Total synthesis of (-)-verrucarol

Article abstract of DOI:10.1021/jo972309f

We have achieved the total synthesis of (-)-verrucarol, a trichothecene sesquiterpenoid obtained as a hydrolysis product of the naturally occurring verrucarin A. Our total synthesis began with the previously reported enantiometrically pure bicyclic α-methylated γ-lactone, which was prepared from D-glucose. The key steps for the total synthesis were (1) aldol-like carbon-carbon bond formation applied to the starting lactone using a four- carbon aldehyde as an electrophile for introduction of the quaternary stereogenic carbon sharing the B and C-rings of the trichothecene skeleton, (2) Dieckmann cyclization of the derived ε-ester lactone for construction of the C-ring equivalent, (3) Barton's decarboxylative oxygenation for conversion of a carboxylic acid functionality in the Dieckmann cyclization product into a hydroxyl group, (4) skeletal enlargement strategy for the crucial trichothecene skeleton construction, and (5) the final stereoselective formation of the exo-epoxy ring at the methylene carbon in the bridge constituting the B and C-rings.

Full text of DOI:10.1021/jo972309f

J . Org. Chem. 1998, 63, 2679-2688
2679
Tota l Syn th esis of (-)-Ver r u ca r ol1
J un Ishihara,2 Rie Nonaka, Yuki Terasawa, Ryota Shiraki, Kazuo Yabu, Hiromi Kataoka,
Yuichi Ochiai, and Kin-ichi Tadano*
Department of Applied Chemistry, Keio University, Hiyoshi, Kohoku-ku, Yokohama 223, J apan
Received December 23, 1997
We have achieved the total synthesis of (-)-verrucarol, a trichothecene sesquiterpenoid obtained
as a hydrolysis product of the naturally occurring verrucarin A. Our total synthesis began with
the previously reported enantiomerically pure bicyclic R-methylated γ-lactone, which was prepared
from D-glucose. The key steps for the total synthesis were (1) aldol-like carbon-carbon bond
formation applied to the starting lactone using a four-carbon aldehyde as an electrophile for
introduction of the quaternary stereogenic carbon sharing the B and C-rings of the trichothecene
skeleton, (2) Dieckmann cyclization of the derived ꢀ-ester lactone for construction of the C-ring
equivalent, (3) Barton’s decarboxylative oxygenation for conversion of a carboxylic acid functionality
in the Dieckmann cyclization product into a hydroxyl group, (4) skeletal enlargement strategy for
the crucial trichothecene skeleton construction, and (5) the final stereoselective formation of the
exo-epoxy ring at the methylene carbon in the bridge constituting the B and C-rings.
In tr od u ction
The trichothecenes are a family of structurally related
sesquiterpenoids isolated from various species of fungi.3-8
The biogenetical origin of these sesquiterpenes is as-
sumed to be trans,cis-farnesol, which is transformed into
a bisabolane, then into a cuparane nucleus, and finally
into a trichothecane skeleton.9,10 Since the isolation of
trichothecin (1) (Figure 1), the first natural product of
the trichothecenes, by Freeman and Morrison in 1948
from the fungus Trichothecium roseum,11,12 numerous
trichothecenes have been isolated from various sources.
A large number of the trichothecenes comprise a common
2-oxatricyclo[7.2.1.03.8]dodec-4-ene core structure (the
A/B/C-ring system) represented by 1, trichodermin (2),
and its alkaline hydrolysis product trichodermol (roridin
C) (3).13,14 However, some trichothecenes lacking this
tricyclic framework such as trichodiene (4), the biogenetic
precursor of the trichothecenes, were found in nature.15,16
In some cases, the hydroxyl group(s) in the core tricyclic
(1) This paper is dedicated to Professor Dieter Seebach on the
occasion of his 60th birthday.
(2) Present address: Division of Chemistry, Graduate School of
Science, Hokkaido University, Sapporo J apan.
(3) Tamm, Ch. Fortschr. Chem. Org. Naturst. 1974, 31, 63.
(4) Tamm, C.; Breitenstein, W. In The Biosynthesis of Mycotoxin-A
Study in Secondary Metabolites; Steyn, J . P., Ed.; Academic Press:
London, 1980; p 69.
(5) Doyle, T. W.; Bradner, W. T. In Anticancer Agents Based on
Natural Product Models; Cassady, J . M., Douros, J . D., Eds.; Academic
Press: New York: 1980; p. 43.
(6) J arvis, B. B.; Mazzola, E. P. Acc. Chem. Res. 1982, 15, 388.
(7) Ueno, Y. Trichothecenes-Chemical, Biological and Toxicological
Aspects, Developments in Food Science-4; Elsevier: New York 1983.
(8) Grove, J . F. Nat. Prod. Rep. 1988, 5, 187.
F igu r e 1.
framework are esterified or macrolactonized.4,6,8,17,18 In
general, the trichothecenes possess an exo-epoxy ring at
the methylene bridge constituting the B- and C-rings.
Other naturally occurring representative trichothecenes,
calonectrin (5),19 anguidine (diacetoxyscirpenol) (6),20,21
(9) Devon, T. K.; Scott, A. I. In Handbook of Naturally Occurring
Compounds; Academic Press: New York 1972; Vol. II, p 55.
(10) (a) Achilladilis, B. A.; Adams, P. M.; Hanson, J . R. J . Chem.
Soc., Perkin Trans.1 1972, 1425. (b) Machida, Y.; Nozoe, S. Tetrahedron
1972, 28, 5113.
(11) Freeman, G. G.; Morrison, R. I. Nature 1948, 162, 30.
(12) Fishman, J .; J ones, E. R. H.; Lowe, G.; Whiting, M. C. J . Chem.
Soc. 1960, 3948.
(13) Godtfredsen, W. O.; Vangedal, S. Proc. Chem. Soc., London
1964, 188.
(14) Abrahamsson, S.; Nilsson, B. J . Chem. Soc., London 1964, 188.;
Acta Chim. Scand. 1966, 20, 1044.
(15) Nozoe, S.; Machida, Y. Tetrahedron Lett. 1970, 2671; Tetrahe-
dron 1972, 28, 5105.
(16) Hesketh, A. R.; Gledhill, L.; Bycroft, B. W.; Dewick, P. M.;
Gilbert, J . Phytochemistry 1993, 32, 93 and references therein.
(17) Roberts, J . S.; Bryson, I. Nat. Prod. Rep. 1984, 1, 115.
S0022-3263(97)02309-8 CCC: $15.00 © 1998 American Chemical Society
Published on Web 04/01/1998

2680 J . Org. Chem., Vol. 63, No. 8, 1998
Ishihara et al.
and verrucarol (7),22 are shown in Figure 1, and these
natural products differ from each other in the oxidation
levels and/or positions of the substituents in the C-ring.
In addition to these structural characteristics, many of
the trichothecenes exhibit significant biological activities
such as antifungal, antibacterial, antiviral, antitumor,
and insecticidal properties.5,7 The biological importance
and structural uniqueness of the trichothecenes have
rendered these sesquiterpenoids attractive and challeng-
ing synthetic targets for 30 years.23 Total syntheses of
2,24 3,25 and 426 were achieved early in the history of the
trichothecene synthesis. In the early 1980s, total (formal)
syntheses of more oxygenated trichothecenes such as 5,27
6,28 and 729 were accomplished. A number of synthetic
efforts for the trichothecene family have been also
disclosed so far.30 Most of the previous total syntheses
and synthetic efforts of the trichothecene family were
carried out in racemic forms; however, a few enantiose-
lective approaches were also explored.31 Furthermore,
some synthetic routes to the tether parts (the macrodi-
lactone part) of the macrocyclic trichothecenes were also
investigated.32 We describe herein our total synthesis
of the naturally derived (-)-verrucarol (7) in detail.33 The
target compound 7 was isolated as an alkaline hydrolysis
product of the macrocyclic trichothecene, varrucarrin A
(8), by Tamm and co-workers in 1962.34,35 The structure
of 8 was determined on the basis of spectroscopic analy-
sis, and its absolute stereochemistry (thence that of 7)
was later confirmed by X-ray crystallography of the
p-iodobenzenesulfonate ester of 8.36 The enantioselective
total synthesis of 7 has not been reported hitherto.
Our total synthesis of 7 started with the previously
reported enantiomerically pure R-methylated bicyclic
γ-lactone 10,37 which was prepared from the highly
functionalized tetrahydrofuran derivative 9 (eq 1).38-40
Our retrosynthetic analysis for 7 from 10 is illustrated
in Scheme 1. In the later stage of the total synthesis,
the exo-epoxide part in 7 would be introduced via the
hydroxyl-directed stereoselective epoxidation of a par-
tially protected trichothecene A. The exo-methylene
derivative A could be obtained by methylenation of a
tricyclic ketone B. For construction of the trichothecene
skeleton consisting in B, we envisaged the base-mediated
ring-enlargement strategy applied to a 6,5,5-membered
intermediate C, which possesses a leaving group (X such
as a mesyloxy) and a vicinal hemiketal hydroxyl group.
(30) Some representative articles on this subject: (a) Welch, S. C.;
Wong, R. Y. Tetrahedron Lett. 1972, 1855. (b) Yamakawa, K.; Kurita,
J .; Sakaguchi, R. Tetrahedron Lett. 1973, 3877. (c) Goldsmith, D. J .;
Lewis, A. J .; Still, W. C., J r. Tetrahedron Lett. 1973, 4807. (d) Masuoka,
N.; Kamikawa, T.; Kubota, T. Chem. Lett. 1974, 751. (e) Fujimoto, Y.;
Yokura, S.; Nakamura, T.; Morikawa, T.; Tatsuno, T. Tetrahedron Lett.
1974, 2523. (f) Masuoka, N.; Kamikawa, T. Tetrahedron Lett. 1976,
1691. (g) Yamakawa, K.; Sakaguchi, R.; Nakamura, T.; Watanabe, K.
Chem. Lett. 1976, 991. (h) Colvin, E. W.; Malchenko, S.; Raphael, R.
A.; Roberts, J . S. J . Chem. Soc., Perkin Trans. 1, 1978, 658. (i)
Nakahara, Y.; Tatsuno, T. Chem. Pharm. Bull. 1980, 28, 1981. (j)
Goldsmith, D. J .; J ohn, T. K.; Kwong, C. D.; Painter, G. R. J . Org.
Chem. 1980, 45, 3989. (k) Kraus, G. A.; Frazier, K. J . Org. Chem. 1980,
45, 4820. (m) Kraus, G. A.; Roth, B. J . Org. Chem. 1980, 45, 4825. (n)
White, J . D.; Matsui, T.; Thomas, J . A. J . Org. Chem. 1981, 46, 3376.
(o) Pearson, A. J .; Ong, C. W. J . Am. Chem. Soc. 1981, 103, 6686. (p)
Ziegler, F. E.; Nangia, A.; Schulte, G. J . Am. Chem. Soc. 1987, 109,
3987. (q) Colvin, E. W.; Egan, M. J .; Kerr, F. W. J . Chem. Soc., Chem.
Commun. 1990, 1200. (r) Ziegler, F. E.; Sobolov, S. B. J . Am. Chem.
Soc. 1990, 112, 2749. (s) Nemoto, H.; Miyata, J . Fukumoto, K.
Hetereocycles, 1996, 42, 165. (t) Nemoto, H.; Miyata, J . Fukumoto, K.
Tetrahedron, 1996, 52, 10363. (u) Nemoto, H.; Miyata, J . Fukumoto,
K. Hetereocycles, 1997, 44, 125.
(31) (a) Hua, D. H.; Venkataraman, S.; Chan-Yu-King, R.; Pauks-
telis, J . V. J . Am. Chem. Soc. 1988, 110, 4741. (b) Gilbert, J . C.; Selliah,
R. D. Tetrahedron Lett. 1992, 33, 6259. (c) Ferrier, R. J .; Hall, D. W.;
Petersen, P. M. Carbohydr. Res. 1993, 239, 143. See also, refs 26o,
27b, 28a, and 28b.
