acid 8 commenced with known optically pure epoxide 3
(Scheme 1).12 BF3‚OEt2-mediated opening of 3 with the
Scheme 1. Synthesis of the Carboxylic Acid Coupling Partner
Figure 2. Readily accessible R-acetoxy ethers undergo Prins
reaction upon treatment with Lewis acids to afford tetrahydropyrans.
readily accessible R-acetoxy ethers as cyclization substrates.10
Upon treatment with Lewis acids, R-acetoxy ethers form
oxocarbenium ions that undergo Prins cyclization to provide
tetrahydropyrans with heteroatoms in the 4-position. Cy-
clization via a chair transition state with anti addition of the
nucleophile across the olefin rationalizes the generally high
observed selectivity for the all-cis product.9c,11 The utility
of this convergent approach for tetrahydropyran construction
was demonstrated in a concise synthesis of the central
tetrahydropyran (C22-C26) of phorboxazole B.9b In this
paper, we report the successful application of this methodol-
ogy to the synthesis of the bis-tetrahydropyran segment
(C3-C19) of the natural product.
vinyllithium reagent derived from vinyl bromide 4 (see the
Supporting Information) provided the tert-butyldimethylsilyl
ether in nearly quantitative yield. Silyl deprotection and
primary selective oxidation of the resulting 1,5-diol with IBX
provided the lactol, which was acetylated to afford 5 in 50%
yield from 3.13 Our plan for establishing the 2,6-trans
stereochemistry of the (C5-C9) pyran ring relied on the
stereoelectronic preference for axial addition of nucleophiles
to cyclic oxocarbenium ions.14 In the event, treatment of 5
with TMSOTf in the presence of 6 afforded the anti-thioester
7 in 79% yield along with the syn-isomer in 14% yield.
Hydrolysis of the anti-product provided 8 in nearly quantita-
tive yield.
With the required carboxylic acid in hand, known homo-
allylic alcohol 1015 was accessed in enantiomerically pure
form (Scheme 2) by Keck asymmetric allylation16 of known
aldehyde 9.15 Following DCC-mediated coupling of 10 and
8, the resulting ester was converted to R-acetoxy ether 11
by reduction and in situ acetylation.
Our initial approach to the C3-C19 segment of phorbox-
azole B envisioned Prins cyclization to construct the C11-
C12 bond of the natural product and required the synthesis
of appropriately functionalized homoallylic alcohol and
carboxylic acid coupling partners. Synthesis of carboxylic
(4) (a) Smith, A. B., III; Minbiole, K. P.; Verhoest, P. R.; Schelhass, M.
J. Am. Chem. Soc. 2001, 123, 10942-10953. (b) Smith, A. B., III; Verhoest,
P. R.; Minbiole, K. P.; Schelhaus, M. J. Am. Chem. Soc. 2001, 123, 4834-
4836.
(5) (a) Pattenden, G.; Gonzalez, M. A.; Little, P. B.; Millan, D. S.;
Plowright, A. T.; Tornos, J. A.; Ye, T. Org. Biomol. Chem 2003, 1, 4173-
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42, 1255-1258.
(6) (a) Williams, D. R.; Kiryanov, A. A.; Emde, U.; Clark, M. P.;
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V.; Hoffmann, H. M. R. Angew. Chem., Int. Ed. 2003, 42, 2711-2716.
(8) For synthetic approaches to the bis-tetrahydropyran segment of the
phorboxazoles, see: (a) Paterson, I.; Steven, A.; Luckhurst, C. A. Org.
Biomol. Chem. 2004, 2, 3026-3038 and references therein. (b) Lucas, B.
S.; Luther, L. M.; Burke, S. D. Org. Lett. 2004, 6, 2965-2968. (c) Zhang,
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Tetrahedron 2002, 58, 6009-6018 and references therein.
Having developed an efficient synthesis of R-acetoxy ether
11, we turned our attention to the key Prins reaction. Despite
conducting an extensive screen of cyclization conditions,
such as BF‚OEt2/HOAc, TFAA/HOAc, and TFA/ethylene
carbonate, we were unable to affect a high-yielding cycliz-
ation. In general, excess Lewis acid was required to induce
starting material consumption. This is presumably due to the
(9) (a) Rychnovsky, S. D.; Hu, Y.; Ellsworth, B. Tetrahedron Lett. 1998,
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