Formal total synthesis of hemibrevetoxin B by an oxiranyl anion strategy

Article abstract of DOI:10.1021/jo980320p

The synthesis of the tetracyclic structure of hemibrevetoxin B (1) was achieved through a linear approach involving sequential coupling of three kinds of sulfonyl-stabilized oxiranyl anions, 5b, 6b, and 7b, to the monocyclic tetrahydropyran 4 containing the requisite substituents. Two iterations of alkylation of an oxiranyl anion and 6-endo cyclization provided the 6,6,6-tricyclic ring system 34, which was efficiently transformed into the 6,6,7-ring system 35 by ring expansion using trimethylsilyldiazomethane. Installation of the final oxepane ring into 38 was carried out using a combination of the oxiranyl anion methodology and ring enlargement just described. Stereoselective introduction of a tertiary methyl group into 41 provided the tetracyclic compound 42a, which contains all the asymmetric centers of 1. Elaboration of 42a to the known compound 2, which was already transformed into hemibrevetoxin B, completed the formal total synthesis of the natural product.

Full text of DOI:10.1021/jo980320p

6200
J . Org. Chem. 1998, 63, 6200-6209
F or m a l Tota l Syn th esis of Hem ibr evetoxin B by a n Oxir a n yl
An ion Str a tegy
Yuji Mori,* Keisuke Yaegashi, and Hiroshi Furukawa
Faculty of Pharmacy, Meijo University 150 Yagotoyama, Tempaku, Nagoya 468-8503, J apan
Received February 19, 1998
The synthesis of the tetracyclic structure of hemibrevetoxin B (1) was achieved through a linear
approach involving sequential coupling of three kinds of sulfonyl-stabilized oxiranyl anions, 5b,
6b, and 7b, to the monocyclic tetrahydropyran 4 containing the requisite substituents. Two
iterations of alkylation of an oxiranyl anion and 6-endo cyclization provided the 6,6,6-tricyclic ring
system 34, which was efficiently transformed into the 6,6,7-ring system 35 by ring expansion using
trimethylsilyldiazomethane. Installation of the final oxepane ring into 38 was carried out using a
combination of the oxiranyl anion methodology and ring enlargement just described. Stereoselective
introduction of a tertiary methyl group into 41 provided the tetracyclic compound 42a , which
contains all the asymmetric centers of 1. Elaboration of 42a to the known compound 2, which was
already transformed into hemibrevetoxin B, completed the formal total synthesis of the natural
product.
In tr od u ction
ration of an enol ether derived from thionolactone by
Nicolaou,6 the Lewis acid-mediated intramolecular allyl-
stannane-aldehyde condensation by Yamamoto,7 and a
double rearrangement-ring expansion of a 6,6-bicyclic
ether to a dioxepane ring by the Nakata group.8 Herein
we report in detail the formal total synthesis of hemi-
brevetoxin B using unique nucleophilic oxiranyl anions
as building blocks.9
Retr osyn th etic An a lysis. The retrosynthetic analy-
sis of hemibrevetoxin B (1) based on a linear approach
is shown in Scheme 1. The two side chains in the target
structure were partially disconnected to provide the key
intermediate 2. We envisioned that the two oxepane
rings of 2 are constructed by the ring expansion of
tetrahydropyrans, so we tentatively regarded the tetra-
cyclic tetrahydropyran 3 as an imaginary precursor. The
indicated C-O and C-C bonds of 3 were disconnected
to unravel the monocyclic diol 4 and three oxiranyl anions
5b, 6b, and 7b, which could be generated from the
corresponding epoxy sulfones 5a , 6a , and 7a , respectively.
The sulfonyl-stabilized oxiranyl anions are unique
nucleophilic epoxides and serve as a new type of func-
tionalized acyl anion equivalent.10,11 Based on our strat-
egy, the use of the sulfonyl-stabilized cis-oxiranyl anions
was expected to induce an efficient C-C bond formation
on an epoxide ring, a stereocontrolled 6-endo mode of
cyclization, and a facile generation of a carbonyl group
One of the most characteristic and interesting classes
of marine toxins produced by dinoflagellates is the
polycyclic ethers. The linear cyclic structure was first
demonstrated in brevetoxin B, the major toxin in the
Florida red tide organism Gymnodinium breve, and its
unprecedented structure was elucidated by X-ray crystal-
lography in 1980.1 Subsequently, the structure of the
most toxic component, brevetoxin A, was also determined
by X-ray crystallography.2 Although several other bre-
vetoxin-type metabolites have been reported,3 a new type
of toxin, hemibrevetoxin B (1), which has about half the
skeleton of brevetoxins, has been recently discovered in
the cultured cells of the same organism.4
Hemibrevetoxin B is the smallest member of the
marine polycyclic ethers. This unique 6,6,7,7-tetracyclic
structure containing 10 stereocenters, an R-vinyl alde-
hyde moiety, and a Z-diene system has attracted the
attention of synthetic chemists, and a variety of ap-
proaches to its synthesis have been explored.5 Recently,
three total syntheses of hemibrevetoxin B have been
accomplished by using new synthetic methods: 6-endo
cyclization and dioxepane ring formation by the hydrobo-
* Corresponding author. Phone: 052-832-1781. Fax: 052-834-8780.
E-mail: mori@meijo-u.ac.jp.
(1) Lin, Y.; Risk, M.; Ray, S. M.; Van Engen, D.; Clardy, J .; Golic,
J .; J ames, J . C.; Nakanishi, K. J . Am. Chem. Soc. 1981, 103, 6773-
6775.
(2) (a) Shimizu, Y.; Chou, H. N.; Bando, H.; Van Duyne, G.; Clardy,
J . C. J . Am. Chem. Soc. 1986, 108, 514-515; (b) Pawlak, J .; Tempesta,
M. S.; Golik, J .; Zagorski, M. G.; Lee, M. S.; Nakanishi, K.; Iwashita,
T.; Gross, M. L.; Tomer, K. B. J . Am. Chem. Soc. 1987, 109, 1144-
1150.
(6) (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.
(7) Kadota, I.; J ung-Youl, P.; Koumura, N.; Pollaud, G.; Matsukawa,
Y.; Yamamoto, Y. Tetrahedron Lett. 1995, 36, 5777-5780.
(8) Morimoto, M.; Matsukura, H.; Nakata, T. Tetrahedron Lett. 1996,
37, 6365-6368.
(9) For a preliminary communication, see: Mori, Y.; Yaegashi, K.;
Furukawa, H. J . Am. Chem. Soc. 1997, 119, 4557-4558.
(10) (a) Ashwell, M.; Clegg, W.; J ackson, R. F. W. J . Chem. Soc.,
Perkin Trans. 1 1991, 897-908; (b) Dunn, S. F. C.; J ackson, R. F. W.
J . Chem. Soc., Perkin Trans. 1 1992, 2863-2870.
(11) For reviews of oxiranyl anions, see: (a) Satoh, T. Chem. Rev.
1996, 96, 3303-3325; (b) Mori, Y. J . Synth. Org. Chem. J pn. 1997,
55, 26-35; (c) Mori, Y. Reviews on Heteroatom Chemistry; Oae, S., Ed.;
MYU: Tokyo, 1997; Vol. 17, pp 183-211.
(3) (a) Shimizu, Y. Chem Rev. 1993, 93, 1685-1698; (b) Yasumoto,
T.; Murata, M. Chem Rev. 1993, 93, 1897-1909.
(4) Prasad, A. V. K.; Shimizu, Y. J . Am. Chem. Soc. 1989, 111, 6476-
6477.
(5) (a) Kadota, I.; Matsukawa, Y.; Yamamoto, Y. J . Chem. Soc.,
Chem. Commun. 1993, 1638-1641; (b) Feng, F.; Murai, A. Chem. Lett.
1992, 1587-1590; (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.
S0022-3263(98)00320-X CCC: $15.00 © 1998 American Chemical Society
Published on Web 08/08/1998

Hemibrevetoxin B Synthesis with Oxiranyl Anions
J . Org. Chem., Vol. 63, No. 18, 1998 6201
Sch em e 1
Sch em e 3
Sch em e 2
epoxidation and the subsequent four-step manipulation.13
The synthesis of two other chiral epoxy sulfones 5a and
7a was carried out according to the procedure developed
by Satoh et al.,14 as shown in Scheme 3. Reactions of
the carbanion generated from optically active (R)-(-)-
chloromethyl p-tolyl sulfoxide 15 (98% ee) with ketone
16 and the unsaturated aldehyde 18 gave a mixture of
two diastereoisomers 17a ,b and 19a ,b, respectively.15
After chromatographic separation, the major chlorohy-
drins 17a and 19a were converted into epoxy sulfones
5a and 7a , respectively, via oxirane formation followed
by oxidation. It is noteworthy that the reaction of 15 with
a saturated aldehyde of 18 caused serious epimerization
at the stereogenic center containing a chlorine atom to
give an unseparable mixture of four diastereoisomers,
whereas only two isomers were obtained when the
unsaturated aldehyde 18 was employed. Presently, no
reasonable explanation can be offered for this result.
Syn th esis of Hem ibr evetoxin B. Tri-O-acetyl-D-
glucal (20) was utilized as the starting material for the
construction of the tetracyclic system of hemibrevetoxin
B (Scheme 4). Treatment of 20 with allyltrimethylsilane
under the reported conditions16 followed by methanolysis
of the resulting diacetate gave diol 21 in 94% overall
yield. Regio- and stereoselective epoxidation of the ring
double bond in 21 was accomplished with m-chloroper-
oxybenzoic acid (m-CPBA) in toluene at 0 °C for 2 h,
leading to an R-epoxy diol that was protected with
benzylidene acetal to give 22 in 46% overall yield.17
Selective reduction of epoxide 22 with LiAlH4 and ben-
as shown in Scheme 2. Theoretically, the coupling
product 10 could suffer ring closure through the 5-exo
and 6-endo mode of cyclization, leading to a tetrahydro-
furan or a tetrahydropyran system, respectively. How-
ever, the strong electron-withdrawing ability of the
sulfonyl group works against the adjacent C-O bond-
breaking in an acid-catalyzed epoxide ring-opening pro-
cess and, consequently, favors the endo-mode pathway,
which yields tetrahydropyranone 11 after elimination of
benzenesulfinic acid.12 Moreover, the resulting ketone
11 can be directly converted to oxepane 12 by a ring
expansion reaction.13 A combination of the stepwise
couplings of three oxiranyl anions 5b, 6b, and 7b to diol
4 and the ring expansion at suitable stages would give
the key intermediate 2. Yamamoto has already described
the conversion of 2 into hemibrevetoxin B,7 so the
synthesis of 2 constitutes the formal total synthesis of
the natural product.
Resu lts a n d Discu ssion
(14) Satoh, T.; Oohara, T.; Ueda, Y.; Yamakawa, K. J . Org. Chem.
1989, 54, 3130-3136.
(15) The stereochemistry of chlorohydrins 17a ,b and 19a ,b were
deduced from the 1H NMR analysis of the corresponding epoxy sulfones
obtained by treatment of the chlorohydrins with tert-BuOK: see
Experimental Section and ref 14.
Syn th esis of Ep oxy Su lfon es. Optically active epoxy
sulfone 6a was synthesized from cis-vinyl sulfone 13 by
(12) (a) Mori, Y.; Yaegashi, K.; Furukawa, H. J . Am. Chem. Soc.
