Asymmetric synthesis of 3-hydroxy-pyrrolidines via tin-lithium exchange and cyclization

Article abstract of DOI:10.1021/ol061615p

We report a method for the synthesis of chiral pyrrolidines using tin-lithium exchange and cyclization reactions. The precursors are formed readily from simple starting materials and undergo tin-lithium exchange by treatment with n-butyllithium. Subsequent intramolecular carbolithiation is stereoselective to give highly enantiomerically enriched pyrrolidines in excellent yields.

Full text of DOI:10.1021/ol061615p

ORGANIC
LETTERS
2006
Vol. 8, No. 20
4469-4471
Asymmetric Synthesis of
3-Hydroxy-pyrrolidines via Tin
Exchange and Cyclization
−Lithium
Guido Christoph,† Christian Stratmann,† Iain Coldham,*,‡ and Dieter Hoppe*,†
Organisch-Chemisches Institut, Westfa¨lische Wilhelms-UniVersita¨t Mu¨nster,
Corrensstrasse 40, D-48149 Mu¨nster, Germany, and Department of Chemistry,
UniVersity of Sheffield, Sheffield S3 7HF, U.K.
dhoppe@uni-muenster.de
Received June 30, 2006
ABSTRACT
We report a method for the synthesis of chiral pyrrolidines using tin
readily from simple starting materials and undergo tin lithium exchange by treatment with n-butyllithium. Subsequent intramolecular carbolithiation
is stereoselective to give highly enantiomerically enriched pyrrolidines in excellent yields.
−lithium exchange and cyclization reactions. The precursors are formed
−
The synthesis of chiral pyrrolidines has attracted much
interest in the past few years due to the presence of this ring
system in natural products1 and as chiral ligands and
promotors in organocatalysis.2
of this methodology to form enantiomerically enriched
3-hydroxy-pyrrolidines.
We planned to prepare the desired enantioenriched R-lithio
carbamate using a s-butyllithium/(-)-sparteine-mediated
deprotonation of the alkyl carbamate 4 (Schemes 1 and 2).5
Subsequent substitution with tributyltin chloride would give
the highly enantioenriched stannane 7 as a stable carbanion
equivalent.6 The cyclization precursors would then be
obtained from 7 by simple N-alkylation.
Recently, we reported a powerful route to 2-substituted
cyclopentanols via tin-lithium exchange and intramolecular
cycloalkylation.3 This type of cyclization makes use of chiral
R-lithio carbamates and has also served well in the synthesis
of vinylpyrrolidines.4 We report herein a further extension
† Westfa¨lische Wilhelms-Universita¨t Mu¨nster.
‡ University of Sheffield.
Scheme 1. Synthesis of Alkyl Carbamate 4
(1) (a) Hoppe, D.; Martinez, M. M. Org. Lett. 2004, 6, 3743. (b)
Coldham, I.; Price, K. N.; Rathmell, R. E. Org. Biomol. Chem. 2003, 1,
2111. (c) Coldham, I.; Snowden, D. J.; Vennall, G. P. Chem.-Eur. J. 2002,
8, 195. (d) Coldham, I.; Hufton, R.; Snowden, D. J. J. Am. Chem. Soc.
1996, 118, 5322. (e) Dieter, R. K.; Chen, N.; Watson, R. T. Tetrahedron
2005, 61, 3221.
(2) (a) Wabnitz, T. C.; Saaby, S.; Jorgensen, K. A. Org. Biomol. Chem.
2004, 2, 828. (b) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43,
5138. (c) Jayasree, S.; List, B. Org. Biomol. Chem. 2005, 3, 719. (d) Houk,
K. N.; List, B. Acc. Chem. Res. 2004, 37, 487. (e) Berkessel, A.; Groeger,
H. In Asymmetric Organocatalysis; John Wiley and Sons: Weinheim, 2005.
(f) Wang, J.; Li, H.; Yujiang, M.; Lou, B.; Xu, D.; Xie, D.; Guo, H.; Wang,
W. J. Org. Chem. 2005, 70, 5678.
(3) Christoph, G.; Hoppe, D. Org. Lett. 2002, 4, 2189.
(4) (a) Martinez, M. M.; Hoppe, D. Eur. J. Org. Chem. 2005, 1427. (b)
Deiters, A.; Wibbeling, B.; Hoppe, D. AdV. Synth. Catal. 2001, 1, 181.
10.1021/ol061615p CCC: $33.50
© 2006 American Chemical Society
Published on Web 08/29/2006

