Stereodivergent methodology for the synthesis of complex pyrrolidines

Article abstract of DOI:10.1021/ja710289k

The intramolecular reaction of oxime ethers and cyclopropane diesters results in the diastereoselective formation of substituted pyrrolo- isoxazolidines which serve as precursors to the ubiquitous pyrrolidine motif. A simple reversal of addition order of catalyst and substrate results in formation of two discrete diastereomers in a highly selective and predictable manner. The adducts are prepared in excellent yields from either enantiomer of an alkoxyamino-tethered cyclopropanediester, allowing efficient access to highly substituted homochiral pyrrolidines.

Full text of DOI:10.1021/ja710289k

Published on Web 02/28/2008
Stereodivergent Methodology for the Synthesis of Complex
Pyrrolidines
Stephen K. Jackson, Avedis Karadeolian, Alex B. Driega, and Michael A. Kerr*
Department of Chemistry, The UniVersity of Western Ontario, 1151 Richmond Street,
London, Ontario, Canada N6A 5B7
Received November 27, 2007; E-mail: makerr@uwo.ca
Abstract: The intramolecular reaction of oxime ethers and cyclopropane diesters results in the diastereo-
selective formation of substituted pyrrolo-isoxazolidines which serve as precursors to the ubiquitous
pyrrolidine motif. A simple reversal of addition order of catalyst and substrate results in formation of two
discrete diastereomers in a highly selective and predictable manner. The adducts are prepared in excellent
yields from either enantiomer of an alkoxyamino-tethered cyclopropanediester, allowing efficient access to
highly substituted homochiral pyrrolidines.
Introduction
Cyclopropanes constitute an important class of synthetic
building blocks due to their rich chemical reactivity.1 Specifi-
cally, those bearing electron-withdrawing substituents undergo
ring opening with a variety of nucleophiles to afford heterocyclic
products.2 The pyrrolidine ring, in particular, is found in a
myriad of natural products, and consequently, numerous meth-
ods exist to access this important heterocycle. However, several
of these strategies often suffer from poor diastereoselectivity,
efficiency, and generality when applied to the assembly of
densely substituted pyrrolidines.3 Currently, the most efficient
method for assembling densely substituted enantiomerically
enriched pyrrolidine rings is via the catalytic enantioselective
1,3-dipolar cycloaddition of azomethine ylides with various
olefins.4 While the method has the potential to efficiently
generate fully substituted pyrrolidine rings with good stereo-
control, it is generally limited to the use of aryl azomethine
ylides and therefore results in formation of pyrrolidines with
2-aryl substitution. Isopropyl or cyclohexyl derivatives are
notable exceptions; however, asymmetric induction is moderate
for these examples.5 2,5-Trans-substituted pyrrolidines, such as
those found in callosine (1)6 and Abbott’s influenza neuramini-
dase inhibitor A-315675 (2),7 are especially difficult to synthe-
size in an efficient manner (Figure 1).8 For example, approaches
to A-315675 have relied on a linear construction of the
pyrrolidine ring through a pyrrolinone intermediate.9 Quinocar-
cin (3)10 and allosecurinine (4)11 are complex natural products
containing a 2,5-cis-substituted pyrrolidine ring. An efficient
Figure 1.
method allowing access to either pyrrolidine diastereomer from
a common starting material would constitute a fundamentally
important contribution to the synthetic arsenal.
(3) For selected classical methods of pyrrolidine synthesis, see: (a) Wojcik,
B.; Adkins, H. J. Am. Chem. Soc. 1934, 56, 2419-2424. (b) Karrer, P.;
Portmann, P. HelV. Chim. Acta 1948, 31, 2088-2092. (c) Adams, E.;
Goldstone, A. J. Biol. Chem. 1960, 235, 3492-3498. (d) Dolfini, J. E.;
Dolfini, D. M. Tetrahedron Lett. 1965, 2053-2058. (e) Basha, F. Z.;
DeBernardis, J. F. Tetrahedron Lett. 1984, 25, 5271-5274. (f) Yoda, H.;
Yamazaki, H.; Kawauchi, M.; Takabe, K. Tetrahedron: Asymmetry 1995,
6, 2669-2672. (g) Jiang, C.; Frontier, A. J. Org. Lett. 2007, 9, 4939-
4942. For anionic cyclization methods of pyrrolidine synthesis, see: (h)
Lorthiois, E.; Marek, I.; Normant, J. F. J. Org. Chem. 1998, 63, 2442-
2450 and references therein. For cycloaddition strategies toward pyrrolidine
synthesis, see: (i) Overman, L. E.; Kakimoto, M.-A. J. Am. Chem. Soc.