(32) (a) Tulshian, D. B.; Fraser-Reid, B. Tetrahedron Lett. 1980, 21,
4549. (b) Tulshian, D. B.; Fraser-Reid, B. J . Am. Chem. Soc. 1981,
103, 474. (c) Still, W. C.; Ohmizu, H. J . Org. Chem. 1981, 46, 5244. (d)
Esmond, R.; Fraser-Reid, B.; J arvis, B. B. J . Org. Chem. 1982, 47, 3360.
(33) The present total synthesis of (-)-verrucarol was published
preliminarily: Ishihara, J .; Nonaka, R.; Terasawa, Y.; Shiraki, R.;
Yabu, K.; Kataoka, H.; Ochiai, Y.; Tadano, K. Tetrahedron Lett. 1997,
38, 8311.
(18) Sugawara, T.; Tanaka, A.; Nagai, K.; Suzuki, K.; Okada, G. J .
Antibiot. 1997, 50, 778.
(19) Gardner, D.; Glen, A. T.; Turner, W. B. J . Chem. Soc., Perkin
Trans.1 1972, 2576.
(20) Sigg, H. P.; Mauli, R.; Flury, E.; Hauser, D. Helv. Chim. Acta
1965, 48, 962.
(21) Dawkins, A. W. J . Chem. Soc. (C) 1966, 116.
(22) Gutzwiller, J .; Mauli, R.; Sigg, H. P.; Tamm, Ch. Helv. Chim.
Acta 1964, 47, 2234.
(23) Leading reviews on this subject: Tori, M. J . Synth. Org. Chem.
J pn. 1981, 39, 642. Heathcock, C. H.; Graham, S. L.; Pirrung, M. C.;
Plavac, F.; White, C. T. In The Total Synthesis of Natural Products;
ApSimon, J ., Ed.; J ohn Wiley and Sons: New York, 1983; Vol. 5, pp
238. McDougal, P. G.; Schmuff, N. R. Prog. Chem. Org. Nat. Prod. 1985,
47, 153.
(24) (a) Colvin, E. W.; Raphael, R. A.; Roberts, J . S. Chem. Commun.
1971, 858. (b) Colvin, E. W.; Malchenko, S.; Raphael, R. A.; Roberts,
J . S. J . Chem. Soc., Perkin Trans. 1, 1973, 1989.
(25) (a) Still, W. C.; Tsai, M.-Y. J . Am. Chem. Soc. 1980, 102 , 3654.
(b) O’Brien, M. K.; Pearson, A. J .; Pinkerton, A. A.; Schmidt, W.;
Willman, K. J . Am. Chem. Soc. 1989, 111, 1499. See also ref 26l.
(26) (a) Welch, S. C.; Prakasa Rao, A. S. C.; Gibbs, C. G.; Wong, R.
Y. J . Org. Chem. 1980, 45, 4077. (b) Suda, M. Tetrahedron Lett. 1982,
23, 427. (c) Schlessinger, R. H.; Schultz, J . A. J . Org. Chem. 1983, 48,
407. (d) Harding, K. E.; Clement, K. S. J . Org. Chem. 1984, 49, 3871.
(e) Gilbert, J . C.; Wiechman, B. E. J . Org. Chem. 1986, 51, 258. (f)
Gilbert, J . C.; Kelly, T. A. J . Org. Chem. 1986, 51, 4485. (g) Kraus, G.
A.; Thomas, P. J . J . Org. Chem. 1986, 51, 503. (h) VanMiddlesworth
F. L. J . Org. Chem. 1986, 51, 5019. (i) Pearson, A. J .; O’Brien, M. K.
J . Chem. Soc., Chem. Commun. 1987, 1445. (j) Snowden, R. L.;
Brauchli, R.; Sonnay, P. Helv. Chim. Acta 1989, 72, 570. (k) Gilbert,
J . C.; Kelly, T. A. Tetrahedron Lett. 1989, 30, 4193. (l) Pearson, A. J .;
O’Brien, M. K. J . Org. Chem. 1989, 54, 4663. (m) Harding, K. E.;
Clement, K. S.; Tseng, C.-Y. J . Org. Chem. 1990, 55, 4403. (n) Tanaka,
M.; Sakai, K. Tetrahedron Lett. 1991, 32, 5581. (o) Gilbert, J . C.;
Selliah, R. D. J . Org. Chem. 1993, 58, 6255.
(34) Ha¨rri, E.; Loeffler, W.; Sigg, H. P.; Sta¨helin, H.; Stoll, Ch.;
Tamm, Ch.; Wiesinger, D. Helv. Chim. Acta 1962, 45, 839.
(35) Tamm, Ch.; Gutzwiller, J . Helv. Chim. Acta 1962, 45, 1726.
(36) McPhail, A. T.; Sim, G. A. Chem. Commun. 1965, 350; J . Chem.
Soc. (C) 1966, 1394.
(37) Ishihara, J .; Nonaka, R.; Terasawa, Y.; Tadano, K.; Ogawa,
S.Tetrahedron: Asymmetry 1994, 5, 2217.
(38) The starting compound 10 was prepared from 9 in overall yields
of 10-15% in 19 steps. Compound 939 was prepared from commercially
available 1,2:5,6-di-O-isopropylidene-R-D-glucofuranose (“diacetone glu-
cose”) in an overall yield of 38% in four steps.
(39) Tadano, K.; Idogaki, Y.; Yamada, H.; Suami, T. J . Org. Chem.
1987, 52, 1201.
(27) (a) Kraus, G. A.; Roth, B.; Frazier, K.; Shimagaki, M. J . Am.
Chem. Soc. 1982, 104, 1114. (b) Tomioka, K.; Sugimori, M.; Koga, K.
Chem. Pharm. Bull. 1987, 35, 906.
(28) (a) Brooks, D. W.; Grothaus, P. G.; Palmer, J . T. J . Org. Chem.
1982, 47, 2820; Idem, Tetrahedron Lett. 1982, 23, 4187. (b) Brooks, D.
W.; Grothaus, P. G.; Mazdiyasni, H. J . Am. Chem. Soc. 1983, 105, 4472.
(29) (a) Schlessinger, R. H.; Nugent, R. A. J . Am. Chem. Soc. 1982,
104, 1116. (b) Trost, B. M.; Rigby, J . H. J . Org. Chem. 1978, 43, 2938.
(c) Trost, B. M.; McDougal, P. G. J . Am. Chem. Soc. 1982, 104, 6110.
(d) Trost, B. M.; McDougal, P. G.; Haller, K. J . J . Am. Chem. Soc. 1984,
106, 383. (e) Roush, W. R.; D'Ambra, T. E. J . Org. Chem. 1980, 45,
3929. (f) Idem, J . Org. Chem. 1981, 46, 5045. (g) Idem, J . Am. Chem.
Soc. 1983, 105, 1058. (h) Koreeda, M.; Ricca, D. J .; Luengo, J . I. J .
Org. Chem. 1988, 53, 5586.
(40) The utility of 9 as an enantiomerically pure starting material
for natural products synthesis, see: Takao, K.; Ochiai, H.; Yoshida,
K.; Hashizuka, T.; Koshimura, H.; Tadano, K.; Ogawa, S. J . Org. Chem.
1995, 60, 8179, and references therein.

Total Synthesis of (-)-Verrucarol
J . Org. Chem., Vol. 63, No. 8, 1998 2681
Sch em e 1
Sch em e 2
as depicted at a later stage. Both adducts were diaster-
eomers relative to the stereogenic carbinol carbon in each
side chain. As anticipated, the aldehyde attacked exclu-
sively from the less sterically congested convex-face of
the enolate generated from 10. Discouragingly, we could
not improve the stereoselectivity in the formation of the
desired 11â after extensive examinations using a variety
of bases and solvents. Lithium or potassium bis(trim-
ethylsilyl)amide (LiHMDS or KHMDS) did not give any
aldol adducts. Addition of HMPA to the LDA-mediated
conditions (HMPA:THF ) 1:10) did not effect the reaction
and 10 was recovered intact. We expected the stereo-
chemical bias in this aldol-like carbon-carbon bond
formation, which may arise from the chelation-controlled
transition state between the enolate oxygen and the
aldehyde carbonyl or between the aldehyde carbonyl and
one of the (methoxy)methoxy oxygens. These factors may
work to some extent for the stereoselective introduction
of the stereogenic carbinol center. Meanwhile, we ex-
amined the stereochemical inversion of 11R into 11â by
an oxidation-reduction strategy. To our delight, sodium
borohydride reduction of 12, prepared from 11R (PCC),
afforded a mixture of 11â and 11R with predominant
formation of the desired former (74% yield of 11â and
13% of 11R).
Next, our synthetic effort was directed to the construc-
tion of the C-ring equivalent via the Dieckmann cycliza-
tion of ester-lactone such as 17 (E in Scheme 1, P )
MOM). Thus, the side chain in the aldol adduct 11â was
modified as follows (Scheme 3). Desilylation of 11â with
tetrabutylammonium fluoride (TBAF) (81%) followed by
selective acylation of the resulting diol 13 with pivaloyl
chloride (PivCl) provided mono ester 14 (87%). The
secondary hydroxyl group in 14 was protected as the
methoxymethyl (MOM) ether, giving 15 (83%). On the
other hand, O-alkylation of 11â with MOMCl proceeded
quite slowly, and the corresponding MOM ether was
obtained less effectively. Deacylation of 15 and succes-
sive J ones’ oxidation of the primary hydroxyl group in
the resulting 16 afforded carboxylic acid, which im-
mediately was esterified with CH2N2 to give the substrate
17 for the Dieckmann cyclization (72%). As we had
experienced in our previous model studies,37 potassium
bis(trimethylsilyl)amide (KHMDS) was the best base of
choice for the Dieckmann cyclization. In the presence of
A similar skeletal rearrangement protocol was initially
disclosed by Trost and McDougal in their racemic ver-
rucarol synthesis.29d For the preparation of the tricyclic
intermediate C, we expected that the Barton methodol-
ogy41 could be workable for a cyclopentyl carboxylic ester
D (a synthetic equivalent to the C-ring). Namely,
transformation of the ester functionality in D by means
of the radically induced decarboxylative oxygenation
would provide a hydroxyl group, which in turn is con-
vertible to a leaving group. This intermediate D could
be prepared by the Dieckmann cyclization of a bicyclic
lactone E carrying a four-carbon γ-hydroxy ester tether.
The intermediate E might be obtained via the aldol
reaction of the starting compound 10 coupled with a
protected 4-hydroxybutanal, which follows by function-
alization of the introduced side chain.
Resu lts a n d Discu ssion
We had previously found that the alkylation of 10 with
allyl bromide proceeded with complete stereoselectivity,
affording a single alkylation product in which the allyl
group is disposed at the less sterically congested R-side.37
Being encouraged by this observation, we executed the
aldol-like reaction of the enolate generated from 10 with
4-(tert-butyldiphenylsilyloxy)butanal.42 The introduction
of the four-carbon side chain at the R-carbon of the
γ-lactone 10 was best achieved by deprotonation with
lithium diisopropylamide (LDA) at -78 °C in a mixture
of THF and toluene (v/v, 5:7) followed by addition of the
aldehyde. As a result, two aldol adducts, 11â (50% yield)
and 11R (50%), were obtained after separation on silica
gel (Scheme 2). The stereochemistry of the newly intro-
duced contiguous stereocenters in 11â and 11R could not
1
be determined unambiguously at this stage by H NMR
analysis. However, the stereochemistry was established
(41) Barton, D. H. R.; Crich, D.; Motherwell, W. B. Tetrahedron
1985, 41, 3901.
(42) Breen, A. P.; Murphy, J . A.; Patterson, C. W.; Wooster, N. F.
Tetrahedron 1993, 49, 10643.

2682 J . Org. Chem., Vol. 63, No. 8, 1998
Ishihara et al.
