Stereocontrolled Total Synthesis of Hemibrevetoxin B

Article abstract of DOI:10.1021/jo9807619

The stereocontrolled total synthesis of hemibrevetoxin B (1) has been achieved in 56 steps and 0.75% overall yield from D-mannose. The intramolecular reaction of γ-alkoxyallylstannane with aldehyde is a key step for the present total synthesis. Thus, the BF₃·OEt₂-mediated reaction of 24 gave 6 as a sole product. We encountered difficulty in the synthesis of γ-alkoxyallylstannane 30 from the corresponding allyl ether 29 in which the γ-alkoxy substituent became sterically quite bulky. This problem was solved by developing the acetal cleavage method for the synthesis of γ-alkoxyallylstannanes. The cyclization of 38 proceeded smoothly to give the key intermediate 5 in a highly stereoselective manner. Construction of the α-vinyl aldehyde and (Z)-diene moieties were performed using Nicolaou's protocol.

Full text of DOI:10.1021/jo9807619

J . Org. Chem. 1998, 63, 6597-6606
6597
Ster eocon tr olled Tota l Syn th esis of Hem ibr evetoxin B
Isao Kadota† and Yoshinori Yamamoto*
Research Center for Organic Resources and Materials Chemistry, Institute for Chemical Reaction Science,
and Department of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, J apan
Received April 22, 1998
The stereocontrolled total synthesis of hemibrevetoxin B (1) has been achieved in 56 steps and
0.75% overall yield from D-mannose. The intramolecular reaction of γ-alkoxyallylstannane with
aldehyde is a key step for the present total synthesis. Thus, the BF3‚OEt2-mediated reaction of 24
gave 6 as a sole product. We encountered difficulty in the synthesis of γ-alkoxyallylstannane 30
from the corresponding allyl ether 29 in which the γ-alkoxy substituent became sterically quite
bulky. This problem was solved by developing the acetal cleavage method for the synthesis of
γ-alkoxyallylstannanes. The cyclization of 38 proceeded smoothly to give the key intermediate 5
in a highly stereoselective manner. Construction of the R-vinyl aldehyde and (Z)-diene moieties
were performed using Nicolaou’s protocol.
In tr od u ction
ported the total and formal total syntheses of 1, respec-
tively. The serious drawback of our previous synthesis6
was that the conversion of allyl ether to γ-alkoxyallyl-
stannane in a certain stage resulted in only 16% yield
(vide post 30), although good yields were obtained in the
other steps. Now, we have found a new method for the
synthesis of γ-alkoxyallylstannanes, and by using this
method the problem has been solved. Herein we describe
in detail the stereocontrolled total synthesis of hemibre-
vetoxin B (1).
In recent years there has been an explosion of interest
in biologically active natural products of marine origin.1
Much attention has been paid to the synthesis of poly-
cyclic ethers due to their unusual structures, biological
activities, and rarity in nature.2 Hemibrevetoxin B (1),
which has a 6,6,7,7-tetracyclic ether skeleton including
10 stereocenters, an R-vinyl aldehyde, and a (Z)-diene
moiety, was isolated from the cultured cells of the red
tide organism Gymnodinium breve by Shimizu in 1989.3
Str a tegy a n d Retr osyn th etic An a lysis
During the past several years we have been studying
the stereoselective synthesis of medium-sized cyclic
ethers via the intramolecular reaction of an allylic
stannane with an aldehyde.9 This methodology is rec-
ognized to be one of the most powerful methods for the
synthesis of oxepane derivatives.10 For example, the
reaction of monocyclic ether 2 with BF3‚OEt2 gave
quantitatively the cyclic ether 3 as the sole product
(Scheme 1).9a,b The characteristic features of this reaction
are not only the high yield and high stereoselectivity but
also the presence of a hydroxy and a vinyl group attached
to the newly formed cyclic ether skeleton. Further
manipulation based on these two functional groups can
lead to aldehyde and γ-alkoxyallylstannane side chains,
thus the repeated use of the cyclization produced the
6,7,7,6-tetracyclic ether 4 which is a part of brevetoxin
The unique structural features have attracted the atten-
tion of synthetic chemists, and a number of strategies
have been investigated.4 The first total synthesis of
hemibrevetoxin B (1) was accomplished by Nicolaou in
1992,5 and the second was achieved by us in 1995.6 More
recently, the Nakata7 and Mori8 groups have also re-
† Institute for Chemical Reaction Science.
(1) For recent reviews, see: (a) Shimizu, Y. Chem. Rev. 1993, 93,
1685-1698. (b) Yasumoto, T.; Murata, M. Chem. Rev. 1993, 93, 1897-
1909.
(2) For recent reviews, see: (a) Alvarez, E.; Candenas, M.-L.; Pe´rez,
R.; Ravelo, J . L.; Mart´ın, J . D. Chem. Rev. 1995, 95, 1953-1980. (b)
Nicolaou, K. C. Angew. Chem., Int. Ed. Engl. 1996, 35, 589-607.
(3) Prasad, A. V. K.; Shimizu, Y. J . Am. Chem. Soc. 1989, 111, 6476-
6477.
(7) Morimoto, M.; Matsukura, H.; Nakata, T. Tetrahedron Lett. 1996,
37, 6365-6368.
(8) Mori, Y.; Yaegashi, K.; Furukawa, H. J . Am. Chem. Soc. 1997,
119, 4557-4558.
(4) (a) Feng, F.; Murai, A. Chem. Lett. 1992, 1587-1590. (b) Kadota,
I.; Matsukawa, Y.; Yamamoto, Y. J . Chem. Soc., Chem. Commun. 1993,
1638-1641. (c) Feng, F.; Murai, A. Chem. Lett. 1995, 23-24. (d) Feng,
F.; Murai, A. Synlett 1995, 863-865. (e) Ishihara, J .; Murai, A. Synlett
1996, 363-365. (f) Nakata. T.; Nomura, S.; Matsukura, H.; Morimoto,
M. Tetrahedron Lett. 1996, 37, 217-220. (g) Matsukura, H.; Morimoto,
M.; Nakata. T. Chem. Lett. 1996, 487-488. (h) Gleason, M. M.;
McDonald, F. E. J . Org. Chem. 1997, 62, 6432-6435.
(5) (a) Nicolaou, K. C.; Reddy, K. R.; Skokotas, G.; Sato, F.; Xiao,
X.-Y. J . Am. Chem. Soc. 1992, 114, 7935-7936. (b) Nicolaou, K. C.;
Reddy, K. R.; Skokotas, G.; Sato, F.; Xiao, X.-Y.; Hwang, C.-K. J . Am.
Chem. Soc. 1993, 115, 3558-3575.
(9) (a) Yamamoto, Y.; Yamada, J .; Kadota, I. Tetrahedron Lett. 1991,
32, 7069-7072. (b) Gevorgyan, V.; Kadota, I.; Yamamoto, Y. Tetrahe-
dron Lett. 1993, 34, 1313-1316. (c) Kadota, I.; Kawada. M.; Gevorgyan,
V.; Yamamoto, Y. J . Org. Chem. 1997, 62, 7439-7446.
(10) (a) Suzuki, T.; Sato, O.; Hirama, M.; Yamamoto, Y.; Murata,
M.; Yasumoto, T.; Harada, N. Tetrahedron Lett. 1991, 32, 4505-4508.
(b) Ravelo, J . L.; Regueiro, A.; Mart´ın, J . D. Tetrahedron Lett. 1992,
33, 3389-3392. (c) Kadota, I.; Matsukawa, Y.; Yamamoto, Y. J . Chem.
Soc., Chem. Commun. 1993, 1638-1641. (d) Alvarez, E.; D´ıaz, M. T.;
Pe´rez, R.; Ravelo, J . L.; Regueiro, A.; Vera, J . A.; Zurita, D.; Mart´ın,
J . D. J . Org. Chem. 1994, 59, 2848-2870. (e) Yamamoto, Y.; Kadota,
I. Bull. Soc. Chim. Belg. 1994, 103, 619-629. (f) Oguri, H.; Hishiyama,
S.; Oishi, T.; Hirama, M. Synlett 1995, 1252-1254.
(6) For a preliminary communication, see: Kadota, I.; Park, J .-Y.;
Koumura, N.; Pollaud, G.; Matsukawa, Y.; Yamamoto, Y. Tetrahedron
Lett. 1995, 36, 5777-5780.
S0022-3263(98)00761-0 CCC: $15.00 © 1998 American Chemical Society
Published on Web 08/28/1998

6598 J . Org. Chem., Vol. 63, No. 19, 1998
Kadota and Yamamoto
Sch em e 1
Sch em e 3a
Sch em e 2. Retr osyn th etic An a lysis of
Hem ibr evetoxin B (1)
a
Conditions: (a) BnBr, KH, THF, rt, 98%; (b) HCl, MeOH, rt,
100%; (c) (i) Bu2SnO, MeOH, reflux; (ii) BnBr, CsF, DMF, rt, 94%;
(d) TESCl, imidazole, DMF, rt, 99%; (e) (i) O3, CH2Cl2, -79 °C,
then Ph3P, rt; (ii) Ph3PdC(Me)CO2Et, benzene, reflux, 91%; (f)
t
DIBALH, CH2Cl2, -78 °C, 87%; (g) (+)-DET, Ti(OiPr)4, BuOOH,
4A molecular sieves, CH2Cl2, -20 °C; (h) (i) SO3‚py, DMSO, Et3N,
CH2Cl2, rt; (ii) Ph3PdCHCO2Me, benzene, reflux, 82% from 14;
(i) TBAF, THF, rt, 100%; (j) CSA, CH2Cl2, rt, 81%.
8 as a benzyl ether led to 9, followed by methanolysis of
the acetonide group to give the diol 10 quantitatively.
Allylic alcohol 14 was produced in five steps as shown in
Scheme 3. Sharpless asymmetric epoxidation of 14 using
(+)-diethyl tartrate (DET) as a chiral auxiliary gave the
epoxide 15, which was converted to ester 17 as illustrated
in Scheme 3. Cyclization of the hydroxy epoxide 17 with
camphorsulfonic acid gave 7 to complete synthesis of the
AB ring system.
Con str u ction of th e C Rin g
B. Encouraged by these successful results, we examined
the retrosynthetic analysis of hemibrevetoxin B (1) as
illustrated in Scheme 2.
The stereocontrolled synthesis of the C ring is shown
in Scheme 4. The secondary hydroxy group of 7 was
protected as an acetate to give 18, debenzylation and
hydrogenation of which afforded the diol 19 in high yield.
The free OH groups were protected with triisopropylsilyl
triflate to give the bis-silyl ether 20 quantitatively.
Reduction of 20 with LiAlH4 afforded the diol 21 in 100%
yield. Selective protection of the primary alcohol followed
by allylation of the secondary alcohol and selective
cleavage of the TES ether under mild acidic conditions
gave the allyl ether 22. Generation of the corresponding
allylic anion by using excess sec-BuLi/TMEDA followed
by trapping with n-Bu3SnCl afforded 23, which was
oxidized to produce the cyclization precursor 24.
Since constructions of the R-vinyl aldehyde and (Z)-
diene moieties have been developed by Nicolaou,5 we
focused our efforts on the synthesis of the potential
precursor 5. Sequential retrosynthetic disassembly of the
bis-oxepane ring system of 5 based on the allylic tin
methodology mentioned above allowed the generation of
the intermediate 7 via 6. The B ring of 7 was then
retrosynthetially broken by an epoxide opening-ring
closure reaction leading to the known starting material
8,11 which can be derived from D-mannose.
Syn th esis of th e AB Rin g System
Aldehyde 24 was then subjected to the cyclization by
treatment with BF3‚OEt2 at -78 °C to give the desired
tricyclic ether 6 in 94% yield with high stereoselectivity.
Although the stereochemistry of 6 was not confirmed at
this stage, we presumed it from the preliminary study
described in Scheme 1. The observed high stereoselec-
tivity can be explained by the well-accepted acyclic
The preparation of AB ring system was carried out
primarily based on a modification of Nicolaou’s method
(Scheme 3).11 Thus, protection of the primary alcohol of
(11) (a) Nicolaou, K. C.; Hwang, C.-K.; Duggan, M. E. J . Am. Chem.
Soc. 1989, 111, 6682-6690. (b) Nicolaou, K. C.; Veale, C. A.; Hwang,
C.-K.; Hutchinson, J .; Prasad, C. V. C.; Ogilvie, W. W. Angew. Chem.,
Int. Ed. Engl. 1991, 30, 299-303.

