Asymmetric deprotonation by BuLi/(-)-sparteine: Convenient and highly enantioselective syntheses of (S)-2-aryl-Boc-pyrrolidines

Article abstract of DOI:10.1021/ja9524661

Highly enantioselective syntheses of (S)-2-aryl-Boc-pyrrolidines (Boc = tert-butoxycarbonyl) can be achieved by treatment of the corresponding (arylmethyl)(3-chloropropyl)-Boc-amines with s-BuLi/(-)-sparteine. The reactions are solvent dependent with the phenyl, p-chlorophenyl, p-fluorophenyl, p-methylphenyl, m-methoxyphenyl, 1-naphthyl, and 2-naphthyl derivatives 1-7- providing 11-17 in yields of 46-75% with enantiomeric excesses of 84-96% in toluene. The 2-thienyl and 3-furyl analogs 8 and 9 afford the (S)-2-heteroaryl-Boc-pyrrolidines 18 and 19 in 51 and 21% yields with 93-96% enantiomeric excesses. The p-methoxyphenyl derivative 10 gives 20 as a racemic product in 42% yield under the same conditions. Reactions of n-BuLi/(-)-sparteine with 1 and 8 give results comparable to those with s-BuLi/(-)-sparteine. Illustrative syntheses of (S)-2-phenyl-(S)-5-methyl-Boc-pyrrolidine (22) and 1,2-(bis-(S)-2-phenylpyrrolindyl)ethane (23) are reported. The mechanism of the reaction is shown to be an asymmetric deprotonation of 1 to give an enantioenriched organolithium intermediate (S)-24 which undergoes cyclization faster than racemization.

Full text of DOI:10.1021/ja9524661

VOLUME 118, NUMBER 4
J ANUARY 31, 1996
© Copyright 1996 by the
American Chemical Society
Asymmetric Deprotonation by BuLi/(-)-Sparteine: Convenient
and Highly Enantioselective Syntheses of
(S)-2-Aryl-Boc-Pyrrolidines
Shengde Wu, Steven Lee, and Peter Beak*
Contribution from the Department of Chemistry, UniVersity of Illinois at Urbana-Champaign,
Urbana, Illinois 61801
ReceiVed July 24, 1995X
Abstract: Highly enantioselective syntheses of (S)-2-aryl-Boc-pyrrolidines (Boc ) tert-butoxycarbonyl) can be
achieved by treatment of the corresponding (arylmethyl)(3-chloropropyl)-Boc-amines with s-BuLi/(-)-sparteine. The
reactions are solvent dependent with the phenyl, p-chlorophenyl, p-fluorophenyl, p-methylphenyl, m-methoxyphenyl,
1-naphthyl, and 2-naphthyl derivatives 1-7 providing 11-17 in yields of 46-75% with enantiomeric excesses of
84-96% in toluene. The 2-thienyl and 3-furyl analogs 8 and 9 afford the (S)-2-heteroaryl-Boc-pyrrolidines 18 and
19 in 51 and 21% yields with 93-96% enantiomeric excesses. The p-methoxyphenyl derivative 10 gives 20 as a
racemic product in 42% yield under the same conditions. Reactions of n-BuLi/(-)-sparteine with 1 and 8 give
results comparable to those with s-BuLi/(-)-sparteine. Illustrative syntheses of (S)-2-phenyl-(S)-5-methyl-Boc-
pyrrolidine (22) and 1,2-(bis-(S)-2-phenylpyrrolindyl)ethane (23) are reported. The mechanism of the reaction is
shown to be an asymmetric deprotonation of 1 to give an enantioenriched organolithium intermediate (S)-24 which
undergoes cyclization faster than racemization.
Recent studies have established that reactions of organo-
lithium species complexed to enantioenriched ligands can afford
highly enantioenriched products.1 We have shown that asym-
metric deprotonation of Boc-pyrrolidine (Boc ) tert-butoxy-
carbonyl) by s-BuLi/(-)-sparteine provides (R)-2-lithio-Boc-
pyrrolidine which subsequently can be reacted with many
electrophiles to give 2-substituted Boc-pyrrolidines with high
enantiomeric excesses.2 However, the lack of a general method
for enantioselective electrophilic arylation of alkylorganolithium
reagents limits this approach for the preparation of enantio-
enriched 2-aryl-Boc-pyrrolidines.3,4,5 We now report lithiation-
cyclizations which afford (S)-2-aryl-Boc-pyrrolidines with high
enantiomeric excesses.
(3) Dieter has recently reported arylations of 2-lithio-Boc-pyrrolidines
by a copper-catalyzed palladium coupling reaction with aryl iodides: Dieter,
R. K.; Li S. Tetrahedron Lett. 1995, 36, 3613. An earlier report from Dieter's
laboratories showed that the enantiointegrity of the 2-lithio-Boc-pyrrolidine
was lost on conversion to the copper derivative and addition to R,â
unsaturated ketones. Dieter, R. K.; Alexander, C. W., Syn. lett. 1993, 407.
(4) Chiral 2-substituted pyrrolidines, which occur widely as natural
products and are useful as chiral auxiliaries, chiral bases, and chiral ligands,
are worthy synthetic targets. For summaries and reviews see: Hart, D. J.
Alkaloids: Chemical and Biological PerspectiVes; Pelletier, S. W., Ed.;
Wiley: New York, 1988; Vol. 6, Chapter 3. Hiemstra, H; Speckamp, W.
N. The Alkaloids; Brossi A., Ed.; Academic Press: New York, 1988.
Whitesell, J. K. Chem. ReV. 1989, 89, 1581. Tomioka, K. Synthesis, 1990,
541.
X Abstract published in AdVance ACS Abstracts, January 15, 1996.
(1) For recent summaries see: Knochel, P. Angew. Chem., Int. Ed. Engl.
1992, 31, 1459. Aggarawal, J. K. Angew. Chem., Int. Ed. Engl. 1994, 33,
175. For recent reports and leading references see: (a) Carstens, A; Hoppe,
D. Tetrahedron 1994, 50, 6097. (b) Thayumanavan, S.; Lee, S.; Liu, C.;
Beak, P. J. Am. Chem. Soc. 1994, 116, 9755.
(5) For our report of the corresponding racemic reaction see: Beak, P.;
Wu, S.; Yum, E. K.; Jun, Y. M. J. Org. Chem. 1994, 59, 276. For formation
of pyrrolidines by cyclization through addition of an R-lithioamine to a
double bond see: Coldham, I.; Hufton, R. Tetrahedron Lett. 1995, 36, 2157.
(2) Beak, P.; Kerrick, S. T.; Wu, S.; Chu, J. J. Am. Chem. Soc., 1994,
116, 3231.
0002-7863/96/1518-0715$12.00/0 © 1996 American Chemical Society

716 J. Am. Chem. Soc., Vol. 118, No. 4, 1996
Wu et al.
