A protocol for an asymmetric synthesis of γ-amino acids

Article abstract of DOI:10.1021/jo301177f

A new and practical method for the asymmetric synthesis of γ-amino acids from β,γ-butenolides by an in situ esterification, condensation, and reduction in a one-pot procedure is described. This method is quite general for the preparation of both enantiomers of aryl or aliphatic γ-amino acids in high yields. These γ-amino-acid derivatives were also shown to be versatile synthetic intermediates for further transformations by their conversion to γ-lactams, δ-amino alcohols, and hydrolysis products in high yields with no racemization.

Full text of DOI:10.1021/jo301177f

Article
pubs.acs.org/joc
A Protocol for an Asymmetric Synthesis of γ-Amino Acids
Leleti Rajender Reddy,* Kapa Prasad, and Mahavir Prashad
Chemical and Analytical Development, Novartis Pharmaceuticals Corporation, East Hanover, New Jersey 07936, United States
S
* Supporting Information
ABSTRACT: A new and practical method for the asymmetric
synthesis of γ-amino acids from β,γ-butenolides by an in situ
esterification, condensation, and reduction in a one-pot pro-
cedure is described. This method is quite general for the pre-
paration of both enantiomers of aryl or aliphatic γ-amino acids in
high yields. These γ-amino-acid derivatives were also shown to
be versatile synthetic intermediates for further transformations by
their conversion to γ-lactams, δ-amino alcohols, and hydrolysis
products in high yields with no racemization.
Scheme 2. Synthesis of N-tert-Butanesulfinyl Ketimine
Ester 6a
INTRODUCTION
■
Enantiomerically enriched γ-amino acids (Scheme 1) are
valuable synthons for the synthesis of γ-lactams, δ-amino
alcohols, and α-substituted pyrrolidines. These building blocks
are routinely utilized for the synthesis of a wide variety of
bioactive natural products, peptido mimetics,1,2 and other
pharmaceutical compounds.3 The asymmetric synthesis of
γ-amino acids continues to be a fundamental challenge, and
significant efforts have been made in this area.4
Table 1. Optimization of Reaction Conditions for the
a
Reduction
Scheme 1. Approach to γ-Amino Acids
b
entry
1
conditions
LiBHEt3, −78 °C
5a (dr)
8a (dr)
60 (98:2)
40 (98:2)
35 (98:2)
0
THF, 6 h
2
L-Selectride, −78 °C
THF, 6 h
65 (98:2)
3
L-Selectride, Ti(OEt)4, −78 °C, THF, 6 h 100 (98:2)
a
Reaction was conducted on a 1.0 mmol scale of 6a, unless otherwise
specified. Conversion and diastereoselectivity were determined by
b
1
The commercially available chiral N-tert-butanesulfinamides
have been widely used as highly efficient auxiliaries in the synthesis
of a variety of optically active amines by virtue of their excellent
diastereocontrol and mild conditions for their cleavage.5,6
Recently, we reported7 an elegant method for the asymmetric
synthesis of α-amino acids by a highly regio- and diastereoselective
reduction of N-tert-butanesulfinyl ketimine esters. Further,
we focused on the asymmetric synthesis of γ-amino acids and
reasoned that a direct method to access enantioenriched γ-amino
acids would be in situ esterification, condensation, and asymmetric
reduction of β,γ-butenolides (3), which has not been described to the
best of our knowledge (Scheme 2).5,6 Herein, we report the results
obtained in this research.
crude H NMR analysis.
RESULTS AND DISCUSSION
■
The choice of using β,γ-butenolides (3) as starting materials to
produce the corresponding ketimine esters is a novel option we
investigated in the present study. As expected, the treatment of
readily available β,γ-butenolide 3a with (S)-N-tert-butanesulfi-
namide (4) (1.1 equiv) in the presence of Ti(OEt)4 (2.0 equiv)8
and EtOH (1.05 equiv) in THF at 40 °C produced N-tert-
butanesulfinyl ketimine ester (6a)9 in 91% yield. Encouraged by
Received: June 11, 2012
Published: June 29, 2012
© 2012 American Chemical Society
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a
Table 2. Asymmetric Synthesis of γ-Amino Acids
a
Reaction conditions 3 (2.0 mmol), 4 (2.2 mmol), EtOH (2.1 mmol), Ti(OEt)4 (4.0 mmol) in THF at 40 °C for 2 days, followed by L-Selectride
b
(2.4 mmol) at −78 °C for 6 h, unless otherwise specified. The diastereoselectivity was determined by 1H NMR analysis. The “≥98:2” dr denotes
that signals for only one diastereomer were observed. (RS)-(4) is used.