Total Synthesis of Hemibrevetoxin B
J . Org. Chem., Vol. 63, No. 19, 1998 6599
Sch em e 4a
titatively (Scheme 5). Further elaboration of 26 was
carried out using the similar methodology as shown in
Scheme 4 to provide 29. In contrast to earlier results in
the synthesis of compound 23, the usual allylic anion
formation followed by trapping with n-Bu3SnCl afforded
30 in only 16% yield along with the recovered starting
material. Deprotonation of the sterically bulky allylic
ether 29 would possibly be quite slow, and the decom-
position of the resulting allylic anion would compete if a
prolonged reaction time was employed. This problem
prompted us to develop a new synthesis of γ-alkoxy-
allylstannanes.
Scheme 6 shows the general synthetic sequence for the
γ-alkoxyallylstannanes via an acetal cleavage.14 We have
found that the combined use of trimethylsilyl iodide
(TMSI) and hexamethyldisilazane (HMDS) is the best
choice for the cleavage of mixed acetals15,16 having the
tributylstannyl group. The acetals are easily prepared
by acid-catalyzed reaction of the corresponding alcohols
and γ-methoxyallylstannane 31.17 As demonstrated in
Table 1, the reaction of secondary alcohol 32, prepared
quantitatively by selective protection of the primary
hydroxy group of 21 with pivaloyl chloride (PvCl)/
pyridine, with 31 in the presence of a catalytic amount
of CSA proceeded smoothly to give the mixed acetal 33
as a 1:1 diastereomeric mixture. It should be noted that
the use of an excess of 31 is required to obtain the mixed
acetals in high yield, otherwise a significant amount of
symmetric acetal is formed as a byproduct. Treatment
of 33 with TMSI and HMDS afforded the desired enol
ether 34 in 83% yield. Interestingly, only (Z)-allylic
stannane was produced, perhaps due to the coordination
of ether oxygen to a tin atom. Encouraged by this
success, the acetal methodology was used to introduce
the allylic stannane moiety efficiently into tricyclic ether
35 (Table 1). It is notable that both of acetal formation
and cleavage were not affected by the bulkiness of the
substrates.
a
Conditions: (a) Ac2O, pyridine, DMAP, CH2Cl2, rt, 97%; (b)
H2, Pd(OH)2-C, MeOH, rt, 99%; (c) TIPSOTf, 2,6-lutidine, DMF,
rt to 70 °C, 100%; (d) LiAlH4, ether, 0 °C, 100%; (e) (i) TESCl,
Et3N, CH2Cl2, -15 °C; (ii) allyl bromide, KH, THF, rt; (iii)
Amberlyst-15, EtOH, rt, 96%; (f) sec-BuLi, TMEDA, THF, -78 °C,
then nBu3SnCl, -78 °C to rt, 69%; (g) SO3‚py, DMSO, Et3N,
CH2Cl2, rt, 90%; (h) BF3‚OEt2, CH2Cl2, -78 °C, 94%.
The final sequence of the synthesis is shown in Scheme
7. Removal of the pivalate protecting group with DIBALH
led to 30, which was oxidized to furnish the aldehyde 38.
The BF3‚OEt2-mediated cyclization of 38 afforded the
tetracyclic ether 5 as a sole product in 98% yield. Again,
perfect stereoselectivity was observed in the cyclization
step. The introduction of a methyl group at the D ring
was performed using Murai protocol.4a Thus, Swern
oxidation of 5 followed by treatment with MeMgBr in
toluene at -78 °C gave an 86:14 mixture of the desired
isomer 39 and its epimer 40. As reported by Nicolaou,
the reaction carried out in ether gave poor selectivity (ca.
1:1).5 The major product 39 was isolated by chromatog-
raphy, and the tertiary alcohol was protected with tert-
butyldimethylsilyl triflate (TBSOTf)/2,6-lutidine to give
41. Ozonolysis of 41 followed by Wittig reaction gave 42,
hydrogenation of which followed by LiAlH4 reduction
F igu r e 1. Presumed transition states of the cyclization of 24.
transition state model (Figure 1).12 To avoid the 1,3-
diaxial repulsion, the allylic stannane moiety and the
carbonyl oxygen of the substrate are oriented to a pseudo-
equatorial position (24A) leading to 6. All of the other
transition state structures (24B, C, and D) do not
contribute to the reaction because of the significant steric
repulsion of the axially oriented groups, as depicted in
Figure 1.13
Syn th esis of th e D Rin g a n d Com p letion of th e
Tota l Syn th esis
(14) For
a preliminary report, see: Kadota, I.; Sakaihara, T.;
Yamamoto, Y. Tetrahedron Lett. 1996, 37, 3195-3198.
(15) Miller, R. D.; McKean, D. R. Tetrahedron Lett. 1982, 23, 323-
326.
Acetylation of 6 followed by ozonolysis and Wittig
reaction afforded R,â-unsaturated ester 26 via 25, quan-
(16) For other examples of this type of transformation, see: (a) (HC-
(OMe)3/TsOH) Wohl, R. A. Synthesis 1974, 38-40. (b) (AlCl3/Et3N)
Barbot, F.; Miginiac, P. Helv. Chim. Acta 1979, 1451-1457. (c)
((CO)5MnSiMe3) Marsi, M.; Gladysz, J . A. Organometallics 1982, 1,
1467-1473. (d) (TiCl4/DBU) Fleet, G. W. J .; J ames, K.; Lunn, R. J .
Tetrahedron Lett. 1986, 27, 3053-3056. (e) (i-Bu3Al) Naruse, Y.;
Yamamoto, H. Tetrahedron Lett. 1986, 27, 1363-1366.
(17) For the synthesis of 31, see: Koreeda, M.; Tanaka, Y. Tetra-
hedron Lett. 1987, 28, 143-146.-
(12) For representative studies on the reaction of allylstannanes
with aldehydes, see: (a) Yamamoto, Y.; Yatagai, H.; Naruta, Y.;
Maruyama, K. J . Am. Chem. Soc. 1980, 102, 7109-7110. (b) Denmark,
S. E.; Weber, E. J . J . Am. Chem. Soc. 1984, 106, 7970-7971. For recent
reviews, see: (c) Yamamoto, Y.; Asao, N. Chem. Rev. 1993, 93, 2207-
2293 and references therein. (d) Nishigaichi, Y.; Takuwa, A.; Naruta,
Y.; Maruyama, K. Tetrahedron 1993, 49, 7395-7426.
(13) For a detailed discussion of this reaction, see ref 9c.

6600 J . Org. Chem., Vol. 63, No. 19, 1998
Kadota and Yamamoto
Sch em e 5a
a
Conditions: (a) Ac2O, pyridine, DMAP, CH2Cl2, rt, 100%; (b) (i) O3, CH2Cl2, -78 °C, then Ph3P, -78 °C to rt; (ii) Ph3PdCHCO2Me,
CH2Cl2, 0 °C to rt, 99%; (c) (i) H2, 10% Pd-C, EtOAc, rt; (d) LiAlH4, ether, 0 °C, 98%; (e) (i) TESCl, Et3N, CH2Cl2, -15 °C; (ii) allyl
bromide, KH, THF, rt; (iii) Amberlyst-15, EtOH, rt, 94%; (f) sec-BuLi, TMEDA, THF, -78 °C, then nBu3SnCl, -78 °C to rt, 16%.
Sch em e 6
considerably longer, the target molecule 1 was obtained
in relatively high yield. The efficiency of the total
synthesis exceeds those of the other synthetic routes by
a factor of 15 to 25 (Nicolaou, overall 0.03% from
D-mannose by 57 steps;5 Nakata, overall 0.05% yield from
geranyl acetate by 57 steps7). Demonstrated in this study
was the power of the intramolecular reaction of γ-alkoxy-
allylstannanes with aldehydes as a tool for the synthesis
of polycyclic ethers (see the conversion of 24 f 6 and 38
f 5). The novel and efficient methods for synthesis of
the cyclization precursors is also deserving of attention
(see Scheme 6 and Table 1).
Ta ble 1. Syn th esis of th e γ-Alk oxya llylsta n n a n es via a n
Aceta l Clea va ge
Exp er im en ta l Section
Gen er a l P r oced u r e. All reactions involving air- and/or
moisture-sensitive materials were carried out under argon
with dry, freshly distilled solvents unless otherwise noted.
Ether and THF were distilled from sodium/benzophenone
ketyl. CH2Cl2, hexane, benzene, triethylamine, pyridine, DMF,
DMSO, HMPA, tributyltin chloride, N,N,N′,N′-tetramethyl-
ethylenediamine (TMEDA), and hexamethyldisilazane (HMDS)
were distilled from CaH2. All other reagents were purchased
at highest commercial quality and used without further
purification. On workup, extracts were dried over MgSO4.
All reactions were monitored by thin-layer chromatography
on Merck precoated aluminum plates (Kieselgel 60 F254, 0.2
mm) by using UV light and p-anisaldehyde solution as a
developing reagent. Column chromatography was performed
with Merck silica gel 60 (70-230 mesh ASTM), and for flash
chromatography, Merck silica gel 60 (230-400 mesh ASTM)
was employed. Yields refer to chromatographically and spec-
troscopically (1H NMR) homogeneous materials.
a
b
3.0 equiv of 31, 0.2 equiv of CSA, CH2Cl2, rt. 5.0 equiv of
TMSI, 7.0 equiv of HMDS, CH2Cl2, -15 °C.
afforded 44 via 43. Oxidation of 44 followed by treatment
with the ylide derived from PhSe(CH2)3P+Ph3Br- and
n-BuLi, and oxidation-syn-elimination using H2O2 and
NaHCO3 afforded diene 45, selective desilylation of which
gave 46. Dess-Martin oxidation followed by treatment
with Eschenmoser’s salt18 afforded 47, which was con-
verted to hemibrevetoxin B (1) by removal of the silyl
protecting groups using SiF4.19 Synthetic hemibrevetoxin
B (1) exhibited physical and spectroscopic data ([R]D, IR,
Chemical shifts are reported in delta (δ) units relative to
tetramethylsilane or to the singlet at 7.26 ppm for chloroform.
Coupling constants are reported in hertz (Hz).
and H and 13C NMR) identical with those of the natural
1
Ben zyl Eth er 9. To a stirred suspension of KH (2.8 g of a
35% suspension in mineral oil, 24.9 mmol, prewashed with
hexane) in THF (50 mL) at 0 °C was added dropwise a solution
of 811 (4.26 g, 16.6 mmol) in THF (40 mL). After 20 min, the
mixture was treated with benzyl bromide (2.4 mL, 19.9 mmol).
The cooling bath was removed, and the reaction mixture was
stirred for another 2 h. The reaction mixture was quenched
with methanol, diluted with ether, and washed with brine. The
organic layer was concentrated and purified by chromatogra-
phy (hexane/EtOAc, 4:1) to give 9 (5.65 g, 98%): colorless oil;
product.3
Con clu sion
The stereocontrolled total synthesis of hemibrevetoxin
B (1) was accomplished with high stereoselectivity in 56
steps and 0.75% overall yield from D-mannose. Although
the linear approach employed makes the synthesis
Rf ) 0.39 (hexane/EtOAc, 4:1); [R]23 +26.6° (c 1.60, CHCl3);
D
(18) (a) Schreiber, J .; Maag, H.; Hashimoto, N.; Eschenmoser, A.
Angew. Chem., Int. Ed. Engl. 1971, 10, 330-331. (b) Takano, S.;
Inomata, K.; Samizu, K.; Tomita, S.; Yanase, M.; Suzuki, M.; Iwabuchi,
Y.; Sugihara, T.; Ogasawara, K. Chem. Lett. 1989, 1283-1284.-
(19) Corey, E. J .; Yi, K. Y. Tetrahedron Lett. 1992, 33, 2289-2290.
