A stereoselective cyclization strategy for the preparation of γ-lactams and their use in the synthesis of α-Methyl-β-proline

Article abstract of DOI:10.1021/jo3015903

A straightforward stereoselective and enantiodivergent cyclization strategy for the construction of γ-lactams is described. The cyclization strategy makes use of chiral malonic esters prepared from enantiomerically enriched monoesters of disubstituted malonic acid. The cyclization occurs with the selective displacement of a substituted benzyl alcohol as the leaving group. A Hammett study illustrates that the cyclization is under electronic control. The resulting γ-lactam can be readily converted into a novel proline analogue.

Full text of DOI:10.1021/jo3015903

Note
pubs.acs.org/joc
A Stereoselective Cyclization Strategy for the Preparation of
γ‑Lactams and Their Use in the Synthesis of α‑Methyl-β-Proline
Souvik Banerjee, Justin Smith, Jillian Smith, Caleb Faulkner, and Douglas S. Masterson*
Department of Chemistry and Biochemistry, The University of Southern Mississippi, 118 College Drive No. 5043, Hattiesburg,
Mississippi 39406, United States
S
* Supporting Information
ABSTRACT: A straightforward stereoselective and enantio-
divergent cyclization strategy for the construction of γ-lactams
is described. The cyclization strategy makes use of chiral
malonic esters prepared from enantiomerically enriched
monoesters of disubstituted malonic acid. The cyclization
occurs with the selective displacement of a substituted benzyl
alcohol as the leaving group. A Hammett study illustrates that
the cyclization is under electronic control. The resulting γ-
lactam can be readily converted into a novel proline analogue.
actams are an important class of amides. Lactams are
frequently found in a number of biologically important
an attempt to better understand the factors controlling the
selectivity of the cyclization we performed a series of cyclization
experiments where substituents were introduced on the para
position of the aromatic ring of the benzyl ester (Scheme 2).
The introduction of substituents on the para position allow
for a Hammett plot to be constructed providing insight into the
electronic factors controlling the selectivity of the cyclization.
We hypothesized that the σp constants22 would provide insight
into the electronic activation of the benzyl ester toward
nucleophilic attack. Figure 1 illustrates the results of the
Hammett analysis with a strong correlation of product ratio to
σp.
The positive slope clearly indicates that electron-withdrawing
substituents favor cyclization to γ-lactam 5 over γ-lactam 6.
This illustrates that benzyl esters with para electron-with-
drawing substituents activate the carbonyl toward nucleophilic
attack by the primary amine resulting in selective formation of
5.
L
molecules and are useful synthetic intermediates in the
preparation of various materials.1,2 Several synthetic methods
have been reported for the preparation of γ-lactams from
readily available precursors.3 For example, γ-lactams have been
prepared utilizing aza-Michael additions,4,5 reduction of nitro
compounds followed by cyclization,6 reduction of γ-azido esters
followed by cyclization,7 ring expansion of β-lactams,8 cyclo-
additions,9 and the imino-Mukaiyama−Aldol reaction.10 Several
methods have also been explored that allow for the
enantioselective formation of γ-lactams utilizing chiral auxil-
iaries,3,6 enatiomerically enriched starting materials,11,12 and
organocatalysts.5,11 Herein, we report on our efforts to prepare
γ-lactams utilizing an enantioselective cyclization strategy and
conversion of the γ-lactam product into an unnatural proline
analogue. The described strategy makes use of the widely
reported enantioselective hydrolysis of prochiral malonate
esters by pig liver esterase (PLE)13−20 followed by a novel
cyclization providing the γ-lactam products.21
We wanted to further develop the stereoselective cyclization
concept to provide 6 as the major product. Being able to
provide 6 as the major product would allow for a potentially
useful enantiodivergent cyclization strategy. The results of the
Hammett study suggest that it would be difficult to obtain high
selectivity in the formation of 6 by exploiting electronic factors
on the benzyl ester alone. We prepared diester 7 from 3 that
would introduce steric hindrance (Scheme 3). The ethyl ester
should serve as the better electrophile from a steric congestion
point of view resulting in stereoselective cyclization to 8.
Product 8 is an analogue of 6 and has the same absolute
stereochemistry as 6.