1979, 101, 1310-1312. (j) Overman, L. E.; Kakimoto, M.-A.; Okazaki,
M. E.; Meier, G. P. J. Am. Chem. Soc. 1983, 105, 6622-6629 and
references therein. (k) Livinghouse, T.; Smith, R. J. Chem. Soc., Chem.
Commun. 1983, 210-211. (l) Anslow, A. S.; Harwood, L. M.; Phillips,
H.; Watkin, D.; Wong, L. F. Tetrahedron: Asymmetry 1991, 2, 1343-
1358. (m) Pearson, W. H.; Szura, D. P.; Postich, M. J. J. Am. Chem. Soc.
1992, 114, 1329-1345. (n) Enders, D.; Meyer, I.; Runsink, J.; Raabe, G.
Tetrahedron 1998, 54, 10733-10752. (o) Karlsson, S.; Han, F.; Ho¨gberg,
H.-E.; Caldirola, P. Tetrahedron: Asymmetry 1999, 10, 2605-2616. (p)
Young, I. S.; Williams, J. L.; Kerr, M. A. Org. Lett. 2005, 7, 953-955.
(q) Carson, C. A.; Kerr, M. A. J. Org. Chem. 2005, 70, 8242-8244. (r)
Boruah, M.; Konwar, D.; Das Sharma, S. Tetrahedron Lett. 2007, 48, 4535-
4537. (s) Saito, S.; Tsubogo, T.; Kobayashi, S. J. Am. Chem. Soc. 2007,
129, 5364-5365. (t) Trost, B. M.; Silverman, S. M.; Stambuli, J. P. J. Am.
Chem. Soc. 2007, 129, 12398-12399.
(1) For recent reviews on the chemistry of cyclopropanes see: (a) Rubin, M.;
Rubina, M.; Gevorgyan, V. Chem. ReV. 2007, 107, 3117-3179. (b) Yu,
M.; Pagenkopf, B. L. Tetrahedron 2005, 61, 321-347. (c) Reissig, H.-U.;
Zimmer, R. Chem. ReV. 2003, 103, 1151-1196. (d) Mochalov, S. S.;
Gazzaeva, R. A. Chem. Heterocycl. Compd. 2003, 39, 975-988.
(2) For construction of the pyrrolidine motif via cyclopropanes, see: (a)
Danishefsky, S.; Regan, J.; Doehner, R. J. Org. Chem. 1981, 46, 5255-
5261. (b) David, O.; Blot J.; Bellec, C.; Fargeau-Bellassoued, M.-C.;
Haviari, G.; Celerier, J.-P.; Lhommet, G.; Gramain, J.-C.; Gardette, D. J.
Org. Chem. 1999, 64, 3122-3131. (c) Bertozzi, F.; Gustafsson, M.; Olsson,
R. Org. Lett. 2002, 4, 3147-3150. (d) Lerchner, A.; Carreira, E. M. Chem.
Eur. J. 2006, 12, 8208- 8219.
9
4196
J. AM. CHEM. SOC. 2008, 130, 4196-4201
10.1021/ja710289k CCC: $40.75 © 2008 American Chemical Society

Synthesis of Complex Pyrrolidines
A R T I C L E S
Scheme 1. Bimolecular Reaction of an Oxime Ether and a
Recently, we have shown that nitrones12 as well as imines3q
react with cyclopropane diesters under Yb(OTf)3 catalysis to
afford tetrahydro-1,2-oxazines and 2,5-substituted pyrrolidines,
respectively. However, the scope of the imine reaction was
restricted to the use of aryl imines, whereas all aliphatic cases
failed to react.
Cyclopropane Diester
It cannot be overstated that a methodology limited to
derivatives of benzaldehyde does not well serve natural product
synthesis. As such, in our continuing studies on the reactivity
of cyclopropane diesters, we considered whether the use of
oxime ethers as nucleophiles in cyclopropane ring opening
would lead to improved substrate scope given that the nucleo-
philicity of the oxime nitrogen should be increased by virtue
of the alpha heteroatom.13 However, it was quickly discovered
that the bimolecular reaction had very limited scope, gave poor
yields, and could only be effected under neat conditions (Scheme
1).
