Nonstabilized N-unsubstituted azomethine ylides: A synthesis of indolizidine 239CD

Article abstract of DOI:10.1021/ol990677v

(equation presented) Treatment of a (2-azaallyl)stannane with HF·pyridine generated a nonstabilized N-unsubstituted azomethine ylide, which was found to undergo an efficient and stereoselective dipolar cycloaddition with phenyl vinyl sulfone to produce a

Full text of DOI:10.1021/ol990677v

ORGANIC
LETTERS
1
999
Vol. 1, No. 2
49-351
Nonstabilized N-Unsubstituted
Azomethine Ylides: A Synthesis of
Indolizidine 239CD
3
Roger B. Clark and William H. Pearson*
Department of Chemistry, UniVersity of Michigan, Ann Arbor, Michigan 48109-1055
wpearson@umich.edu
Received May 19, 1999
ABSTRACT
Treatment of a (2-azaallyl)stannane with HF‚pyridine generated a nonstabilized N-unsubstituted azomethine ylide, which was found to undergo
an efficient and stereoselective dipolar cycloaddition with phenyl vinyl sulfone to produce a trans-2,5-dialkylpyrrolidine that was further
transformed into the dendrobatid alkaloid indolizidine 239CD.
We recently reported a convenient method for the generation
notable features of this route include the tolerance for
aliphatic groups, good trans-2,5 diastereoselectivity in the
pyrrolidine product, mild reaction conditions, and of course
the lack of a substituent at nitrogen. We now wish to report
the application of this method for the synthesis of (()-
and cycloaddition of nonstabilized N-unsubstituted azo-
1
methine ylides 2 (Scheme 1), a rare subclass of these ylides.
Scheme 1
(3) (a) Lown, W. J. In 1,3-Dipolar Cycloaddition Chemistry; Padwa,
A., Ed.; Wiley: New York, 1984; Vol. 1; pp 663-732. (b) Pearson, W. H.
In Studies in Natural Products Chemistry; Rahman, A., Ed.; Elsevier:
Amsterdam, 1988; Vol. 1; pp 323-358. (c) Vedejs, E. In AdVances in
Cycloaddition; Curran, D. P., Ed.; JAI Press: Greenwich, CT, 1988; Vol.
1
; pp 33-51. (d) Tsuge, O.; Kanemasa, S. AdV. Heterocycl. Chem. 1989,
4
5, 231-349. (e) Padwa, A. In ComprehensiVe Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 4; pp 1069-1109.
(
f) Wade, P. A. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming,
I., Eds.; Pergamon: Oxford, 1991; Vol. 4; pp 1111-1168.
4) Azomethine ylides have been used to make indolizidines and
(
pyrrolizidines. See: refs 2 and 3c-e above and (a) Terao, Y.; Aono, M.;
Achiwa, K. Heterocycles 1988, 27, 981-1008. (b) Pandey, G.; Lakshmaiah,
G.; Ghatak, A. Tetrahedron Lett. 1993, 34, 7301-4. During the course of
this work, a related approach to indolizidines and pyrrolizidines involving
the dipolar cycloaddition of stabilized azomethine ylides with alkenes
followed by intramolecular reductive amination was published. See: (c)
Grigg, R.; Hargreves, S.; Redpath, J.; Turchi, S.; Yoganathan, G. Synthesis
1999, 441-446.
Treatment of (2-azaallyl)stannanes 1 with HF‚pyridine
2
produced the ylides 2 by N-protonation and destannylation.
1-3
Compared to other methods for azomethine ylide formation,
(
(
1) Pearson, W. H.; Clark, R. B. Tetrahedron Lett. 1999, in press.
2) For a related approach using other electrophiles to initiate the
(5) For a review on the synthesis of 2,5-disubstituted pyrrolidines that
includes azomethine ylide cycloadditions, see: M. Pichon, B. Figad e` re,
Tetrahedron: Asymmetry 1996, 7, 927-964.
formation of azomethine ylides from (2-azaallyl)stannanes, see: Pearson,
W. H.; Mi, Y. Tetrahedron Lett. 1997, 38, 5441-5444.
1
0.1021/ol990677v CCC: $18.00 © 1999 American Chemical Society
Published on Web 06/15/1999

