Synthetic approaches and total synthesis of natural zoapatanol

Article abstract of DOI:10.1021/jo048115z

(Chemical Equation Presented) The total synthesis of (+)-zoapatanol utilizing an intramolecular Horner-Wadsworth-Emmons olefination and an enantioselective Sharpless dihydroxylation as the key steps has been achieved. An advanced oxepene intermediate has been obtained by applying a ring-closing metathesis to an unsaturated enol ether.

Full text of DOI:10.1021/jo048115z

Synthetic Approaches and Total Synthesis of Natural Zoapatanol
Catherine Taillier, Barbara Gille, Ve´ronique Bellosta,* and Janine Cossy*
Laboratoire de Chimie Organique, associe´ au CNRS, ESPCI, 10 rue Vauquelin,
75231 Paris Cedex 05, France
janine.cossy@espci.fr; veronique.bellosta@espci.fr
Received October 25, 2004
The total synthesis of (+)-zoapatanol utilizing an intramolecular Horner-Wadsworth-Emmons
olefination and an enantioselective Sharpless dihydroxylation as the key steps has been achieved.
An advanced oxepene intermediate has been obtained by applying a ring-closing metathesis to an
unsaturated enol ether.
Introduction
(+)-Zoapatanol 1, montanol 2, tomentanol 3, and
tomentol 4 are diterpenoid oxepanes isolated from the
leaves of the Mexican zoapatle plant Montanoa tomen-
tosa, which Mexican women have been using for centuries
to prepare “tea” to induce menses and labor and to
terminate early pregnancy.1 Recent studies support the
belief that zoapatanol and its metabolites might be
responsible for the observed antifertility activity.2 In
1979, the isolation and the structure of zoapatanol were
described.3 Due to its biological profile and its challenging
structure, several groups have reported six total synthe-
ses of zoapatanol,4 but only one of these was enantio-
selective.5 A number of groups have also described
synthetic approaches.6 Key issues for a successful syn-
FIGURE 1. Oxepane derivatives isolated from Montanoa
tomentosa.
thesis of zoapatanol 1 are the stereocontrolled construc-
tion of the oxepane ring, the introduction of the (E)-
exocyclic double bond, and the installation of the nonenyl
side chain. Since (+)-zoapatanol is isolated as a 1/1
mixture of epimers at C6, control of this stereocenter is
not required.7
We now report two synthetic approaches that have
been realized to construct the oxepane ring of zoapatanol,
utilizing a ring-closing metathesis (RCM) and an intra-
molecular Horner-Wadsworth-Emmons reaction (HWE),
and we report also the total synthesis of (+)-zoapatanol.
(1) (a) Levine, S. D.; Hahn, D. W.; Cotter, M. L.; Greenslade, F. C.;
Kanijoa, R. M.; Pasquale, S. A.; Wachter, M. P.; Mcguire, J. L. J.
Reprod. Chem. 1981, 524. (b) Quijano, L.; Calderon, J. S.; Fisher, N.
K. Phytochemistry 1985, 24, 2337. (c) Oshima, Y.; Cordial, G. A.; Fong,
H. S. Phytochemistry 1986, 25, 2567.
(2) (a) Marcelle, G. B.; Bunyapraphatsara, N.; Cordell, G. A.; Fong,
H. S.; Nicolaou, K. C.; Zipkin, R. E. J. Nat. Prod. 1985, 48, 739. (b)
Kanojia, R. M.; Chin, E.; Smith, C.; Chen, R.; Rowand, D.; Levine, S.
D.; Wachter, M. P.; Adams, R. E.; Hahn, D. W. J. Med. Chem. 1985,
28, 796.
(3) Levine, S. D.; Adams, R. E.; Chen, R.; Cotter, M. L.; Hirsch, A.
F.; Kane, V. V.; Kanijoa, R. M.; Shaw, C. J.; Wachter, M. P.; Chin, E.;
Huetteman, R.; Ostrowski, P.; Mateos, J. L.; Noriega, L.; Guzma´n, A.;
Mijarez, A.; Tovar, L. J. Am. Chem. Soc. 1979, 101, 3404.
(4) (a) Chen, R.; Rowand, D. A. J. Am. Chem. Soc. 1980, 102, 6609.
(b) Nicolaou, K. C.; Claremon, D. E.; Barnett, W. E. J. Am. Chem. Soc.
1980, 102, 6611. (c) Kane, V. V.; Doyle, D. L. Tetrahedron Lett. 1981,
3027. (d) Cookson, R. C.; Liverton, N. J. J. Chem. Soc., Perkin Trans.
1 1985, 1589. (e) Kocienski, P. J.; Love, C. J.; Whitby, R. J. Tetrahedron
1989, 45, 3839.
(6) (a) Davies, M. J.; Heslin, J. C.; Moody, C. J. J. Chem. Soc., Perkin
Trans. 1 1989, 2473. (b) Pain, G.; Desmae¨le, D.; d’Angelo, J. Tetrahe-
dron Lett. 1994, 35, 3085. (c) Shing, T. K. M.; Wong, C.-H.; Yip, T.
Tetrahedron: Asymmetry 1996, 7, 1323. (d) Ovaa, H.; van der Marel,
G. A.; van Boom, J. H. Tetrahedron Lett. 2001, 42, 5749.
(7) Either the epimerization occurred during isolation or purification
of the natural product, or the natural zoapatanol itself is a mixture of
epimers at C6. Kanijoa, R. M.; Wachter, M. P.; Levine, S. D.; Adams,
R. E.; Chen, R.; Chin, E.; Cotter, M. L.; Hirsch, A. F.; Huetteman, R.;
Kane, V. V.; Ostrowski, P.; Shaw, C. J. J. Org. Chem. 1982, 47, 1310.
(5) Trost, B. M.; Greenspan, P. D.; Geissler, H.; Kim, J. H.; Greeves,
N. Angew. Chem., Int. Ed. Engl. 1994, 33, 2182.
10.1021/jo048115z CCC: $30.25 © 2005 American Chemical Society
Published on Web 02/12/2005
J. Org. Chem. 2005, 70, 2097-2108
2097

Taillier et al.
SCHEME 1. Retrosynthetic Analysis of
Zoapatanol
SCHEME 2. Synthetic Approach of (()-Zoapatanol
by Using RCMa
RCM Approach
The first strategy that we envisaged to synthesize
zoapatanol relies on a RCM reaction. The retrosynthetic
analysis revealed that an oxidation of oxepene B should
lead to ketone A, which is a precursor of zoapatanol 1
according to Kane’s synthesis.4c Oxepene B could poten-
tially be obtained by using a RCM applied to the
unsaturated enol ether C in which the two stereogenic
centers could be controlled through application of a
Sharpless asymmetric dihydroxylation of the trisubsti-
tuted (Z)-olefin E. This latter olefin could be synthesized
by using a Suzuki-Miyaura cross-coupling between an
organoborane derived from olefin F and (Z)-vinyl iodide
G (Scheme 1). It was desirable to adopt an orthogonal
protecting group strategy to permit a selective deprotec-
tion of the hydroxy groups. The use of two silylated ethers
of different reactivity, a tert-butyldiphenylsilyl group
(TBDPS) for R, a tert-butyldimethylsilyl group (TBS) for
R′′, and a benzyl group (Bn) for R′ was then envisaged.
To test our strategy, a racemic synthetic approach toward
zoapatanol was first achieved.
Results and Discussion. The synthesis of zoapatanol
started with the preparation of the (Z)-olefin 11 from
vinyl iodide 7 and olefin 10 (Scheme 2). Vinyl iodide 7
was prepared in 3 steps from 1,4-butanediol 5. After
monoprotection of 5 (TBSCl, Et3N, CH2Cl2) the resulting
monosilylated ether was oxidized to aldehyde 6 by using
a Swern oxidation [(COCl)2, DMSO, Et3N, CH2Cl2] with
an overall yield of 94%. Aldehyde 6 was then transformed
to the (Z)-vinyl iodide 7 in 47% yield by treatment with
the R-iodophosphonium ylide prepared from ethyltri-
phenylphosphonium iodide (n-BuLi, then addition of I2
and treatment with NaHMDS).8 Furthermore, olefin 10
could be prepared in 3 steps from propionic acid 8. Thus,
a Reagents and conditions: (a) TBSCl, Et3N, CH2Cl2, 98%. (b)
(COCl)2, DMSO, Et3N, CH2Cl2, 96%. (c) (i) EtP(C6H5)3I, n-BuLi;
I2; NaHMDS; (ii) 6, -20 °C to room temperature, 47%. (d) NaH (1
equiv), LDA (1 equiv), allylBr, 96%. (e) LiAlH4, THF, rt, 94%. (f)
TBDPSCl, imidazole, DMF, rt, 91%. (g) 9-BBN-H, THF, rt. (h) 7,
Pd(PPh3)4, K3PO4, dioxane, 85 °C, 82%. (i) OsO4 cat., NMO,
acetone/H2O (1/6), rt, 61%. (j) NaH, n-Bu4NI, HMPA/THF, BnBr,
rt, 87%. (k) TBAF, THF, rt, 1 h. (l) PDC, DMF, rt. (m) DIBAL-H,
THF, -78 °C. (n) MeP(C6H5)3Br, n-BuLi, THF, -78 °C to room
temperature, 68% (four steps). (o) Ethyl vinyl ether, Hg(OCOCF3)2,
Et3N, 50 °C, 47%. (p) Cl2(PCy3)2RudCHPh (30 mol %), PhH,
50 °C, 70%.
the dianion of 8 was alkylated with allyl bromide (NaH,
then LDA, allyl bromide) leading to 2-methylpent-4-enoic
acid 9 in 96% yield.9 The reduction of 9 by LiAlH4 (THF,
rt) followed by protection of the resulting alcohol
(TBDPSCl, ImH, DMF, rt) led to the desired olefin 10
(86% yield, two steps). To achieve the Suzuki-Miyaura
coupling, olefin 10 was transformed into the correspond-
ing organoborane (9-BBN-H, THF) and this latter com-
pound was treated with the (Z)-vinyl iodide 7 in the
presence of a catalytic amount of Pd(PPh3)4 and K3PO4
in dioxane at 85 °C to afford (Z)-olefin 11 in 82% yield.10
It is worth noting that the (Z)-configuration of 11 was
determined by differential 1H NMR-nOe experiments. To
(9) (a) Creger, P. L. J. Am. Chem. Soc. 1970, 92, 1396. (b) Creger,
P. L. Org. Synth. 1970, 50, 58.
(10) (a) Miyaura, N.; Ishiyama, T.; Sasaki, H.; Ishikawa, M.; Satoh,
M.; Suzuki, A. J. Am. Chem. Soc. 1989, 111, 314. (b) Oh-e, T.; Miyaura,
N.; Suzuki, A. Synlett 1990, 221. (c) Watanabe, T.; Miyaura, N.; Suzuki,
A. Synlett 1992, 207. (d) Miyaura, N.; Suzuki, A. Chem. Rev. 1995,
95, 2457.
(8) (a) Chen, J.; Wang, T.; Zhao, K. Tetrahedron Lett. 1994, 35, 2827.
(b) Arimoto, H.; Kaufman, M. D.; Kobayashi, K.; Qiu, Y.; Smith, A. B.,
III Synlett 1998, 765.
2098 J. Org. Chem., Vol. 70, No. 6, 2005