Scheme 2. Intramolecular Oxime Ether/Cyclopropane Annulation
Given the observation that excessively high concentrations
of substrates were needed to achieve any conversion to product,
it was expected that an intramolecular variant would lead to
improved reactivity as well as improved diastereoselectivity
through a tighter transition state resulting from the high effective
molarity inherent to intramolecular reactions.14 Intramolecular
ring opening would afford oxy-iminium species 10, leading to
bicyclic product 11 through Mannich ring closure (Scheme 2).
In addition, given that homochiral cyclopropane diesters are
readily prepared, we anticipated this method would allow access
Scheme 3
(4) For seminal reports on the asymmetric 1,3-dipolar cycloaddition toward
pyrrolidine synthesis, see: (a) Allway, P.; Grigg, R. Tetrahedron Lett. 1991,
32, 5817-5820. (b) Grigg, R. Tetrahedron: Asymmetry 1995, 6, 2475-
2486. For reviews, see: (c) Pandey, G.; Banerjee, P.; Gadre, S. R. Chem.
ReV. 2006, 106, 4484-4517. (d) Najera, C.; Sansano, J. M. Angew. Chem.,
Int. Ed. 2005, 44, 6272-6276. (e) Husinec, S.; Savic, V. Tetrahedron:
Asymmetry 2005, 16, 2047-2061. (f) Gothelf, K. V.; Jørgensen, K. A.
Chem. ReV. 1998, 98, 863-910.
to enantiopure pyrrolidines through pyrrolo-isoxazolidines such
as 11. In this report, we present the discovery of a stereospecific
annulation reaction involving oxime ether-tethered cyclopropane
diesters with broad substrate scope and exceptional diastereo-
selectivity, affording efficient access to either 2,5-trans- or 2,5-
cis-substituted pyrrolidines from the same starting materials.
(5) Longmire, J. M.; Wang, B.; Zhang, X. J. Am. Chem. Soc. 2002, 124,
13400-13401.
(6) Perez-Castorena, A.-L.; Arciniegas, A.; Alonso, R. P.; Villasenor, J. L.;
Romo de Vivar, A. J. Nat. Prod. 1998, 61, 1288-1291.
(7) Maring, C.; McDaniel, K.; Krueger, A.; Zhao, C.; Sun, M.; Madigan, D.;
DeGoey, D.; Chen, H.-J.; Yeung, M. C.; Flosi, W.; Grampovnik, D.; Kati,
W.; Klein, L.; Stewart, K.; Stoll, V.; Saldivar, A.; Montgomery, D.; Carrick,
R.; Steffy, K.; Kempf, D.; Molla, A.; Kohlbrenner, W.; Kennedy, A.; Herrin,
T.; Xu, Y.; Laver, W. G. Presented at the 14th International Conference
on Antiviral Research. AntiViral Res. 2001, 50, A76; Abstract 129.
(8) For a review on the synthesis of 2,5-trans-pyrrolidines, see: Pichon, M.;
Figade`re, B. Tetrahedron: Asymmetry 1996, 7, 927-964.
Results and Discussion
Synthesis of 2,5-trans-Pyrrolo-isoxazolidines. In the initial
experiment, the oxime ether of benzaldehyde was prepared in
racemic form and treated with 5 mol % Yb(OTf)3 (Scheme 3).
Gratifyingly, pyrrolo-isoxazolidine 11a was obtained in nearly
quantitative yield as a single diastereomer, which was assigned
(vide infra) as the 2,5-trans isomer (pyrrolidine numbering).
With this spectacular result, we wished to probe the scope
and stereochemistry of this new reaction and embarked on an
asymmetric synthesis of cyclopropyl-alkoxylamine 17 which
was required for oxime ether preparation (Scheme 4). Thus,
commercially available (S)-butane triol was protected as the
cyclic ketal, followed by benzylation of the primary alcohol.
