Asymmetric multicomponent [C+NC+CC] synthesis of highly functionalized pyrrolidines catalyzed by silver(I)

Article abstract of DOI:10.1021/ol061113b

Highly functionalized pyrrolidines are obtained in a single chemical step via a mild, efficient, and selective Ag¹-catalyzed asymmetric [C+NC+CC] coupling process. Oppolzer's camphorsultam enables the desired reaction cascade and provides a rel

Full text of DOI:10.1021/ol061113b

ORGANIC
LETTERS
2006
Vol. 8, No. 17
3647-3650
Asymmetric Multicomponent
[C NC CC] Synthesis of Highly
+
+
Functionalized Pyrrolidines Catalyzed by
Silver(I)
Philip Garner,*,† H. U
2
mit Kaniskan,† Jieyu Hu,† Wiley J. Youngs,‡ and
Matthew Panzner‡
Department of Chemistry, Case Western ReserVe UniVersity, CleVeland, Ohio
44106-7078, and Department of Chemistry, UniVersity of Akron, Akron, Ohio 44325
ppg@case.edu
Received May 5, 2006
ABSTRACT
Highly functionalized pyrrolidines are obtained in a single chemical step via a mild, efficient, and selective AgI-catalyzed asymmetric [C
+NC+CC]
coupling process. Oppolzer’s camphorsultam enables the desired reaction cascade and provides a reliable means to control the developing
stereochemistry and purify the products. This three-component reaction provides unprecedented access to structurally diverse pyrrolidines
for both target- and diversity-oriented syntheses.
The pyrrolidine ring is an important structural motif found
in many bioactive molecules. Examples include the neuro-
protective agent kaitocephalin,1,2 the synthetic influenza drug
A-192558,3,4 and the antitumor antibiotic bioxalomycin â1
(Figure 1).5,6 Pyrrolidines also serve as useful molecular
scaffolds for the exploration and exploitation of pharma-
cophore space via diversity-oriented synthesis (DOS).7-9
Such studies have resulted in new drug leads for the treatment
of cancer10 and hepatitis C viral infections.11 Accordingly,
there is a continued need for new reactions that provide
stereocontrolled access to functionalized pyrrolidines.
Recently, we reported a simple synthesis of racemic
functionalized pyrrolidines based on the union of an eno-
lizable aliphatic aldehyde (“C”), an amino acid derivative
† Case Western Reserve University.
‡ University of Akron.
(1) Structure: (a) Shin-ya, K.; Kim, J.-S.; Furihata, K.; Hayakawa, Y.;
Seto, H. Tetrahedron Lett. 1997, 38, 7079. (b) Kobayashi, H.; Shin-ya, K.;
Furihata, K.; Hayakawa, Y.; Seto, H. Tetrahedron Lett. 2001, 42, 4021.
(2) Synthesis: (a) Ma, D.; Yang, J. J. Am. Chem. Soc. 2001, 123, 9706.
(b) Watanabe, H.; Okue, M.; Kobayashi, H.; Kitahara, T. Tetrahedron Lett.
2002, 43, 861. (c) Kawasaki, M.; Shinada, T.; Hamada, M.; Ohfune, Y.
Org. Lett. 2005, 7, 4165.
(3) Development: Kati, W. M.; Montgomery, D.; Carrick, R.; Gubareva,
L.; Maring, C.; McDaniel, K.; Steffy, K.; Molla, A.; Hayden, F.; Kempf,
D.; Kohlbrenner, W. Antimicrob. Agents Chemother. 2002, 46, 1014.
(4) Synthesis: (a) 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. (b) Hanessian, S.; Bayrakdarian, M.; Luo, X. J. Am. Chem. Soc. 2002,
124, 4716; Erratum: J. Am. Chem. Soc. 2003, 125, 4958.
(5) Zaccardi, J.; Alluri, M.; Ashcroft, J.; Bernan, V.; Korshalla, J. D.;
Morton, G. O.; Siegel, M.; Tsao, R.; Williams, D. R.; Maiese, W.; Ellestad,
G. A. J. Org. Chem. 1994, 59, 4045.
Figure 1. Representative pyrrolidine-containing targets.