1996, 118, 8158-8159; (b) Mori, Y. Chem. Eur. J . 1997, 3, 849-852.
(13) Mori, Y.; Yaegashi, K.; Furukawa, H. Tetrahedron 1997, 35,
12917-12932.
(16) Toshima, K.; Ishizuka, T.; Matsuo, G.; Nakata, M. Tetrahedron
Lett. 1994, 35, 5673-5676.

6202 J . Org. Chem., Vol. 63, No. 18, 1998
Mori et al.
Sch em e 4
F igu r e 1. Important NOE interactions in 27 and 33.
epoxy sulfone 26 in 90% yield. Compound 26 was
appropriately designed to undergo an epoxide opening-
ring closure type reaction.12 Treatment with p-TsOH in
CHCl3 at 0 °C led to the desilylation at the secondary
hydroxyl group and the subsequent stereospecific 6-endo
cyclization to afford the bicyclic ketone 27 in 90% yield.
The cyclization was accompanied with inversion of ster-
eochemistry at the carbon undergoing nucleophilic attack
as expected and as supported by the nuclear Overhauser
effect (NOE) experiments depicted in Figure 1. Stereo-
selective reduction of 27 with NaBH4 (>99% de) followed
by desilylation gave the bicyclic diol 29.
Sch em e 5
Installation of the third ring involved the challenging
preparation of an oxepane ring. Unfortunately, several
attempts to couple the triflate 30 derived from 29 with
the oxiranyl anion 6b were unsuccessful due to the
considerable steric hindrance of the methyl group adja-
cent to the reaction site. This unexpected difficulty was
circumvented by inducing the reaction between an ox-
iranyl anion and an aldehyde. The transformation of 29
to an aldehyde 31 was accomplished by bis(triethylsilyl-
ation), followed by regioselective desilylation of the
primary hydroxyl group with pyridinium p-toluene-
sulfonate (PPTS) in CH2Cl2-methanol at -20 °C and
SO3‚pyridine oxidation in 87% overall yield (Scheme 6).
The addition of the aldehyde 31 to a solution of the
oxiranyl anion 6b generated from the epoxy sulfone 6a
with n-BuLi in THF at -100 °C resulted in a low yield
of the coupling product because of the serious decomposi-
tion of the unstable cis-oxiranyl anion.10a To prevent the
decomposition of the oxiranyl anion, an in situ trapping
method was attempted. Thus, a mixture of 6a and 31
in THF-HMPA at -110 °C was treated with n-BuLi. To
our surprise, a very good yield of the coupled product was
obtained as a 3:1 mixture of epimers, from which 32a
and 32b were isolated in 63 and 25% yield, respectively.
It is noteworthy that the deprotonation of 6a by n-BuLi
is much faster than the butyl addition to the aldehyde
31. Exposure of the major isomer 32a to BF3‚OEt2 led
to its clean cyclization to the tricyclic hydroxy ketone 33
in 76% yield, whereas the minor isomer 32b did not
cyclize under the same conditions. In a presumed 6-endo
cyclization transition state for the minor isomer 32b, the
methyl, hydroxyl, and sulfonyl substituents should be
arrayed on the same side of a forming ring, which causes
the serious steric interactions and prevents the cycliza-
tion. The configuration of the hydroxyl group of 33 was
determined on the basis of the NOE interactions as
indicated in Figure 1. The removal of the hydroxy group
of 33 proved to be more problematic, although reduction
zylation of the resulting R-axial alcohol gave the benzyl
ether 23 in 90% yield. Hydroboration of the terminal
olefin in 23 with 9-borabicyclo[3.3.1]nonane (9-BBN-H)
in tetrahydrofuran (THF) followed by oxidative workup
furnished an alcohol, which was benzylated to 24 in 74%
overall yield. The monocyclic diol 4 was obtained from
24 in 92% yield by acid hydrolysis of the benzylidene
acetal.
Regioselective activation and protection of the diol 4
as a triflate 25 were carried out using a one-pot process
(Scheme 5). Thus, the treatment of a solution of 4 and
2,6-lutidine in CH2Cl2 with one equivalent of triflic
anhydride at -78 °C for 30 min followed by the addition
of a slight excess of triethylsilyl triflate gave the triflate
25 in 98% yield. The crucial coupling of 25 with the
oxiranyl anion 5b was accomplished by the addition of
n-BuLi to a mixture of 5a and 25 in THF-hexameth-
ylphosphoramide (HMPA) at -110 °C,18 providing the
(18) (a) Mori, Y.; Yaegashi, K.; Iwase, K.; Yamamori, Y.; Furukawa,
H. Tetrahedron Lett. 1996, 37, 2605-2608; (b) Mori, Y.; Yaegashi, K.;
Iwase, K.; Yamamori, Y.; Furukawa, H. Tetrahedron Lett. 1996, 37,
6959.
(17) Ichikawa, Y.; Isobe, M.; Goto, T. Tetrahedron 1987, 43, 4749-
4758.

Hemibrevetoxin B Synthesis with Oxiranyl Anions
J . Org. Chem., Vol. 63, No. 18, 1998 6203
Sch em e 6
Sch em e 7
Sch em e 8
of the R-oxygenated ketones to the corresponding unsub-
stituted ketone has seen substantial use as a routine
synthetic transformation. Because the introduction of
leaving groups, such as acetyl, methanesulfonyl, and
trifluoromethanesulfonyl groups, to the hydroxyl group
under standard conditions resulted in low product yields,
the direct dehydroxylation was undertaken. After sev-
eral attempts with different reagents and different condi-
tions, it was found that the best yields were obtained
19
using four equivalents of SmI2 in THF-HMPA-
methanol at 0 °C leading to the tricyclic ketone 34 in 64%
yield.
The crucial oxepane formation was accomplished by
one-carbon homologation of the C-ring. Thus, reaction
of 34 with trimethylsilyldiazomethane20 in the presence
of BF3‚OEt2 in CH2Cl2 at -78 °C gave the seven-
membered ketone 35 in 67% yield along with 17% of its
isomeric ketone after acid hydrolysis of the intermediary
trimethylsilyl enol ether (Scheme 7). The electron-
inductive effect of the C-ring oxygen might control the
direction of this ring expansion to a less crowded R-tri-
methylsilyl ketone, and the immediate rearrangement to
the corresponding trimethylsily enol ether under the
reaction conditions prevents the undesirable multiple
homologation of the initially formed ketone.13 Reduction
of 35 under a variety of conditions led to the predominant
formation of the undesired cis alcohol.21 To reverse the
stereoselectivity, 35 was desilylated with Bu4NF in the
presence of acetic acid, and the resulting hydroxy ketone
(36) was subjected to the hydroxy-directed reduction with
The third coupling of triflate 38 with epoxy sulfone 7a
with a three-carbon side chain was performed by an in
situ trapping method; the coupling proceeded unevent-
fully to afford 39 in 96% yield (Scheme 8). When this
epoxy sulfone was subjected to cyclization conditions
using p-TsOH,12 only desilylation of the triethylsilyl
(TES) group was observed. Boron trifluoride etherate
was then used to induce the 6-endo cyclization to give
the tetracyclic ketone 40 in 67% yield. Once again, the
ring expansion reaction was applied using trimethylsi-
lyldiazomethane to afford a new tetracyclic ketone 41 in
62% yield and its isomeric ketone in 3% yield. The NOE
experiments of the tetracyclic ketones 40 and 41 revealed
that both ketones have the correct stereochemistry, as
shown in Scheme 8.
22
Me4NBH(OAc)3 to provide the expected trans-diol 37
as a single diastereoismer.
(19) (a) Molander, G. A.; Hahn, G. J . Org. Chem. 1986, 51, 1135-
1138; (b) Kusuda, K.; Inanaga, J .; Yamaguchi, M. Tetrahedron Lett.
1989, 30, 2945-2948.
The addition of MeMgBr to 41 in toluene5d led to a 4:1
epimeric mixture of products from which the desired 42a
was isolated in 77% yield by chromatography (Scheme
(20) (a) Hashimoto, N.; Aoyama, T.; Shioiri, T. Tetrahedron Lett.
1980, 21, 4619-4622; (b) Maruoka, K.; Concepcion, A. B.; Yamamoto,
H. J . Org. Chem. 1994, 59, 4725-4726; (c) Maruoka, K.; Concepcion,
A. B.; Yamamoto, H. Synthesis 1994, 1283-1290.
(22) (a) Evans, D. A.; Chapman, K. T. Tetrahedron Lett. 1986, 27,
5939-4942; (b) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J . Am.
Chem. Soc. 1988, 110, 3560-3578.
(21) Evans, P. A.; Roseman, J . D.; Garber, L. T. J . Org. Chem. 1996,
61, 4880-4881.

6204 J . Org. Chem., Vol. 63, No. 18, 1998
Mori et al.
Sch em e 9
bond formation and epoxidation of a substrate allows one
to construct a given target in fewer linear steps. Further
applications of this methodology to the synthesis of other
marine natural products are now in progress.
Exp er im en ta l Section
(1R,2S)-1-(ter t-Bu t yld ip h en ylsilyl)oxy-3-ch lor o-2-h y-
d oxy-2-m eth yl-3-(p-tolylsu lfin yl)p r op a n on e (17a ) a n d Its
(2R,3R)-Isom er (17b). To a solution of lithium diisopropyl-
amide (LDA) (3.45 mmol) in THF (5 mL) at -78 °C was added
a solution of (R)-1-chloromethyl p-tolyl sulfoxide (15; 565 mg,
3.00 mmol) in THF (2 mL), and the resulting solution was
stirred at -78 °C for 30 min. To this solution was added a
solution of ketone 16 (1.12 g, 3.60 mmol) in THF (2 mL), and
the mixture was stirred for 30 min at -78 °C. The reaction
was quenched with saturated NH4Cl (2 mL) and extracted with
EtOAc. The extract was washed with water and brine, dried,
and concentrated. Flash chromatography gave (50% ether in
hexane) gave chlorohydrins 17a (861 mg, 57%) and 17b (566
mg, 38%). 17a : colorless oil; [R]2D0 -89.2° (c 0.64, CHCl3); IR
1
(CHCl3) 3545, 1471 cm-1; H NMR (400 MHz, CDCl3) δ 1.10
(9H, s), 1.57 (3H, s), 2.43 (3H, s), 3.16 (1H, s, OH), 3.80 (1H,
d, J ) 10.6 Hz), 3.92 (1H, d, J ) 10.6 Hz), 4.68 (1H, s), 7.26-
7.48 (10H), 7.65-7.70 (4H); FABMS m/z 501 (MH - 35Cl), 503
(MH - 37Cl). 17b: colorless oil; [R]D20 -106.4° (c 0.73, CHCl3);
1
IR (CHCl3) 3545, 1471, 1427, 1113 cm-1; H NMR (400 MHz,
CDCl3) δ 1.07 (9H, s), 1.42 (3H, s), 2.44 (3H, s), 3.32 (1H, s,
OH), 3.70 (1H, d, J ) 10.6 Hz), 3.86 (1H, d, J ) 10.6 Hz), 4.60
(1H, s), 7.26-7.50 (10H), 7.59-7.65 (4H); fast-atom bombard-
ment mass spectrometry (FABMS) m/z 501 (MH - 35Cl), 503
(MH - 37Cl).