c
this result, and with 6a in hand, we explored the asymmetric
reduction.
at −78 °C in THF for 6 h selectively gave only the γ-amino-
acid derivative 5a in 94% yield with high a diastereomeric ratio
(dr ≥ 98:2) (Table 1, entry 3).
The reaction of N-tert-butanesulfinyl ketimine esters (S)-6a
(1 equiv) with LiBHEt3 (1.1 equiv, slow addition by syringe
pump for 1 h) at −78 °C in THF for 6 h produced a mixture of
γ-amino-acid derivative 5a and γ-lactam derivative 8a in a 60:40
ratio (Table 1, entry 1) in high yield (90%). Interestingly, we
found that both products are formed in a high diastereomeric
ratio (dr ≥ 98:2). Encouraged by this result, we investigated
different reaction conditions to get a single product. Reduction
with L-Selectride provided a similar result as did LiBHEt3 (65:35
ratio of 5a and 8a, Table 1, entry 2). We were pleased to find
that the use of Ti(OEt)4 (1.1 equiv) and L-Selectide (1.2 equiv)
These interesting results allowed us to develop the novel
methodology for γ-amino acids from β,γ-butenolides in a one-pot
procedure. Thus, β,γ-butenolide 3a with 4 in the presence of
Ti(OEt)4 (2.0 equiv) and EtOH (1.05 equiv) in THF at 40 °C
for 2 days, followed by addition of L-Selectride (1.2 equiv) at
−78 °C, stirred for 6 h, produced the γ-amino-acid derivative 5a
(Table 2, entry 1) in excellent yield (89%) and a high diastereo-
meric ratio (dr ≥ 98:2). The diastereoselectivity of the reaction
was determined to be ≥98: 2 by 1H NMR analysis of the crude
product. Encouraged by these results, we turned our attention to
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other substituted aromatic β,γ-butenolides such as 3b−3d. They
reacted smoothly under optimal conditions to afford the corre-
sponding γ-amino-acid derivatives 5b−5d (Table 2, entries 2−4,
respectively) in high yields (90−95%) with high diastereomeric
ratios (dr ≥ 98:2). Similarly, the hetero aromatic 3e was reacted
with 4 to produce the γ-amino-acid derivative 5e (Table 2, entry
4) in good yield (88%) and with excellent diastereoselectivity
(dr ≥ 98:2). In the same way, the reaction of aliphatic α-angelic
lactone (3f) gave the γ-amino-acid derivative 5f (Table 2,
entry 5) in high yield (94%) with a high diastereomeric ratio
(dr ≥ 98:2). Noticeably, the reaction of 3d and 3h with (R)-4
under optimal conditions produced the corresponding γ-amino-
acid derivatives ent-5d and ent-5 h (Table 2, entries 7 and 8) in
88% and 95% yield, respectively, with high diastereomeric ratios
(dr ≥ 98:2). The structure and absolute stereochemistry of
(RS,S)-5d were confirmed by single-crystal X-ray diffraction
analysis (see the Supporting Information).
of Ti(OEt)4 to form the γ-keto ester 7, which in turn reacts with 4
to form imine 6. The diastereoselective reduction of imine 6 with
L-Selectride produces the γ-amino-acid derivative 5. The stereo-
chemical model, TS1, explains the observed stereoselectivity of the
product [(SS,R)-5]. The poorly coordinating and rapidly reacting
L-Selectride was posed to attack the electrophilic carbon atom in a
sterically controlled fashion via an open transition state. Hence,
delivery of the hydride would occur from the same face as the
sulfur lone pair to give the (SS,R) diastereomer (TS1).
A key feature of this methodology is the versatility of the
γ-amino-acid derivatives 5 in subsequent transformations.