Deprotection and cyclic sulfate formation afforded 14 in 84%
yield. Displacement of the sulfate with dimethylmalonate gave
cyclopropane 15,15 which was elaborated to the N-phthaloyl-
protected compound 16. Hydrazine deprotection afforded the
desired cyclopropyl-alkoxylamine 17 in excellent yield.16
(9) (a) Hanessian, S.; Bayrakdarian, M.; Luo, X. J. Am. Chem. Soc. 2002, 124,
4716-4721. (b) 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,
5445-5453. (c) Barnes, D. M.; McLaughlin, M. A.; Oie, T.; Rasmussen,
M. W.; Stewart, K. D.; Wittenberger, S. J. Org. Lett. 2002, 4, 1427-1430.
(10) (a) Tomita, F.; Takahashi, K.; Shimizu, K. J. Antibiot. 1983, 36, 463-
467. (b) Takahashi, K.; Tomita, F. J. Antibiot. 1983, 36, 468-470. For
syntheses, see: (c) Kwon, S.; Myers, A. G. J. Am. Chem. Soc. 2005, 127,
16796-16797. (d) Flanagan, M. E.; Williams, R. M. J. Org. Chem. 1995,
60, 6791-6797. (e) Katoh, T.; Kirihara, M.; Nagata, Y.; Kobayashi, Y.;
Arai, K.; Minami, J.; Terashima, S. Tetrahedron 1994, 50, 6239-6258.
(f) Katoh, T.; Kirihara, M.; Nagata, Y.; Kobayashi, Y.; Arai, K.; Minami,
J.; Terashima, S. Tetrahedron Lett. 1993, 34, 5747-5750. (g) Garner, P.;
Ho, W. B.; Shin, H. J. J. Am. Chem. Soc. 1993, 115, 10742-10753. (h)
Garner, P.; Ho, W. B.; Shin, H. J. J. Am. Chem. Soc. 1992, 114, 2767-
2768. (i) Fukuyama, T.; Nunes, J. J. J. Am. Chem. Soc. 1988, 110, 5196-
5198.
(11) (a) Satoda, I.; Murayama, M.; Tsuji, J.; Yoshii, E. Tetrahedron Lett. 1962,
1199-1206. For recent syntheses, see: (b) Honda, T.; Namiki, H.;
Watanabe, M.; Mizutani, H. Tetrahedron Lett. 2004, 45, 5211-5213. (c)
Kammler, R.; Polborn, K.; Wanner, Klaus T. Tetrahedron 2003, 59, 3359-
3368.
(12) (a) Young, I. S.; Kerr, M. A. Angew. Chem., Int. Ed. 2003, 42, 3023-
3026. (b) Young, I. S.; Kerr, M. A. Org. Lett. 2004, 6, 139-141. (c).
Ganton, M. D; Kerr, M. A. J. Org. Chem. 2004, 69, 8554-8557. (d)
Wanapun, D.; Van Gorp, K. A.; Mosey, N. J.; Kerr, M. A.; Woo, T. K.
Can. J. Chem. 2005, 83, 1752-1767. (e) Lebold, T. P.; Carson, C. A.;
Kerr, M. A. Synlett 2006, 364-368. (f) Sapeta, K.; Kerr, M. A. J. Org.
Chem. 2007, 72, 8597-8599.
(14) Kirby, A. J. AdV. Phys. Org. Chem. 1980, 17, 183-278.
(15) Racemic 15 is easily prepared via hydroboration of readily available
(+/-)-2-vinylcyclopropane-1,1-dicarboxylic acid dimethyl ester. See Sup-
porting Information.
(16) This sequence is amenable to multigram scale. (R)-Butane triol is also
commercially available.
(13) Edwards, J. O.; Pearson, R. G. J. Am. Chem. Soc. 1962, 84, 16-24.
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A R T I C L E S
Jackson et al.
Scheme 4. Synthesis of (S)-Cyclopropyl-alkoxylamine 17a
a Conditions: (a) 3-pentanone, TsOH; (b) BnBr, NaH, THF (89%, 2 steps); (c) HCl, MeOH (100%); (d) SOCl2, CCl4, reflux; RuCl3‚H2O, NaIO4, CCl4/
MeOH/H2O, 0 °C (84%); (e) dimethylmalonate, NaH, THF, reflux (71%); (f) H2, Pd/C, MeOH; (g) TsCl, DABCO, CH2Cl2 (93%); (h) N-hydroxyphthalimide,
DBU, DMF (74% recrystallized, % ee ) >99%); (i) N2H4‚H2O, MeOH/CH2Cl2 (1:1) (92%).