We had cause to prepare compound 4 from 3 in our attempt
to determine the absolute stereochemistry of 3 by synthetic
means (Scheme 1). Upon treatment of 4 with hydrazine a
cyclization took place resulting in compounds 5 and 6 as
illustrated in Scheme 1. Interestingly, the 5/6 ratio was 10:1 as
determined by 1H NMR resulting in a selective cyclization that
favored ring closure by attack at the benzyl ester over the ethyl
ester. The cyclization selectivity results in an enantioselective
cyclization strategy as 5 has the R-absolute stereochemistry and
6 has the S-absolute stereochemistry.
The ability to control the cyclization reaction utilizing such a
straightforward set of synthetic manipulations could prove
useful in the enantioselective preparation of γ-lactams from
simple half-ester starting materials such as 3. The 10:1
selectivity was interesting given that both esters are relatively
open toward nucleophilic attack by the amine nucleophile. In
Received: August 3, 2012
© XXXX American Chemical Society
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Scheme 1. Preparation of γ-Lactams (PLE = Crude Pig Liver Esterase)
Scheme 2. Cyclization Using Various Benzyl Esters
of the lactam with various reducing agents and conditions
known to reduce lactams to amines.12,30 However, all attempts
at direct reduction of the lactam resulted in reduction of both
the ester and lactam functional groups providing a complex
mixture of products. The synthetic approach shown in Scheme
4 was used to overcome the over-reduction problem and
ultimately provide the unprotected β-proline analogue in
reasonable overall yield.
Compound 5 was treated with NaH and benzyl bromide to
provide the mixture 9a/9b in good yield (68%). We suspect
that the formation of 9b was due to the presence of benzyl
alcohol in our commercially obtained benzyl bromide leading
to partial transesterification. 1H NMR analysis of the
commercial benzyl bromide indicated a significant quantity of
benzyl alcohol. However, obtaining a mixture of 9a/9b was of
no real significance as the ester would eventually be
transformed into the free acid and the mixture was carried on
through the subsequent steps. The mixture of 9a/9b was
converted in 80% yield to thiolactam 10a/10b using Lawesson
reagent.11 The thiolactam mixture was then easily reduced to
the primary amines 11a/11b by hydrogenation over Raney
nickel catalyst in good yield.31−33 Interestingly, we were able to
Figure 1. Hammett plot.
The results illustrated in Scheme 3 demonstrate that
stereoselective formation of 8 occurs in a 9:1 ratio providing
a route to the (S)-γ-lactam from 3.
We wanted to demonstrate the potential utility of the γ-
lactams prepared above as precursors to unnatural amino acids.
Upon inspection of 5 it is conceivable that a β-proline
analogue23−29 could be readily prepared by reduction of the
lactam to a secondary amine. We attempted a direct reduction
B
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Scheme 3. Selective Cyclization Providing (S)-γ-Lactam 8
Scheme 4. Conversion of 5 into Proline Analogue 13
with stirring. The reaction mixture was allowed to stir for 60 min at rt.
The generated enolate was dripped into a 100 mL solution of 21.4 g of
dibromoethane (114 mmol) in THF over 60 min with stirring under
N2 atmosphere. The reacton mixture was then heated to reflux in
solvent for 12 h. The solution was cooled to rt, diluted with ether (300
mL), washed twice with 1 N HCl, washed with brine, dried over
MgSO4, and filtered, and the solvent was evaporated under reduced
pressure. The resulting pale yellow liquid was distilled to remove the
excess dibromoethane giving 14.6 g (52 mmol, 91%) of 1 as a colorless
liquid. IR (cm−1): 2982, 1726. 1H NMR (CDCl3, 400 MHz): 4.20 (q,
4H, J = 7 Hz), 3.39 (t, 2H, J = 7 Hz), 2.44 (t, 2H, J = 7 Hz), 1.44 (s,
3H), 1.26 (t, 6H, J = 7 Hz). 13C NMR (CDCl3, 100 MHz): 171.0,
61.0, 54.0, 39.0, 27.0, 29.0, 14.0. ESI-MS [C10H18BrO4]+: 281, 283.
HRMS [C10H17BrO4Na]+: calcd 303.0202, found 303.0201.
