Steric and Electronic Influences on the Diastereoselectivity of the Rh2(OAc)4-Catalyzed C-H Insertion in Chiral Ester Diazoanilides: Synthesis of Chiral, Nonracemic 4-Substituted 2-Pyrrolidinones

Article abstract of DOI:10.1021/jo971540q

A series of N-substituted N-(4-methoxyphenyl)-α-(alkoxycarbonyl)-α-diazoacetanilides, 10 and ent-10, wherein the alkoxy unit is a chiral auxiliary group [(-)-7 or (+)-8)], was prepared. The Rh₂(OAc)₄-catalyzed intramolecular C-H insertion reaction of 10 and ent-10, under optimized reaction conditions, was investigated as a route for the preparation of chiral, nonracemic 4-substituted 2-pyrrolidinones. The cyclization reaction led only to 2-pyrrolidinone and 2-azetidinone products; the former products were obtained as major and, in a few cases, as exclusive products. The type and nature of the N-substituent in 10 or ent-10 was found to govern the diastereoselectivity of the reaction. With N-alkyl groups, steric effects play an important role in determining the diastereoselectivity of the reaction. However, with N-arylethyl substituents, electronic effects transmitted by the aryl substituents influenced the diastereoselectivity of the C-H insertion reaction. Specifically, electron-donating substituents were found to markedly attenuate the diastereoselectivity of the reaction. The diastereoselectivity of the reaction ranged from moderate to high (37-98%). A transition-state model to explain the observed diastereoselectivity is provided. The synthetic utility of the method is demonstrated by the stereoselective synthesis of the medicinally important, unnatural amino acid trans-4-cyclohexyl-L-proline 23.

Full text of DOI:10.1021/jo971540q

4218
J . Org. Chem. 1998, 63, 4218-4227
Ster ic a n d Electr on ic In flu en ces on th e Dia ster eoselectivity of th e
Rh 2(OAc)4-Ca ta lyzed C-H In ser tion in Ch ir a l Ester Dia zoa n ilid es:
Syn th esis of Ch ir a l, Non r a cem ic 4-Su bstitu ted 2-P yr r olid in on es
Andrew G. H. Wee,* Baosheng Liu, and Douglas D. McLeod
Department of Chemistry, University of Regina, Regina, Saskatchewan S4S 0A2, Canada
Received August 18, 1997
A series of N-substituted N-(4-methoxyphenyl)-R-(alkoxycarbonyl)-R-diazoacetanilides, 10 and ent-
10, wherein the alkoxy unit is a chiral auxiliary group [(-)-7 or (+)-8)], was prepared. The
Rh2(OAc)4-catalyzed intramolecular C-H insertion reaction of 10 and ent-10, under optimized
reaction conditions, was investigated as a route for the preparation of chiral, nonracemic
4-substituted 2-pyrrolidinones. The cyclization reaction led only to 2-pyrrolidinone and 2-azetidinone
products; the former products were obtained as major and, in a few cases, as exclusive products.
The type and nature of the N-substituent in 10 or ent-10 was found to govern the diastereoselectivity
of the reaction. With N-alkyl groups, steric effects play an important role in determining the
diastereoselectivity of the reaction. However, with N-arylethyl substituents, electronic effects
transmitted by the aryl substituents influenced the diastereoselectivity of the C-H insertion
reaction. Specifically, electron-donating substituents were found to markedly attenuate the
diastereoselectivity of the reaction. The diastereoselectivity of the reaction ranged from moderate
to high (37-98%). A transition-state model to explain the observed diastereoselectivity is provided.
The synthetic utility of the method is demonstrated by the stereoselective synthesis of the
medicinally important, unnatural amino acid trans-4-cyclohexyl-L-proline 23.
In tr od u ction
to catalyze the cyclization of achiral diazocarbonyl
compounds.2a-c,4 However, the stereoselectivities of these
reactions were found to vary with both the type of chiral
rhodium(II) catalyst and the structure of the diazocar-
bonyl compound. The most effective chiral catalysts
developed to date are the rhodium(II) carboxamide-based
Rhodium(II) carbenoids, generated from the reaction
of R-diazocarbonyl compounds with catalytic amounts of
dirhodium(II) complexes, undergo a wide range of syn-
thetically useful transformations.1 In particular, the
intramolecular Rh(II) carbenoid mediated C-H insertion
reaction is now a well-established method for the facile
construction of five-membered carbocycles and hetero-
cycles. Recently, there has been a growing interest in
the development of methods, based on asymmetric rhod-
ium(II) carbenoid C-H insertion, for the synthesis of
chiral, nonracemic cyclic molecules.2 In general, two
approaches have been investigated. The first approach
entails the incorporation of a readily removable, chiral
auxiliary group into the R-diazocarbonyl compound.3
Intramolecular rhodium(II) carbenoid-mediated C-H
insertion and subsequent excision of the auxiliary group
from the cyclic product results in an (net) enantioselective
route to cyclic molecules. The second approach uses
either chiral dirhodium(II) carboxylates or carboxamides
2a,b
catalysts, Rh2(5S/5R-MEPY)4 and Rh2(4S-MEOX)4
which not only provide good to excellent enantio- and/or
diastereocontrol but also effect excellent regiocontrol in
the C-H insertion reaction. These catalysts were found
to be especially useful for the cyclization of select R-dia-
zoacetates to give γ-lactone derivatives in high enantio-
meric excess (91-97%).2b However, in cases where lower
enantio- and diastereoselectivities were obtained, the use
of the newly designed catalysts, Rh2(MACIM)4 and
Rh2(MPPIM)4, resulted in excellent stereocontrol.4f The
results from these studies have been used in the synthe-
sis of natural products.4f,5
On the other hand, fewer studies have reported on the
intramolecular asymmetric C-H insertion in diazoam-
ides. Doyle and co-workers described the Rh2(5S/5R-
(1) Reviews: (a) Khlebnikov, A. F.; Novikov, M. S.; Kostikov, R. R.
Adv. Heterocycl. Chem. 1996, 65, 93. (b) Doyle, M. P. In Comprehensive
Organometallic Chemistry II; Hegedus, L. S., Ed.; Pergamon Press:
New York, 1995; Vol. 12, Chapter 5.2. (c) Padwa, A.; Austin, D. J .
Angew. Chem., Int. Ed. Engl. 1994, 33, 1797. (d) Ye, T.; McKervey, M.
A. Chem. Rev. 1994, 94, 1091. (e) Padwa, A.; Krumpe, K. E. Tetrahe-
dron 1992, 48, 5385. (f) Adams, J .; Spero, D. M. Tetrahedron 1991,
47, 1765. (g) Taber, D. F. Comprehensive Organic Synthesis; Trost, B.
M., Fleming, I., Eds.; Pergamon Press: New York, 1991; Vol. 3,
Chapter 4.2. (h) Doyle, M. P. Chem. Rev. 1986, 86, 919.
(2) Reviews: (a) Doyle, M. P.; McKervey, M. A. Chem. Commun.
1997, 983. (b) Doyle, M. P. Aldrichim. Acta 1996, 29, 3. (c) Hashimoto,
S.-i.; Watanabe, N.; Anada, M.; Ikegami, S. J . Synth. Org. Chem. J pn.
1996, 54, 114. (d) Brunner, H. Angew. Chem., Intl. Ed. Engl. 1992,
31, 1183.
(4) Selected examples of homochiral Rh(II) complexes used in
intramolecular C-H insertion: Rh (II) Ca r boxyla tes: (a) Watanabe,
N.; Ohtake, Y.; Hashimoto, S.-I.; Shiro, M.; Ikegami, S. Tetrahedron
Lett. 1995, 36, 1491 and references therein. (b) Sawamura, M.; Sasaki,
H.; Nakata, T.; Ito, Y. Bull. Chem. Soc. J pn. 1993, 66, 2725. (c)
McKervey, M. A.; Ye, T. Chem. Commun. 1992, 823 and references
cited. Rh (II) “Ca r boxa m id es”: (d) Doyle, M. P.; Winchester, W. R.;
Hoorn, J . A. A.; Lynch, V.; Simonsen, S. H.; Ghosch, R. J . Am. Chem.
Soc. 1993, 115, 9968. (e) Doyle, M. P.; Protopopova, M. N.; Winchester,
W. R.; Daniel, K. L. Tetrahedron Lett. 1992, 33, 7819. (f) Doyle, M. P.;
Protopopova, M. N.; Zhou, Q.-L.; Bode, J . W.; Simonsen, S. H.; Lynch,
V. J . Org. Chem. 1995, 60, 6654 and references cited. R h (II)
P h osp h a te: (g) McCarthy, N.; McKervey, M. A.; Ye, T.; McCann, M.;
Murphy, E.; Doyle, M. P. Tetrahedron Lett. 1992, 33, 5983.
(5) For example: (a) Pyrrolizidine alkaloid: Doyle, M. P.; Kalinin,
A. V. Tetrahedron Lett. 1996, 37, 1371. (b) Lignan lactones: Bode, J .
W.; Doyle, M. P.; Protopova, M. N.; Zhou, Q.-L. J . Org. Chem. 1996,
61, 9146.
(3) (a) Taber, D. F.; Raman, K.; Gaul, M. D. J . Org. Chem. 1987,
52, 28 and references cited. (b) Eliel, E. L.; Wilen, S. H.; Mander, L.
N. Stereochemistry of Organic Compounds; Wiley-Interscience: New
York, 1994; Chapter 12, p 862.