Total Synthesis of Natural Zoapatanol
SCHEME 3. Second Retrosynthetic Analysis of
Zoapatanol
introduce the two contiguous hydroxy groups at C2′ and
C3′, olefin 11 was dihydroxylated (OsO4, NMO, acetone/
H2O (1/6), rt) to produce diol 12 in 61% yield, followed
by transformation to benzyl ether 13. The selective
protection of the secondary alcohol in 12 as a benzyl ether
turned out to be troublesome. Various bases (NaH,
Cs2CO3, KHMDS, t-BuOK) and solvents (THF, DMF or
mixtures of both) were screened. The desired benzylated
product 13 was occasionally observed, but in most cases
the results were not reproducible and decomposition
occurred to a large extent. The best conditions for
obtaining 13 in good yield were the treatment of 12 with
NaH (2.2 equiv) in the presence of n-tetrabutylammo-
nium iodide (40 mol %) and HMPA (3 equiv) followed by
the addition of benzyl bromide (1.1 equiv). After 12 h at
room temperature, compound 13 was isolated in 87%
yield. To achieve the construction of the oxepene ring,
compound 13 had to be transformed to diene 16. After
selective cleavage of the tert-butyl dimethylsilyl ether
(TBAF, THF, rt, 1 h) and oxidation of the resulting
primary alcohol by PDC (DMF, rt), lactone 14 was
obtained in 84% yield (two steps). The reduction of 14
by DIBAL-H (THF, -78 °C) produced the corresponding
lactol, which was treated directly with methyltriphenyl-
phosphonium ylide (MeP(C6H5)3Br, n-BuLi, THF) and
transformed to olefin 15 (44% yield, two steps).11 The
tertiary alcohol of 15 was then etherified by treatment
with Hg(OCOCF3)2 and ethyl vinyl ether (Et3N, 50 °C)12
to afford the desired diene 16 in 47% yield. Compound
16 was next converted to oxepene 17 in 70% yield by
treatment with the “first generation” Grubbs’ catalyst
[Cl2(PCy3)2RudCHPh (30 mol %), PhH, 50 °C].13 The
resulting oxepene 17, in analogy to Kane’s intermediate
that had been transformed to an oxepanone by oxidative
hydroboration (BH3‚THF; H2O2, NaOH) followed by
oxidation (CrO3, C5H5N, CH2Cl2), was expected to lead
to 18.4c Unfortunately, when 17 was subjected to BH3‚THF
and then H2O2, NaOH, no reaction occurred. Moreover,
when 17 was treated with various oxidizing agents
(dimethyldioxirane or m-CPBA in MeOH) to produce a
precursor of ketone 18, only degradation or nonconversion
of 17 was observed.
an intramolecular HWE reaction applied to phosphono-
aldehyde I derived from anti-diol J (Scheme 3). Control
of the two contiguous stereocenters of J could be achieved
by applying a Sharpless asymmetric dihydroxylation to
the (Z)-trisubstituted olefin K, which could be derived
from a Suzuki-Miyaura coupling between vinyl iodide
19 and organoborane L. In this approach, an orthogonal
protecting group strategy for R, R′ was also required.
Therefore we planned to protect the secondary alcohol
in I by a benzyl group and the primary alcohol by a tert-
butyldiphenylsilyl group.
Results and Discussion. The preparation of
(+)-zoapatanol started with the synthesis of the phospho-
noaldehyde 30 from silylated 2-methylpent-4-en-1-ol 10
and (Z)-vinyl iodide 19, which was obtained by treatment
of ethyl but-2-ynoic ester with NaI in acetic acid (70 °C,
95% yield).14 Alkene 10 was treated with 9-BBN-H (9-
BBN dimer, THF, rt) and the resulting organoborane
product was then subjected to a Suzuki-Miyaura cross-
coupling with (Z)-vinyl iodide 19 in the presence of Pd-
(PPh3)4 and K3PO4 (dioxane, 85 °C) to afford the (Z)-R,â-
unsaturated ester 20 in 74% yield.10,15 To transform 20
to 22, the unsaturated ester 20 was reduced with
DIBAL-H and the resulting alcohol was treated with
TBSCl (Et3N, CH2Cl2) to afford 21 with an overall yield
of 46%. After dihydroxylation with OsO4/NMO, compound
21 was transformed to diol 22 (62%), in which the
secondary alcohol was protected as a benzyl ether by
treatment of 22 with NaH and benzyl bromide in the
presence of n-Bu4NI in a mixture of THF/HMPA. The
product obtained in 98% yield appeared not to be the
expected compound 23 but compound 24, which resulted
from the migration of the TBS group to the secondary
alcohol and benzylation of the released primary alcohol.
As the benzyl ether of 24 could not be selectively
deprotected under hydrogenation conditions or by using
BBr3 or Li/NH3(l), the sequence was slightly modified and
the syn-dihydroxylation reaction was carried out on the
R,â-unsaturated ester 20. Thus, the enantioselective
Due to this failure, a second route using a Horner-
Wadsworth-Emmons (HWE) reaction was envisioned to
construct the oxepane ring of zoapatanol.
Horner-Wadsworth-Emmons Approach
The retrosynthetic analysis of oxepinone H revealed
that the oxepene ring with the required stereochemistry
could potentially be constructed through application of
(11) Compound 15 was isolated in an increased overall yield of 68%
by performing the four consecutive steps from 13 without purification
of intermediates.
(12) (a) Germanas, J.; Aubert, C.; Vollhardt, K. P. C. J. Am. Chem.
Soc. 1991, 113, 4006. (b) Nonoshita, K.; Banno, H.; Maruoka, K.;
Yamamoto, H. J. Am. Chem. Soc. 1990, 112, 316. (c) Tulshian, D. P.;
Tsang, R.; Fraser-Reid, B. J. Org. Chem. 1984, 49, 2347.
(13) For RCM reactions on vinyl ethers, in the presence of “first or
second generation” Grubbs’ catalysts see: (a) Tuyen Nguyen, V.; De
Kimpe, N. Tetrahedron Lett. 2004, 45, 3443. (b) Rainier, J. D.; Cox, J.
M.; Allwein, S. P. Tetrahedron Lett. 2001, 42, 179. (c) Chatterjee, A.
K.; Morgan, J. P.; Scholl, M.; Grubbs, R. H. J. Am. Chem. Soc. 2000,
122, 3783. (d) Arisawa, M.; Theerladanon, C.; Nishida, A.; Nakagawa,
M. Tetrahedron Lett. 2001, 42, 8029. (e) Okada, A.; Ohshima, T.;
Shibasaki, M. Tetrahedron Lett. 2001, 42, 8023. (f) Sturino, C. F.;
Wong, J. C. Y. Tetrahedron Lett. 1998, 39, 9623.
(14) Marek, I.; Meyer, C.; Normant, J.-F. Org. Synth. 1997, 74, 194.
(15) (Z)-Configuration of the enoate 20 was confirmed by 1H NMR-
nOe analysis.
J. Org. Chem, Vol. 70, No. 6, 2005 2099

Taillier et al.
SCHEME 4. Synthesis of the Oxepinone 31a
a Reagents and conditions: (a) (i) 9-BBN dimer, THF, rt; (ii) 19, Pd(PPh3)4, K3PO4, dioxane, 85 °C, 74%. (b) DIBAL-H, THF, -78 °C,
75%. (c) TBSCl, Et3N, CH2Cl2, 61%. (d) OsO4 cat., NMO, acetone/H2O (1/6), rt, 62%. (e) BnBr, NaH, n-Bu4NI, HMPA/THF, rt, 98%. (f)
AD-mix-â, H2NSO2Me, t-BuOH/H2O (1/1), 0 °C, 65%, ee 92%. (g) BnBr, Ag2O, n-Bu4NI, CH2Cl2, rt, 74%. (h) LiAlH4, Et2O, 0 °C to room
temperature. (i) MOMCl, NaH, THF, 0 °C to room temperature, 89% (two steps). (j) N2CHCO2Et (10 equiv), [Rh(OAc)2]2 (10 mol %),
toluene, 110 °C. (k) MeP(O)(OMe)2 (10 equiv), n-BuLi (10 equiv), THF, -78 °C, 60% (two steps). (l) TMSBr, CH2Cl2, -40 °C, 84%. (m)
PDC, 4 Å MS, CH2Cl2, 20 °C. (n) NaH, THF, 0 °C to room temperature, 53% (two steps).
Sharplessdihydroxylation(AD-mix-â,H2NSO2Me,t-BuOH/
H2O (1/1), 0 °C) afforded the diol 26 in 65% yield and
resulting crude aldehyde 30, which turned out to be
unstable, was subjected directly to treatment with NaH
in THF to afford oxepinone 31 in 53% overall yield via
an intramolecular Horner-Wadsworth-Emmons cycliza-
tion (Scheme 4).23
The conversion of oxepinone 31 to (+)-zoapatanol was
envisioned to proceed via the oxepane 33 (Scheme 5) and
involve several functional group transformations, namely
the reduction of the R,â-unsaturated ketone to the
corresponding ketone, a Wittig reaction to introduce the
1
92% ee as determined by H NMR spectroscopy of the
corresponding (R)- and (S)-methoxyphenylacetic esters.16
Construction of the phosphono-aldehyde 30 was now
investigated from 26. The selective protection of the
secondary alcohol in 26 as a benzyl ether turned out to
be a difficult task. Among the reagents tested, benzyl
bromide in the presence of silver oxide and n-tetrabutyl-
ammonium iodide was the most effective and afforded
the desired product 27 in 74% yield.17 After reduction of
the carboxylic ester with LiAlH4 in diethyl ether, the
resulting primary hydroxyl group was protected as a
methoxymethyl ether (MOMCl, NaH, THF, 0 °C to rt) to
provide 28 (89%, two steps).18 Rhodium-catalyzed inser-
tion of ethyl diazoacetate (excess N2CHCO2Et, 10 mol %
[Rh(OAc)2]2, toluene, 110 °C)20 followed by the condensa-
tion of an excess of the lithium salt of methyldimeth-
ylphosphonate (10 equiv) with the resulting ester led to
the â-keto-phosphonate 29 in 60% overall yield (two
steps).21 As an intramolecular Horner-Wadsworth-
Emmons reaction was envisioned to construct the ox-
epane 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%)22 and the oxidation of the primary
alcohol was conveniently accomplished with PDC. The
(18) It is worth noting that direct alkylation of the tertiary alcohol
of compound 28 with triphenylchloroacetonylphosphorane, following
a method previously described,19 failed to produce the expected â-keto
phosphorane:
(19) Cossy, J.; Taillier, C.; Bellosta, V. Tetrahedron Lett. 2002, 43,
7263-7266.
(20) (a) Noels, A. F.; Demonceau, A.; Petiniot, N.; Hubert, A. J.;
Teyssie´, P. H. Tetrahedron 1982, 38, 2733. (b) Jones, K.; Toutounji, T.
Tetrahedron 2001, 57, 2427.
(16) The (2S,3S) absolute configuration of 21 was confirmed by the
1H NMR spectra of the two corresponding mandelates, following the
procedure described by: Seco, J. M.; Quin˜oa, E.; Riguera, R. Tetrahe-
dron: Asymmetry 2001, 12, 2915.
(21) Suemune, H.; Akashi, A.; Sakai, K. Chem. Pharm. Bull. 1985,
33, 1055.
(22) Hu, X. E.; Demuth, T. P., Jr. J. Org. Chem. 1998, 63, 1719.
(23) (a) Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863. (b)
Nicoll-Griffith, D. B.; Weiler, L. Tetrahedron 1991, 47, 2733.
(17) Bouzide, A.; Sauve´, G. Tetrahedron Lett. 1997, 38, 5945.
2100 J. Org. Chem., Vol. 70, No. 6, 2005

Total Synthesis of Natural Zoapatanol
SCHEME 5. Debenzylation of 31 and Reactivity of
the Resulting Lactol 32
SCHEME 6. Total Synthesis of (+)-Zoapatanola
unsaturated side chain, and finally the deprotection of
the benzyl protected hydroxy group. When the hydroge-
nation of oxepinone 31 was performed in the presence of
Pd/C (10%) in ethanol for 16 h, the bicyclic lactol 32 was
obtained in good yield (97%). Unfortunately, all the
conditions tested to accomplish a Wittig reaction, a HWE
reaction, or a Peterson reaction on lactol 32 failed to
produce compound 33. Under the best conditions
[EtO2CCH2P(O)(OEt)2, KHMDS, THF, 0 °C to 70 °C],
compound 34, resulting from a HWE reaction followed
by an intramolecular 1,4-addition of the alkoxide onto
the unsaturated ester, was formed in 60% yield.
However, when the hydrogenation of 31 was performed
in the presence of Pd/C (10%) in ethanol for 5 min, the
benzyl protecting group was not affected and oxepanone
18 was isolated in 98% yield (Scheme 6).24 The resulting
oxepanone 18 was then treated with the lithium salt of
triethylphosphonoacetate [EtO2CCH2P(O)(OEt)2, Li-
HMDS, THF, rt] to generate the corresponding R,â-
unsaturated esters (97%) as an inseparable mixture of
E/Z isomers (E/Z ) 70/30 ratio by 1H NMR spectros-
copy).23a,25 After reduction with LiAlH4, the corresponding
stereoisomeric allylic alcohols 35 and 35′ were separated
by SiO2 flash chromatography, and the desired (E)-allylic
alcohol 3526 was obtained in 63% overall yield (from 18).
This latter compound was then protected as a benzyl
ether (BnBr, Ag2O, n-Bu4NI, CH2Cl2) in 98% yield.
Elaboration of the nonenyl side chain present in
(+)-zoapatanol required the conversion of 36 to the
corresponding Weinreb amide 37. This transformation
seemed feasible, as we have recently demonstrated that
a stable tetrahedral intermediate resulting from the
addition of an organolithium to a Weinreb amide can
serve as a carbonyl protecting group during the deben-
zylation of hydroxy groups under Birch reduction condi-
tions.27 After removal of the silyl protecting group of 36,
the resulting primary hydroxy group was oxidized to the
corresponding carboxylic acid (Jones reagent, acetone, 0
°C) and the latter was directly converted to the Weinreb
amide 37 [HN(OMe)Me‚HCl, EDCI, i-Pr2NEt, DMAP
cat., CH2Cl2, rt] with an overall yield of 60% (three
steps).28 Treatment of amide 37 with prenyllithium29
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 room temperature; flash
chromatography, (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 room temperature,
60% (three steps). (h) Prenyllithium, Et2O/THF (1:1), -78 °C. (i)
Li/NH3(l), t-BuOH (20 equiv), THF, -78 °C, 66%.
(THF/Et2O, -78 °C) led to the stable intermediate 38,
which was directly subjected to Birch reduction condi-
tions30 (Li/NH3(l), t-BuOH/THF, -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 6).3,4
In summary, two approaches to zoapatanol have been
carried out: one involving a ring-closing metathesis
reaction of an unsaturated vinyl ether, which produced
an advanced oxepene intermediate for the synthesis of
zoapatanol, and
a second approach which led to
(+)-zoapatanol and involved a Sharpless asymmetric
dihydroxylation to control the contiguous stereocenters.
Furthermore, an intramolecular Horner-Wadsworth-
Emmons cyclization was used to construct the oxepane
core, and an organolithium addition/Birch reduction
sequence was applied on a Weinreb amide to introduce
the ketone at C5 of zoapatanol. By using this methodol-
ogy, the synthesis of structurally related analogues of
zoapatanol might be easily realized.
(24) Boyer, F.-D.; Lallemand, J.-Y. Tetrahedron 1994, 50, 10443.
(25) Magnus, P.; Miknis, G. F.; Press, N. J.; Grandjean, D.; Taylor,
G. M.; Harling, J. J. Am. Chem. Soc. 1997, 119, 6739.
(26) The (E)-configuration of the major stereoisomer 31 was con-
firmed by 1H NMR-nOe analysis.
(27) Taillier, C.; Bellosta, V.; Meyer, C.; Cossy, J. Org. Lett. 2004,
6, 2145.
(28) Tashiro, T.; Bando, M.; Mori, K. Synthesis 2000, 13, 1852.
(29) Prenyllithium was generated by reductive cleavage of phenyl
prenyl ether with lithium in a mixture of Et2O/THF (1/1); see: Birch,
A. J.; Corrie, J. E.; Subba Rao, G. S. R. Aust. J. Chem. 1970, 23, 1811.
(30) (a) Evans, D. E.; Bender, S. L.; Morris, J. J. Am. Chem. Soc.
1988, 110, 2506. (b) Evans, D. E.; Polniaszek, R. P.; DeVries, K. M.;
Guinn, D. E.; Mathre, D. J. J. Am. Chem. Soc. 1991, 113, 7613.
J. Org. Chem, Vol. 70, No. 6, 2005 2101