(2R,3R)-2,3-Epoxy-1-(ter t-bu tyldiph en ylsilyl)oxy-2-m eth -
yl-3-(p-tolylsu lfon yl)p r op a n e (5a ). To a solution of chlo-
rohydrin 17a (853 mg, 1.70 mmol) in CH2Cl2 (5 mL) and
t-BuOH (5 mL) was added t-BuOK (210 mg, 1.87 mmol), and
the mixture was stirred at room temperature for 30 min. The
reaction mixture was diluted with EtOAc and washed with
water and brine. The organic layer was dried and concen-
trated. Flash chromatography (20% EtOAc in hexane) gave
788 mg (100%) of (2R,3R)-2,3-epoxy-1-(tert-butyldiphenylsilyl)-
oxy-2-methyl-3-(p-tolylsulfinyl)propane: [R]2D0 +32.2° (c 1.67,
9). The minor isomer (42b), isolated in 21% yield, showed
a 3.2% NOE enhancement between the newly introduced
methyl and the adjacent methine protons, whereas no
NOE was observed in the major isomer 42a . Desilylation
of 42a with Bu4NF followed by disilylation with tert-
butyldimethylsilyl triflate gave 43 in 78% yield, which
was debenzylated and then disilylated with triisopropyl-
silyl triflate to give the tetrasilylated derivative 44 in 84%
yield. Finally, selective removal of the TBS group at the
primary position by CSA in CH2Cl2-methanol at 0 °C
provided the alcohol 2 [[R]2D5 +24.8° (c 0.21, CHCl3)] in
1
CHCl3); H NMR (600 MHz, CDCl3) δ 1.11 (9H, s), 1.53 (3H,
s), 2.42 (3H, s), 3.70 (1H, s), 3.99 (1H, d, J ) 11.7 Hz), 4.15
(1H, d, J ) 11.7 Hz), 7.32-7.48 (10H), 7.72-7.73 (4H); FABMS
m/z 465 (MH). The (2S,3R)-isomer prepared from 17b in the
same way showed the following data: [R]2D0 -27.7° (c 1.37,
1
1
CHCl3); H NMR (400 MHz, CDCl3) δ 1.01 (9H, s), 1.72 (3H,
74% yield. The H NMR spectrum of 2 was in complete
s), 2.44 (3H, s), 3.64 (1H, d, J ) 12.1 Hz), 3.77 (1H, d, J )
12.1 Hz), 3.90 (1H, s), 7.34-7.44 (8H), 7.60-7.63 (6H); FABMS
m/z 465 (MH).
agreement with that of an authentic sample kindly
provided by Professor Y. Yamamoto, and further elabo-
ration of the side chains of 2 to hemibrevetoxin B (1) has
been already accomplished by Yamamoto and co-work-
ers,7 thereby completing the formal total synthesis of
hemibrevetoxin B.
To a solution of the (2R,3R)-epoxy sulfoxide (782 mg, 1.69
mmol) in CH2Cl2 (8.0 mL) was added m-CPBA (80% purity,
436 mg, 2.02 mmol), and the reaction mixture was stirred at
room temperature for 4 h. The mixture was extracted with
EtOAc and the extract was washed with aqueous Na2S2O3,
NaHCO3, and brine. The organic layer was dried and con-
centrated under reduced pressure. Flash chromatography
(15% EtOAc in hexane) gave epoxy sulfone 5a (788 mg, 97%)
as a colorless oil: [R]D20 -79.8° (c 1.05, CHCl3); IR (CHCl3)
Con clu sion
The present synthesis of hemibrevetoxin B using
oxiranyl anions demonstrated a conceptually new ap-
proach to marine polycyclic ethers containing six- and
seven-membered rings. Although epoxides are widely
recognized to be extremely versatile synthetic intermedi-
ates as electrophiles, because of a high degree of ring
strain, the reactions of epoxides as nucleophiles are less
common. Oxiranyl anions are unique reactive nucleo-
philes and their usefulness in organic synthesis lies in
the direct C-C bond formation on the epoxide ring.
Therefore, oxiranyl anions can be employed as building
blocks for the synthesis of complex natural products.
Eliminating the conventional manipulations of double-
1597, 1427, 1330, 1155 cm-1 1H NMR (270 MHz, CDCl3) δ
;
1.10 (9H, s), 1.50 (3H, s), 2.44 (3H, s), 3.84 (1H, s), 4.24 (1H,
d, J ) 11.8 Hz), 4.31 (1H, d, J ) 11.8 Hz), 7.32-7.45 (10H),
7.68-7.77 (4H); 13C NMR (67.5 MHz, CDCl3) δ 19.37, 19.75,
21.68, 26.86 (3 × C), 63.67, 67.75, 74.46, 127.70, 127.73, 128.43,
129.76, 129.78, 129.99, 133.05, 133.15, 135.52, 135.66, 135.69,
145.39; high-resolution (HR)FABMS m/z calcd for C27H33O4-
SSi (MH) 481.1867, found 481.1874.
(4S,5R)-1-(ter t-Bu t yld ip h en ylsilyl)oxy-5-ch lor o-4-h y-
d r oxy-5-(p-tolylsu lfin yl)-2-p en ten e (19a ) a n d Its (4R,5R)-
Isom er (19b). The experimental procedure as described for
compounds 17a and b was followed by employing sulfoxide
15 (415 mg, 2.20 mmol) and the unsaturated aldehyde 18 (660

Hemibrevetoxin B Synthesis with Oxiranyl Anions
J . Org. Chem., Vol. 63, No. 18, 1998 6205
mg, 2.00 mmol) to give chlorohydrins 19a (494 mg, 48%) and
19b (375 mg, 36%). 19a : colorless oil; [R]2D0 -81.1° (c 0.17,
Cl (5 mL) and extracted with ether. The extract was washed
with water and brine, dried, and concentrated. Flash chro-
matography (10% EtOAc in hexane) gave benzyl ether 23 (2.44
g, 95%) as a colorless oil: [R]2D0 +54.6° (c 1.0, CHCl3); IR
CHCl3); IR (CHCl3) 3545, 1471 cm-1 1H NMR (400 MHz,
;
CDCl3) δ 1.05 (9H, s), 2.44 (3H, s), 2.69 (1H, d, J ) 4.6 Hz,
OH), 4.26 (2H, br s), 4.39 (1H, d, J ) 4.2 Hz), 4.77 (1H, ddd,
J ) 9.0, 4.6, 4.2 Hz), 5.89-6.01 (2H, m), 7.34-7.67 (14H);
FABMS m/z 519 (MH - 35Cl), 521 (MH - 37Cl). 19b: colorless
oil; IR (CHCl3) 3545, 1471 cm-1; 1H NMR (400 MHz, CDCl3) δ
1.05 (9H, s), 2.44 (3H, s), 3.39 (1H, d, J ) 4.1 Hz, OH), 4.25
(2H, t, J ) 2.2 Hz), 4.40 (1H, d, J ) 8.3 Hz), 4.57 (1H, ddd, J
) 8.3, 4.1, 4.1 Hz), 6.47 (2H, m), 7.34-7.68 (14H); FABMS
m/z 515 (MH - 35Cl), 517 (MH - 37Cl).
(CHCl3) 1454, 1381, 1102, 1069 cm-1 1H NMR (600 MHz,
;
CDCl3) δ 2.00 (2H, m), 2.58 (1H, ddd, J ) 14.0, 7.3, 7.3 Hz),
2.93 (1H, ddd, J ) 14.0, 8.1, 7.3 Hz), 3.68 (2H, m), 3.94 (1H,
m), 4.02 (1H, q, J ) 2.9 Hz), 4.25 (2H, m), 4.65 and 4.90 (each
1H, d, J ) 12.5 Hz), 5.06 (1H, dd, J ) 10.2, 1.0 Hz), 5.10 (1H,
dd, J ) 17.2, 1.0 Hz), 5.56 (1H, s), 5.79 (1H, dddd, J ) 17.2,
10.2, 7.3, 7.3 Hz), 7.25-7.52 (10H); 13C NMR (150 MHz, CDCl3)
δ 32.31, 37.51, 59.79, 67.00, 72.45, 72.56, 72.76, 81.14, 102.09,
116.93, 126.19, 127.19, 127.24, 128.20, 128.25, 128.97, 135.73,
(4S,5R)-4,5-Ep oxy-1-(ter t-bu tyld ip h en ylsilyl)oxy-5-(p-
tolylsu lfon yl)p en ta n e (7a ). To a solution of the unsaturated
chlorohydrin 19a (400 mg, 0.78 mmol) in EtOAc (20 mL) was
added 5% Pd-C (150 mg), and the resulting mixture was stirred
for 2 h under a hydrogen atmosphere. The catalyst was
filtered through Celite, and the filtrate was concentrated.
Flash chromatography (30% EtOAc in hexane) gave 358 mg
(90%) of a saturated chlorohydrin. This chlorohydrin (358 mg,
0.69 mmol) was transformed to epoxy sulfone 7a (184 mg, 53%
in two steps) according to the procedure described for com-
pound 5a : [R]2D0 -62.5° (c 1.0, CHCl3); IR (CHCl3) 1597, 1427,
1321, 1155, 1111 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.06 (9H,
s), 1.83 (2H, m), 2.27 (2H, m), 2.43 (3H, s), 3.30 (1H, m), 3.76
(2H, t, J ) 5.9 Hz), 3.92 (1H, d, J ) 3.9 Hz), 7.37-7.85 (14H);
13C NMR (100 MHz, CDCl3) δ 19.20, 21.70, 23.62, 26.85 (3 ×
C), 29.68, 61.09, 63.15, 68.86, 127.66, 128.32, 129.59, 130.05,
133.77, 135.56, 135.94, 145.40; HRFABMS m/z calcd for
137.83, 139.15; HRFABMS m/z calcd for
367.1908, found 367.19096.
C23H27O4 (MH)
Ben zyl 3-(3-O-Ben zyl-4,6-O-ben zylid en e-2-d eoxy-r-D-
a llop yr a n osyl)p r op yl Eth er (24). A solution of olefin 23
(1.90 g, 5.19 mmol) in THF (20 mL) was treated with 9-BBN-H
(18.7 mL of a 0.5 M solution in THF, 9.35 mmol) at 0 °C, and
the resulting solution was stirred at room temperature for 4
h. To this solution were added 3 M NaOH (4.3 mL, 12.9 mmol)
and 30% H2O2 (1.2 mL, 11.75 mmol) at 0 °C, and stirring was
continued for 1 h at room temperature. The reaction mixture
was extracted with ether, washed with water and brine, dried,
and concentrated. Flash chromatography (40% EtOAc in
hexane) gave 1.60 g (80%) of an alcohol. This alcohol was
benzylated according to the procedure described for 23, and
the product was purified by flash chromatography (25% EtOAc
in hexane) to give benzyl ether 24 (1.82 g, 92%) as a colorless
oil: [R]2D0 +36.2° (c 0.75, CHCl3); IR (CHCl3) 1454, 1363, 1211,
C
28H35O4SSi (MH) 495.2023, found 495.2035.
