8528 J . Org. Chem., Vol. 65, No. 25, 2000
Lo´pez-Pelegr´ın et al.
F igu r e 1. Retrosynthetic strategy to the orthogonally protected C21-C27 fragment I of the bryostatins.13
ongoing effort to improve and expand the utility and
applicability of liquid-phase chemistry into asymmetric
organic synthesis we recently reported the linear poly-
styrene-supported syntheses of prostaglandin E methyl
necessary (R,R)-C25,C26 diastereomer. Reduction of the
isoxazoline ring in III followed by in situ hydrolysis then
gives II the ketone group of which can be reduced
stereoselectively to yield the desired anti-diol I, the
ultimate synthetic target.
ester and prostaglandin F2R.
11 Herein, we report the first
polymer-supported synthetic approach to a composite
fragment of the bryostatin natural products. Poly-
(ethylene glycol) (PEG) is explored as a matrix for a novel
synthetic approach to the C21-C27 fragment of the
bryostatins12 that incorporates a stereoselective enzy-
matic transformation.
The particular requirements of the enzymatic trans-
formation guided the choice of PEG as a polymer support.
The required matrix must be compatible with this
biocatalytic transformation and resins, with a few notable
exceptions,15 are incompatible with enzymatic processes.
In addition, the polymer support must be soluble under
both organic and aqueous conditions as demanded by the
enzymatic reaction.
Resu lts a n d Discu ssion
Monomethoxy PEG of 5000 molecular weight (MeO-
PEG5000) was chosen as the specific matrix for this
synthesis. While the loading associated with this par-
ticular support (0.2 mmol/g) is lower than other PEG
The retrosynthetic strategy to the target fragment I
is shown in Figure 1. The crux of the challenge is the
sequential stereoselective generation and orthogonal
protection of the three secondary alcohols at C23, C25, and
C26.
The synthons II-IV are generated following a pre-
liminary [3 + 2] dipolar cycloaddition between a nitrile
oxide, generated in situ from nitroalkane V, and a
suitable dipolarophile.14 With no stereocontrol applied
during the cycloaddition reaction, the C25-stereochemistry
remains undefined at this juncture. However, by exploit-
ing one of the plethora of available enantioselective
enzymatic reductions, it was envisaged that the ketone
of IV could be reduced to give III as pair of diastereomers
that would be separated following cleavage from the
support. This then gives indirect entry to III as the
matrixes we have utilized previously for liquid-phase
16
chemistry, such as PEG3400
,
it provides the optimal
relationship between polymer recovery by precipitation
and ease of NMR interpretation. Furthermore, compari-
son of the integral ratios of polymer-bound intermediates
with the terminal methyl group allows a direct and easy
measure of both loading and conversion after each
synthetic step.
Of primary consideration when developing a polymer-
supported synthesis is the linker strategy. It was antici-
pated that an acid-labile linker, while being completely
stable during the synthetic process, would facilitate
orthogonal cleavage of the final polymer-linked interme-
diate from the support. Therefore, we prepared the
soluble polymer-supported dihydropyran 1, an analogue
of Ellman’s linker utilized in solid-phase chemistry
(Scheme 1).11,17
(10) (a) Gravert, D.; J anda, K. D.; Chem. Rev. 1996, 97, 489. (b)
Wentworth J r., P.; J anda, K. D. Chem. Commun. 1999, 1917.
(11) (a) Chen, S.; J anda, K. D. J . Am. Chem. Soc. 1997, 119, 8724.
(b) Chen, S.; J anda, K. D. Tetrahedron Lett. 1998, 39, 3943.
(12) For other approaches to the synthesis of this fragment: (a)
Masamune, S. Pure Appl. Chem. 1988, 60, 1587. (b) Roy, R.; Rey, A.
W.; Charron, M.; Molino, R. J . Chem. Soc., Chem. Commun. 1989, 1308.
(c) Evans, D. A.; Gauchet-Prunet, J . A.; Carreira, E. M.; Charette, A.
B. J . Org. Chem. 1991, 56, 741. (d) De Brabander, J .; Vanderwalle,
M. Synthesis 1994, 8, 855. (e) Hale, K. J .; Lennon, S. A.; Manaviarar,
S.; J avaid, M. H. Hobbs, C. J . Tetrahedron Lett. 1995, 36, 1359. (f)
Ohmori, K.; Suzuki, T.; Nishiyama, S.; Yamamura, S. Tetrahedron Lett.
1995, 36, 6515.
(15) (a) Rademann, J .; Grøtli, M.; Meldal, M.; Block, K. J . Am. Chem.
Soc. 1999, 121, 5459.
(16) (a) Sieber, F.; Wentworth, P., J r.; Toker, J . D.; Wentworth, A.
D.; Metz, W. A.; Reed, N. N.; J anda, K. D. J . Org. Chem. 1999, 64,
5188. (b) Wentworth, P., J r.; Vandersteen, A. M.; J anda, K. D. Chem.
Commun. 1997, 759. (c) Wentworth, A. D.; Mansoor, U. F.; Wentworth,
P., J r.; J anda, K. D. Organic Lett. 2000, 2, 477.
(17) (a) Thompson, L. A.; Ellman, J . A. Tetrahedron Lett. 1994, 35,
9333. (b) Lee, K. J .; Angulo, A.; Ghazal, P.; J anda, K. D. Org. Lett.
1999, 1, 1859. (c) Lo´pez-Pelegr´ın, J . A.; J anda, K. D. Chem. Eur. J .
2000, in press.
(13) A similar approach to enantiomerically defined 1,2,4-triols has
been utilized previously; see: (a) Ticozzi, C.; Zanarotti, A. Tetrahedron
Lett. 1988, 29, 6167. (b) Ticozzi, C.; Zanarotti, A. Liebigs Ann. Chem.
1989, 12, 1257.
(14) Kozikowski, A. P. Acc. Chem. Res. 1984, 17, 410.