Selective cleavage of the sulfinyl group can be accomplished
under different reaction conditions to obtain different products
in high yields with no loss of stereochemical purity (Scheme 4).
The selective cleavage of the ester group of 5 can be achieved
with 3 N LiOH in THF/water at 0 °C for 1 h in quantitative yield,
without racemization. In addition, straightforward conversion
of γ-amino-acid derivatives 5 to δ-amino alcohols 12 can be
achieved with NaBH4.
A possible mechanism for this reaction is depicted in Scheme 3.
In the first step, β,γ-butenolide 3 reacts with EtOH in the presence
CONCLUSIONS
■
Scheme 3. A Possible Mechanism of the Reaction
In conclusion, we have described a new and practical method
for asymmetric synthesis of γ-amino acids from β,γ-butenolide
by esterification, condensation, and reduction in a one-pot
operation. This method is quite general for the preparation of
enantiomers of either aryl or aliphatic γ-amino acids in good
yields with high diastereoselectivity. These γ-amino-acid
derivatives are versatile synthetic intermediates for further
transformations.
EXPERIMENTAL SECTION
■
General Information. All the reactions were performed under dry
nitrogen gas in glassware that was flame dried and equipped with a
magnetic stirring bar. Thin layer chromatography (TLC) was performed
using silica gel 60 F254 precoated plates (0.25 mm). Flash
chromatography was performed using silica gel (40 μm particle size).
All compounds were judged pure by TLC analysis (single spot, two-
solvent systems) using a UV lamp or PMA for detection purposes.
1H and 13C NMR spectra were recorded on a FT-NMR spectrometer at
500 and 125 MHz, respectively. High-resolution mass spectroscopy
(HRMS) was carried out in the electrospray mode on a premiere time
of flight mass spectrometer. The reaction temperatures refer to internal
reaction temperatures.
Scheme 4. Useful Application for γ-Amino-Acid Derivatives
General Procedure (GP1) for the Synthesis of γ-Amino Acids
5. To a 100 mL, three-necked, round-bottomed flask were added β,γ-
butenolide 3 (2.0 mmol), THF (20 mL), EtOH (2.0 mmol), tert-
butanesulfinamide 4 (2.2 mmol), and Ti(OEt)4 (4.0 mmol) in a
nitrogen atmosphere. The reaction mixture was then heated at reflux at
40 °C for 2 days. After completion, the mixture was allowed to cool to
−78 °C, and L-Selectride (2.4 mmol, 1.0 M solution in THF solution)
was added (by syringe pump for 1 h). After being stirred for 6 h at
−78 °C, the reaction mixture was quenched with a saturated NaHCO3
solution (20 mL) and extracted with ethyl acetate (2 × 25 mL). The
combined organic layer was washed with water and dried under vacuum
to give the crude product. It was purified by column chromatography
(silica gel, ethyl acetate/hexane) to produce the pure γ-amino acid 5.
(R)-Ethyl 4-((S)-1,1-Dimethylethylsulfinamido)-4-(4-methoxy-
phenyl)butanoate 5a. Following the general procedure (GP1),
the reaction of 5-(4-methoxyphenyl)furan-2(3H)-one 3a (380 mg,
2.0 mmol) with (S)-tert-butanesulfinamide (268 mg, 2.2 mmol) gave
605 mg (89%) of pure (R)-ethyl 4-((S)-1,1-dimethylethylsulfinamido)-
4-(4-methoxyphenyl)butanoate 5a as a light yellow solid. Mp:
80−81 °C. 1H NMR (501 MHz, CDCl3): δ 7.19−7.23 (m, 2H),
6.84−6.89 (m, 2H), 4.34−4.41 (m, 1H), 4.05−4.12 (m, 2H), 3.80
(s, 3H), 3.71 (d, J = 2.52 Hz, 1H), 2.19−2.32 (m, 2H), 2.01−2.16 (m,
2H), 1.23 (t, J = 7.06 Hz, 3H), 1.18 (s, 9H). 13C NMR (125 MHz,
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CDCl3): δ 175.2, 159.2, 133.0, 128.7, 113.9, 60.5, 58.1, 55.2, 33.3, 30.8,
22.5, 14.1. HRMS (EI): calcd for C17H28NO4S [M + H], 342.1739;
found, 342.1736.