1
1105, 1027 cm-1; H NMR (600 MHz, CDCl3) δ 1.63 (1H, m),
3-(2,3-An h yd r o-4,6-O-ben zylid en e-r-D-a llop yr a n osyl)-
1.73 (2H, m), 1.96 (1H, br dd, J ) 14.2, 2.9 Hz), 2.02 (1H, ddd,
J ) 14.2, 6.6, 2.9 Hz), 2.37 (1H, m), 3.45-3.53 (2H, m), 3.66
(1H, dd, J ) 10.3, 2.9 Hz), 3.67 (1H, dd, J ) 10.3, 10.3 Hz),
3.88 (1H, m), 4.00 (1H, q, J ) 2.9 Hz), 4.20 (1H, ddd, J ) 10.3,
10.3, 5.1 Hz), 4.25 (1H, dd, J ) 10.3, 5.1 Hz), 4.50 (2H, s),
4.64 and 4.87 (each 1H, d, J ) 12.5 Hz), 5.55 (1H, s), 7.24-
7.51 (15H); 13C NMR (150 MHz, CDCl3) δ 26.96, 29.21, 33.25,
59.54, 70.06, 70.10, 72.58, 72.63, 72.74, 72.89, 81.26, 102.14,
126.24, 127.16, 127.19, 127.47, 127.62, 128.20, 128.26, 128.34,
128.97, 137.88, 138.62, 139.23; HRFABMS m/z calcd for
1-p r op en e (22). To a solution of diol 21 (1.90 g, 11.2 mmol)
in toluene (45 mL) at 0 °C were added Na2HPO4 (6.36 g, 44.8
mmol) and m-CPBA (80% purity, 7.25 g, 33.6 mmol), and the
resulting mixture was stirred at 0 °C for 2 h. The mixture
was filtered though a short pad of Celite, and the filtrate was
concentrated. The residue was purified by flash chromatog-
raphy (80% EtOAc in hexane) to give 1.46 g of an epoxy diol.
A solution of this epoxy diol (1.46 g), benzaldehyde dimethyl
acetal (1.77 mL, 11.78 mmol), and CSA (90.6 mg, 0.39 mmol)
in CH2Cl2 (16 mL) was stirred at room temperature for 48 h.
After addition of Et3N (0.5 mL), the reaction mixture was
concentrated. Flash chromatography (15% EtOAc in hexane)
gave epoxide 22 (1.13 g, 46% in two steps) as a colorless
needles: mp 101-103 °C; [R]2D0 +50.8° (c 1.0, CHCl3); IR
(CHCl3) 1384, 1117, 1076 cm-1; 1H NMR (600 MHz, CDCl3) δ
2.54 (2H, m), 3.41 (1H, dd, J ) 4.8, 3.3 Hz), 3.58 (1H, br d, J
) 4.8 Hz), 3.64 (1H, dd, J ) 10.3, 10.3 Hz), 3.86 (1H, ddd, J )
10.3, 9.2, 5.1 Hz), 3.99 (1H, dd, J ) 9.2, 0.9 Hz), 4.10 (1H,
ddd, J ) 7.2, 7.2, 3.3 Hz), 4.18 (1H, dd, J ) 10.3, 5.1 Hz), 5.13
(1H, dd, J ) 10.3, 1.4 Hz), 5.20 (1H, dd, J ) 17.0, 1.4 Hz),
5.58 (1H, s), 5.86 (1H, dddd, J ) 17.0, 10.3, 7.0, 7.0 Hz), 7.25-
7.51 (5H); 13C NMR (150 MHz, CDCl3) δ 34.67, 51.81, 55.27,
61.07, 69.21, 70.87, 78.17, 102.62, 118.13 (CdC), 126.26,
128.30, 129.17, 133.46 (CdC), 137.19; FABMS m/z 275 (MH).
Anal. Calcd for C16H18O4: C, 70.04; H, 6.62. Found: C, 70.05;
H, 6.65.
3-(3-O-Ben zyl-4,6-O-ben zylid en e-2-d eoxy-r-D-a llop yr a -
n osyl)-1-p r op en e (23). To a solution of epoxide 22 (2.0 g,
7.30 mmol) in ether (80 mL) was added LiAlH4 (561 mg, 14.76
mmol), and the suspension was stirred at room temperature
for 1.5 h. The reaction mixture was quenched with 1 M NaOH
(1.0 mL), and stirring was continued until precipitates formed.
The organic layer was separated by decantation and the
precipitates were washed with ether. The combined organic
layer was dried and concentrated. Flash chromatography
(25% EtOAc in hexane) gave 1.94 g (95%) of an alcohol as
colorless prisms: mp 68-69 °C; [R]2D0 +73.9° (c 1.0, CHCl3).
To a stirred solution of this alcohol (1.93 g, 6.99 mmol) in
dimethylformamide (DMF, 13 mL) was added NaH (60%
suspension in mineral oil, 0.56 g, 14.1 mmol) at 0 °C. After
stirring at room temperature for 30 min, benzyl bromide (1.0
mL, 8.46 mmol) was added and stirring was continued for 3
h. The reaction was quenched with saturated aqueous NH4-
C
30H35O5 (MH) 475.2482, found 475.2449.
Ben zyl 3-(3-O-Ben zyl-2-d eoxy-r-D-a llop yr a n osyl)p r o-
p yl Eth er (4). To a solution of 24 (6.38 g, 13.46 mmol) in
THF (60 mL) and water (9 mL) was added concentrated HCl
(2.2 mL), and the solution was heated at 40 °C for 5 h. The
reaction mixture was neutralized with 25% NH4OH and
extracted with ether. The extract was washed with water and
brine, dried, and concentrated. Flash chromatography (90%
EtOAc in hexane) gave diol 4 (4.76 g, 92%) as colorless
prisms: mp 49-50 °C; [R]2D0 +35.3° (c 0.73, CHCl3); IR
(CHCl3) 3556, 3442, 1454, 1363, 1068 cm-1; 1H NMR (600 MHz,
CDCl3) δ 1.59 (1H, m), 1.70 (2H, m), 1.80 (1H, ddd, J ) 13.9,
4.4, 4.4 Hz), 1.90 (1H, ddd, J ) 13.9, 7.3, 7.3 Hz), 1.98 (1H,
m), 2.25 (1H, dd, J ) 7.3, 4.4 Hz, OH), 2.50 (1H, d, J ) 6.6
Hz, OH), 3.44 (1H, m), 3.52 (1H, m), 3.64 (1H, ddd, J ) 11.7,
7.3, 4.4 Hz), 3.67 (1H, ddd, J ) 6.6, 6.6, 3.7 Hz), 3.72 (1H,
ddd, J ) 11.7, 7.3, 4.4 Hz), 3.75 (2H, m), 3.92 (1H, ddd, J )
7.3, 6.6, 4.4 Hz), 4.48 and 4.50 (each 1 H, d, J ) 12.5 Hz), 4.49
and 4.66 (each 1H, d, J ) 11.0 Hz), 7.26-7.37 (10H); 13C NMR
(150 MHz, CDCl3) δ 26.13, 31.08, 31.20, 61.38, 66.77, 69.98,
70.14, 70.64, 72.93, 73.55, 74.30, 127.56, 127.72, 127.75,
127.98, 128.34, 128.57, 137.60, 138.37. Anal. Calcd for
C
23H30O5: C, 71.46; H, 7.83. Found: C, 71.22; H, 8.07.
Ben zyl 3-(3-O-Ben zyl-2-d eoxy-4-O-tr ieth ylsilyl-6-O-tr i-
flu or om eth a n esu lfon yl-r-D-a llop yr a n osyl)p r op yl Eth er
(25). To a stirred solution of diol 4 (750 mg, 1.94 mmol) in
CH2Cl2 (19 mL) at -78 °C were added 2,6-lutidine (1.12 mL,
9.72 mmol) and Tf2O (343 µL, 2.04 mmol). After stirring at
-78 °C for 30 min, triethylsilyl trifluoromethanesulfonate
(TESOTf) (646 µL, 2.92 mmol) was added and stirring was
continued for 30 min. The reaction was quenched with
saturated aqueous NaHCO3 (4 mL) and extracted with EtOAc.
The extract was washed with water and brine, dried, and

6206 J . Org. Chem., Vol. 63, No. 18, 1998
Mori et al.
concentrated. Flash chromatography (10% EtOAc in hexane)
chromatography (EtOAc) to give diol 29 (621 mg, 98%) as a
colorless oil: [R]2D0 +23.9° (c 1.0, CHCl3); IR (CHCl3) 3597,
3444, 1454, 1363, 1234, 1101, 1041 cm-1; 1H NMR (400 MHz,
CDCl3) δ 1.15 (3H, s), 1.56-1.80 (4H, m), 1.88 (1H, br, OH),
1.90 (1H, ddd, J ) 14.6, 6.3, 2.9 Hz), 1.96 (1H, ddd, J ) 14.6,
3.4, 1.5 Hz), 2.09 (1H, ddd, J ) 11.7, 4.4, 4.4 Hz), 2.28 (1H,
m), 2.36 (1H, br, OH), 3.33 (1H, dd, J ) 9.8, 2.9 Hz), 3.49 (2H,
m), 3.50 and 3.59 (each 1H, d, J ) 11.2 Hz), 3.78 (1H, ddd, J
) 11.7, 9.8, 4.4 Hz), 3.84 (2H, m), 3.93 (1H, dd, J ) 11.7, 4.4
Hz), 4.50 (2H, s), 4.59 and 4.65 (each 1H, d, J ) 12.0 Hz), 7.24-
7.33 (10H); 13C NMR (100 MHz, CDCl3) δ 12.91, 27.03, 29.09,
32.48, 34.24, 62.72, 66.95, 68.12, 70.09, 72.31, 72.89, 73.30,
73.91, 76.69, 77.61, 127.04, 127.42, 127.48, 127.61, 128.34,
138.59, 138.88; HRFABMS m/z: calcd for C27H37O6 (MH)
457.2588, found 457.2557.
gave triflate 25 (1.21 g, 98%) as a pale yellow oil: [R]2D0 +48.3°
(c 1.0, CHCl3); IR (CHCl3) 1454, 1413, 1246, 1146, 958 cm-1
;
1H NMR (400 MHz, CDCl3) δ 0.61 (6H, q, J ) 7.8 Hz), 0.95
(9H, t, J ) 7.8 Hz), 1.57-1.76 (3H, m), 1.81 (1H, ddd, J )
14.1, 5.7, 3.9 Hz), 1.99 (1H, ddd, J ) 14.1, 4.4, 3.4 Hz), 2.12
(1H, m), 3.43 (1H, ddd, J ) 9.8, 5.9, 5.9 Hz), 3.48 (1H, ddd, J
) 9.8, 5.9, 5.9 Hz), 3.72 (2H, m), 3.81 (1H, m), 4.13 (1H, ddd,
J ) 8.3, 5.9, 2.9 Hz), 4.48 (2H, s), 4.56 and 4.63 (each 1H, d,
J ) 11.7 Hz), 4.57 (1H, dd, J ) 11.7, 5.9 Hz), 4.62 (1H, dd, J
) 11.7, 2.9 Hz), 7.24-7.35 (10H); 13C NMR (100 MHz, CDCl3)
δ 4.88 (3 × C), 6.79 (3 × C), 26.52, 29.66, 31.27, 68.94, 69.00,
69.89, 71.59, 71.93, 72.80, 75.31, 76.06, 127.47, 127.61, 127.68
(4 × C), 128.32 (4 × C), 138.19, 138.61; FABMS m/z 519 (M -
Et3Si + 2H).
