrrolidine-3-
carboxylate (3a). Colorless oil (41 mg, 51%, dr = 10:1): νmax (neat)/
cm−1 3300, 3020, 2972, 2865, 1702, 1514; 1H NMR (400 MHz,
DMSO-d6, 25 °C) 8.26 (s, 1H), 7.33−7.27 (m, 3H), 7.20−7.15 (m,
2H), 7.09−7.04 (m, 2H), 6.91−6.85 (m, 2H), 4.78 (s, 2H), 3.75 (s,
3H), 3.67 (dd, J = 10.2, 9.0 Hz, 1H), 3.56 (dd, J = 10.2, 7.6 Hz, 1H),
3.45 (dd, J = 9.0, 7.6 Hz, 1H), 1.32 (s, 3H); 13C NMR (100 MHz,
DMSO-d6, 25 °C) 174.2, 169.9, 159.1, 136.5, 129.7, 128.4, 127.9,
127.4, 127.3, 113.8, 65.9, 56.0, 55.1, 51.5, 43.4, 19.1; HRMS (ESI) m/z
calculated for C20H21NO4 [M + Na]+ 362.1363, found 362.1369.
(3R,4S)-S-Benzyl 3-methyl-2-oxo-4-phenylpyrrolidine-3-carbo-
thioate (3b). Colorless oil (6 mg, ∼17%, dr = 4:1, after purification):
νmax (neat)/cm−1 3042, 2957, 1693, 1514; 1H NMR (600 MHz,
DMSO-d6, 25 °C) major diastereoisomer; 8.37 (s, 1H), 7.35−7.17 (m,
8H), 7.04−7.00 (m, 2H), 3.90 (d, J = 12.0 Hz, 1H), 3.82 (d, J = 12.0
Hz, 1H), 3.76−3.72 (m, 1H), 3.61−3.57 (m, 1H), 3.47 (ddd, J = 9.3,
7.7, 1.5 Hz, 1H), 1.46 (s, 3H); minor diastereoisomer; 8.25 (s, 1H),
7.35−7.17 (m, 8H), 7.08−7.05 (m, 2H), 4.12 (d, J = 12.0 Hz, 1H),
4.10 (d, J = 12.0 Hz, 1H), 4.13−4.09 (m, 1H), 3.67−3.62 (m, 1H),
3.57−3.54 (m, 1H), 0.97 (s, 3H); 13C NMR (150 MHz, DMSO-d6, 25
°C) maj. diastereoisomer 198.1, 173.9, 136.8, 135.9, 128.7, 128.3,
128.2, 128.2, 127.3, 127.0, 62.3, 52.1, 43.3, 32.1, 18.4; min
diastereoisomer 200.0, 174.3, 137.5, 136.6, 128.8, 128.4, 128.3,
128.1, 127.1, 62.0, 48.9, 42.6, 32.5, 14.1 [1 × C arom. not visible
(weak)], HRMS (ESI) m/z calculated for C19H19NO2SNa [M + Na]+
348.1029, found 348.1032.
(3S,4S)-4-Methoxyphenyl 1-hydroxy-3-methyl-2-oxo-4-phenyl-
pyrrolidine-3-carboxylate (3b′). Colorless oil (6 mg, ∼17%, dr =
10:1, after purification): νmax (neat)/cm−1 3500, 3002, 2878, 1654; 1H
NMR (600 MHz, DMSO-d6, 25 °C), major diastereoisomer; 10.21 (s,
1H), 7.41−7.37 (m, 2H), 7.35−7.32 (m, 1H), 7.30−7.27 (m, 2H),
7.10−7.06 (m, 2H), 7.03−6.98 (m, 2H), 4.30−4.26 (m, 1H), 4.01−
3.99 (m, 1H), 3.90−3.87 (m, 1H), 3.77 (s, 3H), 0.95 (s, 3H); 13C
NMR (150 MHz, DMSO-d6, 25 °C) 170.9, 167.3, 157.0, 143.6, 135.8,
128.5, 128.2, 127.5, 122.2, 114.5, 55.4, 53.9, 49.9, 43.0, 14.7; HRMS
(ESI) m/z calculated for C19H19NO5Na [M + Na]+ 364.1155, found
364.1151.
