Asymmetric multicomponent reactions: Diastereoselective synthesis of substituted pyrrolidines and prolines

Article abstract of DOI:10.1021/ol061672i

A novel diastereoselective synthesis of substituted pyrrolidines has been developed. Asymmetric multicomponent reactions of optically active phenyldihydrofuran, N-tosyl imino ester, and silane reagents in a one-pot operation afforded highly substituted py

Full text of DOI:10.1021/ol061672i

ORGANIC
LETTERS
2006
Vol. 8, No. 20
4509-4511
Asymmetric Multicomponent Reactions:
Diastereoselective Synthesis of
Substituted Pyrrolidines and Prolines
Arun K. Ghosh,* Sarang Kulkarni, Chun-Xiao Xu, and Phillip E. Fanwick
Departments of Chemistry and Medicinal Chemistry, Purdue UniVersity,
West Lafayette, Indiana 47907
akghosh@purdue.edu
Received July 7, 2006
ABSTRACT
A novel diastereoselective synthesis of substituted pyrrolidines has been developed. Asymmetric multicomponent reactions of optically active
phenyldihydrofuran, N-tosyl imino ester, and silane reagents in a one-pot operation afforded highly substituted pyrrolidine derivatives
diastereoselectively. The reaction is quite efficient and constructed up to three stereogenic centers in a single operation.
Multicomponent reactions (MCRs) that provide functional-
ized heterocyclic scaffolds in a single operation and in a
stereodefined manner are of enormous importance in syn-
thetic organic and medicinal chemistry. Despite the signifi-
cance and potential of MCRs, there exist only a few versatile
multicomponent reactions that truly generate diverse mol-
ecules with multiple stereocenters.1 Our development of
multicomponent reactions led to syntheses of a variety of
substituted tetrahydrofurans and tetrahydropyrans containing
multiple stereocenters.2 Recently, we described multicom-
ponent reactions with N-tosylimino ester that provided rapid
access to a range of functionalized novel R-amino acids
containing cyclic ether templates.3 As depicted in Scheme
1, multicomponent reactions of N-tosylimino ester with
optically active phenyldihydrofuran (1) at -78 to -20 °C
in the presence of allyltrimethylsilane as the nucleophile and
CH3CN as the additive provided a single diastereomer 2 in
very good yield. Interestingly, in the absence of CH3CN
Scheme 1. Asymmetric Multicomponent Reaction
(1) (1) For recent reviews of multicomponent reactions, see: (a) Ramon,
D. J.; Yus, M. Angew. Chem., Int. Ed. 2005, 44, 1602; (b) Strubing, D.;
Neumann, H.; Hubner, S.; Klaus, S.; Beller, M. Tetrahedron Lett. 2005,
61, 11345; (c) Nair, V.; Sreekumar, V.; Bindu, S.; Suresh, E. Org. Lett.
2005, 7, 2297.
(2) (a) Ghosh, A. K.; Kawahama, R.; Wink, D. Tetrahedron Lett. 2000,
41, 8425. (b) Ghosh, A. K.; Kawahama, R. Tetrahedron Lett. 1999, 40,
1083. (c) Ghosh, A. K.; Kawahama, R. Tetrahedron Lett. 1999, 40, 4751.
(d) Ghosh, A. K.; Kawahama, R. J. Org. Chem. 2000, 65, 5433.
(3) Ghosh, A. K.; Xu, C.-X.; Kulkarni, S. S.; Wink, D. Org. Lett. 2005,
7, 7.
10.1021/ol061672i CCC: $33.50
© 2006 American Chemical Society
Published on Web 08/29/2006