Ep oxy Su lfon e 26. A solution of triflate 25 (1.20 g, 1.90
mmol), epoxy sulfone 5a (1.35 g, 2.81 mmol), and HMPA (1.32
mL, 7.59 mmol) in THF (28 mL) was cooled to -110 °C and
treated with n-BuLi (1.76 mL of a 1.6 M solution in hexane,
2.81 mmol). After stirring at -100 °C for 10 min and then
-80 °C for 10 min, the reaction was quenched with saturated
aqueous NH4Cl (2 mL). The reaction mixture was extracted
with EtOAc, washed with water and brine, dried, and concen-
trated. The residue was subjected to flash chromatography
(30% ether in hexane) to give epoxy sulfone 26 (1.64 g, 90%)
as a colorless oil: [R]D20 +15.4° (c 1.0, CHCl3); IR (CHCl3)
Ald eh yd e 31. To a stirred solution of 29 (120 mg, 0.263
mmol) in CH2Cl2 (2.6 mL) at 0 °C were added 2,6-lutidine (152
µL, 1.316 mmol) and TESOTf (146 µL, 0.658 mmol), and the
reaction mixture was stirred at 0 °C for 30 min. The reaction
was quenched with saturated aqueous NaHCO3 (0.5 mL) and
extracted with EtOAc. The extract was washed with water
and brine, dried, and concentrated. Flash chromatography
(10% EtOAc in hexane) gave a disilyl ether (176 mg, 98%) as
a colorless oil. To a solution of this disilyl ether (154 mg, 0.225
mmol) in CH2Cl2 (2.2 mL) and MeOH (0.22 mL) at -20 °C
was added PPTS (170 mg, 0.675 mmol), and the resulting
mixture was stirred at -20 °C for 2 h. The reaction was
quenched with saturated aqueous NaHCO3 (1.0 mL) and
extracted with EtOAc. The extract was washed with water
and brine, dried, and concentrated. Flash chromatography
(20% EtOAc in hexane) gave an alcohol (118 mg, 92%) as a
colorless oil. To a solution of the resulting alcohol (130 mg,
0.228 mmol) in CH2Cl2 (0.7 mL) and DMSO (1.5 mL) were
added Et3N (0.7 mL) and SO3‚pyridine (290 mg, 1.825 mmol),
and the resulting mixture was stirred at room temperature
for 3 h. The reaction mixture was diluted with EtOAc, and
the organic layer was washed with water and brine, dried, and
concentrated. Flash chromatography (20% EtOAc in hexane)
gave aldehyde 31 (125 mg, 96%) as a pale yellow oil: [R]D20
-5.64° (c 1.0, CHCl3); IR (CHCl3) 1743, 1454, 1363, 1114, 1018,
1
1597, 1427, 1421, 1321, 1153, 1113, 815 769 cm-1; H NMR
(400 MHz, CDCl3) δ 0.60 (6H, q, J ) 7.8 Hz), 0.94 (9H, t, J )
7.8 Hz), 1.07 (9H, s), 1.46 (3H, s), 1.50-1.74 (5H, m), 1.81 (1H,
q, J ) 10.7 Hz), 2.01 (1H, dd, J ) 15.6, 4.4 Hz), 2.29 (3H, s),
2.44 (1H, dd, J ) 15.6, 7.8 Hz), 3.37-3.45 (3H, m), 3.52 (1H,
ddd, J ) 10.7, 4.4, 2.9 Hz), 3.64 (1H, br s), 3.91 (1H, m), 4.12
and 4.24 (each 1H, d, J ) 11.7 Hz), 4.45 and 4.48 (each 1H, d,
J ) 11.7 Hz), 4.51 and 4.55 (each 1H, d, J ) 12.2 Hz), 7.12-
7.66 (24H); 13C NMR (100 MHz, CDCl3) δ 4.95 (3 × C), 6.94 (3
× C), 16.43, 19.33, 21.60, 25.91, 26.85 (3 × C), 27.85, 31.69,
32.20, 64.54, 68.87, 69.10, 69.91, 70.20, 70.58, 72.82, 73.71,
74.42, 74.98, 127.32, 127.48, 127.63, 127.66, 127.71, 128.22,
128.34, 128.42, 128.77, 129.72, 129.79, 129.82, 129.98, 132.94,
134.77, 135.59, 135.64, 135.69, 138.92, 145.01; HRFABMS m/z
calcd for C56H75O8SSi2 (MH) 963.4717, found 963.4758.
1
827 cm-1; H NMR (400 MHz, CDCl3) δ 0.33 (6H, q, J ) 8.3
Hz), 0.91 (9H, t, J ) 8.3 Hz), 1.31 (3H, s), 1.61-1.74 (4H, m),
1.94 (2H, m), 2.10 (1H, ddd, J ) 11.7, 4.4, 4.4 Hz), 2.28 (1H,
m), 3.36 (1H, dd, J ) 9.8, 2.9 Hz), 3.50 (2H, m), 3.81-3.89
(3H, m), 3.90 (1H, dd, J ) 11.2, 4.4 Hz), 4.51 (2H, s), 4.63 and
4.78 (each 1H, d, J ) 12.7 Hz), 7.24-7.36 (10H), 9.41 (1H, s);
13C NMR (100 MHz, CDCl3) δ: 4.88 (3 × C), 6.69 (3 × C), 10.51,
27.06, 29.22, 35.01, 35.10, 62.03, 66.50, 70.12, 72.46, 72.80,
72.90, 73.46, 73.55, 81.92, 127.04, 127.22, 127.50, 127.58,
128.22, 128.34, 139.23, 199.81; HRFABMS m/z: calcd for
Bicyclic Keton e 27. A solution of 26 (1.63 g, 1.69 mmol)
and p-TsOH‚H2O (483 mg, 2.54 mmol) in CHCl3 (17 mL) was
stirred at 0 °C for 30 min and then at room temperature for 3
h. The reaction mixture was quenched with saturated aqueous
NaHCO3 (2 mL) and extracted with EtOAc. The extract was
washed with water and brine, dried, and concentrated. Flash
chromatography (20 f 30% EtOAc in hexane) gave bicyclic
ketone 27 (1.05 g, 90%) as a colorless oil: [R]2D0 +8.82° (c 1.0,
CHCl3); IR (CHCl3) 1718, 1454, 1427, 1361, 1113, 775, 739
1
cm-1; H NMR (400 MHz, CDCl3) δ 0.99 (9H, s), 1.23 (3H, s),
C
32H49O6Si (MH) 569.3296, found 569.3271.
Hyd r oxy Ep oxy Su lfon es 32a a n d 32b. The procedure
1.60-1.82 (3H, m), 1.98 (2H, t, J ) 2.9 Hz), 2.34 (1H, m), 2.41
(1H, dd, J ) 17.6, 10.2 Hz), 2.90 (1H, dd, J ) 17.6, 6.3 Hz),
3.48 (2H, m), 3.53 (1H, dd, J ) 9.8, 2.9 Hz), 3.68 (1H, d, J )
9.8 Hz), 3.87 (1H, m), 3.90 (1H, d, J ) 9.8 Hz), 4.01 (1H, q, J
) 2.9 Hz), 4.36 (1H, ddd, J ) 10.2, 9.8, 6.3 Hz), 4.50 (2H, s),
4.66 and 4.92 (each 1H, d, J ) 12.7 Hz), 7.20-7.41 (16H),
7.63-7.68 (4H); 13C NMR (100 MHz, CDCl3) δ 18.47, 19.23,
26.63 (3 × C), 27.08, 29.15, 33.15, 43.80, 62.22, 69.28, 70.17,
72.18, 72.89, 73.05, 73.20, 74.20, 85.03, 126.97, 127.04, 127.47,
127.61, 128.14, 128.34, 129.59, 133.09, 133.18, 135.64, 138.61,
139.36, 210.08; HRFABMS m/z calcd for C43H53O6Si (MH)
693.3608, found 693.3581.
Bicyclic Diol 29. To a stirred solution of ketone 27 (1.05
g, 1.52 mmol) in MeOH (8 mL) and CH2Cl2 (8 mL) at -78 °C
was added NaBH4 (115 mg, 3.03 mmol), and the mixture was
stirred at -78 °C for 2 h. The reaction mixture was diluted
with EtOAc, washed with water and brine, dried, and concen-
trated. Flash chromatography (30% EtOAc in hexane) gave
alcohol 28 (964 mg, 92%) as a colorless oil. To a solution of
28 (963 mg, 1.39 mmol) in THF (14 mL) was added Bu4NF
(2.08 mL of a 1.0 M solution in THF, 2.08 mmol). After stirring
at room temperature for 2 h, the reaction mixture was
concentrated under reduced pressure and subjected to flash
for 26 was employed with aldehyde 31 (120 mg, 0.211 mmol)
and epoxy sulfone 6a (162 mg, 0.359 mmol), and purification
by flash chromatography (20 f 30% EtOAc in hexane) gave
32a (135 mg, 63%) and 32b (52.8 mg, 25%). 32a : colorless
oil; [R]2D0 +27.7° (c 1.0, CHCl3); IR (CHCl3) 3552, 3446, 1456,
1427, 1323, 1113 cm-1; 1H NMR (400 MHz, CDCl3) δ 0.64 (6H,
m), 0.93 (9H, t, J ) 8.3 Hz), 1.04 (9H, s), 1.20 (3H, s), 1.57-
1.82 (6H, m), 2.13-2.22 (2H, m), 2.38 (1H, d, J ) 9.8 Hz, OH),
3.20 (1H, dd, J ) 9.8, 2.9 Hz), 3.34 (2H, m), 3.65 (1H, q, J )
2.9 Hz), 3.81 (1H, m), 3.90 (1H, ddd, J ) 11.7, 9.8, 4.9 Hz),
4.10 (1H, dd, J ) 11.7, 4.9 Hz), 4.30 (1H, dd, J ) 12.7, 5.4
Hz), 4.38 (1H, d, J ) 9.8 Hz), 4.41 (2H, s), 4.44 and 4.77 (each
1H, d, J ) 13.1 Hz), 4.45 (1H, dd, J ) 12.7, 3.4 Hz), 4.76 (1H,
dd, J ) 5.4, 3.4 Hz), 7.15-7.89 (25H); 13C NMR (100 MHz,
CDCl3) δ 5.44 (3 × C), 6.94 (3 × C), 13.42, 19.20, 26.83 (3 ×
C), 27.11, 29.05, 32.62, 35.27, 61.20, 61.81, 67.69, 69.55, 69.91,
71.44, 72.46, 72.64, 72.72, 72.92, 73.33, 77.51, 80.72, 127.37,
127.52, 127.61, 127.73, 127.76, 128.24, 128.34, 128.73, 129.34,
129.74, 130.08, 132.86, 133.92, 135.17, 135.45, 135.51, 138.16;
HRFABMS m/z calcd for C58H77O10Si2 (MH) 1021.4771, found
1021.4814. 32b: colorless oil; [R]2D0 +41.5° (c 1.0, CHCl3); IR
(CHCl3) 3525, 3456, 1456, 1323, 1113 cm-1; 1H NMR (400 MHz,

Hemibrevetoxin B Synthesis with Oxiranyl Anions
J . Org. Chem., Vol. 63, No. 18, 1998 6207
CDCl3) δ 0.55 (6H, m), 0.84 (3H, s), 0.92 (9H, t, J ) 8.3 Hz),
1.04 (9H, s), 1.51 (1H, q, J ) 11.7 Hz), 1.55-1.72 (3H, m), 1.86
(2H, m), 1.94 (1H, ddd, J ) 11.7, 4.4, 4.4 Hz), 2.20 (1H, m),
3.03 (1H, d, J ) 9.8 Hz, OH), 3.23 (1H, dd, J ) 10.2, 2.9 Hz),
3.45 (2H, m), 3.67 (1H, ddd, J ) 11.7, 10.2, 4.4 Hz), 3.80 (2H,
m), 3.94 (1H, dd, J ) 6.3, 2.0 Hz), 4.01 (1H, dd, J ) 11.7, 4.4
Hz), 4.10 (1H, d, J ) 9.8 Hz), 4.29 (1H, dd, J ) 12.7, 2.0 Hz),
4.36 (1H, dd, J ) 12.7, 6.3 Hz), 4.47 (2H, s), 4.55 and 4.60
(each 1H, d, J ) 11.2 Hz), 7.18-7.82 (25 H); 13C NMR (100
MHz, CDCl3) δ 5.03 (3 × C), 6.84 (3 × C), 11.78, 19.23, 26.85
(3 × C), 27.06, 29.15, 32.33, 34.25, 61.47, 61.83, 66.09, 67.00,
70.06, 71.41, 72.39, 72.72, 72.90, 73.15, 74.86, 79.06, 80.49,
127.40, 127.50, 127.58, 127.71, 128.34, 128.91, 129.28, 129.72,
134.05, 135.51, 135.58, 138.56; FABMS m/z 1021 (MH).