indolizidine 239CD (4), one of several naturally occurring
indolizidines that include a trans-2,5-disubstituted pyrrolidine
in their structures.4
methine ylide 9, available from the (2-azaallyl)stannane 10,
with ethylene or its equivalent. The stannane 10 should be
available from an aldehyde and an R-stannylamine.
,5
10,11
Poison frogs of the species Dendrobates histrionicus yield
The requisite aldehyde 15 was prepared by the route shown
in Scheme 2, beginning with the commercially available
alcohol 11. Oxidation, chain extension, reoxidation, protec-
tion, and unmasking of the aldehyde by oxidative cleavage
of the alkene proceeded smoothly.
four 3,5-disubstituted indolizidines, namely, 223AB, 239AB,
-9
2
39CD, and 195B (Figure 1).6 A retrosynthetic analysis
Scheme 2
Figure 1. Structures of indolizidines 239CD, 239AB, 223AB, and
95B and retrosynthetic analysis of indolizidine 239CD.
The synthesis of the phthalimide 19, the precursor of the
desired R-stannylamine, is shown in Scheme 3. Oxidation
of the commercially available alcohol 16 gave the aldehyde
1
1
7, which was treated with tri-n-butylstannyllithium to
is shown. Formation of the piperidine ring at a late stage
would rely on an intramolecular reductive amination involv-
ing 8, a well-known strategy for indolizidine synthesis. The
provide an R-hydroxy stannane. Without purification, this
9
pyrrolidine 8 would require the cycloaddition of the azo-
Scheme 3
(
6) Tokuyama, T.; Nishimori, N.; Karle, I. L.; Edwards, M. W.; Daly, J.
W. Tetrahedron 1986, 42, 3453-3460.
7) Daly, J. W.; Spande, T. F.; Whittaker, N.; Highet, R. J.; Feigl, D.;
Nishimori, N.; Tokuyama, T.; Myers, C. W. J. Nat. Prod. 1986, 49, 265-
80.
8) (a) Daly, J. W.; Spande, T. F. In Alkaloids: Chemical and Biological
PerspectiVes; Pelletier, S. W., Ed.; Wiley: New York, 1986; Vol. 4; pp
-274. (b) Daly, J. W.; Garraffo, H. M.; Spande, T. F. In The Alkaloids;
Cordell, G. A., Ed.; Academic Press: San Diego, 1993; Vol. 43; pp 185-
88. (c) Daly, J. In The Alkaloids; Cordell, G. A., Ed.; Academic Press:
(
2
(
1
2
New York, 1997; Vol. 50. (d) Daly, J. W.; Garraffo, H. M.; Spande, T. F.
In Alkaloids: Chemical and Biological PerspectiVes; Pelletier, S. W., Ed.;
John Wiley & Sons: New York, 1999; Vol. 13; p 1.
(
9) Many syntheses of these and related indolizidines have been
published. For the latest in a series of reviews covering the synthesis of
indolizidines and pyrrolizidines, see: (a) Michael, J. P. Nat. Prod. Rep.
alcohol was transformed into the bromide 18 in good yield,
which was subjected to displacement chemistry to provide
the pthlalimide 19.
Completion of the synthesis of indolizidine 239CD is
shown in Scheme 4. Hydrazinolysis of the pthalimide 19
1
998, 15, 571-594. For syntheses of indolizidines 195B, 223AB, 239AB,
and 239CD by an approach involving trans-2,5-disubstituted pyrrolidines,
see: (b) Machinaga, N.; Kibayashi, C. J. Org. Chem. 1992, 57, 5178-
5
1
2
189. (c) Machingaga, N.; Kibayashi, C. J. Chem. Soc., Chem. Commun.
991, 405-407. For other approaches to indolizidines 195B, 223AB, and
39AB involving trans-2,5-disubstituted pyrrolidines, see: (d) Thanh, G.
V.; Celerier, J. P.; Lhommet, G. Tetrahedron: Asymmetry 1996, 7, 2211-
212. (e) C e´ lim e` ne, C.; Lhommet, G. Tetrahedron 1998, 54, 10457-10468.
f) Dhimane, H.; Vanucci-Bacqu e´ , C.; Hamon, L.; Lhommet, G. Eur. J.
(10) Pearson, W. H.; Postich, M. J. J. Org. Chem. 1992, 57, 6354-
6357.
2
(
(11) Chong, J. M.; Park, S. B. J. Org. Chem. 1992, 57, 2220-2222.
(12) See ref 1 for a comparison with existing methods for the generation
of nonstabilized N-substituted and N-unsubstituted azomethine ylides.
Regarding nonstabilized N-unsubstituted azomethine ylides, two other
methods for their generation are known, the decarboxylation of imines
derived from the condensation of R-amino acids with aldehydes [leading
references: (a) Tsuge, O.; Kanemasa, S.; Ohe, M.; Takenaka, S. Bull. Soc.
Chem. Jpn. 1987, 60, 4079-4089. (b) Ardill, H.; Grigg, R.; Sridharan, V.;
Surendrakumar, S. Tetrahedron 1988, 44, 4953-4966] and the water-
induced generation of such ylides from N-(silylmethyl)imines [Tsuge, O.;
Kanemasa, S.; Hatada, A.; Matsuda, K. Bull. Soc. Chem. Jpn. 1986, 59,
2537-2545]. The first method suffers from low yields and poor trans:cis
stereoselectivity, while the second is limited to nonenolizable imines with
no branching next to silicon (i.e., monosubstituted azomethine ylides).
Org. Chem. 1998, 1955-1963. For selected additional syntheses of
indolizidine 195B, see: (g) Bloch, R.; Brillet-Fernandez, C.; K u¨ hn, P.;
Mandville, G. Heterocycles 1994, 38, 1589-1594. (h) Solladie, G.; Chu,
G.-H. Tetrahedron Lett. 1996, 37, 111-14. (i) Lee, E.; Kang, T. S.; Chung,
C. K. Bull. Korean Chem. Soc. 1996, 17, 212-14. (j) Somfai, P.; Jarevang,
T.; Lindstrom, U. M.; Svensson, A. Acta Chem. Scand. 1997, 51, 1024-
1
029. For selected additional syntheses of indolizidine 223AB, see: (k)
Watanabe, Y.; Iida, H.; Kibayashi, C. J. Org. Chem. 1989, 54, 4088-97.
l) Taber, D. F.; Deker, P. B.; Silverberg, L. J. J. Org. Chem. 1992, 57,
(
5
1
1
990-5994. (m) Pilli, R. A.; Dias, L. C.; Maldaner, A. O. J. Org. Chem.
995, 60, 717-722. (n) Takahata, H.; Bandoh, H.; Momose, T. Heterocycles
995, 41, 1797-1804. (o) Momose, T.; Toshima, M.; Seki, S.; Koike, Y.;
Toyooka, N.; Hirai, Y. J. Chem. Soc., Perkin Trans. 1 1997, 1315-1321.
350
Org. Lett., Vol. 1, No. 2, 1999

