Synthetic studies on brevetoxin-B. Part 2: Stereoselective synthesis of the EFG-ring system

Article abstract of DOI:10.1016/S0040-4039(00)01340-X

The EFG-ring system of brevetoxin-B, having an α-methyl group on the D-ring, was stereoselectively synthesized based on the stereoselective Michael addition of the α-methyl group, novel ring-expansion reaction, and 6-endo-cyclizations of the vinylepoxide and methylepoxide. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01340-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 7677–7680
Synthetic studies on brevetoxin-B. Part 2: Stereoselective
synthesis of the EFG-ring system
Goh Matsuo, Nobuyuki Hori, Hiroko Matsukura and Tadashi Nakata*
RIKEN (The Institute of Physical and Chemical Research), Wako, Saitama 351-0198, Japan
Received 13 July 2000; revised 3 August 2000; accepted 4 August 2000
Abstract
The EFG-ring system of brevetoxin-B, having an a-methyl group on the D-ring, was stereoselectively
synthesized based on the stereoselective Michael addition of the a-methyl group, novel ring-expansion
reaction, and 6-endo-cyclizations of the vinylepoxide and methylepoxide. © 2000 Elsevier Science Ltd. All
rights reserved.
Keywords: brevetoxin-B; Michael addition; ring-expansion reaction; endo-cyclization.
In the preceding paper,1 we reported the stereoselective synthesis of the ABC-ring system of
brevetoxin-B (BTX-B). We now report the stereoselective synthesis of the EFG-ring system
having an a-methyl group on the D-ring. Our synthesis of the EFG-ring system features the
stereoselective Michael addition for the introduction of the a-methyl group on the D-ring, a
novel ring-expansion reaction for the construction of the E-ring system, and the 6-endo-cycliza-
tions for the construction of the F- and G-ring systems.
In the total synthesis of BTX-B, the stereoselective introduction of the a-methyl group on the
D-ring should be one of the crucial problems.2 We anticipated that the methyl group would be
stereoselectively introduced to an a,b-unsaturated ester or d-lactone by the Michael addition.
The a,b-unsaturated ester 3 and d-lactone 6 were thus synthesized from the diol 1,3 which is a
key intermediate in our total synthesis of hemibrevetoxin B (Scheme 1). The starting material 1,
prepared from geranyl acetate, was converted into the alcohol 2 in three steps: (1) selective
acetylation of the primary alcohol,4 (2) protection of the secondary alcohol as the TBS ether and
(3) alkaline hydrolysis of the acetate. The oxidation of 2 with TPAP5 followed by the Wittig
reaction provided the desired a,b-unsaturated ester 3a, which was treated with TBAF to give the
alcohol 3b. On the other hand, after the oxidation of 2 with TPAP, the aldol reaction with the
lithium enolate of ethyl acetate gave the ester 4. Deprotection of the TBS group with TBAF,
hydrolysis with LiOH and lactonization-acetylation with Ac2O afforded 5, which was treated
with DBU to produce the desired a,b-unsaturated d-lactone 6.
* Corresponding author. Fax: +81 48 462 4666; e-mail: nakata@postman.riken.go.jp
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01340-X