The chemistry proceeded smoothly, and the cyclization
precursors were obtained readily by standard transformations.
Imine formation of 2-amino-ethanol (1) with benzaldehyde,
carbamoylation with CbyCl, and subsequent sodium boro-
hydride reduction gave the alkyl carbamate 4 in 55% overall
yield (Scheme 1).
Treatment of stannane 8 with n-butyllithium led to the five-
membered heterocycle 11 (Scheme 3). The tin-lithium
Scheme 3. Cyclization to Pyrrolidines 11 and 13
Scheme 2. Synthesis of Cyclization Precursors 8 and 9
exchange was rapid, and subsequent 5-exo-trig cycloalky-
lation was stereoselective.8 The trans-configured pyrrolidine
(3S,4R)-11 was isolated in enantio- and diastereomerically
pure form in essentially quantitative yield.9
When the substrate 9 was treated with n-butyllithium, a
5-exo-dig intramolecular carbolithiation of the intermediate
R-lithio carbamate with the alkyne moiety was achieved.10
Protonation of the lithiated intermediate 12 with methanol
yielded the 3-benzylidene-pyrrolidine 13 as a single diaste-
reomer. The (E)-configuration of the double bond is the result
of a syn addition onto the triple bond. The cis position of
the phenyl group and the 5-methylene group is supported
by the strong downfield shift by 1 ppm of one of the
diastereotopic protons.
The enantiomeric excess of the pyrrolidine (2S,3R)-11 was
determined by derivatization into the corresponding (R)-
Mosher ester 15 (Scheme 4). Following established protocols,
the Cby group was removed to give the enantiomerically
pure alcohol 14 in 84% yield. The Mosher ester 15 was
obtained by acylation of the alcohol 14 with (R)-2-methoxy-
2-phenyl-3,3,3-trifluoropropanoyl chloride in pyridine.11
It was found necessary to protect the nitrogen atom of the
secondary amino function of 4 prior to introduction of the
tin group. After trying various possibilities, we found that
N-silyl protection7 with tert-butyldimethylsilyl triflate (TB-
SOTf) and NEt3 gave the precursor 5 (Scheme 2) which
underwent successful enantioselective s-butyllithium/(-)-
sparteine (6) mediated deprotonation. Although hydrolytically
labile, the N-Si bond of 5 survived short aqueous workup.
Trapping with tributyltin chloride after deprotonation af-
forded the enantiopure stannane (S)-7 in 86% yield. The
enantiomeric ratio of stannane 7 was determined to be greater
than 98:2 by chiral HPLC of the methyl carbamate derivative,
obtained by treatment of 7 with methyl chloroformate. The
absolute configuration of 7 is assigned as (S) on the basis of
the known stereoselectivity preference for such stannylation
reactions with related O-alkyl carbamates.5
With the enantioenriched stannane 7 in hand, we were then
able to convert this into suitable cyclization precursors. The
compounds 8 and 9 were chosen and could be formed readily
from 7 by alkylations of the secondary amino function
(Scheme 2).
(8) (a) Woltering, M. J.; Fro¨hlich, R.; Hoppe, D. Angew. Chem. 1997,
109, 1804; Angew. Chem., Int. Ed. 1997, 29, 1764. (b) Woltering, M. J.;
Fro¨hlich, R.; Wibbeling, B.; Hoppe, D. Synlett 1998, 797. (c) Hoppe, D.;
Woltering, M. J.; Oestreich, M.; Fro¨hlich, R. HelV. Chim. Acta 1999, 82,
1860. (d) For a review, see: Marek, I.; Normant, J. F. In Metal-Catalyzed
Cross-Coupling Reactions; Diederich, F., Stang, P. J., Eds.; Wiley-VCH:
Weinheim, 1998; p 271.
(9) Representative Cyclization Procedure. A solution of the allyl
chloride 8 (114 mg, 0.17 mmol) in dry Et2O (3 mL) under an atmosphere
of argon in a flame-dried flask, sealed with a rubber septum, was cooled to
-78 °C. n-Butyllithium (0.10 mL, 0.25 mmol, 1.5 equiv; 2.5 M in hexanes)
was added dropwise, and the mixture was stirred for 2 h. After quenching
with MeOH (0.2 mL) and H2O (0.1 mL) at -78 °C, the mixture was allowed
to warm to room temperature, dried (Na2SO4), filtered, and concentrated
in vacuo. Flash chromatography (silica gel, Et2O/petroleum ether ) 1:4 to
1:1) afforded the product 11 as a colorless oil (57 mg, 0.16 mmol, 95%;
(5) (a) Hoppe, D.; Hintze, F.; Tebben, P. Angew. Chem. 1990, 102, 1457;
Angew. Chem., Int. Ed. 1990, 29, 1422. For reviews, see: (b) Hoppe, D.;
Hense, T. Angew. Chem. 1997, 109, 2376; Angew. Chem., Int. Ed. 1997,
36, 2282. (c) Hoppe, D.; Marr, F.; Bru¨ggemann, M. Organolithiums in
Enantioselective Synthesis. In Topics in Organometallic Chemistry; Hodg-
son, D. M., Ed.; Springer-Verlag: Berlin, 2003; Vol. 5. (d) Basu, A.;
Thayumanayan, S. Angew. Chem. 2002, 114, 740; Angew. Chem., Int. Ed.
2002, 41, 716. (e) Hoppe, D.; Christoph, G. In The Chemistry of
Organolithium Compounds, Asymmetric Deprotonation with Alkyllithiums-
(-)-Sparteine; Rappoport, Z., Marek, I., Eds.; John Wiley and Sons:
Chichester, 2004. (f) Beak, P.; Gallagher, D. J.; Park, Y. S.; Thayumanavan,
S. Acc. Chem. Res. 1996, 29, 552.
20
[R]D ) -39.0 (c ) 1.18, CHCl3)).
(10) (a) Gralla, G.; Wibbeling, B.; Hoppe, D. Org. Lett. 2002, 4, 2193.
(b) Oestreich, M.; Fro¨hlich, R.; Hoppe, D. Tetrahedron Lett. 1998, 39, 1745.
(c) Oestreich, M.; Fro¨hlich, R.; Hoppe, D. Tetrahedron Lett. 1999, 40, 1881.
(d) Oestreich, M.; Fro¨hlich, R.; Hoppe, D. J. Org. Chem. 1999, 64, 8616.
(11) (a) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512. (b)
Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969, 34, 2543.
(6) (a) Still, W. C.; Sreekumar, C. J. Am. Chem. Soc. 1980, 102, 1201.
(b) Tomooka, K.; Igarashi, T.; Nakai, T. Tetrahedron Lett. 1994, 35, 1913.
(7) Roby, J.; Voyer, N. Tetrahedron Lett. 1997, 38, 191.
4470
Org. Lett., Vol. 8, No. 20, 2006