S0022-3263(97)01540-5 CCC: $15.00 © 1998 American Chemical Society
Published on Web 06/05/1998

Synthesis of 4-Substituted 2-Pyrrolidinones
J . Org. Chem., Vol. 63, No. 13, 1998 4219
Sch em e 1
Sch em e 2
MEPY)4 and Rh2(4S-MEOX)4-catalyzed reactions of
N-alkyl-N-tert-butyldiazoamides4d,e to give 4-substituted
2-pyrrolidinones with ee’s in the range 58-78%. 2-Aze-
tidinones (ee 20-80%) were also obtained as minor
products. In connection with our interest in the intramo-
lecular C-H insertion of acyclic N-substituted N-PMP
diazoanilides (PMP ) p-methoxyphenyl),6 we became
interested in developing a route for the synthesis of
chiral, nonracemic 4-substituted 2-pyrrolidinones.7a We
reasoned that diastereoselective rhodium(II) carbenoid-
mediated C-H insertion would be achieved if a chiral
auxiliary group was incorporated into the ester moiety
of our diazoanilides. Herein, we describe the details of
our investigation into the Rh2(OAc)4-catalyzed asym-
metric C-H insertion reaction of chiral ester diazoanil-
ides of type 10 and ent-10, where R* represents the (+)-
camphor- or (-)-borneol-derived auxiliary (-)-7 or (+)-
8. This type of approach for the preparation of optically
active 4-substituted 2-pyrrolidinones has not been re-
ported before. We found that the chiral auxiliary group
was readily removed from the 2-pyrrolidinone products
by decarbalkoxylation and was recovered unchanged and
in good yields. Overall, the reaction proceeded with good
regioselectivity and excellent chemoselectivity. The di-
astereoselectivity of the reaction was found to vary with
the type and nature of the N-substituent in 10 and ent-
10.
phorane gave the enol-ether, which was hydrolyzed (i-
PrOH-HCl) to generate the corresponding aldehyde.
Without isolation, the aldehyde was directly reacted with
p-anisidine in the presence of NaCNBH3 to afford the
product 5g.
The unstable anilines 5 were immediately condensed
with malonic acid, under optimal reaction conditions
(DCC, cat. DMAP, MeCN-CH2Cl2, -40 °C),9a to give good
yields (60-70%) of the amide acids 69b (Scheme 2).
Compounds 6 were then coupled (DCC, DMAP)11a,b to the
appropriate chiral auxiliary, (-)-73a,c or (+)-8,12 to afford
the ester amides 9 or ent-9 in good yields (75-95%).
The conversion of the ester amides 9 to the diazo
derivatives 10 was not trivial. The usual diazotization
8
Resu lts a n d Discu ssion
(8) (a) Borch, R. F.; Bernstein, M. D.; Durst, H. D. J . Am. Chem.
Soc. 1971, 93, 2897. (b) Danheiser, R. L.; Morin, J . M., J r.; Salaski, E.
J . J . Am. Chem. Soc. 1985, 107, 8066.
(9) (a) Ihara, M.; Takahashi, M.; Taniguchi, N.; Yasui, K.; Fukumoto,
K. J . Chem. Soc., Perkin Trans. 1 1989, 897. (b) Other routes were
also examined: Condensation of p-anisidine either with R-methyl(4-
methoxybenzyloxycarbonyl)acetic acid or R-(tert-butyloxycarbonyl)ace-
tic acid followed by deprotection of the R-methyl(4-methoxybenzyl)10
or tert-butyl (TFA-CH2Cl2, 1:10 v/v) groups.
(10) Yoo, S.-E.; Kim, H. R.; Yi, K. Y. Tetrahedron Lett. 1990, 31,
5913.
(11) (a) Neises, B.; Steglich, W. Angew. Chem., Int. Ed. Engl. 1978,
17, 522. (b) Clemens, R. J . Chem. Rev. 1986, 86, 241. (c) The carboxylic
acids were either prepared using standard chemical transformations
(e.g., hydrolysis of nitriles; oxidation of primary alcohols) or were
commercially available.
I. (a ) P r ep a r a tion of Ch ir a l Ester Dia zoa n ilid es
10 a n d en t-10. The diazoanilides 10 and ent-10 used in
this study were prepared according to the routes shown
in Schemes 1 and 2. The p-anisidine derivatives 5 were
prepared, as summarized in Scheme 1, using either
previously developed routes (a and b, 5a ,c,i)6 or via the
anilides 4 (route c, 5b,d ,e,f,h ) using standard chemical
transformations. N-[(3-Nitrophenyl)ethyl]-p-anisidine 5g
was prepared starting from m-nitrobenzaldehyde. Treat-
ment of the latter with (methoxymethylene)triphenylphos-
(12) (a) Coxon, J . M.; Hartshorn, M. P.; Lewis, A. Aust. J . Chem.
1971, 24, 1017. (b) (-)-Camphor was prepared by oxidation of (-)-
borneol according to Stevens’ procedure (Stevens, R. V.; Chapman, K.
T.; Weller, H. N. J . Org. Chem. 1980, 45, 2030.) It was converted to
(+)-8 following the same sequence of steps3a used for the synthesis of
(-)-7.
(6) Wee, A. G. H.; Liu, B.-S.; Zhang, L. J . Org. Chem. 1992, 57, 4404.
(7) (a) Preliminary communication: Wee, A. G. H.; Liu, B.-S.
Tetrahedron Lett. 1996, 37, 145. (b) For a related enantioselective
synthesis of 4-substituted 2-pyrrolidinones, see: Anada, M.; Hash-
imoto, S.-i. Tetrahedron Lett. 1998, 39, 79.

4220 J . Org. Chem., Vol. 63, No. 13, 1998
Wee et al.
Sch em e 3
Sch em e 4
18
cleavage using NaIO4 in aqueous dioxane to give the
cyclic amide alcohol 14a as a mixture of diastereomers.
Various attempts at deoxygenating the C-5 position in
14a were futile. For example, reduction of 14a or its
13
method (MsN3 and DBU as the base),6,14 which had
served us well in other cases, was found to be inefficient;
only low yields (25%) of diazo compounds 10 were
obtained. We reasoned that the R-methylene hydrogens
in the â-dicarbonyl unit may be sterically shielded by the
auxiliary group, and consequently, approach of the bulky
DBU base to the R-hydrogen may be hindered. After
many experiments, we found that 9 or ent-9 was ef-
ficiently diazotized by the use of KH in either dry ether
or DME. Consistently good yields (75-90%) of diazo
products 10 or ent-10 were obtained with the exception
of 10g. In the latter case, no diazo product was obtained
from 9g under the improved conditions, and only starting
material was recovered (90%). The use of catalytic
amounts (10 mol %) of 18-crown-6 as a phase-transfer
catalyst did not yield positive results. Eventually, we
found that the use of NaH as the base-promoted diazo-
tization and 10g was obtained in 40% yield. No further
attempts were made to optimize the yield of 10g.
The inefficiency in the diazotization of 9g may be
attributed to the formation of an insoluble, stable potas-
sium chelate such as 11 that does not further react with
MsN3 to give 10g. On the other hand, the formation of
the sodium chelate is less likely because of its lower
stability due to the smaller size of the sodium ion. As a
result, diazotization is observed.
trifluoroacetate derivative with Et3SiH mediated by
19a
BF3‚OEt2
or CF3CO2H19b only gave low yields of the
desired (S)-14c. The major product formed was 15, which
resulted from an E1-type elimination from the acylimin-
ium ion intermediate.20 It was decided that deoxygen-
ation under neutral conditions may be more conducive
for the formation of (S)-14c. Toward this end, the
phenylthio derivative 14b was prepared by treatment of
14a with thiophenol in the presence of Mg(OTf)2,21 a mild
Lewis acid. Reduction of 14b with tributyltin hydride
under free-radical reaction conditions22 gave (S)-(-)-14c
([R]23 -1.66 (c 4.5, CHCl3) in 95% yield. The ee of (S)-
D
(-)-14c (tR ) 14.0 min) was >98% on the basis of HPLC
analysis.
II. (a ) Op tim iza tion Stu d ies: Rh 2(OAc)4-Ca ta -
lyzed C-H In ser tion Rea ction of en t-10a a n d 10c.
Our initial efforts (Scheme 4) were aimed at establishing
optimal reaction conditions for the C-H insertion reac-
tion. We were interested in determining the regioselec-
tivity23 of the reaction (2-pyrrolidinone 16c/18a : 2-aze-
tidinone 17c/19a ) and, in particular, the diastereo-
selectivity of the C-H insertion in the formation of the
2-pyrrolidinone 16c or 18a . Compounds ent-10a and 10c
also permitted us to assess the influence of the N-
substituent on the outcome of the reaction and especially
whether metallocarbenoid addition24 to the aryl moiety
would be competitive with C-H insertion in the reaction
of 10c.
(b) P r ep a r a tion of (S)-(-)-N-(4-Meth oxyp h en yl)-
4-m eth yl-2-p yr r olid in on e (14c). We next diverted our
attention to the preparation of the reference compound
(S)-(-)-14c15a that was used in the HPLC analysis of 20i
and 21i (vide infra; note that 14c and 21i are the same).
It should be noted that (S)-(-)-4-methyl-2-pyrrolidinone
has been reported15b previously but the N-PMP derivative
is unknown.
(18) Review: Shing, T. K. M. In Comprehensive Organic Synthesis;
Trost, B. M., Fleming, I., Eds.; Pergamon Press: New York, 1991; Vol.
7, p 703.
(19) (a) Kraus, G. A.; Frazier, K. A.; Roth, B. D.; Taschner, M. J .;
Neuenschwander, K. J . Org. Chem. 1981, 46, 2417. (b) Kursanov, D.;
Parnes, Z. N.; Loim, N. M. Synthesis 1974, 633.
(20) (a) Hiemstra, H.; Speckamp, W. N. In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: New York,
1991, Vol. 2, p 1047. (b) Zaugg, H. E. Synthesis 1984, 85, 181.
(21) Corey, E. J .; Shimoji, K. Tetrahedron Lett. 1983, 24, 169.
(22) Neumann, W. P. Synthesis 1987, 655.
The known16 γ-lactone 12 [[R]23 +29.2 (c 3.9, CHCl3)
D
(lit.16 [R]23 +30.5 (c 1.2, CHCl3)] was subjected to ring
D
opening17 with Et2AlCl-p-anisidine complex to give the
secondary alcohol 13a (Scheme 3). Desilylation of 13a
produced the diol 13b, which was subjected to glycol
(13) Taber, D. F.; Ruckle, R. E., J r.; Hennessy, M. J . J . Org. Chem.
1986, 51, 4077.
(14) Regitz, M. Synthesis 1972, 381.
