Ring expansion of azetidinium ylides: Rapid access to the pyrrolizidine alkaloids turneforcidine and platynecine

Article abstract of DOI:10.1021/ol050915o

(Chemical Equation Presented) Azetidinecarboxylate esters react readily with metallocarbenes in an inter- or intramolecular fashion to generate azetidinium ylides. Efficient [1,2]-shift by the ester-substituted carbon furnishes ring-expanded pyrrolidine p

Full text of DOI:10.1021/ol050915o

ORGANIC
LETTERS
2005
Vol. 7, No. 14
2949-2952
Ring Expansion of Azetidinium Ylides:
Rapid Access to the Pyrrolizidine
Alkaloids Turneforcidine and
Platynecine
John A. Vanecko and F. G. West*,†
Department of Chemistry, UniVersity of Utah, 315 South 1400 East,
Room 2020, Salt Lake City, Utah 84112-0850
frederick.west@ualberta.ca
Received April 25, 2005
ABSTRACT
Azetidinecarboxylate esters react readily with metallocarbenes in an inter- or intramolecular fashion to generate azetidinium ylides. Efficient
[1,2]-shift by the ester-substituted carbon furnishes ring-expanded pyrrolidine products. In the case of substrate 1, this provides access to the
pyrrolizidine alkaloids turneforcidine and platynecine via a high-yield, five-step sequence starting with readily available methyl 1-benzylazetidine-
2-carboxylate.
The Stevens [1,2]-shift1 of cyclic ammonium ylides permits
the efficient construction of functionalized pyrrolidines,
piperidines, or other azacycles.2 In this process, an exocyclic
ammonium substituent that can support a transient radical
center3,4 migrates to the neighboring ylide carbon. One of
the most convenient strategies for generating such ylides
involves the transition metal-catalyzed decomposition of
diazocarbonyl compounds with pendant amino groups.5
When the amine (1) is part of a preexisting ring system, this
approach furnishes transient spirocyclic ylides 2 whose
[1,2]-shift leads to fused bicyclic products 3 with bridgehead
nitrogen atoms (Scheme 1).6 The spiro-to-fused strategy is
especially appealing as a route to the necine base class of
† Current address: Department of Chemistry, University of Alberta, W5-
67 Chemistry Centre, Edmonton, AB, T6G 2G2, Canada.
(1) (a) Sato, Y.; Shirai, N. Yakugaku Zasshi 1994, 114, 880-887.
(b) Marko´, I. E. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming,
I., Eds.; Pergamon: Oxford, 1991; Vol. 3, pp 913-974. Lepley, A. R.;
Guimanini, A. G. In Mechanisms of Molecular Migrations; Thyagarajan,
B. S., Ed.; Interscience: New York, 1971; Vol. 3, pp 297-440.
(2) (a) Harada, M.; Nakai, T.; Tomooka, K. Synlett 2004, 365-367.
(b) Glaeske, K. W.; Naidu, B. N.; West, F. G. Tetrahedron: Asymmetry
2003, 14, 917-920. (c) Zaragoza, F. Synlett 1995, 237-238. (d) West, F.
G.; Naidu, B. N.; Tester, R. W. J. Org. Chem. 1994, 59, 6892-6894.
(e) West, F. G.; Naidu, B. N. J. Org. Chem. 1994, 59, 1-6056. (f) West,
F. G.; Naidu, B. N. J. Am. Chem. Soc. 1993, 115, 1177-1178. For related
ammonium ylide [2,3]-shift chemistry, see: (g) Clark, J. S.; Middleton, M.
D. Org. Lett. 2002, 4, 765-768. (h) Smith, S. C.; Bentley, P. D. Tetrahedron
Lett. 2002, 43, 899-902. (i) Clark, J. S.; Hodgson, P. B.; Goldsmith, M.
D.; Street, L. J. J. Chem. Soc., Perkin Trans. 1 2001, 3312-3324.
(j) Pedrosa, R.; Andres, C.; Delgado, M. Synlett 2000, 893-895.
(3) For mechanistic studies in support of radical pair intermediates in
[1,2]-shifts, see: (a) Heard, G. L.; Yates, B. F. Aust. J. Chem. 1995, 48,
1413-1423. (b) Ollis, W. D.; Rey, M.; Sutherland, I. O. J. Chem. Soc.,
Perkin Trans. 1 1983, 1009-27. See also ref 2d.
(4) For a recent report that suggests an alternative ion-pair-mediated
mechanism, see: Hanessian, S.; Mauduit, M. Angew. Chem., Int. Ed. 2001,
40, 3810-3813.
(5) Review: Clark, J. S.; West, F. G. In Nitrogen, Oxygen and Sulfur
Ylides in Synthesis: A Practical Approach; Clark, J. S., Ed.; Oxford
University Press: Oxford, 2002; pp 115-134.
(6) (a) Saba, A. Tetrahedron Lett. 2003, 44, 2895-2989. (b) Vanecko,
J. A.; West, F. G. Org. Lett. 2002, 4, 2813-2816. (c) Padwa, A.; Beall, L.
S.; Eidell, C. K.; Worsencroft, K. J. J. Org. Chem. 2001, 66, 2414-2421.
(d) Chelucci, G.; Saba, A.; Valenti, R.; Bacchi, A. Tetrahedron: Asymmetry
2000, 11, 3449-3453. (e) Naidu, B. N.; West, F. G. Tetrahedron 1997,
53, 16565-16574. (f) Wright, D. L.; Weekly, R. M.; Groff, R.; McMills,
M. C. Tetrahedron Lett. 1996, 37, 2165-2168.
10.1021/ol050915o CCC: $30.25
© 2005 American Chemical Society
Published on Web 06/09/2005