Taillier et al.
<4). The aqueous layer was extracted with diethyl ether (2 ×
20 mL) and the combined organic extracts were washed with
brine (2 × 10 mL), dried over MgSO4, filtered, and concen-
trated under reduced pressure. Purification by flash chroma-
tography on silica gel (petroleum ether/EtOAc gradient 95/05
to 80/20) afforded 1.09 g (96%) of acid 9 as a colorless oil. IR
Experimental Section
4-(tert-Butyldimethylsilanyloxy)butanal (6). To a solu-
tion of oxalyl chloride (2.1 mL, 24 mmol, 1.2 equiv) in CH2Cl2
(30 mL) cooled at -78 °C was added dropwise a solution of
DMSO (3.3 mL, 21 mmol, 1.1 equiv) in CH2Cl2 (32 mL). After
5 min, a solution of 4-(tert-butyldimethylsilanyloxy)butan-1-
ol31 (4.0 g, 20 mmol, 1.0 equiv) in CH2Cl2 (26 mL) was added.
The reaction mixture was then stirred for 15 min at -78 °C
and triethylamine (14.0 mL, 100 mmol, 5.00 equiv) was added
in one portion. After 10 min at -78 °C, the mixture was
allowed to warm to room temperature and diluted with CH2Cl2
(140 mL). The organic layer was successively washed with a
saturated aqueous solution of NH4Cl (30 mL) and brine (2 ×
30 mL). The combined organic extracts were dried over MgSO4,
filtered, and concentrated under reduced pressure. Purification
by flash chromatography on silica gel (petroleum ether/EtOAc:
90/10) afforded 3.88 g (96%) of aldehyde 632 as a colorless oil.
1
(film) 3440, 1720, 1640 cm-1; H NMR δ 11.3 (br s, 1H), 5.75
(m, 1H), 5.10-4.85 (m, 2H), 2.61-2.32 (m, 2H), 2.25-2.12 (m,
1H), 1.17 (d, J ) 7.0 Hz, 3H); 13C NMR δ 182.5 (s), 134.9 (d),
116.9 (t), 39.0 (d), 37.3 (t), 16.1 (q); MS-EI m/z (rel intensity)
114 (M+•, 15), 99 (M - CH3+, 27), 73 (12), 71 (13), 69 (M -
COOH+, 100), 68 (23), 67 (27), 56 (18).
tert-Butyl(2-methylpent-4-enyloxy)diphenylsilane (10).
To a stirred suspension of LiAlH4 (1.9 g, 50 mmol, 1.0 equiv)
in anhydrous THF (100 mL) was slowly added a solution of
2-methylpent-4-enoic acid 9 (5.7 g, 50 mmol, 1.0 equiv) in THF
(10 mL). After 16 h at room temperature, the reaction mixture
was cooled to 0 °C and cautiously treated with water (1.9 mL),
then with a 15% aqueous solution of NaOH (1.9 mL), and then
with water (5.7 mL). After 1 h of stirring at room temperature,
the resulting suspension was filtered through Celite. The
insoluble salts were washed with diethyl ether (2 × 20 mL)
and the filtrate was dried over MgSO4. Filtration and concen-
tration under reduced pressure gave 4.7 g (94%) of 2-methyl-
pent-4-en-1-ol, which was directly engaged in the next step
without further purification.
IR (film) 2720, 1730, 1260, 1100, 840, 780 cm-1 1H NMR δ
;
9.78 (t, J ) 1.8 Hz, 1H), 3.65 (t, J ) 5.9 Hz, 2H), 2.50 (td, J )
7.2 and 1.8 Hz, 2H), 1.85 (m, 2H), 0.88 (s, 9H), 0.04 (s, 6H);
13C NMR δ 202.4 (d), 61.9 (t), 40.6 (t), 25.8 (q, 3C), 25.3 (t),
18.1 (s), -5.6 (q, 2C); MS-EI m/z (rel intensity) 201 (M - H+,
1), 187 (M - CH3+, 1), 145 (67), 127 (10), 115 (12), 75 (100),
73 (12), 59 (11); HRMS (CI+, CH4) calcd for C10H21O2Si (M -
H) 201.1311, found 201.1325.
6-(tert-Butyldimethylsilanyloxy)-2-iodohex-2-ene (7).
To a suspension of ethyltriphenylphosphonium iodide (0.80 g,
2.0 mmol, 1.2 equiv) in THF (10 mL) was added a solution of
n-BuLi (0.80 mL, 2.5 mol‚L-1 in hexanes, 2.0 mmol, 1.2 equiv)
at room temperature. After complete dissolution, the orange
solution was added via cannula to a solution of iodine (0.46 g,
1.8 mmol, 1.1 equiv) in THF (15 mL) cooled to -78 °C. After
5 min of stirring at -78 °C, the suspension was warmed to
-20 °C and a solution of NaHMDS (0.90 mL, 2 mol‚L-1 in THF,
1.8 mmol, 1.1 equiv) was added dropwise. The resulting red
solution was then stirred for 5 min at -20 °C and aldehyde 6
(0.34 g, 1.70 mmol, 1.00 equiv) was added neat. The reaction
mixture was then warmed to room temperature and diluted
with diethyl ether (50 mL) and washed successively with a
saturated aqueous solution of NH4Cl (20 mL) and brine (2 ×
10 mL). The combined organic extracts were dried over MgSO4,
filtered, and concentrated under reduced pressure. Purification
by flash chromatography on silica gel (petroleum ether/EtOAc:
98/02) next afforded 272 mg (47%) of vinyl iodide 7 as a pale
yellow oil. IR (film) 1255, 1100, 835, 775 cm-1; 1H NMR δ 5.42
(tq, J ) 6.6 and 1.5 Hz, 1H), 3.61 (t, J ) 6.4 Hz, 2H), 2.47 (br
s, 3H), 2.17-2.07 (m, 2H), 1.65-1.53 (m, 2H), 0.89 (s, 9H),
0.04 (s, 6H); 13C NMR δ 134.9 (d), 100.9 (s), 62.4 (t), 33.4 (q),
33.1 (t), 31.4 (t), 25.8 (q, 3C), 18.1 (s), -5.4 (q, 2C); MS-EI m/z
(rel intensity) 339 (M - H+, 1), 325 (M - CH3+, 1), 283 (M -
t-Bu+, 100), 255 (52), 215 (39), 185 (40), 155 (21), 81 (28), 75
(25); HRMS (CI+, CH4) calcd for C8H16IOSi (M - t-Bu)
283.00152, found 283.00155.
To a solution of 2-methylpent-4-en-1-ol (1.0 g, 10 mmol, 1.0
equiv) in DMF (10 mL) were added imidazole (1.7 g, 25 mmol,
2.5 equiv) and tert-butyldiphenylsilyl chloride (2.6 mL, 10
mmol, 1.0 equiv). After 12 h at room temperature, the reaction
mixture was hydrolyzed with a saturated aqueous solution of
NH4Cl (5 mL). The aqueous layer was extracted with diethyl
ether (2 × 20 mL) and the combined organic extracts were
washed with water (2 × 10 mL), dried over MgSO4, filtered,
and concentrated under reduced pressure. The crude material
was then purified by flash chromatography on silica gel
(petroleum ether/EtOAc: 95/05) to give 3.06 g (91%) of alkene
10 as a colorless oil. IR (film) 1640, 1590, 1430, 1110, 710,
1
700 cm-1; H NMR δ 7.77-7.68 (m, 4H), 7.48-7.38 (m, 6H),
5.81 (m, 1H), 5.10-4.97 (m, 2H), 3.56 (br d, J ) 6.3 Hz, 2H),
2.31 (m, 1H), 1.96 (m, 1H), 1.80 (m, 1H), 1.12 (s, 9H), 0.97 (d,
J ) 6.6 Hz, 3H); 13C NMR δ 137.2 (d), 135.5 (d, 4C), 133.9 (s,
2C), 129.4 (d, 2C), 127.5 (d, 4C), 115.6 (t), 68.3 (t), 37.5 (t),
35.6 (d), 26.8 (q, 3C), 19.2 (s), 16.3 (q); MS-EI m/z (rel intensity)
281 (M - t-Bu+, 58), 225 (11), 203 (19), 200 (19), 199 (100),
183 (23), 181 (18), 135 (14), 123 (15), 105 (14), 77 (17); HRMS
(CI+, CH4) calcd for C22H31OSi (M + H+) 339.2144, found
339.2146.
(Z)-1-(tert-Butyldimethylsilanyloxy)-10-(tert-butyldi-
phenylsilanyloxy)-5,9-dimethyldec-4-ene (11). To tert-
butyl(2-methylpent-4-enyloxy)diphenylsilane 10 (1.6 g, 4.6
mmol, 1.1 equiv) at 0 °C was added dropwise a solution of
9-BBN-H (10 mL, 0.5 M in THF, 5.0 mmol, 1.2 equiv). The
solution was stirred at 0 °C until complete conversion of the
starting alkene (approximatively 2 h, followed by TLC).
Besides, a suspension of K3PO4 (1.4 g, 6.3 mmol, 1.5 equiv)
and iodide 7 (1.4 g, 4.2 mmol, 1.0 equiv) in freshly distilled
dioxane (12.5 mL) was degassed 30 min by argon bubbling.
The solution of borane and Pd(PPh3)4 (0.12 g, 0.10 mmol, 0.025
equiv) were then added to the iodide solution and the reaction
mixture was heated for 5 h at 85 °C. After cooling to room
temperature, the unreacted borane was oxidized by addition
2-Methylpent-4-enoic Acid (9).33 Propionic acid (0.70 g,
10 mmol, 1.0 equiv) was added to a mixture of NaH (0.40 g,
60% in oil, 11 mmol, 1.1 equiv) and diisopropylamine (1.5 mL,
11 mmol, 1.1 equiv) in THF (12 mL) at room temperature.
After 10 min of heating at reflux, the solution was cooled to a
temperature between 0 and 10 °C and a solution of n-BuLi
(4.4 mL, 2.5 mol‚L-1 in hexanes, 11 mmol, 1.1 equiv) was added
slowly. The mixture was briefly heated to reflux to complete
the metalation and was then cooled to 0 °C. Allyl bromide (0.90
mL, 10 mmol, 1.0 equiv) was added and the mixture was
warmed to 30 °C. After 2 h, an aqueous solution of HCl (1
mol‚L-1) was added to the reaction mixture at 0 °C (until pH
of an aqueous solution of sodium acetate (0.8 mL, 3 mol‚L-1
)
and hydrogen peroxide (30%, 0.8 mL). After 1 h of stirring at
room temperature, the red solution was diluted with diethyl
ether (40 mL) and washed with a saturated aqueous solution
of NH4Cl (20 mL) and brine (2 × 20 mL). The combined organic
extracts were dried over MgSO4, filtered, and concentrated in
vacuo. The crude material was purified by flash chromatog-
raphy (Hexane/Et2O gradient 100/0 to 98/02) to give 1.90 g
(82%) of (Z)-alkene 11 as a colorless oil. IR (film) 1640, 1470,
1460, 1430, 1260, 1100, 870, 710, 700 cm-1; 1H NMR δ 7.75-
(31) Nicolaou, K. C.; Prasad, C. V. C.; Hwang, C.-K.; Duggan, M.
E.; Veale, C. A. J. Am. Chem. Soc. 1989, 111, 5321.
(32) Bonini, C.; Checconi, M.; Rigghi, G.; Rossi, L. Tetrahedron 1995,
51, 4111.
(33) Batterby, A. R.; Westwood, S. W. J. Chem. Soc., Perkin Trans.
1 1987, 1679
2102 J. Org. Chem., Vol. 70, No. 6, 2005