(15) (a) See the Supporting Information. (b) Langlois, N.; Dahuson,
N. Tetrahedron Lett. 1996, 37, 3993. (b) Meyers, A. I.; Synder, L. J .
Org. Chem. 1993, 58, 36.
(16) Hanessian, S.; Murray, P. J . Tetrahedron 1987, 43, 5055.
(17) Barrett, A. G. M.; Bezoidenhoudt, B. C. B.; Dhanak, K.;
Gasiecki, A. F.; Howell, A. R.; Lee, A. C.; Russell, M. A. J . Org. Chem.
1989, 54, 3321.
(23) Although we found6 that 2-pyrrolidinone products are usually
favored, we felt that it was necessary to reevaluate the regioselectivity
in these systems because it is well-known that structural changes in
the diazo substrate can have a significant influence on the regioselec-
tivity of the reaction. For example, see Doyle, M. P.; Pieters, R. J .;
Taunton, J .; Pho, H. Q.; Padwa, A.; Hertzog, D. L.; Precedo, L. J . Org.
Chem. 1991, 56, 820 and references therein.
(24) Padwa, A.; Austin, D. J .; Price, A. T.; Semones, M. A.; Doyle,
M. P.; Protopova, M. N.; Winchester, W. R.; Tran, A. J . Am. Chem.
Soc. 1993, 115, 8672.

Synthesis of 4-Substituted 2-Pyrrolidinones
J . Org. Chem., Vol. 63, No. 13, 1998 4221
Ta ble 1. Rh 2(OAc)4-Ca ta lyzed C-H In ser tion in Com p ou n d s en t-10a a n d 10c
20/21
entry
compound
solvent, T (°C)
yielda (%)
16:17 or 18:19b
yieldc (%)
% eed
1
2
3
4
5
6
7
8
ent-10a
ent-10a
ent-10a
ent-10a
10c
10c
10c
10c
(CH2Cl)2, rt
(CH2Cl)2, 83
CH2Cl2, rt
CH2Cl2, 40
(CH2Cl)2, rt
(CH2Cl)2, 83
CH2Cl2, rt
83
75
70
64
90
88
86
96
7.3:1
2.3:1
4.3:1
2.6:1
29:1
17:1
28:1
23:1
80
88
92
80
94
82
87
84
40
42
47
55
67
57
64
79
CH2Cl2, 40
a
b
Combined yield of 16/17 or 18/19. Ratio is based on the isolated yields of 2-pyrrolidinone and 2-azetidinone. c Isolated yields of 20
d
or 21. Determined by HPLC analysis of 20 or 21 on a Chiralcel OB column.
25a
The reactions were catalyzed by 5 mol % of Rh2(OAc)4
in either dry CH2Cl2 or (CH2Cl)225b for 16-20 h. In these
studies, only the 2-pyrrolidinone and 2-azetidinone de-
rivatives were formed, and we did not detect the forma-
tion of δ-lactam and cycloaddition products in the reac-
tion of ent-10a and 10c, respectively. The less polar
2-azetidinone and more polar 2-pyrrolidinone products
were separated using flash chromatography and were
each obtained as a mixture of diastereomers. In the case
of the 2-pyrrolidinone products, their formation should
in principle result in four possible diastereomers; how-
ever, TLC analysis of the 2-pyrrolidinone 18a revealed
the presence of at least two very closely moving diaster-
eomers. No further attempts were made, at this stage,
to separate the two (or more) diastereomers because 18a
would be decarboxylated at a later stage. Due to the
complex nature of the 1H NMR spectra of each of the
diastereomeric mixtures, it was not possible to determine
the ratio of the diastereomers in the 2-azetidinone and
2-pyrrolidinone products.
by the type of solvent nor the reaction temperature
(compare Table 1, entries 5, 7 and 6, 8). In all conditions
examined, excellent regioselectivity was obtained.
The diastereoselectivity of the reaction in ent-10a and
10c showed a dependence on the type of solvent used and
the reaction temperature. In ent-10a , there was a
tradeoff between regioselectivity and diastereoselectivity
in the reaction. In general, a lower diastereoselectivity
was realized in (CH2Cl)2 than in CH2Cl2 regardless of
whether the reaction was conducted at room temperature
or at reflux temperature (compare Table 1, entries 1, 2
and 3, 4). The best diastereoselectivity was achieved
when the reaction was conducted in CH2Cl2 at 40 °C
(Table 1, entry 4). For compound 10c, it was found that
the diastereoselectivity of the reaction at room temper-
ature was similar in (CH2Cl)2 and CH2Cl2 (compare Table
1, entries 5 and 7); however, at reflux temperature, there
was a significant decrease in diastereoselectivity when
(CH2Cl)2 was used as the solvent. In contrast, high
diastereoselectivity was obtained in refluxing CH2Cl2
(compare Table 1, entries 6 and 8).
The decarboxylation27a of 16c and 18a proceeded
efficiently to give 2-pyrrolidinones 20c and 21a . As well,
the chiral alcohol (-)-7 or (+)-8 were recovered in good
yields (85-95%). Unfortunately, the decarboxylation of
the 2-azetidinones under the same conditions led only
to the decomposition of starting material, and conse-
quently, we did not further pursue this area. Compounds
20c and 21a were subjected to HPLC analysis using a
Chiralcel OB column, and the results are shown in Table
1.
It is evident that the regioselectivity in the reaction of
compound ent-10a is more sensitive to the type of
solvent28 used and the reaction temperature than 10c.
At rt, the regioselectivity of the reaction in (CH2Cl)2 is
much higher than in CH2Cl2; however, at reflux, the
regioselectivity was markedly lower, and similar in both
solvents (compare Table 1, entries 1, 3 and 2, 4). In 10c,
the regioselectivity of the reaction was neither affected
From the above studies, it was concluded that the
conditions that are conducive for optimal regio- and
diastereoselections in the reaction of compounds of type
10 are the use of CH2Cl2 as solvent and a reaction
temperature of 40 °C.
(b ) R h 2(OAc)4-Ca t a lyzed Cycliza t ion of Com -
p ou n d s 10a ,b ,d -i a n d en t-10c,d ,h ,i. The Rh(II)-
catalyzed reaction of compounds with different N-sub-
stituents (Scheme 4) was studied to determine the
influence of steric and electronic effects on the diaste-
reoselectivity of the reaction. The diazo compounds were
cyclized under the optimized reaction conditions, and the
results are summarized in Table 2. In general, the
2-pyrrolidinones, 16 or 18, were produced as major and,
in a few cases, as exclusive products. An exception,
however, was noted in the case of 10e (compare Table 2,
entry 8 to entries 6, 7, 9, and 11). Its cyclization gave
an equal amount of 2-pyrrolidinone 16e and 2-azetidi-
none 17e products. The absence of regioselection in this
case is attributed to the o-methoxy methoxy group,29
which sterically hinders approach of the metallocarbenoid
to the benzylic C-H bond. Consequently, this makes the
enthalpically less favorable 2-azetidinone pathway more
competitive. As expected, we did not detect any cycload-
dition products from the reaction of the N-arylethyl
systems.
(25) (a) Oxindole derivatives that resulted from aromatic substitu-
tion were also formed in the Rh2(acam)4-catalyzed reactions of ent-
10a and 10c. This outcome is in accord with literature results.26a The
oxindole products were decarboxylated, and the diagnostic features in
their 1H NMR spectra are the aromatic (3H) proton signals in the
region δ 6.70-6.90 and the singlet due to the C-3 methylene hydrogens
at δ 3.48-3.50.26b (b) When dry benzene was used, TLC analysis of
the reaction mixture showed that the reaction was not as “clean”.
(26) (a) Brown, D. S.; Elliot, M. C.; Moody, C. J .; Mowlem, T. J .;
Marino, J . P., J r.; Padwa, A. J . Org. Chem. 1994, 59, 2447. (b) Wee, A.
G. H.; Liu, B.-S. Tetrahedron 1994, 50, 609.
(27) (a) Krapcho, A. P. Synthesis 1982, 805 and 893. For other
decarboxylation methods, see: Meyers, A. I.; Snyder, L. J . Org. Chem.
1992, 57, 3814 and references therein.
(28) For a discussion on the dramatic influence of solvent polarity
on the chemoselectivity of the Rh(II)-carbenoid mediated reaction,
see: Davies, H. M. L.; Matasi, J . J .; Ahmed, G. J . Org. Chem. 1996,
61, 2305 and references therein.
The 2-pyrrolidinones 16 and 18 were decarboxylated
and then subjected to HPLC analysis as before. From
the results in Table 2, it is apparent that the diazoanil-
(29) Charton, M. Prog. Phys. Org. Chem. 1971, 8, 235.

4222 J . Org. Chem., Vol. 63, No. 13, 1998
Wee et al.
config
Ta ble 2. Rh 2(OAc)4-Ca ta lyzed Rea ction of 10 a n d en t-10: Regioselectivity a n d Dia ster eoselectivity
2-pyrrolidinone/2-azetidinone
20 or 21
eee (%)
entry
compound
yieldb (%)
16:17cor 18:19c
yieldd (%)
[R]D
1
2
3
4
5
6
7
8
9
10
11
12
13
10a
75
64
84
96
90
85
78
74
90
82
76
81
75
3.4:1
2.6:1
5:1
23:1
44:1
100:0
100:0
1:1
80
92
84
98
87
84
96
84
76
70
80
75
78
45
47
98
79
80
50
52
37
67
77
75
30
32
+1.69
-2.10
+4.45
-10.5
+9.98
-15.2
+15.9
+4.13
-6.20
-5.88
+4.83
-0.51
+0.58
(R)-20
(S)-21
(S)-20
(S)-20
(R)-21
(S)-20
(R)-21
(S)-20
(S)-20
(S)-20
(R)-21
(S)-21
(R)-20
ent-10a a
10b
10ca
ent-10c
10d
ent-10d
10e
10f
10g
ent-10h
10i
100:0
ndf
100:0
4:1
4:1
ent-10i
a
b
Results from Table 1, entries 4 and 8, respectively, were included for comparison. Isolated, combined yield of 2-pyrrolidinones and
2-azetidinones: 16/17 or 18/19. c Ratio was based on the isolated yields of 16:17 or 18:19. Isolated yields of 20 or 21. e Determined
using a Chiralcel OB column. f Not determined. Obtained as an inseparable mixture of 16g and 17g. The presence of 17g was evidenced
by the 2-azetidinone νmax(CdO) at 1761 cm-1. Ratio could not be determined by 1H NMR because of extensive signal overlap.
d
ides 10a and ent-10a , with the linear N-hexyl group,
reacted with modest diastereoselectivity (Table 2, entries
1 and 2), whereas 10b, possessing a sterically more
demanding N-(cyclohexyl)ethyl group, reacted with very
high diastereoselectivity (Table 2, entry 3). More inter-
estingly, the diastereoselectivity in the reaction of the
N-(arylethyl)diazoanilides was found to be dependent on
the nature of the substituent(s) in the phenyl moiety. In
the unsubstituted 10c and ent-10c, the products 20c and
21c were obtained in 80% ee (Table 2, entries 4 and 5).