10.1021/ol061113b CCC: $33.50
© 2006 American Chemical Society
Published on Web 07/20/2006

(“NC”), and an electron-deficient alkene (“CC”) in what may
be termed a three-component [C+NC+CC] coupling reac-
tion.12 The underlying cascade of molecular events was built
on the 1,3-dipolar cycloaddition of an azomethine ylide to
an electron-deficient dipolarophile. This concerted process
is a powerful synthetic transformation13 that creates two new
C-C bonds and up to four chiral centers in a single step.
Absolute stereocontrol during the 1,3-dipolar cycloaddition
has been achieved using either chiral, nonracemic substrates
or auxiliaries. The latter approach is, of course, more general,
but it still suffers from certain limitations. Catalytic asym-
metric versions of this cycloaddition reaction that proceed
via metalated azomethine ylides14 have recently been devel-
oped.15 However, this technology is still limited in terms
of the structural variability of both the aldehyde (aromatic al-
dehydes are usually employed) and dipolarophile components.
We now report an exceedingly mild, efficient, and selective
AgI-catalyzed asymmetric [C+NC+CC] synthesis of pyr-
rolidines. The method combines the advantages of a reliable
multipurpose, reusable auxiliary and metal catalysis. A key
feature of this reaction is the use of Oppolzer’s chiral glycyl
sultam as the amine component. The value of azomethine
ylides incorporating this chiral auxiliary has been previously
demonstrated with preformed aldimines using both thermal16
and zinc-mediated17 tautomerization. In the present case, the
sultam facilitates the desired reaction cascade and provides
a reliable means to control the absolute stereochemistry of
the products independent of existing chirality. Grigg had
previously noted the benefits of using silver(I) salts for the
generation of metalloazomethine ylides from preformed
enolizable aliphatic imines.18 Significantly, the asymmetric
three-component reaction19 technology described herein
permits unprecedented variation of the aldehyde component,
enabling the synthesis of highly functionalized pyrrolidines.
Even though numerous examples of three-component
reactions based on the cascade imine f azomethine ylide
f 1,3-dipolar cycloaddition sequence have been reported
(see ref 12 for a comprehensive listing), development of a
general asymmetric [C+NC+CC] coupling reaction remains
a challenging goal.20 This is especially true in the case of
enolizable aldehydes, where the following requirements must
be met (Scheme 1). First, the aldehyde I must cleanly and
Scheme 1. AgI-Catalyzed Asymmetric [C+NC+CC] Coupling
Reaction Cascadea
(6) For a comprehensive review of the bioxalomycins and related
tetrahydroisoquinoline antibiotics, see: Scott, J. D.; Williams, R. M. Chem.
ReV. 2002, 102, 166.
(7) MaClean, D.; Schullek, J. R.; Murphy, M. M.; Ni, Z.-J.; Gordon, E.
M.; Gallop, M. A. Proc. Natl. Acad. Sci. U.S.A. 1997, 94, 2805.
(8) (a) Hanessian, S.; Bayrakdarian, M. Bioorg. Med. Chem. Lett. 2000, 10,
427. (b) Hanessian, S.; Bayrakdarian, M. Tetrahedron Lett. 2002, 43, 9441.
(9) Lo, M. M.-C.; Neimann, C. S.; Nagayama, S.; Perlstein, E. O.;
Schreiber, S. L. J. Am. Chem. Soc. 2004, 126, 16077.
a X* ) Oppolzer’s D- or L-camphorsultam.
(10) Ding, K.; Lu, Y.; Nikolovska-Coleska, Z.; Qiu, S.; Ding, Y.; Gao,
W.; Stuckey, J.; Krajewski, K.; Roller, P. P.; Tomita, Y.; Parrish, D. A.;
Deschamps, J. R.; Wang, S. J. Am. Chem. Soc. 2005, 127, 10130.
(11) Burton, G.; Ku, T. W.; Carr, T. J.; Kiesow, T.; Sarisky, R. T.; Lin-
Goerke, J.; Baker, A.; Earnshaw, D. L.; Hofmann, G. A.; Keenan, R. M.;
Dhanak, D. Bioorg. Med. Chem. Lett. 2005, 15, 1553.