1
IR (neat) 3080, 2950, 1645 cm-1; H NMR (270 MHz, CDCl3)
δ 7.38-7.25 (m, 5H), 5.86 (dddd, J ) 17.0, 10.0, 8.0, 8.0 Hz,
1H), 5.16-5.03 (m, 2H), 4.52 (d, J ) 12.0, 1H), 4.47 (d, J )
12.0 Hz, 1H), 4.29 (ddd, 8.0, 6.0, 6.0 Hz, 1H), 3.85 (t, J ) 6.5

Total Synthesis of Hemibrevetoxin B
J . Org. Chem., Vol. 63, No. 19, 1998 6601
Sch em e 7a
a
Conditions: (a) DIBALH, CH2Cl2, -78 °C, 96%; (b) SO3‚py, DMSO, Et3N, CH2Cl2, rt, 79%; (c) BF3‚OEt2, CH2Cl2, -78 °C, 98%; (d) (i)
(COCl)2, DMSO, CH2Cl2, then Et3N, -78 °C to rt; (ii) MeMgBr, toluene, -78 °C to rt, 83% (39:40 ) 86:14); (e) TBSOTf, 2,6-lutidine,
CH2Cl2, rt, 85%; (f) (i) O3, CH2Cl2, -78 °C, then Ph3P, -78 °C to rt; (ii) Ph3PdCHCO2Me, CH2Cl2, rt, 82%; (g) H2, 10% Pd-C, EtOAc, rt,
94%; (h) LiAlH4, 0 °C, 93%; (i) (i) SO3‚py, DMSO, Et3N, CH2Cl2, rt; (ii) PhSe(CH2)3P+Ph3Br-, nBuLi, HMPA, -78 °C to rt; (iii) H2O2,
NaHCO3, THF, rt, 74%; (j) TBAF, THF, rt, 91%; (k) (i) Dess-Martin periodinane, CH2Cl2, rt; (ii) Me2(CH2)N+I-, Et3N, CH2Cl2, rt, 89%;
(l) SiF4, CH2Cl2-CH3CN (1:1), rt, 76%.
Hz, 1H), 3.74-3.62 (m, 2H), 3.55-3.42 (m, 2H), 2.42 (ddddd,
J ) 14.0, 7.0, 4.0, 1.5, 1.5 Hz, 1H), 2.24 (ddddd, J ) 14.0, 8.5,
7.0, 1.5, 1.5 Hz, 1H), 2.0 (ddd, J ) 14.0, 6.0, 4.5 Hz, 1H), 1.85-
1.50 (m, 5H), 1.48 (s, 3H), 1.34 (s, 3H). Anal. Calcd for
TESCl (2.8 mL, 16.8 mmol), and the mixture was stirred for 2
h at 0 °C. The mixture was diluted with ether and washed
with water, aqueous NaHCO3, and brine. The organic layer
was concentrated and purified by chromatography (hexane/
EtOAc, 10:1) to give 12 (7.07 g, 99%): colorless oil; Rf ) 0.28
C
21H30O4: C, 72.80; H, 8.73. Found: C, 72.96; H, 8.92.
(hexane/EtOAc, 10:1); [R]25 +16.7° (c 1.23, CHCl3); IR (neat)
D
Diol 10. A solution of 9 (1.62 g, 4.68 mmol) in methanol
1
3070, 2960, 1645 cm-1; H NMR (270 MHz, CDCl3) δ 7.40-
(30 mL) was treated with concentrated HCl (30 µL) and stirred
at room temperature. After 5 h, the resulting mixture was
concentrated and purified by chromatography (hexane/EtOAc,
1:1) to give 10 (1.43, 100%): colorless needles; mp 87-88 °C
7.20, (m, 10H), 5.78 (dddd, J ) 18.0, 9.0, 7.0, 7.0 Hz, 1H), 5.07-
4.98 (m, 2H), 4.56 (s, 2H), 4.51 (d, J ) 12.0 Hz, 1H), 3.87 (ddd,
J ) 7.0, 7.0, 4.0 Hz, 1H), 3.73 (t, J ) 3.0 Hz, 1H), 3.65-3.38
(m, 4H), 2.25 (dddd, J ) 7.0, 7.0, 1.5, 1.5 Hz, 2H), 1.95-1.50
(m, 6H), 0.95 (t, J ) 8.0 Hz, 9H), 0.60 (q, J ) 8.0 Hz, 6H).
Anal. Calcd for C31H46O4Si: C, 72.90; H, 9.08. Found: C,
72.87; H, 9.11.
(ether); Rf ) 0.12 (hexane/EtOAc, 1:1); [R]24 +18.7° (c 1.05,
D
CHCl3); IR (KBr) 3600-3200, 3080, 2960, 1645 cm-1; 1H NMR
(270 MHz, CDCl3) δ 7.38-7.25 (m, 5H), 5.77 (dddd, J ) 16.5,
10.5, 7.0, 7.0 Hz, 1H), 5.14-5.05 (m, 2H), 4.52 (d, J ) 12.0
Hz, 1H), 4.47 (d, J ) 12.0 Hz, 1H), 3.98 (ddd, J ) 8.5, 6.0, 2.5
Hz, 1H), 3.88 (ddd, J ) 10.5, 5.0, 3.0 Hz, 1H), 3.63 (t, J ) 3.0
Hz, 1H), 3.61-3.40 (m, 3H), 2.45-2.15 (m, 4H), 1.82-1.45 (m,
6H). Anal. Calcd for C18H26O4: C, 70.56; H, 8.55. Found: C,
70.28; H, 8.52.
Un sa tu r a ted Ester 13. Ozone was passed through a
solution of 12 (5.33 g, 10.4 mmol) in CH2Cl2 (100 mL) at -78
°C until the solution turned blue. The excess ozone was
removed with a stream of oxygen, followed by addition of
triphenylphosphine (4.10 g, 15.6 mmol). The mixture was
allowed to warm to room temperature, concentrated, and
dissolved in benzene (100 mL). To the solution of crude
aldehyde was added (carboethoxyethyliden)triphenylphos-
phorane (7.50 g, 20.8 mmol), and the mixture was refluxed.
After 1 h, the reaction mixture was concentrated and diluted
with hexane. The resulting triphenylphosphine oxide was
filtered off, and the solvent was removed in vacuo. The residue
was purified by chromatography (hexane/EtOAc, 4:1) to give
13 (5.63 g, 91%): colorless oil; Rf ) 0.42 (hexane/EtOAc, 4:1);
[R]24D +13.7° (c 1.10, CHCl3); IR (neat) 3050, 2970, 1715, 1650
Alcoh ol 11. A mixture of 10 (4.79 g, 15.6 mmol) and
dibutyltin oxide (4.28 g, 17.2 mmol) in absolute methanol (150
mL) was refluxed for 1.5 h. The solvent was then removed in
vacuo, and the residue was dried azeotropically with toluene
(100 mL) and dissolved in DMF (150 mL). Benzyl bromide
(2.2 mL, 18.7 mmol) and CsF (2.8 g, 18.7 mmol) were added,
and the mixture was stirred at room temperature. After 12
h, the reaction mixture was diluted with ether and washed
with water and brine. The organic layer was concentrated and
purified by chromatography (hexane/EtOAc, 2:1) to give 11
(4.93 g, 98% based on 84% conversion) and recovered 10 (748
1
cm-1; H NMR (270 MHz, CDCl3) δ 7.40-7.20 (m, 10H), 6.80
mg, 16%): colorless oil; Rf ) 0.22 (hexane/EtOAc, 2:1); [R]25
(brt, J ) 7.0 Hz, 1H), 4.58 (s, 2H), 4.50 (d, J ) 12.0 Hz, 1H),
4.45 (d, J ) 12.0 Hz, 1H), 4.17 (q, J ) 7.0 Hz, 2H), 3.99-3.90
(m, 1H), 3.70-3.40 (m, 5H), 2.50-2.20 (m, 2H), 1.95-1.50 (m,
6H), 1.80 (d, J ) 1.0 Hz, 3H), 1.26 (t, J ) 7.0 Hz, 3H), 0.95 (t,
J ) 8.0 Hz, 9H), 0.61 (q, J ) 8.0 Hz, 6H). Anal. Calcd for
D
+26.5° (c 1.96, CHCl3); IR (neat) 3600-3200, 3080, 2940, 1645
1
cm-1; H NMR (270 MHz, CDCl3) δ 7.40-7.20 (m, 10H), 5.79
(dddd, J ) 17.5, 9.5, 7.0 7.0 Hz, 1H), 5.09-5.00 (m, 2H), 4.62
(d, J ) 11.5 Hz, 1H), 4.54 (d, J ) 11.5 Hz, 1H), 4.51 (d, J )
12.0 Hz, 1H), 4.46 (d, J ) 12.0 Hz, 1H), 3.98 (ddd, J ) 8.5,
6.0, 2.5 Hz, 1H), 3.77-3.69 (m, 3H), 2.41 (d, J ) 3.5 Hz, 1H),
2.40-2.18 (m, 2H), 1.80-1.50 (m, 6H). Anal. Calcd for
C
35H52O6Si: C, 70.43; H, 8.78. Found: C, 70.14; H, 8.72.
Allylic Alcoh ol 14. To a stirred solution of 13 (1.20 g, 2.01
mmol) in CH2Cl2 (30 mL) at -78 °C was added DIBALH (4.4
mL, 1.0 M in CH2Cl2, 4.4 mmol) dropwise. After 0.5 h, the
mixture was diluted with ether and washed with aqueous
sodium potassium tartrate and brine. The organic layer was
C
25H32O4: C, 75.73; H, 8.13. Found: C, 75.79; H, 8.11.
Silyl Eth er 12. To a mixture of 11 (5.57 g, 14.0 mmol) and
imidazole (1.90 g, 28.0 mmol) in CH2Cl2 at 0 °C was added

6602 J . Org. Chem., Vol. 63, No. 19, 1998
Kadota and Yamamoto
concentrated and purified by chromatography (hexane/EtOAc,
(dd, J ) 9.8, 2.5 Hz, 1H), 2.36-2.20 (m, 1H), 2.10 (ddd, J )
11.5, 4.5, 4.5 Hz, 1H), 1.95-1.55 (m, 6H), 1.33 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 167.4, 151.8, 139.2, 138.5, 128.3, 128.2,
127.6, 127.4, 127.2, 127.1, 118.9, 77.5, 73.6, 72.8, 72.6, 72.4,
70.7, 70.1, 62.5, 51.6, 34.5, 33.0, 29.1, 27.0, 14.6; HRMS (EI)
calcd for C30H38O7 510.2618, found 510.2591. Anal. Calcd for
C30H38O7: C, 70.57; H, 7.50. Found: C, 70.13; H, 7.61.
Aceta te 18. To a stirred solution of 7 (2.8 g, 5.48 mmol),
pyridine (980 µL, 12 mmol), and 4-(dimethylamino)pyridine
(DMAP, 20 mg) in CH2Cl2 (50 mL) was added acetic anhydride
(1.0 mL, 11 mmol). After 20 h, the reaction mixture was
concentrated and purified by chromatography (hexane/EtOAc,
2:1) to give 18 (2.95 g, 97%): colorless oil; Rf ) 0.30 (hexane/
EtOAc, 2:1); [R]27D +27.2° (c 1.60, CHCl3); IR (neat) 3050, 2970,
2:1) to give 14 (0.97 g, 87%): colorless oil; Rf ) 0.30 (hexane/
EtOAc, 2:1); [R]27 +13.9° (c 1.60, CHCl3); IR (neat) 3600-
D
3200, 3050, 2970, 1460 cm-1
;
1H NMR (270 MHz, CDCl3) δ
7.40-7.20 (m, 10H), 5.45 (brt, J ) 7.0 Hz, 1H), 4.57 (s, 2H),
4.51 (d, J ) 12.0 Hz, 1H), 4.46 (d, J ) 12.0 Hz, 1H), 3.98 (brs,
2H), 3.84 (ddd, J ) 9.0, 6.0, 4.0 Hz, 1H), 3.72 (t, J ) 3.0 Hz,
1H), 3.64 (ddd, 9.0, 3.0, 3.0 Hz, 1H), 3.60-3.51 (m, 1H), 3.50-
3.40 (m, 2H), 2.35-2.10 (m, 2H), 1.90-1.45 (m, 6H), 1.63 (brs,
3H), 0.94 (t, J ) 8.0 Hz, 9H), 0.60 (q, J ) 8.0 Hz, 6H). Anal.
Calcd for C33H50O5Si: C, 71.44; H, 9.08. Found: C, 71.14; H,
9.01.
Un sa tu r a ted Ester 16. A stirred mixture of powdered
activated 4A molecular sieves, allylic alcohol 14 (960 mg, 1.73
mmol), and CH2Cl2 (20 mL) was cooled to - 20 °C and treated
sequentially with (+)-diethyl tartrate (356 µL, 2.08 mmol) and
titanium(IV) isopropoxide (515 µL, 1.73 mmol). After 10 min,
tert-butyl hydroperoxide (1.2 mL, 3.0 M in 2,2,4-trimethyl-
pentane, 3.6 mmol) was added, and the mixture was stirred
for 12 h at -20 °C. The reaction mixture was diluted with
ether (30 mL), and while the solution was vigorously stirred,
aqueous Na2SO4 (3 mL) was added. After 1 h, the suspension
was removed by filtration through a Celite pad. The filtrate
was concentrated to give crude 15 which was used directly.