Chiral auxiliary-mediated approaches to enantioenriched
2-arylpyrrolidines have been reported. Burgess and Meyers
have used (R)-phenylglycinol for highly enantioselective syn-
theses of 2-phenyl- and 2-alkylpyrrolidines.6 The same auxiliary
was used by Higashiyama and co-workers to prepare enan-
tioenriched 2-aryl and 2,5-diarylpyrrolidines.7 Savoia and co-
workers have used (S)-valine as the chiral auxiliary for the
synthesis of enantioenriched 2-phenylpyrrolidine.8
Catalytic methods have been developed for syntheses of
enantioenriched 2-arylpyrrolines and -pyrrolidines. Ozawa and
Hayashi have reported palladium acetate 2(R)-BINAP asym-
metric arylations of carbonates of 2-pyrrolidines give 5-aryl-
2-pyrrolidines in good enantiomeric excess along with 5-aryl-
3-pyrrolines with poor enantioenrichments.9 An especially
efficient approach to enantioenriched 2-substituted pyrrolidines
has been reported by Willoughby and Buchwald who used an
enantioselective chiral titanocene-based catalyst to reduce 2-aryl-
and 2-alkyl-1-pyrrolidines to 2-aryl- and 2-alkylpyrrolidines with
very high enantioselectivities.10
We can report convenient highly enantioselective syntheses
of (S)-2-aryl-Boc-pyrrolidines by lithiation of (arylmethyl)(3-
chlorophenyl)-Boc-amines with BuLi/(-)-sparteine. Mecha-
nistic analysis shows that enantioselectivity is introduced by
asymmetric deprotonation at the benzylic position by the
organolithium/chiral ligand complex.
Enantioselective Lithiation-Cyclizations of 1-9. Treat-
ment of 1 with 1.5-2.0 equiv of s-BuLi/(-)-sparteine at -78
°C in different solvents gives (S)-11 in the yields and enantio-
selectivities summarized in Table 1. The absolute configuration
was assigned to (S)-11 by removal of the Boc group and
comparison of the optical rotation to authentic (S)-2-phenyl-
pyrrolidine.6 The enantiomeric excess was determined by
derivitization of the pyrrolidine with 3,5-dinitrobenzyl chloride
and HPLC comparison of the racemic and enantioenriched 3,5-
dinitrobenzamides on the Pirkle chiral stationary phase (S)-N1N-
naphthylleucine column.12
The data in Table 1 show the enantioselectivities for the
lithiation-cyclization of 1 to (S)-11 to be solvent dependent.
An essentially racemic product is obtained in THF. Reactions
in diethyl ether (Et2O), tert-butyl methyl ether (t-BuOMe), or
Et2O:pentane provide (S)-11 in moderate enantiomeric excess
while in pentane the enantiomeric excess is 80%.13 Toluene
affords a 72% yield and 96% enantioselectivity. A reaction of
1 in toluene on a 1 g scale with one recrystallization gave (S)-
11 from 1 in 58% overall yield with >98% ee. Although the
trend of enantioselectivity in Table 1 is generally consistent with
an expected increase in influence of the chiral ligand for an
organolithium species as the solvent becomes less effective in
binding, the improvement in enantioselectivity in toluene relative
to pentane does not fit that trend, although solubility may be
an important factor.
Results and Discussion
Synthesis of Reactants. Treatment of 3-chloropropylamine
hydrochloride with di-tert-butyl dicarbonate in THF provided
(3-chloropropyl)-Boc-amine, which on reaction with NaH and
the appropriate arylmethyl bromide afforded the products 1-10
in 42-63% yields.11 Benzyl [3-(mesyloxy)propyl]-Boc-amine
Analogous lithiation-cyclization reactions were carried out
for the (arylmethyl)(3-chloropropyl)-Boc-amines 1-10. Treat-
ment of each substrate with 1.5-2.0 equiv of BuLi/(-)-sparteine
at -78 °C in toluene for 6-8 h gives the (S)-2-arylpyrrolidines
11-20 with high enantioselectivity as shown in Table 2. The
S configuration is assigned by analogy to the formation of (S)-
11 and by consistency with elution order in the determinations
(21a) was prepared by reaction of 3-amino-1-propanol with
benzaldehyde, followed by reduction with LiAlH4, reaction with
di-tert-butyl carbonate, and treatment with mesyl chloride.
Reaction of 21a with LiBr gave benzyl(3-bromopropyl)-Boc-
amine (21b). The trimethylstannyl derivative 25 was synthe-
sized in low yield from benzyl-Boc-amine by dilithiation,
reaction with trimethyltin chloride, and alkylation with 1-bromo-
3-chloropropane. The preparation of 1-d1 followed the route
used for 21a with lithium aluminum deuteride used in the
reduction step to incorporate the deuterium. The mesylate 21a-
d1 was converted to the labeled chloride 1-d1 by treatment with
lithium chloride.
(12) Pirkle, W. H.; McCune, J. E. J. Chromatogr. 1989, 479, 471, 271.
(13) A limitation of pentane is that 2-7 have lower solubilities at lower
temperatures. In toluene, these compounds are soluble at -78 °C.
(14) The racemic pyrrolidine of 12 has been reported. (a) Maryanoff, B.
E.; Vaught, J. L.; Shank, R. P.; McComsey, D. F.; Costanzo, M. J.; Nortey,
S. O. J. Med. Chem. 1990, 33, 2793. (b) Elslager, E. F.; Johnson, J. L.;
Werbel, L. M. J. Med. Chem. 1981, 24, 140. (c) Elslager, E. F.; Clarke, J.;
Werbel, L. M.; Worth, D. F.; Davoll, J. J. Med. Chem. 1972, 15, 827.
(15) The racemic pyrrolidine of 13 has been reported. (a) Viswanathan,
N.; Sidhaye, A. R. Tetrahedron Lett. 1979, 52, 5025. (b) Seeman, J. I.;
Secor, H. V.; Forrest, G. J. Labelled Compd. Radiopharm. 1979, 16, 387.
(16) The racemic pyrrolidine of 14 has been reported. (a) See ref. 15a.
(b) Severin, T.; Poehlmann, H. Chem. Ber. 1977, 110, 491.
(17) The racemic pyrrolidine of 15 has been reported. (a) Ferrand, G.;
Barbanton, J.; Depin, J.; Chavernac, G. CA Patent 1327364, 1995; Chem.
Abstr. 1995, 122, 31318. (b) Wettlaufer, D. G.; Nemoto, P. A. US Patent
5338739, 1994; Chem. Abstr. 1994, 121, 280538. (c) Ferrand, G.; Barbanton,
J.; Depin, J.; Chavernac, G. EP Patent 360685, 1990; Chem. Abstr. 1990,
113, 115096.
(6) (a) Burgess, L. E.; Meyers, A. I. J. Org. Chem. 1992, 57, 1656. (b)
The original source for the determination of the absolute configuration of
2-phenylpyrrolidine was by correlation with the absolute configuration of
2-phenylglutaric acid. Morlacchi, F.; Losacco, V.; Tortorella, V. Gazz. Chim.
Ital. 1975, 105, 349.
(7) Higashiyama, K.; Inoue, H.; Takahashi, H. Tetrahedron 1994, 50,
1083.
(8) Manescalchi, F.; Nardi, A. R.; Savoia, D. Tetrahedron Lett. 1994,
35, 2775.
(9) Ozawa, F.; Hayashi, T. J. Organomet. Chem. 1992, 428, 267.
(10) Willoughby, C. A.; Buchwald, S. L. J. Org. Chem. 1994, 116, 11703.
(11) The yields were not optimized, and trace amounts of elimination
products were observed. The alternative approach with 1-bromo-3-chloro-
propane and Boc-phenylmethylamine under the same alkylation conditions
gave less than 20%of 1 with the elimination product, N-Boc-N-allyl-N-
benzylamine, as the major product.
(18) The racemic pyrrolidines of 16 and 17 have been reported. Grande,
M. T.; Sollhuber, M. M. Chem. Scr. 1988, 28, 411.
(19) (a) The enantioenriched pyrrolidine of 20 has been reported in ref.
7. The racemic pyrrolidine of 20 has been reported: (b) Wettlaufer, D. G.;
Nemoto, P. A. US Patent 5338739, 1994; Chem. Abstr. 1994, 121, 280538.
(c) Viswanathan, N.; Sidhaye, A. R. Tetrahedron Lett. 1979, 52, 5025.