chromatography (30% ether in hexane) gave ketone 35 (120
mg, 67%) and its isomeric ketone (30.8 mg, 17%). 35: colorless
oil; [R]2D0 +46.8° (c 1.0, CHCl3); IR (CHCl3) 1712, 1454, 1429,
1
1209, 1090, 823 cm-1; H NMR (400 MHz, acetone-d6) δ 1.02
(9H, s), 1.46 (3H, s), 1.55-1.67 (4H, m), 1.68 (1H, q, J ) 11.7
Hz), 1.91-1.97 (3H, m), 2.03 (1H, ddd, J ) 11.7, 4.4, 4.4 Hz),
2.30 (1H, m), 2.38 (1H, ddd, J ) 12.7, 6.3, 2.0 Hz), 3.02 (1H,
ddd, J ) 15.1, 12.7, 2.9 Hz), 3.24 (1H, dd, J ) 11.7, 4.4 Hz),
3.46 (3H, m), 3.77-3.81 (2H, m), 3.83-3.89 (2H, m), 3.92 (1H,
dd, J ) 10.7, 3.9 Hz), 3.99 (1H, dd, J ) 3.9, 2.4 Hz), 4.45 (2H,
s), 4.60 and 4.78 (each 1H, d, J ) 12.2 Hz), 7.22-7.47 (16H),
7.67-7.79 (4H); 13C NMR (100 MHz, CDCl3) δ 14.69, 19.13,
26.65 (3 × C), 27.03, 29.15, 33.12, 33.28, 38.40, 39.29, 63.03,
66.03, 70.12, 72.49, 72.59, 72.84, 73.53, 73.71, 76.69, 81.66,
87.88, 126.96, 127.14, 127.47, 127.56, 127.61, 127.68, 128.17,
128.32, 129.69, 129.75, 132.83, 132.91, 135.61, 135.69, 138.62,
215.79; HRFABMS m/z calcd for C47H59O7Si (MH) 763.4027,
found 763.4041.
Tr icyclic Hyd r oxy Keton e 33. To a solution of 32a (89.7
mg, 0.088 mmol) in CHCl3 (0.8 mL) at 0 °C was added BF3‚
OEt2 (16.2 µL, 0.132 mmol), and the solution was stirred at 0
°C for 1 h. The reaction was quenched with saturated aqueous
NaHCO3 (0.2 mL) and extracted with EtOAc. The extract was
washed with water and brine, dried, and concentrated. Flash
chromatography (25% EtOAc in hexane) gave hydroxy ketone
33 (51.2 mg, 76%) as a colorless oil: [R]2D0 +9.39° (c 1.0,
Tr icyclic Diol 37. To a solution of 35 (110 mg, 0.144 mmol)
in THF (1.5 mL) at 0 °C were added AcOH (16.6 µL, 0.288
mmol) and Bu4NF (217 µL of a 1.0 M solution in THF, 0.217
mmol). After stirring at room temperature for 5 h, the reaction
mixture was concentrated and subjected to flash chromatog-
raphy (80% EtOAc in hexane) to give hydroxy ketone 36 (71.1
mg, 94%) as a colorless oil. A solution of 36 (71.1 mg, 0.136
mmol) in MeCN (0.2 mL) was added to a stirred solution of
Me4NBH(OAc)3 (250 mg, 0.950 mmol) in AcOH (1.0 mL) and
MeCN (1.0 mL) at -20 °C. After stirring at -20 °C for 3 h,
saturated aqueous NH4Cl (0.3 mL) was added and the reaction
mixture was warmed to room temperature. Saturated aqueous
potassium sodium tartrate (0.3 mL) was added to the mixture
and stirring continued for 20 min. After addition of MgSO4
(100 mg), the mixture was diluted with EtOAc and passed
through a short pad of silica gel. The filtrate was concentrated
and subjected to flash chromatography (80% EtOAc in hexane)
to give diol 37 (67.8 mg, 95%) as a colorless oil: [R]2D0 +7.91°
CHCl3); IR (CHCl3) 3525, 1736, 1454, 1427, 1113, 823 cm-1
;
1H NMR (400 MHz, CDCl3) δ 1.01 (9H, s), 1.19 (3H, s), 1.64-
1.78 (4H, m), 1.93 (1H, ddd, J ) 14.6, 6.3, 2.9 Hz), 2.01 (1H,
dd, J ) 14.6, 2.9 Hz), 2.19 (1H, ddd, J ) 11.7, 4.4, 4.4 Hz),
2.32 (1H, m), 2.96 (1H, br, OH), 3.48 (1H, dd, J ) 9.8, 2.4 Hz),
3.52 (2H, m), 3.86 (1H, s), 3.88-3.93 (3H, m), 3.96 (2H, d, J )
4.4 Hz), 4.07 (1H, dd, J ) 11.7, 4.4 Hz), 4.30 (1H, t, J ) 4.4
Hz), 4.52 (2H, s), 4.55 and 4.68 (each 1H, d, J ) 12.2 Hz), 7.23-
7.71 (20H); 13C NMR (100 MHz, CDCl3) δ 13.85, 19.23, 26.67
(3 × C), 27.01, 29.04, 30.48, 32.36, 62.22, 62.87, 69.61, 70.01,
72.36, 72.52, 72.90, 73.50, 73.97, 76.21, 78.43, 80.62, 127.12,
127.52, 127.56, 127.63, 128.35, 128.49, 129.59, 133.29, 133.41,
135.51, 135.56, 135.68, 135.73, 138.51, 202.37; HRFABMS m/z
calcd for C46H57O8Si (MH) 765.3846, found 765.3822.
(c 0.54, CHCl3); IR (CHCl3) 3600, 3438, 1454, 1363, 1113 cm-1
;
Tr icyclic Keton e 34. To a stirred mixture of hydroxy
ketone 33 (48.3 mg, 0.063 mmol) and 0.1 M SmI2 in THF (3.16
mL, 0.316 mmol) at 0 °C were added HMPA (0.6 mL) and
MeOH (25.6 µL, 0.632 mmol), and the resulting mixture was
stirred at 0 °C for 2 h. The reaction mixture was poured into
saturated aqueous NaHCO3 and extracted with EtOAc. The
extract was washed with water and brine, dried, and concen-
trated. Flash chromatography (20% EtOAc in hexane) gave
ketone 34 (30.2 mg, 64%) as a colorless oil: [R]2D0 +15.3° (c
1.0, CHCl3); IR (CHCl3) 1724, 1454, 1427, 1113, 823 cm-1; 1H
NMR (400 MHz, acetone-d6) δ 1.01 (9H, s), 1.29 (3H, S), 1.57-
1.75 (4H, m), 1.98 (2H, t, J ) 3.4 Hz), 2.11 (1H, ddd, J ) 11.2,
4.4, 4.4 Hz), 2.36 (1H, m), 2.60 and 2.64 (each 1H, d, J ) 16.1
Hz), 3.48 (1H, dd, J ) 9.8, 2.9 Hz), 3.50 (2H, t, J ) 6.3 Hz),
3.74 (1H, dd, J ) 11.2, 4.4 Hz), 3.82 (1H, m), 3.91 (2H, m),
3.98 (1H, ddd, J ) 11.2, 9.8, 4.4 Hz), 4.06 (1H, dd, J ) 11.2,
3.9 Hz), 4.13 (1H, dd, J ) 3.9, 2.9 Hz), 4.49 (2H, s), 4.63 and
4.76 (each 1H, d, J ) 12.7 Hz), 7.21-7.47 (16H), 7.74-7.77
(4H); 13C NMR (100 MHz, CDCl3) δ 16.30, 19.21, 26.67 (3 ×
C), 27.01, 29.14, 31.11, 33.17, 54.10, 62.70, 62.72, 63.10, 70.11,
72.59, 72.85, 73.53, 73.61, 73.84, 76.64, 84.22, 126.96, 127.19,
127.47, 127.58, 128.21, 128.34, 129.57, 129.62, 133.18, 135.66,
135.76, 138.64, 139.31, 205.57; HRFABMS m/z calcd for
1H NMR (400 MHz, acetone-d6) δ 1.19 (3H, s), 1.46 (1H, q, J
) 11.7 Hz), 1.47-1.83 (6H, m), 1.91-1.96 (3H, m), 2.11 (1H,
ddd, J ) 13.2, 13.2, 3.4 Hz), 2.29 (1H, m), 3.32 (1H, dd, J )
9.8, 2.4 Hz), 3.36-3.52 (5H, m), 3.63 (1H, ddd, J ) 6.3, 6.3,
3.9 Hz), 3.64 (1H, dd, J ) 11.7, 4.4 Hz), 3.72-3.80 (2H, m),
3.83 (1H, q, J ) 2.9 Hz), 3.90 (1H, d, J ) 3.9 Hz), 3.97 (1H,
dddd, J ) 3.9, 3.9, 3.9, 2.4 Hz), 4.46 (2H, s), 4.60 and 4.82
(each 1H, d, J ) 12.7 Hz), 7.19-7.39 (10H); 13C NMR (100
MHz, CDCl3) δ 15.58, 27.03, 28.30, 29.17, 33.03, 33.38, 35.12,
63.15, 64.58, 70.17, 71.90, 72.41, 72.64, 72.85, 73.48, 73.91,
77.20, 79.45, 85.92, 126.99, 127.02, 127.45, 127.60, 128.14,
128.34, 139.61; HRFABMS m/z calcd for
C31H43O7 (MH)
527.3006, found 527.3047.