NMR (400 MHz, CDCl3, 25 °C) 9.67 (s, 1H), 7.29−7.23 (m, 5H),
7.09−7.04 (m, 2H), 6.93−6.88 (m, 2H), 5.16 (d, J = 11.8 Hz, 1H),
5.12 (d, J = 11.8 Hz, 1H), 4.87 (dd, J = 13.5, 11.0 Hz, 1H), 4.74 (dd, J
= 13.5, 3.9 Hz, 1H), 4.16 (dd, J = 11.0, 3.9 Hz, 1H), 3.82 (s, 3H), 1.25
(s, 3H); 13C NMR (100 MHz, CDCl3, 25 °C) 197.6, 170.2, 160.3,
134.5, 130.8, 129.1, 129.0, 128.7, 126.8, 114.3, 76.5, 68.0, 60.2, 55.5,
47.3, 16.9; HRMS (ESI) m/z calculated for C20H21NO6 [M + Na]+
394.1261, found 394.1269.
General Procedure for anti-Selective Decarboxylation to γ-
Nitrothioesters 5a−5g. The conjugate addition product 2 (0.1
mmol, 1 equiv) was placed in a 5 mL round-bottom flask, and 50% v/v
trifluoroacetic acid in CH2Cl2 (1 mL) was added. The resulting
mixture was stirred at room temperature for 10 min and then
concentrated under reduced pressure. A small amount of CH2Cl2 (<1
mL) was added to the residue and evaporated again, which was
repeated 3 times to fully remove any remaining TFA. After the
resulting solid was dried in vacuo for ca. 15 min, a 1 M solution of
triethylamine in CH2Cl2 (1 mL, 10 equiv) was added. The mixture was
stirred at room temperature for 3 min and concentrated under reduced
pressure. The resulting crude product was immediately purified by
flash column chromatography on silica gel using a gradient of a
mixture of hexane:EtOAc from 15:1 to 5:1, to afford product 5. All
given yields are based on a 0.1 mmol reaction scale.
(2R,3R)-S-(4-Methoxyphenyl)-2-methyl-4-nitro-3-phenylbutane-
thioate (5a). White solid (28 mg, 80%, anti-isomer): νmax (neat)/cm−1
1
3010, 2951, 1681, 1533, 1492, 1244; H NMR (400 MHz, CDCl3, 25
°C) 7.39−7.27 (m, 3H), 7.25−7.19 (m, 2H), 7.11−7.04 (m, 2H),
6.93−6.85 (m, 2H), 4.85 (dd, J = 13.0, 5.4, 1H), 4.78 (dd, J = 13.0, 9.7,
1H) 3.87 (ddd, J = 9.7, 7.8, 5.4, Hz, 1H), 3.80 (s, 3H), 3.14 (dq, J =
7.8, 7.0 Hz, 1H), 1.34 (d, J = 7.0 Hz, 3H); 13C NMR (100 MHz,
CDCl3, 25 °C) 200.5, 160.9, 137.1, 136.1, 129.0, 128.4, 128.2, 117.7,
115.0, 77.3, 55.5, 51.0, 46.7, 15.2; HRMS (ESI) m/z calculated for
C18H19NO4S [M + Na]+ 368.0927, found 368.0932; The enantiomeric
excess was determined by HPLC using a Chiracel AD-H column (n-
hexane/i-PrOH 90:10, 25 °C) at 0.8 mL/min, UV detection at 210
nm, tR = (major) = 20.5 min.
(3R,4R)-3-Allyl-4-phenylpyrrolidin-2-one (3c). From pure anti-5f.