Asymmetric Deprotonation by BuLi/(-)-Sparteine
J. Am. Chem. Soc., Vol. 118, No. 4, 1996 717
Table 1. Enantioselective Conversion of 1 to (S)-11 with s-BuLi/
(-)-Sparteine in Different Solvents at -78 °C
of enantiomeric excess by chromatography on the (S)-N1N-
naphthylleucine column.12 Since n-BuLi is a more available
reagent, reaction of 1 with n-BuLi/(-)-sparteine was carried
out and found to afford (S)-11 in 55% yield with 93% ee in
toluene. Reaction with t-BuLi/(-)-sparteine affords almost
racemic 11 in 14% yield, although the same base/ligand
combination in ether provides (S)-11 in 63% yield with 33%
ee. The p-substituted phenyl derivatives 2-5 give the expected
pyrrolidines (S)-12, (S)-13, (S)-14, and (S)-15 in useful yields
with enantiomeric excess of 84%, 87%, 84%, and 96%,
respectively. The (1-naphthylmethyl)-Boc-amine and 2-naph-
thylmethyl-Boc amine derivatives 6 and 7 give moderate yields
of (S)-16 and (S)-17 with enantiomeric excess of 93% and 90%
ee with s-BuLi/(-)-sparteine. Enantiomeric excesses of 93%
and 96% are also observed for (S)-18 and (S)-19 from the
heteroaromatic Boc-amine derivatives 8 and 9 but the yields
are lower. With 8, n-BuLi/(-)-sparteine is also effective.
solvent
yield (%)
eea (%)
THF
t-BuOMe
Et2O
Et2O:pentane (1:1)
pentane
toluene
58
64
59
40
54
72
3
58
64
70
80
96
a The error is estimated as (5%.
Table 2. Enantioselective Lithiation-Cyclizations of 1-9 with
BuLi/(-)-Sparteine To Provide (S)-11-19 in Toluene at -78 °C
reactant
Ar
product
base
yield (%) eea (%)
1
1
1
2
3
4
5
6
7
8
8
9
10
Ph-
Ph-
Ph-
(S)-11
(S)-11
(S)-11
s-BuLi
n-BuLi
t-BuLib
72
55
14
62
69
75
46
68
70
52
51
21
42
96
93
-8c
84
87
84
96
93
90
93
93
96
3
p-ClPh-
p-FPh-
(S)-12d s-BuLi
(S)-13e s-BuLi
p-MePh-
(S)-14f
s-BuLi
m-MeOPh- (S)-15g s-BuLi
1-naphthyl
2-naphthyl
3-thienyl
3-thienyl
3-furyl
(S)-16h s-BuLi
(S)-17h s-BuLi
(S)-18
(S)-18
(S)-19
20i
n-BuLi
s-BuLi
s-BuLi
s-BuLi
However, the reaction of (p-methoxybenzyl)(3-chloropropyl)-
Boc-amine (10) with s-BuLi/(-)-sparteine gives 20 as a racemic
product in modest yield. This lack of enantioselectivity is not
attributable to the presence of a methoxy group as a competing
site of complexation as shown by the fact that 5 undergoes
cyclization-lithiation under the same conditions to provide (S)-
15 with a high enantiomeric excess.20 A brief investigation of
the effect of the leaving group on the reaction was carried out
with the mesylate 21a and the bromide 21b. From the mesylate,
(S)-11 was obtained in very low yield but with high ee, while
the bromide gave (S)-11 in lower yield and enantioselectivity
than from 1.
p-MeOPh-
a The error is (5%. b In ether (S)-11 is obtained in 63% yield with
33% ee. c The major enantiomer is (R)-11. d See ref 14. e See ref 15.
f See ref 16. g See ref 17. h See ref 18. i See ref 19.
followed by reduction with lithium aluminum hydride provides
the chiral diamine (S,S)-23 in 49% overall yield.
Pathway of the Lithiation-Cyclization of 1 to (S)-11. The
enantioselective formation of (S)-11 from 1 could involve either
asymmetric deprotonation or asymmetric substitution. Under
the first possibility, enantioselective deprotonation of 1 with a
BuLi/(-)-sparteine complex would provide (S)-24, an enan-
tioenriched organolithium intermediate which would cyclize to
(S)-11 faster than it racemizes.22,23 Under the pathway of
asymmetric substitution, deprotonation of 1 would provide
racemic 24 either directly or by subsequent rapid racemization,
and this intermediate would cyclize enantioselectively to (S)-
11 under the influence of (-)-sparteine. Precedents for both
pathways have been reported for analogous systems.2,24,25
The alternative mechanisms can be distinguished by experi-
ments with 1-d1.23-25 If the asymmetric induction occurs
through asymmetric deprotonation with cyclization faster than
A combination of this lithiation-cyclization with our earlier
enantioselective substitutions of Boc pyrrolidine is illustrated
by the synthesis of (S)-5-phenyl-(S)-2-methyl-Boc-pyrrolidine
[(S,S)-22]. Lithiation of (S)-11 with s-BuLi/(-)-sparteine gives
(S)-5-phenyl-(R)-2-lithio-Boc-pyrrolidine, which reacts with
dimethyl sulfate to provide (S,S)-22 in 45% yield with a
diastereomeric ratio of 93:7 in favor of the syn diastereomer.21
(22) The assumption is that the cyclization of (S)-24 would proceed with
retention of configuration at the benzylic position.17 This is not necessarily
the case, and the intermediency of (R)-24 which reacts with inversion is
also possible.1
The conversion of (S)-11 to the C2-symmetric chiral pyrrol-
idine-based diamine (S,S)-23 has been carried out. Cleavage
of the Boc group of (S)-11 and reaction with oxalyl chloride
(23) Schlosser and Limat have found that deprotonation of benzylmethyl-
Boc-amine with s-BuLi/(-)-sparteine is highly asymmetric but that race-
mization is rapid and that the configuration of the subsequent asymmetric
substitution is highly solvent dependent. Schlosser, M. Private communica-
tion, June 1994. Contribution by M. Schlosser and D. Limat at the Chiral-2
Workshop in Gwatt, March 1995, Symposium Brochure, p A-4.
(24) Hoppe, D.; Paetau, M.; Hintze, F. Angew. Chem., Int. Ed. Engl.
1993, 32, 394.
(20) The source of the low enantiomeric excess with 10 has not been
determined. Equilibration by a ring-opening ring sequence promoted by
the p-methoxy group is possible. It is also noted that a p-methoxy group
has been reported to have a deleterious effect on a lateral lithiation. Clark,
R. D.; Muchowski, J. M.; Fisher, L. E.; Flippin, L. A.; Nephe, D. B.;
Souchet, M. Synthesis 1991, 871
(21) The R configuration of the organolithium intermediate is assigned
by analogy to our previous work.2
(25) Beak, P.; Du, H. J. Am. Chem. Soc. 1993, 115, 2516.

718 J. Am. Chem. Soc., Vol. 118, No. 4, 1996
Wu et al.