imine was mixed with phenyl vinyl sulfone, and the mixture
was warmed to 50 °C and treated with HF‚pyridine for 10
min. Workup provided the pyrrolidine 22 as a nearly equal
mixture of four isomers in 73% overall yield from the
pthalimide 19. Removal of the ketal and intramolecular
reductive amination proceeded in good yield to produce 23,
again as a mixture of four isomers. We were not able to
determine the stereo- and regiochemistry of either 22 or 23.
Reductive cleavage of the benzyl ether and the sulfone was
initially a troublesome transformation but was found to be
efficient with lithium and ammonia. The four isomers of 23
converged to a single compound, indolizidine 239CD (4),
thus providing evidence that 22 and 23 were a mixture of
regio- and stereoisomers at the sulfone position and that the
cycloaddition had proceeded with high trans-2,5 stereo-
selectivity.
Scheme 4
In conclusion, our recent method for the synthesis of trans-
2
,5-dialkyl-N-unsubstituted-pyrrolidines has proven to be
effective for use in more complex situations, resulting in a
convergent, efficient, and relatively short synthesis of in-
dolizidine 239CD (4). Significant features of the synthesis
are the efficiency, stereoselectivity, and mildness of the
azomethine ylide cycloaddition. Prior to our work, access
to nonstabilized N-unsubstituted azomethine ylides such as
1
2
those described herein had been very limited.
Acknowledgment. Support for this research was provided
by the National Institutes of Health.
gave an amine, which was not purified but directly condensed
with the aldehyde 15 under typical imine formation condi-
tions to produce the (2-azaallyl)stannane 20. The unpurified
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