Scheme 1
Scheme 2
than the [2,3]-shift,15 is sufficiently slow to permit the
intervention of the undesired pathway. The strained azeti-
dinium ylide 2a presented an interesting question: Could
release of ring-strain lower the barrier to homolytic cleavage
and allow the [1,2]-shift pathway to compete with the
fragmentation process? With this in mind, we chose to
examine the behavior of methyl 1-benzylazetidine-2-car-
boxylate 516 in the presence of ethyl diazoacetate and various
transition metal catalysts.
pyrrolizidine alkaloids,7 as exemplified by turneforcidine8
and platynecine.9 Successful application of this approach
would convert an azetidinecarboxylate 1a with a pendant
diazoketone into pyrrolizidines 3a/4a,10 in which the ester
and ketone are properly positioned for reduction to the C-7
and C-9 secondary and primary alcohols found in many of
the naturally occurring pyrrolizidines. Here we describe the
successful execution of this strategy, including the synthesis
of (()-turneforcidine and (()-platynecine from methyl
1-benzylazetidine-2-carboxylate, in five steps.
We anticipated that ylide 6 would be generated under these
conditions (Scheme 3), and its behavior might offer insight
A potential limitation in the application of the spiro-ylide
methodology to pyrrolizidines was the availability of alterna-
tive ylide decomposition pathways. In the case of five-
membered ylides containing an endocyclic carbonyl, we11
and Padwa12 had observed products derived from an apparent
proton-transfer/fragmentative ring-opening process, isolated
to the exclusion of any of the desired [1,2]-shift products
(Scheme 2). In sharp contrast, Clark has obtained high yields
of five-membered ylide-derived products when the available
rearrangement pathway involves a concerted [2,3]-shift.13,14
On the basis of these results, we inferred that the stepwise
[1,2]-shift, which is generally observed to occur less readily
Scheme 3
(7) Review: Liddell, J. R. Nat. Prod. Rep. 2002, 19, 773-781.
(8) Previous syntheses of turneforcidine: (a) Wee, A. G. H. J. Org. Chem.
2001, 66, 8513-8517. (b) An, D. K.; Duncan, D.; Livinghouse, T.; Reid,
P. Org. Lett. 2001, 3, 2961-2963. (c) Niwa, H.; Kuroda, A.; Sakata, T.;
Yamada, K. Bull. Chem. Soc. Jpn. 1997, 70, 2541-2543. (d) Knight, D.
W.; Share, A. C.; Gallagher, P. T. J. Chem. Soc., Perkin Trans. 1 1997,