White, gummy solid (4 mg, ∼17%): νmax (neat)/cm−1 3440, 3034,
2962, 2865, 1682; 1H NMR (600 MHz, DMSO-d6, 25 °C) 7.84 (br. s,
1H), 7.33−7.28 (m, 2H), 7.25−7.21 (m, 1H), 7.21−7.18 (m, 2H),
5.67 (dddd, J = 17.2, 10.3, 7.0, 6.2 Hz, 1H), 4.89−4.85 (m, 1H), 4.80
(dq, J = 17.2, 1.7 Hz, 1H), 3.68−3.59 (m, 2H), 3.30−3.27 (m, 1H),
2.67 (ddd, J = 9.4, 8.0, 5.2 Hz, 1H), 2.19−2.11 (m, 1H), 1.54 (dddt, J
= 15.1, 9.6, 7.0, 1.4 Hz, 1H); 13C NMR (150 MHz, DMSO-d6, 25 °C)
177.1, 140.8, 136.5, 128.3, 127.8, 126.7, 115.5, 46.2, 44.9, 42.9, 30.0;
HRMS (ESI) m/z calculated for C13H15NONa [M + Na]+ 224.1046,
found 224.1051.
(2R,3R)-S-(4-Methoxyphenyl)-3-(4-fluorophenyl)-2-methyl-4-ni-
trobutanethioate (5b). White solid (28 mg, 78%, anti-isomer): νmax
(neat)/cm−1 3006, 2969, 1692, 1542; 1H NMR (400 MHz, CDCl3, 25
°C) 7.24−7.17 (m, 2H), 7.11−7.00 (m, 4H), 6.94−6.85 (m, 2H), 4.82
(dd, J = 12.9, 5.2, 1H), 4.73 (dd, J = 12.9, 9.9, 1H), 3.87−3.79 (m,
1H), 3.81 (s, 3H), 3.11 (dq, J = 8.5, 7.0 Hz, 1H), 1.35 (d, J = 7.0 Hz,
3H); 13C NMR (100 MHz, CDCl3, 25 °C) 200.3, 162.5 (d, J = 274
Hz), 161.0, 136.1, 132.8 (d, J = 3 Hz), 130.1 (d, J = 8 Hz) 117.5, 115.9
(d, J = 22 Hz), 115.1, 77.6, 55.5, 51.0, 46.2, 15.5; HRMS (ESI) m/z
calculated for C18H18FNO4S [M + Na]+ 386.0833, found 386.0838;
The enantiomeric excess was determined by HPLC using a Chiracel
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The Journal of Organic Chemistry
Article
AD-H column (n-hexane/i-PrOH 90:10, 25 °C) at 0.8 mL/min, UV
detection at 210 nm, tR = (major) = 25.2 min.
PrOH 90:10, 25 °C) at 0.8 mL/min, UV detection at 254 nm, tR =
(major) = 41.1 min, (minor) = 49.4 min.
(2R,3R)-S-(4-Methoxyphenyl)-3-(4-chlorophenyl)-2-methyl-4-ni-
trobutanethioate (5c). White solid (27 mg, 71%, anti-isomer, 95%
ASSOCIATED CONTENT
* Supporting Information
Additional experimental details, NMR spectra including NOEs,
HPLC traces, and crystal structures (CIF). This material is
available free of charge via the Internet at http://pubs.acs.org.
1
■
ee): νmax (neat)/cm−1 3021, 2972, 1680, 1549, 1515, 1496, 1250; H
S
NMR (400 MHz, CDCl3, 25 °C) 7.36−7.30 (m, 2H), 7.19−7.15 (m,
2H), 7.11−7.06 (m, 2H), 6.93−6.88 (m, 2H), 4.82 (dd, J = 13.0, 5.1
Hz, 1H), 4.73 (dd, J = 13.0, 9.9 Hz, 1H), 3.86−3.79 (m, 1H), 3.81 (s,
3H), 3.11 (dq, J = 8.3, 7.0 Hz, 1H), 1.35 (d, J = 7.0 Hz, 3H); 13C
NMR (100 MHz, CDCl3, 25 °C) 200.3, 161.0, 136.1, 135.6, 134.2,
129.8, 129.2, 117.4, 115.1, 77.3, 55.5, 50.8, 46.2, 15.5; HRMS (ESI)
m/z calculated for C18H18ClNO4S [M + Na]+ 402.0537, found
402.0543; The enantiomeric excess was determined by HPLC using a
Chiracel AD-H column (n-hexane/i-PrOH 90:10, 25 °C) at 0.8 mL/
min, UV detection at 210 nm, tR = (minor) = 27.1 min, (major) = 30.4
min.
