Stereoselective synthesis of pyrrolidines from N-allyl oxazolidines via hydrozirconation-cyclization

Article abstract of DOI:10.1021/ol0517776

(Chemical Equation Presented) A new diastereoselective synthesis of pyrrolidines from readily available chiral N-allyl oxazolidines is presented. The construction of the pyrrolidine ring is achieved via a tandem hydrozirconation-stereoselective Lewis acid

Full text of DOI:10.1021/ol0517776

ORGANIC
LETTERS
2005
Vol. 7, No. 22
4887-4889
Stereoselective Synthesis of
Pyrrolidines from N-Allyl Oxazolidines
via Hydrozirconation−Cyclization
Jean-Luc Vasse, Antoine Joosten, Cle´ment Denhez, and Jan Szymoniak*
Re´actions Se´lectiVes et Applications, CNRS (UMR 6519) and UniVersite´ de Reims,
51687 Reims Cedex 2, France
jan.szymoniak@uniV-reims.fr
Received July 27, 2005
ABSTRACT
A new diastereoselective synthesis of pyrrolidines from readily available chiral N-allyl oxazolidines is presented. The construction of the
pyrrolidine ring is achieved via a tandem hydrozirconation stereoselective Lewis acid mediated cyclization sequence.
−
The pyrrolidine ring is common to numerous natural
products1 and medicinal drugs. Enantiopure pyrrolidines have
been used as synthetic building blocks, chiral auxiliairies,2
catalysts, and ligands for asymmetric synthesis.3 Although
many syntheses of pyrrolidines have been reported,4 there
is still a need for the development of general and simple
methods for the preparation of optically pure compounds.
Among the strategies implying an intramolecular cyclization
to build the pyrrolidine ring, only a few methods involve
carbon-carbon bond-forming reactions.5 Carbon-nitrogen
bond-forming reactions are most common, including in situ
reduction reactions,6 electrophilic C-C double bond activa-
tions,7 metal carbenoid N-H insertions,8 metal-catalyzed
hydroamination reactions,9 and those requiring the presence
of a leaving group.10
Here we present a synthetic methodology that allows the
preparation of enantiopure pyrrolidines via a carbon-carbon
(5) (a) Pedrosa, R.; Andre´s, C.; Duque-Soladana, J. P.; Mendiguchia, P.
Eur. J. Org. Chem. 2000, 3727-3730. (b) Bustos, F.; Gorgojo, J. M.; Suero,
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Labonne, A.; Jacquot, Y.; Chassaing, G.; Lavielle, S.; Karoyan, P. J. Org.
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43-46.
(1) (a) O’Hagan, D. Nat. Prod. Rep. 2000, 17, 435-446 and references
therein. (b) Daly, J. W.; Spende, T. F. In Alkaloids: Chemical and Biological
PerspectiVes; Pelletier, S. W., Ed.; Wiley: New York, 1986; Vol. 4, Chapter
1.
(2) (a) White, J. D.; Xu, Q.; Lee, C.-S.; Valeriote, F. A. Org. Biol. Chem.
2004, 2, 2092-2102. (b) Whitesell, J. K. Chem. ReV. 1989, 89, 1581-
1590. (c) Nyerges, M.; Bendell, D.; Arany, A.; Hibbs, D. E.; Coles, S. J.;
Hursthouse, M. B.; Groundwater, P. W.; Meth-Cohn, O. Synlett 2003, 947-
950.
(3) (a) Hoang, L.; Bahmanyar, S.; Houk, K. N.; List, B. J. Am. Chem.
Soc. 2003, 125, 16-17. (b) Rogers, C. J.; Dickerson, T. J.; Brogan, A. P.;
Janda, K. D. J. Org. Chem. 2005, 70, 3705-3708. (c) Fache, F.; Schultz,
E.; Tommasino, M. L.; Lemaire, M. Chem. ReV. 2000, 100, 2159-2231.