To a stirred solution of 15 (1.73 mmol) obtained above,
DMSO (5 mL), and triethylamine (1.7 mL, 12.1 mmol) in CH2-
Cl2 (15 mL) at 0 °C was added sulfur trioxide pyridine complex
(1.4 g, 8.65 mmol), and the mixture was stirred at room
temperature. After 2 h, the reaction mixture was diluted with
ether and washed with water and brine. The organic layer
was concentrated to give the corresponding aldehyde which
was immediately subjected to the next reaction without
purification.
To the crude aldehyde in benzene (15 mL) was added methyl
(triphenylphosphoranylidene)acetate (870 mg, 2.60 mmol), and
the mixture was stirred at room temperature. After 11 h, the
reaction mixture was concentrated and diluted with hexane.
The resulting triphenylphosphine oxide was filtered off, and
the solvent was removed in vacuo. The residue was purified
by chromatography (hexane/EtOAc, 4:1) to give 16 (882 mg,
82%): colorless oil; Rf ) 0.28 (hexane/EtOAc, 4:1); [R]28D +17.5°
(c 1.68, CHCl3); IR (neat) 3040, 2960, 1730, 1660 cm-1; 1H NMR
(270 MHz, CDCl3) δ 7.40-7.20 (m, 10H), 6.75 (d, J ) 16.0 Hz,
1H), 6.01 (d, J ) 16.0 Hz, 1H), 4.60 (d, J ) 12.0 Hz, 1H), 4.55
(d, J ) 12.0 Hz, 1H), 4.50 (d, J ) 12.0 Hz, 1H), 4.46 (d, J )
12.0 Hz, 1H), 4.00-3.90 (m, 1H), 3.72 (s, 3H), 3.70-3.60 (m,
3H), 3.50-3.40 (m, 2H), 2.98 (t, J ) 6.0 Hz, 1H), 2.00-1.50
(m, 8H), 1.39 (s, 3H), 0.94 (t, J ) 8.0 Hz, 9H), 0.60 (q, J ) 8.0
Hz, 6H). Anal. Calcd for C36H52O7Si: C, 69.20; H, 8.39.
Found: C, 69.14; H, 8.43.
1
1760, 1740, 1665 cm-1; H NMR (300 MHz, CDCl3) δ 7.40-
7.20 (m, 10H), 6.92 (d, J ) 15.8 Hz, 1H), 6.13 (d, J ) 15.8 Hz,
1H), 4.77 (d, J ) 12.4 Hz, 1H), 4.75 (dd, J ) 11.8, 4.6 Hz, 1H),
4.63 (d, J ) 12.4 Hz, 1H), 4.49 (s, 2H), 3.95-3.80 (m, 3H),
3.75 (s, 3H), 3.55-3.45 (m, 2H), 3.42 (dd, J ) 10.0, 2.7 Hz,
1H), 2.25 (ddd, J ) 11.5, 4.7, 4.7 Hz, 2H), 2.08 (s, 3H), 1.95-
1.90 (m, 2H), 1.80-1.55 (m, 4H), 1.39 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 169.6, 167.0, 149.9, 139.0, 138.60, 128.3, 128.2,
127.6, 127.4, 127.2, 127.1, 119.5, 75.5, 73.8, 73.4, 72.9, 72.6,
72.5, 71.8, 70.1, 62.0, 51.6, 33.0, 31.1, 29.1, 27.0, 21.1, 15.9;
HRMS (EI) calcd for C32H40O8 552.2724, found 552.2703. Anal.
Calcd for C32H40O8: C, 69.55; H, 7.30. Found: C, 69.18; H,
7.35.
Diol 19. Palladium hydroxide on carbon (270 mg) was
added to a stirred solution of 18 (2.75 g, 4.98 mmol) in
methanol (50 mL). A hydrogen atmosphere was introduced
using a hydrogen-filled balloon by repeated evacuations (water
aspirator). After 16 h, the catalyst was filtered off. The
filtrate was concentrated and purified by chromatography
(EtOAc) to give 19 (1.85 g, 99%): colorless oil; Rf ) 0.30
(EtOAc); [R]29 +31.9° (c 2.29, CHCl3); IR (neat) 3650-3200,
D
1
2960, 1745 cm-1; H NMR (270 MHz, CDCl3) δ 4.84 (dd, J )
11.5, 4.5 Hz, 1H), 4.01 (ddd, J ) 3.0, 2.5, 2.5 Hz, 1H), 3.90-
3.80 (m, 1H), 3.78 (ddd, J ) 12.0, 9.5, 4.5 Hz, 1H), 3.67 (t, J )
6.0 Hz, 2H), 3.25 (dd, J ) 9.5, 2.5 Hz, 1H), 2.40 (t, J ) 7.0 Hz,
2H), 2.35-2.20 (m, 1H), 2.17 (ddd, J ) 11.0, 4.5, 4.5 Hz, 1H),
2.06 (s, 3H), 2.05-1.55 (m, 8H), 1.27 (s, 3H). Anal. Calcd for
C
18H30O8: C, 57.74; H, 8.08. Found: C, 57.68; H, 8.02.
Bis-silyl Eth er 20. To a stirred solution of 19 (1.71 g, 4.57
mmol) and 2,6-lutidine (1.9 mL, 16 mmol) in DMF (50 mL) at
0 °C was added triisopropylsilyl trifluoromethanesulfonate
(TIPSOTf, 3.1 mL, 11.4 mmol), and the mixture was heated
at 70 °C. After 17 h, the reaction was quenched with methanol
at 0 °C, diluted with ether and washed with water and brine.
The organic layer was concentrated and purified by chroma-
tography (hexane/EtOAc, 4:1) to give 20 (3.14 g, 100%):
Alcoh ol 17. To a stirred solution of 16 (4.22 g, 6.75 mmol)
in THF (70 mL) was added tetrabutylammonium fluoride (8.1
mL, 1.0 M in THF, 8.1 mmol). After 1 h, the mixture was
concentrated and purified by chromatography (hexane/EtOAc,
1:1) to give 17 (3.44 g, 100%): colorless oil; Rf ) 0.32 (hexane/
colorless oil; Rf ) 0.31 (hexane/EtOAc, 4:1); [R]23 +29.6° (c
D
1.43, CHCl3); IR (neat) 2950, 1750 cm-1; H NMR (270 MHz,
1
CDCl3) δ 4.65 (dd, 12.0, 4.5 Hz, 1H), 4.24 (ddd, J ) 3.0, 2.5,
2.5 Hz, 1H), 3.85-3.65 (m, 4H), 3.66 (s, 3H), 3.19 (dd, J ) 9.5,
2.5 Hz, 1H), 2.60-2.25 (m, 3H), 2.19 (ddd, J ) 11.0, 4.5, 4,5
Hz, 1H), 2.05 (s, 3H), 2.05-1.45 (m, 8H), 1.21 (s, 3H), 1.09-
1.04 (m, 42H). Anal. Calcd for C36H70O8Si2: C, 62.93; H,
10.27. Found: C, 62.68; H, 10.23.
EtOAc, 1:1); [R]29 +33.2° (c 1.71, CHCl3); IR (neat) 3600-
D
3200, 3040, 2940, 1730, 1655 cm-1; 1H NMR (270 MHz, CDCl3)
δ 7.40-7.20 (m, 10H), 6.75 (d, J ) 16.0 Hz, 1H), 6.01 (d, J )
16.0 Hz, 1H), 4.66 (d, J ) 11.5 Hz, 1H), 4.51 (d, J ) 11.5 Hz,
1H), 4.49 (s, 2H), 4.00 (ddd, J ) 9.0, 5.0, 5.0 Hz, 1H), 3.80-
3.55 (m, 3H), 3.72 (s, 3H), 3.55-3.40 (m, 2H), 2.99 (t, J ) 6.0
Hz, 1H), 2.47 (d, J ) 5.0 Hz, 1H), 1.95-1.50 (m, 8H), 1.40 (s,
3H). Anal. Calcd for C30H38O7: C, 70.57; H, 7.50. Found: C,
70.16; H, 7.58.
Diol 21. To a stirred suspension of LiAlH4 (330 mg, 8.73
mmol) in ether (50 mL) at 0 °C was added dropwise a solution
of 20 (4.0 g, 5.82 mmol) in ether (20 mL). After 0.5 h, the
reaction mixture was quenched with a minimum amount of
brine, and the mixture was stirred vigorously for 0.5 h. The
resulting white precipitate was removed by filtration through
a Celite pad. The filtrate was concentrated and purified by
chromatography (hexane/EtOAc, 1:1) to give 21 (3.55 g, 99%):
Bicycle 7. A solution of 7 (3.44 g, 6.74 mmol) in CH2Cl2
(100 mL) was treated with camphorsulfonic acid (465 mg, 2.0
mmol). After 13 h, the reaction mixture was quenched with
triethylamine (1 mL), concentrated, and purified by chroma-
tography (hexane/EtOAc, 1:1) to give 7 (2.8 g, 81%): colorless
oil; Rf ) 0.31 (hexane/EtOAc, 1:1); [R]23D +17.6° (c 1.87, CHCl3);
colorless oil; Rf ) 0.33 (hexane/EtOAc, 1:1); [R]25 +21.5° (c
D
1
1.92, CHCl3); IR (neat) 3600-3100, 2950 cm-1; H NMR (270
MHz, CDCl3) δ 4.23 (ddd, J ) 3.0, 2.5, 2.5 Hz, 1H), 3.86-3.71
(m, 2H), 3.69 (t, J ) 6.0 Hz, 2H), 3.62 (ddd, J ) 6.0, 6.0, 1.5
Hz, 2H), 3.51 (dd, J ) 6.5, 4.5 Hz, 1H), 3.15 (dd, 9.5, 3.0 Hz,
1H), 2.40-2.25 (m, 1H), 2.07 (ddd, J ) 11.5, 5.0, 5.0 Hz, 1H),
2.00 (ddd, J ) 14.0, 7.0, 3.0 Hz, 1H), 1.90-1.35 (m, 9H), 1.17
(s, 3H), 1.09-1.04 (m, 42H). Anal. Calcd for C33H68O6Si2: C,
64.23; H, 11.11. Found: C, 63.82; H, 11.09.
1
IR (neat) 3600-3200, 3040, 2960, 1730, 1660 cm-1; H NMR
(300 MHz, CDCl3) δ 7.40-7.20 (m, 10H), 7.16 (d, J ) 15.8,
1H), 6.15 (d, J ) 15.8 Hz, 1H), 4.79 (d, J ) 12.5 Hz, 1H), 4.64
(d, J ) 12.5 Hz, 1H), 4.49 (s, 2H), 3.80-3.75 (m, 3H), 3.76 (s,
3H), 3.60 (dd, J ) 12.0, 4.5 Hz, 1H), 3.55-3.42 (m, 2H), 3.37

Total Synthesis of Hemibrevetoxin B
J . Org. Chem., Vol. 63, No. 19, 1998 6603
Allyl Eth er 22. To a stirred solution of 21 (3.55 g, 5.75
mmol) and triethylamine (960 µL, 6.7 mmol) in CH2Cl2 at -15
°C was added dropwise triethylsilyl chloride (TESCl, 1.1 mL,
6.33 mmol). After 1 h, the reaction mixture was diluted with
ether and washed with water, aqueous NaHCO3, and brine.
The organic layer was concentrated to give the crude mono-
silyl ether which was used directly.
