60% overall yield (two steps).15 As an intramolecular
Horner-Wadsworth-Emmons reaction was envisaged to
construct the oxepane ring of zoapatanol, the methoxymethyl
ether group had to be transformed into an aldehyde. Thus,
after removal of the methoxymethyl ether protecting group
with TMSBr, the corresponding hydroxy phosphonate was
obtained (84%),16 and oxidation of the primary alcohol was
conveniently accomplished with PDC. The resulting crude
aldehyde, which turned out to be unstable was subjected
directly to treatment with NaH in THF to afford oxepinone
17 in 53% overall yield, via intramolecular Horner-
Wadsworth-Emmons cyclization (Scheme 2).17
Scheme 3. Synthesis of (+)-(2′S,3′R)-Zoapatanola
To convert the oxepinone 17 to (+)-zoapatanol, several
functional group transformations were required. First of all,
a catalytic hydrogenation of oxepinone 17 (10% Pd/C, EtOH,
5 min) was effected to afford ketone 18 chemoselectively.
The benzyl protecting group was not affected under these
conditions.18 The resulting oxepanone 18 was then treated
with the lithium salt of triethylphosphonoacetate (EtO2C-
CH2-P(O)(OEt)2, LiHMDS, THF, rt) to generate the cor-
responding R,â-unsaturated esters (97%) as an inseparable
1
mixture of E/Z isomers (E/Z ) 70/30 ratio by H NMR
spectroscopy).17a,19 After reduction with LiAlH4, the corre-
sponding stereomeric allylic alcohols 19 and 20 were
separated by SiO2 flash chromatography, and the desired (E)-
isomer 1920 was obtained in 63% overall yield from 18. The
allylic alcohol 19 was then protected as a benzyl ether (BnBr,
Ag2O, n-Bu4NI, CH2Cl2) in 98% yield. Elaboration of the
nonenyl side-chain present in (+)-zoapatanol first required
conversion of 21 to the corresponding Weinreb amide 22
since it was assumed that a stable tetrahedral intermediate
resulting from the addition of prenyllithium to the Weinreb
amide could serve as a latent carbonyl protecting group
during the debenzylation of the hydroxy groups by a Birch
reduction.21
a Reagents and conditions: (a) H2, Pd/C (10%), EtOH, 5 min,
98%; (b) EtO2CCH2P(O)(OEt)2 (10 equiv), LiHMDS, THF, rt,
97%, E/Z ) 70/30; (c) LiAlH4, Et2O, 0 °C to rt; flash chromatog-
raphy, E isomer: 63%, Z isomer: 27% from 18 (two steps); (d)
BnBr, Ag2O, n-Bu4NI, CH2Cl2, rt, 98%; (e) n-Bu4NF, THF, rt, (f)
CrO3/H2SO4, acetone, 0 °C; (g) HN(OMe)Me‚HCl, EDCI, i-Pr2NEt,
DMAP cat, CH2Cl2, 0 °C to rt, 60% (three steps); (h) prenyllithium,
Et2O/THF (1:1), -78 °C; (i) Li, NH3(l), t-BuOH (20 equiv), THF,
-78 °C, 66%.
-78 °C) to afford the desired (+)-zoapatanol, in 66% yield.
The analytical and spectral data were in agreement with those
previously reported in the literature for (+)-zoapatanol
(Scheme 3).1,4
After removal of the silyl protecting group in 21, the
resulting primary hydroxy group was oxidized to the cor-
responding carboxylic acid (Jones reagent, acetone, 0 °C)
and the latter was directly converted to the Weinreb amide
22 (HN(OMe)Me‚HCl, EDCI, i-Pr2NEt, DMAP cat, CH2-
Cl2, rt) with an overall yield of 60% (three steps).22 Treatment
of amide 22 with prenyllithium23 (Et2O, THF, -78 °C) led
to the stable intermediate 23, which was directly subjected
to the Birch reduction conditions24 (Li, NH3(l), t-BuOH/THF,
In conclusion, we have achieved an enantioselective total
synthesis of natural (+)-(2′S,3′R)-zoapatanol 1 using Suzuki
cross-coupling and Sharpless asymmetric dihydroxylation
chemistry as key steps. An intramolecular Horner-Wad-
sworth-Emmons cyclization was employed to construct the
oxepane core, and an organolithium addition/Birch reduction
tactic was applied on a Weinreb amide at the end of the
synthesis to access (+)-zoapatanol. The latter process could
provide the opportunity to synthesize structurally related
analogues.
(15) Suemune, H.; Akashi, A.; Sakai, K. Chem. Pharm. Bull. 1985, 33,
1055-1061.
Acknowledgment. C.T. thanks the MRES for a grant.
(16) Hu, X. E.; Demuth, T. P., Jr. J. Org. Chem. 1998, 63, 1719-1723.
(17) (a) Maryanoff, B. E.; Reitz, A. B. Chem. ReV. 1989, 89, 863-927.
(b) Nicoll-Griffith, D. B.; Weiler, L. Tetrahedron 1991, 47, 2733-2750.
(18) Boyer, F.-D.; Lallemand, J.-Y. Tetrahedron 1994, 50, 10443-10458.
(19) Magnus, P.; Miknis, G. F.; Press, N. J.; Grandjean, D.; Taylor, G.
M.; Harling, J. J. Am. Chem. Soc. 1997, 119, 6739-6748.
(20) (E)-Configuration of the major stereoisomer 19 was confirmed by
1H NMR-NOE analysis.
Supporting Information Available: Experimental pro-
cedure and characterization data of the key derivatives 12,
13, 15, 17, 1. This material is available free of charge via
(21) See preceding paper: Taillier, C.; Bellosta, V.; Meyer, C.; Cossy,
J. Org. Lett. 2004, 6, 2145-2148.
OL049433N
(22) Tashiro, T.; Bando, M.; Mori, K. Synthesis 2000, 13, 1852-1862.
(23) Prenyllithium was generated by reductive cleavage of phenylprenyl
ether with lithium in a mixture of Et2O/THF (1/1); see: Birch, A. J.; Corrie,
J. E. T.; Subba Rao, G. S. R. Aust. J. Chem. 1970, 23, 1811.
(24) (a) Evans, D. E.; Bender, S. L.; Morris, J. J. Am. Chem. Soc. 1988,
110, 2506-2526. (b) Evans, D. E.; Polniaszek, R. P.; DeVries, K. M.;
Guinn, D. E.; Mathre, D. J. J. Am. Chem. Soc. 1991, 113, 7613-7630.
Org. Lett., Vol. 6, No. 13, 2004
2151