Synthesis of Diethyl 2-Methyl-2-[2-(1,3-dioxoisoindolin-2-
yl)ethyl)malonate (2). A 100 mL solution of 6 g of 1 (21 mmol) in
DMF was placed in a 250 mL sealed tube. A 4.6 g (25 mmol) portion
of potassium phthalimide was added to the sealed tube. The reaction
mixture was stirred at 90 °C overnight. The reaction mixture was
cooled to rt, diluted with 300 mL of H2O, and extracted with Et2O (3
× 200 mL). The combined organic layer was washed with water (10 ×
100 mL), washed with brine (2 × 100 mL), dried over MgSO4,
filtered, and evaporated under reduced pressure giving the crude
product as a white solid. The crude was recrystallized from cold Et2O
giving 6.2 g (18 mmol, 86%) of 2 was a white solid: Rf = 0.48 (30%
EtOAc/hexanes). IR (cm−1): 3000, 1773, 1721, 1709. Mp = 68 °C. 1H
NMR (CDCl3, 400 MHz): 7.84 (m, 2H), 7.71 (m, 2H), 4.18 (q, 4H, J
= 7 Hz), 3.74 (m, 2H), 2.25 (m, 2H), 1.54 (s, 3H), 1.27 (t, 6H, J = 7
Hz). 13C- NMR (CDCl3, 75 MHz): 171.7, 168.0, 134.0, 132.0, 123.4,
62.0, 52.5, 34.0, 33.9, 20.0, 14.0. HRMS [C18H21NO6Na+]: calcd
370.1261, found 370.1257.
isolate 11a by radial chromatography and obtain good analytical
data on 11a (see the Supporting Information). The 11a/11b
mixture was then subjected to saponification giving 12 in 78%
yield. Amino acid 12 was then converted to the α-methyl-β-
proline analogue 13 in 91% yield by hydrogenation over Pd/C
catalyst. The overall yield of 13 from 5 is 28% over the five
straightforward steps shown in Scheme 4.
We have shown that enantioselective γ-lactam formation is
possible from 4 with judicious choice of benzyl ester. The
highest level of selectivity was observed using 4d containing a
para nitro substituent on the benzyl ester. The cyclization
selectivity has a strong correlation to σp as demonstrated in the
Hammett analysis. The positive slope of the Hammett plot
indicates that electron withdrawing substituents in the para
position of the benzyl ester activate the benzyl ester carbonyl
toward electrophilic attack. We have demonstrated that γ-
lactam 5 can be readily converted into 13 providing
straightforward access to a new class of proline analogue.
EXPERIMENTAL SECTION
■
General Methods. THF, CH2Cl2, and DMF were dried by passage
through activated alumina. All reagents were used as received unless
otherwise stated. Melting points were obtained in open capillary tubes
and are uncorrected. Flash chromatography was performed using P-60
silica gel, and TLC analysis was performed using silica precoated TLC
plates. Radial chromatography was performed on normal-phase
precoated silica rotors. HRMS was obtained using ESI/FTICR-MS,
and low-resolution MS were obtained by ESI/ion trap. Pig liver
esterase (PLE) refers to the commercially available crude preparation.
Synthesis of Diethyl 2-(2-Bromoethyl)-2-methylmalonate
(1). A volume of 100 mL of dry THF was added to 2.5 g of NaH
(63 mmol, 60% suspension in mineral oil) under a N2 atmosphere.
The THF solution was cooled to 0 °C. A 50 mL solution of 10 g of
diethyl-2-methylmalonate (57 mmol) in THF was added over 30 min,
Synthesis of (R)-2-(N-Ethylphthalimido)-3-ethoxy-2-methyl-
3-oxopropanoic Acid (3). A 10 g portion of 2 (29 mmol) was
dispersed in 1000 mL of rapidly stirring phosphate buffer (0.1 N, pH
7.4). A 97 mg portion of pig liver esterase (PLE) (27 units/mg, 90
units per mmol of the substrate) was added to the buffer. The pH was
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maintained at 7.4 with an auto buret set to deliver 1 equiv of 1 N
NaOH solution. The hydrolysis proceeded for 2 days. The reaction
mixture was acidified with 12 M HCl to pH 1 and extracted three
times with 600 mL of Et2O. The combined organic layer was dried
over MgSO4, filtered, and concentrated under reduced pressure giving
crude product as colorless viscous oil. The crude product was purified
by flash chromatography (40% EtOAc/hexanes) giving 7.2 g (22.5
mmol, 71%) of 3 as a white solid. The % ee was determined to be 92%
preparation of 4a−e. A 9.4 g portion of product (22.3 mmol, 72%) was
obtained after purification as colorless liquid. Rf = 0.24 (40% Et2O/
hexanes). [α]24D = −5.3 (c = 1, CHCl3). IR (cm−1): 2983, 1773, 1708.