To a stirred suspension of KH (790 mg of a 35% suspension
in mineral oil, 6.9 mmol, prewashed with hexane) in THF (30
mL) at 0 °C were added consecutively allyl bromide (600 mL,
6.9 mmol) and a solution of the secondary alcohol obtained
above in THF (20 mL). The cooling bath was removed, and
the reaction mixture was stirred for 0.5 h. The reaction was
quenched with methanol at 0 °C and diluted with ether. The
organic layer was washed with brine and concentrated to give
crude allyl ether which was used for the next reaction without
purification.
was added a solution of 24 (1.30 g, 1.38 mmol) dropwise. After
the reaction mixture was stirred for 0.5 h at -78 °C, the
reaction was quenched with triethylamine (2 mL). The
resulting mixture was diluted with ether, washed with brine,
and concentrated. The residue was dissolved in ether (5 mL)
and stirred with aqueous KF (5 mL) vigorously for 1 h. The
resulting white precipitate (n-Bu3SnF) was filtered off, and
the filtrate was extracted with ether. The organic layer was
washed with brine and concentrated. The residue was purified
by chromatography (hexane/EtOAc, 10:1) to give 6 (850 m g,
94%): colorless needles, mp 137-138 °C (hexane); Rf ) 0.20
(hexane/EtOAc, 10:1); [R]27 +19.8° (c 1.06, CHCl3); IR (KBr)
D
3450, 2960 cm-1; 1H NMR (270 MHz, CDCl3) δ 5.80 (ddd, J )
17.0, 10.5, 6.5 Hz, 1H), 5.34 (brd, J ) 17.0 Hz, 1H), 5.18 (brd,
J ) 10.5 Hz, 1H), 4.20 (ddd, J ) 3.0, 3.0, 2.5 Hz, 1H), 4.00
(dd, J ) 6.0, 4.5 Hz, 1H), 3.86-3.72 (m, 3H), 3.69 (t, J ) 6.0
Hz, 2H), 3.61 (dd, J ) 12.0, 4.0 Hz, 1H), 3.20 (dd, 9.5, 2.5 Hz,
1H), 2.37-2.20 (m, 1H), 2.08-1.90 (m, 3H), 1.85-1.74 (m, 3H),
1.70-1.47 (m, 5H), 1.23 (s, 3H), 1.14-0.98 (m, 42H). Anal.
Calcd for C36H70O6Si2: C, 66.00; H, 10.77. Found: C, 65.80;
H, 10.68.
The crude allyl ether was dissolved in ethanol (50 mL) and
stirred with Amberlyst-15 (200 mg) at room temperature. After
0.5 h, the resin was filtered off, and the filtrate was concen-
trated and purified by chromatography (hexane/EtOAc, 4:1)
to give 22 (3.64 g, 96%): colorless oil; Rf ) 0.33 (hexane/EtOAc,
Aceta te 25. The experimental procedure followed was as
described for compound 18. For 25: colorless oil; Rf ) 0.32
4:1); [R]23 +34.6° (c 1.84, CHCl3); IR (neat) 3600-3200, 2960
D
cm-1; 1H NMR (270 MHz, CDCl3) δ 5.89 (dddd, J ) 17.0, 10.5,
5.0, 5.0 Hz, 1H), 5.26 (dddd, J ) 17.0, 3.0, 2.5, 2.5 Hz, 1H),
5.15 (dddd, J ) 10.5, 3.0, 2.5, 2.5 Hz, 1H), 4.22 (ddd, J ) 3.0,
3.0, 2.5 Hz, 1H), 4.10 (dddd, J ) 12.5, 5.0, 1.5, 1.5 Hz, 1H),
3.90 (dddd, J ) 12.5, 5.0, 1.5, 1.5 Hz, 1H), 3.82 (ddd, J ) 10.5,
6.5, 3.5 Hz, 1H), 3.76-3.65 (m, 1H), 3.70 (t, J ) 6.5 Hz, 2H),
3.60 (ddd, J ) 6.5, 6.5, 1.0 Hz, 2H), 3.20-3.12 (m, 2H), 2.40-
2.26 (m, 1H), 2.21 (ddd, J ) 11.5, 5.0, 5.0 Hz, 1H), 2.00 (ddd,
J ) 14.0, 7.0, 3.0 Hz, 1H), 1.90-1.25 (m, 9H), 1.16 (s, 3H),
1.15-1.00 (m, 42H). Anal. Calcd for C36H72O6Si2: C, 65.80;
H, 11.04. Found: C, 65.37; H, 11.16.
(hexane/EtOAc, 10:1); [R]26 +25.6° (c 1.30, CHCl3); IR (neat)
D
2950, 1745 cm-1; 1H NMR (270 MHz, CDCl3) δ 5.80 (ddd, J )
17.0, 10.5, 5.0 Hz, 1H), 5.36 (ddd, J ) 17.0, 1.5, 1.5 Hz, 1H),
5.15 (ddd, J ) 10.5, 1.5, 1.5 Hz, 1H), 5.00 (brd, J ) 7.0 Hz,
1H), 4.24-4.17 (m, 2H), 3.86-3.71 (m, 2H), 3.70 (t, J ) 6.0
Hz, 2H), 3.56 (dd, J ) 12.0, 4.5 Hz, 1H), 3.20 (dd, J ) 9.5, 2.5
Hz, 1H), 2.40-2.27 (m, 1H), 2.11 (s, 3H), 2.06-1.47 (m, 11H),
1.14-0.98 (m, 42H). Anal. Calcd for C38H72O7Si2: C, 65.47;
H, 10.41. Found: C, 65.08; H, 10.09.
Un sa tu r a ted Ester 26. Ozone was passed through a
solution of 25 (1.48 g, 2.12 mmol) in dichloromethane (50 mL)
at -78 °C until the solution turned blue. The excess ozone
was removed with a stream of oxygen, followed by addition of
triphenylphosphine (1.1 g, 4.2 mmol). The mixture was
allowed to warm to room temperature, concentrated, and
dissolved in CH2Cl2 (50 mL). To the solution of crude aldehyde
was added methyl (triphenylphosphoranylidene)acetate (1.4
g, 4.2 mmol), and the mixture was stirred at room tempera-
ture. After 17 h, the reaction mixture was concentrated and
diluted with hexane. The resulting triphenylphosphine oxide
was filtered off, and the solvent was removed in vacuo. The
residue was purified by chromatography (hexane/EtOAc, 4:1)
to give 26 (1.60 g, 100%): colorless oil; Rf ) 0.44 (hexane/
EtOAc, 4:1); [R]26D +9.8° (c 1.50, CHCl3); IR (neat) 2950, 1730,
Allylic Sta n n a n e 23. To a solution of 22 (198 mg, 0.30
mmol) and TMEDA (100 µL, 0.66 mmol) in THF (3 mL) at
-78 °C was added sec-BuLi (660 µL of a 1.0 M solution in
cyclohexane, 0.66 mmol), and the resulting mixture was stirred
for 1 h. To this yellow solution was added tributyltin chloride
(120 µL, 0.45 mmol), and the mixture was allowed to warm to
room temperature. The reaction mixture was quenched with
water and extracted with ether. The organic layer was washed
with brine and concentrated. The residue was purified by
chromatography (hexane/EtOAc/Et3N, 200:20:1) to give 23 (92
mg, 69% based on 46% conversion) and 22 (107 mg, 54%). For
23: colorless oil; Rf ) 0.21 (hexane/EtOAc, 10:1); [R]23D +21.4°
(c 1.16, CHCl3); IR (neat) 3600-3200, 2950, 1650 cm-1 1H
;
1
NMR (270 MHz, CDCl3) δ 5.78 (d, J ) 6.0 Hz, 1H), 4.52 (ddd,
J ) 9.0, 9.0, 6.0 Hz, 1H), 4.26-4.21 (m, 1H), 3.86-3.68 (m,
2H), 3.69 (t, J ) 6.0 Hz, 2H), 3.63-3.55 (m, 2H), 3.36 (dd, J )
11.5, 6.5 Hz, 1H), 3.18 (dd, J ) 9.5, 2.5 Hz, 1H), 2.40-2.25
(m, 1H), 2.15 (ddd, J ) 11.5, 5.0, 5.0 Hz, 1H), 2.00 (ddd, J )
14.0, 7.0, 3.0 Hz, 1H), 1.85-1.25 (m, 21H), 1.21 (s, 3H), 1.09-
1.04 (m, 42H), 0.88 (t, J ) 7.0 Hz, 9H), 0.86-0.80 (m, 6H).
Anal. Calcd for C48H98O6Si2Sn: C, 60.93; H, 10.44. Found:
C, 60.67; H, 10.39.
1660 cm-1; H NMR (270 MHz, CDCl3) δ 6.88 ((dd, J ) 15.0,
4.0 Hz, 1H), 6.13 (dd, J ) 15.0, 2.0 Hz, 1H), 5.04 (brd, J ) 6.5
Hz, 1H), 4.36 (ddd, J ) 4.0, 2.0, 2.0 Hz, 1H), 4.24-4.19 (m,
1H), 3.87-3.75 (m, 1H), 3.75-3.67 (m, 1H), 3.74 (s, 3H), 3.70
(t, J ) 6.0 Hz, 2H), 3.56 (dd, J ) 12.0, 4.5 Hz, 1H), 3.20 (dd,
J ) 10.0, 2.5 Hz, 1H), 2.40-2.25 (m, 1H), 2.12 (s, 3H), 2.04-
1.47 (m, 11H), 1.24 (s, 3H), 1.12-1.00 (m, 42H); HRMS (EI)
calcd for C37H67O9Si2 (M - C3H7) 711.4324, found 711.4368.
Anal. Calcd for C40H74O9Si2: C, 63.62; H, 9.88. Found: C,
63.32; H, 9.69.
Ald eh yd e 24. To a stirred solution of 23 (203 mg, 0.21
mmol), DMSO (0.5 mL), and triethylamine (153 µL, 1.1 mmol)
in CH2Cl2 (3 mL) at 0 °C was added sulfur trioxide pyridine
complex (100 mg, 0.63 mmol), and the mixture was stirred at
room temperature. After 4 h, the reaction mixture was diluted
with ether and washed with water and brine. The organic
layer was concentrated and purified by chromatography (hex-
ane/EtOAc/Et3N, 200:20:1) to give 24 (179 mg, 90%): colorless
Sa tu r a ted Ester 27. A catalytic amount of 10% palladium
on carbon was added to a stirred solution of 26 (465 mg, 0.62
mmol) in EtOAc (7 mL). A hydrogen atmosphere was intro-
duced using a hydrogen-filled balloon by repeated evacuations
(water aspirator). After 16 h, the catalyst was filtered off. The
filtrate was concentrated and purified by chromatography
(hexane/EtOAc, 4:1) to give 27 (469 mg, 100%): colorless oil;
oil; Rf ) 0.47 (hexane/EtOAc, 10:1); [R]27 +26.4° (c 1.55,
Rf ) 0.37 (hexane/EtOAc, 4:1); [R]24 +20.6° (c 1.00, CHCl3);
D
D
CHCl3); IR (neat) 2950, 1735, 1650 cm-1; 1H NMR (270 MHz,
CDCl3) δ 9.75 (s, 1H), 5.79 (d, J ) 6.0 Hz, 1H), 4.56 (ddd, J )
9.0, 9.0, 6.0 Hz, 1H), 4.26-4.20 (m, 1H), 3.86-3.68 (m, 2H),
3.69 (t, J ) 6.0 Hz, 2H), 3.38 (dd, J ) 11.5, 6.5 Hz, 1H), 3.18
(dd, J ) 9.5, 2.5 Hz, 1H), 2.62-2.50 (m, 2H), 2.40-1.90 (m,
3H), 1.85-1.25 (m, 21H), 1.20 (s, 3H), 1.09-1.04 (m, 42H), 0.87
(t, J ) 7.0 Hz, 9H), 0.86-0.80 (m, 6H). Anal. Calcd for
IR (neat) 2950, 1745 cm-1; 1H NMR (270 MHz, CDCl3) δ 4.87
(brd, J ) 6.0 Hz, 1H), 4.22-4.18 (m, 1H), 3.86-3.71 (m, 2H),
3.70 (t, J ) 6.0 Hz, 2H), 3.66 (s, 3H), 3.58 (ddd, J ) 10.0, 4.0,
1.0 Hz, 1H), 3.34 (dd, J ) 12.0, 4.5 Hz, 1H), 3.18 (dd, J ) 9.5,
2.5 Hz, 1H), 2.45-2.25 (m, 3H), 2.08 (s, 3H), 2.05-1.40 (m,
13H), 1.19 (s, 3H), 1.15-1.00 (m, 42H). Anal. Calcd for
C
40H76O9Si2: C, 63.45; H, 10.12. Found: C, 63.16; H, 10.05.
C
48H96O6Si2Sn: C, 61.06; H, 10.25. Found: C, 61.03; H, 10.21.
