Oxiranyl anions in organic synthesis: Application to the synthesis of hemibrevetoxin B

Full text of DOI:10.1021/ja9701523

J. Am. Chem. Soc. 1997, 119, 4557-4558
4557
Scheme 1. Retrosynthetic Analysis of Hemibrevetoxin B
Oxiranyl Anions in Organic Synthesis: Application
to the Synthesis of Hemibrevetoxin B
Yuji Mori,* Keisuke Yaegashi, and Hiroshi Furukawa
Faculty of Pharmacy, Meijo UniVersity
150 Yagotoyama, Tempaku, Nagoya 468, Japan
ReceiVed January 17, 1997
Hemibrevetoxin B (1),1 isolated from cultured cells of the
red tide organism Gymnodinium breVe, is the smallest member
of the polycyclic ether marine toxins and has about half of the
skeleton of brevetoxins.2 The unique 6,6,7,7-tetracyclic struc-
ture containing 10 stereocenters, an R-vinyl aldehyde moiety,
and a Z-diene system has attracted the attention of synthetic
chemists, and a variety of approaches have been explored.3
Recently, the total syntheses of hemibrevetoxin B have been
accomplished by using new synthetic methods: 6-endo-cycliza-
tion and dioxepane ring formation by the hydroboration of enol
ether derived from thionolactone by Nicolaou,4 the Lewis acid
mediated intramolecular allylstannane-aldehyde condensation
by Yamamoto,5 and a double rearrangement-ring expansion
of a 6,6-bicyclic ether to a dioxepane ring by the Nakata group.6
In this paper, we report a new approach to the synthesis of
hemibrevetoxin B based on recent oxiranyl anion methodology
developed in our laboratory.7 The strategy is illustrated by the
stereocontrolled synthesis of 2, which is elaborated by sequential
coupling of three sulfonyl-stabilized oxiranyl anions 4b, 5b, and
6b to the monocyclic diol 3. Since Yamamoto has already
described the conversion of 2 into hemibrevetoxin B,5 our
synthesis of 2 constitutes the formal total synthesis of the natural
product.
The starting point for these investigations was the regiose-
lective activation and protection of the two hydroxyl groups of
38 by a one-pot procedure7 to give triflate 7 in 98% yield.
Treatment of a mixture of 4a9 and 7 with n-BuLi in THF/HMPA
at -110 °C7,10 provided the coupled product 8 in 90% yield.
Stereospecific 6-endo-cyclization of 8 using p-toluenesulfonic
acid (p-TsOH) led to the bicyclic ketone 9 in 90% yield.
Reduction with NaBH4 followed by desilylation gave 10 as the
sole product.
Installation of the third ring involved the challenging prepara-
tion of the oxepane ring. Unfortunately, several attempts to
couple a triflate derived from 10 with the oxiranyl anion 5b
were unsuccessful due to the considerable steric hindrance of
the methyl group adjacent to the reaction site. This unexpected
difficulty was circumvented by the reaction between an oxiranyl
anion and an aldehyde. Thus, 10 was converted to aldehyde
11 by bis(silylation), followed by regioselective mono(desily-
lation) and SO3‚pyr oxidation. In order to prevent the decom-
position of the unstable cis-oxiranyl anion,10b the addition of
5b7 to 11 was carried out by employing an in situ trapping
method as described for 7 f 8, furnishing a 3:1 mixture of
products (88%), from which 12 was isolated in 63% yield. It is
noteworthy that the lithiation of 5a by n-BuLi is much faster
than the butyl addition to the aldehyde. Exposure of 12 to
BF3‚OEt2 led to its clean cyclization to the tricyclic hydroxy
ketone 13 (76%), whose hydroxyl group was removed by
11
treatment with SmI2 to give the ketone 14 in 64% yield.
The crucial oxepane formation was accomplished by one-
carbon homologation of a 3-oxotetrahydropyran ring. The
reaction of 14 with (trimethylsilyl)diazomethane (TMSCHN2)12
in the presence of BF3‚OEt2 gave the seven-membered ketone
15 in 67% yield along with 17% of the isomeric ketone after
acid hydrolysis of the intermediary trimethylsilyl enol ether.
Formation of the sily enol ether in this ring expansion prevents
the undesirable multiple homologation of the initially formed
ketone and practically allows one-step access to an oxepane
from a tetrahydropyran ring system. The stereoselective reduc-
tion of 15 proved to be more problematic, leading to the
predominant formation of the undesired cis-alcohol under a
variety of conditions.13 In order to reverse the stereoselectivity,
15 was desilylated and subjected to the hydroxy-directed
reduction with Me4NBH(OAc)3,14 providing the trans-alcohol
16 as a single diastereoismer.
(1) Prasad, A. V. K.; Shimizu, Y. J. Am. Chem. Soc. 1989, 111, 6476-
6477.
(2) For a review, see: Shimizu, Y. Chem ReV. 1993, 93, 1685-1698.
(3) (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.
The third coupling of triflate 17 with epoxy sulfone 6a9
having a C3 side chain proceeded uneventfully to afford 18
(96%), which, upon treatment with p-TsOH followed by
BF3‚OEt2, gave the tetracyclic ketone 19 in 67% yield. Repeat
of the ring expansion with TMSCHN2 provided ketone 20 in
62% yield. The addition of MeMgBr in toluene3d led to a 4:1
(4) (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.
(5) Kadota, I.; Jung-Youl, P.; Koumura, N.; Pollaud, G.; Matsukawa,
Y.; Yamamoto, Y. Tetrahedron Lett. 1995, 36, 5777-5780.
(6) Morimoto, M.; Matsukura, H.; Nakata, T. Tetrahedron Lett. 1996,
37, 6365-6368.
(11) (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.
(7) Mori, Y.; Yaegashi, K.; Furukawa, H. J. Am. Chem. Soc. 1996, 118,
8158-8159.
(8) Prepared from tri-O-acetyl-D-glucal in nine steps. The details will
be described in a full paper.
(12) (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.
(9) Prepared according to the following: Satoh, T.; Oohara, T.; Ueda,
Y.; Yamakawa, K. J. Org. Chem. 1989, 54, 3130-3136.
(10) (a) Mori, Y.; Yaegashi, K.; Iwase, K.; Yamamori, Y.; Furukawa,
H. Tetrahedron Lett. 1996, 37, 2605-2608. (b) Ashwell, M.; Clegg, W.;
Jackson, R. F. W. J. Chem. Soc., Perkin Trans. 1 1991, 897-908. (c) Dunn,
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S0002-7863(97)00152-2 CCC: $14.00 © 1997 American Chemical Society