Table 3. Reactions of 1 and 1-d1 with s-BuLi/(-)-Sparteine To
Provide (S)-11 and (S)-11-d1 in Diethyl Ether
reactant reaction conditions
1-d1 (96% d1)
a
yield ee d1
(%) (%) (%)
1
6 h
6 h
53 65b
43 30b 88
45 46 46
1, 1-d1 (50% d1) 6 h
1-d1 (96% d1)
0.5 equiv of s-BuLi, 0.55 equiv of 18c 44 91
(-)-sparteine, 3.75 h
1
0.5 equiv of s-BuLi, 0.55 equiv of 26c 60
(-)-sparteine, 3.75 h
a The deuterium incorporation was determined by FIMS. The error
is (5%. b The enantioenrichment was shown not to be dependent on
the reaction time. c The yield is relative to s-BuLi.
racemization of the enantioenriched intermediate, significant
differences should be observed between the reaction of 1 and
of racemic 1-d1. The possibilities are outlined for the racemic
mixture of (R)-1-d1 and (S)-1-d1. The R enantiomer of 1-d1
would be expected to undergo deprotonation fully analogous
to 1 and lead to (S)-24-d1 and (S)-11-d1. However, the reaction
of (S)-1-d1, which has the deuterium in the preferred position
for enantioselective removal, could follow three possible
courses: the enantiomer (S)-1-d1 could undergo removal of the
deuterium at a slower rate than reaction of 1, undergo removal
of the hydrogen, or be unreactive.26 If the deuterium is removed
to give (S)-24 (Case A), the deuterium content of (S)-11-d1
would be less than that of the reactant 1-d1, but the enantiomeric
excess of (S)-11-d1 would be comparable to that of (S)-11 from
1. In this case, the facial selectivity in the deprotonation would
override the kinetic isotope effect. If the hydrogen is removed
from (S)-1-d1 to give (R)-24-d1 (Case B), the product would be
(R)-11-d1 and the enantiomeric excess of 11-d1 would be eroded
relative to the reaction of 1. In this case, the kinetic isotope
effect would override the enantioselectivity. If neither the
deuterium nor the hydrogen is removed from (S)-1-d1 (Case
C), then the product would be (S)-11-d1 with a deuterium content
comparable to that of 1-d1 and an enantiomeric excess compa-
rable to that from 1, but a reduced yield relative to that of (S)-
11 from 1. In this case, recovered 1-d1 would be enriched in
(S)-1-d1.
(S)-11-d1 would be formed with a deuterium content comparable
to that of 1-d1, and (S)-11-d1 would have an enantiomeric excess
comparable to that of (S)-11 from 1. If the pathway involves
initial asymmetric deprotonation, rapid racemization, and sub-
sequent asymmetric substitution and if a high isotope effect is
operative, the results of Case C above would be expected.23,24
The lithiation-cyclizations for 1 and 1-d1 were carried out
in diethyl ether, which gives a lower enantioselectivity than
toluene and has the advantage of a more easily measured
response in enantioselectivities to any changes in reaction
energetics. The results of the comparison are summarized in
Table 3.
Comparisons of the enantioenrichments and deuterium con-
tents in (S)-11 and (S)-11-d1 from the reactions of 1 and 1-d1,
respectively, are shown in the first two entries. The deuterium
content of (S)-11-d1 is close to that of 1-d1. However, the yield
of (S)-11-d1 is reduced relative to (S)-11. Moreover, the 82:17
ratio of 65% ee for (S)-11 from 1 becomes a 65:35 ratio of
30% ee for (S)-11-d1 from 1-d1. This difference in enantio-
enrichment and yield is consistent with a combination of Cases
B and C and indicates that the pathway of the formation of
(S)-11 from 1 by s-BuLi/(-)-sparteine is predominately asym-
metric deprotonation.27 Apparently (R)-1-d1 behaves as does 1
with s-BuLi /(-)-sparteine while (S)-1-d1 loses its hydrogen,
albeit more slowly than does 1.
The competitive reaction of a mixture of 1 and 1-d1 shows,
as expected, an enantioenrichment between the two extremes.
The reaction of 1-d1 with a deficient amount of s-BuLi /(-)-
sparteine also provides an enantioenrichment between the two
extremes, also as expected. With the deficiency of base, more
of (R)-1-d1 should react than (S)-1-d1. The reaction with 1 in
the last entry is a comparison control experiment.
Another test for the possibility of asymmetric substitution
has been carried out by the transmetalation of the racemic tin
precursor 25 in the presence of (-)-sparteine to generate a
racemic 24. If the asymmetric induction can proceed through
enantioselective substitution, racemic 24 should complex with
(-)-sparteine and (S)-11 should be formed with 65% enantio-
meric excess. The transmetallation of 25 and cyclization in the
presence of (-)-sparteine provided nearly racemic 11 in 44%
If the asymmetric induction occurs only through asymmetric
substitution, the enantiodetermining steps occur after the lithia-
tion. In this case there is no chiral preference in the depro-
tonation and 24-d1 should be selectively formed due to the large
deuterium isotope effect at -78 °C.5,24,26 The subsequent
cyclization would proceed under the influence of (-)-sparteine,
(26) Kaiser, B.; Hoppe, D. Angew. Chem., Int. Ed. Engl. 1995, 34, 323.
(27) Similar results were observed in toluene and in pentane.

Asymmetric Deprotonation by BuLi/(-)-Sparteine
J. Am. Chem. Soc., Vol. 118, No. 4, 1996 719
5 mL) and the combined ether extracts were washed with 5%
phosphoric acid (10 mL) and water (2 × 10 mL), dried (MgSO4),
filtered, and concentrated in Vacuo. The crude product was further
purified by chromatography (EtOAc/hexane, 1/9) to give (S)-11 as a
colorless oil which solidified at 0 °C (178 mg, 72%): Rf ) 0.39 (9:1
yield. Thus, the possibility of reaction mainly by asymmetric
substitution is unlikely.28
1
hexane/ethyl acetate); mp 58-60 °C; H-NMR (CDCl3, 300 MHz) δ
1.16, 1.43 (s, s, 9H), 1.83-1.91 (m, 3H), 2.28 (m, 1H), 3.59 (m, 2H),
4.74, 4.90 (m, m, 1H), 7.14-7.31 (m, 5H); 13C-NMR (CDCl3, 75 MHz)
δ (23.2, 23.3), (28.2, 28.4), (36.0, 36.0), 47.1, 61.3, 79.1, 125.4, 126.
5, 128.1, 154.5. Anal. Calcd for C15H21NO2: C, 72.87, H, 8.50, N,
5.66. Found: C, 72.89, H, 8.57, N, 5.66. The enantiomeric excess of
(S)-11 could be measured directly by chiral stationary phase HPLC on
the Whelk-0 column (2.5% iPrOH/hexane; flow rate 1.00 mL/min; Rf
of minor peak: 11.1 min, Rf of major peak: 26.0 min). However, the
peak from the minor enantiomer was interfered with by trace amounts
of unknown highly UV absorptive materials.
In summary, the present results provide convenient methodol-
ogy for syntheses of (S)-2-aryl-Boc-pyrrolidines in high enan-
tiomeric excesses.29 The mechanism of the enantioselective
induction is enantioselective deprotonation by a BuLi/(-)-
sparteine complex to yield an enantioenriched lithiated species
which undergoes cyclization more rapidly than racemization.
The methodology of the present work should also be applicable
to enantioselective syntheses and mechanistic analysis of a
number of related systems.
Enantiomeric Analysis of (S)-11. To a solution of (S)-11 (74 mg,
0.26 mmol) in methylene chloride (2 mL) at ambient temperature was
added excess trifluoroacetic acid (15%, 30 mL). The reaction mixture
was stirred for 3 h at ambient temperature. The solution was
concentrated in Vacuo, diluted with 10% NaOH (3 mL), and extracted
with ether. the combined extracts were washed with water, dried
(MgSO4), filtered, and concentrated in Vacuo to give (S)-2-phenyl-
pyrrolidine as a light yellow oil (37.4 mg, 86%); [R]D ) -18.6°, c )
1
Experimental Section
0.88 lit.6a [R]D ) -22.4°); H-NMR (CDCl3, 300 MHz) δ 1.67-2.20
(m, 4H), 2.54 (s, 1H), 2.99 (m, 1H), 3.18 (m, 1H), 4.15, (t, 1H, J )
7.71 Hz), 7.23-7.38 (m, 5H); 13C-NMR (CDCl3, 75 MHz) δ 25.5,
34.3, 46.9, 47.1, 62.2, 79.2, 125.5, 126.5, 128.2, 154.6.