additive, this multicomponent reaction typically afforded
tetrahydrofuran derivative 2 along with varying amounts
(15-30%) of pyrrolidine derivative 3a as the byproduct.
Presumably, a Lewis acid catalyzed intramolecular rear-
rangement led to the formation of pyrrolidine derivative 3.
The presence of CH3CN additive completely prevented the
formation of pyrrolidine derivative 3. Pyrrolidine rings are
inherent to numerous bioactive natural products and medici-
nal agents.4 The biological significance of functionalized
pyrrolidines and prolines continues to stimulate interest in
their design and synthesis. In this context, a number of
practical synthetic methodologies have been developed
recently.5 In our continuing interest in probing enzyme-active
sites with designed ligands containing heterocyclic tem-
plates,6 we sought to optimize the above multicomponent
reaction conditions so as to synthesize functionalized pyr-
rolidine heterocycles in a stereopredictable manner. Herein
we report asymmetric multicomponent reactions of optically
active phenyldihydrofuran, N-tosylimino ester, and silane
reagents in a one-pot operation to afford functionalized
pyrrolidine and proline derivatives diastereoselectively.
ester (1 equiv) in CH2Cl2 were treated with TiCl4 (1 M
solution in CH2Cl2, 1.2 equiv) at -78 °C for 1 h. Allyltri-
methylsilane (3 equiv) was added, and the resulting mixture
was allowed to warm to 23 °C and stirred for 1 h. After this
period, the reaction was quenched with saturated aqueous
NaHCO3 solution. Standard workup and flash chromatog-
raphy over silica provided pyrrolidine derivative 3a in 72%
yield as a single diastereomer (by 1H and 13C NMR analysis).
Reduction of 3a with NaBH4 in the presence of CaCl2 in a
mixture of EtOH and THF afforded diol 4 in 88% yield.
The assignment of stereochemistry of the three new chiral
centers of 3a was made on the basis of the X-ray structure
of 4 in Figure 1 as well as extensive NOESY experiments.10
As mentioned above, the multicomponent reaction of
N-tosylimino ester,7 5-phenyldihydrofuran (1),8,9 and allyl-
trimethylsilane in the absence of CH3CN additive provided
phenyltetrahydrofuran 2 along with pyrrolidine derivative 3a
as the byproduct. We anticipated that the formation of
pyrrolidine byproduct 3a evolved from phenyltetrahydrofuran
2 by a TiCl4-promoted formation of benzylic carbocation
followed by intramolecular ring closure with the sulfonamide.
To examine this presumption, phenyltetrahydrofuran 2 was
treated with 1.2 equiv of TiCl4 in CH2Cl2 at -78 °C, and
the resulting mixture was warmed to 23 °C for 2 h. Indeed,
phenyltetrahydrofuran 2 smoothly converted to pyrrolidine
derivative 3a as a single diastereomer in 90% yield. We then
optimized the multicomponent reaction conditions to provide
pyrrolidine derivative 3a. Thus, asymmetric multicomponent
reactions leading to effective synthesis of various function-
alized pyrrolidines were carried out as follows. Optically
active phenyldihydrofuran (1, 1.2 equiv) and N-tosylimino
Figure 1. ORTEP drawing of X-ray structure of 4.
The optical purity of compound 4 was determined by its
conversion to the corresponding Mosher ester.11 The 19F
NMR analysis of the Mosher esters established that the
optical purity was 87% ee. Compound 3a was also converted
to proline derivative 5 by saponification using aqueous LiOH
followed by exposure of the resulting acid to Na-Hg in
methanol at reflux.12 Proline derivative 5 was obtained in
72% yield in a two-step sequence.
We investigated the feasibility of this reaction protocol
with a number of nucleophiles, and the results are sum-
marized in Table 1. Multicomponent reactions with allyl-
tributylstannane in the presence of 1.2 equiv of TiCl4
proceeded with excellent diastereoselectivity (dr ) 99/1,
Table 1, entry 2) and good yield. When triethylsilane was
used as a nucleophile, pyrrolidine derivatives were obtained
(4) (a) Trost, B. M.; Pinkerton, A. B.; Kremzow, D. J. Am. Chem. Soc.
2000, 122, 12007. (b) Leclercq, S.; Braekman, J. C.; Daloze, D.; Pasteels,
J. M. In Progress in the Chemistry of Organic Natural Products; Herz,
W., Falk, H., Kirby, G. W., Moore, R. E., Eds.; Springer-Verlag: New
York, 2000; Vol. 79, p 115. (c) DeGoey, D. A.; Chen, H.-J.; Flosi, W. J.;
Grampovnik, D. J.; Yeung, C. M.; Klein, L. L.; Kempf, D. J. J. Org. Chem.
2002, 67, 5445. (d) Hanessian, S.; Bayrakdariyan, M.; Luo, X. J. Am. Chem.
Soc. 2002, 124, 4716.
(5) For recent syntheses of pyrrolidines: (a) David, F. A.; Xu, H.; Wu,
Y.; Zhang, J. Org. Lett. 2006, 8, 2273. (b) Cabrera, S.; Arrayas, R. G.;
Carretero, J. C. J. Am. Chem. Soc. 2005, 127, 16394. (c) Hanessian, S.;
Yun, H.; Hou, Y.; Tintelnot-Blomely, M. J. Org. Chem. 2005, 70, 6746.
(d) Liu, Z.; Rainier, J. D. Org. Lett., 2005, 7, 131. (e) Garner, P.; Kaniskan,
H. U. J. Org. Chem. 2005, 70, 10868. (f) Kumareswaran, R.; Shin, S.;
Gallou, I.; RajanBabu, T. V. J. Org. Chem. 2004, 69, 7157.
(6) Ghosh, A. K.; Kincaid, J. F.; Cho, W.; Walters, D. E.; Krishnan,
K.; Hussain, K. A.; Cho, H.; Rudall, C.; Holland, L.; Buthod, J. Bioorg.
Med. Chem. Lett. 1998, 8, 687.
(10) Crystal data for 4: C22H27NO4S; MW ) 401.53; colorless crystal;
crystal system, block; space group, P21; cell parameters, a ) 13.99719-
(11) Å, b ) 10.4573(4) Å, c ) 14.4138(11) Å, R )96.230(3)°, V ) 2097.3-
(2) Å3, Z ) 4; Mo KR radiation (λ ) 0.71073 Å, T ) 150 K), R1 ) 0.045,
wR2 ) 0.076 (I > 2σ(I)); R1 ) 0.081, wR2 ) 0.089 (all data).
Crystallographic data has been deposited with the Cambridge Crystal-
lographic Data Center (deposition no. 611303). These data can be obtained
free of charge via the Internet at www.ccdc.cam.ac.uk/data_request/cif, by
email to data_request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ, U.K.
(11) Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969, 34,
2543.
(7) (a) Tschaen, D. M.; Turos, E.; Weinreb, S. M. J. Org. Chem. 1984,
49, 5058. (b) Weinreb, S. M. Top. Curr. Chem. 1997, 190, 131.
(8) Phenyldihydrofuran was prepared using asymmetric Heck reactions
in optically enriched form, see: (a) Ozawa, F.; Kubo, A.; Hayashi, T.
Tetrahedron Lett. 1992, 33, 1485. (b) Ozawa, F.; Kubo, A.; Hayashi, T. J.
Am. Chem. Soc. 1991, 113, 1417.
(12) (a) Birkinshaw, T. N.; Holmes, A. B. Tetrahedron Lett. 1987, 28,
813; (b) Chavez, F.; Sherry, A. D. J. Org. Chem. 1989, 54, 2990.
(9) Optical purity of 5-phenyl dihydrofuran was 88% ee.
4510
Org. Lett., Vol. 8, No. 20, 2006