Total Synthesis of Natural Zoapatanol
7.67 (m, 4H), 7.48-7.37 (m, 6H), 5.16 (br t, J ) 6.6 Hz, 1H),
3.64 (t, J ) 6.6 Hz, 2H), 3.56 (dd, Jsyst AB ) 9.9 Hz, J ) 5.7 Hz,
1H), 3.49 (dd, Jsyst AB ) 9.9 Hz, J ) 6.2 Hz, 1H), 2.11-1.98
(m, 4H), 1.70 (br s, 3H), 1.65-1.18 (m, 7H), 1.10 (s, 9H), 0.96
(d, J ) 6.6 Hz, 3H), 0.93 (s, 9H), 0.08 (s, 6H); 13C NMR δ 135.6
(s), 135.5 (d, 4C), 134.0 (s, 2C), 129.3 (d, 2C), 127.4 (d, 4C),
124.5 (d), 68.8 (t), 62.7 (t), 35.6 (d), 33.2 (t), 33.0 (t), 31.9 (t),
26.8 (q, 3C), 25.9 (q, 3C), 25.3 (t), 24.0 (t), 23.3 (q), 19.2 (s),
18.2 (s), 16.8 (q), -5.4 (q, 2C); MS-EI m/z (rel intensity) 552
(M+•, 1), 495 (M - t-Bu+, 2), 363 (19), 313 (20), 271 (18), 253
(43), 199 (100), 197 (35), 165 (30), 137 (30), 135 (33), 109 (92),
95 (86), 81 (84); HRMS (CI+, CH4) calcd for C34H57O2Si2 (M +
H+) 553.3897, found 553.3914.
(14). A TBAF solution (1.2 mL, 1 mol‚L-1 in THF, 1.2 mmol,
1 equiv) was added to a solution of 13 (0.78 g, 1.20 mmol, 1.0
equiv) in THF (30 mL). After 1 h at room temperature, the
reaction mixture was diluted with diethyl ether (60 mL) and
washed with brine (2 × 30 mL). The organic layer was dried
over MgSO4, filtered, and concentrated under reduced pressure
to afford 672 mg (100%) of crude (4R*,5S*)-4-benzyloxy-10-
(tert-butyldiphenylsilanyloxy)-5,9-dimethyldecane-1,5-diol as
a colorless oil, which was engaged in the next step without
further purification.
The crude intermediate diol (0.6 g, 1 mmol, 1 equiv) was
dissolved in DMF (2 mL) and the resulting solution was added
to a stirred solution of PDC (1.3 g, 3.5 mmol, 3.5 equiv) in DMF
(6 mL), at 0 °C. After 30 min, diethyl ether (30 mL) was added
and the mixture was filtered through florisil. The filtrate was
then washed with water (3 × 5 mL) and brine (10 mL). The
combined extracts were dried over MgSO4, filtered, and
concentrated in vacuo to afford 0.56 g (100%) of lactone 14 as
a colorless oil, which was engaged in the next step without
further purification. An analytical sample was obtained after
purification by flash chromatography (petroleum ether/EtOAc:
(4R*,5S*)-1-(tert-Butyldimethylsilanyloxy)-10-(tert-
butyldiphenylsilanyloxy)-5,9-dimethyldecane-4,5-diol (12).
To a mixture of water (1 mL), acetone (6 mL), and NMO (0.107
g, 0.90 mmol, 1 equiv), at 0 °C, was added OsO4 (0.563 mL,
2.5% in t-BuOH, 0.045 mmol, 0.05 equiv). A solution of alkene
11 (0.50 g, 0.90 mmol, 1.0 equiv) in acetone (2.5 mL) was then
added dropwise at 0 °C. After 30 min, the reaction mixture
was stirred for 12 h at room temperature. The reaction was
stopped by addition of a mixture of water (2.5 mL), florisil (605
mg), and Na2S2O3‚5H2O (160 mg). After 30 min of stirring, the
mixture was filtered and the solvent was evaporated under
reduced pressure. The aqueous residue was then diluted with
brine (7.5 mL) and extracted with EtOAc (3 × 15 mL). The
combined organic extracts were dried over MgSO4, filtered, and
concentrated in vacuo. Purification by flash chromatography
on silica gel (petroleum ether/EtOAc: 85/15) afforded 322 mg
(61%) of diol 12 as a colorless oil. IR (film) 3410, 1640, 1470,
90/10). IR (film) 1730, 1590, 1425, 1105, 710, 700 cm-1 1H
;
NMR δ 7.72-7.65 (m, 4H), 7.45-7.28 (m, 11H), 4.68 (d syst
AB, J ) 11.8 Hz, 1H), 4.49 (d syst AB, J ) 11.8 Hz, 1H), 3.58-
3.40 (m, 3H), 2.71 (dt, Jsyst AB ) 18.4, J ) 7.5 Hz, 1H), 2.49
(dt, Jsyst AB) 18.4 Hz, J ) 6.6 Hz, 1H), 2.10-1.98 (m, 2H),
1.76-1.50 (m, 3H), 1.45-1.00 (m, 4H), 1.40 (s, 3H), 1.08 (s,
9H), 0.92 (d, J ) 6.3 Hz, 3H); 13C NMR δ 170.4 (s), 137.6 (s),
135.5 (d, 4C), 133.9 (s, 2C), 129.4 (d, 2C), 128.3 (d, 2C), 127.8
(d), 127.5 (d, 6C), 85.7 (s), 74.1 (d), 71.1 (t), 68.7 (t), 40.3 (t),
35.5 (d), 33.3 (t), 26.8 (q, 3C), 26.0 (t), 21.4 (q), 20.6 (t), 20.3
(t), 19.2 (s), 16.7 (q); MS-EI m/z (rel intensity) 393 (7), 315
(28), 199 (54), 181 (10), 139 (14) 135 (18), 91 (100), 85 (16).
Anal. Calcd for C35H46O4Si: C, 75.23; H, 8.30. Found: C, 75.49;
H, 8.24.
1430, 1260, 1110, 870 cm-1 1H NMR δ 7.71-7.64 (m, 4H),
;
7.44-7.34 (m, 6H), 3.79-3.62 (m, 2H), 3.56-3.36 (m, 3H),
1.80-1.65 (m, 4H), 1.65-1.20 (m, 8H), 1.15 (m, 1H), 1.15 (s,
3H), 1.06 (s, 9H), 0.94 (d, J ) 7.3 Hz, 3H), 0.92 (s, 9H), 0.09
(s, 6H); 13C NMR δ 135.5 (d, 4C), 134.0 (s, 2C), 129.3 (d, 2C),
127.4 (d, 4C), 78.0 (d), 74.3 (s), 68.8 (t), 63.4 (t), 36.4 (t), 35.6
(d), 33.8 (t), 29.8 (t), 26.6 (t), 26.8 (q, 3C), 25.8 (q, 3C), 23.3
(q), 20.6 (t), 19.2 (s), 18.2 (s), 16.8 (q), -5.5 (q, 2C); MS-EI m/z
(rel intensity) 511 (M - H2O - t-Bu+, 12), 397 (11), 379 (12),
305 (12), 199 (100), 181 (20), 163 (36), 135 (22), 105 (21). Anal.
Calcd for C34H58O4Si2: C, 69.57; H, 9.96. Found: C, 69.39; H,
9.95.
(4R*,5S*)-5-Benzyloxy-10-(tert-butyldiphenylsilanyl-
oxy)-6-methylundec-1-en-6-ol (15). To a solution of lactone
14 (0.52 g, 0.92 mmol, 1 equiv) in anhydrous ether (4 mL), at
-78 °C, was slowly added a solution of diisobutylaluminum
hydride (0.92 mL, 1 M in hexanes, 0.92 mmol, 1 equiv). After
1 h at -78 °C, the reaction mixture was diluted with diethyl
ether (20 mL) and poured into a saturated aqueous solution
of Rochelle’s salt (20 mL). After the mixture was stirred for 1
h at room temperature, the organic layer was separated and
the aqueous layer was extracted with diethyl ether (3 × 40
mL). The combined organic extracts were washed with a
saturated aqueous solution of Rochelle’s salt (20 mL), dried
over MgSO4, filtered, and concentrated under reduced pressure
to afford 516 mg of crude lactol as a colorless oil. The crude
material was directly engaged in the next step without further
purification.
To a suspension of methyltriphenylphosphonium bromide
(0.56 g, 1.60 mmol, 2 equiv) in anhydrous THF (8 mL) at room
temperature was added dropwise a solution of n-BuLi (0.64
mL, 2.5 M in hexanes, 1.60 mmol, 2 equiv). The ylide solution
was next added via cannula to a solution of crude lactol (0.44
g, 0.80 mmol) in anhydrous THF (4 mL), at -78 °C. After 20
min at -78 °C, the mixture was warmed to room temperature
over 1 h and the stirring was continued for 1 h at room
temperature. The reaction mixture was then poured into a
saturated aqueous solution of NH4Cl (20 mL) and the aqueous
layer was extracted with diethyl ether (3 × 40 mL). The
combined extracts were successively washed with water (20
mL) and brine (20 mL), dried over MgSO4, filtered, and
concentrated under reduced pressure. The crude material was
purified by flash chromatography on silica gel (petroleum
ether/E.E.: 80/20) to give 304 mg (68%, four steps) of alkene
15 as a colorless oil. IR (film) 3400, 1640, 1460, 1425, 1105,
910 cm-1; 1H NMR δ 7.75-7.69 (m, 4H), 7.50-7.30 (m, 11H),
5.89 (ddt, J ) 17.3, 10.3, and 7.0 Hz, 1H), 5.15-5.02 (m, 2H),
4.76 (d syst AB, J ) 11.4 Hz, 1H), 4.65 (d syst AB, J ) 11.4
Hz, 1H), 3.61-3.45 (m, 2H), 3.33 (dd, J ) 7.4 and 4.8 Hz, 1H),
(4R*,5S*)-4-Benzyloxy-1-(tert-butyldimethylsilanyloxy)-
10-(tert-butyldiphenylsilanyloxy)-5,9-dimethyldecan-5-
ol (13). To a suspension of NaH (45 mg, 60% in oil, 1.1 mmol,
2.2 equiv) in THF (2 mL) at 0 °C was added a solution of diol
12 (0.30 g, 0.5 mmol, 1.0 equiv) and HMPA (0.27 mL, 1.5 mmol,
3.0 equiv) in THF (1 mL). After 30 min at 0 °C, the solution
was stirred for 1 h at room temperature. The reaction mixture
was cooled at 0 °C and benzyl bromide (73 µL, 0.61 mmol, 1.2
equiv) and n-Bu4NI (75 mg, 0.20 mmol, 0.4 equiv) were added.
After 20 h at room temperature, the reaction mixture was
diluted with diethyl ether (10 mL) and then poured into a
saturated aqueous solution of NH4Cl (5 mL). The aqueous layer
was extracted with diethyl ether (3 × 10 mL) and the combined
organic extracts were washed with water (2 × 5 mL), dried
over MgSO4, filtered, and concentrated under reduced pres-
sure. The crude material was purified by flash chromatography
(petroleum ether/Et2O: 95/05) to give 294 mg (87%) of benzyl
ether 13 as a colorless oil. IR (film) 3450, 1580, 1470, 1425,
1255, 1100, 830, 710, 700 cm-1; 1H NMR δ 7.72-7.65 (m, 4H),
7.46-7.28 (m, 11H), 4.73 (d syst AB, J ) 11.2 Hz, 1H), 4.60 (d
syst AB, J ) 11.2 Hz, 1H), 3.73-3.58 (m, 2H), 3.57-3.42 (m,
2H), 3.29 (br dd, J ) 7.7 and 2.9 Hz, 1H), 2.20-1.10 (m, 12H),
1.18 (s, 3H), 1.07 (s, 9H), 0.94 (d, J ) 7.5 Hz, 3H), 0.91 (s,
9H), 0.07 (s, 6H); 13C NMR δ 138.5 (s), 135.5 (d, 4C), 134.0 (s,
2C), 129.3 (d, 2C), 128.3 (d, 2C), 127.5 (d, 2C), 127.5 (d), 127.4
(d, 4C), 86.7 (d), 75.0 (s), 74.5 (t), 68.8 (t), 63.1(t), 37.3 (t), 35.6
(d), 33.8 (t), 30.2 (t), 26.9 (t), 26.8 (q, 3C), 25.8 (q, 3C), 23.7 (q,
C), 20.6 (t), 19.2 (s), 18.2 (s), 16.7 (q), -5.4 (q, 2C).
(5R*,6S*)-5-Benzyloxy-6-[5-(tert-butyldiphenylsilanyl-
oxy)-4-methylpentyl]-6-methyltetrahydro-2H-pyran-2-one
J. Org. Chem, Vol. 70, No. 6, 2005 2103