4558 J. Am. Chem. Soc., Vol. 119, No. 19, 1997
Communications to the Editor
Scheme 2a
a (a) Tf2O, 2,6-lutidine, CH2Cl2, -78 °C, then TESOTf, 98%; (b) TESOTf, 2,6-lutidine, CH2Cl2, -78 °C, 98%; (c) PPTS, CH2Cl2/MeOH, -20
°C, 92%; (d) SO3‚Py, DMSO/CH2Cl2, Et3N, 96%; (e) SmI2, HMPA, THF, MeOH, 0 °C,64%; (f) same as a, 83%; (g) Bu4NF, THF, 97%; (h)
TBSOTf, 2,6-lutidine, CH2Cl2, 80%; (i) Pd(OH)2/C, H2, MeOH, 92%; (j) TIPSOTf, 2,6-lutidine, 70 °C, 91%; (k) CSA, CH2Cl2/MeOH, 0 °C, 74%.
epimeric mixture of products from which 21 was isolated in
77% yield by chromatography. Finally, desilylation of 21
followed by bis(silylation) with tert-butyldimethylsilyl trifluo-
romethanesulfonate, debenzylation, bis(silylation) with triiso-
propylsilyl trifluoromethanesulfonate, and regioselective removal
of the primary TBS group provided the alcohol 2 ([R]25D +24.8°
(c 0.21, CHCl3)) in 48% overall yield. The 1H NMR spectrum
of 2 was in complete agreement with that of an authentic sample
kindly provided by Professor Y. Yamamoto, thereby completing
the formal total synthesis of hemibrevetoxin B.
polycyclic ethers containing six- and seven-membered rings.
Oxiranyl anions are unique reactive nucleophiles and the
coupling with electrophiles represents an extraordinary means
by which epoxides can be directly incorporated into organic
molecules. Further applications of this methodology to the
synthesis of other marine natural products are in progress.
Supporting Information Available: Characterization data for
compounds 2 and 7-21 and 1H NMR spectra of authentic and synthetic
2 (10 pages). See any current masthead page for ordering and Internet
access instructions.
The present synthesis of hemibrevetoxin B using oxiranyl
anions demonstrated a conceptually new approach to marine
JA9701523