7678
Scheme 1. (a) AcCl, 2,4,6-collidine, CH2Cl2, −78°C; (b) TBSCl, imidazole, DMF, rt; (c) K2CO3, MeOH, rt (92% from
1); (d) TPAP, NMO, MS-4A, CH2Cl2, rt; (e) Ph3PꢀCHCO2Me, toluene, 100°C (85% from 2); (f) TBAF, THF, rt
(77%); (g) EtOAc, LDA, THF, −78°C (84% from 2); (h) TBAF, THF, rt; (i) LiOH, aq. THF, 0°C; (j) Ac2O, pyridine,
rt (78% from 4); (k) DBU, benzene, rt (88%)
The Michael reactions of 3a, 3b and 6 with Me2CuLi were then examined (Scheme 2). The
reaction of the a,b-unsaturated ester 3a with Me2CuLi in Et2O at 0°C gave no adduct, while 3b
stereoselectively afforded the desired a-methyl adduct 7 as the sole product, although the yield
was moderate (51%). On the other hand, the Michael reaction of 6 under the same conditions
proceeded smoothly with complete stereoselection and in high yield, giving the desired 8 (89%).
The stereoselective Michael additions would take place via coordination of the reagent and the
hydroxyl group in 3b, and via axial attack of the reagent in 6.
Scheme 2.
Having accomplished the introduction of the a-methyl group on the D-ring with complete
stereoselection, we then examined the construction of the E-ring system based on our ring-
expansion reaction using a chloromethanesulfonate (monochlate) (Scheme 3).6 The reduction of
8 with LiAlH4, protection of the resulting diol as the benzyl ether, and deprotection of the
acetonide afforded the diol 9. Selective protection of the alcohols in 9 with AcCl-2,4,6-collidine4
followed by ClCH2SO2Cl (McCl)-2,6-lutidine gave the required monochlate 10. Upon treatment
with Zn(OAc)2 in AcOH–H2O (1:1) at reflux, the ring-expansion of 10 took place to give the
seven-membered ether, which was treated with K2CO3 in methanol to give the oxepane 11,
corresponding to the E-ring, in 88% yield from 9.
Scheme 3. (a) LiAlH4, Et2O, 0°Cꢀrt; (b) BnBr, n-Bu4NI, NaH, THF, 0°Cꢀrt; (c) CSA, MeOH, rt (93% from 8); (d)
AcCl. 2,4,6-collidine, CH2Cl2, −78°C; (e) McCl, 2,6-lutidine, CH2Cl2, 0°C; (f) Zn(OAc)2, aq. AcOH, reflux; (g)
K2CO3, MeOH, rt (88% from 9)

7679
Next, the construction of the F-ring system, which has 1,3-diaxial dimethyl groups on the
tetrahydropyran ring, was examined (Scheme 4). The oxepane 11 was converted into the epoxy
alcohol 14 via carbon elongation and the Sharpless asymmetric epoxidation (AE).7 The
treatment of 11 with triflic anhydride followed by TMSOTf8 gave the triflate 12, which was
treated with NaCN and then TMSOTf9 to give the nitrile 13. The nitrile 13 was then converted
into an epoxy alcohol 14 in four steps: (1) DIBAH reduction, (2) the Wittig reaction using
Ph3PꢀC(Me)CO2Et, (3) DIBAH reduction and (4) the Sharpless AE7 using (−)-DIPT. After
deprotection of the TMS group, the direct cyclization of 14 with PPTS10 gave the undesired
5-exo-cyclized compound, as anticipated, due to the steric hindrance of the dimethyl groups. We
then examined the cyclization using epoxides having a styryl11 or vinyl group,12 which should
activate the 6-endo-cyclization. The oxidation of 14 with TPAP followed by the Wittig reactions
with Ph3PꢀCHPh and Ph3PꢀCH2 afforded the styryl and vinyl epoxides, 15 (82%) and 16 (87%),
respectively. After deprotection of the TMS group in 15 and 16 with TBAF, treatment of the
resulting alcohols with PPTS produced the 6-endo-cyclization to give the desired 2,3-trans-tetra-
hydropyrans 17 and 18, corresponding to the F-ring, in 55 and 88% yield, respectively. Although
the 6-endo-cyclization of the styrylepoxides usually gave a higher yield than that of the
vinylepoxides, this is the only exception that we have examined so far.
Scheme 4. (a) Tf2O, 2,6-lutidine, CH2Cl2, −78°C, then TMSOTf, −78°C; (b) NaCN, DMSO, 35°C; (c) TMSOTf,
2,6-lutidine, CH2Cl2, 0°C (72% from 11); (d) DIBAH, CH2Cl2, −78°C; (e) Ph3PꢀC(Me)CO2Et, toluene, 100°C (96%
from 13); (f) DIBAH, toluene, −78°C (93%); (g) t-BuOOH, (−)-DIPT, Ti(Oi-Pr)4, MS-4A, CH2Cl2, −20°C (85%); (h)
TPAP, NMO, MS-4A, CH2Cl2, rt; (i) Ph3P+MeBr−, NaHMDS, THF, 0°C (87% from 14); (j) TBAF, THF, rt; (k)
PPTS, CH2Cl2, 0°C (88% from 16); (l) TBSOTf, 2,6-lutidine, CH2Cl2, 0°C; (m) BH3·THF, THF, 0°Cꢀrt, then aq.
NaOH, H2O2 (67% from 18); (n) TPAP, NMO, MS-4A, CH2Cl2, rt; (o) Ph3PꢀC(Me)CO2Et, toluene, 100°C (93% in
2 steps); (p) DIBAH, toluene, −78°C (87%); (q) MCPBA, CH2Cl2, 0°C (93%); (r) TBAF, THF, 40°C; (s) CSA,
CH2Cl2, 0°C (72% from 21)
Finally, the construction of the G-ring system was carried out. The protection of the alcohol
18 with TBSOTf and subsequent hydroboration/oxidation afforded an alcohol, which was
subjected to TPAP-oxidation followed by the Wittig reaction using Ph3PꢀC(Me)CO2Et to give
the ester 19. The reduction of 19 with DIBAH followed by MCPBA treatment stereoselectively
gave the b-epoxide 21.13 After deprotection of the TBS group in 21, treatment of the resulting

