Scheme 1. Synthesis of Epohelmin A Model 11
Figure 2. NMR data of epoxycyclooctanes (5 and 6) and
pyrrolizidin-1-ols (7 and 8).
pyrrolizidin-1-ols 4 look quite different than 9-oxa-4-
azabicyclo[6.1.0]nonanes 3, the only difference is the forma-
tion of a C-N bond and cleavage of a C-O bond so that
the 2D NMR correlations used to assign the structure of
epohelmins A and B as 1 and 2 will be equally applicable
to the stereoisomers of 4.
This analysis suggests that epohelmins A and B are two
of the four stereoisomers of 4. If this is the case, the
stereochemical analysis of 1 and 2 is based on the wrong
skeleton and may not be applicable to the stereochemistry
of 4. We decided that the stereochemistry was best deter-
mined by the synthesis of model 3-alkylpyrrolizidin-1-ols
such as 11. Aldol addition of the kinetic enolate of 2-unde-
canone to N-Cbz-phenylalaninal followed by reductive
pyrrolidine formation and methylation led to all four isomers
of preussin (2-benzyl-1-methyl-5-(nonyl)pyrrolidin-3-ol).6
This short sequence seemed ideal since at this time we did
not know the stereochemistry of the epohelmins.
of lithium enolates to N-Cbz-phenylalaninal; the zinc enolate
added stereoselectively.6 Addition of zinc and lithium
enolates of ethyl acetate to N-Boc-prolinal afforded 2:1 to
4:1 mixtures of isomers favoring the Felkin-Anh product.9
We decided to prepare oxazolidinone 14 to prove the
stereochemistry of aldol product 10. Treating 10 with K2-
CO3 did not form the expected oxazolidinone but instead
resulted in hydrolysis and double dehydration to give pyrrole
12.10 Reduction of the ketone with NaBH4 in MeOH followed
by treatment with K2CO3 in 1:1 2-propanol/water for 18 h
at 70 °C provided oxazolidinone 13 in 71% overall yield as
a mixture of stereoisomers. Dess-Martin oxidation afforded
the desired oxazolidinone ketone 14 in 99% yield. The
coupling constant between the methine hydrogens of 14 is
7.3 Hz as in related compounds indicating that the hydrogens
are cis; in similar compounds with anti hydrogens the
coupling constant is 4.0 Hz.11 This established that the enolate
of 2-heptanone added to 9 with high Felkin-Anh selectivity
to give 10.
The stereochemistry at C3 of epohelmin A model 11 was
established by the NOE between H1 and H3. We had not
expected the reductive cyclization to be stereoselective
because reductive cyclization of related pyrrolidine ketones
lacking the hydroxyl group gave 1:1 mixtures of 3-alkylpyr-
rolizidines.12 Presumably, the hydroxyl group blocks the
bottom face so that hydrogenation occurs preferentially from
the top face to give 11.
Treatment of 2-heptanone with LDA in THF at -78 °C
provided the kinetic enolate, which was treated with N-Cbz-
(S)-prolinal (9)7 to afford 10 with excellent stereoselectivity
in 95% yield (see Scheme 1). Hydrogenolysis (1 atm) of 10
over Pd(OH)2 in MeOH for 12 h liberated the secondary
amine, which reacted with the ketone to form an iminium
salt or enamine, which was reduced to give pyrrolizidinol
11 in 71% yield. Several minor byproducts were formed that
may include diastereomers of 11 other than epohelmin B
model 16. Similar results were obtained with other Pd
1
catalysts. As expected, the H and 13C NMR spectra of 11
vary as a function of pH. The epohelmins were isolated using
an eluent containing HOAc, suggesting that the natural
products were isolated as acetate salts. We were pleased to
1
find that the H and 13C NMR spectra of a CDCl3 solution
We now turned our attention to the preparation of an
epohelmin B model. As suggested by Ebizuka and Shibuya,
we suspected that epohelmins A and B differed in the
alcohol, not alkyl, stereochemistry. Changing the stereo-
chemistry at the alkyl group should change the 13C NMR
of 11 containing 0.85-0.90 equiv of HOAc corresponded
precisely with those of the ring portion of epohelmin A.8
We had not expected either step in the formation of 11 to
be stereoselective. Kitahara obtained mixtures in the addition
(5) Christine, C.; Ikhiri, K.; Ahond, A.; Mourabit, A. A.; Poupat, C.;
Potier, P. Tetrahedron 2000, 56, 1837-1850.
(6) (a) Okue, M.; Watanabe, H.; Kitahara, T. Tetrahedron 2001, 57,
4107-4110. (b) Okue, M.; Watanabe, H.; Kasahara, K.; Yoshida, M.;
Horinouchi, S.; Kitahara, T. Biosci. Biotechnol. Biochem. 2002, 66, 1093-
1096.
(9) (a) Andre´s, J. M.; Pedrosa, R.; Pe´rez, A.; Pe´rez-Encabo, A.
Tetrahedron 2001, 57, 8521-8530. (b) Hanson, G. J.; Baran, J. S.; Lindberg,
T. Tetrahedron Lett. 1986, 27, 3577-3580.
(10) For a similar compound see: Pommelet, J. C.; Jourdain, F.;
Dhimane, H. Molecules 2000, 5, 1130-1138.
(7) (a) Langley, D. R.; Thurston, D. E. J. Org. Chem. 1987, 52, 91-97.
(b) Corey, E. J.; Shibata, S.; Bakshi, R. K. J. Org. Chem. 1988, 53, 2861-
2863. (c) Dolbeare, K.; Pontoriero, G. F.; Gupta, S. K.; Mishra, R. K.;
Johnson, R. L. Bioorg. Med. Chem. 2003, 11, 4103-4112.
(8) We thank Prof. M. Shibuya for a complete set of 1D and 2D NMR
spectra of epohelmins A and B.
(11) (a) Parker, K. A.; O’Fee, R. J. Am. Chem. Soc. 1983, 105, 654-
655. (b) Kiyooka, S.-i.; Nakano, M.; Shiota, F.; Fujiyama, R. J. Org. Chem.
1989, 54, 5409-5411. (c) St-Denis, Y.; Chan, T.-H. J. Org. Chem. 1992,
57, 3078-3085.
(12) Provot, O.; Ce´le´rier, J.-P.; Lhommet, G. J. Heterocycl. Chem. 1998,
35, 371-376.
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Org. Lett., Vol. 7, No. 20, 2005