The presence of electron-donating methoxy substituents
in the phenyl ring attenuated the diastereoselectivity of
the reaction (Table 2, entries 6-9). Specifically, lower
ee’s of 20 and 21 were obtained when a methoxy group
was located ortho and/or para to the benzylic position
(Table 2, entries 6-8). Moving the methoxy group to the
meta position resulted in a significant increase in the
diastereoselectivity (Table 2, entry 9). In contrast, the
presence of an electron-withdrawing NO2 group that is
located either meta or para to the benzylic position was
found to have little influence on the diastereoselectivity
of the reaction. Thus, 10g and ent-10h afforded 2-pyr-
rolidinones 20g and 21h , which had ee’s in the range of
75-77%. This outcome is comparable to the result
obtained for 10c and ent-10c (Table 2, entries 10, 11 vs
4, 5).
Sch em e 5
dinone [[R]23D +27 (c 0.74, MeOH) (lit.31 [R]D +37.5)] and
(R)-4-phenyl-2-pyrrolidinone [[R]23D -28.3 (c 0.5, MeOH)
(lit.31 [R]D -37.8)], respectively. With the exception of
20i and 21i, the absolute configuration of C-4 in 21a was
inferred from that of 20a and in 20d -g and 21d ,h from
that of 20c and 21c, respectively. From these results,
we conclude that the chiral ester diazoanilides of type
10 undergo cyclization to give 2-pyrrolidinones of type
20, whereas diazoanilides ent-10 cyclize to give 21.
In the case of the cyclization of 10i and ent-10i, HPLC
analysis (see Experimental Section) showed that for the
decarboxylated 2-pyrrolidinone product derived from 10i,
the ratio of 20i to 21i is 1:1.8, whereas for the decar-
boxylated 2-pyrrolidinone product derived from ent-10i
the ratio of 20i to 21i is 2:1. The results indicate that
the sense of induction at C-4 for the cylization of 10i and
ent-10i is S and R, respectively.
In the case of 10i and ent-10i, the cyclization proceeded
with low diastereoselectivity to afford the 2-pyrrolidino-
nes 20i and 21i, respectively (Table 2, entries 12 and 13).
The low diastereoselectivity may be due to the small
steric size of the N-propyl group. Unexpectedly and
unlike the results obtained from the reaction of 10a ,c
and ent-10a , it was found that the sense of induction at
the new C-4 stereocenter in 20i and 21i was reversed.
(c) Assign m en t of Absolu te Con figu r a tion a t C-4.
The absolute configuration of C-4 in compounds 20a -c
and 21c was assigned by comparison of the specific
optical rotation of their derivatives with those reported
for known compounds. Thus, 20a was converted, as
III. Rea ction P a th w a y. The four chairlike,1g rapidly
interconvertible32 transition-state conformers 24-27
(Chart 1) can be considered to be involved in the cycliza-
tion of 10. (For the sake of clarity, we have shown only
the transition states for the reaction of the diazoanilide
10. The enantiomeric transition states would apply for
summarized in Scheme 5, to 22a ([R]23 +11.1; c 1.6,
D
CH2Cl2). Compound 22a was dextrorotatory, whereas
the known15b (S)-enantiomer ([R]23 -30.5) was levoro-
D
(30) (a) Thottathil, J . K.; Moniot, J . L.; Mueller, R. H.; Wong, M. K.
Y.; Kissick, T. P. J . Org. Chem. 1986, 51, 3140. (b) Squibb-23 was
decarboxylated according to the procedure described by: Hashimoto,
M.; Eda, Y.; Osanai, Y.; Iwai, T.; Aoki, S. Chem Lett. 1986, 893. The
pyrrolidine product was then benzoylated to give 22b.
(31) Zelle, R. E. Synthesis 1991, 1023.
tatory. Further, the specific optical rotation of compound
22b that was prepared from 20b (Scheme 5), and Squibb-
2330a,b showed excellent agreement in both the sign and
magnitude. As well, compounds 20c and 21c were
N-deprotected to give the known (S)-4-phenyl-2-pyrroli-
(32) Seeman, J . I. Chem. Rev. 1986, 86, 42.

Synthesis of 4-Substituted 2-Pyrrolidinones
J . Org. Chem., Vol. 63, No. 13, 1998 4223
Ch a r t 1
tivity observed for the reaction of 10e may further be
attributed to the “ortho” effect29 of the methoxy group.
The above model, however, cannot reconcile the results
obtained for the cyclization of 10i (and ent-10i) in which
the sense of induction is reversed. We do not have an
explanation for this unusual phenomenon at this time.
IV. Syn th esis of (2S,4S)-4-Cycloh exyl-2-p yr r olid i-
n ecar boxylic Acid (tr a n s-4-cycloh exyl-L-pr olin e) (23).
The pyrrolidine moiety is widespread in nature and is
found in many alkaloids34a-e as well as in natural34f and
unnatural amino acids.34g-k Because of the biological
activity usually associated with these molecules,35 there
is strong interest in developing new methods for the
synthesis of this important ring system. The above-
described method permits the ready preparation of chiral,
nonracemic 4-substituted 2-pyrrolidinones from simple
starting materials. Since 2-pyrrolidinones are versatile
intermediates for the synthesis of pyrrolidine-type com-
pounds, we explored the possibility of using compound
20b for the synthesis of trans-4-cyclohexyl-L-pyrrolidine
23,30a an unnatural amino acid that is used in the
synthesis of the antihypertensive agent Fosinopril
Sodium.30a,34g
ent-10a ,c,d ,h .) The transition states 26 and 27, however,
are destabilized by the presence of severe nonbonded
interactions: in 26, there is an R/naphthyl interaction,
and in 27, there are the syn R/CO2R* as well as
H/naphthyl interactions. Therefore, the cyclization of 10
should proceed preferentially via the lowest and second
lowest energy transition states 24 and 25. However, it
should be noted that the involvement of 26 and 27 cannot
be ruled out.
We envisaged the C-H insertion in 24 and 25 is
initiated by the interaction of the vacant p-orbital of the
rhodium(II) carbenoid carbon with the target C-H
bond.33 The degree of interaction depends on the “electron-
richness” of the C-H bond. That is, for a less electron-
rich C-H bond the interaction occurs farther along the
reaction coordinate, which would result in a more com-
pact transition state (TS). On the other hand, for a more
electron-rich C-H bond the interaction occurs earlier
along the reaction coordinate, which would result in a
less compact (open) TS.
For compounds 10a ,b,c,g, compact transition states
are involved, which means that any destabilizing steric
interactions present in the transition states 24 and 25
will be fully manifested. The TS 25a ,b,c,g would be
destabilized because of the presence of a steric interaction
between the CO2R* group and a pseudoaxial substituent
R. This would lead to the preferential formation of
compounds 20a ,b,c,g via 24. The highest diastereose-
lectivity was realized for the N-(cyclohexyl)ethyl system
10b, and we attribute this to a strong preference of the
bulky cyclohexyl moiety for the pseudoequatorial position
that is possible only in TS 24b (R ) C6H11). On the other
hand, the reaction of compounds 10d -f is envisaged to
involve less compact transition states 24d -f and 25d -f
due to the activating influence of the methoxy groups33b
on the benzylic C-H bond. Consequently, any destabi-
lizing steric interactions that are present will be small
and the energy difference between 24 and 25 will
decrease. Carbon-hydrogen insertion via both transition
states will become competitive, resulting in an attenua-
tion of diastereoselectivity. The poorer diastereoselec-
The adopted approach was to prepare the cyclic hemi-
aminal 29a from compound 20b. Cyanation at C-2 in
29a using acyliminium chemistry20 followed by hydrolysis
of the cyano group should complete the installation of
the carboxylic acid function. However, the diastereose-
lectivity of the cyanation reaction is also of interest to
us because literature precedence36 indicates that the
diastereoselectivity of the reaction of ∆1-pyrrolidinium
ions with nucleophiles depends not only on the structure
of each of the reactants but, more importantly, on the
type of N-substituent. For example, with an N-acyl
substituent, there is a preference for the incoming
nucleophile to add cis to a preexisting substituent,36a,b
whereas with a N-benzyl group, there is a preference for
nucleophilic addition to occur trans to a preexisting
substituent.36c
To address the synthesis of 23 (Scheme 6) and the
diastereoselectivity question, compound 20b was N-
deprotected to give (S)-4-cyclohexyl-2-pyrrolidinone, which
(34) (a) Numata, A.; Ibuka, T. In The Alkaloids; Brossi, A., Ed.;
Academic Press: New York, 1987; Vol. 31, p 194. (b) Massiot, G.;
Delaude, C. In The Alkaloids; Brossi, A., Ed.; Academic Press: New
York, 1986, Vol. 27, p 270. (c) Martin, S. F. In The Alkaloids; Brossi,
A., Ed.; Academic Press: New York, 1987; Vol. 30, p 252. (d) Yang,
M.-H.; Chen, Y.-Y.; Huang, L. Phytochemistry 1988, 27, 445. (e)
Hashimoto, K.; Shirahama, H. Tetrahedron Lett. 1991, 32, 2625. (f)
Shinozaki, H. In Kainic Acids As A Tool In Neurobiology; McGeer, E.