(d) Chiral Reagents for Asymmetric Synthesis; Paquette, L. A., Ed.; Wiley:
Chichester, 2003.
(7) (a) Kim, J. H.; Long, M. J. C.; Kim, J. Y.; Park, K. H. Org. Lett.
2004, 6, 2273-2276. (b) Schlummer, B.; Hartwig, J. F. Org. Lett. 2002, 4,
1471-1474. (c) Miura, K.; Hondo, T.; Nakagawa, T.; Takahashi, T.;
Hosomi, A. Org. Lett. 2000, 2, 385-388. (d) Dondas, H. A.; de Kimpe, N.
Tetrahedron Lett. 2005, 46, 4179-4182.
(8) Davies, F. A.; Wu, Y.; Xu, H.; Zhang, J. Org. Lett. 2004, 6, 4523-
4525.
(4) (a) Pichon, M.; Figade`re, B. Tetrahedron: Asymmetry 1996, 7, 927-
964 and references therein. (b) Katritzky, A. R.; Cui, X.-J. Yang, B.; Steel,
P. J. J. Org. Chem. 1999, 64, 1979-1985. (c) Ballini, R.; Bosica, G.; Fiorini,
D.; Palmieri, A.; Petrini, M. Chem. ReV. 2005, 105, 933-972. (d) Galliford,
C. V.; Beenen, M. A.; Nguyen, S. T.; Scheidt, K. A. Org. Lett. 2003, 5,
3487-3490. (e) Besev, M.; Engman, L. Org. Lett. 2002, 4, 3023-3025.
(f) Pearson, W. H. Pure Appl. Chem. 2002, 74, 1339-1347.
(9) (a) Bajracharya, G. B.; Huo, Z.; Yamamoto, Y. J. Org. Chem. 2005,
70, 4883-4886. (b) Bexrud, J. A.; Beard, J. D.; Leitch, D. C.; Schafer, L.
L.Org. Lett. 2005, 7, 1959-1962. (c) Kim, J. Y.; Livinghouse, T. Org.
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10.1021/ol0517776 CCC: $30.25
© 2005 American Chemical Society
Published on Web 10/06/2005

bond-forming cyclization reaction. To our knowledge, no
such approach involving a C-metalated aminal intermediate
has been reported. Recently, our group described a new
diastereoselective synthesis of di- and trisubstituted cyclo-
propanes from allylic ethers and acetals.11 This reaction
involves a hydrozirconation followed by the Lewis acid
promoted deoxygenative ring formation (Scheme 1).
Scheme 3. Synthesis and Hydrozirconation of
N-Allyloxazolidines
Scheme 1. Synthesis of Cyclopropanes from Allylic Ethers and
or 0 °C with 2:1 or 3.2:1 diastereomeric ratios, respectively,
in favor of 2a (entries 1 and 2). The selectivity could be
further increased by lowering the reaction temperature to -70
°C; unfortunately the yield dropped to 43% (entry 3). When
TMSOTf, AlCl3, and AlMe3 were used as Lewis acids, the
pyrrolidine was obtained in good yields but with a moderate
diastereoselectivity of 2:1, 2.7:1, and 3:1, respectively (entries
4-6). The level of stereoselectivity could be increased to
6:1 when ZnCl2 was used (entry 7). The best diastereo-
selectivity of 10:1 was obtained with TiCl4. In this case, when
an equimolar quantity of TiCl4 was employed, the chloride
3a was obtained instead of 2a (entry 8). We noticed,
however, that the reaction also took place with a sub-
stoichiometric amount (15 mol %) of TiCl4. By using this
procedure, 2a was isolated in 62% yield and with the same
10:1 diastereoisomeric ratio (entry 9). Finally, the catalytic
process also proved to operate with BF3‚OEt2 (entry 10).