Tr icyclic Tr ifla te 38. The procedure for 25 was employed
with diol 37 (69.3 mg, 0.132 mmol) and purification by flash
chromatography (20% EtOAc in hexane) gave triflate 38 (84.9
mg, 83%) as a colorless oil: [R]2D0 +9.78° (c 1.0, CHCl3); IR
(CHCl3) 1454, 1415, 1211, 1146, 1093, 960 cm-1; 1H NMR (400
MHz, CDCl3) δ 0.59 (6H, q, J ) 7.8 Hz), 0.95 (9H, t, J ) 7.8
Hz), 1.12 (3H, s), 1.57 (1H, q, J ) 11.7 Hz), 1.58-1.84 (6H,
m), 1.91 (2H, br s), 2.01 (1H, ddd, J ) 11.7, 4.4, 4.4 Hz), 2.05
(1H, ddd, J ) 13.3, 13.3, 2.0 Hz), 2.25 (1H, m), 3.34 (1H, dd,
J ) 9.8, 2.4 Hz), 3.48 (2H, m), 3.57 (1H, dd, J ) 12.2, 4.4 Hz),
3.76-3.85 (4H, m), 3.90 (1H, ddd, J ) 5.4, 2.9, 2.9 Hz), 4.37
(1H, dd, J ) 10.3, 5.9 Hz), 4.41 (1H, dd, J ) 10.3, 4.4 Hz),
4.49 (2H, s), 4.58 and 4.81 (each 1H, d, J ) 12.2 Hz), 7.22-
7.35 (10H); 13C NMR (100 MHz, CDCl3) δ 4.75 (3 × C), 6.77 (3
× C), 15.46, 27.06, 28.11, 29.25, 32.79, 33.43, 34.93, 63.13,
70.17, 71.26, 72.41, 72.64, 72.84, 73.56, 73.96, 76.44, 76.95,
78.96, 83.01, 126.92, 126.99, 127.45, 127.60, 128.09, 128.32,
138.67, 139.67; FABMS m/z 773 (MH).
C
46H57O7Si (MH) 749.3870, found 749.3903.
Tr icyclic Keton e 35. To a stirred solution of ketone 34
(175 mg, 0.235 mmol) in CH2Cl2 (2.4 mL) at -78 °C were added
BF3‚OEt2 (34.7 µL, 0.282 mmol) and TMSCHN2 (124 µL of a
2.0 M solution in hexane, 0.247 mmol), and the resulting
solution was stirred at -78 °C for 3 h and then allowed to
warm to -20 °C over 1 h. The reaction was quenched with
saturated aqueous NaHCO3 (0.4 mL) and extracted with
EtOAc. The extract was washed with water and brine, dried,
and concentrated. The oily residue was dissolved in CH2Cl2
(1.2 mL) and MeOH (1.2 mL) and the solution was treated
with PPTS (88.7 mg, 0.353 mmol). After stirring at room
temperature for 2 h, the reaction was quenched with saturated
aqueous NaHCO3 and extracted with EtOAc. The extract was
washed with water and brine, dried, and concentrated. Flash
Ep oxy Su lfon e 39. The procedure for 26 was employed
with triflate 38 (81.8 mg, 0.106 mmol), epoxy sulfone 7a (105
mg, 0.212 mmol), and N,N′-dimethylpropyleneurea (DMPU)
(38.4 µL), and purification by flash chromatography (45% ether
in hexane) gave epoxy sulfone 39 (114 mg, 96%) as a colorless
oil: [R]2D0 +22.8° (c 1.0, CHCl3); IR (CHCl3) 1599, 1454, 1321,

6208 J . Org. Chem., Vol. 63, No. 18, 1998
Mori et al.
1111, 818 cm-1; 1H NMR (400 MHz, CDCl3) δ 0.43 (6H, q, J )
8.3 Hz), 0.83 (9H, t, J ) 8.3 Hz), 1.06 (9H, s), 1.11 (3H, s),
1.46 (1H, q, J ) 11.7 Hz), 1.48 (1H, m), 1.54-1.63 (2H, m),
1.64-1.82 (3H, m), 1.87 (1H, ddd, J ) 11.7, 4.4, 4.4 Hz), 1.88-
1.91 (3H, m), 1.97 (1H, m), 2.15-2.24 (3H, m), 2.34 (3H, s),
3.29 (2H, m), 3.41-3.51 (4H, m), 3.53 (1H, dd, J ) 11.7, 4.4
Hz), 3.69-3.76 (3H, m), 3.81 (2H, m), 4.46 (2H, s), 4.45 and
4.80 (each 1H, d, J ) 12.2 Hz), 7.20-7.43 (20H), 7.65-7.80
(4H, Ar); 13C NMR (100 MHz, CDCl3) δ 4.72 (3 × C), 6.79 (3 ×
C), 15.71, 19.20, 21.63, 23.87, 26.86 (3 × C), 27.08, 29.28, 30.27,
33.02, 33.40, 34.29, 34.60, 63.06, 63.38, 64.89, 70.16, 72.36,
72.61, 72.82, 73.51, 73.94, 75.11, 75.54, 76.67, 76.87, 80.29,
126.86, 126.91, 127.42, 127.56, 127.63, 128.24, 128.30, 128.93,
129.51, 129.74, 133.87, 134.92, 135.59, 139.71, 144.97; HR-
FABMS m/z calcd for C65H89O10SSi2 (MH) 1117.5710, found
1117.5753.
mmol) in toluene (0.3 mL) was added. After stirring at -78
°C for 2 h, the reaction was quenched with saturated aqueous
NH4Cl (0.2 mL) and extracted with EtOAc. The extract was
washed with water and brine, dried, and concentrated. Flash
chromatography (36% EtOAc in hexane) gave 42a (17.4 mg,
77%) and 42b (4.8 mg, 21%). 42a : colorless oil; [R]2D0 +18.6°
(c 1.0, CHCl3); IR (CHCl3) 3597, 3456, 1454, 1429, 1090, 702
1
cm-1; H NMR (400 MHz, CDCl3) δ 1.05 (9H, s), 1.09 (3H, s),
1.18 (3H, s), 1.30 (1H, m), 1.53-1.91 (17H, m), 2.00 (1H, ddd,
J ) 11.7, 3.9, 3.9 Hz), 2.09 (1H, m), 2.28 (1H, m), 3.19 (1H, br
d, J ) 10.3 Hz), 3.26 (1H, dd, J ) 12.2, 3.9 Hz), 3.29 (1H, dd,
J ) 10.3, 2.4 Hz), 3.32 (2H, br s), 3.48 (2H, m), 3.70 (2H, m),
3.81 (3H, br s), 4.49 (2H, s), 4.60 and 4.78 (each 1H, d, J )
12.7 Hz), 7.23-7.44 (16H), 7.66-7.68 (4H); 13C NMR (100
MHz, CDCl3) δ 16.10, 19.21, 23.38, 26.90 (4 × C), 27.01, 28.94,
29.14, 29.43, 29.92, 33.07, 33.38, 37.67, 38.14, 63.48, 64.10,
70.17, 72.38, 72.57, 72.80, 73.53, 73.86, 74.61, 77.40, 82.13,
84.65, 86.15, 88.16, 126.96, 127.04, 127.43, 127.58, 128.14,
128.32, 129.52, 134.03, 134.05, 135.58, 138.67, 139.61; HR-
FABMS m/z calcd for C54H73O8Si (MH) 877.5707, found
877.5673. 42b: colorless oil; [R]2D0 +24.9° (c 0.49, CHCl3); IR
Tet r a cyclic Ket on e 40. A solution of epoxy sulfone 39
(111 mg, 0.099 mmol) and p-TsOH‚H2O (28.4 mg, 0.149 mmol)
in CHCl3 (1.0 mL) was stirred at 0 °C for 3 h. After addition
of saturated aqueous NaHCO3 (0.1 mL), the reaction mixture
was extracted with EtOAc. The extract was washed with
water and brine, dried, and concentrated. Flash chromatog-
raphy (40% EtOAc in hexane) gave an alcohol (90.1 mg, 90%).
A solution of the alcohol (77.2 mg, 0.077 mmol) in CHCl3 (1.0
mL) at 0 °C was treated with BF3‚OEt2 (14.2 µL, 0.116 mmol),
and the resulting reaction mixture was stirred at room
temperature for 30 min. The reaction was quenched with
saturated aqueous NaHCO3 (0.2 mL) and extracted with
EtOAc. The extract was washed with water and brine, dried,
and concentrated. Flash chromatography (25% EtOAc in
hexane) gave tetracyclic ketone 40 (48.5 mg, 74%) as a colorless
oil: [R]2D0 +9.62° (c 0.85, CHCl3); IR (CHCl3) 1726, 1454, 1427,
(CHCl3) 3587, 3465, 1454, 1429, 1211, 1088 cm-1 1H NMR
;
(400 MHz, CDCl3) δ 1.05 (9H, s), 1.11 (3H, s), 1.16 (3H, s),
1.48 (1H, m), 1.50-1.86 (14H, m), 1.89 (2H, m), 1.97-2.14 (3H,
m), 2.28 (1H, m), 3.13 (1H, br d, J ) 10.2 Hz), 3.23 (1H, dd, J
) 12.2 Hz, 3.4 Hz), 3.28 (1H, br dd, J ) 8.8, 8.8 Hz), 3.29 (1H,
dd, J ) 9.8, 2.4 Hz), 3.43 (1H, m), 3.48 (2H, m), 3.69 (2H, m),
3.78-3.84 (3H, m), 4.49 (2H, s), 4.59 and 4.78 (each 1H, d, J
) 12.7 Hz), 7.23-7.44 (16H), 7.66-7.68 (4H); 13C NMR (100
MHz, CDCl3) δ 15.72, 19.20, 25.66, 25.93, 26.88 (4 × C), 27.01,
29.05, 29.14, 29.58, 33.02, 33.40, 36.97, 37.43, 63.46, 63.85,
70.17, 72.39, 72.57, 72.80, 73.50, 73.81, 74.70, 77.38, 82.50,
83.80, 85.70, 89.31, 126.96, 127.04, 127.43, 127.60, 128.14,
128.30, 129.54, 133.97, 134.03, 135.58, 139.59; FABMS m/z
877 (MH).
1
1097, 1025 cm-1; H NMR (400 MHz, CDCl3) δ 1.04 (9H, s),
1.23 (3H, s), 1.52-1.74 (7H, m), 1.80-2.06 (7H, m), 2.10 (1H,
m), 2.29 (1H, m), 2.37 (1H, dd, J ) 15.6, 10.3 Hz), 2.86 (1H,
dd, J ) 15.6, 5.9 Hz), 3.31 (1H, dd, J ) 9.8, 2.4 Hz), 3.39 (1H,
m), 3.42 (1H, dd, J ) 12.2, 3.9 Hz), 3.49 (2H, m), 3.58 (1H,
ddd, J ) 10.3, 10.3, 5.9 Hz), 3.62 (1H, dd, J ) 7.8, 3.9 Hz),
3.67 (2H, t, J ) 6.4 Hz), 3.78-3.85 (3H, m), 4.49 (2H, s), 4.61
and 4.77 (each 1H, d, J ) 12.7 Hz), 7.23-7.44 (16H), 7.64-
7.67 (4H); 13C NMR (100 MHz, CDCl3) δ 17.09, 19.18, 25.68,
26.86 (3 × C), 27.03, 28.16, 28.39, 29.15, 32.85, 33.33, 38.12,
46.17, 63.23, 63.67, 70.14, 72.43, 72.62, 72.82, 73.61, 73.84,
77.51, 80.06, 80.52, 80.83, 82.11, 126.97, 127.10, 127.45,
127.58, 128.17, 128.32, 129.52, 133.93, 133.97, 135.58, 138.65,
139.53, 205.89; HRFABMS m/z calcd for C52H67O8Si (MH)
847.4601, found 847.4637.