G., Olney, J . W., McGeer, P. L., Eds.; Raven Press: New York, 1978;
pp 17-35. (g) Sasaki, N. A.; Dockner, M.; Chiaroni, A.; Riche, C.; Potier,
P. J . Org. Chem. 1997, 62, 765 and references cited. (h) Anderson, N.
G.; Lust, D. A.; Colapret, K. A.; Simpson, J . H.; Malley, M. F.;
Gougoutas, J . Z. J . Org. Chem. 1996, 61, 7955. (i) Thaisrivongs, S.;
Pals, D. T.; Furner, S. R.; Knoll, L. T. J . Med. Chem. 1988, 31, 1369.
(j) Karanewski, D. S.; Badia, M. C.; Cushman, D. W.; Deforrest, J . M.;
Dejeneka, T.; Lee, V. G.; Loots, M. J .; Petrillo, E. W. J . Med. Chem.
1990, 33, 1459. (k) Kennewell, P. D.; Mathani, S. S.; Taylor, J . B.;
Sammes, P. G. J . Chem. Soc., Perkin Trans. 1 1980, 2542.
(35) For example: Neuroexcitatory activity: (a) Reference 34f.
Glycosidase inhibitors: (b) Fleet, G. W. J .; Witty, D. R. Tetrahedron:
Asymmetry 1990, 1, 119. (c) Horenstein, B. A.; Zabinski, R. F.;
Schramm, V. L. Tetrahedron Lett. 1993, 34, 7213. Fungiside: (d)
Eckert, J . W.; Rahm, M. L.; Koldezen, M. J . J . Agric. Food Chem. 1972,
20, 104.
(36) (a) Shono, T.; Matsumura, Y.; Tsubata, K.; Uchida, K. J . Org.
Chem. 1986, 51, 2590. (b) Renaud, P.; Seebach, D. Helv. Chim. Acta
1986, 69, 1704. (c) Shiosaki, K.; Rapoport, H. J . Org. Chem. 1985, 50,
1229.
(33) (a) Doyle, M. P.; Westrum, L. J .; Wendelmoed, N. E. W.; See,
M. M.; Boone, W. P.; Bagheri, V.; Pearson, M. M. J . Am. Chem. Soc.
1993, 115, 958. (b) Taber, D. F.; Song, Y. J . Org. Chem. 1996, 61, 6706.

4224 J . Org. Chem., Vol. 63, No. 13, 1998
Wee et al.
Sch em e 6
diastereoselectivity. Geometry optimization of the pyr-
rolidinium ion intermediate 31,15a which is involved in
the conversion 29a f 29b, at the AM1 level39 showed
that one of the cyclohexyl R-methylene units is directed
toward the center of the pyrrolidinium moiety. The
â-face (i.e., cis to cyclohexyl group) of the iminium moiety
is, therefore, more hindered because of steric shielding
by the hydrogens of the R-methylene unit. Consequently,
preferential attack by the cyanide anion from the less
hindered R-face is observed to afford trans-29b as the
major product.
Con clu sion s
With one exception (10e), the Rh2(OAc)4-catalyzed
C-H insertion reaction of diazoanilides 10 and ent-10
proceeds efficiently to give predominantly 4-substituted
3-(alkoxycarbonyl)-2-pyrrolidinones. The reaction was
highly regioselective and showed excellent chemoselec-
tivity. The diastereoselectivity of the reaction is depend-
ent on the type and nature of the N-substituent. With
N-alkyl groups, steric effects govern the diastereoselec-
tivity of the reaction. However, with N-arylethyl sub-
stituents, electronic effects transmitted by the aryl
substituents influenced the diastereoselectivity of the
C-H insertion reaction. Specifically, electron-donating
substituents were found to attenuate the diastereoselec-
tivity of the reaction. The 4-substituted 3-(alkoxycarbo-
nyl)-2-pyrrolidinones were readily decarboxylated to give
good yields of chiral, nonracemic 4-substituted 2-pyrro-
lidinones, and the chiral alcohols, (-)-7 and (+)-8, were
recovered in high yields. Although the sense of asym-
metric induction in the newly created C-4 stereocenter
in compounds 20 and 21a -h is predictable on the basis
of the type of chiral ester auxiliary [(-)-7 or (+)-8] that
was used, we found that this trend was reversed in the
case of the cyclization of compounds 10i and ent-10i. This
outcome may represent a limiting case for this method
for the synthesis of chiral nonracemic 4-substituted
2-pyrrolidinones. Studies on the use of homochiral Rh(II)
carboxylates for catalyzing the C-H insertion of com-
pounds 10 is in progress, and the results will be reported
at a later date. The synthetic utility of the method is
demonstrated by the stereoselective synthesis of the
medicinally important, unnatural amino acid (2S,4S)-4-
cyclohexyl-2-pyrrolidinecarboxylic acid 23. The readily
accessible 20b was converted in five steps (51% overall
yield) to give synthetic-23 and its (2R,4S)-epimer in a
ratio of 4.4:1.
was N-acylated with Boc2O under Grieco conditions37 to
afford 28. Selective reduction of the lactam carbonyl with
LiEt3BH38 at -78 °C gave the alcohol 29a as an insepa-
rable mixture of diastereomers. This alcohol was directly
treated with Me3SiCN in the presence of BF3‚OEt2 to give
the cyano derivative 29b again as an inseparable mixture
of diastereomers. The use of TiCl4 as the Lewis acid in
this reaction only resulted in the decomposition of alcohol
29a . Unfortunately, we were not able to ascertain the
diastereoselectivity of the reduction and cyanation reac-
1
tions by H NMR analysis of products 29a ,b because of
extensive signal overlap and complication from the
rotational isomerism arising from restricted rotation
about the N-Boc moiety.
Treatment of 29b with concentrated HCl at reflux
caused hydrolysis of the cyano unit and the N-Boc
protecting group to give a mixture of the HCl salts,
23‚HCl and 30‚HCl, in quantitative yield. At this
juncture, we also prepared the HCl salt of Squibb-23 and
compared its 1H NMR spectrum in D2O with that of
23‚HCl/30‚HCl. This revealed that the desired trans-4-
cyclohexyl-L-proline was formed as the major diastere-
omer. The ratio of trans/cis diastereomers was 4.4:1 on
the basis of the integration of the H-2 double doublet
centered at δ 4.38 (trans) and δ 4.29 (cis). The mixture
23‚HCl/30‚HCl was desalted (Dowex 50W-X8) to afford
the amino acids 23/30 in quantitative yield. An analyti-
cal sample of pure synthetic-23 was obtained by recrys-
tallization from water and it showed [R]D and spectro-
scopic properties identical to those obtained for Squibb-
23.
Exp er im en ta l Section
Gen er a l Meth od s. Only diagnostic absorptions in the
infrared spectrum are reported. 1H (200 MHz) and 13C (50.3
MHz) NMR spectra were recorded in CDCl3 unless stated
otherwise. Tetramethylsilane (δH ) 0.00) and the CDCl3
resonance (δC ) 77.0) were used as internal references. Where
applicable, the positions of the signals of minor diastereomers
are enclosed in square brackets. Elemental analyses and high-
resolution electron impact (70 eV) and chemical ionization
mass spectral analyses were performed at the Chemistry
Department, University of Saskatchewan, Canada. Reaction
progress was monitored by thin-layer chromatography on
Merck silica gel 60F254 precoated (0.25 mm) on aluminum-
backed sheets. Air- and moisture-sensitive reactions were
The observed diastereoselectivity for the cyanation step
is interesting in light of the results that have been
reported36 for similar reactions. It has been shown36c that
acid hydrolysis of the cyano group does not lead to
epimerization of the R-carbon (C-2 in this case). On the
basis of this fact, we conclude that the cyanation step
(29a f 29b ) had also occurred with a 4.4:1 trans/cis
(37) (a) Flynn, D. L.; Zelle, R. E.; Grieco, P. A. J . Org. Chem. 1983,
48, 2224. (b) Hansen, M. M.; Harkness, A. R.; Coffey, D. S.; Bordwell,
F. G.; Zhao, Y. Tetrahedron Lett. 1995, 36, 8949.
(38) Pedregal, C.; Ezquera, J .; Escribano, A.; Carreno, M. C.; Ruano,
J . L. C. Tetrahedron Lett. 1994, 35, 2053.
(39) Calculations performed using Hyperchem v. 4.0. ∆Hf ) +53.8582
kcal/mol.

Synthesis of 4-Substituted 2-Pyrrolidinones
J . Org. Chem., Vol. 63, No. 13, 1998 4225
4.2, CHCl3). IR νmax: 3048, 1693, 1601, 1586, 1513 cm-1 1H
NMR, δ: 2.82 (dd, 1H, J ) 17.2, 8.6 Hz), 2.92 (dd, 1H, J )
17.2, 8.6 Hz), 3.72-3.98 (m, 2H), 3.75 (s, 3H), 3.80 (s, 3H),
4.12 (t, 1H, J ) 7.5 Hz), 6.89-6.99 (m, 2H), 6.90 (d, 2H, J )
8.8 Hz), 7.18-7.31 (m, 2H), 7.52 (d, 2H, J ) 8.8 Hz). 13C NMR,
δ: 32.0, 38.1, 54.5, 55.1, 55.2, 110.5, 113.8, 120.5, 121.6, 127.1,
128.1, 129.3, 132.4, 156.3, 157.2, 173.0. Anal. Calcd for
conducted under a static pressure of argon. All organic
extracts were dried over anhydrous Na2SO4. Chromatogarphic
purification implies flash chromatography,40 which was per-
formed on Merck silica gel 60 (230-400 mesh). HPLC analysis
of compounds 20 and 21 was performed using a Chiralcel OB
column (1.5 mm × 250 mm) with in-line UV detection (λ )
254 nm). The eluent was hexane/2-propanol (70:30 v/v) unless
otherwise stated, and a flow rate of 1.5 mL/min was used.