Diol 28. The experimental procedure followed was as
Tr icycle 6. To a stirred solution of boron trifluoride
etherate (200 µL, 1.66 mmol) in CH2Cl2 (30 mL) at -78 °C
described for compound 21. For 28: colorless needles; mp
137-139 °C (hexane); Rf ) 0.34 (hexane/EtOAc, 1:1); [R]26
D

6604 J . Org. Chem., Vol. 63, No. 19, 1998
Kadota and Yamamoto
1
+18.2° (c 1.52, CHCl3); IR (neat) 3600-3100, 2950 cm-1; H
NMR (270 MHz, CDCl3) δ 4.20 (ddd, J ) 3.0, 2.5, 2.5 Hz, 1H),
3.85-3.72 (m, 3H), 3.69 (t, J ) 6.0 Hz, 2H), 3.66 (ddd, J )
6.0, 6.0, 1.5 Hz, 2H), 3.50-3.43 (m, 1H), 3.44 (dd, J ) 12.0,
4.0 Hz, 1H), 3.20 (dd, J ) 9.5, 2.5 Hz, 1H), 2.40-2.23 (m, 1H),
2.05-1.93 (m, 3H), 1.85-1.40 (m, 14H), 1.20 (s, 3H), 1.10-
1.00 (m, 42H). Anal. Calcd for C37H74O7Si2: C, 64.67; H,
10.85. Found: C, 64.38; H, 10.65.
28.3, 27.2, 25.3, 18.3, 18.3, 18.1, 16.1, 12.4, 12.0. Anal. Calcd
for C42H82O8Si2: C, 65.41; H, 10.72. Found: C, 64.97; H, 10.41.
Mixed Aceta l 36. The experimental procedure followed
was as described for compound 33. 36: colorless oil; Rf ) 0.28
(hexane/EtOAc, 10:1); IR (neat) 2925, 1732 cm-1; 1H NMR (300
MHz, CDCl3) δ 4.37-4.29 (m, 1H), 4.22-4.17 (m, 1H), 4.06 (t,
J ) 6.2 Hz, 2H), 3.85-3.55 (m, 6H), 3.40 (dd, J ) 12.5, 4.5
Hz, 1H), 3.26 (s, 1.5H), 3.23 (s, 1.5H), 3.19 (dd, J ) 9.5, 2.5
Hz, 1H), 2.35-2.20 (m, 1H), 2.05-1.25 (m, 31H), 1.19 (s, 12H),
1.10-1.05 (m, 42H), 0.89 (t, J ) 7.2 Hz, 9H), 0.85-0.80 (m,
6H). Anal. Calcd for C58H116O9Si2Sn: C, 61.52; H, 10.32.
Found: C, 61.28; H, 10.02.
Allyl Eth er 29. The experimental procedure followed was
as described for compound 22. For 29: colorless oil; Rf ) 0.20
(hexane/EtOAc, 4:1); IR (neat) 3600-3200, 2950 cm-1; 1H NMR
(270 MHz, CDCl3) δ 5.90 (dddd, J ) 17.0, 10.0, 5.5, 5.5 Hz,
1H), 5.27 (dddd, J ) 17.0, 1.5, 1.5, 1.5 Hz, 1H), 5.16 (dddd, J
) 10.0, 1.5, 1.5, 1.5 Hz, 1H), 4.21-4.16 (m, 1H), 4.00 (dddd, J
) 12.5, 5.5, 1.5, 1.5 Hz, 1H), 3.81 (dddd, J ) 12.5, 5.5, 1.5, 1.5
Hz, 1H), 3.80-3.59 (m, 7H), 3.52 (dd, J ) 12.0, 4.5 Hz, 1H),
3.45 (brd, J ) 6.0 Hz, 1H), 3.17 (dd, J ) 9.5, 3.0 Hz, 1H), 2.38-
2.20 (m, 1H), 2.02-1.40 (m, 15H), 1.19 (s, 3H), 1.10-1.00 (m,
42H).
P iva la te 32. To a stirred solution of 21 (100 mg, 0.16
mmol) and pyridine (26 µL, 0.32 mmol) in CH2Cl2 (1 mL) at 0
°C was added pivaloyl chloride (23 µL, 0.19 mmol), and the
mixture was stirred for 20 h at room temperature. The
mixture was diluted with ether, washed with water and brine,
and concentrated. The residue was purified by chromatogra-
phy (hexane/EtOAc, 4:1) to give 32 (12 mg, 100%): colorless
oil; Rf ) 0.28 (hexane/EtOAc, 4:1); [R]20D +21.5° (c 3.16, CHCl3);
IR (neat) 2943, 1730 cm-1; 1H NMR (270 MHz, CDCl3) δ 4.26-
4.21 (m, 1H), 4.08-3.93 (m, 2H), 3.82 (ddd, J ) 10.5, 7.0, 4.0
Hz, 1H), 3.77 (dd, J ) 10.5, 6.0 Hz, 1H), 3.69 (t, J ) 6.0 Hz,
2H), 3.56-3.46 (m, 1H), 3.15 (dd, J ) 9.5, 2.5 Hz, 1H), 2.39-
2.23 (m, 1H), 2.08 (ddd, J ) 11.5, 5.0, 5.0 Hz, 1H), 1.98 (ddd,
J ) 14.0, 7.0, 3.0 Hz, 1H), 1.85-1.40 (m, 9H), 1.20 (s, 9H),
1.17 (s, 3H), 1.09-1.04 (m, 42). Anal. Calcd for C38H76O7Si2:
C, 65.09; H, 10.92. Found: C, 65.07; H, 10.77.
En ol Eth er 37. The experimental procedure followed was
as described for compound 34. For 37: colorless oil; Rf ) 0.28
(hexane/EtOAc, 10:1); [R]19 -11.9° (c 1.34, CHCl3); IR (neat)
D
2925, 1732, 1651 cm-1; 1H NMR (300 MHz, CDCl3) δ 5.67 (br
d, J ) 6.0 Hz, 1H), 4.53 (ddd, J ) 9.0, 9.0, 6.0 Hz, 1H), 4.06 (t,
J ) 6.5 Hz, 2H), 3.85-3.55 (m, 6H), 3.20 (dd, J ) 9.5, 2.5 Hz,
1H), 2.35-2.20 (m, 1H), 2.00-1.25 (m, 29H), 1.19 (s, 12H),
1.10-1.05 (m, 42H), 0.89 (t, J ) 7.2 Hz, 9H), 0.88-0.80 (m,
6H); 13C NMR (75 MHz, CDCl3) δ 178.5, 139.7, 106.7, 84.9,
83.7, 79.6, 72.8, 72.6, 67.6, 64.2, 63.2, 62.35, 38.7, 26.5, 34.9,
33.3, 31.8, 30.6, 29.5, 29.2, 27.4, 27.2, 25.4, 25.0, 18.3, 18.1,
15.7, 13.8, 12.4, 12.0, 9.4, 6.4. Anal. Calcd for C57H112O8Si2-
Sn: C, 62.22; H, 10.26. Found: C, 62.87; H, 10.33.
Alcoh ol 30. To a stirred solution of 37 (464 mg, 0.42 mmol)
in CH2Cl2 (5 mL) at -78 °C was added DIBALH (1.1 mL, 1.0
M in CH2Cl2, 1.1 mmol) dropwise. After 0.5 h, the mixture
was diluted with ether and washed with aqueous sodium
potassium tartrate and brine. The organic layer was concen-
trated and purified by chromatography (hexane/EtOAc/Et3N,
200:50:1) to give 30 (408 mg, 96%): colorless oil; Rf ) 0.20
(hexane/EtOAc, 4:1); [R]22 -21.0° (c 1.51, CHCl3); IR (neat)
D
3600-3200, 2943, 1651 cm-1
;
1H NMR (300 MHz, CDCl3) δ
5.68 (brd, J ) 6.0 Hz, 1H), 4.54 (ddd, J ) 9.6, 8.5, 6.2 Hz, 1H),
4.23-4.18 (m, 1H), 3.85-3.57 (m, 8H), 3.43 (dd, J ) 12.1, 4.4
Hz, 1H), 3.20 (dd, J ) 9.8, 2.6 Hz, 1H), 2.35-2.20 (m, 1H),
2.05-1.23 (m, 29H), 1.20 (s, 3H), 1.10-1.00 (m, 42H), 0.90 (t,
J ) 7.2 Hz, 9H), 0.88-0.82 (m, 6H); 13C NMR (75 MHz, CDCl3)
δ 139.6, 106.5, 84.7, 83.9, 79.2, 76.8, 72.6, 72.4, 67.4, 65.7, 63.1,
62.4, 62.2, 36.4, 34.7, 33.1, 31.9, 30.4, 29.3, 29.2, 29.1, 27.3,
24.7, 18.2, 17.9, 15.5, 15.1, 13.6, 12.2, 11.9, 9.2, 6.2. Anal.
Calcd for C52H104O7Si2Sn: C, 61.44; H, 10.31. Found: C, 61.64;
H, 10.18.
Mixed Aceta l 33. To stirred solution of 32 (112 mg, 0.16
mmol) and 3117 (170 µL, 0.48 mmol) in CH2Cl2 (1 mL) was
added camphorsulfonic acid (CSA, 4 mg, 0.016 mmol). After
1 h, the reaction was quenched with triethylamine and filtered
through Al2O3. The filtrate was concentrated and purified by
chromatography (hexane/EtOAc/Et3N, 200:10:1) to give 33 (144
mg, 85%) as a 1:1 diastereomeric mixture: colorless oil; Rf )
0.12 and 0.18 (hexane/EtOAc, 20:1); IR (neat) 2955, 1731 cm-1
;
1H NMR (270 MHz, CDCl3) δ 4.50 (t, J ) 5.0 Hz, 0.5H), 4.48
(t, J ) 5.0 Hz, 0.5H), 4.35-4.13 (m, 2H), 4.10-3.70 (m, 5H),
3.54 (dd, J ) 6.5, 4.5 Hz, 1H), 3.27 (s, 1.5H), 3.24 (dd, J ) 9.5,
2.5 Hz, 1H), 3.19 (s, 1.5H), 2.70-2.50 (m, 1H), 2.10-1.15 (m,
22H), 1.04-0.92 (m, 15H). Anal. Calcd for C54H110O8Si2Sn:
C, 61.05; H, 10.44. Found: C, 60.89; H, 10.66.
Ald eh yd e 38. The experimental procedure followed was
as described for compound 24. For 38: colorless oil; Rf ) 0.46
(hexane/EtOAc, 4:1); [R]23 -16.1° (c 1.10, CHCl3); IR (neat)
D
1
2943, 1728, 1651 cm-1; H NMR (300 MHz, CDCl3) δ 9.76 (s,
1H), 5.67 (brd, J ) 6.0 Hz, 1H), 4.55 (ddd, J ) 9.5, 8.6, 6.0 Hz,
1H), 4.23-4.18 (m, 1H), 3.85-3.57 (m, 8H), 3.38 (dd, J ) 12.1,
4.4 Hz, 1H), 3.20 (dd, J ) 9.9, 2.5 Hz, 1H), 2.59 (ddd, J ) 17.0,
8.0, 8.0 Hz, 1H), 2.46 (ddd, J ) 17.0, 8.0, 8.0 Hz, 1H), 2.35-
2.20 (m, 1H), 2.00-1.25 (m, 27H), 1.18 (s, 3H), 1.10-1.00 (m,
42H), 0.89 (t, J ) 7.2 Hz, 9H), 0.87-0.83 (m, 6H); 13C NMR
(75 MHz, CDCl3) δ 202.0, 139.6, 106.9, 84.6, 83.1, 79.5, 76.9,
72.8, 72.5, 67.5, 63.2, 62.2, 40.8, 36.5, 34.9, 33.1, 30.5, 29.4,
29.2, 28.1, 27.3, 24.9, 18.3, 18.2, 18.0, 15.7, 13.7, 12.4, 12.0,
9.4, 6.3. Anal. Calcd for C52H102O7Si2Sn: C, 61.58; H, 10.14.
Found: C, 61.65; H, 10.19.