1H NMR (CDCl3, 400 MHz): 7.83 (m, 2H), 7.70 (m, 2H), 7.22 (d,
2H, J = 8 Hz), 7.14 (d, 2H, J = 8 Hz), 5.11 (m, 2H), 4.10 (m, 2H),
3.73 (m, 2H), 2.34 (s, 3H), 2.26 (m, 2H), 1.55 (s, 3H), 1.16 (t, 3H, J =
7 Hz). 13C NMR (CDCl3, 100 MHz): 171.4, 171.3, 168.0, 138.0,
134.0, 132.5, 132.0, 129.0, 128.0, 123.0, 67.0, 62.0, 52.0, 34.0, 21.0,
20.0, 14.0. HRMS [C24H25NO6Na+]: calcd 446.1574, found 446.1565.
Synthesis of (S)-1-(4-Nitrobenzyl)-3-ethyl-2-methyl-[2-(1,3-
dioxoisoindolin-2yl)ethyl]malonate (4d). Compound 4d was
synthesized following the general synthetic procedure for the
preparation of 4a−e. A 10.27 g portion of product (22.6 mmol,
73%) was obtained after purification as a white solid. Mp = 65 °C. Rf =
0.1 (40% Et2O/hexanes). [α]24 = +1.4 (c = 1, CHCl3). IR (cm−1):
2983, 1773, 1729, 1707, 1517. 1DH NMR (CDCl3, 400 MHz): 8.23 (d,
2H, J = 8 Hz), 7.83 (m, 2H), 7.72 (m, 2H), 7.52 (d, 2H, J = 8 Hz),
5.25 (m, 2H), 4.16 (m, 2H), 3.74 (m, 2H), 2.29 (m, 2H), 1.59 (s, 3H),
1.21 (t, 3H, J = 7 Hz). 13C NMR (CDCl3, 100 MHz): 171.2, 171.1,
168.0, 148.0, 143.0, 134.0, 132.0, 128.0, 124.0, 123.0, 66.0, 62.0, 52.0,
34.0, 33.8, 20, 14. HRMS [C23H22N2O8Na+]: calcd 477.1268, found
477.1266.
by chiral HPLC (Chiralcel OJ-H, 305 nm, 5% Ipr-OH/hexane) tR(S)
=
52.93 min (area = 307.51), tR(R) = 55.56 min (area = 7596.17). Rf =
0.35 (40:60 EtOAc/hexanes). [α]24D = +9.7 (c = 1, MeOH). Mp = 83
°C. IR (cm−1): 3100 (broad), 2923, 1751, 1684, 1608. 1H NMR
(CDCl3, 300 MHz): 8.38 (bs, 1H), 7.84 (m, 2H), 7.73 (m, 2H), 4.21
(q, 2H, J = 7 Hz), 3.77 (t, 2H, J = 8 Hz), 2.28 (m, 2H), 1.56 (s, 3H),
1.30 (t, 3H, J = 7 Hz). 13C NMR (CDCl3, 75 MHz): 175.0, 173.0,
169.0, 135.0, 133.0, 24.0, 62.0, 53.0, 35.0, 34.6, 20.0, 14.0. HRMS
[C16H17NO6Na+]: calcd 342.0948, found 342.0945. The stereo-
chemistry of 3 was determined to be (R) by conversion to the
known 14 and comparison of the optical rotation. Compound 5 was
saponified using 1 N NaOH/EtOH at reflux over 1 h to provide the
carboxylic acid that was subjected to a Curtius rearrangement to obtain
the free amine that was subsequently treated with (BOC)2O providing
the target compound 14. [α]24 = −16 (c = 0.35, CHCl3)].34
Synthesis of (S)-1-(4-Trifluoromethylbenzyl)-3-ethyl-2-
methyl-[2-(1,3-dioxoisoindolin-2yl)ethyl]malonate (4e). Com-
pound 4e was synthesized following the general synthetic procedure
for the preparation of 4a−e. A10.8 g portion of product (22.6 mmol,
87%) was obtained after purification as a colorless liquid. Rf = 0.26
D
(40% Et2O/hexanes). [α]24 = −8.33 (c = 3, CHCl3). IR (cm−1):
D
1
2983, 1773, 1709. H NMR (CDCl3, 400 MHz): 7.83 (m, 2H), 7.71
(m, 2H), 7.62 (d, 2H, J = 8 Hz), 7.46 (d, 2H, J = 8 Hz), 5.20 (s, 2H),
4.12 (m, 2H), 3.73 (m, 2H), 2.29 (m, 2H), 1.57 (s, 3H), 1.17 (t, 3H, J
= 7 Hz). 13C NMR (CDCl3, 100 MHz): 171.3, 171.2, 168.0, 139.0,
134.0, 132.0, 130.0 (q, J = 33 Hz), 128.0, 125.0 (q, J = 4 Hz), 123.0,
122.0, 66.0, 62.0, 52.0, 34.0, 33.8, 20.0, 14.0. HRMS
[C24H22F3NO6Na+] calcd 500.1291, found 500.1278.