Sch em e 3
Sch em e 4
To overcome this difficulty, we took advantage of Barton-
Crich’s decarboxylative oxygenation strategy for conver-
sion of the ester functionality into a hydroxyl group.41,43
Therefore, the diastereomeric mixture of 19 was saponi-
fied with aqueous KOH and the carboxylic acid 20 was
obtained as a single product (81%) (Scheme 4). That both
19R and 19â afforded the same carboxylic acid 20 was
confirmed by the alkaline hydrolysis of each diastere-
omer. The structure of 20 was not determined unam-
biguously, but we tentatively assigned it to be the
R-anomer as depicted on the basis of the similarity of the
1H NMR spectra of 19R and 20. The carboxylic acid 20
was subjected to the decarboxylative oxygenation condi-
tions reported by Barton and co-workers.41 The initially
formed thiohydroxamic ester was decarboxylated to leave
a methylene radical on the cyclopentyl ring which was
then trapped by a molecular oxygen. Reductive workup
in the presence of t-BuSH finally provide a hydroxylated
product (21) as an inseparable diastereomeric mixture.
These diastereomers were readily separated as their
acetates 22R (58%) and 22â (40%) after acetylation. We
first expected that the attack of molecular oxygen on the
methylene radical, generated from the thiohydroxamic
ester intermediate, occurred favorably from the less
sterically congested convex side of the right-half bicyclic
ring, providing 21â stereoselectively. However, no speci-
fied stereoselectivity was observed in the present case.
The structural determination of 22R and 22â was achieved
1.5 molar equiv of this base (used as solution in toluene)
at -78 °C, the substrate 17 underwent smooth cycliza-
tion, and the cyclized product 18 (D in Scheme 1, P )
MOM, P′ ) H) was obtained as a 5:3 inseparable
diastereomeric mixture after quenching by a THF solu-
tion including camphorsulfonic acid (82%). To avoid the
retro-Dieckmann cyclization, the hemiketal hydroxyl
groups in the mixture 18 were immediately protected
with (tert-butyldimethyl)silyl trifluoromethanesulfonate
(TBSOTf) to give the TBS ethers 19R (52%) and 19â
(29%), which were separated by chromatography on silica
gel. The structure of the major isomer 19R was deter-
1
mined by the H NMR spectroscopic analysis including
NOE difference experiments as shown in Scheme 3. A
NOE (1.6%) was observed between Hb and the angular
Me, but no NOEs were observed between the angular
methyl and Ha or between Ha and Hb. Furthermore, a
significant increase (15.6%) of NOE was observed be-
tween Ha and Hc. At this stage, we were able to confirm
the stereochemistry of the quaternary carbon and the
carbinol carbon in the aldol adduct 11â.
We next investigated the conversion of the ester
functionality in the Dieckmann cyclization products
19R,â into a hydroxyl group. In our previous studies
using a model compound37 which lacks a hydroxyl group
in the C-ring equivalent, we noticed that a Baeyer-
Villiger oxidative rearrangement strategy for insertion
of an oxygen between the cyclopentyl ring carbon and a
methyl ketone side chain did not proceed. Namely, the
ester in the Dieckmann cyclization product was straight-
forwardly converted into a methyl ketone via (1) reduc-
tion to an aldehyde, (2) a Grignard addition with MeMg-
Br, and (3) PCC oxidation. Subjection of the resulting
methyl ketone to m-chloroperbenzoic acid (m-CPBA)
resulted in complete recovery of the starting substrate.
1
on the basis of the H NMR spectral analysis, including
(43) Some recent applications of the Barton’s radically induced
decarboxylation for natural products synthesis: Corey, E. J .; Hong,
B.-c. J . Am. Chem. Soc. 1994, 116, 3149; Hatakeyama, S.; Kawamura,
M.; Takano, S. J . Am. Chem. Soc. 1994, 116, 4081; Schultz, A. G.;
Holoboski, M. A.; Smyth, M. S. J . Am. Chem. Soc. 1996, 118, 6120;
Trost, B. M.; Higuchi, R. I. J . Am. Chem. Soc. 1996, 118, 10094.
Stamos, D. P.; Chen, S. S.; Kishi, Y. J . Org. Chem. 1997, 62, 7552.

Total Synthesis of (-)-Verrucarol
J . Org. Chem., Vol. 63, No. 8, 1998 2683
Sch em e 5
Sch em e 6
Sch em e 7
NOE experiments. As shown in Scheme 4, significant
signal enhancement was observed at the ring proton
bearing the acetoxyl group in 22R when the angular
methyl was irradiated. This phenomenon was not ob-
served in the case of 22â. At a later stage, we recognized
that the isomer 21â was solely effective for the crucial
ring enlargement. Therefore, we looked into the stere-
ochemical conversion of 21R into 21â. Fortunately,
oxidation of 21R, prepared from 22R by Dibal-H reduc-
tion, with PDC and successive reduction of the resulting
ketone 23 with Dibal-H provided 21â almost exclusively
(>20:1, 68%). The 1H NMR analysis of the reduction
mixture revealed the predominant formation of 21â, and
a trace amount of 21R could be removed after acetylation.
The fact that the hydride delivery to 23 occurred from
the (seemingly) more hindered R-side can be explained
by the neighboring bulky (tert-butyldimethylsilyl)oxy
group effectively shielding the â-side from the attack of
the hydride.
The key skeletal rearrangement for the construction
of the trichothecene framework was next investigated.
The hydroxyl group in 21â was mesylated to introduce a
leaving group (99%) (Scheme 5). The mesylate 24 was
treated with TBAF for desilylation. The expected ring
enlargement occurred simultaneously with removal of the
mesyloxy group as depicted. The desired trichothecene
skeleton was constructed to afford 25 in a yield of 97%.
The stereochemistry of the methine carbon bearing the
mesyloxy group was crucial for this smooth ring enlarge-
ment. We examined similar ring enlargement for the
R-mesylate prepared from 21R, which did not give any
skeletal rearrangement product.
The final stage of the total synthesis was stereoselec-
tive introduction of the exo-epoxy group at the carbonyl
carbon in 25. It was apparent from the previous total
syntheses29 that the aimed stereoselective epoxidation of
the exo-methylene group in 26, prepared by usual Wittig
methylenation (73%), was only possible when the hy-
droxyl group in the C-ring was unprotected (Scheme 6).
Thus, the MOM groups in 26 were deprotected with
bromotrimethylsilane at -30 °C. The resulting diol 27
(78%) was the naturally derived trichothecene known to
be 12,13-deoxyverrucarol, which was isolated by Breiten-
stein and Tamm as an alkaline hydrolysis product of the
antibiotic verrucarin K.44 The spectral data of the
synthetic 27 were in good accordance with those of the
naturally derived product, including the sign and mag-
nitude of the optical rotations. Thus, our present work
confirmed the absolute stereochemistry of natural (-)-
12,13-deoxyverrucarol (27) as depicted.
The conversion of 27 into (-)-verrucarol (7) was as
follows. To avoid undesired epoxidation of the A-ring
carbon-carbon double bond, the protection of the primary
hydroxyl group in 27 was required. Intramolecular
bromoetherification of the diol 27 with N-bromosuccin-
imide (NBS) in acetone afforded the bromo ether 31
(58%).29a,g On the other hand, we examined the regiose-
lective silylation of the primary hydroxyl in 27 with
TBSOTf. As a result, mono-O-silyl derivative 28 (40%)
and di-O-silyl derivative 29 (39%) were obtained without
significant selectivity. Contrary to our expectation, the
primary hydroxyl group was difficult to protect prefer-
entially. Compound 28 was subjected to the intramo-
lecular bromo ether formation conditions, giving 30,
which was then desilylated to give 31 (96% yield).
m-CPBA epoxidation of 31 gave 32 stereoselectively
(91%).29a,g Finally, reduction of 32 with a zinc-silver
couple45 in EtOH provided (-)-verrucarol 7 (81%) (Scheme
1
7).29e The comparison of properties (mp, TLC, H, 13C
NMR, and IR) of the synthetic 7 with those of a natural
specimen verified its identity.
In summary, the total synthesis of (-)-verrucarol,
which was derived from the naturally occurring verru-
carin A, was accomplished. Our enantioselective total
synthesis commenced with the enantiomerically pure
bicyclic R-methylated γ-lactone, which had been prepared
from D-glucose. The key steps for the total synthesis were
(1) the aldol-like four-carbon side chain elongation at the
(45) Denis, J . M.; Girard, C.; Conia, J . M. Synthesis 1972, 549.
Tokoroyama, T.; Matsuo, K.; Kanazawa, R. Bull. Chem. Soc. J pn. 1980,
53, 3383.
(44) Breitenstein, W.; Tamm, Ch. Helv. Chim. Acta 1977, 60, 1522.

2684 J . Org. Chem., Vol. 63, No. 8, 1998
Ishihara et al.
11R (359 mg, 0.63 mmol) in CH2Cl2 (7 mL) were added
molecular sieves (4A powder, 364 mg) and PCC (564 mg, 2.53
mmol). The mixture was stirred for 90 min then silica gel (500
mg) was added. The solvent was removed by concentration,
and the residue was transferred to a short silica gel column,
which was eluted with excess Et2O. The ethereal eluate was
concentrated to give 12 (358 mg) as a colorless oil, which was
used in the next step without further purification. 12: TLC,
Rf 0.53 (EtOAc/hexane, 1:3); IR (neat) 2930, 2860, 1770, 1700
cm-1; 1H NMR (270 MHz) δ 1.05 (s, 9 H), 1.46 (s, 3 H), 1.17-
2.17 (m, 6 H), 1.75 (s, 3 H), 2.70-2.82 (m, 2 H), 3.26 (s, 3 H),
3.23, 3.43 (ABq, J ) 9.9 Hz, 1 H × 2), 3.67 (t, J ) 6.2 Hz, 2
H), 4.41 (s, 2 H), 4.64 (d, J ) 5.1 Hz, 1 H), 5.58-5.66 (m, 1 H),
7.33-7.48, 7.60-7.69 (2 m, total 10 H).
R-carbon of the starting lactone, (2) Dieckmann cycliza-
tion for the construction of the C-ring equivalent, (3) the
Barton’s decarboxylative oxygenation for conversion of
a carboxylic functionality in the cyclization product into
a hydroxyl group, (4) the skeletal enlargement for the
trichothecene skeleton construction, and (5) the final
stereoselective exo-epoxy formation.
Exp er im en ta l Section
Melting points are uncorrected. Specific rotations were
measured in a 10 mm cell. 1H NMR spectra were recorded at
270 or 400 MHz in CDCl3 solution with tetramethylsilane as
an internal standard. 13C NMR spectra were recorded at 67.5
MHz, 75 Hz, or 100 MHz in CDCl3 solution. Thin-layer
chromatography (TLC) was performed with a glass plate
coated with Kieselgel 60 GF254 (Merck). The crude reaction
mixtures and extractive materials were purified by chroma-
tography on silica gel 60 K070 (Katayama Chemicals). Unless
otherwise described, reactions were carried out at ambient
temperature. Combined organic extracts were dried over
anhydrous Na2SO4. Solvents were removed from reaction
mixture or combined organic extracts by concentration under
reduced pressure using an evaporator with a water bath at
35-45 °C. Solvents were dried (drying reagent in brackets)
and distilled prior to use: tetrahydrofuran (THF) [LiAlH4, then
Na/benzophenone ketyl], N,N-dimethylforamide (DMF) [CaH2],
CH2Cl2 [CaH2], benzene [CaH2], dimethyl sulfoxide (DMSO)
[CaH2], pyridine [NaOH], and toluene [CaH2].
To a cold (0 °C) stirred solution of 12 (358 mg) in MeOH (7
mL) was added NaBH4 (72 mg, 1.90 mmol). After the mixture
was stirred for 2 h, additional NaBH4 (23 mg, 0.61 mmol) was
added. The mixture was stirred for an additional 45 min,
diluted with saturated aqueous NH4Cl (5 mL), and extracted
with CHCl3 (5 mL × 3). The combined organic layer was dried
and concentrated. The residue was purified by column chro-
matography on silica gel (EtOAc/hexane, 1:9, 1:7, then 1:5) to
give 265 mg (74% for 2 steps) of 11â and 46 mg (13%) of 11R.