(12) Garner, P.; Kaniskan, H. U¨ . J. Org. Chem. 2005, 70, 10868.
(13) Reviews: (a) Kanemasa, S.; Tsuge, O. In AdVances in Cycloaddition;
Curran, D. P., Ed.; JAI Press: Greenwich, CT, 1993; Vol. 3, pp 99-159.
(b) Grigg, R.; Sridharan, V. In AdVances in Cycloaddition; Curran, D. P.,
Ed.; JAI Press: Greenwich, CT, 1993; Vol. 3, pp 161-204. (c) Kanemasa,
S. Synlett 2002, 1371. (d) Harwood, L. M.; Vickers, R. J. In Synthetic
Applications of 1,3-Dipolar Cycloaddition Chemistry Toward Heterocycles
and Natural Products; Padwa, A., Pearson, W. H., Eds.; Wiley: Hoboken,
NJ, 2003; pp 169-252. (e) Broggini, G.; Molteni, G.; Terraneo, A.; Zecchi,
G. Heterocycles 2003, 59, 823. (f) Pearson, W. H.; Stoy, P. Synlett 2003,
903. (g) Najera, C.; Sansano, J. M. Curr. Org. Chem. 2003, 7, 1105.
(14) (a) Barr, D.; Grigg, R.; Gunaratne, H. Q. N.; Kemp, J.; McMeekin,
P.; Sridharan, V. Tetrahedron 1988, 44, 557. (b) Tsuge, O.; Kanemasa, S.;
Yoshioka, M. J. Org. Chem. 1988, 53, 1384.
quickly condense with the amine component II to give the
intermediate imine III. The aldehydes and their imines must
resist tautomerization to their corresponding enols and
enamines, respectively. The amine component must not react
in a nucleophilic sense with activated dipolarophiles V.
Second, reactive azomethine ylide IV must be generated from
the imine without any unwanted ancillary reactivity during
the net tautomerization process. Third, the azomethine ylide
IV must be efficiently trapped by the dipolarophile V to
afford the pyrrolidine VI. Competitive heterocycloaddition
to either the aldehyde (oxazolidine formation) or the imine
(imidazolidine formation) must be minimized. After this
gauntlet of potential side reactions is run, the goal of
controlling both relative and absolute stereochemistry during
the 1,3-dipolar cycloaddition reaction must be dealt with.
(15) (a) Gothelf, A. S.; Gothelf, K. V.; Hazell, R. G.; Jørgensen, K. A.
Angew. Chem., Int. Ed. 2002, 41, 4236. (b) Longmire, J. M.; Wang, B.;
Zhang, X. J. Am. Chem. Soc. 2002, 124, 13400. (c) Chen, C.; Li, X.;
Schreiber, S. L. Ibid. 2003, 125, 10174. (d) Oderaotoshi, Y.; Cheng, W.;
Fujitomi, S.; Kasano, Y.; Minakata, S.; Komatsu, M. Org. Lett. 2003, 5,
5043. (e) Kno¨pfel, T. F.; Aschwanden, P.; Ichikawa, T.; Watanabe, T.;
Carreira, E. M. Angew. Chem., Int. Ed. 2004, 43, 5971. (f) Stohler, R.;
Wahl, F.; Pfaltz, A. Synthesis 2005, 1431. (g) Zeng, W.; Zhou, Y.-G. Org.
Lett. 2005, 7, 5055. (h) Yan, X.-X.; Peng, Q.; Zhang, Y.; Zhang, K.; Hong,
W.; Hou, X.-L.; Wu, Y.-D. Angew. Chem., Int. Ed. 2006, 45, 1979.
(16) Garner, P.; Dogan, O¨ .; Youngs, W. J.; Kennedy, V. O.; Protasiewicz,
J.; Zaniewski, R. Tetrahedron 2001, 57, 71.