Taillier et al.
2.39 (m, 1H), 2.29-2.10 (m, 2H), 1.82-1.25 (m, 9H), 1.22 (s,
3H), 1.11 (s, 9H), 0.99 (d, J ) 6.3 Hz, 3H); 13C NMR δ 138.5
(s), 138.5 (d), 135.5 (d, 4C), 134.0 (s, 2C), 129.4 (d, 3C), 128.4
(d, 3C), 127.6 (d), 127.5 (d, 4C), 114.8 (t), 86.1 (d), 75.1 (s),
74.8 (t), 68.8 and 68.7 (t), 37.3 (t), 35.7 and 35.6 (d), 33.8 (t),
31.0 (t), 30.0 (t), 26.8 (q, 3C), 23.7 (q), 20.7 (t), 20.6 (s), 16.8
(q); MS-EI m/z (rel intensity) 501 (M - t-Bu+,1), 483 (M - t-Bu
- H2O+,1), 393 (9), 305 (31), 200 (15), 199 (79), 197 (12), 183
(11), 181 (11), 177 (19), 139 (23), 135 (22), 127 (10), 121 (13),
109 (29), 95 (18), 91 (100), 81 (12); HRMS (CI+, NH3) calcd for
C36H54O3NSi (M + NH4+) 576.3873, found 576.3860; HRMS
(CI+, CH4) calcd for C36H51O3Si (M + H+) 559.3607, found
559.3596.
diphenylsilane 10 (1.55 g, 4.58 mmol, 1.1 equiv) at 0 °C was
added dropwise a solution of 9-BBN dimer (0.615 g, 2.52 mmol,
0.6 equiv) in anhydrous THF (10 mL, 0.5 M). The solution was
stirred at 0 °C until complete conversion of the starting alkene
(ca. 2 h, followed by TLC). Besides, a suspension of K3PO4 (1.33
g, 6.26 mmol, 1.50 equiv) and iodide 1934 (1.0 g, 4.2 mmol, 1
equiv) in freshly distilled dioxane (12 mL) was degassed 30
min by argon bubbling. The solution of borane and Pd(PPh3)4
(0.12 g, 0.10 mmol, 2.5 mol %) were then added to the iodide
and the reaction mixture was heated 5 h at 85 °C. After cooling
to room temperature, the unreacted borane was oxidized by
addition of an aqueous solution of sodium acetate (1.2 mL, 3
mol‚L-1) and hydrogen peroxide (30%, 1.2 mL). After 1 h of
stirring at room temperature, the red solution was diluted with
diethyl ether (50 mL) and washed with a saturated aqueous
solution of NH4Cl (25 mL) and with a saturated aqueous
solution of NaCl (2 × 20 mL). The combined organic extracts
were dried over MgSO4, filtered, and concentrated in vacuo.
Purification by flash chromatography on silica gel (petroleum
ether/diethyl ether: 95/05 to 80/20) afforded 1.40 g (74%) of
alkene 20 as a colorless oil. IR (film) 1710, 1645, 1425, 1255,
1150, 1110 cm-1; 1H NMR δ 7.74-7.64 (m, 4H), 7.48-7.34 (m,
6H), 5.67 (br s, 1H), 4.15 (q, J ) 7.2 Hz, 2H), 3.54 (dd, J ) 9.6
and 5.7 Hz, 1H), 3.47 (dd, J ) 9.6 and 6.3 Hz, 1H), 2.62 (br t,
J ) 7.4 Hz, 2H), 1.88 (d, J ) 1.5 Hz, 3H), 1.77-1.15 (m, 5H),
1.28 (t, J ) 7.2 Hz, 3H), 1.09 (s, 9H), 0.96 (d, J ) 6.6 Hz, 3H);
13C NMR δ 66.2 (s), 160.3 (s), 135.5 (d, 4C), 134.0 (s, 2C), 129.3
(d, 2C), 127.4 (d, 4C), 116.0 (d), 68.8 (t), 59.2 (t), 35.5 (d), 33.4
(t), 33.0 (t), 26.8 (q, 3C), 25.5 (t), 25.0 (q), 19.2 (s), 16.7 (q),
14.2 (q); MS-EI m/z (rel intensity) 437 (M - CH3+, 1), 407 (M
OEt+, 3), 396 (32), 395 (M - t-Bu+, 100), 227 (17), 199 (34),
183 (14), 181 (11), 123 (12), 95 (11); HRMS (CI+, CH4) calcd
for C28H41O3Si (M + H+) 453.2825, found 453.2815.
(6S*,7R*)-(7-Benzyloxy-2,6-dimethyl-6-vinyloxy)undec-
10-enyloxy-tert-butyldiphenylsilane (16). In a tube fitted
with a screw-cap was placed a solution of alcohol 15 (600 mg,
1.07 mmol, 1 equiv) in ethyl vinyl ether (5 mL). Triethylamine
(150 µL, 1.07 mmol, 1 equiv) and mercuric trifluoroacetate (573
mg, 1.34 mmol, 1.25 equiv) were successively added and the
reaction mixture was heated to 50 °C. After 2.5 h, the reaction
mixture was hydrolyzed at room temperature with a saturated
aqueous solution of NaHCO3 (5 mL). The biphasic mixture was
stirred 20 min at room temperature and the aqueous layer
was extracted with diethyl ether (3 × 15 mL). The combined
organic extracts were washed with water and with a saturated
aqueous solution of NaHCO3 (3 × 10 mL), dried over MgSO4,
filtered, and concentrated under reduced pressure. Purification
by flash chromatography on silica gel (petroleum ether/Et2O,
gradient 98/02 to 90/10) afforded 298 mg (47%) of diene 16, as
a colorless oil, and 209 mg (35%) of unreacted alcohol 15. IR
(film) 1630, 1460, 1425, 1390, 1165, 1110 cm-1 1H NMR δ
;
7.71-7.64 (m, 4H), 7.46-7.28 (m, 11H), 6.52 (dd, J ) 13.6 and
6.2 Hz, 1H), 5.84 (ddt, J ) 17.3, 10.3, and 6.6 Hz, 1H), 5.09-
4.97 (m, 2H), 4.67 (d syst AB, J ) 11.4 Hz, 1H), 4.58 (d syst
AB, J ) 11.4 Hz, 1H), 4.41 (d, J ) 13.6 Hz, 1H), 4.03 (d, J )
6.2 Hz, 1H), 3.55-3.38 (m, 3H), 2.33 (m, 1H), 2.13 (m, 1H),
1.90-1.26 (m, 9H), 1.23 (s, 3H), 1.07 (s, 9H), 0.93 (d, J ) 7.7
Hz, 3H); 13C NMR δ 146.5 (d), 138.7 (s), 138.6 (d), 135.5 (d,
4C), 134.0 (s, 2C), 129.3 (d, 3C), 128.2 (d, 3C), 127.5 (d, 4C),
127.4 (d), 114.7 (t), 90.4 (t), 83.3 (d), 82.3 (s), 74.3 (t), 68.7 (t),
36.1 (t), 35.5 (d), 33.5 (t), 30.9 (t), 30.0 (t), 26.8 (q, 3C), 20.1
(t), 19.9 (q), 19.2 (s), 16.8 (q); HRMS (CI+, NH3) calcd for
C38H56O3NSi (M + NH4+) 602.4029, found 602.4033.
(Z)-1-(tert-Butyldimethylsilanyloxy)-8-(tert-butyldi-
phenylsilanyloxy)-3,7-dimethyloct-2-ene (21) To a solution
of ester 20 (1.0 g, 2.2 mmol, 1 equiv) in anhydrous diethyl ether
(20 mL) at -78 °C was added dropwise a solution of diiso-
butylaluminum hydride (4.64 mL, 1 mol‚L-1 in hexanes, 4.64
mmol, 2.1 equiv). After 30 min at -78 °C, the cold reaction
mixture was poured into a saturated aqueous solution of
Rochelle’s salt (20 mL). The mixture was diluted with diethyl
ether (20 mL) and, after 2 h of stirring at room temperature,
the two phases were separated. The aqueous layer was
extracted with diethyl ether (2 × 20 mL) and the combined
organic extracts were washed with brine, dried over MgSO4,
filtered, and concentrated under reduced pressure. Purification
by flash chromatography on silica gel (petroleum ether/Et2O
70/30 then 60/40) afforded 0.68 g (75%) of allylic alcohol as a
colorless oil. The alcohol (0.600 g, 1.46 mmol, 1 equiv) was then
diluted in DMF (4 mL) and imidazole (0.250 g, 3.65 mmol, 2.5
equiv) and tert-butyldimethylsilyl chloride (0.220 g, 1.46 mmol,
1.0 equiv) were added. After 12 h at room temperature, the
reaction mixture was hydrolyzed with a saturated aqueous
solution of NH4Cl (5 mL). The aqueous layer was extracted
with diethyl ether (3 × 20 mL) and the combined organic
extracts were washed with water (2 × 10 mL), dried over
MgSO4, filtered, and concentrated under reduced pressure. The
crude material was then purified by flash chromatography on
silica gel (petroleum ether/Et2O: 80/20) to give 465 mg (61%)
of silylated ether 21 as a colorless oil. IR (film) 1470, 1460,
{5-[(2S*,3R*)-3-Benzyloxy-2-methyl-2,3,4,5-tetrahydro-
oxepin-2-yl]-2-methylbutoxy}tert-butyldiphenylsilane
(17). A solution of diene 16 (76 mg, 0.13 mmol) in freshly
distilled benzene (30 mL, 4.3 × 10-3M) was degassed for 20
min by argon bubbling. The solution was then heated to 50
°C and Grubbs’ catalyst Cl2(PCy3)2RudCHPh (32 mg, 39 µmol,
30%) was added in three portions over a period of 3 h. Heating
was continued 4 h after the end of addition. The reaction
mixture was then allowed to cool to room temperature and
the solvent was evaporated under reduced pressure. The crude
material was purified by flash chromatography (petroleum
ether/Et2O: 95/05) to give 50 mg (70%) of oxepene 17 as a
colorless oil. IR (film) 1650, 1425, 1265, 1110, 745 cm-1 1H
;
NMR δ 7.71-7.66 (m, 4H), 7.45-7.28 (m, 11H), 6.04 (dt, J )
6.3 and 1.5 Hz, 1H), 4.99 (apparent q, J ) 6.3 Hz, 1H), 4.68
(dd, Jsyst AB ) 11.8 Hz, J ) 1.1 Hz, 1H), 4.45 (dd, Jsyst AB
)
11.8 Hz, J ) 1.1 Hz, 1H), 3.56-3.36 (m, 3H), 2.28 (m, 1H),
2.06-1.55 (m, 6H), 1.47-1.25 (m, 4H), 1.23 (s, 3H), 1.07 (s,
9H), 0.93 (2d, J ) 6.6 Hz, 2 × 1.5H); 13C NMR δ 143.5 (d),
138.5 (s), 135.5 (d, 4C), 134.0 (s, 2C), 129.3 (d, 2C), 128.2 (d,
2C), 128.1 (d, 2C), 127.6 (d), 127.4 (d, 4C), 113.6 (d), 83.6 and
83.5 (d), 82.2 (s), 71.4 (t), 68.8 (t), 38.6 (t), 35.6 (d), 33.6 (t),
26.8 (q, 3C), 24.5 (t), 21.1 (t), 20.5 and 20.4 (t), 19.3 (s), 19.2
(q), 16.8 (q); MS-EI m/z (rel intensity) 499 (M - t-Bu+,1), 391
(12), 200 (11), 199 (63), 197 (10), 183 (13), 181 (10), 175 (15),
139 (16), 135 (15), 91 (100). Anal. Calcd for C36H48O3Si: C,
77.65; H, 8.69. Found: C, 77.70; H, 8.87.
1425, 1250, 1105, 835 cm-1 1H NMR δ 7.72-7.66 (m, 4H),
;
7.48-7.36 (m, 6H), 5.33 (apparent t, J ) 6.6 Hz, 1H), 4.18 (dd,
J ) 6.6 and 1.1 Hz, 2H), 3.57-3.43 (m, 2H), 2.06-1.98 (m,
2H), 1.71 (d, J ) 1.1 Hz, 3H), 1.67 (m, 1H), 1.50-1.27 (m, 4H),
1.08 (s, 9H), 0.94 (d, J ) 6.6 Hz, 3H), 0.92 (s, 9H), 0.09 (s,
6H); 13C NMR δ 137.7 (s), 135.5 (d, 4C), 134.0 (s, 2C), 129.4
(d, 2C), 127.4 (d, 4C), 124.9 (d), 68.7 (t), 59.8 (t), 35.6 (d), 32.9
(t), 32.3 (t), 26.8 (q, 3C), 25.9 (q, 3C), 25.4 (t), 23.3 (q), 19.2 (s),
18.3 (s), 16.7 (q), -5.2 (q, 2C); MS-EI m/z (rel intensity) 524
(M+•,1), 335 (21), 313 (24), 271 (25), 253 (40), 211 (21), 209
(34), 200 (19), 199 (100), 197 (26), 195 (21), 183 (17), 181 (17),
137 (62), 135 (27), 95 (44), 91 (20), 81 (99), 75 (59), 73 (19).
(Z)-Ethyl 8-(tert-Butyldiphenylsilanyloxy)-3,7-dimethyl-
oct-2-enoate (20). To tert-butyl(2-methylpent-4-enyloxy)-
2104 J. Org. Chem., Vol. 70, No. 6, 2005