2089-2097. (e) Hudlicky, T.; Seoane, G.; Lovelace, T. C. J. Org. Chem.
1988, 53, 2094-2099. (f) Chamberlin, A. R.; Chung, J. Y. L. J. Org. Chem.
1985, 50, 4425-4431. (g) Ohsawa, T.; Ihara, M.; Fukumoto, K.; Kametani,
T. J. Org. Chem. 1983, 48, 3644-3648. (h) Aasen, A. J.; Culvenor, C. C.
J. Aust. J. Chem. 1969, 22, 2657-2662.
(9) Previous syntheses of platynecine: (a) Zhou, C.-Y.; Yu, W.-Y.; Chan,
P. W. H.; Che, C.-M. J. Org. Chem. 2004, 69, 7072-7082. (b) de Faria,
A. R.; Salvador, E. L.; Correira, C. R. D. J. Org. Chem. 2002, 67, 3651-
3661. (c) Denmark, S. E.; Parker, D. L.; Dixon, J. A. J. Org. Chem. 1997,
62, 435-436. (d) Kang, S. H.; Kim, G. T.; Yoo, Y. S. Tetrahedron Lett.
1997, 38, 603-606. (e) Fleet, G. W. J.; Seijas, J. A.; Vazqueztato, M. P.
Tetrahedron 1991, 47, 525-530. (f) Roder, E.; Bourauel, T.; Wiedenfeld,
H. Liebigs Ann. Chem. 1990, 607-609. (g) Rueger, H.; Benn, M.
Heterocycles 1983, 1331-1334. See also refs 8c, 8e, and 8f.
(10) For previous preparation of 3a and/or 4a, see refs 8c, 8e, and 8f.
(11) Naidu, B. N. Ph.D. Dissertation, University of Utah, Salt Lake City,
UT, 1994.
into the reactivity of azetidinium ylides toward ring expan-
sion. Ylide 6 possesses two groups on nitrogen that might
reasonably be expected to participate in [1,2]-shift processes.
Migration of the benzyl substituent would lead to azetidine
7, while migration of the ester-substituted carbon would
furnish pyrrolidine 8. In prior studies, we have found that
(14) For related observations involving oxonium ylide [1,2]- and
[2,3]-shifts, see: (a) Marmsa¨ter, F. P.; Vanecko, J. A.; West, F. G.
Tetrahedron 2002, 58, 2027-2040. (b) Marmsa¨ter, F. P.; Vanecko. J. A.;
West, F. G. Org. Lett. 2004, 6, 1657-1660.
(15) (a) Ammonium ylides: Jemison, R. W.; Laird, T.; Ollis, W. D.;
Sutherland, I. O. J. Chem. Soc., Perkin Trans. 1 1980, 1450-1461.
(b) Sulfonium ylides: Vedejs, E.; Arnost, M. J.; Hagen, J. P. J. Org. Chem.
1979, 44, 3230-3238. (c) Oxonium ylides: West, F. G.; Eberlein, T. H.;
Tester, R. W. J. Chem. Soc., Perkin Trans. 1 1993, 2857-2859.
(16) Rodebaugh, R. M.; Cromwell, N. H. J. Heterocycl. Chem. 1968,
309.
(12) Padwa, A.; Hasegawa, T.; Liu, B.; Zhang, Z. J. Org. Chem. 2000,
65, 7124-7133.
(13) Clark, J. S.; Hodgson, P. B.; Goldsmith, M. D.; Blake, A. J.; Cooke,
P. A.; Street, L. J. J. Chem. Soc., Perkin Trans. 1 2001, 3325-3337.
2950
Org. Lett., Vol. 7, No. 14, 2005