General. Compounds which were not submitted for or did not pass
elemental analysis were judged to be of >95% purity based on H-
1
NMR, 13C-NMR, MS, and GLC analyses unless stated otherwise. The
NMR spectra of such compounds are provided. sec-Butyllithium (s-
BuLi) as a solution in cyclohexane, n-butyllithium (n-BuLi) as a solution
in hexanes, and tert-butyllithium (t-BuLi) as a solution in pentane were
obtained from Lithium Corp. and were titrated by using N-pivaloyl-
o-toluidine as the indicator.30 All reactions involving air-sensitive
reagents were performed under nitrogen or argon using syringe-septum
cap techniques.
To a mixture of (S)-2-phenylpyrrolidine in THF (2 mL) and 3,5-
dinitrobenzoyl chloride (47 mg, 0.2 mmol) in THF (2 mL) was added
triethylamine (30 mL). The resulting mixture was stirred for 2 h at
ambient temperature. The solution was concentrated in Vacuo, diluted
with 10% NaOH, and extracted with ether. The combined ethereal
extracts were washed with 10% HCl and water, dried (MgSO4), filtered,
and concentrated in Vacuo to give the 2-phenyl-N-(3,5-dinitrobenzoyl)-
pyrrolidine as a light yellow solid (83.7 mg, 90%): 1H-NMR (CDCl3,
300 MHz) δ 1.97-2.14 (m, 3H), 2.35-2.47 (m, 1H), 3.97 (m, 2H),
4.74, 5.35 (m, m, 1H, ratio: 2:1), 6.93 (m, 1H), 7.19-7.38 (m, 4H),
8.26 (s, 1H), 8.70-9.20 (s,s,s, 2H).
The enantiomeric purity of (S)-2-phenyl-N-Boc-pyrrolidine was
determined to be 96% by chiral stationary phase HPLC of the 3,5-
dinitrobenzamide derivative on the (S)-N1N-naphthylleucine column
using racemic material as a standard (Rf of minor peak: 41.7 min, Rf
of major peak: 46.7 min).12
Boc-(S)-2-(p-chlorophenyl)pyrrolidine (12).14 Enantioselective cy-
clization of 2 was carried out using the standard procedure above to
give 12 (175 mg, 62%): mp 55-57 °C; 1H-NMR (CDCl3, 300 MHz)
δ 1.19, 1.43 (s, s, 9H), 1.85 (m, 3H), 2.29 (m, 1H), 3.57 (m, 2H), 4.72,
4.90 (s,s 2H), 7.07-7.26 (d, d, 4H, J ) 8.18 Hz, J ) 8.45 Hz); 13C-
NMR (CDCl3, 75 MHz) δ (23.1, 23.4), (28.2, 28.4), 34.8, 36.0), (47.1,
47.3), (60.0, 60.7), 79.4, 126.9, (128.2, 128. 5), (132.1, 132.1), 143.7,
154.4. Anal. Calcd for C15H20ClNO2: C, 64.05; H, 7.11; N, 4.98.
Found: C, 64.06; H, 7.18; N, 4.93.
Boc-3-chloropropylamine. To a solution of di-tert-butyldicarbonate
(10.4 g, 50.0 mmol) and triethylamine (6.30 g, 60 mmol) in THF (100
mL) was added 3-chloropropylamine hydrochloride (6.96 g, 54.0 mmol)
at 0 °C. The resulting mixture was stirred for 20 min, warmed to
ambient temperature, and then stirred for 18 h. The mixture was diluted
with 50 mL of 10% sodium bicarbonate solution and extracted with
ether (2 × 40 mL). The extracts were washed with brine, dried
(MgSO4), concentrated, and Kugelrohr distilled to give N-Boc-3-
chloropropylamine as a clear oil (8.25 g, 85%): 1H-NMR (CDCl3, 300
MHz) δ 1.42 (s, 9H), 1.91 (m, 2H), 3.25 (m, 2H), 3.59 (t, 2H, J )
6.33 Hz), 4.70 (m, 1H); 13C-NMR (CDCl3, 100 MHz) δ 28.2, 32.4,
37.7, 42.2, 79.0, 155.9. Anal. Calcd for C8H16NO2Cl: C, 49.61; H,
8.33; N, 7.23; O, 16.52; Cl, 18.31. Found: C, 49.82; H, 8.22; N, 7.27;
Cl, 18.26.
General Procedure for the Preparation of Boc-(arylmethyl)(3-
chloropropyl)amines 1-10. Sodium hydride (400 mg, 60% dispersion
in mineral oil) was washed with three portions of hexane. Then THF
(15 mL) and N-(tert-butoxycarbonyl)-3-chloropropylamine (1.03 g, 5
mmol) in THF (5 mL) and the arylmethyl bromide (7.5 mmol) were
added and heated to reflux for 4 h. Water (10 mL) was added, and the
solution was extracted by ether (3 × 20 mL). The combined extracts
were washed with water, dried (MgSO4), and concentrated in Vacuo.
The crude product was purified by chromatography to give 1-10 in
42-63% yields.
Boc-(S)-2-phenylpyrrolidine [(S)-11]. A solution of 1 (283 mg, 1
mmol) in toluene was transferred to the reaction mixture of (-)-
sparteine (364 mg, 1.5 mmol) and s-BuLi (1.3 mL, 1.2 M in
cyclohexane) at -78 °C. The resulting reaction mixture was stirred at
-78 °C for 5 h. Then water (5 mL) and ether (10 mL) were added to
quench the reaction. The aqueous layer was extracted with ether (3 ×
(28) The possibility that the tin lithium exchange and the deprotonation
do not produce the same organolithium intermediate with respect to
complexation with (-)-sparteine on the time scale of the experiment is more
difficult to rule out, however.
The enantiomeric purity of 12 was determined to be 84% by chiral
stationary phase HPLC of the 3,5-dinitrobenzamide derivative of 2-(p-
chlorophenyl)pyrrolidine on the (S)-N1N-naphthylleucine column (Rf
of minor peak: 39.6 min, Rf of major peak: 47.5 min).
Boc-(S)-2-(p-fluorophenyl)pyrrolidine (13).15 Enantioselective cy-
clization of 3 was carried out using the standard procedure above to
give 13 (182 mg, 69%): mp 69-71 °C; 1H-NMR (CDCl3, 300 MHz)
δ 1.18, 1.43 (s, s, 9H), 1.85 (m, 3H), 2.29 (m, 1H), 3.60 (m, 2H), 4.72,
4.90 (s, s 2H), 7.03-7.26 (m, 4H); 13C-NMR (CDCl3, 75 MHz) δ (23.2,
23.2), (28.2, 28.3), (35.0, 36.1), (47.1, 47.1), (59.9, 60.7), 79.3, (114.7,
114.8), (126.9, 127.0), 140.0,154.5, 159.9, 163.2. Anal. Calcd for
C15H21FNO2: C, 67.92; H, 7.54; N, 5.28. Found: C, 67.91; H, 7.54;
N, 5.22.