Total Synthesis of Natural Zoapatanol
Anal. Calcd for C32H52O2Si2: C, 73.22; H, 9.98. Found: C,
73.25; H, 10.06.
the mixture was cooled at 0 °C and solid methanesulfonamide
(67 mg, 0.67 mmol, 1 equiv) was added in one portion. After
20 min at 0 °C, a solution of alkene 20 (0.32 g, 0.71 mmol, 1
equiv) in toluene (1 mL) was added via cannula and the
reaction mixture was vigorously stirred for 30 h at 0 °C. After
dilution with EtOAc (3 mL) at 0 °C and addition of Na2SO3
portionwise (ca. 1 g), the mixture was stirred for 1 h at room
temperature. The aqueous layer was then extracted with
EtOAc (3 × 15 mL) and the combined organic extracts were
washed with water, dried over MgSO4, filtered, and concen-
trated in vacuo. Purification by flash chromatography on silica
gel (petroleum ether/EtOAc: 80/20) afforded 0.222 g (65%) of
diol 26 as a colorless oil. [R]20D +6.9 (c 1.10, CHCl3); IR (film)
(2R*,3S*)-1-(tert-Butyldimethylsilanyloxy)-8-(tert-
butyldiphenylsilanyloxy)-3,7-dimethyloctane-2,3-diol (22).
To a solution of alkene 21 (0.25 g, 0.48 mmol, 1 equiv) in a
mixture of water and tert-butyl alcohol (1:1, 5 mL) at room
temperature were successively added K3Fe(CN)6 (0.47 g, 1.43
mmol, 3 equiv), K2CO3 (0.200 g, 1.43 mmol, 3 equiv), DABCO
(27 mg, 0.24 mmol, 0.5 equiv), and OsO4 (30 mL, 4% in water,
4.8 mmol, 0.01 equiv).35 After 16 h at room temperature, the
reaction mixture was diluted with water (5 mL) and Na2SO3
(ca. 250 mg) was added. After the mixture was stirred for 2 h
at room temperature, the aqueous layer was extracted with
EtOAc (5 × 10 mL) and the combined organic extracts were
dried over MgSO4, filtered, and concentrated under reduced
pressure. The crude material was purified by flash chroma-
tography (petroleum ether/EtOAc: 95/05) to give 195 mg (73%)
of diol 22 as a colorless oil. IR (film) 3400 (br), 1245, 1060 (br),
3460 (br), 1730, 1470, 1460, 1425, 1385, 1110, 710, 700 cm-1
;
1H NMR rotamers δ 7.71-7.65 (m, 4H), 7.47-7.35 (m, 6H),
4.31 (m, 2H), 4.02 (2d, J ) 6.6 Hz, 1H), 3.53 (dd, J ) 9.7 and
5.7 Hz, 1H), 3.47 (dd, J ) 9.7 and 5.7 Hz, 1H), 3.16 (d, J ) 6.6
Hz, 1H), 2.53 (s, 1H), 1.75-1.26 (m, 7H), 1.34 and 1.33 (2t, J
) 7.2 Hz, 3H), 1.23 (s, 3H), 1.07 (s, 9H), 0.95 (d, J ) 7.0 Hz,
3H); 13C NMR rotamers δ 173.3 (s), 135.5 (d, 4C), 134.0 (s,
2C), 129.4 (d, 2C), 127.4 (d, 4C), 76.2 and 76.1 (d), 73.8 (s),
68.8 (t), 61.9 (t), 38.1 and 38.0 (t), 35.6 and 35.5 (d), 33.5 (t),
26.8 (q, 3C), 22.8 and 22.7 (q), 20.5 (t), 19.2 (s), 16.7 and 16.6
(q), 14.1 (q); MS-EI m/z (rel intensity) 367 (1), 326 (12), 325
(42), 200 (19), 199 (100), 181 (12), 139 (24), 109 (12). Anal.
Calcd for C28H42O5Si: C, 69.10; H, 8.70. Found: C, 68.79; H,
9.01.
Ethyl (2S,3S)-2-Benzyloxy-8-(tert-butyldiphenylsilanyl-
oxy)-3-hydroxy-3,7-dimethyloctanoate (27). To a solution
of diol 26 (0.954 g, 1.96 mmol) in anhydrous CH2Cl2 (20 mL)
at room temperature were successively added benzyl bromide
(235 mL, 1.96 mmol, 1 equiv), n-Bu4NI (0.362 g, 0.981 mmol,
0.5 equiv), and freshly prepared silver oxide (0.455 g, 1.96
mmol, 1 equiv)36 in three portions over a period of 30 min. After
5 h at room temperature with exclusion of light, the reaction
mixture was filtered through Celite and concentrated under
reduced pressure. The crude material was purified by flash
chromatography (petroleum ether/Et2O: 80/20) to give 836 mg
(74%) of monobenzylated diol 27 as a colorless oil. [R]20D -26.7
(c 1.0, CHCl3); IR (film) 3425 (br), 1735, 1460, 1425, 1385, 1265,
1190, 1110, 1025 cm-1; 1H NMR rotamers δ 7.71-7.64 (m, 4H),
7.47-7.28 (m, 11H), 4.75 (d syst AB, J ) 11.4 Hz, 1H), 4.41 (d
syst AB, J ) 11.4 Hz, 1H), 4.27 (m, 2H), 3.84 (s, 1H), 3.56-
3.40 (m, 2H), 2.68 (br s, 1H), 1.70-1.09 (m, 10H), 1.24 (s, 3H),
1.06 (s, 9H), 0.89 (d, J ) 6.6 Hz, 3H); 13C NMR δ 171.2 (s),
137.0 (s), 135.5 (d, 4C), 134.0 (s, 2C), 129.3 (d, 2C), 128.3 (d,
2C), 128.1 (d, 2C), 127.9 (d), 127.4 (d, 4C), 83.9 and 83.8 (d),
73.6 (s), 72.9 (t), 68.8 (t), 60.9 (t), 38.4 and 38.3 (t), 35.7 and
35.6 (d), 33.5 (t), 26.8 (q, 3C), 23.3 and 23.2 (q), 20.5 and 20.4
(t), 19.2 (s), 16.7 (q), 14.2 (q); MS-EI m/z (rel intensity) 367
(1), 326 (14), 325 (51), 200 (20), 199 (100), 181 (13), 139 (24),
109 (11). Anal. Calcd for C35H48O5Si: C, 72.88; H, 8.39.
Found: C, 72.83; H, 8.42.
(2R,3S)-2-Benzyloxy-8-(tert-butyldiphenylsilanyloxy)-
1-methoxymethoxy-3,7-dimethyloctan-3-ol (28). To a sus-
pension of lithium aluminum hydride (65 mg, 1.71 mmol, 2
equiv) in anhydrous diethyl ether (2 mL) at 0 °C was added a
solution of ester 27 (0.500 g, 0.868 mmol) in diethyl ether (2
mL). After 5 min at 0 °C and 1 h at room temperature, the
reaction mixture was cooled to 0 °C and treated successively
with water (65 µL), then with a 15% aqueous solution of NaOH
(65 µL), and finally with water (195 µL). After 1 h of stirring
at room temperature, the resulting suspension was filtered
through Celite. The insoluble salts were washed with diethyl
ether (2 × 25 mL) and the filtrate was dried over MgSO4.
Filtration and concentration under reduced pressure give 463
mg of (2R,3S)-2-benzyloxy-8-(tert-butyldiphenylsilanyloxy)-3,7-
dimethyloctan-1,3-diol, which was directly engaged in the next
step without further purification.
1
825 cm-1; H NMR δ 7.72-7.65 (m, 4H), 7.48-7.36 (m, 6H),
3.80 (d, J ) 4.4 Hz, 2H), 3.56-3.40 (m, 3H), 2.86 (d, 1H), 2.78
(s, 1H), 1.78-1.26 (m, 6H), 1.21 (s, 3H), 1.15 (m, 1H), 1.08 (s,
9H), 0.95 (d, J ) 6.6 Hz, 3H), 0.93 (s, 9H), 0.12 (s, 6H); 13C
NMR δ 135.5 (d, 4C), 133.9 (s, 2C), 129.4 (d, 2C), 127.4 (d,
4C), 75.1 (d), 74.0 (s), 68.7 (t), 64.1 (t), 38.7 (t), 35.6 and 35.5
(d), 33.7 (t), 26.8 (q, 3C), 25.7 (q, 3C), 23.1 (q), 20.8 and 20.7
(t), 19.2 (s), 18.0 (s), 16.7 (q), -5.6 (q), -5.7 (q); MS-EI m/z
(rel intensity) 483 (M - H2O - t-Bu+, 8), 325 (11), 311 (11),
305 (22), 267 (10), 239 (10), 227 (14), 213 (17), 200 (19), 199
(100), 197 (21), 195 (14), 183 (14), 181 (16), 139 (18), 135 (79),
115 (13), 109 (24), 107 (13), 93 (15), 89 (34), 75 (30), 73 (34).
Anal. Calcd for C32H54O4Si2: C, 68.76; H, 9.74. Found: C,
68.67; H, 9.87.
(2R*,3S*)-1-Benzyloxy-2-(tert-butyldimethylsilanyloxy)-
8-(tert-butyldiphenylsilanyloxy)-3,7-dimethyloctan-3-
ol (24). To a stirred suspension of NaH (16 mg, 60% in oil,
0.39 mmol, 2.2 equiv) in THF (1 mL) at 0 °C was added
dropwise a mixture of diol 22 (0.10 g, 0.18 mmol, 1.0 equiv),
HMPA (93 µL, 0.54 mmol, 3.0 equiv), benzyl bromide (32 µL,
0.27 mmol, 1.5 equiv), and n-Bu4NI (26 mg, 0.07 mmol, 0.4
equiv) in THF (1 mL). After 15 min at 0 °C and 1 h at room
temperature, the reaction mixture was diluted with diethyl
ether (5 mL) and poured into a mixture of ice/water. The
aqueous layer was first neutralized by addition of a saturated
aqueous solution of NH4Cl (ca. 5 mL) and, then, extracted with
diethyl ether (3 × 10 mL). The combined organic extracts were
washed with brine (5 mL), dried over MgSO4, filtered, and
concentrated under reduced pressure. Purification by flash
chromatography on silica gel (petroleum ether/Et2O gradient
98/02 to 90/10) next afforded 114 mg (98%) of benzylated ether
24 as a colorless oil. IR (film) 3480 (br), 1470, 1460, 1425, 1390,
1360, 1255, 1110, 835 cm-1 1H NMR δ 7.75-7.68 (m, 4H),
;
7.49-7.28 (m, 11H), 4.57 (d syst AB, J ) 11.8 Hz, 1H), 4.51 (d
syst AB, J ) 11.8 Hz, 1H), 3.78-3.63 (m, 2H), 3.60-3.45 (m,
3H), 2.82 (d, J ) 4.4 Hz, 1H), 1.72 (m, 1H), 1.62-1.22 (m, 6H),
1.17 (s, 3H), 1.10 (s, 9H), 0.97 (d, J ) 7.0 Hz, 3H), 0.93 (s,
9H), 0.14-0.11 (m, 6H); 13C NMR δ 137.6 (s), 135.5 (d, 4C),
134.0 (s, 2C), 129.4 (d, 2C), 128.3 (d, 2C), 127.6 (d, 3C), 127.4
(d, 4C), 76.4 (d), 74.1 (s), 73.4 (t), 72.2 (t), 68.9 (t), 38.5 (t),
35.8 and 35.7 (d), 33.8 (t), 26.8 (q, 3C), 25.8 (q, 3C), 22.8 and
22.7 (q), 20.4 (t), 19.2 (s), 18.0 (s), 16.8 and 16.7 (q), -4.1 (q),
-5.1 (q); MS-EI m/z (rel intensity) 483 (M - t-Bu - PhCH2OH+,
3), 325 (24), 199 (50), 194 (19), 139 (12), 137 (13), 135 (48),
109 (12), 91 (100), 75 (11), 73 (13); Anal. Calcd for C39H60O4Si2:
C, 72.17; H, 9.32. Found: C, 71.99; H. 9.49.
Ethyl (2S,3S)-8-(tert-Butyldiphenylsilanyloxy)-2,3-di-
hydroxy-3,7-dimethyloctanoate (26). To a stirred mixture
of water and tert-butyl alcohol (1/1, 7 mL) at room temperature
was added AD-mix-â (0.976 g). Once the two phases were clear,
To a stirred suspension of NaH (76 mg, 60% in oil, 1.9 mmol,
2.2 equiv) in anhydrous THF (2 mL) at 0 °C were added
(34) (a) Marek, I.; Alexakis, A.; Normant, J.-F. Tetrahedron Lett.
1991, 32, 5329. (b) Ma, S.; Lu, X.; Li, Z. J. Org. Chem. 1992, 57, 709.
(35) Minato, M.; Yamamoto, K.; Tsuji, J. J. Org. Chem. 1990, 55,
766.
(36) Tanabe, M.; Peter, R. H. Org. Synth. 1983, 60, 92.
J. Org. Chem, Vol. 70, No. 6, 2005 2105

Taillier et al.
successively a solution of the crude intermediate diol (0.463
g, 0.868 mmol, 1 equiv) in THF (3 mL) and methoxymethyl
chloride (73 mL, 0.95 mmol, 1.1 equiv). After 5 min at 0 °C
and 3 h at room temperature, the reaction mixture was
hydrolyzed with water (2 mL) and extracted with EtOAc (3 ×
15 mL). The combined organic extracts were washed with brine
(5 mL), dried over MgSO4, filtered and concentrated in vacuo.
The crude material was purified by flash chromatography
(petroleum ether/Et2O gradient 80/20 to 60/40) to give 0.445
g (89% from 27, 2 steps) of compound 28 as a colorless oil.
+ NH4+) 760.4010, found 760.4017. Anal. Calcd for C40H59O9-
SiP: C, 64.66; H, 8.00. Found: C, 64.30; H, 8.22.
(6R,7S)-6-Benzyloxy-7-[5-(tert-butyldiphenylsilanyloxy)-
4-methylpentyl]-7-methyl-6,7-dihydrooxepin-3-one (31).
To a solution of phosphonate 29 (91 mg, 12.3 µmol) in
anhydrous CH2Cl2 (1.5 mL) at -40 °C was added bromotri-
methylsilane (65 µL, 0.50 mmol, 4 equiv). After 30 min at -40
°C, the reaction mixture was poured into a saturated aqueous
solution of NaHCO3 (7.5 mL). The aqueous layer was then
extracted with dichloromethane (3 × 20 mL) and the combined
organic extracts were washed with brine, dried over MgSO4,
filtered, and concentrated under reduced pressure. Purification
by flash chromatography on silica gel (EtOAc) afforded 72 mg
(84%) of the deprotected alcohol as a colorless oil.
[R]20 -10.1 (c 1.0, CHCl3); IR (film) 3460 (br), 1470, 1460,
D
1
1425, 1385, 1150, 1110, 1040 cm-1; H NMR δ 7.71-7.64 (m,
4H), 7.47-7.27 (m, 11H), 4.87 (d syst AB, J ) 11.4 Hz, 1H),
4.66 (s, 2H), 4.59 (d syst AB, J ) 11.4 Hz, 1H), 3.83 (dd, Jsyst AB
) 10.7 Hz, J ) 3.7 Hz, 1H), 3.72 (dd, J
) 10.7 Hz, J )
syst AB
To a stirred solution of this intermediate alcohol (65 mg,
94 µmol, 1 equiv) in dry dichloromethane (2 mL) were added
pyridinium dichromate (107 mg, 29 µmol, 3 equiv) and mo-
lecular sieves 4 Å (213 mg). After stirring for 2 h at room
temperature, the reaction mixture was diluted with ether (25
mL) and stirring was continued for 20 min. The resulting
suspension was filtered through a pad of Celite (washed with
2 × 25 mL of diethyl ether) and the filtrate was concentrated
in vacuo to afford the crude aldehyde 30, which was used in
the next step without further purification. A solution of the
crude aldehyde in anhydrous THF (25 mL) was then added
dropwise via cannula to a suspension of sodium hydride (60%
dispersion in oil, 38 mg, 0.94 mmol, 10 equiv) in dry THF (20
mL) at 0 °C. After 15 min at 0 °C, the cooling bath was
removed and the reaction mixture was stirred for 1 h at room
temperature. The reaction mixture was then poured into a
saturated aqueous solution of NH4Cl (10 mL) and the aqueous
layer was extracted with diethyl ether (3 × 25 mL). The
combined organic extracts were dried over MgSO4, filtered, and
concentrated in vacuo. Purification by flash chromatography
on silica gel (petroleum ether/EtOAc 90/10) afforded 29 mg
(53%) of cyclic enone 31 as a colorless oil. [R]20D - 64.0 (c 1.0,
CHCl3); IR (film) 1685, 1465, 1455, 1425, 1385, 1375, 1265,
1105, 740, 710, 700 cm-1; 1H NMR δ 7.69-7.63 (m, 4H), 7.45-
7.24 (m, 11H), 6.71 (dd, J ) 12.0 and 4.0 Hz, 1H), 6.12 (d, J )
12.0 Hz, 1H), 4.67 (d syst AB, J ) 11.8 Hz, 1H), 4.41 (d syst
AB, J ) 11.8 Hz, 1H), 4.20 (br d, Jsyst AB ) 18.0 Hz, 1H), 4.04
(d, J ) 4.0 Hz, 1H), 4.02 (dd, Jsyst AB ) 18.0 Hz, J ) 4.0 Hz,
1H), 3.50 (dd, Jsyst AB ) 10.1 and 6.1 Hz, 1H), 3.45 (dd, Jsyst AB
) 10.1 and 6.8 Hz, 1H), 1.73-1.22 (m, 7H), 1.20 (s, 3H), 1.05
(s, 9H), 0.92 (2d, J ) 6.6 Hz, 2 × 1.5H); 13C NMR (CDCl3) δ
205.5 (s), 146.3 (d), 137.2 (s), 135.5 (d, 4C), 133.9 (s, 2C), 131.0
(d), 129.4 (d, 2C), 128.3 (d, 2C), 127.8 (d, C), 127.7 (d, 2C),
127.4 (d, 4C), 82.0 (d), 79.3 (s), 72.5 (t), 69.9 (t), 68.7 (t), 37.7
(t), 35.6 and 35.5 (d), 33.5 (t), 26.8 (q, 3C), 20.6 (t), 19.2 (q),
19.1 (s), 16.8 (q); MS-EI m/z (rel intensity) 513 (M - t-Bu+, 6),
357 (9), 281 (10), 253 (16), 207 (49), 200 (18), 199 (100), 181
(16), 139 (18), 117 (19), 91 (72). Anal. Calcd for C36H46O4Si:
C, 75.75; H, 8.12. Found: C, 75.71; H, 8.22.
(4S,5R)-4-[5-(tert-Butyldiphenylsilanyloxy)-4-methyl-
pentyl]-4-methyl-3,8-dioxabicyclo[3.2.1]octan-1-ol (32).
To a solution of enone 31 (27 mg, 47 µmol) in absolute ethanol
(2 mL) was added Pd/C (5 mg, 10%, 4.7 µmol, 10% mol). The
mixture was stirred under 1 atm of hydrogen at room tem-
perature. After 16 h of stirring, the reaction mixture was
filtered through Celite (rinsing with Et2O) and the volatiles
were evaporated under reduced pressure. The crude material
was purified by flash chromatography (petroleum ether/Et2O:
60/40) to give 22 mg (97%) of hemiketal 32 as a colorless oil.
IR (film) 3350 (br), 1465, 1455, 1425, 1365, 1260, 1200, 1110,
820, 740, 710, 700 cm-1; 1H NMR δ 7.69-7.62 (m, 4H), 7.46-
7.33 (m, 6H), 3.93 (d, J ) 6.6 Hz, 1H), 3.69 (d syst AB, J )
10.7 Hz, 1H), 3.53-3.38 (m, 3H), 3.02 (s, 1H), 2.20 (m, 1H),
2.09-1.89 (m, 2H), 1.71-1.59 (m, 2H), 1.47-1.08 (m, 6H), 1.32
(2s, 2 × 1.5H), 1.05 (s, 9H), 0.92 and 0.90 (2d, J ) 6.6 Hz, 2 ×
1.5H); 13C NMR δ 135.5 (d, 4C), 133.9 (s, 2C), 129.4 (d, 2C),
127.4 (d, 4C), 102.1 (s), 81.0 (d), 74.8 (s), 69.0 (t), 68.7 and
68.6 (t), 38.1 (t), 35.5 and 35.4 (d), 33.7 (t), 33.0 (t), 26.7 (q,
6.3 Hz, 1H), 3.55-3.40 (m, 3H), 3.39 (s, 3H), 2.48 (s, 1H), 1.79-
1.11 (m, 7H), 1.19 (s, 3H), 1.06 (s, 9H), 0.93 (d, J ) 6.6 Hz,
3H); 13C NMR δ 138.4 (s), 135.5 (d, 4C), 134.0 (s, 2C), 129.3
(d, 2C), 128.2 (d, 2C), 127.7 (d, 2C), 127.6 (d), 127.4 (d, 4C),
96.6 (t), 85.7 (s), 84.0 and 83.9 (d), 73.8 and 73.7 (t), 68.8 and
68.7 (t), 68.1 (t), 55.3 (q), 38.3 and 38.2 (t), 35.7 and 35.6 (d),
33.7 (t), 26.8 (q, 3C), 23.2 and 23.1 (q), 20.5 and 20.4 (t), 19.2
(s), 16.7 and 16.6 (q); MS-EI m/z (rel intensity) 481 (1), 351
(22), 326 (17), 325 (60), 305 (10), 291 (16), 200 (16), 199 (85),
139 (23), 135 (51), 91 (100); HRMS (CI+, NH3) calcd for
C35H5405NSi (M + NH4+) 596.3771, found 596.3765. Anal.
Calcd for C35H50O5Si: C, 72.62; H, 8.71. Found: C, 72.58; H,
8.84.
Dimethyl 3-{(1S)-1-[(1R)-1-Benzyloxy-2-methoxymeth-
oxyethyl]-6-(tert-butyldiphenylsilanyloxy)-1,5-dimethyl-
hexyloxy}-2-oxopropylphosphonate (29). To a solution of
alcohol 28 (500 mg, 0.865 mmol) and rhodium acetate (38 mg,
86 µmol, 10 mol %) in refluxing toluene (5 mL) was added
dropwise, over a period of 2 h, a solution of ethyl diazoacetate
(1.82 mL, 17.3 mmol, 20 equiv) in toluene (40 mL). After
cooling to room temperature, the reaction mixture was filtered
through a short pad of Celite and concentrated under reduced
pressure. Purification by flash chromatography on silica gel
(petroleum ether/Et2O gradient: 90/10 to 60/40) afforded a
mixture of inseparable products (1.10 g), as a colorless oil, in
which the major component is ethyl {(1S)-1-[(1R)-1-benzyloxy-
2-methoxymethoxyethyl]-6-(tert-butyldiphenylsilanyloxy)-1,5-
dimethylhexyloxy}acetate. This ester was directly engaged in
the next step without further purification.
To a solution of methyldimethylphosphonate (290 µL, 2.66
mmol, 10.1 equiv) in anhydrous THF (4 mL) at -78 °C was
added a solution of n-BuLi (1.06 µL, 2.5 M in hexanes, 2.64
mmol, 10 equiv). After 30 min at -78 °C, a solution of the
crude ester (176 mg, 0.26 mmol, 1 equiv) in dry THF (2 mL)
was added via cannula to the solution of phosphonate anion
and the mixture was stirred for 1 h at -78 °C. The reaction
mixture was then poured into an aqueous solution of citric acid
(5%, 10 mL) and the aqueous layer was extracted with diethyl
ether (3 × 30 mL). The combined organic extracts were dried
over MgSO4, filtered, and concentrated in vacuo. Purification
by flash chromatography on silica gel (EtOAc) afforded 118
mg (60%) of phosphonate 29 as a colorless oil. [R]20 - 2.8 (c
D
1.0, CHCl3); IR (film) 1720, 1460, 1425, 1260, 1110, 1030, 740,
1
710, 700 cm-1; H NMR δ 7.69-7.61 (m, 4H), 7.45-7.22 (m,
11H), 4.87 (d syst AB, J ) 11.4 Hz, 1H), 4.65 (s, 2H), 4.54 (d
syst AB, J ) 11.4 Hz, 1H), 4.17-3.96 (m, 3H), 3.73 (m, 1H),
3.77 (s, 3H), 3.73 (s, 3H), 3.59 (dd, J ) 6.6 and 1.8 Hz, 1H),
3.53-3.39 (m, 2H), 3.37 (s, 3H), 3.18 (br d, JH-P ) 22.4 Hz,
2H), 1.77-1.18 (m, 7H), 1.16 (s, 3H), 1.05 (s, 9H), 0.89 (2d, J
) 6.6 Hz, 3H); 13C NMR δ 200.8 and 200.7 (s), 138.6 (s), 135.5
(d, 4C), 133.9 (s, 2C), 129.4 (d, 2C), 128.1 (d, 2C), 127.5 (d,
2C), 127.4 (d, 4C), 127.3 (d), 96.7 (t), 81.8 and 81.7 (d), 79.6
(s), 73.5 and 73.4 (t), 69.1 (t), 68.9 and 68.8 (t), 68.3 (t), 55.2
(q), 52.9 (q), 52.8 (q), 36.8 (t, JC-P ) 121.6 Hz), 35.9 (t), 35.6
and 35.5 (d), 33.5 (t), 26.8 (q, 3C), 20.4 and 20.3 (t), 19.2 (q),
18.8 (s), 16.6 and 16.5 (q); MS-CI+ (NH3) m/z (rel intensity)
760 (M + NH4+, 100), 184 (13); HRMS (CI+, NH3) calcd for (M
2106 J. Org. Chem., Vol. 70, No. 6, 2005