(1R,6R,7S)-7-[(1R)-1,4-Dih yd r oxybu tyl]-3,7-d im eth yl-6-
(m eth oxym eth oxy)m eth yl-9-oxa bicyclo[4.3.0]n on -2-en -8-
on e (13). To a cold (0 °C) stirred solution of 11â (1.63 g, 2.88
mmol) in THF (20 mL) was added TBAF (1.0 M solution in
THF, 3.74 mL, 3.74 mmol). The solution was stirred for 20
min and the solvent was removed by concentration. The
residue was purified by column chromatography on silica gel
(acetone/toluene, 1:3) to give 13 (0.766 g, 81%) as a colorless
(1R,6R,7S)-7-[(1R a n d 1S)-4-[(ter t-Bu tyld ip h en ylsilyl-
oxy)-1-h yd r oxybu tyl]-3,7-d im eth yl-6-(m eth oxym eth oxy)-
m eth yl-9-oxa bicyclo[4.3.0]n on -2-en -8-on e (11â) a n d (11r).
The reaction was carried out under Ar. To a cold (0 °C) stirred
solution of diisopropylamine (2.13 mL, 15.2 mmol) in THF (7
mL) was added n-BuLi (1.58 M solution in hexanes, 9.61 mL,
15.2 mmol). The solution was stirred at 0 °C for 1 h and then
cooled to -78 °C. To this was added a solution of 10 (730 mg,
3.04 mmol) in a mixture of THF (7 mL) and toluene (14 mL).
The resulting solution was stirred at -78 °C for 30 min, then
a solution of 4-(tert-butyldiphenylsilyl)oxybutanal42 (8.16 g,
25.0 mmol) in a mixture of THF and toluene (each 10 mL) was
added. After 15 min of stirring at -78 °C, the solution was
diluted with saturated aqueous NH4Cl (5 mL) and poured into
EtOAc (300 mL). The whole was washed with saturated
aqueous NH4Cl (150 mL) and saturated brine (150 mL × 2).
The organic layer was dried and concentrated. The residue
was purified by column chromatography on silica gel (EtOAc/
hexane, 1:15, 1:9, 1:7, then 1:5) to give 860 mg (50%) of 11â
and 861 mg (50%) of 11R. 11R as a colorless oil: TLC, Rf 0.44
oil: TLC, Rf 0.21 (acetone/toluene, 1:3); [R]21 +2.0 (c 0.49,
D
CHCl3); IR (neat) 3450, 2950, 1750, 1675 cm-1; 1H NMR (270
MHz) δ 1.20 (s, 3 H), 1.64-2.07 (m, 8 H), 1.78 (s, 3 H), 2.17-
2.39 (br, 1 H), 3.40 (s, 3 H), 3.62-3.72 (m, 2 H), 3.64, 3.70
(ABq, J ) 10.6 Hz, 1 H × 2), 3.80-4.02 (br, 1 H), 4.12-4.16
(m, 1 H), 4.56 (d, J ) 5.1 Hz, 1 H), 4.63, 4.66 (ABq, J ) 6.6
Hz, 1 H × 2), 5.61-5.63 (m, 1 H); 13C NMR (75 MHz) δ 11.6,
22.9, 23.4, 26.6, 29.5, 29.9, 45.7, 56.2, 56.9, 62.9, 65.1, 70.2,
73.8, 97.0, 116.3, 142.5, 178.7.
(1R,6R,7S)-7-[(1R)-1-H yd r oxy-4-(p iva loyloxy)b u t yl]-
3,7-d im et h yl-6-(m et h oxym et h oxy)m et h yl-9-oxa b icyclo-
[4.3.0]n on -2-en -8-on e (14) . To a cold (0 °C) stirred solution
of 13 (1.14 g, 3.46 mmol) in pyridine (15 mL) was added
pivaloyl chloride (0.63 mL, 5.19 mmol). The solution was
stirred for 70 min, then EtOH (1 mL) was added. This was
diluted with H2O (50 mL). The whole was extracted with
CHCl3 (50 mL × 3), and the combined extracts were dried and
concentrated. The residue was purified by column chroma-
tography on silica gel (acetone/toluene, 1:15) to give 14 (1.24
g, 87%) as a colorless oil: TLC, Rf 0.58 (acetone/toluene, 1:3);
(EtOAc/hexane, 1:3); [R]22 -10.7 (c 0.99, CHCl3); IR (neat)
D
1
3450, 2960, 1760, 1675 cm-1; H NMR (270 MHz) δ 1.05 (s, 9
[R]23 +4.0 (c 0.83, CHCl3); IR (neat) 3475, 2930, 1765, 1730,
D
1
H), 1.13 (s, 3 H), 1.69-1.84 (m, 3 H), 1.92-2.14 (m, 5 H), 1.75
(s, 3 H), 3.36 (s, 3 H), 3.51, 3.97 (ABq, J ) 9.9 Hz, 1 H × 2),
3.60-3.76, 3.91-4.02 (2 m, 2 H × 2), 4.56, 4.62 (ABq, J ) 6.6
Hz, 1 H × 2), 4.86 (d, J ) 4.4 Hz, 1 H), 5.57-5.59 (m, 1 H),
7.32-7.47, 7.60-7.69 (2 m, total 10 H); 13C NMR (100 MHz) δ
15.5, 19.1, 23.4, 24.0, 26.7, 29.2, 30.2, 45.5, 55.7, 64.6, 64.9,
75.3, 75.9, 117.5, 127.7, 127.8, 129.8, 132.8, 133.0, 135.6, 141.1,
179.1. 11â as a colorless oil: TLC, Rf 0.35 (EtOAc/hexane,
1680 cm-1; H NMR (270 MHz) δ 1.19 (s, 3 H), 1.19 (s, 9 H),
1.55-2.09 (m, 8 H), 1.77 (s, 3 H), 3.40 (s, 3 H), 3.54 (dd, J )
1.1, 2.6 Hz, 1 H), 3.65, 3.72 (ABq, J ) 10.6 Hz, 1 H × 2), 4.05-
4.16 (m, 3 H), 4.55 (d, J ) 5.1 Hz, 1 H), 4.62, 4.65 (ABq, J )
6.6 Hz, 1 H × 2), 5.61-5.63 (m, 1 H); 13C NMR (75 MHz) δ
11.3, 22.9, 23.3, 25.7, 26.6, 27.2, 28.5, 45.7, 56.2, 56.9, 63.9,
65.1, 69.1, 73.6, 97.0, 116.3, 142.5, 178.4, 178.6; HRMS calcd
for C22H36O7 (M+) m/z 412.2461, found 412.2467.
1:3); [R]22 +3.7 (c 1.33, CHCl3); IR (neat) 3450, 2930, 1765,
(1R,6R,7S)-7-[(1R)-1-(Meth oxym eth oxy)-4-(pivaloyloxy)-
b u t yl]-3,7-d im et h yl-6-(m et h oxym et h oxy)m et h yl-9-oxa -
bicyclo[4.3.0]n on -2-en -8-on e (15). To a cold (0 °C) stirred
solution of 14 (1.20 g, 2.90 mmol) in CHCl3 (12 mL) were added
diisopropylethylamine (5.05 mL, 29.0 mmol) and MOMCl (1.10
mL, 14.5 mmol). The solution was heated under reflux for 4.5
h and then diluted with 0.2 M HCl solution (50 mL). This
was extracted with CHCl3 (40 mL × 3). The combined extracts
were dried and concentrated. The residue was purified by
column chromatography on silica gel (EtOAc/hexane, 1:5) to
give 15 (1.10 g, 83%) as a colorless oil: TLC, Rf 0.59 (EtOH/
toluene, 1:6); [R]23D +17.1 (c 1.09, CHCl3); IR (neat) 2970, 2930,
D
1
1675 cm-1; H NMR (270 MHz) δ 1.04 (s, 9 H), 1.18 (s, 3 H),
1.54-1.71 (m, 1 H), 1.80-2.09 (m, 7 H), 1.77 (s, 3 H), 3.38 (s,
3 H), 3.60, 3.73 (ABq, J ) 11.0 Hz, 1 H × 2), 3.55-3.77 (m, 3
H), 4.07-4.15 (m, 1 H), 4.51 (d, J ) 5.1 Hz, 1 H), 4.59, 4.63
(ABq, J ) 6.6 Hz, 1 H × 2), 5.56-5.64 (m, 1 H), 7.33-7.47,
7.62-7.72 (2 m, total 10 H); 13C NMR (100 MHz) δ 11.8, 19.1,
22.9, 23.4, 26.6, 26.8, 29.2, 29.4, 45.6, 56.1, 56.8, 64.0, 65.0,
70.3, 73.8, 76.7, 116.4, 127.6, 129.6, 133.7, 135.5, 135.6, 142.4,
178.9.
P CC Oxid a tion of 11r a n d Red u ction of th e Resu ltin g
Keton e 12 w ith Na BH4. Ster eoselective F or m a tion of
11â. (1R,6R,7S)-7-[4-(ter t-Bu tyld ip h en ylsilyloxy)-1-oxo-
b u t yl]-3,7-d im et h yl-6-(m et h oxym et h oxy)m et h yl-9-oxa -
bicyclo[4.3.0]n on -2-en -8-on e (12). To a stirred solution of
1760, 1725, 1680 cm-1 1H NMR (270 MHz) δ 1.12 (s, 3 H),
;
1.20 (s, 9 H), 1.25-1.38 (m, 1 H), 1.58-1.73 (m, 2 H), 1.76 (s,
3 H), 1.85-2.23 (m, 5 H), 3.36 (s, 3 H), 3.38 (s, 3 H), 3.48, 3.83

Total Synthesis of (-)-Verrucarol
J . Org. Chem., Vol. 63, No. 8, 1998 2685
(ABq, J ) 10.3 Hz, 1 H × 2), 3.78 (dd, J ) 3.3, 6.2 Hz, 1 H),
4.07 (t, J ) 6.2 Hz, 2 H), 4.59 (s, 2 H), 4.60, 4.65 (ABq, J ) 6.6
Hz, 1 H × 2), 5.52-5.58 (m, 1 H); 13C NMR (100 MHz) δ 16.6,
23.4, 23.5, 26.4, 27.2, 28.4, 38.7, 45.1, 56.0, 56.1, 56.3, 64.0,
65.2, 75.8, 86.6, 97.0, 116.6, 142.0, 178.4, 181.6.; HRMS calcd
for C24H39O8 (M+ - H) m/z 455.2645, found 455.2633.
(s, 1 H × 5/9), 3.86 (d, J ) 4.8 Hz, 1 H × 5/9), 3.95 (d, J ) 4.4
Hz, 1 H × 4/9), 4.06 (dd, J ) 6.2, 11.0 Hz, 1 H × 4/9), 4.30 (dd,
J ) 5.9, 7.7 Hz, 1 H × 5/9), 4.39 (s, 1 H × 4/9), 4.54, 4.58 (ABq,
J ) 6.6 Hz, each 1 H × 4/9), 4.55, 4.59 (ABq, J ) 6.4 Hz, each
1 H × 5/9), 4.66, 4.70 (ABq, J ) 6.6 Hz, each 1 H × 5/9), 4.69,
4.74 (ABq, J ) 6.6 Hz, each 1 H × 4/9), 5.53-5.55 (m, 1 H);
13C NMR (67.5 MHz) δ 9.8, 10.6, 21.5, 23.4, 23.6, 27.0, 27.1,
31.2, 32.2, 45.4, 45.7, 50.7, 51.3, 51.9, 52.0, 55.2, 55.7, 59.7,
60.4, 66.1, 66.7, 75.0, 76.8, 77.2, 78.0, 78.3, 96.0, 96.4, 96.7,
110.7, 112.6, 118.5, 119.3, 139.4, 140.2, 171.0, 173.1; HRMS
calcd for C20H31O8 (M+ - H) m/z 399.2019, found 399.2002.