Rhodium(II) acetate [Rh2(OAc)4] was purchased from Strem
Chemicals Inc. (Newburyport, MA) and was dried under high
vacuum (0.05 Torr) at 100 °C before use. Dichloromethane,
1,2-dichloroethane, chloroform, DME, and acetonitrile were
dried by distillation from calcium hydride. THF and diethyl
ether were dried by distillation from sodium using sodium
benzophenone ketyl as indicator.
Gen er a l P r oced u r e for th e Deca r boxyla tion of 2-P yr -
r olid in on es 16 or 18. A diastereomeric mixture of 16 or 18
(1 mmol), NaCl (2 mmol), and aqueous DMSO (6 mL, 3:1 v/v
DMSO-H2O) was refluxed under Ar for 4-12 h. The reaction
was diluted with water (6 mL) and extracted with EtOAc (3
× 5 mL). The combined organic extracts were washed with
brine (3 × 5 mL), dried, filtered, and evaporated. The crude
product 20 or 21 was purified by chromatography. The chiral
auxiliary (-)-7 or (+)-8 was recovered unchanged in 85-95%
yield.
.
C
18H19NO3: C, 72.69; H, 6.44; N, 4.71. Found: C, 72.49; H,
6.51; N, 4.67.
(S)-(-)-1-(4-Met h oxyp h en yl)-4-(3-m et h oxyp h en yl)-2-
p yr r olid in on e (20f). Yield: 76%. HPLC: ethanol. [R]23
:
D
-6.29 (c 0.8, CHCl3). IR νmax: 3054, 1693, 1602, 1586, 1513
cm-1 1H NMR, δ: 2.78 (dd, 1H, J ) 16.8, 8.1 Hz), 3.00 (dd,
.
1H, J ) 16.8, 8.1 Hz), 3.67 (quintet, 1H, J ) 8.1 Hz), 3.82 (s,
3H), 3.82 (s, 3H), 3.86 (dd, 1H, J ) 8.1, 7.1 Hz), 4.15 (t, 1H, J
) 8.1 Hz), 6.78-6.96 (m, 3H), 6.92 (d, 2H, J ) 8.8 Hz), 7.24
(m, 1H), 7.51 (d, 2H, J ) 8.8 Hz). 13C NMR, δ: 37.2, 40.0,
55.2, 55.5, 56.0, 112.2, 112.9, 114.1, 119.0, 122.0, 130.0, 132.3,
143.4, 156.7, 160.0, 172.6. Anal. Calcd for C18H19NO3: C,
72.69; H, 6.44; N, 4.71. Found: C, 72.41; H, 6.45; N, 4.62.
(S)-(-)-1-(4-Meth oxyp h en yl)-4-(3-n itr op h en yl)-2-p yr r o-
lid in on e (20g). Yield: 70%. HPLC: ethanol. [R]23 -5.88
D
(c 0.9, CHCl3). IR νmax: 3058, 1693, 1612, 1583, 1530, 1513
cm-1
.
1H NMR δ: 2.70 (dd, 1H, J ) 16.2, 8.1 Hz), 3.01 (dd,
1H, J ) 16.2, 8.1 Hz), 3.70-3.81 (m, 1H), 3.74 (s, 3H), 3.81 (t,
1H, J ) 7.4 Hz), 4.17 (t, 1H, J ) 7.4 Hz), 6.85 (d, 2H, J ) 8.8
Hz), 7.43 (d, 2H, J ) 8.8 Hz), 7.46 (d, 1H, J ) 7.8 Hz), 7.56 (t,
1H, J ) 7.8 Hz), 8.09 (d, 1H, J ) 7.8 Hz), 8.11 (s, 1H). 13C
NMR δ: 37.0, 40.0, 55.7, 114.3, 122.1, 122.1, 122.5, 130.2,
132.0, 133.0, 144.0, 157.1, 162.8, 171.8. Anal. Calcd for
(R)-(+)-4-Bu t yl-1-(4-m et h oxyp h en yl)-2-p yr r olid in on e
(20a ). Yield: 88%. Mp (Et2O/petroleum ether): 69-70.5 °C.
[R]23 +2.07 (c 1.2, CHCl3). IR νmax: 3079, 1691, 1645, 1614,
D
1514 cm-1
.
1H NMR, δ: 0.93 (t, 3H, J ) 7.6 Hz), 1.23-1.60
(m, 6H), 2.26 (dd, 1H, J ) 15.7, 7.1 Hz), 2.41 (quintet, 1H, J
) 7.1 Hz), 2.70 (dd, 1H, J ) 15.7, 7.1 Hz), 3.45 (dd, 1H, J )
9.3, 6.8 Hz), 3.78 (s, 3H), 3.87 (dd, 1H, J ) 9.3, 6.8 Hz), 6.88
(d, 2H, J ) 8.8 Hz), 7.48 (d, 2H, J ) 8.8 Hz). 13C NMR, δ:
14.0, 22.5, 29.5, 31.5, 34.1, 39.0, 54.8, 55.3, 114.0, 121.6, 132.6,
156.4, 173.3. Anal. Calcd for C15H21NO2: C, 72.83; H, 8.56;
N, 5.67. Found: C, 72.74; H, 8.93; N, 5.48.
C
17H16N2O4: C, 65.36; H, 5.17; N, 8.97. Found: C, 65.56; H,
5.16; N, 8.66.
(R )-(+)-4-Me t h yl-1-(4-m e t h oxyp h e n yl)-2-p yr r olid i-
n on e (20i). Yield: 78%. [R]23 +0.58 (c 1.0, CHCl3). Anal.
D
Calcd for C12H15NO2: C, 70.21; H, 7.37; N, 6.83. Found: C,
70.34; H, 7.56; N, 6.68.
(S)-(-)-4-Bu t yl-1-(4-m et h oxyp h en yl)-2-p yr r olid in on e
(21a ). Yield: 87%. [R]23D: -1.79 (c 1.4, CHCl3). EIMS (m/z,
rel intensity): 247 (M, 58), 136 (M - C6H12 - CO, 100).
(R )-(+)-1-(4-Me t h oxyp h e n yl)-4-p h e n yl-2-p yr r olid i-
n on e (21c). Yield: 87%. Mp (EtOAc/petroleum ether): 92-
(S)-(+)-4-Cycloh exyl-1-(4-m eth oxyp h en yl)-2-p yr r olid i-
n on e (20b). Yield: 87%. HPLC: hexane/2-propanol 90:10.
[R]23D: + 4.45 (c 0.85, CHCl3). IR νmax: 3054, 1689, 1513 cm-1
.
1H NMR, δ: 0.88-1.10 (m, 2H), 1.16-1.44 (m, 5H), 1.62-1.87
(m, 4H), 2.20 (dd, 1H, J ) 15.1, 8.0 Hz), 2.24-2.41 (m, 1H),
2.63 (dd, 1H, J ) 15.1, 8.0 Hz), 3.54 (t, 1H, J ) 8.3 Hz), 3.77-
3.87 (m, 1H), 3.80 (s, 3H), 6.99 (d, 2H, J ) 8.8 Hz), 7.49 (d,
2H, J ) 8.8 Hz). 13C NMR, δ: 25.9, 26.0, 26.3, 30.6, 31.0, 37.3,
37.7, 42.2, 53.4, 55.4, 114.0, 121.7, 132.6, 156.5, 173.6. EIMS
(m/z, rel intensity): 273 (M, 82), 136 (M - c-C6H11CHdCH2 -
CO, 100). Anal. Calcd for C17H23NO2: C, 74.68; H, 8.49; N,
5.13. Found: C, 74.42; H, 8.84; N, 5.04.
94 °C. [R]23
:
+9.98 (c 3.0, CHCl3). Anal. Calcd for
17H17NO2: C, 76.37; H, 6.41; N, 5.24. Found: C, 76.30; H,
6.31; N, 5.38.
(R )-(+)-1-(4-M e t h o x y p h e n y l)-4-[3,4-(m e t h y le n e -
d ioxy)p h en yl]-2-p yr r olid in on e (21d ). Yield: 96%.
HPLC: ethanol. [R]23 +15.9 (c 1.3, CHCl3). Anal. Calcd for
D
C
D
C
18H17NO4: C, 69.43; H, 5.51; N, 4.51. Found: C, 69.43; H,
5.51; N, 4.51.
(S )-(-)-1-(4-Me t h oxyp h e n yl)-4-p h e n yl-2-p yr r olid i-
(R)-(+)-1-(4-Met h oxyp h en yl)-4-(4-n it r op h en yl)-2-p yr -
n on e (20c). Yield: 84%. Mp (EtOAc/petroleum ether): 92.5-
r olid in on e (21h ). Yield: 81%. HPLC: ethanol. [R]23
:
.
95 °C. [R]23 -10.5 (c 2.2, CHCl3). IR νmax: 3053, 1692, 1604
D
D
+4.83 (c 1.0, CHCl3). IR νmax: 3054, 1694, 1606, 1514 cm-1
cm-1
.
1H NMR, δ: 2.68 (dd, 1H, J ) 16.7, 8.7 Hz), 2.92 (dd,
1H NMR δ: 2.76 (dd, 1H, J ) 16.0, 6.8 Hz), 3.09 (dd, 1H, J )
16.0, 6.8 Hz), 3.73-3.95 (m, 1H), 3.80 (s, 3H), 3.89 (t, 1H, J )
6.9 Hz), 4.24 (t, 1H, J ) 6.9 Hz), 6.92 (d, 2H, J ) 8.2 Hz), 7.48
(d, 2H, J ) 8.2 Hz), 7.52 (d, 2H, J ) 8.2 Hz), 8.23 (d, 2H, J )
8.2 Hz). 13C NMR δ: 37.0, 39.7, 55.4, 114.2, 122.0, 124.3,
127.7, 131.8, 147.2, 149.4, 156.9, 171.6. Anal. Calcd for
1H, J ) 16.7, 8.7 Hz), 3.50-3.79 (m, 1H), 3.70 (s, 3H), 3.77 (t,
1H, J ) 8.2 Hz), 4.06 (t, 1H, J ) 8.2 Hz), 6.83 (d, 2H, J ) 8.8
Hz), 7.13-7.35 (m, 5H), 7.43 (d, 2H, J ) 8.8 Hz). Anal. Calcd
for C17H17NO2: C, 76.37; H, 6.41; N, 5.24. Found: C, 76.17;
H, 6.40; N, 5.62.