Simply mixing aldehyde I, chiral glycyl sultam II (X* )
Oppolzer’s camphorsultam),21 and electron-deficient alkene
V in THF in the presence of a catalytic amount of AgOAc
resulted in the clean production of highly functionalized
pyrrolidines VI (see Table 1). The reaction proceeds through
(18) Grigg, R.; Montgomery, J.; Somasunderam, A. Tetrahedron 1992,
48, 10431.
(19) Ramo´n, D. J.; Yus, M. Angew. Chem., Int. Ed. 2005, 44, 1602.
(20) For a nice example of such a process, see: Onishi, T.; Sebahar, P.
R.; Williams, R. M. Org. Lett. 2003, 5, 3135. Also see ref 9.
(17) Dogan, O¨ .; O¨ ner, I.; U¨ lku, D.; Arici, C. Tetrahedron: Asymmetry
2002, 13, 2099.
3648
Org. Lett., Vol. 8, No. 17, 2006

Table 1. AgI-Catalyzed Asymmetric [C+NC+CC] Synthesis of Pyrrolidinesa
a Procedure: To a stirred mixture of glycyl sultam (0.37 mmol, 1.1 equiv) and AgOAc (5 mol %) in dry THF (1 mL) was added aldehyde (0.33 mmol,
1.0 equiv) followed by dipolarophile (3.0 equiv) at room temperature. The reaction was stirred in the dark under Ar for the indicated time (TLC monitoring
of aldehyde and/or 1H NMR monitoring of imine), at which point the mixture was partitioned between saturated aq NH4Cl (5 mL) and DCM (4 × 10 mL).
The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The cycloadducts were purified by flash chromatography
1
and recrystallization as required. Minor products were tentatively assigned as diastereomers on the basis of characteristic H NMR signals for H2 between
δ4 and 5. b Yield of pure product after flash chromatography. c Minor amounts (<5%) of additional products were also detected.
the imine III, which forms very quickly in situ (NMR
evidence) without the need for any special dehydrating
additives. Because these reactions require AgI as the catalyst
and result in the production of 2,5-cis disubstituted pyrro-
lidines, we surmise that they proceed via the intermediacy
of a metalated (E,E)-azomethine ylide IV. No added base is
necessary, an observation that is reminiscent of the bifunc-
tional AgOAc-catalyzed [3+2] cycloaddition reported by
Zeng and Zhou (ref 15g). Entries 1-5 show that the catalytic
asymmetric [C+NC+CC] coupling reaction can be per-
formed with a diverse set of mono- and 1,2-diactivated
alkenes. Entries 6-10 show that the aldehyde component
can be varied to include sterically hindered (entry 7),
heteroalkyl-substituted (entries 8-10), and chiral (entries 9
and 10) aldehydes.
These AgI-catalyzed [3+2] cycloadditions are regioselec-
tive with monoactivated alkenes, and they exhibited high
endo selectivity.22 The kinetic diastereofacial selectivity of
the 1,3-dipolar cycloadditions was typically good as judged
by 1H NMR analysis of the reaction at various times and of
the crude products after workup. When flash chromatography
failed to provide pure material, further purification of the
major product could generally be accomplished by simple
recrystallization. The relative stereochemical assignments for
the major cycloadducts 1-10 are based on a combination
of J-coupling data and NOE experiments (Supporting
Information). The absolute stereochemistry of these cycload-
ducts is based on the X-ray crystallographic analysis of
cycloadduct 4 (Figure 2).23
Org. Lett., Vol. 8, No. 17, 2006
3649

minimal R-epimerization. The resulting thiol ester structures
can be varied by employing different thiols to facilitate
chromatographic separation of the products. The reactions
shown below are illustrative, cleanly producing thiol esters
11 and 13 in the indicated yields.25 We have previously
shown that the removal of Oppolzer’s sultam from similar
2-pyrrolidinyl acylsultams may also be accomplished via
hydrolysis, transesterification, or reduction (see ref 16).
Figure 2. ORTEP diagram from the X-ray crystallographic analysis
of cycloadduct 4.