The enantiomeric excess of (S)-13 could be measured directly by
chiral stationary phase HPLC on the Whelk-0 column (Rf of minor
peak: 10.2 min, Rf of major peak: 24.6 min). The enantiomeric purity
of 13 was determined to be 87% by chiral stationary phase HPLC of
the 3,5-dinitrobenzamide derivative of 2-(p-fluorophenyl)pyrrolidine
(29) The cyclization to form six-membered rings was attempted, but we
were unable to obtain high ee’s and good yields.
(30) Suffert, J. J. Org. Chem. 1989, 54, 509.

720 J. Am. Chem. Soc., Vol. 118, No. 4, 1996
Wu et al.
on the (S)-N1N-naphthylleucine column (Rf of minor peak: 40.6 min,
Rf of major peak: 47.3 min).
The enantiomeric purity of 19 was determined to be 96% by chiral
stationary phase HPLC of the 3,5-dinitrobenzamide derivative of 2-(3-
furyl)pyrrolidine on the (S)-N1N-naphthylleucine column (Rf of minor
peak: 49.6 min, Rf of major peak: 53.7 min).31
Boc-(S)-2-(p-tolyl)pyrrolidine (14).16 Enantioselective cyclization
of 4 was carried out using the standard procedure described above to
give 14 (165 mg, 65%): mp 65-66 °C; 1H-NMR (CDCl3, 300 MHz)
δ 1.19, 1.45 (s,s, 9H), 1.79 (m, 3H), 2.29 (m, 1H), 2.31 (s, 3H), 3.60
(m, 2H), 4.73, 4.74 (s,s, 2H), 7.07-7.26 (d,d, 4H).13C-NMR (CDCl3,
75 MHz) δ 21.0, (23.1, 23.1), (28.2, 28.5), (35.0, 36.0), (47.0, 47.2),
(60.0, 61.1), 79.1, (125.3, 125.4), (128.7, 129.0), 135.9, (142.0, 142.1),
154.6. Anal. Calcd for C16H23NO2: C, 73.56; H, 8.81; N, 5.36.
Found: C, 73.63; H, 8.89; N, 5.34.
Boc-2-(p-methoxyphenyl)pyrrolidine (20).19 Cyclization of 10 was
carried out using the standard procedure above (116 mg, 42%): 1H-
NMR (CDCl3, 300 MHz) δ 1.19 and 1.43 (s, s, 9H), 1.76-1.90 (m,
3H), 2.19-2.38 (m, 1H), 3.59 (brs, 2H), 3.78 (s, 3H), 4.76, 4.90 (s,s
1H), 6.83 (d, J ) 8.6 Hz, 2H), 7.08 (d, J ) 8.6 Hz, 4H).32
The enantiomeric purity of 20 was measured as 3% by chiral
stationary phase HPLC of the 3,5-dinitrobenzamide derivative of 2-(p-
methoxyphenyl)pyrrolidine on the (S)-N1N-naphthylleucine column (Rf
of minor peak: (Rf of minor peak: 38.5 min, Rf of major peak: 44.9
min).
One Gram Scale Preparation of Boc-(S)-2-phenylpyrrolidine [(S)-
11]. A solution of 1 (1.13g, 4 mmol) in toluene (40 mL) was transferred
to the reaction mixture of (-)-sparteine (1.52 g, 6.26 mmol) and s-BuLi
(4.8 mL, 1.26 M in cyclohexane) at -78 °C. The resulting reaction
mixture was stirred at -78 °C for 8 h, and then water and ether were
added to quench the reaction. The aqueous layer was extracted with
ether. The combined ether extracts were washed with 5% phosphoric
acid and water, dried (MgSO4), filtered, and concentrated in Vacuo.
The crude product was further purified by chromatography (EtOAc/
hexane, 1/9) to give (S)-11 as a colorless oil which solidified at 0 °C
(0.65 g, 66%).
The enantiomeric purity of (S)-11 was determined to be 92% by
chiral stationary phase HPLC of the 3,5-dinitrobenzamide derivative
of 2-phenyl-N-(tert-butoxycarbonyl)pyrrolidine on the (S)-N1N-naph-
thylleucine column.
The product (0.6 g, 92% ee) was dissolved in hexane (3 mL) and
allowed to stand at 0 °C overnight. Needle-like crystals were obtained
by filtration (0.53 g, 88%). The enantiomeric purity of (S)-11 was
determined to be >98% by chiral stationary phase HPLC of the 3,5-
dinitrobenzamide derivative of 2-phenyl-N-(tert-butoxycarbonyl)-
pyrrolidine on the (S)-N1N-naphthylleucine column.
The enantiomeric purity of 14 was determined to be 86% by chiral
stationary phase HPLC of the 3,5-dinitrobenzamide derivative of 2-(p-
methylphenyl)pyrrolidine on the (S)-N1N-naphthylleucine column (Rf
of minor peak: 36.1 min, Rf of major peak: 41.3 min).
Boc-(S)-2-(m-methoxyphenyl)pyrrolidine (15).17 Enantioselective
cyclization of 5 was carried out using the standard procedure above to
give 15 (128 mg, 46%): 1H-NMR (CDCl3, 300 MHz) δ 1.20, 1.41
(bs, bs, 9H), 1.84 (m, 3H), 2.27 (m, 1H), 3.59 (m, 2H), 3.77 (s, 3H),
4.80 (m, 1H); 6.70-6.75 (m, 3H), 7.16-7.22 (m, 1H); 13C-NMR
(CDCl3, 75 MHz) δ 23.3, 28.3, 35.9, 47.1, 55.2, 61.2, 79.2, 111.2,
111.7, 117.9, 129.2, 154.6, 159.6.
The enantiomeric purity of 15 was determined to be 96% by chiral
stationary phase HPLC of the 3,5-dinitrobenzamide derivative of 2-(m-
methoxyphenyl)pyrrolidine on the (S)-N1N-naphthylleucine column (Rf
of minor peak: 37.0 min, Rf of major peak: 41.5 min).
Boc-(S)-2-(1-naphthyl)pyrrolidine (16).18 Enantioselective cy-
clization of 6 was carried out using the standard procedure above to
give 16 (204 mg, 68%): mp 101-103 °C; 1H-NMR (CDCl3, 300 MHz)
δ 1.10, 1.49 (s,s, 9H), 1.91 (m, 3H), 2.44 (m, 1H), 3.50-3.78 (m, 2H),
5.59, 5.79 (d, d 2H, J ) 6.55 Hz), 7.20-8.02 (m, 7H); 13C-NMR
(CDCl3, 75 MHz) δ (23.0, 23.5), (28.1, 28.5), (33.3, 34.4), (46.9, 47.3),
(58.0, 58.2), (79.2, 79.4), (121.4, 121.4), (123.0, 123.3), (125.3, 125.8),
(127.1, 127.3), (128.8, 128.8), (128.8, 130.3), (133.8, 139.9), (154.0,
154.6). Anal. Calcd for C19H23NO2: C, 76.76; H, 7.74; N, 4.71.
Found: C, 76.69; H, 7.76; N, 4.74.
Boc-(S)-2-phenyl-(R)-5-methylpyrrolidine [(S,S)-22]. To a solu-
tion of (S)-11 (>98% ee) (130 mg, 0.53 mmol) in ether (2.5 mL) at
-78 °C were added (-)-sparteine (291 mg, 1.20 mmol) and sec-
butyllithium (1 mL, 1.20 M, 1.20 mmol) in ether (2.5 mL, precooled
to -78 °C for 15 min). The resulting mixture was stirred at -78 °C
for 8 h, and then dimethyl sulfate (253 mL, 216 mg, 2 mmol) was
slowly added. This mixture was stirred continuously for another 1 h.