Acetals
We envisioned that in an analogous way oxazolidines
might be transformed into pyrrolidines. The retrosynthetic
approach is depicted in Scheme 2. The pyrrolidine ring could
Scheme 2. Retrosynthetic Approach
To further explore the reaction, various oxazolidines were
tested (Table 2). Oxazolidines bearing phenyl or substituted
phenyl groups (entries 1-3) as well as heteroaromatic groups
(entries 4 and 5) on the C2 atom afforded 2-substituted
pyrrolidines (2a-e) in moderate to good yields. In the case
of 2d and 2e the low yields originate from the competitive
reduction of the aminal function.
The reaction could also be accomplished with oxazolidines
bearing C2-alkyl substituents, i.e., n-C5H11 and i-Pr (entries
be thus constructed by the Lewis acid promoted ring closure
starting from the zirconocene intermediate I, preformed from
II. The stereochemistry at the R-position would be controlled
by using a rigid N-allyl oxazolidine as chiral auxiliary.
According to this strategy, the required allyl side chain should
be preinstalled by alkylation of a relevant amino alcohol.12
The model oxazolidine 1a was prepared in two steps from
readily available (R)-2-phenylglycinol (Scheme 3). The
reaction with allyl bromide and subsequent condensation with
benzaldehyde afforded 1a in 79% isolated yield, in the almost
pure diastereomeric form according to 1H NMR. The
hydrozirconation of 1a was carried out at room temperature
in CH2Cl2 by using 1 equiv of Schwartz reagent. The reaction
went to completion within 1 h, as proven by deuteriolysis,
without alteration of the diastereoselectivity.
Table 1. Effect of Lewis Acid on the Ring-Closure Step
entry Lewis acid (mol %) T (°C)
dr
product yield (%)
1
2
3
4
5
6
7
8
9
BF3‚OEt2 (100)
BF3‚OEt2 (100)
BF3‚OEt2 (100)
TMSOTf (100)
AlCl3 (100)
AlMe3 (100)
ZnCl2 (100)
TiCl4 (100)
20
0
2:1
3.2:1
6.3:1
2:1
2.7:1
3:1
2aa (65)b
2a (60)b
2a (43)c
2a (58)c
2a (60)c
2a (55)c
2a (51)c
3a (69)c,d
2a (62)b
2a (64)c
-70
20
20
20
20
20
20
0
6:1
10:1
10:1
3:1
To achieve the ring-closure step, several Lewis acids were
tested (Table 1). A complete conversion was observed using
a stoechiometric amount of BF3‚OEt2 at room temperature
TiCl4 (15)
BF3‚OEt2 (15)
10
a The optical rotation of the main diastereoisomer was identical to that
previously reported.13 b Isolated products. c NMR yield. d Configuration
assigned by analogy.
(11) Gandon, V.; Szymoniak, J. Chem. Commun. 2002, 1308-1309.
(12) Takayasu, Y.; Jumpei, S.; Kimio, H. Heterocycles 2000, 58, 431-
447.
4888
Org. Lett., Vol. 7, No. 22, 2005

low yields. However, when BF3‚OEt2 was employed, the
pyrrolidines 5a and 5b were formed with a complete
selectivity as trans isomers. Accordingly, the oxazolidines
4b and 4c with the transposed R1 and R2 groups afforded
solely the same pyrrolidine 5b. Therefore, BF3‚OEt2 appeared
to be an appropriate Lewis acid to achieve highly trans-
stereoselective formation of 2,5-disubstituted pyrrolidines.
