Scheme 3a
a Reagents and conditions: (a) 0.15% (R)-14, H2, 1400 psi, 1 day. (b) Piv-Cl, pyridine/CH2Cl2. (c) (CH2O)n, 2 equiv Me2AlCl, CH2Cl2,
-80 to 15 °C in 15 min. (d) Swern [O] then Et3N, 5 h. (e) NaBH4, CeCl3, MeOH, -20 °C. (f) 1.5% (S)-14, H2, 1700 psi, 5 days, (97%
ee). (g) 22-OH, DCC, 4-Me2N-pyridine, CH2Cl2. (h) (PPh3)3RhCl, H2, PhH.
(heat), these selection rules should prevail.6 This proposal
also implies that acquiring either of compounds 3, 4, or 5
can offer an easy access to target 1. To test our proposal,
we initiated a synthetic investigation, preliminary results of
which are reported herein.
to the corresponding epimeric mixture (ê,S)-21, made from
17 by a selective catalytic hydrogenation over Wilkinson
catalyst to (ê,S)-20 and a subsequent esterification.10
After much experimentation, we selected a Michael
addition with a â-keto-sulfoxide for the macrocyclization step
(Scheme 4). Thus, tetrapropylammonium perruthenate (TPAP),
Our synthesis started with commercial trans-trans farnesol
(13), containing 15 of the 20 carbons of the target skeleton
(Scheme 3). Following the precedents,7 enantioselective
catalytic hydrogenation, with (R)-14 catalyst,8 gave dienol
15.9,10 After alcohol protection, Prins reaction11 on pivalate
16 afforded alcohol 17.10 Swern oxidation12 and a subsequent
in situ isomerization of the terminal double bond into
conjugation gave aldehyde 18.10 Reduction13 provided allyl
alcohol 19,10 the substrate for another enantioselective
catalytic hydrogenation.7,9 Since we had found no precedent
for the analogous hydrogenation of a tetrasubstituted allylic
alcohol, we selected (S)-148 on the basis of the only example
of a corresponding reduction of a tetrasubstituted carboxylic
acid.14 The excellent ee of alcohol (S,S)-20 was determined
by comparing the iso-propyl signals in the 1H NMR spectra
of (S,S)-21, an ester with (S)-Trolox methyl ether15 (22-OH),
Scheme 4a
(6) Biosynthesis of 2 may involve further oxidation in ring A, followed
by transketalization and an epimerization of the iso-propyl group.
(7) (a) Takaya, H.; Ohta, T.; Sayo, N.; Kumobayashi, H.; Akutagawa,
S.; Inoue, S.; Kasahara, I.; Noyori, J. Am. Chem. Soc. 1987, 109, 1596-
1597. (b) R. Mashima, K.; Kusano, K.; Ohta, T.; Noyori, R.; Takaya, H. J.
Chem. Soc., Chem. Commun. 1989, 1208-1210. (c) Imperiali, B.; Zim-
merman, J. W. Tetrahedron Lett. 1988, 29, 5343-5344.
(8) Used to be available from Aldrich then, now from Fluka (cat. no.):
(R)-14, 37,765-1; 14800 and (S)-14, 37,767-8; 14801, respectively.
(9) Reproduction of this reaction became difficult. Early experiments,
conducted with catalyst from Aldrich, gave pure 15 and 20 (<4%
overhydrogenation) with excellent conversions. Later, after switching to
Fluka, these results deteriorated to necessitate an extra purification step on
a AgNO3-impregnated silica column. See also refs 8 and 10.
(10) See Supporting Information for experimental details.
(11) Cartaya-Marin, C.-P.; Jackson, A. C.; Snider, B. B. J. Org. Chem.
1984, 49, 2443-2446.
a Reagents and conditions: (a) TPAP/NMO, CH2Cl2, 0 to 23
°C, 0.5 h. (b) PhSOCH2Li, THF, -80 to 0 °C, 15 h. (c) Dess-
Martin periodinane, CH2Cl2, NaHCO3, 23 °C. (d) CH2dCHLi, THF,
-80 °C, 1 h. (e) MeCN, Cs2CO3, 23 °C, 4 h, 1.7 mM. (f) PhMe,
CaCO3, reflux, 1.5 h.
(12) Mancuso, A. J.; Swern, D. Synthesis 1981, 165-185.
(13) Luche, J. L. J. Am. Chem. Soc. 1978, 100, 2226.
N-methylmorpholine N-oxide (NMO) oxidation16 of alcohol
(S,S)-20 to aldehyde 23 afforded the electrophile for func-
tionalization at this terminus. During condensation with
PhSOCH2Li, deprotection of the other terminus also occurred
(14) Ohta, T.; Takaya, H.; Kitamura, M.; Nagai, K.; Noyori, R. J. Org.
Chem. 1987, 52, 3176-3178.
(15) Walther, W.; Vetter, W.; Vecchi, M.; Schneider, H.; Mu¨ller, R. K.;
Netscher, T. Chimia 1991, 45, 121-123.
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