General Procedure for the Synthesis of 4a−e. A 250 mL
round-bottom flask was charged with 9.9 g of 3 (31 mmol), 4.3 g of
K2CO3 (31 mmol), 100 mL of anhydrous DMF, and a stirbar. A
solution of the appropriately substituted benzyl bromide (28 mmol) in
20 mL of anhydrous DMF was slowly added over 15 min. The reaction
was allowed to stir approximately 12 h under a nitrogen atmosphere.
The reaction mixture was then diluted with 100 mL of water, and the
resulting mixture was washed with Et2O (3 × 100 mL). The combined
ether layer was washed with water (5 × 100 mL) and brine (2 × 100
mL) and dried over MgSO4, and the solvent was removed under
reduced pressure. The product was isolated by flash chromatography
(40% Et2O/hexanes).
Synthesis of (R)-Ethyl 3-Methyl-2-oxopyrrolidine-3-carbox-
ylate (5). A volume of 930 μL (10.2 mmol) 35% hydrazine in water
was added to a solution of 3.8 g (9.3 mmol) of 4a in 50 mL of MeOH.
The mixture was heated to reflux solvent overnight. A white precipitate
was observed within 1 h of reflux. The reaction mixture was allowed to
cool to rt, and the resulting mixture was filtered. The filtrate was
evaporated under reduced pressure. The resulting residue was taken up
in CH2Cl2 and washed with water. The organic layer was dried over
MgSO4, evaporated under reduced pressure, and purified by column
chromatography using 30% hexanes/EtOAc giving 1.2 g of a 10:1
mixture of 5:6 as a white solid. The mixture was further recrystallized
in cold Et2O giving 1 g (6 mmol, 64.5%) of pure 5 as white crystals. Rf
(5) = 0.31 (30% hexanes/EtOAc). Mp = 63 °C. [α]23D = +19.0 (c = 2,
MeOH). IR (cm−1): 3245, 2985, 1726, 1698, 1660. 1H NMR (CDCl3,
400 MHz): 7.06 (bs, 1H), 4.20 (m, 2H), 3.47 (m, 1H), 3.36 (m, 1H),
2.64 (m, 1H), 2.02 (m, 1H), 1.45 (s, 3H), 1.28 (t, 3H, J = 7 Hz), 13C
NMR (CDCl3, 100 MHz): 177.0, 172.0, 61.0, 51.0, 40.0, 34.0, 20.0,
14.0. HRMS [C8H13NO3Na+]: calcd 194.0788, found 194.0795.
Synthesis of (S)-1-tert-Butyl-3-ethyl-2-methyl-[2-(1,3-dioxoi-
soindolin-2yl)ethyl]malonate (7). A volume of 600 μL of concd
H2SO4 was added to a solution of 2 g of 3 (6 mmol) in 30 mL CH2Cl2
in a 100 mL sealed tube. The solution was cooled to −7 °C. A volume
of 6 mL condensed isobutylene was added to the solution. The tube
was sealed tightly and allowed to stir overnight at rt. The tube was
uncapped and allowed to stir for 2 h at ambient pressure to allow
excess isobutylene to evaporate. The solution was diluted with 30 mL
of CH2Cl2 and gently washed three times with 1 N NaOH (50 mL).
The CH2Cl2 layer was dried over MgSO4, evaporated under reduced
pressure, and chromatographed (40% EtOAc/hexanes) giving 1.8 g (5
mmol, 83%) of 7 as colorless viscous liquid. The viscosity of the
material made removal of residual solvent impractical, and 7 was
utilized in the subsequent reaction without further purification. Rf =
Synthesis of (S)-1-Benzyl-3-ethyl-2-methyl-[2-(1,3-dioxoi-
soindolin-2-yl)ethyl]malonate (4a). Compound 4a was synthe-
sized following the general synthetic procedure for the preparation of
4a−e. An 11 g portion of product (27 mmol, 87%) was obtained after
flash chromatography purification as a colorless liquid. Rf = 0.2 (40%
Et2O/hexanes). [α]24 = −3.08 (c = 1, CHCl3). IR (cm−1): 2980,
D
1
1773, 1708. H NMR (CDCl3, 400 MHz): 7.83 (m, 2H), 7.70 (m,
2H), 7.33 (m, 5H), 5.15 (m, 2H), 4.10 (m, 2H), 3.74 (m, 2H), 2.28
(m, 2H), 1.56 (s, 3H), 1.16 (t, 3H, J = 7 Hz). 13C NMR (CDCl3, 100
MHz): 171.4, 171.3, 168.0, 135.5, 134.0, 132.0, 128.5, 128.3, 128.1,
123.0, 67.0, 61.0, 52.0, 33.8, 33.8, 20.0, 14.0. HRMS [C23H23NO6Na+]:
calcd 432.1417, found 432.1406.