AUTHOR INFORMATION
Corresponding Author
*E-mail: helma.wennemers@org.chem.ethz.ch.
Notes
■
The authors declare no competing financial interest.
(2R,3R)-S-(4-Methoxyphenyl)-3-(4-bromophenyl)-2-methyl-4-ni-
trobutanethioate (5d). White solid (28 mg, 66%, anti-isomer): νmax
(neat)/cm−1 3009, 2972, 1678, 1595, 1537, 1489; 1H NMR (400
MHz, CDCl3, 25 °C) 7.51−7.44 (m, 2H), 7.14−7.05 (m, 4H), 6.94−
6.87 (m, 2H), 4.82 (dd, J = 13.0, 5.2 Hz, 1H), 4.73 (dd, J = 13.0, 9.9
Hz, 1H), 3.86−3.77 (m, 1H), 3.81 (s, 3H), 3.11 (dq, J = 8.2, 7.0 Hz,
1H), 1.34 (d, J = 7.0 Hz, 3H), 13C NMR (100 MHz, CDCl3, 25 °C)
200.3, 161.0, 136.13, 136.09, 132.1, 130.1, 122.3, 117.4, 115.1, 77.2,
55.5, 50.7, 46.3, 15.5; HRMS (ESI) m/z calculated for C18H18BrNO4S
[M + Na]+ 446.0032, found 446.0034; The enantiomeric excess was
determined by HPLC using a Chiracel AD-H column (n-hexane/i-
PrOH 90:10, 25 °C) at 0.8 mL/min, UV detection at 210 nm, tR =
(minor) = 25.3 min, (major) = 29.1 min.
(2R,3R)-S-(4-Methoxyphenyl)-3-(4-methoxyphenyl)-2-methyl-4-
nitrobutanethioate (5e). White solid (30 mg, 80%, pure anti-isomer):
νmax (neat)/cm−1 3014, 2969, 1679, 1550, 1514, 1495, 1249; 1H NMR
(400 MHz, CDCl3, 25 °C) 7.17−7.07 (m, 4H), 6.92−6.84 (m, 4H),
4.82 (dd, J = 12.8, 5.3 Hz, 1H), 4.73 (dd, J = 12.8, 9.8 Hz, 1H), 3.84−
3.77 (m, 1H), 3.81 (s, 3H), 3.80 (s, 3H), 3.15−3.06 (dq, J = 8.3, 7.0
Hz, 1H), 1.33 (d, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3, 25
°C) 200.6, 160.9, 159.4, 136.1, 129.4, 129.0, 117.8, 115.0, 114.3, 77.7,
55.5, 55.4, 51.1, 46.1, 15.3; HRMS (ESI) m/z calculated for
C19H21NO5S [M + Na]+ 398.1033, found 398.1035; The enantiomeric
excess was determined by HPLC using a Chiracel AD-H column (n-
hexane/i-PrOH 90:10, 25 °C) at 0.8 mL/min, UV detection at 210
nm, tR = (minor) = 26.4 min, (major) = 31.5 min.
ACKNOWLEDGMENTS
■
SPF thanks the German Research Foundation (DFG) for a
fellowship (FR3418/1-1). We thank the Swiss National Science
Foundation for supporting this research and are grateful to the
University of Basel, where parts of this research were carried
out.