Scheme 2. Stereochemical Models
Table 1. Structures and Diastereoselectivities of Pyrrolidine
Derivativesa
benium ion 7 which minimizes nonbonding interactions in
the transition state. Reaction of 7 with allytrimethylsilane at
-78 to -20 °C in the presence of CH3CN would provide
tetrahydrofuran 2 as described previously.3 However in the
absence of CH3CN, Lewis acid activation of tetrahydrofuran
would result in a new oxonium ion 8. The SN2 nucleophilic
attack of sulfonamide nucleophile (NTs) to the LA-activated
oxonium ion 8 may account for the observed complete
inversion for 3a and 3c-f (Table 1, entries 1, 2, and 5-8).
Alternatively, oxonium ion 8 may subsequently lead to a
benzylic carbonium ion 9. Further rotation of the carbon-
carbon bond around the benzylic carbonium ion could
provide an alternate carbonium ion 10. An intramolecular
SN1 attack by the NTs is likely to proceed through 9 over
10 to provide 3a predominantly because of the absence of
developing nonbonding interactions between the phenyl ring
and the bulky metal alkoxide. The proposed models account
for the observed diastereoselectivity with triethylsilane and
tributyltinhydride (Table 1, entries 3 and 4) where steric bulk
of metal alkoxide is considerably reduced.
a All reactions were carried out as described in the text. b Yields refer
to the isolated product. c Diastereomeric ratio determined by 1H NMR and
13C NMR.
as a mixture of diastereomers (dr ) 90/10, Table 1, entry
3). The corresponding reactions with tributyltin hydride also
provided pyrrolidine derivative 3b. However, diastereose-
lectivity and yield were further reduced (Table 1, entry 4).
We then examined a number of enolsilanes and ketene acetals
as the nucleophiles. These reactions were considerably
sluggish in the presence of 1.2 equiv of TiCl4. Multicom-
ponent reactions with enolsilane 6a in the presence of 1.2
equiv of TiCl4 at -78 to +23 °C provided a mixture (∼1:1)
of tetrahydrofuran and pyrrolidine derivatives. The use of
4.2 equiv of TiCl4, however, afforded only pyrrolidine
derivative 3c as a single diastereomer in 63% yield (Table
1, entry 5). The corresponding reaction with tert-butyl enol
ether 6b also gave a single diastereomer 3d in excellent yield
(Table 1, entry 6). These reactions with ketene acetals 6c
and 6d also proceeded with excellent diastereoselectivity.
Lewis acid catalyzed formation of pyrrolidines as well as
a high degree of diastereoselectivity associated with these
reactions can be rationalized on the basis of the proposed
models in Scheme 2. As described previously,3 we presume
that reaction of phenyldihydrofuran and N-tosylimino ester
in the presence of TiCl4 at -78 °C would furnish oxocar-
In summary, we have developed highly diastereoselective
TiCl4-catalyzed multicomponent coupling reactions to pro-
vide functionalized pyrrolidines with multiple stereocenters.
The overall process is quite efficient and the protocol has
constructed up to three contiguous asymmetric centers in a
single operation. Further studies are under investigation in
our laboratory.
Acknowledgment. Financial support by the National
Institutes of Health (GM 53386) is gratefully acknowledged.
Supporting Information Available: Experimental pro-
cedures, spectral data for compounds 3-5, and 1H NMR and
13C NMR spectra for compounds 3-5. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL061672I
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