Synthesis of (S)-1-(4-Fluorobenzyl)-3-ethyl-2-methyl-[2-(1,3-
dioxoisoindolin-2yl)ethyl]malonate (4b). Compound 4b was
synthesized following the general synthetic procedure for the
preparation of 4a−e. A 9.95 g portion of product (23.3 mmol, 75%)
was obtained after purification as a colorless liquid. Rf = 0.25 (40%
Et2O/hexanes). [α]24D = −3.7 (c = 1, CHCl3). IR (cm−1): 2984, 1773,
1708. 1H NMR (CDCl3, 400 MHz): 7.83 (m, 2H), 7.71 (m, 2H), 7.33
(m, 2H), 7.03 (m, 2H), 5.11 (m, 2H), 4.10 (m, 2H), 3.72 (m, 2H),
2.26 (m, 2H), 1.55 (s, 3H), 1.16 (t, 3H, J = 7 Hz). 13C NMR (CDCl3,
1
100 MHz): 171.4, 171.3, 163.0 (d, J = 250 Hz), 134.0, 132.0, 131.0
4
3
2
(d, J = 3.6 Hz), 130.0 (d, J = 8.5 Hz), 123.0, 115.0 (d, J = 22 Hz),
123.0, 66.0, 62.0, 52.0, 33.8, 33.7, 20.0, 14.0. HRMS
[C23H22FNO6Na+]: calcd 450.1323, found 450.1312.
1
0.51 (40% EtOAc/hexanes). IR (cm−1): 2979, 1774, 1709. H NMR
Synthesis of (S)-1-(4-Methylbenzyl)-3-ethyl-2-methyl-[2-
(1,3-dioxoisoindolin-2yl)ethyl]malonate (4c). Compound 4c
was synthesized following the general synthetic procedure for the
(CDCl3, 400 MHz): 7.84 (m, 2H), 7.71 (m, 2H), 4.17 (m, 2H), 3.72
(m, 2H), 2.19 (m, 2H), 1.50 (s, 3H), 1.48 (s, 9H), 1.28 (t, 3H, J = 7
D
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Note
Hz). 13C NMR (CDCl3, 100 MHz) 172.0, 170.5, 168.0, 134.0, 132.2,
123.3, 82.0, 61.0, 53.0, 34.0, 33.8, 28.0, 20.0, 14.0. HRMS
[C20H25NO6Na+]: calcd 398.1574, found 398.1568.
The product was purified by radial chromatography using 20%
hexanes/CH2Cl2 to give 0.25 g (1.01 mmol, 72%) of 11a as a colorless
liquid: Rf = 0.32 (20% hexanes/CH2Cl2). IR (cm−1): 2974, 2790,
1725, 1452. [α]24D = −8 (c = 1, CHCl3). 1H NMR (CDCl3, 400 MHz)
(11a): 7.3 (m, 5H), 4.13 (q, 2H, J = 7 Hz), 3.61 (m, 2H), 2.94 (d, 1H,
J = 9 Hz), 2.64 (m, 2H), 2.41 (m, 2H), 1.65 (m, 1H), 1.33 (s, 3H),
1.25 (t, 3H, J = 7 Hz). 13C NMR (CDCl3, 100 MHz) (11a): 177.0,
139.0, 128.5, 128.2, 127.0, 64.0, 61.0, 60.0, 54.0, 48.0, 36.0, 25.0, 14.0.
HRMS [C15H21NO2Na+]: calcd 270.1464, found 270.1463.