En ol Eth er 34. To a stirred solution of 33 (50 mg, 0.047
mmol) and hexamethyldisilazane (50 µL, 0.24 mmol) in CH2-
Cl2 (1 mL) at -15 °C was added trimethylsilyl iodide (TMSI,
20 mL, 0.14 mmol). After 1.5 h, the reaction was quenched
with aqueous NaHCO3 and extracted with ether. The organic
layer was washed with brine, concentrated, and purified by
chromatography (hexane/EtOAc/Et3N, 200:10:1) to give 34 (40
mg, 83%): colorless oil; Rf ) 0.28 (hexane/EtOAc, 20:1); [R]21
D
+32.9° (c 1.04, CHCl3); IR (neat) 2956, 1732, 1651 cm-1; H
1
NMR (270 MHz, CDCl3) δ 5.76 (brd, J ) 6.0 Hz, 1H), 4.71
(ddd, J ) 9.0, 9.0, 5.0 Hz, 1H), 4.30-4.10 (m, 3H), 4.05-3.80
(m, 3H), 3.52 (dd, J ) 11.5, 4.5 Hz, 1H), 3.25 (dd, J ) 10.0,
2.5 Hz, 1H), 2.70-2.55 (m, 1H), 2.45 (ddd, J ) 12.0, 5.0, 5.0
Hz, 1H), 2.05-1.40 (m, 24H), 1.37 (s, 3H), 1.32 (s, 9H), 1.25-
1.20 (m, 42H), 1.15-1.04 (m, 6H), 1.06 (t, J ) 7.0 Hz, 9H).
Anal. Calcd for C53H106O7Si2Sn: C, 61.79; H, 10.37. Found:
C, 61.41; H, 10.24.
Tetr a cycle 5. The experimental procedure followed was
as described for compound 6. For 5: colorless needles; mp 94-
95 °C (hexane); Rf ) 0.14 (hexane/EtOAc, 4:1); [R]23 +29.6°
D
(c 1.19, CHCl3); IR (KBr) 3600-3200, 2943 cm-1; 1H NMR (300
MHz, CDCl3) δ 5.91 (ddd, J ) 17.0, 10.5, 6.0 Hz, 1H), 5.32
(ddd, J ) 17.0, 1.5, 1.5 Hz, 1H), 5.20 (ddd, J ) 10.5, 1.0, 1.0
Hz, 1H), 4.21-4.17 (m, 1H), 3.85-3.65 (m, 5H), 3.60-3.40 (m,
3H), 3.23 (dd, J ) 12.2, 3.8 Hz, 1H), 3.18 (dd, J ) 9.5, 2.6 Hz,
1H), 2.37-2.21 (m, 1H), 2.18-2.09 (m, 1H), 2.05-1.46 (m,
14H), 1.19 (s, 3H), 1.08-1.00 (m, 42H); 13C NMR (75 MHz,
CDCl3) δ 137.8, 115.9, 87.2, 84.8, 83.9, 82.5, 77.3, 74.1, 73.0,
72.7, 67.7, 63.2, 62.7, 37.2, 36.5, 33.0, 30.6, 29.7, 29.4, 29.3,
28.9, 18.3, 18.0, 16.2, 12.4, 12.0. Anal. Calcd for C40H76O7-
Si2: C, 66.25; H, 10.56. Found: C, 66.19; H, 10.59.
P iva la te 35. The experimental procedure followed was as
described for compound 32. 35: colorless oil; Rf ) 0.39
(hexane/EtOAc, 4:1); [R]20 +14.8° (c 2.03, CHCl3); IR (neat)
D
1
3452, 2943, 1730 cm-1; H NMR (300 MHz, CDCl3) δ 4.24-
4.18 (m, 1H), 4.14-4.00 (m, 2H), 3.86-3.66 (m, 5H), 3.48-
3.35 (m, 2H), 3.20 (dd, J ) 9.5, 2.5 Hz, 1H), 2.40-2.24 (m,
1H), 2.05-1.40 (m, 15H), 1.19 (s, 12H), 1.12-1.02 (m, 42H);
13C NMR (75 MHz, CDCl3) δ 178.7, 85.7, 79.5, 75.3, 72.9, 72.6,
67.7, 64.2, 63.2, 62.4, 38.7, 36.5, 35.0, 33.0, 31.2, 30.6, 29.4,
Alcoh ol 39. To a stirred solution of DMSO (13 µL, 0.18
mmol) in CH2Cl2 (0.5 mL) at -78 °C was added oxalyl chloride

Total Synthesis of Hemibrevetoxin B
J . Org. Chem., Vol. 63, No. 19, 1998 6605
(10 µL, 0.11 mmol). After this mixture was stirred for 10 min,
a solution of 5 (26 mg, 0.036 mmol) in CH2Cl2 (0.5 mL) was
added dropwise, and the resulting mixture was stirred for 0.5
h at that temperature. Triethylamine (50 µL, 0.36 mmol) was
then added, and the resulting mixture was allowed to warm
to room temperature with stirring. The mixture was diluted
with ether and washed with water and brine. The organic
layer was concentrated to give the crude ketone which was
used for the next reaction without purification: Rf ) 0.49
(hexane/EtOAc, 4:1); IR (neat) 2943, 1720, 1637 cm-1; 1H NMR
(300 MHz, CDCl3) δ 5.77 (ddd, J ) 17.2, 10.6, 4.6 Hz, 1H),
5.46 (ddd, J ) 17.2, 1.8, 1.8 Hz, 1H), 5.25 (ddd, J ) 10.6, 1.8,
1.8 Hz, 1H), 4.37 (ddd, J ) 4.6, 2.0, 2.0 Hz, 1H), 4.24-4.18
(m, 1H), 3.86-3.72 (m, 2H), 3.70 (t, J ) 4.6, 2.0, 2.0 Hz, 2H),
3.56 (ddd, J ) 9.5, 9.5, 4.1 Hz, 1H), 3.46 (dd, J ) 12.1, 3.9 Hz,
1H), 3.22 (dd, J ) 7.3, 2.5 Hz, 1H), 3.12 (ddd, J ) 7.7, 7.7, 4.8
Hz, 1H), 2.86 (dd, J ) 12.1, 10.5 Hz, 1H), 2.40-1.50 (m, 15H),
1.18 (s, 3H), 1.10-1.04 (m, 42H).
(m, 2H), 3.74 (s, 3H), 3.69 (t, J ) 6.0 Hz, 2H), 3.44-3.30 (m,
2H), 3.22 (dd, J ) 12.1, 3.8 Hz, 1H), 3.17 (dd, J ) 9.7, 2.2 Hz,
1H), 2.34-2.10 (m, 2H), 2.05-1.48 (m, 14H), 1.17 (s, 3H),
1.10-1.02 (m, 45H), 0.87 (s, 9H), 0.09 (s, 9H), 0.08 (s, 3H); 13
C
NMR (75 MHz, CDCl3) δ 167.0, 146.9, 120.1, 86.4, 86.3, 84.6,
82.6, 77.3, 77.2, 72.9, 72.6, 67.6, 63.2, 62.6, 51.4, 37.3, 36.4,
33.0, 30.5, 29.5, 29.4, 28.9, 25.7, 25.0, 18.2, 18.0, 16.0, 12.4,
12.0, -2.2, -2.4. Anal. Calcd for C49H94O9Si3: C, 64.57; H,
10.39. Found: C, 64.82; H, 10.35.
Sa tu r a ted Ester 43. The experimental procedure followed
was as described for compound 27. For 43: colorless oil; Rf )
0.27 (hexane/EtOAc, 10:1); [R]21 +29.8° (c 1.29, CHCl3); IR
D
(neat) 2943, 1744 cm-1; H NMR (300 MHz, CDCl3) δ 4.22-
1
4.16 (m, 1H), 3.85-3.63 (m, 4H), 3.67 (s, 3H), 3.36-3.25 (m,
2H), 3.25-3.12 (m, 3H), 2.46 (ddd, J ) 15.6, 8.5, 5.5 Hz, 1H),
2.34 (ddd, J ) 15.6, 15.6, 8.5 Hz, 1H), 2.20-1.46 (m, 18H),
1.18 (s, 3H), 1.10 (s, 3H), 1.15-1.00 (m, 42H), 0.83 (s, 9H),
0.06 (s, 3H), 0.05 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 174.1,
87.4, 86.5, 84.7, 82.5, 77.3, 77.0, 72.9, 72.6, 67.6, 63.2, 62.6,
51.5, 37.4, 36.4, 33.0, 31.6, 30.5, 29.4, 28.8, 25.8, 25.7, 23.9,
18.2, 18.0, 16.2, 12.4, 12.0, -2.2, -2.3. Anal. Calcd for
To a solution of the crude ketone in toluene (1 mL) at -78
°C was added methylmagnesium bromide (14 µL, 3.0 M in
ether, 0.042 mmol), and the mixture was stirred for 1 h at
that temperature. The reaction was quenched with water and
extracted with ether. The organic layer was washed with brine
and concentrated. The residue was purified by chromatogra-
phy (hexane/EtOAc, 4:1) to give 39 (19 mg, 71%) and 40 (3
mg, 11%). For 39: colorless oil; Rf ) 0.18 (hexane/EtOAc, 4:1);
C
49H96O9Si3: C, 64.42; H, 10.59. Found: C, 64.51; H, 10.67.
Alcoh ol 44. The experimental procedure followed was as
described for compound 21. For 44: solid; Rf ) 0.37 (hexane/
EtOAc, 4:1); [R]20D +30.1° (c 1.31, CHCl3); IR (KBr) 3600-3200,
1
2945 cm-1; H NMR (300 MHz, CDCl3) δ 4.21-4.17, (m, 1H),
[R]20D +36.7° (c 1.83, CHCl3); IR (neat) 3600-3200, 2942 cm-1
;
3.85-3.62 (m, 6H), 3.42-3.13 (m, 5H), 2.38-1.45 (m, 20H),
1.19 (s, 3H), 1.10 (s, 3H), 1.10-1.00 (m, 42H), 0.83 (s, 9H),
0.07 (s, 3H), 0.06 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 88.4,
86.5, 84.8, 82.5, 77.2, 77.1, 72.9, 72.6, 67.6, 63.2, 62.8, 62.6,
37.4, 36.4, 33.0, 30.5, 30.2, 29.5, 29.4, 28.8, 26.4, 25.7, 23.8,
18.2, 18.0, 16.2, 12.3, 12.0, -2.2, -2.3.
1H NMR (300 MHz, CDCl3) δ 5.88 (ddd, J ) 17.2, 10.6, 5.3
Hz, 1H), 5.28 (ddd, J ) 17.2, 1.8, 1.8 Hz, 1H), 5.19 (ddd, J )
10.6, 1.8, 1.8 Hz, 1H), 4.21-4.17 (m, 1H), 3.85-3.73 (m, 3H),
3.69 (t, J ) 6.0 Hz, 2H), 3.50-3.32 (m, 2H), 3.24 (ddd, J )
12.1, 3.9 Hz, 1H), 3.18 (dd, J ) 9.8, 2.5 Hz, 1H), 2.46-1.45
(m, 16H), 1.18 (s, 3H), 1.10-1.03 (m, 45H); 13C NMR (75 MHz,
CDCl3) δ 135.7, 115.5, 87.9, 86.0, 84.9, 82.4, 77.3, 74.5, 73.0,
72.7, 67.7, 63.2, 62.6, 37.4, 36.5, 33.0, 30.6, 29.7, 29.4, 29.1,
24.5, 18.3, 18.0, 16.2, 12.4, 12.0. Anal. Calcd for C41H78O7-
Si2: C, 66.62; H, 10.64. Found: C, 66.26; H, 10.30. For 40:
Dien e 45. To a stirred solution of 44 (44 mg, 0.050 mmol),
DMSO (50 µL), and triethylamine (35 µL, 0.15 mmol) in CH2-
Cl2 (1 mL) at 0 °C was added sulfur trioxide pyridine complex
(24 mg, 0.15 mmol), and the mixture was stirred at room
temperature. After 1 h, the reaction mixture was diluted with
ether and washed with water and brine. The organic layer
was concentrated and purified by chromatography (hexane/
EtOAc, 10:1) to give the corresponding aldehyde (36 mg,
81%): colorless oil; Rf ) 0.29 (hexane/EtOAc, 10:1).
colorless oil; Rf ) 0.32 (hexane/EtOAc, 4:1); [R]20 +30.4° (c
D
1
1.29, CHCl3); IR (neat) 3600-3200, 2942 cm-1; H NMR (300
MHz, CDCl3) δ 5.94 (ddd, J ) 17.2, 10.6, 5.3 Hz, 1H), 5.33
(ddd, J ) 17.2, 1.8, 1.8 Hz, 1H), 5.27 (ddd, J ) 10.6, 1.8, 1.8
Hz, 1H), 4.21-4.17 (m, 1H), 3.85-3.71 (m, 3H), 3.69 (t, J )
6.0 Hz, 2H), 3.54-3.36 (m, 2H), 3.22 (dd, J ) 11.9, 3.9 Hz,
1H), 3.17 (dd, J ) 10.1, 2.6 Hz, 1H), 2.36-1.46 (m, 16H), 1.18
(s, 3H), 1.16 (s, 3H), 1.10-1.01 (m, 42H); 13C NMR (75 MHz,
CDCl3) δ 134.6, 117.2, 89.3, 85.8, 83.9, 82.8, 77.3, 74.6, 73.0,
72.7, 67.6, 63.2, 62.6, 37.2, 36.6, 33.0, 30.6, 29.4, 29.2, 25.7,
18.3, 18.0, 15.8, 12.4, 12.0. Anal. Calcd for C41H78O7Si2: C,
66.62; H, 10.64. Found: C, 66.75; H, 10.54.