58.4, 55.5, 33.3, 30.7, 22.6, 21.1, 14.2. HRMS (EI): calcd for
C17H28NO3S [M + H], 326.1790; found, 326.1788.
(R)-Ethyl 4-((R)-1,1-Dimethylethylsulfinamido)pentanoate
ent-5f. Following the general procedure (GP1), the reaction of 5-
methylfuran-2(3H)-one 3f (198 mg, 2.0 mmol) with (S)-tert-butane-
sulfinamide (268 mg, 2.2 mmol) gave 470 mg (95%) of (R)-ethyl 4-((R)-
1,1-dimethylethylsulfinamido)pentanoate ent-5f as a viscous liquid.
1H NMR (401 MHz, CDCl3): δ 4.07−4.18 (m, 2H), 3.31−3.43 (m,
1H), 3.08 (d, J = 7.83 Hz, 1H), 2.39 (t, J = 7.58 Hz, 2H), 1.72−1.86 (m,
2H), 1.31 (d, J = 6.57 Hz, 3H), 1.26 (t, J = 7.07 Hz, 3H), 1.21 (s, 98 H).
13C NMR (125 MHz, CDCl3): δ 173.3, 60.3, 55.7, 52.4, 32.8, 30.7, 23.3,
(R)-Ethyl 4-((S)-1,1-Dimethylethylsulfinamido)-4-phenylbu-
tanoate 5b. Following the general procedure (GP1), the reaction of
5-phenylfuran-2(3H)-one 3b (320 mg, 2.0 mmol) with (S)-tert-
butanesulfinamide (268 mg, 2.2 mmol) gave 568 mg (91%) of pure
(R)-ethyl 4-((S)-1,1-dimethylethylsulfinamido)-4-phenylbutanoate 5b
as a viscous liquid. 1H NMR (501 MHz, CDCl3): δ 77.19−7.43 (m, 5H),
4.36−4.53 (m, 1H), 3.98−4.17 (m, 2H), 3.85 (d, J = 2.84 Hz, 1H),
2.22−2.39 (m, 2H), 2.05−2.20 (m, 2H), 1.22 (t, J = 7.09 Hz, 3H), 1.18
(s, 9H). 13C NMR (125 MHz, CDCl3): δ 173.2, 141.4, 126.5, 127.4,
60.5, 58.8, 55.5, 33.3, 30.8, 22.6, 14.1. HRMS (EI): calcd for C16H26NO3S
[M + H], 312.1633; found, 312.1635.
(R)-Ethyl 4-((S)-1,1-Dimethylethylsulfinamido)-4-(naphtha-
len-2-yl)butanoate 5c. Following the general procedure (GP1), the
reaction of 5-(naphthalen-2-yl)furan-2(3H)-one 3c (420 mg, 2.0 mmol)
with (S)-tert-butanesulfinamide (268 mg, 2.2 mmol) gave 650 mg (90%)
of pure (R)-ethyl 4-((S)-1,1-dimethylethylsulfinamido)-4-(naphthalen-
2-yl)butanoate 5c as a white solid. Mp: 78−79 °C. 1H NMR (401 MHz,
CDCl3): δ 7.67−7.89 (m, 4H), 7.36−7.53 (m, 3H), 4.55−4.64 (m, 1H),
3.94−4.14 (m, 3H), 2.10−2.44 (s and t, 12H). 13C NMR (125 MHz,
CDCl3): δ 173.3, 138.5, 133.2, 133.1, 128.6, 127.9, 127.7, 127.1, 126.3,
126.1, 124.9, 60.6, 59.6, 55.6, 33.0, 30.9, 22.6, 14.1. HRMS (EI): calcd
for C20H28NO3S [M + H], 362.1790; found, 362.1788.
22.5, 14.1. HRMS (EI): calcd for C11H24NO3S [M+ H], 250.1477; found,
250.1479.