Table 1. Diastereoselective Synthesis of
Scheme 5
2,5-trans-Pyrrolo-isoxazolidines from E-Oxime Ethers
reaction was found to be extremely broad and found to be
compatible with oxime ethers derived from all classes of
aldehydes. Electron-donating (Table 1, entry c) and -withdraw-
ing (Table 1, entries b, d) aromatic oxime ethers cyclized in
high yields to the corresponding 2,5-trans products 11 with
exceptional diastereoselectivity. Pyridyl aldehyde was also well
tolerated, affording the pyrrolo-isoxazolidine product in high
yield and excellent diastereoselectivity (Table 1, entry e).
R,â-Unsaturated oxime ethers were also found to be viable
substrates (Table 1, entries g, h). Cyclization of the E isomers
proceeded with complete diastereoselectivity in the case of the
2-methyl cinnamaldehyde derivative and good selectivity for
the parent cinnamaldehyde derivative (10:1). Gratifyingly,
aliphatic oxime ethers (Table 1, entries i-k) were useful
substrates for this reaction. We were especially pleased to
observe that alpha chiral (R)-2-silyloxy aldehyde 18 (Table 1,
entry k) was a superb substrate for the annulation reaction. The
bulky tert-butyl diphenylsilyloxy group effectively inhibits
formation of the Z isomer, and cyclization of the crude oxime
ether affords the product without racemization in excellent yield
and high diastereoselectivity. The one-step, high-yielding as-
sembly of product 11k as a single homochiral diastereomer is
remarkable given that the pyrrolidine core of such a compound
would task current pyrrolidine-forming methodologies.
a Isolated yield of single diastereomer. Isomeric ratio determined by 1H
NMR analysis of crude mixture. b % ee > 99% for this representative
example. See Supporting Information. c Enantiopure (S)-cyclopropyl-
alkoxylamine 17 was employed. In all other cases, the racemic form was
employed. d 8:1 (E:Z) mixture of oxime ethers was employed. Product
isomers were inseparable. e 10:8:1 (E/E:E/Z:Z/Z) mixture of oxime ethers
was employed.
Interestingly, bis-aldehydes could also be employed (Table
1, entries l, m). Pyridine 2,6-dicarboxaldehyde was converted
to the E/E-bis-oxime ether as the sole isomer. Cyclization of
this substrate led to C2-symmetric compound 11l as a single
diastereomer. Use of glyoxal, however, resulted in a mixture
of oxime ether isomers, which converged to C2-symmetric
With alkoxylamine 17 in hand, a number of cyclopropyl-
oxime ethers were prepared from aryl, akenyl, or aliphatic
aldehydes, and the major E isomers were obtained after flash
chromatography. As depicted in Table 1, the scope of the
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Synthesis of Complex Pyrrolidines
A R T I C L E S
Figure 2. Proposed model for observed diastereoselectivity.
Figure 3. Modification allowing selective formation of cis- or trans-diastereomers.
diastereomer 11m as well as diastereomer 11m′ in a ratio (7:5)
comparable to that of the initial oxime ether mixture. Finally,
the Z-enantiopure ketoxime of methyl benzoylformate (Table
1, entry n) was prepared and cyclized in high yield to
enantiopure adduct 11n bearing a tetrasubstituted stereogenic
center.
The crystal structure of 11f revealed a 2,5-trans disposition of
the substituents about the pyrrolidine moiety with inversion of
configuration of the initial cyclopropane stereogenic carbon. The
enantiomeric excess was determined for representative examples
from each class of oxime ether and consistently found to be
>99% (Table 1, entries b, f, j, k, n). Importantly, this confirmed
that the reaction proceeds in all cases without racemization to
afford enantiopure adducts.
Consistent with the observed diastereoselectivity is the
mechanistic model depicted in Figure 2. Cyclization of E-oxime
9 proceeds likely through a stepwise mechanism,17 affording
E-oxy-iminium intermediate 19. Mannich ring closure by the
malonate nucleophile on the oxy-iminium re face leads to the
trans-substituted product 11 in a stereospecific manner. In
contrast, the minor Z-oxime isomer of 9 gives rise to the cis-
substituted adduct 21 through Z-oxy-iminium intermediate 20.