The readily available and reusable camphor-derived sultam
serves five important roles in the asymmetric [C+NC+CC]
coupling reaction sequence: (1) it reduces the nucleophilicity
of the amine component, thus preventing unwanted Michael
addition; (2) it facilitates azomethine ylide formation by
enhancing the R-acidity of the intermediate imine; (3) it
controls the diastereofacial selectivity of the 1,3-dipolar
cycloaddition in a predictable manner via the (E,E)-azome-
thine ylide depicted in Figure 3; (4) it tends to make the
In summary, the AgI-catalyzed asymmetric [C+NC+CC]
coupling reaction described herein provides convenient
access to a variety of highly functionalized pyrrolidine
structures at ambient temperature in a single chemical step.
In addition to providing enantiomerically enriched products
unavailable using existing 1,3-dipolar cycloaddition meth-
odology, the process is unique in its ability to incorporate
structurally diverse and enolizable aldehydes. Because the
aldehyde component provides the most potential for intro-
ducing structural diversity into the [C+NC+CC] process,
this mild reaction can serve as an asymmetric “linchpin” in
the middle and latter stages of a synthesis. We anticipate
that this reaction will be of considerable value for both target-
and diversity-oriented syntheses.
Acknowledgment. The authors thank the donors of the
Petroleum Research Fund, administered by the American
Chemical Society, and the National Science Foundation (CHE-
0553313) for financial support. We also thank the NSF for
funds to purchase the X-ray diffractometer (CHE-0116041).
Figure 3. Rationale for auxiliary-controlled facial selectivity.
cycloadducts crystalline, facilitating their purification; and
(5) it serves as a convenient handle for further synthetic
transformations. The examples with N-Boc (S)-phenylalanal
(entries 9 and 10) show that this chiral auxiliary can dominate
the stereochemical outcome of the [C+NC+CC] process
even with aldehydes possessing resident chirality. The re-
ported methodology nicely complements the 1,3-dipolar cy-
cloadditions of Williams’ and Harwood’s morpholin-2-one-
derived azomethine ylides, which cannot involve N-metalated
azomethine ylides and necessarily lead to 2,5-trans disub-
stituted pyrrolidines via (E,Z)-azomethine ylides (see ref 20).
To expand the practical utility of the AgI-catalyzed
asymmetric [C+NC+CC] process, chemoselective removal
of the chiral auxiliary was demonstrated. The use of buffered
thiolate24 for this purpose is particularly meritorious in that
it enables the rapid and chemoselective conversion of the
acylsultam moiety to a synthetically useful thiolester with
Supporting Information Available: Characterization
data for all new compounds are provided. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL061113B
(22) Two stereoisomeric endo 1,3-dipolar cycloaddition transition states
are possible with dimethyl fumarate.
(23) CCDC-614445 (cycloadduct 4) contains the supplementary crystal-
lographic data for this paper. These data can be obtained free of charge
from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
datarequest/cif.
(24) (a) Damon, R. E.; Coppola, G. M. Tetrahedron Lett. 1990, 31, 2849.
(b) Narasuka, K.; Saitou, M.; Iwasawa, N. Tetrahedron: Asymmetry 1991,
2, 1305. (c) Miyazaki, T.; Han-ya, Y.; Tokuyama, H.; Fukuyama, T. Synlett
2004, 477.
(25) Auxiliary Removal: To a stirred, cooled solution of thiolate
(prepared by adding 1.5 equiv of n-BuLi to a cooled solution of 3 equiv of
anhydrous thiol in THF) was slowly added a cooled solution of cycloadduct
in dry THF (final concentration of cycloadduct is ∼0.1 M). After confirming
by TLC analysis that the starting material was consumed, the reaction
mixture was partitioned between an aqueous buffer (pH 9-12) and DCM.
The combined organic layers were dried over MgSO4 and concentrated to
yield a colorless oil, which was subjected to flash column chromatography
to give the pure thiol ester and free camphorsultam.
(21) (a) Vandewalle, M.; Van den Eycken, J.; Oppolzer, W.; Vullioud,
C.; Tetrahedron 1986, 42, 4035. (b) For an improved preparation of this
auxiliary, see: Davis, F. A.; Towson, J. C.; Weismiller, M. C.; Lal, S.;
Carroll, P. J. J. Am. Chem. Soc. 1988, 110, 8477.
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