2752 J . Org. Chem., Vol. 67, No. 9, 2002
Marshall and Bourbeau
Sch em e 2
Sch em e 3
F igu r e 2. Comparison of Wittig condensations on various
aldehyde precursors leading to potential segments of the C13-
C22 segment of callystatin A.
followed by Swern oxidation of alcohol 19 effected conver-
sion to aldehyde 20.10 To this was added the (M)-
allenylzinc reagent 21, prepared in situ from the mesylate
of (S)-3-butyn-2-ol and Et2Zn in the presence of 5 mol %
Pd(OAc)2‚PPh3.11 The expected anti adduct 22 was thereby
produced in 72% yield as a single diastereomer.12 Partial
Following this plan, we prepared the C1-C6 aldehyde
5 uneventfully as outlined in Scheme 1. As noted above,
the route differs somewhat from that used by previous
workers.
13
hydrogenation of alkyne 22 over Pd on BaSO4 and
Further elaboration of aldehyde 5 to the C1-C12
segment 14 of callystatin A commenced with Still-
Horner-Emmons condensation of phosphono ester 7 with
the (R)-aldehyde 6 to afford the (Z)-conjugated ester 8
in high yield with 6-8:1 stereoselectivity (Scheme 2).7
The derived alcohol 9 was converted to bromide 10 with
CBr4 and Ph3P. The ylide, prepared from bromide 10 by
sequential treatment with Bu3P and then KO-t-Bu,
condensed with aldehyde 5 in situ to yield diene 12 in
88% yield for the two steps. Cleavage of the TES ether
followed by treatment of the free alcohol with I2 and
Ph3P-imidazole8 completed the synthesis of this segment.
Construction of the C13-C22 polypropionate subunit
of callystatin A began with BF3‚OEt2-promoted addition
of the (M)-allenylstannane 16 to the (R)-aldehyde 15 and
protection of the resulting syn,syn adduct 17 as the TBS
ether 18 (Scheme 3).9 Hydrogenolysis of benzyl ether 18
with concomitant reduction of the terminal alkynyl group
ozonolysis of the resulting olefin 23 led to aldehyde 24.
Attempted reduction of the ozonide with dimethyl sulfide
resulted in total decomposition of the product. However,
the use of Ph3P proved highly satisfactory.
The TMS ether of aldehyde 24 (R ) TMS) proved
completely unreactive toward homologation with the
R-triphenylphosphonium propionate Wittig reagent, in
contrast to previous reactions of this reagent with I (R
) TMS), the all-syn isomer of aldehyde 24, which
proceeded in near-quantitative yield (Figure 2).3,9 Fur-
thermore, we have previously converted the PMB ether
I (R ) PMB) of the all-syn aldehyde to the conjugated
ester II in excellent yield by condensation with the same
propionate Wittig reagent.9b However, the anti,anti ana-
logue V failed to react under identical or even more
forcing conditions (refluxing toluene).14 Borrowing a page
from the Kobayashi synthesis,1 albeit on a conversion
(10) Mancusso, A. J .; Huang, S.-L.; Swern, D. J . Org. Chem. 1978,
43, 2480. Cf. Tidwell, T. T. Synthesis 1990, 857.
(11) Marshall, J . A. Chem. Rev. 2000, 100, 3163. Marshall, J . A.;
Adams, N. D. J . Org. Chem. 1999, 64, 5201.
(7) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405.
Marshall, J . A.; DeHoff, B. S.; Cleary, D. G. J . Org. Chem. 1986, 51,
1735.
(8) Garegg, P. J .; Samuelsson, B. J . Chem. Soc., Perkin Trans. 1
1982, 681. Corey, E. J .; Pyne, S. G.; Su, W. Tetrahedron Lett. 1983,
24, 4883.
(9) Marshall, J . A.; Chem. Rev. 1996, 96, 31. For a previous synthesis
of an all syn isomer of this subunit, see: Marshall, J . A.; Fitzgerald,
R. N. J . Org. Chem. 1999, 64, 3798.
(12) Experimental details for the preparation of compounds 17-20
and 22 will be disclosed in a forthcoming publication (Marshall, J . A.;
Schaff, G. M. J . Org. Chem., in press).
(13) Adams, M. A. Duggen, A. J .; Smolanoff, J .; Meinwald, J . J . Am.
Chem. Soc. 1979, 101, 5364.
(14) Marshall, J . A.; Chobanian, H. R. Unpublished results.