Total Synthesis of Natural Zoapatanol
3C), 23.5 (t), 20.8 and 20.7 (t), 19.2 (s), 18.2 (q), 16.8 and 16.7
(q); MS-EI m/z (rel intensity) 425 (M - t-Bu+, 1), 407 (M -
t-Bu - H2O+, 5), 329 (12), 317 (27), 253 (12), 207 (14), 200
(18), 199 (100), 193 (16), 181 (19), 139 (23), 135 (25), 109 (15),
107 (11), 93 (14), 81 (15), 69 (16), 55 (11).
concentrated under reduced pressure. Analysis of the 1H NMR
spectrum of the crude material indicated the formation of two
geometric isomers E/Z (70/30 ratio). After purification by flash
chromatography on silica gel (petroleum ether/Et2O 90/10),
0.24 g (97%) of a diastereomeric mixture E/Z (70/30) of
unsaturated esters was obtained as a colorless oil. This
mixture was dissolved in diethyl ether (4 mL) and the resulting
solution was added to a suspension of lithium aluminum
hydride (28 mg, 0.74 mmol, 2 equiv) in anhydrous diethyl ether
(3 mL), at 0 °C. After 5 min at 0 °C and 1 h at room
temperature, the reaction mixture was cooled to 0 °C and
treated successively with water (28 µL), then with a 15%
aqueous solution of NaOH (28 µL), and finally with water (84
µL). After 1 h of stirring at room temperature, the resulting
suspension was filtered through Celite. The insoluble salts
were washed with diethyl ether (2 × 15 mL) and the filtrate
was dried over MgSO4. After filtration and concentration under
reduced pressure, the crude material was purified by flash
chromatography (petroleum ether/Et2O gradient: 80/20 to 50/
50) to afford 140 mg (63%) of alcohol 35 and 59 mg (27%) of
its geometric isomer 35′, as colorless oils.
Major diastereomer 35: Rf 0.4 (petroleum ether/EtOAc 70/
30); [R]20D -4.0 (c 1.0, CHCl3); IR (film) 3380, 1470, 1460, 1425,
1390, 1110, 825, 740, 710, 700 cm-1; 1H NMR δ 7.69-7.63 (m,
4H), 7.44-7.22 (m, 11H), 5.44 (t, J ) 6.6 Hz, 1H), 4.61 (d syst
AB, J ) 11.6 Hz, 1H), 4.39 (d syst AB, J ) 11.6 Hz, 1H), 4.17
(d, J ) 6.6 Hz, 2H), 4.12 (d syst AB, J ) 14.3 Hz, 1H), 3.99 (d
syst AB, J ) 14.3 Hz, 1H), 3.54-3.39 (m, 2H), 3.29 (m, 1H),
2.55 (m, 1H), 2.13 (m, 1H), 1.93 (m, 1H), 1.83-1.10 (m, 9H),
1.16 (s, 3H), 1.05 (s, 9H), 0.92 (2d, J ) 6.8 Hz, 2 × 1.5H); 13C
NMR δ 142.9 (s), 138.5 (s), 135.5 (d, 4C), 134.0 (s, 2C), 129.3
(d, 3C), 128.2 (d, 3C), 127.5 (d), 127.4 (d, 4C), 123.5 (d), 84.6
and 84.5 (d), 79.9 (s), 71.7 (t), 68.9 (t), 68.6 (t), 58.7 (t), 39.6
(t), 35.7 and 35.6 (d), 33.7 (t), 26.8 (q, 3C), 26.5 (t), 24.1 (t),
20.6 and 20.5 (t), 19.2 (s), 17.7 and 17.6 (q), 16.8 (q); MS-EI
m/z (rel intensity) 435 (M - t-Bu - PhCH2OH+, 4), 267 (11),
201 (14), 200 (18), 199 (100), 139 (19), 135 (14), 109 (15), 93
(12), 81 (14), 55 (11). Anal. Calcd for C38H52O4Si: C, 75.95; H,
8.72. Found: C, 75.85; H, 8.89.
Ethyl {(4S,5R)-4-[5-(tert-Butyldiphenylsilanyloxy)-4-
methylpentyl]-4-methyl-3,8-dioxabicyclo[3.2.1]octan-1-
yl}acetate (34). To a solution of ethyl triethylphosphono-
acetate (17 µL, 86 µmol, 2.8 equiv) in anhydrous THF (0.5 mL)
at 0 °C was added dropwise a solution of KHMDS (0.34 mL,
0.5 M in toluene, 0.17 mmol, 5.5 equiv). After 5 min at 0 °C,
a solution of compound 32 (15 mg, 31 µmol, 1 equiv) in THF
(1 mL) was added and after 2 h of stirring at room tempera-
ture, the reaction mixture was heated overnight at 70 °C,
cooled to room temperature, hydrolyzed with water (1 mL),
and extracted with diethyl ether (3 × 5 mL). The combined
organic extracts were dried over MgSO4, filtered, and concen-
trated under reduced pressure. Purification by flash chroma-
tography on silica gel (petroleum ether/Et2O gradient 95/05
to 70/30) afforded 10 mg (60%) of 34 as a colorless oil. IR (film)
1
1730, 1460, 1425, 1370, 1265, 1110, 745, 710, 700 cm-1 ; H
NMR δ 7.69-7.62 (m, 4H), 7.46-7.32 (m, 6H), 4.15 (q, J )
3
7.3 Hz, 2H), 3.83 (d, J ) 6.6 Hz, 1H), 3.79 (d, J ) 11.0 Hz,
1H), 3.53-3.39 (m, 3H), 2.64 (d, J ) 14.5 Hz, 1H), 2.55 (d, J
) 14.5 Hz, 1H), 2.18-1.10 (m, 14H), 1.26 (s, 3H), 1.04 (s, 9H),
0.91 (m, 3H); 13C NMR δ 169.8 (s), 135.5 (d, 4C), 133.9 (s, 2C),
129.3 (d, 2C), 127.4 (d, 4C), 81.1 (d), 79.1 (s), 75.0 (s), 69.5 (t),
68.7 and 68.6 (t), 60.4 (t), 40.7 (t), 38.9 (t), 35.5 and 35.4 (d),
33.7 (t), 31.5 (t), 26.7 (q, 3C), 24.8 (t), 22.5 (t), 19.2 (s), 18.1
(q), 16.8 and 16.7 (q), 14.2 (q); MS-EI m/z (rel intensity) 446
(M - EtOAc - t-Bu+, 1), 222 (2), 177 (27), 176 (10), 150 (12),
149 (100).
(6R,7S)-6-Benzyloxy-7-[5-(tert-butyldiphenylsilanyloxy)-
4-methylpentyl]-7-methyloxepan-3-one (18). To a solution
of enone 31 (250 mg, 440 µmol) in absolute ethanol (15 mL)
was added Pd/C (47 mg, 10%, 44 µmol, 10% mol). The mixture
was stirred under 1 atm of hydrogen at room temperature and,
after 5 min (caution: the time is important), was filtered
through Celite (rinsing with Et2O). The filtrate was concen-
trated under reduced pressure and the crude material was
purified by flash chromatography (petroleum ether/Et2O 80/
Minor diastereomer 35′: Rf 0.45 (petroleum ether/EtOAc 70/
30); [R]20D -4.7 (c 1.0, CHCl3); IR (film) 3390, 1425, 1110, 740,
20) to give 245 mg (98%) of ketone 18 as a colorless oil. [R]20
710, 700 cm-1; H NMR δ 7.69-7.63 (m, 4H), 7.45-7.22 (m,
1
D
+5.6 (c 1.0, CHCl3); IR (film) 1715, 1460, 1425, 1265, 1105,
11H), 5.43 (t, J ) 6.6 Hz, 1H), 4.61 (d syst AB, J ) 11.7 Hz,
1H), 4.41 (d syst AB, J ) 11.7 Hz, 1H), 4.30 (d syst AB, J )
16.1 Hz, 1H), 4.20-4.00 (m, 2H), 4.13 (d syst AB, J ) 16.1
Hz, 1H), 3.54-3.39 (m, 2H), 3.27 (dd, J ) 9.5 and 3.5 Hz, 1H),
2.37 (m, 1H), 2.22 (m, 1H), 2.00 (m, 1H), 1.75-1.10 (m, 9H),
1
740, 710, 700 cm-1; H NMR δ 7.69-7.63 (m, 4H), 7.46-7.24
(m, 11H), 4.62 (d syst AB, J ) 11.4 Hz, 1H), 4.38 (d syst AB,
J ) 11.4 Hz, 1H), 4.13 (d syst AB, J ) 18.7 Hz, 1H), 3.94 (d
syst AB, J ) 18.7 Hz, 1H), 3.54-3.41 (m, 2H), 3.39 (dd, J )
8.8 and J ) 3.1 Hz, 1H), 2.69 (m, 1H), 2.54 (m, 1H), 2.09 (m,
1H), 1.85 (m, 1H), 1.72-1.18 (m, 7H), 1.15 (s, 3H), 1.05 (s, 9H),
0.92 (2d, J ) 6.6 Hz, 2 × 1.5H); 13C NMR δ 214.6 (s), 137.9
(s), 135.5 (d, 4C), 134.0 (s, 2C), 129.4 (d, 2C), 128.2 (d, 2C),
127.6 (d), 127.5 (d, 2C), 127.4 (d, 4C), 83.0 and 82.9 (d), 80.6
(s), 71.8 (t), 70.5 (t), 68.8 (t), 39.5 (t), 36.9 (t), 35.6 and 35.5
(d), 33.6 (t), 26.8 (q, 3C), 22.3 (t), 20.5 and 20.4 (t), 19.2 (s),
16.9 (q), 16.8 (q); MS-EI m/z (rel intensity) 515 (M - t-Bu+,
6), 347 (8), 255 (7), 207 (12), 200 (8), 199 (45), 139 (10), 135
(11), 109 (11), 91 (100). Anal. Calcd for C36H48O4Si: C, 75.48;
H, 8.45. Found: C, 75.32; H, 8.56.
2-{(E)-(6R,7S)-6-Benzyloxy-7-[5-(tert-butyldiphenyl-
silanyloxy)-4-methylpentyl]-7-methyloxepan-3-ylidene}-
ethanol (35) and 2-{(Z)-(6R,7S)-6-Benzyloxy-7-[5-(tert-
butyldiphenylsilanyloxy)-4-methylpentyl]-7-methyl-
oxepan-3-ylidene}ethanol (35′). To a solution of ethyl
triethylphosphonoacetate (0.77 mL, 3.85 mmol, 10.1 equiv) in
anhydrous THF (2 mL) at 0 °C was added dropwise a solution
of LiHMDS (3.85 mL, 1 M in THF, 3.85 mmol, 10 equiv). After
5 min at 0 °C, a solution of ketone 18 (0.22 g, 0.385 mmol, 1
equiv) in THF (7 mL) was added. After 1 h at 0 °C and 30 min
at room temperature, the reaction mixture was poured into a
saturated aqueous solution of NH4Cl (20 mL) and extracted
with diethyl ether (3 × 30 mL). The combined organic extracts
were washed with brine, dried over MgSO4, filtered, and
1.13 (s, 3H), 1.05 (s, 9H), 0.92 (2d, 3J ) 6.6 Hz, 2 × 1.5H); 13
C
NMR δ 144.3 (s), 138.6 (s), 135.5 (d, 4C), 134.0 (s, 2C), 129.3
(d, 3C), 128.1 (d, 3C), 127.4 (d, 4C), 127.3 (d), 122.3 (d), 84.3
and 84.2 (d), 80.2 (s), 71.7 (t), 68.9 (t), 62.2 (t), 58.2 (t), 39.7
(t), 35.7 and 35.6 (d), 33.7 (t), 31.3 (t), 28.1 (t), 26.8 (q, 3C),
20.4 (t), 19.2 (s), 16.9 (2q, 2C); MS-EI m/z (rel intensity) 435
(M - t-Bu - PhCH2OH+, 4), 417 (3), 267 (12), 201 (15), 200
(19), 199 (100), 139 (19), 135 (14), 121 (11), 109 (15), 93 (13),
81 (16), 55 (12).
E-{5-[(2S,3R)-3-Benzyloxy-6-(2-benzyloxyethylidene)-
2-methyloxepan-2-yl]-2-methylpentyloxy}-tert-butyldi-
phenylsilane (36). To a solution of alcohol 35 (186 mg, 0.310
mmol) in anhydrous CH2Cl2 (7 mL) were successively added
at room temperature benzyl bromide (41 µL, 0.34 mmol, 1.1
equiv), n-Bu4NI (57 mg, 0.15 mmol, 0.5 equiv), and freshly
prepared silver oxide (79 mg, 0.34 mmol, 1.1 equiv).36 After
18 h of stirring at room temperature, the reaction mixture was
filtered through Celite and concentrated under reduced pres-
sure. Purification of the crude material by flash chromatog-
raphy on silica gel (pentane/Et2O: 80/20) afforded 209 mg (98%)
of dibenzylated compound 36 as a colorless oil. [R]20 -2.3 (c
D
1.02, CHCl3); IR (film) 1450, 1425, 1105, 1070, 740, 710, 700
cm-1 ; 1H NMR δ 7.71-7.65 (m, 4H), 7.47-7.24 (m, 16H), 5.48
(t, J ) 6.3 Hz, 1H), 4.62 (d syst AB, J ) 11.8 Hz, 1H), 4.53 (s,
2H), 4.41 (d syst AB, J ) 11.8 Hz, 1H), 4.16 (d syst AB, J )
J. Org. Chem, Vol. 70, No. 6, 2005 2107