To a stirred suspension of PhSe(CH2)3P+Ph3Br- (49 mg, 0.09
mmol) in THF (1 mL) at -78 °C was added n-BuLi (52 µL,
1.57 M in hexane, 0.082 mmol). After this mixture was stirred
for 0.5 h, HMPA (14 µL) and a solution of the aldehyde
obtained above in THF (0.5 mL) were sequentially added, and
the resulting mixture was allowed to warm to room temper-
ature. After 0.5 h, the reaction was quenched with water and
extracted with ether. The organic layer was washed with brine
and concentrated.
To a solution of the crude selenide in THF (1 mL) were
added NaHCO3 (84 mg, 1.0 mmol) and H2O2 (0.3 mL of 30%
solution), and the mixture was stirred for 4 h at room
temperature. The reaction mixture was diluted with ether and
washed with water and brine. The organic layer was concen-
trated and purified by chromatography (hexane/EtOAc, 10:1)
Silyl Eth er 41. A stirred solution of 39 (102 mg, 0.14
mmol) and 2,6-lutidine (49 µL, 0.42 mmol) in CH2Cl2 (2 mL)
was treated with tert-butyldimethylsilyl trifluoromethane-
sulfonate (TBSOTf, 71 µL, 0.31 mmol) at room temperature.
After 9 h, the reaction mixture was diluted with ether and
washed with water and brine. The organic layer was concen-
trated and purified by chromatography (hexane/EtOAc, 20:1)
to give 41 (101 mg, 85%): colorless oil; Rf ) 0.20 (hexane/
to give 45 (34 mg, 91%): colorless oil; Rf ) 0.49 (hexane/EtOAc,
EtOAc, 20:1); [R]20D +35.3° (c 1.40, CHCl3); IR (KBr) 2943 cm-1
;
10:1); [R]23 +20.3° (c 1.60, CHCl3); IR (neat) 2943 cm-1; H
1
D
1H NMR (300 MHz, CDCl3) δ 5.89 (ddd, J ) 17.2, 10.6, 3.8
Hz, 1H), 5.27 (ddd, J ) 17.2, 2.0, 2.0 Hz, 1H), 5.12 (ddd, J )
10.6, 2.0, 2.0 Hz, 1H), 4.21-4.16 (m, 1H), 3.86-3.71 (m, 3H),
3.69 (t, J ) 6.0 Hz, 2H), 3.46-3.28 (m, 2H), 3.24 (dd, J ) 12.1,
3.8 Hz, 1H), 3.17 (dd, J ) 9.8, 2.5 Hz, 1H), 2.37-1.45 (m, 16H),
1.18 (s, 3H), 1.08-1.02 (m, 45H), 0.94 (s, 9H), 0.08 (s, 3H),
0.05 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 135.9, 114.1, 87.6,
86.2, 85.1, 82.4, 77.3, 77.2, 72.9, 72.6, 67.6, 63.2, 62.6, 37.5,
37.4, 36.4, 33.1, 30.5, 29.7, 29.4, 28.9, 25.7, 24.7, 18.3, 18.2,
18.0, 16.2, 12.4, 12.0, -2.2, -2.3. Anal. Calcd for C47H92O7-
Si3: C, 66.14; H, 10.88. Found: C, 66.12; H, 10.71.
NMR (300 MHz, CDCl3) δ 6.65 (ddd, J ) 16.9, 10.8, 10.8 Hz,
1H), 6.03 (t, J ) 10.8 Hz, 1H), 5.48-5.37 (m, 1H), 5.30 (d, J )
16.9 Hz, 1H), 5.10 (d, J ) 10.8 Hz, 1H), 4.22-4.17 (m, 1H),
3.85-3.72 (m, 2H), 3.69 (t, J ) 6.0 Hz, 2H), 3.34-3.14 (m, 5H),
2.40-1.30 (m, 20H), 1.16 (s, 3H), 1.10-1.03 (m, 45H), 0.83 (s,
9H), 0.06 (s, 3H), 0.05 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
132.7, 132.1, 129.7, 117.1, 86.9, 86.3, 85.1, 82.4, 77.3, 72.9, 72.6,
67.6, 63.2, 62.6, 37.5, 36.4, 33.2, 30.5, 30.1, 29.6, 29.4, 28.8,
25.7, 24.7, 24.0, 18.3, 18.2, 18.0, 16.3, 12.4, 12.0, -2.2, -2.3.
Alcoh ol 46. The experimental procedure followed was as
described for compound 17. For 46: colorless oil; Rf ) 0.20
Un sa tu r a ted Ester 42. The experimental procedure fol-
lowed was as described for compound 26. For 42: colorless
(hexane/EtOAc, 4:1); [R]21 +23.8° (c 0.95, CHCl3); IR (neat)
D
3600-3200, 2943 cm-1; 1H NMR (300 MHz, CDCl3) δ 6.65 (ddd,
J ) 16.9, 11.0, 11.0 Hz, 1H), 6.03 (t, J ) 11.0 Hz, 1H), 5.49-
5.39 (m, 1H), 5.20 (d, J ) 16.9 Hz, 1H), 5.10 (d, J ) 11.0 Hz,
1H), 4.21-4.17 (m, 1H), 3.90-3.73 (m, 2H), 3.70-3.60 (m, 2H),
3.33-3.14 (m, 5H), 2.45-1.30 (m, 20H), 1.17 (s, 3H), 1.10-
oil; Rf ) 0.31 (hexane/EtOAc, 10:1); [R]20 +36.3° (c 1.39,
D
1
CHCl3); IR (KBr) 2945, 1728, 1661 cm-1; H NMR (300 MHz,
CDCl3) δ 7.03 (dd, J ) 15.6, 3.1 Hz, 1H), 6.07 (dd, J ) 15.6,
2.0 Hz, 1H), 4.22-4.16 (m, 1H), 4.02-3.97 (m, 1H), 3.85-3.71

6606 J . Org. Chem., Vol. 63, No. 19, 1998
Kadota and Yamamoto
1.04 (m, 24H), 0.83 (s, 9H), 0.06 (s, 3H), 0.05 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 132.7, 132.1, 129.7, 117.1, 86.9, 86.3, 85.1,
82.2, 72.8, 67.5, 63.0, 62.8, 37.5, 36.7, 32.9, 30.8, 30.2, 30.1,
29.6, 28.7, 25.7, 24.7, 23.9, 18.2, 18.0, 16.3, 12.4, -2.2, -2.3.
Anal. Calcd for C42H78O7Si2: C, 67.15; H, 10.47. Found: C,
67.56; H, 10.36.
evacuations (water aspirator). After 1.5 h, the reaction was
quenched with aqueous NaHCO3 and extracted with EtOAc.
The extract was washed with brine, concentrated, and purified
by chromatography (hexane/EtOAc, 1:1) to give 1 (3.3 mg,
76%): colorless oil; Rf ) 0.12 (hexane/EtOAc, 1:1); [R]22D +102°
(c 0.09, CHCl3) {lit.3 [R]22 +115° (c 0.1, CHCl3)}; IR (neat)
D
1
3600-3200, 2929, 1670 cm-1; H NMR (500 MHz, CD2Cl2) δ
Ald eh yd e 47. A stirred solution of 46 (19 mg, 0.025 mmol)
in CH2Cl2 (0.5 mmol) was treated with Dess-Martin periodi-
nane (32 mg, 0.075 mmol). After 0.5 h of stirring, the reaction
mixture was diluted with ether and washed with aqueous
Na2S2O3, NaHCO3, and brine. The organic layer was concen-
trated to give crude aldehyde which was used directly.
To a solution of the crude aldehyde obtained above and
triethylamine (70 µL, 0.5 mmol) in CH2Cl2 (0.5 mmol) was
added methylenedimethylammonium chloride (24 mg, 0.13
mmol), and the mixture was stirred for 15 h at room temper-
ature. The reaction mixture was diluted with ether and
washed with water and brine. The organic layer was concen-
trated and purified by chromatography (hexane/EtOAc, 10:1)
to give 47 (17 mg, 89%): colorless oil; Rf ) 0.20 (hexane/EtOAc,
9.52 (s, 1H), 6.69 (dddd, J ) 16.9, 11.1, 10.1, 1.1 Hz, 1H), 6.37
(d, J ) 0.9 Hz, 1H), 6.09 (d, J ) 0.9 Hz, 1H), 6.04 (t, J ) 11.0
Hz, 1H), 5.50-5.44 (m, 1H), 5.21 (d, J ) 16.9 Hz, 1H), 5.10 (d,
J ) 10.1 Hz, 1H), 4.01-3.98 (m, 1H), 3.94-3.88 (m, 1H), 3.75
(ddd, J ) 11.0, 10.1, 4.6 Hz, 1H), 3.35-3.30 (m, 2H), 3.26 (dd,
J ) 11.9, 4.1 Hz, 1H), 3.20 (dd, J ) 9.6, 2.8 Hz, 1H), 3.16 (dd,
J ) 14.7, 9.9 Hz, 1H), 2.46 (dd, J ) 14.5, 5.0 Hz, 1H), 2.34-
2.29 (m, 2H), 2.28-2.26 (m, 1H), 2.22-2.14 (m, 1H), 1.97-
1.30 (m, 14H), 1.19 (s, 3H), 1.07 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 194.9, 148.4, 136.4, 133.1, 132.6, 130.0, 117.3, 87.2,
86.3, 85.4, 82.6, 78.4, 74.7, 72.5, 71.0, 66.7, 62.9, 38.6, 37.9,
33.9, 33.2, 31.9, 30.7, 30.0, 29.3, 25.1, 23.7, 17.0; HRMS (FAB)
calcd for C28H43O7 (M + H) 491.3009, found 491.2965.
10:1); [R]21D +45.2° (c 0.60, CHCl3); IR (neat) 2945, 1695 cm-1
;
1H NMR (300 MHz, CDCl3) δ 9.54 (s, 1H), 6.65 (ddd, J ) 16.9,
10.5, 10.5 Hz, 1H), 6.31 (s, 1H), 6.08 (s, 1H), 6.03 (t, J ) 10.5
Hz, 1H), 5.49-5.39 (m, 1H), 5.20 (d, J ) 16.9 Hz, 1H), 5.09 (d,
J ) 10.5 Hz, 1H), 4.24-4.20 (m, 1H), 4.00-3.82 (m, 2H), 3.39
(dd, J ) 14.7, 11.8 Hz, 1H), 3.30-3.14 (m, 4H), 2.40-1.30 (m,
18H), 1.16 (s, 3H), 1.13-1.05 (m, 24H), 0.83 (s, 9H), 0.06 (s,
3H), 0.05 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 194.6, 148.2,
135.7, 132.8, 132.1, 129.7, 117.1, 86.9, 86.2, 85.1, 82.3, 72.7,
70.9, 67.6, 62.7, 37.5, 36.8, 32.9, 31.8, 30.1, 29.7, 28.8, 25.7,
24.7, 24.0, 18.3, 18.1, 16.2, 12.4, -2.1, -2.3; HRMS (FAB) calcd
for C43H76O7Si2Na (M + Na) 783.5028, found 783.4989.
Hem ibr evetoxin B (1). A cooled (0 °C) solution of 47 (6.7
mg, 8.8 µmol) in a 1:1 mixture of CH2Cl2-CH3CN (1 mL) was
stirred under SiF4 gas introduced using a balloon by repeated
Ack n ow led gm en t. This work was financially sup-
ported by a Grant-in-Aid for Scientific Research from
the Ministry of Education, Science and Culture of
J apan, the Shorai Foundation for Science and Technol-
ogy, the Terumo Life Science Foundation, the Founda-
tion for Chemical Materials, and a grant from the
Mitsubishi Chemical Company. We thank Prof. Takeshi
Yasumoto and Dr. Mari Yamashita (Faculty of Agricul-
ture, Tohoku University) for their mass spectrometric
assistance.
J O9807619