(1R,6R,7S)-7-[(1R)-4-Hyd r oxy-1-(m eth oxym eth oxy)bu -
t yl]-3,7-d im e t h yl-6-(m e t h oxym e t h oxy)m e t h yl-9-oxa -
bicyclo[4.3.0]n on -2-en -8-on e (16). To a cold (0 °C) stirred
solution of 15 (1.08 g, 2.36 mmol) in MeOH (12 mL) was added
MeONa (1.0 M solution in MeOH, 4.72 mL, 4.72 mmol). The
solution was stirred for 16 h and neutralized with Amberlite
IR-120 [H+]. The resin was removed by filtration and washed
well with MeOH. The combined filtrate and washings were
concentrated. The residue was purified by column chroma-
tography on silica gel (EtOH/toluene, 1:8) to give 16 (0.88 g,
100%) as a colorless oil: TLC, Rf 0.45 (EtOH/toluene, 1:6);
[R]25D +21.9 (c 1.01, CHCl3); IR (neat) 3480, 2930, 2880, 1755,
1675 cm-1; 1H NMR (270 MHz) δ 1.14 (s, 3 H), 1.26-1.37 (m,
1 H), 1.54-2.06 (m, 6 H), 1.76 (s, 3 H), 2.09-2.26 (m, 1 H),
3.37 (s, 3 H), 3.40 (s, 3 H), 3.46, 3.88 (ABq, J ) 10.3 Hz, 1 H
× 2), 3.66 (td, J ) 6.2, 1.5 Hz, 2 H), 3.82 (dd, J ) 3.7, 6.2 Hz,
1 H), 4.58-4.68 (m, 5 H), 5.54-5.56 (m, 1 H); 13C NMR (100
MHz) δ 16.6, 23.4, 23.5, 26.4, 27.9, 31.9, 45.2, 56.0, 56.1, 56.4,
62.3, 65.3, 75.8, 86.5, 97.1, 116.6, 142.0, 181.7; HRMS calcd
for C19H32O7(M+) m/z 372.2149, found 372.2182.
(1S,3R,8R,9S,10R,12R a n d -12S)-1-(ter t-Bu tyld im eth -
ylsilyloxy)-12-(m eth oxyca r bon yl)-10-(m eth oxym eth oxy)-
8-[(m eth oxym eth oxy)m eth yl]-5,9-dim eth yl-2-oxatr icyclo-
[7.3.0.03,8]d od ec-4-en e (19â a n d 19r). The following reaction
was best achieved in a 100∼150 mg scale and was carried out
under Ar. To a cold (0 °C) solution of the diastereomeric
mixture 18 obtained above (109 mg, 0.27 mmol) in CH2Cl2 (2
mL) were added 2,6-lutidine (0.25 mL, 2.17 mmol) and tert-
butyldimethylsilyl trifluoromethanesulfonate (0.25 mL, 1.09
mmol). The mixture was stirred at 0 °C for 1 h, diluted with
EtOAc (10 mL), and washed with saturated aqueous NaHCO3
(5 mL) and saturated brine (5 mL × 2). The organic layer
was dried and concentrated. The residue was purified by
column chromatography on silica gel (EtOAc/hexane, 1:8) to
give a diatereomeric mixture 19 (105 mg, 75%). In a separate
experiment using 41.5 mg of the mixture 18, two diasteremers
19R and 19â were obtained in homogeneous form after
repeated chromatography on silica gel (EtOAc/hexane, 1:11)
in 52% (27.8 mg) and 29% (15.3 mg) yields, respectively. 19R
(1R,6R,7S)-7-[(1R)-3-(Met h oxyca r b on yl)-1-(m et h oxy-
m eth oxy)p r op yl]-3,7-d im eth yl-6-(m eth oxym eth oxy)m e-
th yl-9-oxa bicyclo[4.3.0]n on -2-en -8-on e (17). To a cold (0
°C) stirred solution of 16 (912 mg, 2.46 mmol) in acetone (15
mL) was added J ones reagent (2.67 M solution, 1.38 mL, 3.69
mmol). The solution was stirred at 0 °C for 2 h, and 2-propanol
(5 mL) was added and then diluted with H2O (100 mL). This
was extracted with CHCl3 (50 mL × 3). The combined extracts
were dried and concentrated. The residue was dissolved in a
mixture of CHCl3 (5 mL) and Et2O (10 mL). At 0 °C with
stirring, an ethereal solution of diazomethane was added to
the solution until the yellow color persisted. The solution was
stirred at 0 °C for 10 min and gradually warmed to ambient
temperature. The solvents were removed by concentration.
The residue was purified by column chromatography on silica
gel (EtOAc/hexane, 1:4) to give 17 (713 mg, 72%) as a colorless
as a colorless oil: TLC, Rf 0.42 (EtOAc/hexane, 1:5); [R]27
D
-62.1 (c 1.06, CHCl3); IR (neat) 2950, 2930, 2880, 2850, 1740,
1680 cm-1; 1H NMR (270 MHz) δ 0.04, 0.19 (2s, 3 H × 2), 0.88
(s, 9 H), 1.07 (s, 3 H), 1.69 (s, 3 H), 1.73-2.10 (m, 5 H), 2.38
(ddd, J ) 1.4, 6.2, 12.8 Hz, 1 H), 2.96 (d, J ) 9.2 Hz, 1 H),
3.34 (s, 3 H), 3.37 (s, 2 H), 3.38 (s, 3 H), 3.66 (s, 3 H), 3.84 (d,
J ) 4.8 Hz, 1 H), 4.37 (dd, J ) 6.2, 11.0 Hz, 1 H), 4.53, 4.56
(ABq, J ) 6.6 Hz, 1 H × 2), 4.68, 4.77 (ABq, J ) 6.6 Hz, 1 H
× 2), 5.40-5.46 (m, 1 H); 13C NMR (67.5 Hz) δ -3.5, -3.1, 11.0,
18.1, 21.1, 23.3, 25.9, 27.1, 32.8, 44.6, 51.1, 54.3, 55.2, 55.7,
61.1, 66.4, 76.2, 79.6, 96.6, 96.8, 113.7, 118.8, 138.8, 172.6;
HRMS calcd for C26H45O8Si (M+ - H) m/z 513.2883, found
513.2875. 19â as a colorless oil: TLC, Rf 0.55 (EtOAc/hexane,
oil: TLC, Rf 0.60 (EtOAc/hexane, 1:1); [R]25 +36.6 (c 1.01,
D
CHCl3); IR (neat) 2925, 2850, 1760, 1740, 1680 cm-1; 1H NMR
(270 MHz) δ 1.14 (s, 3 H), 1.26-1.37 (m, 1 H), 1.76 (s, 3 H),
1.88-2.06 (m, 4 H), 2.28-2.48, 2.54-2.66 (2m, 2H, 1 H), 3.36
(s, 3 H), 3.40 (s, 3 H), 3.50, 3.86 (ABq, J ) 10.6 Hz, 1 H × 2),
3.67 (s, 3 H), 3.76 (dd, J ) 2.8, 7.9 Hz, 1 H), 4.57-4.66 (m, 5
H), 5.54-5.56 (m, 1 H); 13C NMR (67.5 MHz) δ 16.7, 23.3, 23.4,
26.3, 26.8, 32.4, 45.2, 56.0, 56.2, 65.0, 75.8, 86.6, 97.0, 97.6,
116.6, 142.0, 173.6, 181.5; HRMS calcd for C20H32O8 (M+) m/z
400.2097, found 400.2092.
1:3); [R]27 -5.4 (c 1.12, CHCl3); IR (neat) 2945, 2920, 2875,
D
2845, 1735, 1670 cm-1; 1H NMR (270 MHz) δ 0.05, 0.08 (2s, 3
H × 2), 0.84 (s, 9 H), 1.15 (s, 3 H), 1.71 (s, 3 H),1.73-2.43 (m,
6 H), 2.95 (dd, J ) 8.1, 10.6 Hz, 1 H), 3.34, 3.37 (2s, 3 H × 2),
3.39 (s, 2 H), 3.65 (s, 3 H), 3.92 (d, J ) 4.8 Hz, 1 H), 4.08 (dd,
J ) 7.0, 10.3 Hz, 1 H), 4.53, 4.56 (ABq, J ) 6.6 Hz, 1 H × 2),
4.67, 4.71 (ABq, J ) 7.0 Hz, 1 H × 2), 5.49-5.55 (m, 1 H); 13
C
NMR (67.5 Hz) δ -3.2, -2.1, 10.3, 18.2, 20.6, 23.4, 26.1, 27.0,
34.3, 45.2, 51.5, 54.1, 55.3, 55.7, 60.7, 66.5, 75.4, 78.7, 96.4,
96.8, 114.2, 118.8, 139.5, 172.2; HRMS calcd for C25H43O8Si
(M+ - CH3) m/z 499.2727, found 499.2729.
Mixtu r e of (1R,3R,8R,9S,10R,12R a n d -12S)-1-Hyd r oxy-
12-(m et h oxyca r b on yl)-10-(m et h oxym et h oxy)-8-[(m et h -
oxym eth oxy)m eth yl]-5,9-dim eth yl-2-oxatr icyclo[7.3.0.03,8]-
d od ec-4-en e (18). The following reaction was carried out
under Ar. To a cold (-78 °C) solution of potassium bis-
(trimethylsilazide) (0.5 M solution in toluene, 5.34 mL, 2.67
mmol) in THF (10 mL) was added a THF (15 mL) solution of
17 (713 mg, 1.78 mmol). The solution was stirred at -78 °C
for 15 min and diluted with a THF (5 mL) solution of DL-10-
camphorsulfonic acid (1.24 g, 5.34 mmol). The resulting
solution was stirred at -78 °C for 5 min and then diluted with
saturated aqueous NH4Cl (300 mL). This was extracted with
CHCl3 (150 mL × 3). The combined extracts were dried and
concentrated. The residue was purified by column chroma-
tography on silica gel (EtOAc/hexane, 1:4) to give an insepa-
rable (5:3,1H NMR analysis) diastereomeric mixture of 18 (585
mg, 82%) as a colorless oil: TLC, Rf 0.58 (EtOAc/hexane, 1:1);
(1S,3R,8R,9S,10R,12R)-1-(ter t-Bu tyld im eth ylsilyloxy)-
10-(m eth oxym eth oxy)-8-[(m eth oxym eth oxy)m eth yl]-5,9-
d im eth yl-2-oxa tr icyclo[7.3.0.03,8]d od ec-4-en -12-ca r boxy-
lic Acid (20). To a solution of the mixture of 19R and 19â
(ca. 5:3, 472 mg, 0.92 mmol) in MeOH (4 mL) was added
aqueous KOH solution (4 M, 4 mL). The solution was heated
at 80 °C for 6 h and, after cooling to ambient temperature,
neutralized with 1 M aqueous HCl solution. This was diluted
with H2O (20 mL) and extracted with CHCl3 (20 mL × 3). The
combined extracts were dried and concentrated. The residue
was purified by column chromatography on silica gel (acetone/
toluene, 1:8) to give 20 (372 mg, 81%) as colorless crystals:
mp 108-110 °C; TLC, Rf 0.28 (EtOAc/hexane, 1:2); IR (neat)
2950, 2930, 2850, 1735, 1715 cm-1; 1H NMR (270 MHz) δ 0.06
(s, 3 H), 0.18 (s, 3 H), 0.87 (s, 9 H), 1.09 (s, 3 H), 1.71 (s, 3 H),
1.75-2.21 (m, 5 H), 2.31-2.44 (m, 1 H), 3.00 (dd, J ) 2.4, 10.4
Hz, 1 H), 3.34, 3.37 (2s, 3 H × 2), 3.40 (s, 2 H), 4.01 (d, J ) 4.9
Hz, 1 H), 4.29 (dd, J ) 6.7, 9.8 Hz, 1 H), 4.53, 4.56 (ABq, J )
6.7 Hz, 1 H × 2), 4.66, 4.74 (ABq, J ) 6.7 Hz, 1 H × 2), 5.50-
5.54 (m, 1 H); 13C NMR (100 Hz) δ -3.4, -3.1, 11.0, 18.0, 21.0,
1
IR (neat) 3450, 2950, 2925, 2880, 1735, 1675 cm-1; H NMR
(270 MHz) δ 1.11, 1.73 (2s, each 3H × 4/9), 1.15, 1.72 (2s, each
3H × 5/9), 1.81-2.26, 2.41-2.53 (2m, 5H, 1 H), 2.95 (dd, J )
8.2, 11.9 Hz, 1 H × 4/9), 3.11 (dd, J ) 7.7, 9.9 Hz, 1 H × 5/9),
3.35, 3.40 (2s, each 3 H × 4/9), 3.36, 3.38 (2s, each 3 H × 5/9),
3.42-3.49 (m, 2 H), 3.73, 3.74 (2s, 3 H × 4/9, 3 H × 5/9), 3.79

2686 J . Org. Chem., Vol. 63, No. 8, 1998
Ishihara et al.