(S )-(-)-1-(4-M e t h o x y p h e n y l)-4-[3,4-(m e t h y le n e -
C
17H16N2O4: C, 65.36; H, 5.17; N, 8.97. Found: C, 65.21; H,
d ioxy)p h en yl]-2-p yr r olid in on e (20d ).
Yield:
84%.
5.23; N, 8.83.
HPLC: ethanol. Mp (EtOAc/petroleum ether): 119.5-121.5
(S )-(-)-4-Me t h yl-1-(4-m e t h oxyp h e n yl)-2-p yr r olid i-
°C. [R]23 -15.5 (c 1.0, CHCl3). IR νmax: 3053, 1691, 1610,
D
n on e (21i). Yield: 81%. [R]23D: -0.51 (c 1.0, CHCl3). IR
1512 cm-1
.
1H NMR, δ: 2.71 (dd, 1H, J ) 16.6, 8.8 Hz), 2.96
ν
max: 3050, 1690, 1612, 1586, 1513 cm-1 1H NMR, δ: 1.21
.
(dd, 1H, J ) 16.6, 8.8 Hz), 3.63 (quintet, 1H, J ) 8.8 Hz), 3.79
(t, 1H, J ) 8.8 Hz), 3.80 (s, 3H), 4.10 (t, 1H, J ) 8.8 Hz), 5.96
(s, 2H), 6.69-6.83 (m, 3H), 6.91 (d, 2H, J ) 8.8 Hz), 7.50 (d,
2H, J ) 8.8 Hz). 13C NMR, δ: 37.0, 40.3, 55.5, 56.2, 101.1,
107.1, 108.5, 114.1, 120.0, 121.8, 132.2, 135.0, 146.7, 148.1,
156.7, 172.5. Anal. Calcd for C18H17NO4: C, 69.43; H, 5.51;
N, 4.51. Found: C, 69.59; H, 5.48; N, 4.43.
(d, 3H, J ) 5.9 Hz), 2.23 (dd, 1H, J ) 15.9, 7.3 Hz), 2.45-2.65
(m, 1H), 2.74 (dd, 1H, J ) 15.9, 8.3 Hz), 3.40 (dd, 1H, J ) 9.4,
5.8 Hz), 3.79 (s, 3H), 3.90 (dd, 1H, J ) 9.4, 7.4 Hz), 6.90 (d,
2H, J ) 8.3 Hz), 7.49 (d, 2H, J ) 8.3 Hz). 13C NMR, δ: 19.5,
26.3, 40.7, 55.4, 56.2, 113.9, 121.7, 132.6, 156.4, 173.4. Anal.
Calcd for C12H15NO2: C, 70.21; H, 7.37; N, 6.83. Found: C,
70.35; H, 7.37; N, 6.59.
(S)-(+)-1-(4-Met h oxyp h en yl)-4-(2-m et h oxyp h en yl)-2-
p yr r olid in on e (20e). Yield: 84%. HPLC: hexane/2-pro-
panol, gradient elution, 90:10, 80:20, 60:40. [R]23D: +4.13 (c
4-Bu tyl-1-(ter t-bu tyloxyca r bon yl)-2-p yr r olid in e (22a ).
CAN (444 mg, 0.81 mmol) was dissolved in water (2.5 mL) and
added to a solution of 20a (67 mg, 0.27 mmol) in MeCN (5
mL) at 0 °C. After 30 min, excess solid Na2SO3 was added to
destroy unreacted CAN. Then the solvent was evaporated, the
(40) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923.

4226 J . Org. Chem., Vol. 63, No. 13, 1998
Wee et al.
organic residue taken into EtOAc (10 mL), and the organic
layer washed with brine (10 mL), dried, filtered, and evapo-
rated. Chromatographic purification gave 4-butyl-2-pyrroli-
The faster eluting component was assigned to 20i. The
2-pyrrolidinone derived from 10i showed the ratio (based on
relative peak areas) of 20i:21i is 1:1.8, whereas the 2-pyrro-
lidinone formed from ent-10i indicated the ratio of 20i:21i is
2:1. Addition of a small amount of (S)-14c to the 2-pyrrolidi-
none derived from 10i caused an increase in the peak area of
the slower moving component 21i (tR ) 14 min).
dinone (79%). IR νmax: 3244, 1696 cm-1 1H NMR δ: 0.91 (t,
.
3H, J ) 7.6 Hz), 1.18-1.54 (m, 6H), 2.00 (dd, 1H, J ) 19.2,
10.3 Hz), 2.26-2.53 (m, 2H), 3.02 (dd, 1H, J ) 8.8, 6.4 Hz),
3.49 (t, 1H, J ) 8.8 Hz).
A solution of 4-butyl-2-pyrrolidinone (30 mg, 0.21 mmol) in
dry THF (5 mL) was cooled to 0 °C, under Ar, and then treated
with LiAlH4 (16 mg, 0.41 mmol). After being stirred briefly
at 0 °C, the cooling bath was removed and the mixture was
warmed to room temperature and then refluxed for 15 h. The
reaction mixture was treated with 1 M aqueous NaOH (1.5
mL) at 0 °C, and then ether (2 mL) was added followed by
Boc2O (137 mg, 0.63 mmol). The mixture was stirred for 4 h
at room temperature and then filtered through a short pad of
anhydrous Na2SO4. The filtrate was evaporated, and the
residue was chromatographed to give 22a (66%). [R]23D: +11.1
(S)-1-(ter t-Bu tyloxyca r bon yl)-4-cycloh exyl-2-p yr r olid i-
n on e (28). Compound 16b (565 mg, 0.976 mmol) was decar-
boxylated [NaCl (171 mg, 2.93 mmol); 25 mL DMSO-water
(10:1 v/v)] to afford after chromatography (6:1 petroleum ether/
EtOAc), 232 mg (87%) of crystalline 20b. Compound 20b
(322.8 mg, 1.182 mmol) was oxidized using CAN (1.98 g, 3.612
mmol) as described above (20b f 22b) to give 4-cyclohexyl-
2-pyrrolidinone (179 mg, 91%). A small amount of sample for
spectroscopic characterization was purified by chromatography
(8:1 then 2:1 CH2Cl2/acetone). Mp: 125-125.5 °C (CH2Cl2/
acetone). [R]22D: -5.56 (c 0.9, CHCl3). IR νmax: 3418, 3215,
(c 1.6, CH2Cl2) [for the (S)-enantiomer, lit.15b [R]23 -30.5 (c
1697, 1449 cm-1 1H NMR, δ: 0.72-1.38 (m, 6H), 1.52-1.88
.
D
0.83, CH2Cl2)]. IR νmax: 1698, 1542 cm-1
.
1H NMR δ: 0.91
(m, 5H), 1.90-2.44 (m, 3H), 3.07 (t, 1H, J ) 8.3 Hz), 3.43 (t,
1H, J ) 8.7 Hz), 6.62 (br s, 1H). 13C NMR, δ: 26.0, 26.4, 30.7,
31.2, 41.3, 42.3, 46.6, 178.1.
(br t, 3H, J ) 7.6 Hz), 1.21-1.45 (m, 7H), 1.50 (s, 9H) 1.89-
2.20 (m, 2H), 2.85 (br q, 1H, J ) 8.3 Hz), 3.12-3.65 (m, 3H).
1-Ben zoyl-4-cycloh exylp yr r olid in e (22b) fr om 2-P yr -
r olid in on e (20b). The N-PMP in 20b (39.5 mg) was oxida-
tively removed (239 mg of CAN in 1 mL of water and 3 mL of
MeCN] according to the procedure as described for the conver-
sion of 20a to 22a . The crude 4-cyclohexyl-2-pyrrolidinone (18
mg) was dissolved in dry THF (2 mL), and LiAlH4 (6.4 mg)
was added. The mixture was refluxed for 10 h and then cooled
to 0 °C, and aqueous 1 M NaOH (1.5 mL) was added. After
being stirred briefly at 0 °C, ether (3 mL) was added followed
by benzoyl chloride (0.1 mL). Workup as described previously
followed by chromatographic purification gave 22b in 18 mg
4-Cyclohexyl-2-pyrrolidinone (224 mg, 1.33 mmol) was dis-
solved in dry CH2Cl2 (2.7 mL), and dry Et3N (0.24 mL, 1.33
mmol), DMAP (164 mg, 1.34 mmol), and Boc2O (600 mg, 2.75
mmol) were added sequentially at room temperature. After
being stirred for 17 h, the solvent was removed and the residue
was columned (20:1 petroleum ether/EtOAc) to yield 257 mg
of 28 (72%). Mp: 90.5-90.8 °C (EtOAc/petroleum ether).
[R]23D: -1.68 (c 1.5, CHCl3). IR νmax: 1785, 1753, 1714, 1368,
1316 cm-1 1H NMR, δ: 0.75-1.37 (m, 6H), 1.52 (s, 9H), 1.58-
.
1.89 (m, 5H), 1.89-2.38 (m, 1H), 2.24 (dd, 1H, J ) 16.7, 10.7
Hz), 2.66 (dd, 1H, J ) 16.7, 8.3 Hz), 3.33 (dd, 1H, J ) 10.8,
8.6 Hz), 3.86 (dd, 1H, J ) 10.8, 8.0 Hz). 13C NMR, δ: 26.0,
26.2, 28.0, 30.5, 31.0, 37.0, 38.0, 42.0, 50.6, 82.8, 150.2, 174.1.
(77%). HPLC: hexane/2-propanol, 90:10; tR ) 14.9 min. [R]23
:
D
+99.4 (c 0.9, CH2Cl2). Mp: 60.5-63 °C. IR νmax: 1718, 1637,
1581 cm-1 1H NMR (1:1 mixture of rotamers) δ: 0.78-1.39
.