General Procedure (GP2) for the Hydrolysis of Ester 5. To a
round-bottomed flask containing LiOH (120 mg, 10 mmol, 10 equiv)
was added distilled H2O (7.5.0 mL), and the resulting solution was
cooled to 0 °C. A solution of 5 (1.0 mmol, 1.0 equiv) in THF (2.5 mL)
was added to the reaction flask. The resulting solution was stirred at 0 °C
for 1 h. The reaction mixture was then concentrated to remove the THF,
and the remaining material was diluted with distilled H2O (5 mL) and
EtOAc (10 mL). The reaction mixture was neutralized with a saturated
NaHSO4 solution to pH ∼2. The organic layers were separated, washed
with water (2 × 5 mL), dried over Na2SO4, filtered, and concentrated
under reduced pressure. The product 11 was isolated, with no further
purification, as a white solid.
(R)-Ethyl 4-((S)-1,1-Dimethylethylsulfinamido)-4-(4-methyl-
phenyl)butanoate 5d. Following the general procedure (GP1),
the reaction of 5-(4-methylphenyl)furan-2(3H)-one 3d (348 mg,
2.0 mmol) with (S)-tert-butanesulfinamide (268 mg, 2.2 mmol) gave
618 mg (95%) of pure (R)-ethyl 4-((S)-1,1-dimethylethylsulfinamido)-
(R)-4-((S)-1,1-Dimethylethylsulfinamido)-4-(4-methoxyphenyl)-
butanoic Acid 11a. Following the general procedure (GP2), hydrolysis
of (R)-ethyl 4-((S)-1,1-dimethylethylsulfinamido)-4-(4-methoxy-
phenyl)butanoate 5a (341 mg, 1.0 mmol) with LiOH (120 mg,
5 mmol) produced compound (R)-4-((S)-1,1-dimethylethylsulfinami-
do)-4-(4-methoxyphenyl)butanoic acid 11a (292 mg, 93%) as a white
1
4-(4-methylphenyl)butanoate 5d as a viscous liquid. H NMR (401
1
MHz, CDCl3): δ 7.16 (q, J = 8.08 Hz, 4H), 4.29−4.47 (m, 1H), 4.09 (q,
J = 7.07 Hz, 2H), 3.75 (d, J = 2.53 Hz, 1H), 2.34 (s, 3H), 2.17−2.32
(m, 2H), 1.96−2.17 (m, 2H), 1.23 (t, J = 7.06 Hz, 3H), 1.19 (s, 9H).
13C NMR (125 MHz, CDCl3): δ 173.2, 138.1, 137.4, 129.2, 127.4, 60.6,
58.4, 33.3, 30.7, 22.6, 21.1, 14.1. HRMS (EI): calcd for C17H28NO3S
[M + H], 326.1790; found, 326.1794.
solid. Mp: 125−128 °C. H NMR (501 MHz, CDCl3): δ 10.45 (br s,
1H), 7.24 (d, J = 8.51 Hz, 2H), 6.87 (d, J = 8.83 Hz, 2H), 4.81 (s, 1H),
4.39 (t, J = 6.46 Hz, 1H), 3.80 (s, 3H), 2.14−2.34 (m, 3H), 1.91−2.05
(m, 1H), 1.20 (s, 9H). 13C NMR (125 MHz, CDCl3): δ 176.9, 159.2,
132.9, 128.9, 114.0, 58.4, 55.9, 55.2, 33.4, 30.7, 22.7. HRMS (EI): calcd
for C15H22NO4S [M − H], 312.1270; found, 312.1274.
(R)-Ethyl 4-((S)-1,1-Dimethylethylsulfinamido)-4-(thiophen-
2-yl)butanoate 5e. Following the general procedure (GP1), the
reaction of 5-(thiophen-2-yl)furan-2(3H)-one 3e (332 mg, 2.0 mmol)
with (S)-tert-butanesulfinamide (268 mg, 2.2 mmol) gave 558 mg (88%)
of pure (R)-ethyl 4-((S)-1,1-dimethylethylsulfinamido)-4-(thiophen-2-
yl)butanoate 5e as a viscous liquid. 1H NMR (401 MHz, CDCl3): δ 7.30
(dd, J = 5.05, 3.03 Hz, 1H), 7.18 (d, J = 2.02 Hz, 1H), 7.02 (dd, J = 5.05,
1.26 Hz, 1H), 4.52−4.59 (m, 1H), 4.09 (q, J = 7.16 Hz, 2H), 3.95 (d, J =
3.54 Hz, 1H), 2.27−2.39 (m, 2H), 2.09−2.20 (m, 2H), 1.23 (t, J = 7.20
Hz, 3H), 1.20 (s, 9H). 13C NMR (125 MHz, CDCl3): δ 173.2, 142.5,
126.2, 126.1, 122.4, 60.5, 55.5, 54.7, 32.4, 30.6, 22.6, 14.1. HRMS (EI):
calcd for C14H24NO3S2 [M + H], 318.1198; found, 318.1195.