Synthesis of 2,5-cis-Pyrrolo-isoxazolidines. We recognized
that a shortcoming to our annulation methodology was the fact
that access to the Z-oxime ether, and consequently the 2,5-cis
In order to gain insight into the nature of the diastereoselec-
tivity of the reaction, we investigated the annulation of the minor
Z isomer of 9b (Scheme 5). The Z-oxime ether of 9b was treated
with Yb(OTf)3 and cyclized to the 2,5-cis diastereomer 21b
exclusively, while the E-oxime of 9b cyclized to the trans
product 11b. In a separate experiment, an 8:1 (E:Z) mixture of
oxime ether isomers 9i derived from isobutyrylaldehyde was
subjected to the same cyclization conditions and resulted in
formation of an 8:1 (trans:cis) mixture of diastereomeric
products (Scheme 5c and Table 1, entry i). These observations
confirmed that the stereochemical outcome of the reaction was
entirely dependent on the geometry of the initial oxime ether.
To confirm the absolute and relative configuration of the
adducts, the enantiomerically pure E-oxime ether of 6-bromo-
naphthalene-2-carboxaldehyde was cyclized to afford a crystal-
line compound suitable for X-ray analysis (Table 1, entry f).
(17) For mechanistic insight on the related nitrone cycloaddition with cyclo-
propane diesters, see: Karadeolian, A.; Kerr, M. A. J. Org. Chem. 2007,
72, 10251-10253 and ref 12d.
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A R T I C L E S
Scheme 6
Jackson et al.
cis-substituted pyrrolo-isoxazolidine 21a as a single diastereomer
in 98% yield. Importantly, this result confirmed that by simply
reVersing the order of addition of the substrate and catalyst
the stereochemical outcome of the reaction could be controlled.
Substrate scope for this new protocol was examined and also
found to be extremely general. Electron-rich (Table 2, entry c)
and electron-poor (Table 2, entries b, d) aromatic aldehydes
cyclized cleanly and in high yields. Furyl and napthyl substrates
were also well tolerated (Table 2, entries e-g). We were again
pleased to observe that the reaction with linear or branched
aliphatic aldehydes proceeded with exceptional diastereoselec-
tivity. Remarkably, however, in all but one case (Table 2, entry
o), the diastereocontrol was absolute with no detectable trace
of the trans isomer. Especially gratifying was the observation
that (R)-2-siloxy aldehyde 18 cleanly cyclized with excellent
diastereoselectivity and in good yield (Table 2, entry o). In
addition, the one-pot reaction proceeds without racemization
to afford enantiopure products. The enantiomeric excess was
determined for several adducts derived from differing classes
of aldehydes (Table 2, entries g, m, o) and found to be >99%
in all cases. Isolation of compound 22 was possible, and the ee
of the tosylated derivative was found to be >99%, further
demonstrating the conservation of enantiomeric integrity during
the initial cyclization of 17 to 22.
adduct, was as the minor product of oxime ether formation. In
order to complement the existing method for 2,5-trans adduct
formation, a means to selectively form the Z-oxy-iminium
intermediate 20 (Figure 2) was required in order to gain access
to the 2,5-cis adduct 21. This dilemma was solved with the
realization that generation of isoxazolidine 22 prior to reaction
with an aldehyde would likely afford the requisite Z-oxy-
iminium species 20 as the preferred geometry due to minimized
A1,3 interactions18 between the pendant malonate and R group
(Figure 3). Mannich cyclization of this species then gives rise
to the desired cis-substituted product 21.
We were delighted to find that this was indeed the case. In
the event, cyclopropyl-alkoxylamine 17 was treated with
catalytic Yb(OTf)3 to afford isoxazolidine 22 with complete
conversion (Scheme 6). Benzaldehyde was then added to the
same reaction pot, which resulted in production of the desired
Cleavage of the Pyrrolo-isoxazolidine N-O Bond. To
demonstrate the utility of the methodology to access highly
substituted pyrrolidine rings, we turned our attention to N-O
Table 2. Diastereoselective Synthesis of 2,5-cis-Pyrrolo-isoxazolidines
a Isolated yield. Only the cis-diastereomer was observed by 1H NMR analysis of crude reaction mixture except where noted. b % ee > 99% for this
representative example. See Supporting Information. c Enantiopure (S)-cyclopropyl-alkoxylamine 17 was employed. In all other cases, the racemic form was
employed. d Cis:trans of crude mixture.