23.3, 25.8, 26.0, 27.0, 33.3, 44.6, 54.1, 55.3, 55.7, 61.2, 66.4,
76.6, 79.5, 96.6, 96.8, 113.4, 118.8, 139.0, 177.1. Anal. Calcd
for C25H43O8Si: C, 60.09; H, 8.67. Found: C, 59.67; H, 8.86.
(1R,3R,8R,9S,10R,12S a n d -12R)-12-Acetoxy-1-(ter t-bu -
t yld im e t h ylsilyloxy)-10-(m e t h oxym e t h oxy)-8-[(m e t h -
oxym eth oxy)m eth yl]-5,9-dim eth yl-2-oxatr icyclo[7.3.0.03,8]-
d od ec-4-en e (22â) a n d (22r). To a solution of 20 (305 mg,
0.61 mmol) in CH2Cl2 (48 mL) were added 4-(dimethylamino)-
pyridine (372 mg, 3.04 mmol), 1-ethyl-3-(3-(dimethylamino)-
propyl)carbodiimide hydrochloride (504 mg, 3.04 mmol), 2-mer-
captopyridine N-oxide (542 mg, 4.26 mmol), and tert-butyl-
mercaptan (1.37 mL, 12.2 mmol). To the resulting solution
was bubbled a stream of dry oxygen for 14.5 h with stirring.
This was diluted with 0.2 M aqueous HCl solution (150 mL)
and extracted with CH2Cl2 (60 mL × 3). The combined
extracts were dried and concentrated. The residue was
purified by column chromatography on silica gel (EtOAc/
hexane, 1:9 to 1:6) to give an inseparable diastereomeric
mixture of 21â and 21R which was used for acetylation.
The diastereomeric mixture of 21 obtained above (237 mg)
was stirred with acetic anhydride (2 mL) in pyridine (2 mL)
for 10 h and the solution was concentrated. The residue was
purified by column chromatography on silica gel (EtOAc/
hexane, 1:9 to 1:6) to give diastereomerically homogeneous 22â
(103 mg, 40%) and 22R (150 mg, 58%) contaminated with a
small amount of unacetylated 21. Pure 22R was obtained by
rechromatography on silica gel. 22R as a colorless oil: TLC,
as described in the preparation of 21R using diisobutylalumi-
num hydride (1.0 M solution, 0.295 mL) at -78 °C for 25 min.
Purification of crude product by column chromatography on
silica gel (EtOAc/hexane, 1:5) gave 21â (45.3 mg, 97%) as a
colorless oil: TLC, Rf
0.39 (EtOAc/hexane, 1:3); [R]24 -54.1 (c
D
0.86, CHCl3); IR (neat) 3500, 2960, 2930, 2890, 2850, 1680
cm-1; 1H NMR (270 MHz) δ 0.07, 0.17 (2s, 3 H × 2), 0.92 (s, 9
H), 1.14 (s, 3 H), 1.71 (s, 3 H), 1.78-2.13 (m, 5 H), 2.18 (d, J
) 2.9 Hz, 1 H), 2.44 (ddd, J ) 6.2, 8.1, 14.3 Hz, 1 H), 3.35,
3.38 (2s, 3 H × 2), 3.44 (s, 2 H), 3.73-3.84 (m, 2 H), 4.18 (dd,
J ) 6.2, 8.1 Hz, 1 H), 4.54, 4.58 (ABq, J ) 6.6 Hz, 1 H × 2),
4.66, 4.70 (ABq, J ) 6.6 Hz, 1 H × 2), 5.46-5.53 (m, 1 H); 13
C
NMR (75 MHz) δ -3.6, -3.1, 11.5, 18.2, 20.9, 23.4, 26.0, 27.0,
39.0, 45.8, 55.4, 55.7, 60.0, 67.1, 75.6, 77.4, 96.0, 96.8, 114.1,
119.3, 138.9; HRMS calcd for C24H45O7Si (M+ + H) m/z
473.2935, found 473.2943.
P DC Oxid a tion of 21r follow ed by Diba l-H Red u ction
of th e Resu ltin g Keton e 23. Ster eoselective F or m a tion
of 21â. (1R,3R,8R,9S,10R)-1-(ter t-Bu tyld im eth ylsilyloxy)-
10-(m eth oxym eth oxy)-8-[(m eth oxym eth oxy)m eth yl]-5,9-
d im eth yl-2-oxa tr icyclo[7.3.0.03,8]d od ec-4-en -12-on e (23).
To a solution of 21R (23.6 mg, 0.050 mmol) in CH2Cl2 (1 mL)
was added pyridinium dichromate (PDC) (94 mg, 0.25 mmol)
and molecular sieves (4A powder, 94 mg). The mixture was
stirred at ambient temperature for 8 h and 94 mg of each PDC
and molecular sieves was added. The mixture was stirred for
an additional 3 h, then the solvent was removed by concentra-
tion. The residue was transferred to a short silica gel column.
The column was eluted with excess Et2O. The ethereal eluate
was concentrated to give 23 (23.5 mg, 100%) as a colorless oil:
[R]24D -25.6 (c 0.68, CHCl3); IR (neat) 2930, 2890, 2850, 1765,
1680 cm-1; 1H NMR (270 MHz) δ 0.10, 0.17 (2s, 3 H × 2), 0.84
(s, 9 H), 1.10 (s, 3 H), 1.71 (s, 3 H), 1.86-2.20 (m, 4 H), 2.37
(dd, J ) 9.5, 19.1 Hz, 1 H), 2.93 (dd, J ) 7.5, 18.8 Hz, 1 H),
3.36, 3.38 (2s, 3 H × 2), 3.46, 3.51 (ABq, J ) 10.3 Hz, 1 H ×
2), 4.09 (d, J ) 4.4 Hz, 1 H), 4.22 (dd, J ) 7.7, 9.5 Hz, 1 H),
4.56, 4.59 (ABq, J ) 6.6 Hz, 1 H × 2), 4.67, 4.74 (ABq, J ) 7.0
Hz, 1 H × 2), 5.53-5.55 (m, 1 H); 13C NMR (75 MHz) δ -3.4,
9.1, 18.5, 21.1, 23.5, 25.8, 26.6, 29.7, 41.4, 46.0, 55.4, 56.0, 60.7,
67.1, 74.2, 77.4, 78.6, 96.7, 96.8, 108.5, 119.7, 138.5, 206.7;
HRMS calcd for C24H42O7Si (M+) m/z 470.2700, found 470.2715.
Rf 0.32 (EtOAc/hexane, 1:4); [R]29 -53.2 (c 1.02, CHCl3);IR
D
(neat) 2955, 2930, 2890, 2860, 1745 cm-1; 1H NMR (270 MHz)
δ 0.05, 0.06 (2s, 3 H × 2), 0.84 (s, 9 H), 1.06 (s, 3 H), 1.71 (s,
3 H), 1.75-2.06 (m, 5 H), 2.11 (s, 3 H), 2.24 (dt, J ) 13.9, 8.4
Hz, 1 H), 3.34, 3.36 (2s, 3 H × 2), 3.41, 3.45 (ABq, J ) 10.3
Hz, 1 H × 2), 3.97 (d, J ) 4.0 Hz, 1 H), 4.21 (t, J ) 8.1 Hz, 1
H), 4.53, 4.57 (ABq, J ) 6.2 Hz, 1 H × 2), 4.63, 4.68 (ABq, J
) 6.6 Hz, 1 H × 2), 4.87 (dd, J ) 4.4, 8.4 Hz, 1 H), 5.58-5.60
(m, 1 H). 22â as a colorless oil: TLC, Rf 0.39 (EtOAc/hexane,
1:4); [R]31 -13.7 (c 1.06, CHCl3); IR (neat) 2960, 2930, 2890,
D
2860, 1740, 1680 cm-1
;
1H NMR (270 MHz) δ 0.01 (s, 6 H),
0.90 (s, 9 H), 1.15 (s, 3 H), 1.70 (s, 3 H), 1.64-2.17 (m, 5 H),
2.05 (s, 3 H), 2.66 (ddd, J ) 7.0, 8.1, 14.7 Hz, 1 H), 3.35 (s, 6
H), 3.44 (s, 2 H), 3.83 (d, J ) 4.0 Hz, 1 H), 4.14 (dd, J ) 6.2,
8.1 Hz, 1 H), 4.53, 4.58 (ABq, J ) 6.6 Hz, 1 H × 2), 4.62, 4.67
(ABq, J ) 7.0 Hz, 1 H × 2), 4.70 (dd, J ) 3.7, 6.6 Hz, 1 H),
5.48-5.50 (m, 1 H); 13C NMR (100 Hz) δ -3.7, -2.9, 10.6, 18.2,
20.7, 21.5, 23.5, 25.9, 26.9, 38.0, 46.0, 55.4, 55.7, 60.3, 67.2,
76.8, 76.9, 96.1, 96.7, 112.6, 119.6, 138.5, 170.3.
Compound 23 (23.5 mg) was dissolved in CH2Cl2 (1 mL).
To the solution was added diisobutylaluminum hydride (1 M
solution in hexane, 0.099 mL) at -78 °C then the mixture was
stirred at -78 °C for 20 min and quenched with H2O (0.1 mL).
The resulting gels were removed by filtration through a Celite
pad and washed with EtOAc. The combined filtrate and
washings were dried and concentrated. The residue was
purified by column chromatography on silica gel (EtOAc/
hexane, 1:8 to 1:6) to give an inseparable mixture of 21â and
(1R,3R, 8R,9S,10R,12R)-1-(ter t-Bu tyld im eth ylsilyloxy)-
10-(m eth oxym eth oxy)-8-[(m eth oxym eth oxy)m eth yl]-5,9-
d im et h yl-2-oxa t r icyclo[7.3.0.03,8]d od ec-4-en -12-ol (21r).
The following reaction was carried out under Ar. To a cold
(-78 °C) stirred solution of 22R (28.5 mg, 0.055 mmol) in CH2-
Cl2 (1 mL) was added diisobutylaluminum hydride (1.0 M
solution in hexane, 0.16 mL, 0.16 mmol). The mixture was
stirred at -78 °C for 45 min, quenched with H2O (0.1 mL),
and warmed gradually. The resulting gels were removed by
filtration through a Celite pad and washed well with EtOAc.
The combined filtrate and washings were dried and concen-
trated. The residue was purified by column chromatography
on silica gel (EtOAc/hexane, 1:6) to give 21R (25.9 mg, 99%)
1
21R (16.1 mg, 68%) in a ratio of more than 20:1 (270 MHz H
NMR analysis).
(1R,3R,8R,9S,10R,12S)-1-(ter t-Bu tyld im eth ylsilyloxy)-
12-m esyloxy-10-(m eth oxym eth oxy)-8-[(m eth oxym eth oxy)-
m e t h yl]-5,9-d im e t h yl-2-oxa t r icyclo[7.3.0.03,8]d od e c-4-
en e (24). To a solution of 21â (45.3 mg, 0.096 mmol) in
pyridine (1 mL) was added methanesulfonyl chloride (0.022
mL, 0.29 mmol). The mixture was stirred for 4 h and
additional methanesulfonyl chloride (0.022 mL) was added
after 3 h. The mixture was stirred for an additional 3 h and
diluted with 5 mL of H2O. This was extracted with CHCl3 (5
mL × 3). The combined extracts were dried and concentrated.