(S)-4-((S)-1,1-Dimethylethylsulfinamido)pentanoic Acid 11f.
Following the general procedure (GP2), hydrolysis of (S)-ethyl 4-((S)-
1,1-dimethylethylsulfinamido)pentanoate 5a (250 mg, 1.0 mmol) with
LiOH (120 mg, 5 mmol) produced compound (S)-4-((S)-1,1-dimethy-
lethylsulfinamido)pentanoic acid 11f (208 mg, 95%) as a viscous liquid.
1H NMR (501 MHz, CDCl3): δ 10.52 (br s, 1H), 3.67 (d, J = 7.57 Hz,
1H), 3.29−3.50 (m, 1H), 2.29−2.44 (m, 2H), 1.66−1.88 (m, 2H), 1.30
(d, J = 6.62 Hz, 3H), 1.22 (s, 9H). 13C NMR (125 MHz, CDCl3): δ
177.2, 56.2, 52.7, 32.7, 30.6, 22.9, 22.7. HRMS (EI): calcd for
C9H18NO3S [M − H], 220.1007; found 220.1010.
General Procedure (GP3) for Synthesis of γ-Lactam 9. To a
solution of 5 (1 mmol) in THF (5 mL) was added a 1 N HCl solution
(4 mL). After the mixture was stirred at room temperature for 12 h, it was
diluted with ethyl acetate (20 mL) and water (10 mL) and neutralized with
saturated K2CO3 solutions to pH ∼12. The organic phase was separated
and washed with water (2 × 10 mL). The organic layer contracted to
dryness to yield pure γ-lactam 9.
(S)-Ethyl 4-((S)-1,1-Dimethylethylsulfinamido)pentanoate 5f.
Following the general procedure (GP1), the reaction of 5-methylfuran-
2(3H)-one 3f (196 mg, 2.0 mmol) with (S)-tert-butanesulfinamide
(268 mg, 2.2 mmol) gave 468 mg (94%) of (S)-ethyl 4-((S)-1,1-
1
dimethylethylsulfinamido)pentanoate 5f as a viscous liquid. H NMR
(401 MHz, CDCl3): δ 4.06−4.19 (m, 2H), 3.30−3.44 (m, 1H), 2.95 (d, J =
7.57 Hz, 1H), 2.38 (t, J = 7.41 Hz, 2H), 1.72−1.89 (m, 2H), 1.31 (d, J =
6.31 Hz, 3H), 1.26 (t, J = 7.25 Hz, 3H), 1.21 (s, 9H). 13C NMR (125 MHz,
CDCl3): δ 173.2, 60.3, 55.7, 52.4, 32.9, 30.7, 23.3, 22.5, 14.1. HRMS (EI):
calcd for C11H24NO3S [M + H], 250.1477; found, 250.1475.
(S)-Ethyl 4-((R)-1,1-Dimethylethylsulfinamido)-4-(4-methyl-
phenyl)butanoate ent-5d. Following the general procedure (GP1),
the reaction of 5-(4-methylphenyl)furan-2(3H)-one 3d (349 mg,
2.0 mmol) with (R)-tert-butanesulfinamide (268 mg, 2.2 mmol) gave
601 mg (88%) of pure (S)-ethyl 4-((R)-1,1-dimethylethylsulfinamido)-
4-(4-methylphenyl)butanoate ent-5d as a white solid. Mp: 85−86 °C.