Disilyl Eth er 43. A solution of 42a (8.6 mg, 9.8 µmol) in
THF (0.1 mL) was treated with Bu4NF (20 µL of a 1.0 M
solution in THF, 20 µmol) and the solution was stirred at room
temperature for 15 h. After evaporation of the solvent, the
residue was purified by flash chromatography (10% acetone
in EtOAc) to give a diol (6.1 mg, 97%). To a solution of this
diol (5.7 mg, 8.9 µmol) in CH2Cl2 (0.1 mL) at 0 °C were added
2,6-lutidine (7.2 µL, 63 µmol) and TBSOTf (6.2 µL, 27 µmol).
After stirring at room temperature for 3 h, the reaction
mixture was treated with saturated aqueous NaHCO3 (0.1 mL)
and extracted with EtOAc. The extract was washed with
water and brine, dried, and concentrated. Flash chromatog-
raphy (14% EtOAc in hexane) gave disilyl ether 43 (6.2 mg,
80%) as a colorless oil: [R]2D0 +21.7° (c 0.48, CHCl3); IR
Tetr a cyclic Keton e 41. The procedure for 35 was em-
ployed with ketone 40 (37.4 mg, 0.044 mmol), BF3‚OEt2 (6.5
µL, 0.053 mmol), and TMSCHN2 (24.3 µL, 0.048 mmol).
Purification by flash chromatography (50% ether in hexane)
gave tetracyclic ketone 41 (23.6 mg, 62%) and its isomeric
ketone (1.2 mg, 3%). 41: colorless oil; [R]2D0 +48.0° (c 0.69,
CHCl3); IR (CHCl3) 1712, 1454, 1429, 1109, 701 cm-1; 1H NMR
(400 MHz, CDCl3) δ 1.04 (9H, s), 1.18 (3H, s), 1.51-1.78 (10H,
m), 1.86-2.04 (6H, m), 2.17 (1H, m), 2.56-2.33 (2H, m), 2.82
(1H, ddd, J ) 12.2, 12.2, 2.0 Hz), 2.98 (1H, ddd, J ) 8.3, 8.3,
5.4 Hz), 3.33 (1H, dd, J ) 9.8, 2.4 Hz), 3.46 (1H, dd, J ) 10.3,
3.9 Hz), 3.47-3.52 (3H, m), 3.65 (2H, t, J ) 5.9 Hz), 3.73 (1H,
dd, J ) 8.8, 3.9 Hz), 3.80-3.86 (3H, m), 4.50 (2H, s), 4.61 and
4.79 (each 1H, d, J ) 12.7 Hz), 7.23-7.43 (16H), 7.64-7.66
(4H); 13C NMR (100 MHz, CDCl3) δ 17.44, 19.18, 26.85 (3 ×
C), 27.01, 28.44, 29.04, 29.17, 30.35, 31.36, 32.76, 33.43, 36.65,
38.04, 63.36, 63.52, 70.16, 72.46, 72.69, 72.82, 73.92, 74.06,
77.23, 80.44, 84.44, 86.53, 86.66, 126.96, 127.09, 127.45,
127.56, 127.60, 128.16, 128.32, 129.56, 133.85, 133.87, 135.56,
138.65, 139.58, 216.37; HRFABMS m/z calcd for C53H69O8Si
(MH) 861.4758, found 861.4794.
(CHCl3) 1462, 1375, 1255, 1087 cm-1 1H NMR (400 MHz,
;
CDCl3) δ 0.05 (6H, s), 0.06 (6H, s), 0.83 (9H, s), 0.90 (9H, s),
1.09 (3H, s), 1.21 (3H, s), 1.25 (2H, m), 1.46-1.96 (15H, m),
2.00 (1H, ddd, J ) 11.7, 4.4, 4.4 Hz), 2.16 (1H, m), 2.28 (1H,
m), 3.19 (1H, br d, J ) 10.3 Hz), 3.24-3.39 (4H, m), 3.48 (2H,
m), 3.57-3.70 (2H, m), 3.81 (3H, m), 4.49 (2H, s), 4.59 and
4.78 (each 1H, d, J ) 12.7 Hz), 7.23-7.35 (10H); 13C NMR (100
MHz, CDCl3) δ -5.24, -5.22, -2.20, -2.16, 16.12 (2 × C),
23.84, 25.75 (3 × C), 26.03 (3 × C), 26.93, 27.03, 28.81, 29.15,
29.55, 29.71, 30.50, 33.13, 33.41, 37.51, 37.77, 63.49, 63.66,
70.20, 73.39, 72.62, 72.82, 73.55, 73.87, 77.13, 77.41, 82.17,
85.01, 86.17, 88.53, 126.97, 127.04, 127.43, 127.58, 128.14,
128.32, 137.93; HRFABMS m/z calcd for C50H83O8Si2 (MH)
867.5622, found 867.5635.
Tetr a silyl Eth er 44. A mixture of 43 (5.5 mg, 6.5 µmol)
and Pd(OH)2-C (20 mg) in MeOH (0.2 mL) was stirred under
a hydrogen atmosphere for 1 h. The mixture was filtered
through Celite and the filtrate was concentrated. Flash
chromatography (EtOAc) gave an diol (4.0 mg, 92%). To a
stirred solution of this diol (3.7 mg, 5.4 µmol) in DMF (0.1 mL)
at 0 °C were added 2,6-lutidine (6.2 µL, 54 µmol) and TIPSOTf
(7.2 µL, 27 µmol), and the resulting solution was heated at 70
°C for 4 h. The reaction was quenched with saturated aqueous
NaHCO3 (0.1 mL) and extracted with EtOAc. The extract was
washed with water and brine, dried, and concentrated. Flash
Tetr a cyclic Alcoh ols 42a a n d 42b. A 0.92 M solution of
MeMgBr in THF (282 µL, 0.259 mmol) was charged in a flask
flushed with argon. After removal of the solvent under
reduced pressure, the flask was flushed with argon and
charged with toluene (0.2 mL). To this stirred and cold
solution at -78 °C a solution of ketone 41 (22.3 mg, 0.026

Hemibrevetoxin B Synthesis with Oxiranyl Anions
J . Org. Chem., Vol. 63, No. 18, 1998 6209
chromatography (14% EtOAc in hexane) gave tetrasilyl ether
44 (4.9 mg, 91%) as a colorless oil: [R]2D0 +22.8° (c 0.38,
CHCl3); IR (CHCl3) 1462, 1383, 1255, 1090 cm-1; 1H NMR (400
MHz, CDCl3) δ 0.05 (6H, s), 0.06 (6H, s), 0.83 (9H, s), 0.90
(9H, s), 1.06 (42H, m), 1.09 (3H, s), 1.19 (3H, s), 1.23 (2H, m),
1.46-2.03 (16H, m), 2.13 (1H, m), 2.29 (1H, m), 3.17 (1H, dd,
J ) 10.3, 2.4 Hz), 3.20 (1H, br d, J ) 10.3 Hz), 3.22 (1H, dd,
J ) 12.2, 4.4 Hz), 3.27-3.37 (2H, m), 3.57-3.71 (4H, m), 3.73-
3.83 (2H, m), 4.19 (1H, br d, J ) 2.4 Hz); 13C NMR (100 MHz,
CDCl3) δ -5.24 (2 × C), -2.29 (2 × C), 12.01 (3 × C), 12.38 (3
× C), 16.30 (3 × C), 18.03 (3 × C), 18.24 (6 × C), 23.92, 25.73
(4 × C), 26.01 (3 × C), 26.95, 28.84, 29.43, 29.58, 30.50, 30.55,
33.07, 36.44, 37.58, 37.61, 62.62, 63.23, 63.64, 67.65, 72.66,
72.95, 77.17, 82.33, 82.58, 85.08, 86.64, 88.49; HRFABMS m/z
calcd for C54H111O8Si4 (MH) 999.7350, found 999.7369.
Com p ou n d 2. A soution of tetrasilyl ether 44 (4.6 mg, 4.6
µmol) and CSA (0.3 mg, 1.4 µmol) in MeOH (0.05 mL) and
CH2Cl2 (0.05 mL) was stirred at 0 °C for 1 h. The reaction
was quenched with saturated aqueous NaHCO3 (0.1 mL) and
extracted with EtOAc. The extract was washed with water
and brine, dried, and concentrated. Flash chromatography
(18% EtOAc in hexane) gave 2 (3.0 mg, 74%) as a colorless oil:
[R]2D0 +24.8° (c 0.21, CHCl3); IR (CHCl3) 3473, 1462, 1377,
1255, 1103, 1014, 883 cm-1; 1H NMR (400 MHz, CDCl3) δ 0.06
(3H, s), 0.07 (3H, s), 0.83 (9H, s), 0.83-1.06 (42H, m), 1.10
(3H, s), 1.19 (3H, s), 1.32 (2H, m), 1.50-2.03 (17H, m), 2.16
(1H, m), 2.30 (1H, m), 3.18 (1H, dd, J ) 9.8, 2.4 Hz), 3.20 (1H,
br d, J ) 8.8 Hz), 3.21 (1H, dd, J ) 12.2, 4.4 Hz), 3.29-3.41
(2H, m), 3.67 (2H, t, J ) 6.3 Hz), 3.69 (2H, t, J ) 6.3 Hz),
3.73-3.83 (2H, m), 4.19 (br d, J ) 2.4 Hz); 13C NMR (100 MHz,
CDCl3) δ -2.29, -2.16, 12.01 (3 × C), 12.38 (3 × C), 16.19,
18.03 (6 × C), 18.24 (6 × C), 23.84, 25.71 (4 × C), 26.37, 28.79,
29.43, 29.51, 30.25, 30.55, 33.05, 36.44, 37.46 (2 × C), 62.62,
62.92, 63.23, 67.64, 72.66, 72.95, 77.13, 77.20, 82.48, 84.80,
86.54, 88.42; HRFABMS m/z calcd for C48H97O8Si3 (MH)
885.6486, found 885.6449.
Ack n ow led gm en t. I thank Professor Y. Yamamoto
1
(Tohoku University) for providing the H NMR spectra
of 2 and hemibrevetoxin B and Professor R. F. W.
J ackson (University of Newcastle) for giving us useful
comments on sulfonyl-stabilized oxiranyl anions. This
work was supported by the Grant-in-Aid for Scientific
Research on Priority Area no. 09672175 from the
Ministry of Education, Science, Sports and Culture of
J apanese Government.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra for
compounds 2, 4, 25-29, and 31-44 (25 pages). This material
is contained in libraries on microfiche, immediately follows this
article in microfilm version of the journal, and can be ordered
from the ACS; see any current masthead page for ordering
information.
J O980320P