Then water was added at -78 °C. The two layers were separated, and
the aqueous layer was extracted with ethyl ether. The combined extracts
were washed with aqueous H3PO4 and water, dried (MgSO4), filtered,
and evaporated in Vacuo. The crude product was further purified by
chromatography (EtOAc/hexane 1/9) to give (S,S)-22 as a colorless
oil (60 mg, 45%): 1H-NMR (diastereomerically enriched compound)
(CDCl3, 300 MHz) δ 1.07-120 (bs, 9H), 1.38 (d, J ) 6.30 Hz, 3H),
1.58 (m, 1H), 1.88 (m, 1H), 2.00 (m, 1H), 2.23 (m, 1H), 4.15 (m, 1H),
4.75 (m, 1H), 7.17-7.32 (m, 5H); 13C-NMR (CDCl3, 125 MHz) δ 21.0,
28.1, 31.7, 34.7, 54.5, 63.0, 79.0, 125.5, 126.3, 128.1, 144.9, 154.7;
HRMS calcd for C16H23NO2 (M+) 261.1729, found 261.1724 (0.5
mDa).
The enantiomeric purity of 16 was determined to be 93% by chiral
stationary phase HPLC of the 3,5-dinitrobenzamide derivative of 2-(1-
naphthyl)pyrrolidine on the (S)-N1N-naphthylleucine column (Rf of
minor peak: 33.1 min, Rf of major peak: 36.8 min).
Boc-(S)-2-(2-naphthyl)pyrrolidine (17).18 Enantioselective cy-
clization of 7 was carried out using the standard procedure above to
give 17 (205 mg, 70%): mp 95-96 °C; 1H-NMR (CDCl3, 300 MHz)
δ 1.14, 1.47 (s, s, 9H), 1.90 (m, 3H), 2.36 (m, 1H), 3.68 (m, 2H), 4.94,
5.15 (s, s 2H), 7.25-7.80 (m, 7H). 13C-NMR (CDCl3, 75 MHz) δ
23.19, (28.16, 28.36), (35.81, 35.85), (47.16, 47.19), (61.36, 61.38),
79.26, (123.79, 124.14), (125.34, 125.91), (126.00, 127.59), (127.65,
127.73), (127.97, 128.01), (132.45, 133.27), (154.65, 154.68). Anal.
Calcd for C19H23NO2: C, 76.76; H, 7.74; N, 4.71. Found: C, 76.74;
H, 7.72; N, 4.71.
The enantiomeric purity of 17 was determined to be 90% by chiral
stationary phase HPLC of the 3,5-dinitrobenzamide derivative of 2-(2-
naphthyl)pyrrolidine on the (S)-N1N-naphthylleucine column (Rf of
minor peak: 42.7 min, Rf of major peak: 52.0 min).
Boc-(S)-2-(3-thienyl)pyrrolidine (18). Enantioselective cyclization
of 8 was carried out using the standard procedure above to give 18
The ratio of diastereomers was measured by GC isothermal condi-
tions at 150 °C (86% de).
1
(127 mg, 51%): mp 42-44 °C; H-NMR (CDCl3, 300 MHz) δ 1.28
1,2-Bis((S)-2-phenylpyrrolidinyl)ethane (23). A solution of (S)-
11 (97% ee) (0.605g, 2.45 mmol) in methylene chloride (25 mL) at
ambient temperature was treated with excess trifluroacetic acid (15%,
3.75 mL) and stirred for 3 h at ambient temperature. The solution
was concentrated in Vacuo, diluted with 10% NaOH (20 mL), and
extracted with ether (3 × 20 mL), and the combined extracts were
washed with water (2 × 20 mL), dried (MgSO4), filtered, and
concentrated in Vacuo to give the (S)-2-phenylpyrrolidine as a light
yellow oil (0.3 g, 83%): 1H-NMR (CDCl3, 300 MHz) δ 1.67-2.20
(m, 4H), 2.54 (s, 1H), 2.99 (m, 1H), 3.18 (m, 1H), 4.15 (t, 1H, J )
7.71 Hz), 7.23-7.38 (m, 5H); 13C-NMR (CDCl3, 75 MHz) δ 25.5,
34.3, 47.0, 47.1, 62.2, 79.1, 125.5, 126.5, 128.2, 154.6.
(bs, 9H), 1.89 (m, 3H), 2.19 (m, 1H), 3.53 (m, 2H), 4.89 (m, 2H), 6.91
(m, 2H), 7.25 (m, 1H); 13C-NMR (CDCl3, 75 MHz) δ 23.3, 28.3, 34.7,
46.5, 57.1, 79.2, 119.6, 125.5, 125.9, 145.6, 154.6. Anal. Calcd for
C13H19NO2S: C, 61.66; H, 7.50; N, 5.53. Found: C, 61.60; H, 7.47;
N, 5.58.
The enantiomeric purity of 18 was determined to be 93% by chiral
stationary phase HPLC of the 3,5-dinitrobenzamide derivative of 2-(3-
thienyl)pyrrolidine on the (S)-N1N-naphthylleucine column (Rf of minor
peak: 49.6 min, Rf of major peak: 54.6 min).
Boc-(S)-2-(3-furyl)pyrrolidine (19). Enantioselective cyclization
of 9 was carried out using the standard procedure above to give 19 (50
mg, 21%): 1H-NMR (CDCl3, 300 MHz) δ 1.38 (s, 9H), 1.88 (m, 3H),
2.15 (m, 1H), 3.45 (m, 2H), 4.81 (m, 1H), 6.27 (s, 1H), 7.24 (s, 1H),
7.32 (s, 1H); 13C-NMR (CDCl3, 75 MHz) δ 23.4, 28.4, 33.5, 46.2,
52.9, 79.3, 109.0, 128.2, 138.8, 142.9, 154.5.
(31) Compound 19 was not characterized in detail due to the impractical
yield.
(32) Compound 20 was not characterized in detail due to the low ee.

Asymmetric Deprotonation by BuLi/(-)-Sparteine
J. Am. Chem. Soc., Vol. 118, No. 4, 1996 721
To a solution of (S)-2-phenylpyrrolidine (0.30 g, 2.04 mmol) in
methylene chloride (15 mL) were added triethylamine (0.2 mL) and
oxalyl chloride (0.132 g, 1.02 mmol) at -78 °C, and the resulting
mixture was stirred for 3 h at ambient temperature. The solvent was
evaporated in Vacuo, and the residue was taken up with ether (30 mL),
then washed successively with water (10 mL), 5% HCl (10 mL), and
water (2 × 20 mL), and dried (MgSO4). The crude product was further
purified by chromatography (EtOAc/hexane, 2/3) to give the diamide
as a colorless oil which was solidified at 0 °C (0.21 g, 50%); 1H-NMR
(CDCl3, 300 MHz) δ 1.61 (m, 3H), 1.91 (m, 2H), 2.10 (m, 1H), 2.47
(m, 1H), 2.87 (m, 1H), 3.63-3.90 (m, 4H), 4.52 (t, 1H), 5.23 (t, 1H),
7.07-7.37 (m, 10H).
chloride (3.2 mL, 3.2 mmol, 1.0 M soln in hexane), was added. The
reaction solution was stirred for another 10 min, and then quenched at
-78 °C with 30 mL of 0.5 M H3PO4 (aq). This was allowed to warm
to ambient temperature, the layers were separated, and the aqueous
layer was extracted with diethyl ether. The organic extracts were
washed with NaHCO3 (aq) and NaCl (aq), dried (MgSO4), filtered,
and concentrated in Vacuo. Purification by flash chromatography (silica;
20:1 hexane/ethyl acetate) yielded Boc R-trimethylstannylbenzylamine
as a clear, yellow oil (0.82 g, 76%): Rf ) 0.38 (20:1 hexane/ethyl
acetate). 1H-NMR (CDCl3, 300 MHz) δ 7.28-7.01 (m, 5H), 5.19 (brs,
1H), 4.01 (d, J ) 4.0 Hz, 1H), 1.47 (s, 9H), 0.01 (s, 9H). 13C-NMR
(CDCl3, 75 MHz) δ 157.3, 145.0, 128.3, 124.6, 124.2, 79.3, 46.8, 28.3,
-7.7.