1H NMR (401 MHz, CDCl3): δ 7.16 (q, J = 8.17 Hz, 4H), 4.36−4.43
(R)-5-(4-Methoxyphenyl)pyrrolidin-2-one 9a. Following the
general procedure (GP3), the reaction of 5a (340 mg, 1.0 mmol) with a
1 N HCl solution (4 mL) gives the (R)-5-(4-methoxyphenyl)pyrrolidin-2-
one 9a (185 mg, 96%) as a white solid. Mp: 100−102 °C. 1H NMR (501
MHz, CDCl3): δ 7.21 (d, J = 8.83 Hz, 2H), 6.88 (d, J = 8.83 Hz, 2H), 6.67
(br s, 1H), 4.69 (t, J = 7.09 Hz, 1H), 3.79 (s, 3H), 2.29−2.63 (m, 3H),
1.78−2.02 (m, 1H). 13C NMR (125 MHz, CDCl3): δ 178.5, 159.2, 134.5,
126.3, 114.2, 57.6, 55.3, 31.4, 30.4. HRMS (EI): calcd for C11H14NO2 [M +
H], 192.1025; found, 192.1023.
(S)-5-Methylpyrrolidin-2-one 9f. Following the general procedure
(GP3), the reaction of 5a (250 mg, 1.0 mmol) with a 1 N HCl solution
(4 mL) gives the (S)-5-methylpyrrolidin-2-one 9f (93 mg, 94%) as a
viscous liquid. 1H NMR (501 MHz, CDCl3): δ 7.62 (br s, 1H), 3.75−
3.98 (m, 1H), 2.33−2.54 (m, 2H), 2.19−2.34 (m, 1H), 1.55−1.75
(m, 1H), 1.26 (d, J = 6.31 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ
(m, 1H), 4.09 (q, J = 7.24 Hz, 2H), 3.77 (d, J = 2.78 Hz, 1H), 2.34
(s, 3H), 2.04−2.31 (m, 4H), 1.23 (t, J = 7.20 Hz, 3H), 1.19 (s, 9H).
13C NMR (125 MHz, CDCl3): δ 173.3, 138.1, 137.5, 129.2, 127.5, 60.6,
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178.8, 50.9, 30.6, 28.9, 21.9. HRMS (EI): calcd for C5H10NO [M + H],
100.0762; found, 100.0758.
Notes
The authors declare no competing financial interest.
General Procedure (GP4) for Synthesis of Amine 10. To a
solution of 5 (1 mmol) in MeOH (5 mL) was added 1 N HCl solution
(in dioxane, 3 mL). After the mixture was stirred at room temperature
for 1 h, it was concentrated to dryness and diethyl ether (20 mL) was
added. The solid was collected by filtration, washed with diethyl ether
(20 mL), and dried at room temperature for 2 h under vacuum to yield a
pure hydrochloride salt of 10.
(R)-4-Ethoxy-1-(4-methoxyphenyl)-4-oxobutan-1-aminium
Chloride 10a. Following the general procedure (GP4), the reaction of
5a (340 mg, 1.0 mmol) with a 1 N HCl solution (in dioxane, 3 mL) gives
the (R)-4-ethoxy-1-(4-methoxyphenyl)-4-oxobutan-1-aminium chlo-
ride 10a (242 mg, 89%) as a white solid. Mp: >200 °C dec. 1H NMR
(501 MHz, CDCl3): δ 7.16−7.25 (m, 2H), 6.76−6.90 (m, 2H), 4.10
(q, J = 7.25 Hz, 2H), 3.88 (t, J = 6.94 Hz, 1H), 3.79 (s, 3H), 2.19−2.34
(m, 2H), 1.88−2.07 (m, 2H), 1.23 (t, J = 7.25 Hz, 3H). 13C NMR
(125 MHz, CDCl3): δ 173.5, 158.7, 137.7, 127.3, 113.3, 60.2, 55.2, 54.9,
34.4, 31.3, 14.2. HRMS (EI): calcd for C13H20NO3 [M + H], 238.1443;
found, 238.1445.
(S)-5-Ethoxy-5-oxopentan-2-aminium Chloride 10f. Following
the general procedure (GP4), the reaction of 5a (250 mg, 1.0 mmol)
with a 1 N HCl solution (in dioxane, 3 mL) gives the (S)-5-ethoxy-5-
oxopentan-2-aminium chloride 10f (175 mg, 92%) as a white solid. Mp:
>200 °C dec. 1H NMR (501 MHz, CDCl3): δ 8.34 (br s, 3H), 4.13 (q,
J = 6.94 Hz, 2H), 3.42−3.59 (m, 1H), 2.41−2.63 (m, 2H), 2.18 (dd, J =
13.87, 6.94 Hz, 1H), 1.87−2.08 (m, 1H), 1.45 (d, J = 6.31 Hz, 3H), 1.25
(t, J = 7.25 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 172.5, 60.7, 51.8,
47.8, 30.3, 29.6, 18.4, 14.1. HRMS (EI): calcd for C7H16NO2 [M + H],
146.1181; found, 146.1184.