13 was found to have a significant value for its specific
20
rotation, [R]D ) -25.4 (c ) 0.41, CH2Cl2).
Scheme 4. Structure Elucidation of Cyclization Product 11
In summary, we have demonstrated that s-butyllithium/
(-)-sparteine (6) can be used to prepare the enantioenriched
stannane 7 by stereoselective deprotonation of a N-silyl-
protected â-aminoalkyl carbamate. This compound acts as
a stable carbanion equivalent. Tin-lithium exchange and
intramolecular cyclization lead to the formation of enantio-
merically and diastereomerically pure 3-hydroxy-pyrro-
lidines. The enantiomerically pure compound 7 may serve
as a versatile key intermediate for the synthesis of further
hydroxy-pyrrolidines or other chiral amines.
The diastereomeric ratio of the pyrrolidine 15 was
determined by 19F NMR spectroscopy to be higher than 98:
2, consequently leading to an enantiomeric excess of higher
than 96% ee. The trans configuration of 11 was determined
by NOE spectroscopic experiments. On the basis of literature
precedent, the tin-lithium exchange and subsequent cycliza-
tion are assumed to occur with retention of configuration at
the carbanion center.1-5,8
Acknowledgment. This work was supported by the
Deutsche Forschungsgemeinschaft (Sonderforschungs-
bereich 424). C.S. gratefully acknowledges a fellowship of
the International NRW Graduate School of Chemistry at
Mu¨nster. We thank Mrs. C. Weitkamp, WWU Mu¨nster, for
her skillful technical assistance.
Supporting Information Available: Additional descrip-
tions and characterizations and spectroscopic data of all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
The enantiomeric excess of pyrrolidine 13 could not be
determined. However, it is expected that the product 13
would have been formed with high enantioselectivity because
the precursor 7 is highly enantioenriched and there is high
selectivity in the formation of the product 11. The product
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Org. Lett., Vol. 8, No. 20, 2006
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