The residue was purified by column chromatography on silica
gel (EtOAc/hexane, 1:4) to give 24 (52.4 mg, 99%) as a colorless
as a colorless oil: TLC, Rf 0.39 (EtOAc/hexane, 1:3); [R]27
D
-45.5 (c 1.00, CHCl3); IR (neat) 3510, 2955, 2930, 2890, 2850,
1680 cm-1; 1H NMR (270 MHz) δ 0.04, 0.12 (2s, 3 H × 2), 0.86
(s, 9 H), 1.04 (s, 3 H), 1.73 (s, 3 H), 1.78-2.21 (m, 6 H), 2.95
(d, J ) 3.7 Hz, 1 H), 3.33, 3.36 (2s, 3 H × 2), 3.40 (s, 2 H), 3.74
(dd, J ) 3.7, 6.2 Hz, 1 H), 3.96 (d, J ) 4.8 Hz, 1 H), 4.16 (dd,
J ) 6.2, 11.0 Hz, 1 H), 4.52, 4.56 (ABq, J ) 6.2 Hz, 1 H × 2),
oil: TLC, Rf 0.38 (EtOAc/hexane, 1:2); [R]21 -12.7 (c 0.81,
D
CHCl3); IR (neat) 2960, 2930, 2890, 2860, 1680 cm-1; 1H NMR
(270 MHz) δ 0.04, 0.19 (2s, 3 H × 2), 0.91 (s, 9 H), 1.13 (s, 3
H), 1.70 (s, 3 H), 1.74-2.14 (m, 4 H), 2.25 (ddd, J ) 3.7, 5.1,
15.0 Hz, 1 H), 2.47 (ddd, J ) 5.5, 7.3, 15.0 Hz, 1 H), 3.03 (s, 3
H), 3.35, 3.37 (2s, 3 H × 2), 3.41, 3.47 (ABq, J ) 10.6 Hz, 1 H
× 2), 3.77 (d, J ) 4.4 Hz, 1 H), 4.25 (dd, J ) 5.1, 7.3 Hz, 1 H),
4.54, 4.57 (ABq, J ) 6.6 Hz, 1 H × 2), 4.62-4.69 (m, 3 H),
5.45-5.52 (m, 1 H); 13C NMR (75 Hz) δ -3.5, -3.0, 11.4, 18.2,
20.9, 23.4, 25.9, 27.0, 37.1, 39.4, 45.8, 55.4, 55.7, 60.5, 66.9,
4.64, 4.68 (ABq, J ) 6.6 Hz, 1 H × 2), 5.52-5.54 (m, 1 H); 13
C
NMR (75 MHz) δ -4.0, -3.2, 10.7, 17.9, 21.2, 23.4, 25.7, 27.1,
38.2, 45.5, 55.3, 55.7, 60.6, 66.5, 76.2, 76.8, 78.1, 96.2, 96.8,
112.6, 118.3, 139.9; HRMS calcd for C24H44O7Si (M+) m/z
472.2856, found 472.2850.
(1R,3R, 8R,9S,10R,12S)-1-(ter t-Bu tyld im eth ylsilyloxy)-
10-(m eth oxym eth oxy)-8-[(m eth oxym eth oxy)m eth yl]-5,9-
d im eth yl-2-oxa tr icyclo[7.3.0.03,8]d od ec-4-en -12-ol (21â).
Compound 22â (51.1 mg, 0.099 mmol) was converted into 21â

Total Synthesis of (-)-Verrucarol
J . Org. Chem., Vol. 63, No. 8, 1998 2687
76.3, 76.7, 82.9, 96.0, 96.7, 112.4, 118.8, 139.2; HRMS calcd
(1R,3S,4S,5R,8R,9S,10R)-4-Br om o-10-h yd r oxy-12-m eth -
yle n e -5,9-d im e t h yl-2,6-d ioxa t e t r a cyclo[7.2.2.5,81.03,8]-
tetr a d eca n e (31). To a solution of 27 (4.0 mg, 0.016 mmol)
in acetone (1 mL) was added N-bromosuccinimide (4.3 mg,
0.024 mmol). The mixture was stirred at 0 °C for 15 min and
diluted with saturated brine (10 mL). This was extracted with
CHCl3 (5 mL × 3). The combined extracts were dried and
concentrated. The residue was purified by column chroma-
tography on silica gel to give 31 (3.1 mg, 58%) as colorless
crystals: mp 105-107 °C; TLC, Rf 0.30 (EtOAc/hexane, 3:2);
[R]25D -55.7 (c 0.12, CHCl3); IR (neat) 3440, 2970, 2930, 2875,
for C25H46O9SiS (M+) m/z 550.2632, found 550.2636.
(1R ,3R ,8R ,9S ,10R )-10-(Me t h oxym e t h oxy)-8-[(m e t h -
oxym eth oxy)m eth yl]-5,9-dim eth yl-2-oxatr icyclo[7.2.1.03.8]-
d od ec-4-en -12-on e (25). To a solution of 24 (51.1 mg, 0.093
mmol) in THF (2 mL) was added TBAF (1.0 M solution in THF,
0.23 mL, 0.23 mmol) at 0 °C. The mixture was stirred at 0 °C
for 40 min and then at ambient temperature for 1.5 h and
concentrated. The residue was purified by column chroma-
tography on silica gel (EtOAc/hexane, 1:4) to give 25 (30.8 mg,
97%) as a colorless oil: TLC, Rf 0.39 (EtOAc/hexane, 1:2); [R]26
D
1
1680 cm-1; H NMR (270 MHz) δ 0.93 (s, 3 H), 1.27 (s, 3 H),
-6.3 (c 0.82, CHCl3); IR (neat) 2940, 2890, 1760, 1680 cm-1
;
1H NMR (270 MHz) δ 1.09 (s, 3 H), 1.53-1.68 (m, 2 H), 1.71
(s, 3 H), 1.83 (ddd, J ) 3.3, 5.5, 15.8 Hz, 1 H), 1.91-2.08 (m,
2 H), 2.65 (dd, J ) 8.4, 15.8 Hz, 1 H), 3.35, 3.36 (2s, 3 H × 2),
3.43, 3.55 (ABq, J ) 10.6 Hz, 1 H × 2), 3.94 (d, J ) 5.1 Hz, 1
H), 4.16 (d, J ) 5.9 Hz, 1 H), 4.55, 4.58 (ABq, J ) 6.6 Hz, 1 H
× 2), 4.59, 4.67 (ABq, J ) 6.6 Hz, 1 H × 2), 5.01 (dd, J ) 3.3,
8.4 Hz, 1 H), 5.45-5.51 (m, 1 H); 13C NMR (75 Hz) δ 8.0, 21.4,
23.2, 27.9, 33.5, 49.2, 55.45, 55.53, 55.6, 66.4, 68.1, 73.6, 76.7,
95.2, 96.9, 117.7, 141.0, 213.1; HRMS calcd for C18H28O6 (M+)
m/z 340.1886, found 340.1865.
1.32-1.48 (m, 1 H), 1.66 (ddd, J ) 3.3, 5.1, 15.4 Hz, 1 H), 1.71-
1.91 (m, 2 H), 2.11-2.28 (m, 1 H), 2.62 (dd, J ) 7.3, 15.4 Hz,
1 H), 3.75 (s, 2 H), 3.83 (dd, J ) 2.6, 8.8 Hz, 1 H), 4.23 (dd, J
) 1.8, 8.8 Hz, 1 H), 4.30-4.40 (br, 1 H), 4.59 (d, J ) 5.1 Hz, 1
H), 4.73 (s, 1 H), 5.20 (s, 1 H); 13C NMR (75 MHz) δ 10.2, 18.4,
24.3, 27.8, 29.7, 40.3, 41.0, 55.0, 66.6, 67.6, 72.4, 73.2, 79.3,
106.4, 150.2; HRMS calcd for C15H21O3Br (M+) m/z 328.0674,
found 328.0678.
(1R,3R,8R,9S,10R)-10-(ter t-Bu t yld im et h ylsilyloxy)-8-
h ydr oxym eth yl-5,9-dim eth yl-12-m eth ylen e-2-oxatr icyclo-
[7.2.1.03.8]dodec-4-en e (28) an d (1R,3R,8R,9S,10R)-10-(ter t-
B u t y ld im e t h y ls ily lo x y )-8-[(t er t -b u t y ld im e t h y ls ily l-
oxy)m et h yl]-5,9-d im et h yl-12-m et h ylen e-2-oxa t r icyclo-
[7.2.1.03.8]d od ec-4-en e (29). The following reaction was
carried out under Ar. To a cold (-78 °C) solution of 27 (10.8
mg, 0.043 mmol) in CH2Cl2 (1 mL) were added 2,6-lutidine
(0.015 mL, 0.13 mmol) and tert-butyldimethylsilyl trifluo-
romethanesulfonate (TBSOTf) (0.012 mL, 0.052 mmol). The
mixture was stirred for 44 h while 2,6-lutidine (total 0.17 mL,
1.42 mmol) and TBSOTf (total 0.13 mL, 0.57 mmol) were added
in 7 portions. The mixture was quenched with H2O (0.1 mL),
diluted with EtOAc (10 mL), and washed with saturated brine
(5 mL × 2). The organic layer was dried and concentrated.
The residue was purified by column chromatography on silica
gel to give 28 (6.2 mg, 40%) and 29 (8.0 mg, 39%). 28 as a
colorless oil: TLC, Rf 0.46 (EtOAc/hexane, 1:4); IR (neat) 3440,
2960, 2930, 2855, 1680 cm-1; 1H NMR (270 MHz) δ 0.07, 0.08
(2s, 3 H × 2), 0.88 (s, 9 H), 1.08 (s, 3 H), 1.45-1.58 (m, 2 H),
1.63 (ddd, J ) 2.9, 5.1, 14.7 Hz, 1 H), 1.69 (s, 3 H), 1.80-2.06
(m, 3 H), 2.41 (dd, J ) 7.0, 15.0 Hz, 1 H), 3.56, 3.75 (ABq, J )
11.7 Hz, 1 H × 2), 3.65 (d, J ) 5.9 Hz, 1 H), 4.35 (d, J ) 5.1
Hz, 1 H), 4.63 (dd, J ) 2.9, 7 3 Hz, 1 H), 4.65 (d, J ) 0.7 Hz,
1 H), 5.08 (s, 1 H), 5.39-5.42 (m, 1 H). 29 as a colorless oil:
TLC, Rf 0.85 (EtOAc/hexane, 1:2); IR (neat) 2960, 2930, 2860,
1680 cm-1; 1H NMR (270 MHz) δ 0.00, 0.02, 0.06 (3s, 3H, 3 H,
6 H), 0.87, 0.89 (2s, 9 H × 2), 1.06 (s, 3 H), 1.23-1.48 (m, 1
H), 1.53-1.86 (m, 2 H), 1.66 (s, 3 H), 1.91-2.01 (m, 2 H), 2.39
(dd, J ) 7.0, 15.0 Hz, 1 H), 3.42, 3.63 (ABq, J ) 10.6 Hz, 1 H
× 2), 3.57 (d, J ) 5.9 Hz, 1 H), 4.21 (dd, J ) 3.3, 6.2 Hz, 1 H),
4.33 (d, J ) 5.5 Hz, 1 H), 4.55 (dd, J ) 2.9, 7.0 Hz, 1 H), 4.63
(d, J ) 0.9 Hz, 1 H), 5.06 (s, 1 H), 5.31-5.38 (m, 1 H).