Taillier et al.
14.3 Hz, 1H), 4.07 (d, J ) 6.3 Hz, 2H), 4.05 (d syst AB, J )
14.3 Hz, 1H), 3.56-3.40 (m, 2H), 3.30 (br d, J ) 9.1 Hz, 1H),
2.53 (m, 1H), 2.18-1.10 (m, 10H), 1.17 (s, 3H), 1.07 (s, 9H),
0.94 and 0.93 (2d, J ) 6.6 Hz, 2 × 1.5H); 13C NMR δ 143.8 (s),
138.6 (s), 138.2 (s), 135.5 (d, 6C), 134.0 (s), 129.3 (d, 2C), 128,2
(d, 2C), 128.1 (d, 2C), 127.6 (d, 2C), 127.4 (d, 6C), 127.3 (s),
120.9 (d), 84.7 and 84.6 (d), 79.8 (s), 72.1 (t), 71.7 (t), 68.9 (t),
68.6 (t), 65.9 (t), 39.7 (t), 35.7 and 35.6 (d), 33.7 (t), 26.8 (q,
3C), 26.6 (t), 24.3 (t), 20.5 and 20.4 (t), 19.2 (s), 17.6 and 17.5
(q), 16.8 (q). Anal. Calcd for C45H58O4Si: C, 78.21; H, 8.46.
Found: C, 78.19; H, 8.59.
E-5-[3-(2S,3R)-Benzyloxy-6-(2-benzyloxyethylidene)-2-
methyloxepan-2-yl]-N-methoxy-2,N-dimethylpentan-
amide (37). To a solution of compound 36 (100 mg, 144 µmol)
in anhydrous THF (10 mL) at 0 °C was added a solution of
TBAF (0.58 mL, mol‚L-1 in THF, 0.58 mmol, 2 equiv). After
30 min at 0 °C and 16 h at room temperature, the reaction
mixture was hydrolyzed with a saturated aqueous solution of
NH4Cl (10 mL) and extracted with diethyl ether (3 × 20 mL).
The combined organic extracts were dried over MgSO4 and
filtered. After concentration under reduced pressure, 276 mg
of crude alcohol was obtained as a colorless oil, which was
directly oxidized to the corresponding carboxylic acid.
To prepare a solution of Jones reagent, concentrated sulfuric
acid (0.21 mL, 37%) was added to CrO3 (274 mg, 2.74 mmol).
The resulting mixture was stirred at room temperature and
the volume of the solution was completed to 2 mL by addition
of water (Caution: exothermic). The solution of Jones reagent
(110 µL) was then added to a solution of crude alcohol (144
µmol) in acetone (5 mL) at 0 °C. After 30 min of stirring at 0
°C, 2-propanol (0.4 mL) and water (2 mL) were added and the
mixture was stirred 1 h at room temperature. Acetone was
evaporated under reduced pressure and the resulting aqueous
layer was extracted with EtOAc (3 × 30 mL). The combined
organic extracts were dried over MgSO4 and filtered. After
concentration under reduced pressure, 134 mg of crude acid
was obtained as a colorless oil, which was directly transformed
to the corresponding Weinreb amide.
To a solution of crude acid (144 µmol) in anhydrous CH2Cl2
(2 mL) were added N,O-dimethylhydroxylamine hydrochloride
(22 mg, 0.022 mmol, 1.5 equiv) and DMAP (4.0 mg, 28 µmol,
20% mol). After complete dissolution, the solution was cooled
to 0 °C and diisopropylamine (38 µL, 0.022 mmol, 1.5 equiv)
and EDCI (42 mg, 0.022 mmol, 1.5 equiv) were added. After
30 min of stirring at 0 °C and 16 h at room temperature, the
reaction mixture was washed with a saturated aqueous
solution of NaHCO3. The aqueous layer was extracted with
EtOAc (3 × 30 mL) and the combined organic extracts were
washed with water, dried over MgSO4, filtered, and concen-
trated under reduced pressure. The crude material was
purified by flash chromatography (CH2Cl2/EtOAc: 90/10) to
give 44 mg (60%, 3 steps) of Weinreb amide 37 as an oil. IR
(film) 1725, 1665, 1465, 1455, 1110, 1070, 740, 700 cm-1; 1H δ
7.38-7.25 (m, 10H), 5.46 (t, J ) 6.6 Hz, 1H), 4.61 (dd, Jsyst AB
) 11.8 Hz, J ) 1.1 Hz, 1H), 4.51 (s, 2H), 4.40 (d syst AB, J )
11.8 Hz, 1H), 4.15 (d syst AB, J ) 14.3 Hz, 1H), 4.06 (d, J )
6.3 Hz, 2H), 4.04 (d syst AB, J ) 14.3 Hz, 1H), 3.67 and 3.65
(2s, 2 × 1.5H), 3.30 and 3.27 (2t, J ) 2.9 Hz, 2 × 0.5H), 3.18
(2s, 2 × 1.5H), 2.87 (m, 1H), 2.52 (m, 1H), 2.18-1.19 (m, 9H),
1.17 and 1.16 (2s, 3H), 1.11 (d, J ) 6.6 Hz, 3H); 13C NMR δ (s,
CdO, not detected), 143.7 and 143.6 (s), 138.5 and 138.4 (s),
138.1 (s), 128,2 (d, 2C), 128.1 (d, 2C), 127.6 (d, 2C), 127.5 (d,
2C), 127.4 (d), 127.3 (d), 121.0 (d), 84.7 (d), 79.7 (s), 72.1 (t),
71.7 and 71.6 (t), 68.6 (t), 65.8 (t), 61.3 (q), 39.3 and 39.2 (t),
35.1 and 34.9 (d), 34.2 and 34.1 (t), 32.1 (q), 26.5 (t), 24.3 (t),
21.1 and 20.9 (t), 17.5 and 17.4 (q), 17.3 and 17.2 (q); MS-CI+
(NH3) m/z (rel intensity) 527 (M + NH4+, 100), 437 (15), 202
(37), 182 (16), 141 (19), 124 (30), 106 (45); HRMS (CI+, NH3)
calcd for C31H4705N2 (M + NH4+) 527.3485, found 527.3488.
(+)-(2′S,3′R)-Zoapatanol (1).4b,e,5,7 To a solution of phenyl
prenyl ether (162 mg, 1.00 mmol, 20 equiv) in a mixture of
anhydrous diethyl ether and tetrahydrofuran (1/1, 2 mL) was
added lithium (235 mg, 34 mmol) portionwise. A few drops of
anhydrous methanol were first added to clean the surface of
lithium. The mixture was then vigorously stirred at room
temperature until the solution turned yellow. The reaction
mixture was then cooled to 15 °C and stirring was continued
for 2 h at 15 °C. The supernatant solution of organolithium
reagent was then added via cannula to a solution of the
Weinreb amide 37 (25 mg, 49 µmol, 1 equiv) in dry THF (1
mL) at -78 °C. After 10 min at -78 °C (conversion of 37 was
monitored by TLC), the reaction mixture was added dropwise
to a solution of lithium (108 mg, 15.6 mmol) in ammoniac (ca.
20 mL) at -78 °C, in the presence of a mixture of tert-butyl
alcohol and tetrahydrofuran (1/4, 0.5 mL). After 5 min at -78
°C, solid NH4Cl was added portionwise until complete dispari-
tion of the dark blue color. The reaction mixture was then
diluted with diethyl ether (10 mL) and ammonia was evapo-
rated. Water (10 mL) was further added and the aqueous layer
was extracted with diethyl ether (3 × 15 mL). The combined
organic extracts were dried over MgSO4, filtered, and concen-
trated in vacuo. The crude residue was purified by flash
chromatography on silica gel (EtOAc) and zoapatanol 1 (11
mg, 33 µmol, 66%) was isolated as a colorless oil. Physical and
spectral data match those previously reported in the literature.
Rf 0.6 (EtOAc); [R]20D +4.16 (c 0.31, CHCl3) {lit.5 [R]20D +12.00
(c 0.31, CHCl3)};37 IR (film) 3390 (br), 1707, 1450, 1375, 1100,
1
1060, 1025, 740 cm-1; H NMR δ 5.47 (br t, J ) 7.0 Hz, 1H),
5.30 (br t, J ) 7.0 Hz, 1H), 4.20 (d, J ) 7.0 Hz, 2H), 4.13 (br
s, 2H), 3.55 (m, 1H), 3.16 (d, J ) 7.0 Hz, 2H), 2.59 (q, J ) 7.0
Hz, 1H), 2.48 (m, 1H), 2.23 (m, 1H), 1.73 (br s, 3H), 1.63
(apparent s, 3H), 1.85-1.20 (m, 10H), 1.16 and 1.15 (2s, 2 ×
1.5H), 1.09 (d, J ) 7.0 Hz, 3H); 13C NMR δ 213.1 (s), 143.3 (s),
135.4 (s), 123.1 (d), 115.9 (d), 79.7 (s), 76.3 and 76.1 (d), 69.1
(t), 58.6 (t), 45.7 (d), 40.8 and 40.7 (t), 38.0 and 37.9 (t), 33.3
(t), 31.5 (t), 25.6 (q), 23.3 and 23.2 (t), 20.9 and 20.8 (t), 18.3
(q), 18.0 (q), 16.5 (q); MS-CI+ (NH3) m/z (%) 356 (M + NH4
,
+
100), 341 (8), 321 (9), 274 (7), 228 (10), 124 (7); HRMS (CI+,
NH3) calcd for C20H38O4N (M + NH4+) 356.2801, found
356.2806.
Acknowledgment. C.T. thanks the MRES for a
grant.
Supporting Information Available: Tables of compari-
son of the NMR data of synthetic zoapatanol 1 with those
reported in the literature; copies of the NMR spectra of
compounds 6, 7, 9, 10, 11, 13, 15, 16, 20, 32, 34, 35′, 37, and
zoapatanol 1. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO048115Z
(37) The comparison of the obtained [R]20 value with the optical
D
rotation of the natural zoapatanol is not possible since the latter has
never been published.
2108 J. Org. Chem., Vol. 70, No. 6, 2005