Synthesis of (R)-1-Benzyl-3-methylpyrrolidine-3-carboxylic
Acid (12). A 0.13 g portion of LiOH (6 mmol) was added to a
solution of 0.46 g (2 mmol) of 11a in 12 mL of 3:2 H2O/EtOH. The
reaction was stirred at rt for 24 h and determined to be complete by
TLC. The mixture was acidified to pH 3 (4 N HCl), and the water
layer was evaporated under reduced pressure giving a colorless gummy
residue. The gummy residue was triturated with MeOH multiple
times, and the MeOH fractions were dried over MgSO4. The solvent
was removed under reduced pressure giving 0.34 g (1.56 mmol, 78%)
of 12 as a colorless liquid: Rf = 0.13 (5% MeOH/CH2Cl2). IR (cm−1):
3371(broad), 2946, 2615, 1712, 1455. [α]2D3 = −11.3 (c = 1, MeOH).
1H NMR (CD3OD, 400 MHz): 7.58 (m, 2H), 7.50 (m, 3H), 4.44 (m,
Synthesis of (S)-tert-Butyl 3-Methyl-2-oxopyrrolidine-3-car-
boxylate (8). A volume of 398 μL (4.4 mmol) of 35% hydrazine in
water was added to a solution of 1.5 g (4 mmol) 7 in 25 mL MeOH.
The mixture was heated to reflux solvent overnight. A white precipitate
was observed within 1 h of reflux. The reaction mixture was allowed to
cool to rt and the solution was filtered. The filtrate was evaporated
under reduced pressure and taken up in CH2Cl2. The resulting mixture
was washed with water, and the organic layer was dried over MgSO4,
evaporated under reduced pressure, and chromatographed using 30%
hexanes/EtOAc giving 0.62 g of a 9:1 mixture of 8:5 as a white solid.
The mixture was further recrystallized in cold Et2O giving 0.52 g (2.6
mmol, 65%) pure 8 as a white solid: Rf (8) = 0.27 (30% hexanes/
EtOAc). Mp = 130 °C. IR (cm−1): 3255, 2970, 1727, 1688, 1660.
[α]2D3 = −14.3 (c = 1, CH2Cl2). H NMR (CDCl3, 400 MHz): 6.44
1
(bs, 1H), 3.45 (m, 1H), 3.33 (m, 1H), 2.55 (m, 1H), 2.0 (m, 1H), 1.46
(s, 9H), 1.39 (s, 3H). 13C NMR (CDCl3, 100 MHz): 177.0, 171.0,
81.0, 51.0, 40.0, 34.0, 28.0, 20.0. HRMS [C10H17NO3Na+]: calcd
222.1101, found 222.1097.
2H), 3.87 (d, 1H, J = 12 Hz), 3.51 (m, 2H), 3.21 (d, 1H, J = 12 Hz),
2.58 (m, 1H), 2.09 (m, 1H), 1.47 (s, 3H). 13C NMR (CD3OD, 100
MHz): 176.0, 130.4, 130.2, 129.7, 129.0, 61.0, 58.0, 53.0, 35.0, 22.0.
HRMS [C13H17NO2Na+]: calcd 242.1151, found 242.1145.
Synthesis of (R)-Ethyl 1-Benzyl-3-methyl-2-oxopyrrolidine-
3-carboxylate (9a/9b). A solution of 3.6 g (22 mmol) of 5 in 20 mL
of anhydrous THF was added slowly to a suspension of 0.62 g NaH
(26 mmol) in 10 mL of THF at 0 °C under a N2 atmosphere. The
reaction mixture was allowed to stir for 5 min. A volume of 3.3 mL
(4.75 g, 24 mmol) of BnBr was added dropwise to the reaction
mixture at 0 °C. The reaction mixture was allowed to stir for 10 min at
0 °C and then allowed to warm to rt. The reaction was continued for 1
h at rt. A volume of 15 mL of dry DMF was added to the reaction
mixture, which continued to stir for 2 h. The reaction mixture was
poured into 25 mL of H2O. The water layer was extracted with Et2O
(3 × 50 mL). The combined ether layer was washed with water (5 ×
30 mL), dried over MgSO4, evaporated under reduced pressure, and
chromatographed (gradient, 15−20% EtOAc/hexanes) giving 3.8 g
(15 mmol, 68%) of a 4:1 (as determined by NMR) inseparable
mixture of 9a and 9b as a colorless oil. The mixture was utilized in the
next step without further purification. Rf = 0.27 (20% EtOAc/
hexanes). IR (cm−1): 2979, 1735, 1685. 1H NMR (CDCl3, 400 MHz)
(9a/9b mixture): 7.29 (m, 7.5H), 5.16 (m, 0.5H), 4.6 (m, 1.25H),
4.36 (m, 1.27H), 4.17 (m, 2H), 3.33 (m, 1.26H), 3.17 (m, 1.25H),
2.46 (m, 1.25H), 1.89 (m, 1.27H), 1.50 (s, 0.76H), 1.47 (s, 3H), 1.23
(t, 3H, J = 7 Hz). ESI-MS [C15H20NO3, 9a]+: calcd 261.3, found 262.2.