(1R ,3R ,8R ,9S ,10R )-10-(Me t h oxym e t h oxy)-8-[(m e t h -
oxym et h oxy)m et h yl]-5,9-d im et h yl-12-m et h ylen e-2-oxa -
tr icyclo[7.2.1.03.8]d od ec-4-en e (26). The following reaction
was carried out under Ar. A THF solution of (methylene)-
triphenylphosphorane was prepared as follows. To a suspen-
sion of methyltriphenylphosphonium bromide (265 mg, 0.74
mmol) in THF (1.6 mL) was added n-BuLi (1.66 M solution in
hexane, 0.41 mL, 0.67 mmol) at - 78 °C. The mixture was
stirred for 20 min, and the resulting solution was used as the
Wittig reagent. To a solution of 25 (30.5 mg, 0.090 mmol) in
THF (1 mL) was added the ylide solution prepared above (0.96
mL, 0.31 mmol). The resulting solution was heated at 60 °C
with stirring for 1 h, and the ylide solution was added (0.54
mL). The solution was stirred at 60 °C for additional 1 h. The
solution was cooled to ambient temperature and saturated
aqueous NH4Cl (5 mL) was added. The whole was extracted
with CHCl3 (5 mL × 3). The combined extracts were dried
and concentrated. The residue was purified by column chro-
matography on silica gel (EtOAc/hexane, 1:6) to give 26 (22.0
mg, 73%) as a colorless oil: TLC, Rf 0.50 (EtOAc/hexane, 1:2);
[R]23 -79.7 (c 0.44, CHCl3); IR (neat) 2930, 2890, 1680 cm-1
;
D
1H NMR (270 MHz) δ 1.15 (s, 3 H), 1.43-2.04 (m, 5 H), 1.68
(s, 3 H), 2.47 (dd, J ) 7.3, 15.0 Hz, 1 H), 3.36 (s, 6 H), 3.40,
3.58 (ABq, J ) 10.6 Hz, 1 H × 2), 3.77 (d, J ) 5.5 Hz, 1 H),
4.40 (d, J ) 5.5 Hz, 1 H), 4.57 (s, 2 H), 4.61, 4.67 (ABq, J )
7.0 Hz, 1 H × 2), 4.71 (s, 1 H), 4.75 (dd, J ) 2.9, 7.3 Hz, 1 H),
5.11 (s, 1 H), 5.31-5.43 (m, 1 H); 13C NMR (75 MHz) δ 11.5,
20.4, 23.3, 28.1, 38.3, 43.2, 52.1, 55.35, 55.42, 66.7, 68.5, 77.6,
78.9, 95.3, 97.0, 104.9, 119.0, 140.2, 153.1; HRMS calcd for
C
19H30O5 (M+) m/z 338.2093, found 338.2105.
(1R,3R,8R,9S,10R)-8-Hyd r oxym eth yl-5,9-d im eth yl-12-
m eth ylen e-2-oxa tr icyclo[7.2.1.03.8]d od ec-4-en -10-ol, (-)-
12,13-Deoxyver r u ca r ol (27). The following reaction was
carried out under Ar. To a cold (-30 °C) solution of 26 (7.9
mg, 0.023 mmol) in CH2Cl2 (1 mL) were added bromotrimeth-
ylsilane (0.012 mL, 0.094 mmol) and molecular sieves (4A
powder, 6.2 mg). The mixture was stirred at -30 °C for 5.5
h, and saturated aqueous NaHCO3 (5 mL) was added. The
whole was extracted with CH2Cl2 (5 mL × 6). The combined
extracts were dried and concentrated. The residue was
purified by column chromatography on silica gel (acetone/
toluene, 1:6 to 1:3) to give 27 (4.5 mg, 78%) as amorphous
solids: TLC, Rf 0.31 (acetone/toluene, 1:2); [R]26D -93.3 (c 0.18,
CHCl3); IR (neat) 3400, 2960, 2930, 2855, 1680 cm-1; 1H NMR
(270 MHz) δ 1.17 (s, 3 H), 1.40-2.06 (m, 7 H), 1.66 (s, 3 H),
2.55 (dd, J ) 7.7, 15.4 Hz, 1 H), 3.58, 3.78 (ABq, J ) 11.7 Hz,
1 H × 2), 3.70 (d, J ) 5.5 Hz, 1 H), 4.39 (d, J ) 5.1 Hz, 1 H),
4.71 (dd, J ) 2.6, 7.7 Hz, 1 H), 4.72 (s, 1 H), 5.14 (s, 1 H),
5.38-5.45 (m, 1 H); 13C NMR (75 MHz) δ 11.5, 20.3, 23.3, 28.2,
40.3, 43.9, 52.5, 63.0, 66.4, 73.4, 78.6, 105.6, 119.1, 140.5, 152.6;
HRMS calcd for C15H22O3 (M+) m/z 250.1569, found 250.1564.
To a solution of 29 (8.0 mg, 0.016 mmol) in THF (1 mL)
was added TBAF (1.0 M solution in THF) in 3 portions (0.020
mL, 0.034 mL, 0.017 mL after 0, 1.3, and 4 h). The solution
was stirred for total 5.5 h, then the solvent was removed by
concentration. The residue was purified by column chroma-
tography on silica gel to give (4.0 mg, 95%) of 27.
Com p ou n d 31 fr om 28. To a solution of 28 (5.6 mg, 0.015
mmol) in acetone (1 mL) was added N-bromosuccinimide (4.2
mg, 0.023 mmol). The mixture was stirred at 0 °C for 10 min
and diluted with EtOAc (10 mL). This was washed with
saturated brine (5 mL × 2). The combined extracts were dried
and concentrated. The residue was purified by column chro-
matography on silica gel (EtOAc/hexane, 1:25) to give 30 (6.4
mg); TLC, Rf 0.68 (EtOAc/hexane, 1:4); IR (neat) 2980, 2930,
1
2855, 1680 cm-1; H NMR (270 MHz) δ 0.03, 0.04, (2s, 3 H ×
2), 0.84 (s, 3 H), 0.85 (s, 9 H), 1.26 (s, 3 H), 1.32-1.45 (m, 1
H), 1.63-1.90 (m, 3 H), 2.10-2.26 (m, 1 H), 2.47 (dd, J ) 7.0,
15.0 Hz, 1 H), 3.67-3.78 (m, 2 H), 3.82 (dd, J ) 2.6, 8.8 Hz, 1
H), 4.22 (dd, J ) 1.8, 8.4 Hz, 1 H), 4.32 (dd, J ) 2.9, 7.0 Hz,
1 H), 4.55 (d, J ) 5.1 Hz, 1 H), 4.66 (s, 1 H), 5.13 (s, 1 H).

2688 J . Org. Chem., Vol. 63, No. 8, 1998
Ishihara et al.
To a solution of 30 (6.4 mg, 0.014 mmol) in THF (1 mL)
was added TBAF (1.0 M solution in THF, 0.022 mL, 0.022
mmol). The mixture was stirred at 0 °C for 2 h and then at
ambient temperature for 3 h and the solvent was removed by
concentration. The residue was purified by column chroma-
tography on silica gel (EtOAc/hexane, 1:6 to 1:1) to give 31
(4.5 mg, 96%).
insoluble materials were removed by filtration through a Celite
pad and washed with EtOAc. The combined filtrate and
washings were concentrated. The residue was partitioned
between CHCl3 (5 mL) and saturated brine (10 mL). The
aqueous layer was extracted with EtOAc (5 mL × 2). The
combined organic layers were dried and concentrated. The
residue was purified by column chromatography on silica gel
(acetone/toluene, 1:6 to 1:3) to give 7 (2.6 mg, 81%) as colorless
crystals: mp 144-147 °C; TLC, Rf 0.10 (acetone/toluene, 1:3);
Ep oxid a tion of 31. F or m a tion of Ep oxid e 32. To a
solution of 31 (4.5 mg, 0.014 mmol) in CH2Cl2 (1 mL) were
added m-chloroperbenzoic acid (5.1 mg, 0.021 mmol) and
NaHCO3 (4.0 mg, 0.048 mmol). The mixture was stirred for
16 h and diluted with 10% aqueous NaHSO3 (5 mL) and then
saturated aqueous NaHCO3 (5 mL). This was extracted with
CHCl3 (5 mL × 3). The combined extracts were dried and
concentrated. The residue was purified by column chroma-
tography on silica gel (acetone/toluene, 1:8 to 1:6) to give 32
(4.3 mg, 91%) as white crystals: mp 179-181 °C; TLC, Rf 0.29
[R]21 -40.6 (c 0.13, CHCl3); IR (neat) 3420, 2965, 2935, 2855
D
cm-1; 1H NMR (400 MHz) δ 0.95 (s, 3 H), 1.69-2.11 (m, 7 H),
1.72 (s, 3 H), 2.58 (dd, J ) 7.7, 15.8 Hz, 1 H), 2.86 (d, J ) 3.7
Hz, 1 H), 3.11 (d, J ) 3.7 Hz, 1 H), 3.57, 3.77 (ABq, J ) 12.1
Hz, 1 H × 2), 3.62 (d, J ) 5.5 Hz, 1 H), 3.82 (d, J ) 5.5 Hz, 1
H), 4.62 (dd, J ) 2.9, 7.3 Hz, 1 H), 5.41-5.46 (m, 1 H); 13C
NMR (100 MHz) δ 7.3, 20.9, 23.3, 28.2, 39.9, 43.8, 47.6, 48.9,
62.5, 65.7, 66.5, 74.5, 78.6, 118.7, 141.1; HRMS calcd for
(acetone/toluene. 1:4); [R]25 -41.0 (c 0.21, CHCl3); IR (neat)
C
15H22O4 (M+) m/z 266.1518, found 266.1520.
D
3490, 2930, 2875 cm-1
;
1H NMR (270 MHz) δ 0.73 (s, 3 H),
1.28 (s, 3 H), 1.47-1.58 (m, 1 H), 1.71-2.28 (m, 4 H), 2.64
(dd, J ) 7.3, 15.8 Hz, 1 H), 2.78 (d, J ) 3.7 Hz, 1 H), 3.13 (d,
J ) 3.7 Hz, 1 H), 3.69-3.81 (m, 3 H), 3.98 (d, J ) 5.5 Hz, 1
H), 4.23 (dd, J ) 1.8, 8.8 Hz, 1 H), 4.27-4.38 (m, 1 H); 13C
NMR (100 MHz) δ 6.3, 19.0, 24.3, 27.8, 29.7, 40.2, 40.5, 46.4,
47.0, 54.3, 66.1, 67.7, 73.2, 73.5, 79.4; HRMS calcd for
Ack n ow led gm en t. We thank Professors Christoph
Tamm (Basel University) and Bruce B. J arvis (Mary-
land University) for their kind supply of naturally
derived verrucarol for our comparison.
1
Su p p or tin g In for m a tion Ava ila ble: Copies of H NMR
C
14H18O4Br (M+-CH3) m/z 329.0388, found 329.0403.
spectra and of 13C NMR spectra of 11R, 11â, 13-18, 19R, 19â,
20, 21R, 21â, 22â, 23-27, 31, 32, synthetic (-)-verrucarol (7),
and naturally derived (-)-verrucarol and also 1H NMR spectra
of 12, 22R, and 28-30 (51 pages). This material is contained
in libraries on microfiche, immediately follows this article in
the microfilm version of the journal, and can be ordered from
the ACS; see any current masthead page for ordering
information.
(1R,3R,8R,9S,10R)-12-Ep oxy-8-h yd r oxym eth yl-5,9-d im -
eth yl-2-oxa tr icyclo[7.2.1.03.8]d od ec-4-en -10-ol, (-)-Ver r u -
ca r ol (7). A zinc-silver couple was prepared according to the
literature method.45 Compound 32 (4.2 mg, 0.012 mmol) was
dissolved in a mixture of THF and EtOH (5:1, 1.2 mL), and
the zinc-silver couple (5.1 mg), prepared from silver acetate
(1 mg) and activated zinc (125 mg), was added. The mixture
was refluxed for 83.5 h with stirring while each 10 mg of the
zinc-silver couple was added for an interval of 20 h. The
J O972309F