HRMS: calcd for
252.1600.
C15H25NO3 (M - 15) 252.1599, found
(m, 6H), 1.41-2.22 (m, 8H), 3.10 and 3.25 (t, 1H, J ) 10.0
Hz), 3.38-3.68 (m, 2H), 3.74-3.94 (m, 1H), 7.32 (m) and 8.10
(d, J ) 6.5 Hz) (5H). 13C NMR, δ: 25.96, 26.02, 26.03, 26.33,
28.73, 30.58, 31.31, 31.50, 31.90, 32.00, 41.33, 41.71, 44.04,
45.94, 46.39, 49.79, 50.50, 53.85, 127.04, 127.07, 128.19,
129.70, 129.74, 129.97, 133.01, 136.92, 137.18, 163.93, 169.56.
HRMS: calcd for C17H23NO 257.1779, found 257.1778.
(2S,4S)- a n d (2R,4S)-1-(ter t-Bu tyloxyca r bon yl)-2-cy-
a n o-4-cycloh exylp yr r olid in e (29b). Compound 28 (126 mg,
0.47 mmol) was dissolved in dry THF (12 mL) and cooled to
-78 °C. A 1 M solution of LiEt3BH (0.6 mL, 0.56 mmol) was
added slowly, and the reaction was stirred for 1.5 h at -78
°C. The mixture was quenched with saturated aqueous
NaHCO3 (1 mL) and warmed slowly to 0 °C. H2O2 (30%, 5
drops) was added, and the mixture was stirred for 20 min.
Then THF was evaporated, and the aqueous layer was
extracted with CH2Cl2 (3 × 20 mL). The combined organic
extracts were dried, filtered, and evaporated. The crude
alcohol 29a was obtained in quantitative yield and was used
without purification in the next step. IR νmax: 3562-3175,
1-Ben zoyl-4-cycloh exylp yr r olid in e (22b) fr om Squ ibb-
23. Squibb-2330a (35 mg, 0.15 mmol) was suspended in
cyclohexanol (0.5 mL). Then a mixture of cyclohexanol and
2-cyclohexenone (0.3 mL, 50:1 v/v)30b was added, and the
mixture was immersed into an oil bath set at 158 °C. There
was gas evolution, and the color of the mixture turned brown.
After 10 h, the mixture was cooled to room temperature, ether
(3 mL) was added, and the mixture was extracted with 1 M
HCl (3 × 2 mL). Fresh ether (3 mL) was added to the acidic,
aqueous layer followed by benzoyl chloride (0.1 mL). The
mixture was cooled to 0 °C, and aqueous 10% NaOH (3 mL)
was added. After 10 min, the ether layer was separated, the
aqueous phase was re-extracted with ether (2 × 3 mL), and
the combined organic phases were washed with brine (5 mL),
dried, filtered, and evaporated. The crude product was chro-
matographed (initially using 20:1 petroleum ether-ether then
2:1 petroleum ether-EtOAc) to give the 13.6 mg of product
1681, 1393, 1366 cm-1
.
Alcohol 29a (82 mg, 0.31 mmol) was dissolved in dry CH2Cl2
(5 mL), and Me3SiCN (91 µL, 0.632 mmol) was added. The
mixture was cooled to -78 °C, and BF3‚OEt2 (83 µL, 0.67
mmol) was added dropwise to the mixture. After 2 h, the
reaction was quenched at -78 °C with saturated aqueous
NaHCO3 (2 mL). The organic layer was separated, and the
aqueous layer was extracted with CH2Cl2 (3 × 15 mL). The
combined organic extracts were dried, filtered, and evaporated,
and the residue was purified by chromatography (20:1 petro-
leum ether/EtOAc) to give recovered alcohol 29a (10 mg) and
the oily cyano product 29b (66 mg, 78%; 89% based on
recovered starting material) as a mixture of diastereomers.
Cyano product 29b: IR νmax: 2239, 1704, 1478, 1450, 1393
(35%). Mp: 58-60 °C. [R]23
: +102 (c 0.50, CH2Cl2).
D
HRMS: calcd for C17H23NO 257.1779, found 257.1778. Mixed
mp: 58.5-61.5 °C. NMR data are identical to 22b prepared
from 20b.
HP LC An a lysis of Deca r boxyla ted 2-P yr r olid in on es
Der ived fr om Cycliza tion of 10i a n d en t-10i. Racemic 14c,
which was prepared by the decarboxylation of the known (()-
3-(carbomethoxy)-1-(4-methoxyphenyl)-4-methyl-2-pyrrolidi-
none,6 was used for determining conditions for optimal sepa-
ration. A baseline separation of the two enantiomers was
achieved. Each of the two decarboxylated 2-pyrrolidinones
(from 10i and ent-10i) showed two peaks, one at tR ) 10 min
and the other at tR ) 14 min. A comparison of the retention
times with that obtained for the reference compound (S)-14c
(tR ) 14 min) identified the slower eluting component as 21i.
cm-1 1H NMR, δ: 0.82-1.37 (m, 6H), 1.50 (s, 9H), 1.57-1.98
.
(m, 6H), 2.10-2.42 (m, 2H), 2.82-3.06 (m, 1H), 3.48-3.89 (m,
1H), 4.56 (dd, 1H, J ) 19.8, 8.1 Hz). 13C NMR, δ: 26.2, 27.0,
28.3, 31.4, 31.8, 34.8, 35.5, 41.2, 43.3, 44.4, 47.7, 50.0, 50.3,
81.3, 118.5, 183.1. HRMS: calcd for C16H26N2O2 (M+) 278.1994,
found 278.2002.
(2S,4S)- a n d (2R,4S)-4-Cycloh exyl-2-p yr r olid in eca r -
boxylic a cid ‚HCl (23‚HCl/30‚HCl). Compound 29b (44 mg,
0.16 mmol) was dissolved in concentrated HCl (2 mL) and then
heated to reflux. The reaction was stirred at reflux for 22 h.
Then the reaction mixture was washed with Et2O (2 × 5 mL).

Synthesis of 4-Substituted 2-Pyrrolidinones
J . Org. Chem., Vol. 63, No. 13, 1998 4227
The aqueous layer was evaporated to give 23‚HCl/30‚HCl in
13C NMR δ (CD3OD): 27.2, 27.4, 32.8, 33.1, 34.9, 42.3, 44.7,
50.7, 62.6. HRMS: calcd for C11H19NO2 (M - 15) 152.1439,
found 152.1435.
quanititative yield (37 mg). At this stage, we also prepared
1
the HCl salt of Squibb-23 and compared its H NMR spectrum
with that of our synthetic material. Synthetic Sample. [R]22
:
D
-4.9 (c 1.0, MeOH). 1H NMR, δ (D2O): 0.70-1.32 (m, 6H),
1.36-1.73 (m, 5H), 1.85-2.13 (m, 2H), 2.31 (dd, J ) 5.3, 3.4
Hz) and [2.41, m ] (1H), 2.94 (t, 1H, J ) 10.9 Hz), 3.55 (dd, J
) 11.2, 6.4 Hz) and [3.45, d, J ) 7.8 Hz] (1H), 4.38 (dd, J )
9.1, 3.9 Hz) and [4.29, dd, J ) 10.7, 7.8 Hz](1H). 13C NMR, δ
(D2O): 29.2, [29.5], 34.6, 34.9, [35.0], 36.1, [36.5], 43.8, [44.0],
Ack n ow led gm en t. Support for this work from the
Natural Sciences and Engineering Research Council,
Canada, and the University of Regina is gratefully
acknowledged. We thank Dr. J . K. Thottathil and
Bristol-Myers Squibb, NJ , for a generous gift of trans-
4-cyclohexyl-L-proline (Squibb-23). We thank Dr. K.
Marat, Regional High Field NMR Center, Manitoba, for
high-field NMR spectra and for performing the NOE
experiments and Mr. K. Thoms, University of
Saskatchewan, for the elemental and HRMS analyses.
We thank the reviewers for helpful comments and
suggestions.
46.3, [47.9], 53.2, [53.1], 63.3, 176.1. Squibb-23‚HCl. [R]22
:
D
-5.6 (c 2.2, MeOH). 1H NMR, δ (D2O): 0.70-1.32 (m, 6H),
1.36-1.73 (m, 5H), 1.85-2.13 (m, 2H), 2.16-2.41 (m, 1H), 2.94
(t, 1H, J ) 11.2 Hz), 3.55 (dd, 1H, J ) 11.3, 6.4 Hz), 4.38 (dd,
1H, J ) 8.9, 4.1 Hz). 13C NMR, δ (D2O): 29.2, 29.5, 34.6, 34.9,
36.0, 43.9, 46.3, 53.3, 63.2, 175.8.
The mixture of 23‚HCl/30‚HCl was subjected to ion-
exchange chromatography (Dowex 50W-8X, 200-400 mesh)
using 5% aqueous NH4OH as the eluent. The amino acid
fractions were evaporated to dryness and extracted with hot
MeOH. The methanol extracts were evaporated to give 23/30
in quantitative yield. An analytical sample of synthetic-23 was
obtained by recrystallization from H2O. Mp (H2O): 265.3-
265.5 °C (lit.30a mp 265-267 °C). [R]22D: -40.0 (c 0.5, MeOH)
[lit. [R]30aD -39.5 (c 1.14, MeOH)]. IR νmax (KBr): 3272-2801,
Su p p or tin g In for m a tion Ava ila ble: Procedure for the
preparation and spectroscopic and/or analytical data for
compounds 5g, 6, 9, 10, and 13-19 as well as a ball and stick
rendering of AM1-minimized pyrrolidinium ion 31 (26 pages).
This material is contained in libraries on microfiche, im-
mediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
1618, 1385, 1349 cm-1 1H NMR δ (CD3OD): 0.83-1.42 (m,
.
6H), 1.51-2.08 (m, 7H), 2.22-2.46 (m, 1H), 2.88 (t, 1H, J )
10.5 Hz), 3.53 (dd, 1H, J ) 11.3, 6.7 Hz), 3.92-4.10 (m, 1H).
J O971540Q