ESI-MS [C20H22NO3, 9b]+: calcd 324.6, found 324.1.
Synthesis of (R)-3-Methylpyrrolidine-3-carboxylic Acid (13).
A 0.3 g (2.3 mmol) portion of 12 was dissolved in 15 mL of MeOH
and added to 0.03 g of Pd/C (10% by weight). The solution was
allowed to stir overnight under a H2 atmosphere at rt. The resulting
mixture was filtered through Celite, and the filtrate was evaporated
under reduced pressure giving 0.27 g (2.1 mmol, 91%) of 13 as a white
solid. Mp = 98 °C. IR (cm−1): 3392 (broad), 3177, 2877, 1704. [α]24
D
= −20.4 (c = 0.33, MeOH). 1H NMR (CD3OD, 400 MHz): 3.78 (m,
1H), 3.48 (m, 1H), 3.38 (m, 1H), 3.10 (d, 1H, J = 12 Hz), 2.49 (m,
1H), 2.01 (m, 1H), 1.45 (s, 3H). 13C NMR (CD3OD, 100 MHz):
176.0, 53.0, 48.5, 45.0, 35.0, 21.0. HRMS [(C6H11NO2)2Na+]: calcd
281.1472, found 281.1468.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H NMR and 13C NMR spectra of all new compounds. This
information is available free of charge via the Internet at http://
pubs.acs.org.
Synthesis of (S)-Ethyl 1-Benzyl-3-methyl-2-thioxopyroli-
dine-3-carboxylate (10a/10b). A 5.3 g (13 mmol) portion of
Lawesson’s reagent was added to a solution of 3.8 g (15 mmol) of 9a/
9b mixture in 20 mL of anhydrous toluene under a N2 atmosphere.
The reaction mixture was heated to 95 °C and stirred overnight. The
toluene layer was evaporated under reduced pressure and the residue
was chromatographed (20% EtOAc/hexanes) giving 3.3 g (12 mmol,
80%) of a 4:1 mixture (as determined by NMR) of 10a:10b as a
colorless oil. The conversion of lactam (9a) to the corresponding
thiolactam (10a) was confirmed by comparing the 13C NMR chemical
shift of the lactam (9a) carbonyl carbon (172 ppm) to the thiolactam
(10a) carbonyl carbon (202 ppm). The mixture of 10a/10b was
utilized in the next step without further purification. Rf = 0.35 (20%
EtOAc/hexanes). IR (cm−1): 2980, 1733, 1505, 1449. 1H NMR
(CDCl3, 400 MHz) (10a/10b mixture): 7.29 (m, 7.3H), 5.18 (m,
2H), 4.82 (m, 1.23H), 4.16 (q, 2H, J = 7 Hz), 3.70 (m, 1.24H), 3.51
(m, 1.25H), 2.51(m, 1.23H), 1.92 (m, 1.32H), 1.61 (s, 0.68H), 1.58 (s,
3H), 1.21 (t, 3H, J = 7 Hz). ESI-MS [C15H20NO2S, 10a]+: calcd 277.4,
found 278.1. ESI-MS [C20H22NO2S, 10b]+: calcd 340.1, found 340.2.
Synthesis of (R)-Ethyl 1-Benzyl-3-methylpyrrolidine-3-car-
boxylate (11a). A 0.5 g portion of 10a/10b was dissolved in 15 mL
of 4:1 THF/EtOH. A 0.05 g portion of Raney-Ni slurry in water (10%
by weight) was added to the solution. The solution was stirred
vigorously under a H2 atmosphere for 4 h, at which point the reaction
was found to be complete by TLC. The mixture was filtered through a
Celite bed, and the filtrate was evaporated under reduced pressure.
AUTHOR INFORMATION
Corresponding Author
*E-mail: douglas.masterson@usm.edu.
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Science Foundation for a CAREER
award (MCB-0844478). We thank the National Science
Foundation for instrument grants used to obtain the mass
spectrometry and NMR facilities used in conducting this
research (CHE-0639208, DBI-0619455, CHE-0840390). We
thank the American Chemical Society for Project SEED
funding (CF) and the ACS Division of Organic Chemistry
for a Graduate Research Symposium Travel Award (SB). We
also thank the Department of Chemistry and Biochemistry for
continued support of our research programs.
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