REFERENCES
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1
cm−1 3035, 2956, 1690, 1558, 1244; H NMR (400 MHz, CDCl3, 25
°C) 7.38−7.27 (m, 3H), 7.25−7.19 (m, 2H), 7.07−6.99 (m, 2H),
6.91−6.84 (m, 2H), 5.87−5.73 (m, 1H), 5.19−5.16 (m, 1H), 5.15−
5.12 (m, 1H), 4.87 (dd, J = 13.0, 5.3, 1H), 4.79 (dd, J = 13.0, 9.8, 1H),
3.89 (ddd, J = 9.8, 8.0, 5.3 Hz, 1H), 3.80 (s, 3H), 3.13 (ddd, J = 8.5,
8.0, 5.0 Hz, 1H), 2.52 (ddd apt. t., J = 14.4, 8.5, 7.3, 1.2, 1H), 2.43
(ddd apt. t., J = 14.3, 6.5, 5.0, 1.4, 1H); 13C NMR (100 MHz, CDCl3,
25 °C) 199.3, 160.9, 136.7, 136.0, 133.7, 129.0, 128.5, 128.3, 118.7,
117.8, 115.0, 77.4, 56.0, 55.5, 45.6, 34.1; HRMS (ESI) m/z calculated
for C20H21NO4S [M + H]+ 372.1264, found 372.1270; The
enantiomeric excess was determined by HPLC using a Chiracel AD-
H column (n-hexane/i-PrOH 90:10, 25 °C) at 0.8 mL/min, UV
detection at 254 nm, tR = (major) = 26.6 min, (minor) = 32.7 min.
(2R,3R)-S-(4-Methoxyphenyl)-4-nitro-3-phenyl-2-propargylbuta-
nethioate (5g). White solid (26 mg, 70%, pure anti-isomer): νmax
(neat)/cm−1 3290, 3041, 2973, 2866, 1685, 1548, 1249, 1055; 1H
NMR (400 MHz, CDCl3, 25 °C) 7.39−7.29 (m, 3H), 7.25−7.21 (m,
2H), 7.12−7.04 (m, 2H), 6.94−6.86 (m, 2H), 4.98 (dd, J = 13.2, 5.4
Hz, 1H), 4.89 (dd, J = 13.2, 9.6 Hz, 1H), 4.06 (ddd, J = 9.6, 7.8, 5.4
Hz, 1H), 3.80 (s, 3H), 3.25 (ddd, J = 7.8, 6.8, 6.5 Hz, 1H), 2.69 (ddd, J
= 17.0, 6.5, 2.7 Hz, 1H), 2.55 (ddd, J = 17.0, 6.8, 2.7 Hz, 1H), 2.19 (t, J
= 2.7 Hz, 1H); 13C NMR (100 MHz, CDCl3, 25 °C) 198.1, 161.1,
136.1, 135.9, 129.0, 128.6, 128.5, 117.3, 115.1, 79.8, 77.5, 72.2, 55.5,
54.4, 45.2, 19.8; HRMS (ESI) m/z calculated for C20H19NO4S [M +
H]+ 370.1108, found 370.1111; The enantiomeric excess was
determined by HPLC using a Chiracel AD-H column (n-hexane/i-
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(20) For details, see the Supporting Information.
(21) At room temperature a catalyst loading of 1 mol % did not allow
for complete conversion to the product. This is likely due to the
formation of a small amount of carboxylic acid by hydrolysis of the
thioester at rt (detected by TLC analysis), which subsequently
deactivates the catalyst. At lower temperature this hydrolysis is
suppressed.
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stationary phase HPLC chromatograms recorded under identical
conditions of all other anti-configured compounds 5 show either single
peaks or two peaks in a ratio of ≥93:7, suggesting that the
enantiomeric integrity is either fully retained or only slightly eroded
(see Supporting Information).
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(24) The absolute configuration of the 1,4-addition product was
determined by X-ray crystal structure analysis of 2a-Cl bearing a p-
chlorophenyl thioester moiety. The NMR spectra and chiral stationary
phase HPLC chromatograms of 2a-Cl, 2a as well as the other
conjugate addition products derived from MTM 1a are comparable
suggesting that also the stereochemical course of these reactions is
comparable. The relative stereochemistry was determined by NOE
spectroscopic analysis of 3a. For more details, see the Supporting
Information.
(25) Malonates bearing two different oxoesters reacted with similar
stereoselectivities as the MTMs with nitrostyrene showing that the
functional groups on the esters are critical for the stereoselectivity. The
absolute and relative configuration of 2a′ was determined by
derivatization and comparison with literature known compounds and
NOE analysis. For more details, see the Supporting Information.
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