General Procedure (GP5) for the Amino Alcohol 12. To a
solution of 5 (1 mmol) in MeOH (5 mL) was added NaBH4 (10.0 mmol,
10 equiv). After the mixture was stirred at room temperature for 1 h, it was
quenched with water (20 mL) and extracted with ethyl acetate (2 × 20 mL).
The combined organic layers were washed with water (20 mL) and con-
centrated to dryness to obtain pure amino alcohol 12.
(S)-N-(R)-4-(Hydroxy-1-(naphthalen-2-yl)butyl)-2-methylpro-
pane-2-sulfinamide 12c. Following the general procedure (GP5), the
reaction of 5c (340 mg, 1.0 mmol) with NaBH4 (380 mg, 10.0 mmol)
gives the (S)-N-(R)-4-(hydroxy-1-(naphthalen-2-yl)butyl)-2-methyl-
propane-2-sulfinamide (311 mg, 98%) as a white solid. Mp: 110−111 °C.
1H NMR (401 MHz, CDCl3): δ 7.70−7.86 (m, 4H), 7.37−7.51 (m, 3H),
4.48−4.62 (m, 1H), 4.10 (br s, 1H), 3.46−3.72 (m, 2H), 3.35 (br s, 1H),
1.87−2.09 (m, 2H), 1.40−1.66 (m, 2H), 1.15 (s, 9H). 13C NMR (125 MHz,
CDCl3): δ 139.5, 133.2, 132.9, 128.4, 127.6, 126.8, 126.2, 125.0, 62.0, 59.5,
55.6, 35.2, 29.2, 22.6. HRMS (EI): calcd for C18H26NO2S [M + H],
320.1684; found, 320.1682.
(S)-N-(R)-4-(Hydroxy-1-(thiophen-2-yl)butyl)-2-methylpro-
pane-2-sulfinamide 12e. Following the general procedure (GP5),
the reaction of 5e (318 mg, 1.0 mmol) with NaBH4 (380 mg, 10.0
mmol) gives the (S)-N-(R)-4-(hydroxy-1-(thiophen-2-yl)butyl)-2-
methylpropane-2-sulfinamide 12e (268 mg, 97%) as a white solid.
Mp: 89−91 °C. 1H NMR (401 MHz, CDCl3): δ 7.27 (dd, J = 4.55, 2.27
Hz, 1H), 7.15 (s, 1H), 7.01 (d, J = 4.80 Hz, 1H), 4.51 (d, J = 2.27 Hz,
1H), 4.02 (br s, 1H), 3.51−3.78 (m, 3H), 1.93 (q, J = 7.07 Hz, 2H),
1.49−1.63 (m, 2H), 1.18 (s, 9H). 13C NMR (125 MHz, CDCl3): δ
143.4, 126.2, 126.0, 122.1, 61.8, 55.6, 55.3, 34.6, 28.9, 22.6. HRMS (EI):
calcd for C12H22NO2S2 [M + H], 276.1092; found, 276.1090.
ACKNOWLEDGMENTS
■
We thank Dr. Guanmin Wu from Novartis Pharmaceutical
Corporation for helpful suggestions.
DEDICATION
■
Dedicated to Dr. J. S. Yadav (Director, IICT, India) on the
occasion of his 62nd birthday.
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ASSOCIATED CONTENT
■
S
* Supporting Information
Copies of NMR spectra for all the compounds and X-ray
crystallographic data for compound ent-5d. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
(6) (a) Reddy, L. R.; Hu, B.; Prashad, M.; Pasad, K. Org. Lett. 2008, 10,
*reddylrajender@yahoo.com.
3109. (b) Reddy, L. R.; Das, S. G.; Liu, Y.; Prashad, M. J. Org. Chem.
6300
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