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Synthesis of Complex Pyrrolidines
A R T I C L E S
Table 3. Accessing the Pyrrolidine Ring: N-O Bond Cleavagea
prone to isomerization due to severe diaxial interactions.
Suppression of a likely retro-Mannich isomerization pathway
was achieved by hydrogenation in methanolic HCl to afford
diastereomerically pure pyrrolidine salts 24 (Table 3). Aromatic
and aliphatic cis- or trans-adducts could be cleaved under these
conditions; however, the cis-adducts required higher pressures
of H2.
As an alternative method to suppress retro-Mannich isomer-
ization, the trans-adducts19 could be diastereoselectivity dealkox-
ycarbonylated. Selected examples were subjected to Krapcho20
conditions, affording the decarbonylated products in high yields
and good diastereoselectivity, favoring the 2,3-trans-isomers
(Scheme 7). Hydrogenation of the major diastereomer of 25
and 27 in the presence of Boc2O then led to N-protected 2,3,5-
substituted, diastereomerically pure pyrrolidines 26 and 28.
Compound 29 was elaborated to the corresponding pyrrolidine
though Zn-mediated N-O bond cleavage to avoid debromina-
tion.
Conclusion
In summary, we discovered an annulation reaction involving
oxime ether-tethered cyclopropanes which affords enantiopure
pyrrolo-isoxazolidines in a highly diastereoselective and ste-
reodivergent manner. Use of an alkyl tether in the reaction serves
several purposes. Not only does it facilitate the reaction (the
bimolecular case failed), but it allows for a pyrrolidine product
with direct N-protection. Cleavage of the N-O bond then
converts the protecting group into a handle, allowing further
elaboration at the 5-position of the newly formed pyrrolidine.
Altering the order of aldehyde and catalyst addition leads to
the selective formation of either 2,5-cis- or 2,5-trans-substituted
pyrrolidine products from the same starting materials. An
extremely broad substrate scope has been demonstrated for both
methods, and it is possible to access either 2,5-cis- or 2,5-trans-
substituted pyrrolidines, including those with branched alkyl
substitution, demonstrating the power of this new transformation.
This methodology constitutes a highly efficient way to access
pyrrolidine-based natural products and will be the subject of
future reports from our laboratory.
a Pd/C (10 mol %), H2 (1 or 4.4 atm), HCl, MeOH.
Scheme 7. Elaboration of trans-Adducts to Highly Substituted
Pyrrolidinesa
Acknowledgment. We gratefully acknowledge financial
support from the Natural Sciences and Engineering Research
Council of Canada (NSERC) and Merck Frosst. S.K.J. and A.K.
are NSERC (PGSD) and OGS scholars, respectively. We thank
Dr. Michael Jennings for X-ray crystallography, Prof. Nathan
Jones for the use of his GC/MS, and Prof. Michael Chong for
the use of his polarimeter. We also thank Prof. Brian Pagenkopf
for helpful discussions.
a Conditions: (a) NaCN, DMSO, 140 °C, 15 min, microwave; (b)
Pd(OH)2/C (10 mol %), H2 (1 atm), Boc2O, MeOH; (c) Zn, AcOH.
Supporting Information Available: Experimental procedures,
full characterization for all new compounds, as well as cif file.
This material is available free of charge via the Internet at
http://pubs.acs.org.
bond cleavage. Hydrogenation of the adducts under standard
conditions (Pd/C, MeOH, H2, 1 atm) led to partial epimerization
at C2. The trans-tert-butyl-substituted adduct 11j was especially
JA710289K
(18) (a) Johnson, F.; Malhotra, S. K. J. Am. Chem. Soc. 1965, 87, 5492-5493.
(b) Johnson, F.; Dix, D. T. J. Am Chem. Soc. 1971, 93, 5931-5932. (c)
Haller, R.; Ziriakus, W. Tetrahedron 1972, 28, 2863-2869.
(19) The cis-adducts underwent extensive decomposition upon attempted
demethoxycarbonylation.
(20) (a) Krapcho, A. P.; Glynn, G. A.; Grenon, B. J. Tetrahedron Lett. 1967,
215-217. (b) Krapcho, A. P.; Mundy, B. P. Tetrahedron 1970, 26, 5437-
5446.
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J. AM. CHEM. SOC. VOL. 130, NO. 12, 2008 4201