To a solution of Boc-R-(trimethylstannyl)benzylamine (808 mg, 2.18
mmol) in 4.5 mL of THF at 0 °C was added sodium hydride (131 mg,
60% dispersion in mineral oil, 3.27 mmol). After the mixture was
stirred for 15 min, 1-bromo-3-chloropropane (0.323 mL, 3.27 mmol)
was added, and this allowed to warm to ambient temperature. After 7
h, the reaction mixture was quenched with NH4Cl (aq). The aqueous
layer was extracted with diethyl ether. The combined organic layers
were dried (MgSO4), filtered, and concentrated. Purification by flash
chromatography (silica; 30:1 hexane/ethyl acetate) yielded 25 as a clear
and colorless oil (114 mg, 12%): Rf ) 0.37 (30:1 hexane/ethyl acetate);
1H-NMR (CDCl3, 300 Mhz) δ 7.26-6.94 (m, 5H), 3.68 (s, 1H), 3.63
and 3.17 (m, 2H), 3.48 (t, J ) 6.3 Hz, 2H), 1.95 (qt, J ) 6.6 Hz, 2H)
1.51 (s, 9H), -0.03 (s, 9H); 13C-NMR (CDCl3, 125 MHz) δ 157.4,
143.8, 128.3, 124.5, 124.4, 80.0, 54.9, 46.7, 42.3, 31.5, 28.4, -6.7.
Transmetalation of 25 to 11. To a solution of 25 (110 mg, 0.246
mmol) and of (-)-sparteine (91 µL, 0.34 mmol) in 2.5 mL of diethyl
ether at -78 °C was added s-BuLi (0.308 mL, 1.2 M, 0.369 mmol).
After 5 h, the reaction mixture was quenched at -78 °C with 5 mL of
0.5 M H3PO4 (aq) and allowed to warm to ambient temperature. The
layers were separated, and the aqueous layer was extracted with diethyl
ether (2 × 5 mL). The combined organic extracts were dried (MgSO4),
filtered, and concentrated in Vacuo. Purification on a preparatory TLC
plate (silica; 9:1 hexane/ethyl acetate) yielded a white solid (27 mg,
44%). The enantiomeric excess was measured as 5% in favor of the
S enantiomer by chiral stationary phase HPLC (Whelk-0 column; 2.5%
2-propanol in hexane; 1.0 mL/min).
A THF (10 mL) solution of the diamide (0.21 g) was added to a
stirred suspension of LiAlH4 (0.1 g) in THF (10 mL) at 0 °C, and then
the reaction mixture was heated to reflux for 3 h. After the solution
was cooled to ambient temperature, aqueous sodium sulfate was added
dropwise to the reaction mixture. The resulting precipitate was removed
by filtration. The filtrate was dried (MgSO4) and concentrated. The
product (S,S)-23 was obtained as a white solid (0.16 g, 83%): mp 82-
1
83 °C; H-NMR (CDCl3, 300 MHz) δ 1.64-1.89 (m, 6H), 2.10 (m,
5H), 2.65 (m, 2H), 3.21 (m, 4H), 7.20-7.28 (m, 10H); 13C-NMR
(CDCl3, 75 MHz) δ 22.5, 34.9, 53.2, 53.8, 70.5, 126.8, 127.5, 128.2,
143.4. Anal. Calcd for C22H28N2: C, 82.50; H, 8.75; N, 8.75.
Found: C, 82.39; H, 8.78; N, 8.73.
General Procedure for the Cyclization of 1 and 1-d1 To Provide
(S)-11 and (S)-11-d1. To a solution of (-)-sparteine (0.375 mL, 1.63
mmol) in 5.1 mL of Et2O at -78 °C was added sec-butyllithium (1.28
mL, 1.2 M, 1.53 mmol). After 5 min, a solution of 1 (289 mg, 1.02
mmol) in 5.1 mL of Et2O at -78 °C was added. After being stirred
for 6 h, the reaction mixture was quenched at -78 °C with 10 mL of
0.5 M H3PO4 (aq) and allowed to warm to ambient temperature. The
layers were separated and the aqueous layer was extracted with Et2O
(2 × 10 mL). The combined organic extracts were dried (MgSO4),
filtered, and concentrated in Vacuo. Purification by flash chromatog-
raphy (9:1 hexane/ethyl acetate) yielded a white solid (135 mg, 53%).
The enantiomeric excess was determined to be 65% in favor of the S
enantiomer by chiral stationary phase HPLC (Whelk-0 column; 2.5%
2-propanol in hexane; 1.0 mL/min). The deuterium enrichment of (S)-
11-d1 was determined by FIMS: 1H-NMR (CDCl3, 300 MHz) δ 7.31-
7.15 (m, 5H), 3.62 (brs, 2H), 2.30 (brs, 1H), 1.84 (m, 3H) 1.44 and
1.18 (brs, 9H); 13C-NMR (CDCl3, 125 MHz) δ 154.6, 145.0, 128.0,
126.4, 125.4, 79.1, 60.9 (t, J ) 21.8 Hz); 47.0, 35.8, 28.1, 23.1.
Boc-N-(3-chloropropyl) r-(trimethylstannyl)benzylamine (25). A
solution of benzylamine (3.00 g, 28.0 mmol) in CH2Cl2 (33 mL) was
cooled to 0 °C, and a CH2Cl2 solution (17 mL) of di-tert-butyl
dicarbonate (6.05 g, 27.7 mmol) was added dropwise over 5 min. The
resulting solution was stirred for 30 min at 0 °C and for 1 h at ambient
temperature and then concentrated in Vacuo. Recrystallization from
hexane gave Boc-benzylamine as white crystals (3.7 g, 64%): mp 52-
Acknowledgment. We are grateful to the National Institutes
of Health-Institute of General Medicine and the National
Science Foundation for support of this work.
Supporting Information Available: The specific prepara-
tions of 1-10, solvent and organolithium reagent effects on the
enantioselective cyclizations of 1, organolithium reagent effect
on the enantioselective cyclization of 8, the preparations and
cyclizations of 21a and 21b, the preparation of 1-d1, and NMR
spectra as criterion of purity of 2-5, 15, 19, 20, and 25 are
provided (30 pages). This material is contained in many
libraries on microfiche, immediately 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.
1
53 °C; Rf ) 0.38 (20:1 hexane/ethyl acetate); H-NMR (CDCl3, 300
Mhz) δ 7.26-6.94 (m, 5H), 3.68 (s, 1H), 3.63 and 3.17 (m, 2H), 3.48
(t, J ) 6.3 Hz, 2H), 1.95 (qt, J ) 6.6 Hz, 2H) 1.51 (s, 9H), -0.03 (s,
9H); 13C-NMR (CDCl3, 125 MHz) δ 157.4, 143.8, 128.3, 124.5, 124.4,
80.0, 54.9, 46.7, 42.3, 31.5, 28.4, -6.7.
To a solution of Boc-N-benzylamine (603 mg, 2.91 mmol) and
TMEDA (0.966 mL, 6.40 mmol) in 5.8 mL of THF at -78 °C was
added s-BuLi (5.33 mL, 6.40 mmol, 1.2 M). After 30 min, trimethyltin
JA9524661