To account for the observed stereoselectivity, we tenta-
tively assumed that two competing mechanistic pathways
were involved in the cyclization step. Whereas the minor
diastereoisomer would result from an iminium intermediate
with a formal retention of configuration, the major diaste-
reoisomer would result from either a highly stereoselective
SN2-like process or an iminium intermediate with inversion
of configuration (Figure 1). According to our results and as
Table 2. Synthesis of 2-Substituted Pyrrolidines
entrya
R
Lewis acid
dr
product yield (%)b,c
1
2
3
4
5
6
7
8
Ph
2-BrC6H4
2-MeOC6H4 TiCl4
TiCl4
TiCl4
10:1
7.4:1
4:1
>12:1
>12:1
5.5:1
7:1
2a (62)
2b (53)
2c (55)
2d (31)
2e (43)
2f (52)
2g (49)
2g (48)
2-furyl
3-furyl
nC5H11
iPr
TiCl4
TiCl4
TiCl4
TiCl4
iPr
BF3‚OEt2
1:4
a Conditions: 1 equiv of Cp2Zr(H)Cl, 15 mol % of the Lewis acid, 0 °C,
CH2Cl2. b Yields refer to isolated products starting from N-allylphenyl-
glycinol. c Yield refers to combined isomers.
6-8). With TiCl4 as a Lewis acid, 2-substituted pyrrolidines
2a-f were obtained with a generally good diastereoselec-
tivity. A reversal of diastereoselectivity with BF3‚OEt2 vs
TiCl4 was observed for the oxazolidine with the i-Pr group
on the C2 atom (entries 7 and 8). In most cases, the
diastereomeric pyrrolidines could easily be separated by
column chromatography. The chiral auxiliary could be
removed after reaction leading to N-deprotected pyrrolidines.
As example, diastereoisomerically pure 2f was submitted to
hydrogenolysis (H2, Pd/C) to afford (R)-2-pentylpyrrolidine
in 76% yield.14
We noticed that the title reaction is not limited to the
preparation of 2-substituted pyrrolidines. When using ox-
azolidines with an R-substituted N-allyl chain, 2,5-disubsti-
tuted pyrrolidines could be obtained. Examples are given in
Scheme 4. In contrast to the results obtained with the
Figure 1. Competing reaction pathways: SN2-like versus iminium
far as oxazolidines with a nonsubstituted N-allyl chain are
concerned, the iminium-involving pathway would be gener-
ally favored with BF3‚OEt2, whereas an SN2-like process
would be enhanced with TiCl4. Within this context, the
inversion of stereoselectivity with BF3‚OEt2 versus TiCl4 for
the major stereoisomer obtained from the oxazolidine bearing
a ramified substituent (i-Pr) on C2 (entries 7 and 8) could
be due to a marked facial discrimination. Starting from
oxazolidines with an R-substituted N-allyl chain, trans 2,5-
pyrrolidines were exclusively obtained when BF3‚OEt2 was
used as a Lewis acid. A unique and highly stereoselective
iminium-involving pathway could operate in these cases,
resulting in the formal retention of the configuration on the
C2 atom. Additional studies are desirable, however, to give
a better insight into the stereochemical outcome of these
reactions.
Scheme 4. Stereoselective Synthesis of 2,5-Disubstituted
Pyrrolidines
In conclusion, we have described a new carbon-carbon
bond-forming cyclization reaction that allows a stereoselec-
tive construction of the pyrrolidine ring. Simplicity of the
procedure, readily available starting materials and a possible
stereocontrol of the reaction are noteworthy. Work aimed at
further exploring its synthetic scope is currently underway.
oxazolidines bearing a nonsubstituted N-allyl chain, the use
of TiCl4 led to nonstereoselective reactions (dr = 1:1) and
Acknowledgment. We thank the CNRS and the Ministe`re
de l’Education Nationale for their financial support.
(13) Burgess, L. E.; Meyers, A. I. J. Org. Chem. 1992, 57, 1656-1662.
(14) Furthermore, several methods are known for an efficient deprotection
of the similarly substituted N-pyrrolidines; see: (a) Katrizky, A. B.; Cui,
X.-L.; Yang, B.; Steel, P. J. Tetrahedron Lett. 1998, 39, 1697-1700. (b)
Higashiyama, K.; Inoue, H.; Takahashi, H. Tetrahedron 1994, 50, 1083-
1092.
Supporting Information Available: Experimental pro-
cedures and spectral data for compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL0517776
Org. Lett., Vol. 7, No. 22, 2005
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