either CH2Ar or CH2CO2R groups undergo efficient
migration.2f,17 However, in a previous case (9) in which both
possibilities were available, we observed exclusive migration
of the benzyl group.17,18 This selectivity was rationalized in
terms of the greater stability of the putative benzylic radical
intermediate. In contrast to this result, when racemic 5 was
treated with ethyl diazoacetate and 10 mol % Cu(tfacac)2 in
refluxing toluene, the exclusive product was pyrrolidine
diester 8 (82%; 1:1 mixture of diastereomers).19 Rhodium-
(II) acetate and other soluble copper catalysts (Cu(acac)2 and
Cu(tfacac)2) gave qualitatively comparable results, although
with somewhat lower yields. Under no circumstances was
the benzyl [1,2]-shift product 7 isolated. 3-Carboxyproline
derivatives such as 8 are of interest as rigid aspartic acid
analogues.20 This constitutes an exceedingly short and
convenient route to such compounds. Moreover, these
results suggested that the corresponding spirocyclic azeti-
dinium ylide might undergo efficient rearrangement to the
pyrrolizidine system in competition with the undesired
fragmentation.
gave comparable or slightly lower yields, and the dia-
stereomer ratio did not vary to any great extent with catalyst
or reaction conditions.23 This mixture was then carried on
through the known sequence8f,h to prepare (()-turneforcidine
and (()-platynecine. Ketone reduction (H2, PtO2) gave
hydroxyester 11 (88% based on the starting ratio) and lactone
12 (71% based on the starting ratio), which were easily
separable. Each was then treated with LiAlH4 to give the
natural products in high overall yield.
The optimized conditions were also investigated for
homologous diazoketone 1b, prepared from commercially
available proline benzyl ester hydrochloride and 10 (Scheme
5).24 Under these conditions, only trace amounts of the
Scheme 5
Given the positive results with 5, we then set out to
examine the intramolecular version of this ring expansion.
Reductive debenzylation of 5 under transfer hydrogenation
conditions (Pd/C, ammonium formate)21 followed by im-
mediate coupling of the volatile intermediate with 4-bromo-
1-diazobutan-2-one 1022 furnished substrate 1a in high yield
(Scheme 4). Treatment of 1a with Cu(acac)2 or Rh2(OAc)4
desired indolizidines 3b and 4b were obtained, along with a
side product that resisted characterization. However, lower
reaction temperatures (reflux in benzene or CH2Cl2) did
furnish 50-62% of 3b/4b as an inseparable mixture. After
a survey of a variety of catalysts, solvents, and reaction
temperatures, Rh2(OAc)4 in refluxing benzene was found to
provide the best result. The aforementioned side product was
the main component isolated from all experiments carried
out in refluxing toluene. Indolizidines 3b and 4b were
significantly more sensitive than their pyrrolizidine coun-
terparts 3a/4a, undergoing substantial decomposition after
as little as 30 min at rt. As a result, no attempt at further
elaboration was made.
Scheme 4
We have shown that ammonium ylides derived from
azetidine-2-carboxylates undergo efficient ring-expansion via
the Stevens [1,2]-shift. The intermolecular process offers a
short route to 3-carboxyproline derivatives, while the intra-
molecular variant has been used in a five-step synthesis of
(20) (a) Carpes, M. J. S.; Miranda, P. C. M. L.; Correia, C. R. D.
Tetrahedron Lett. 1997, 38, 1869-1872. (b) Cotton, R.; J. A. N. C.; North,
M. Tetrahedron 1995, 51, 8525-8544. (c) Baldwin, J. E.; Adlington, R.
M.; Gollins, D. W. Tetrahedron 1995, 51, 5169-5180. (d) Sasaki, N. A.;
Pauly, R.; Fontaine, C.; Chiaroni, A.; Riche, C.; Potier, P. Tetrahedron
Lett. 1994, 35, 241-244.
provided an inseparable mixture of diastereomers 3a and 4a
in 81-82% yield (3.6:1 dr). Other soluble copper(II) catalysts
(21) Ram, S.; Spicer, L. D. Tetrahedron Lett. 1987, 28, 515-516.
(22) Rosenquist, N. R.; Chapman, O. L. J. Org. Chem. 1976, 41, 3326-
3327.
(17) West, F. G.; Glaeske, K. W.; Naidu, B. N. Synthesis 1993, 977-
980.
(23) However, epimerization of the initial product mixture could be
effected via slow elution through a silica gel column using a less polar
eluant to furnish 3a + 4a in a 94:6 ratio. For n related example, see ref 13.
(24) Saba and co-workers have recently reported a similar approach to
indolizidines using doubly stabilized metallocarbene intermediates: Muroni,
D.; Saba, A.; Culeddu, N. Tetrahedron: Asymmetry 2004, 15, 2609-2614.
(18) Complete preference for benzylic migration in ring expansion of
morpholinium ylides has also been noted. See refs 6a and 6d.
(19) For other recent examples of azetidinefpyrrolidine rearrangement,
see: (a) Kim, S.; Yoon, J.-Y. Synthesis 2000, 1622-1630. (b) Couty, F.;
Durrat. F.; Evano, G.; Prim, D. Tetrahedron Lett. 2004, 45, 7525-7528.
Org. Lett., Vol. 7, No. 14, 2005
2951

turneforcidine and platynecine from readily available methyl
1-benzylazetidine-2-carboxylate. Preliminary studies indicate
that these conditions may also be applicable to indolizidine-
containing targets. Further studies to enhance the diastereo-
selectivity of the intermolecular reaction and to explore
the question of chirality transfer via the transient quater-
nary ammonium center in the case of enantiomerically
pure azetidine starting materials will be reported in due
course.
Acknowledgment. This work was supported by the
donors of the Petroleum Research Fund, administered by the
American Chemical Society.
Supporting Information Available: Experimental pro-
cedures and spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL050915O
2952
Org. Lett., Vol. 7, No. 14, 2005