7680
alcohol with CSA stereoselectively effected the 6-endo-cyclization without any activation to give
the trans-fused six–six–seven-membered ether 22 in 72% yield. The cyclic product 22 corre-
sponds to the EFG-ring system of BTX-B.
In summary, the EFG-ring system having an a-methyl group on the D-ring was synthesized
with complete stereoselection based on the stereoselective Michael addition of the methyl group,
the ring-expansion of a tetrahydropyran to an oxepane, and the 6-endo-cyclizations of the
vinylepoxide and methylepoxide.
Acknowledgements
This work was supported in part by Special Project Funding for Basic Science (Multibio-
probe) from RIKEN. The authors thank Dr. H. Koshino for the NMR spectral measurements,
Ms. K. Kobayashi for the X-ray crystallographic analysis, and Ms. K. Harata for the mass
spectral measurements.
References
1. Matsuo, G.; Matsukura, H.; Hori, N.; Nakata, T. Tetrahedron Lett. 2000, 41, 7673.
2. Nicolaou, K. C.; Theodorakis, E. A.; Rutjes, F. P. J. T.; Sato, M.; Tiebes, J.; Xiao, X.-Y.; Hwang, C.-K.;
Duggan, M. E.; Yang, Z.; Couladouros, E. A.; Sato, F.; Shin, J.; He, H.-M.; Bleckman, T. J. Am. Chem. Soc.
1995, 117, 10239.
3. Nakata, T.; Nomura, S.; Matsukura, H.; Morimoto, M. Tetrahedron Lett. 1996, 37, 217.
4. Ishihara, K.; Kurihara, H.; Yamamoto, H. J. Org. Chem. 1993, 58, 3791.
5. For a review, see: Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis 1994, 639.
6. (a) Hori, N.; Nagasawa, K.; Shimizu, T.; Nakata, T. Tetrahedron Lett. 1999, 40, 2145. (b) Nakata, T.; Nomura,
S.; Matsukura, H. Tetrahedron Lett. 1996, 37, 213.
7. Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5976.
8. Mori, Y.; Yaegashi, K.; Furukawa, H. J. Am. Chem. Soc. 1996, 118, 8158.
9. During the reaction with NaCN, a part of TMS group was deprotected. Thus, the resulting alcohol was again
silylated.
10. Miyashita, M.; Yoshikoshi, A.; Grieco, P. A. J. Org. Chem. 1977, 42, 3772.
11. (a) Matsukura, H.; Morimoto, M.; Koshino, H.; Nakata, T. Tetrahedron Lett. 1997, 38, 5545. (b) Matsukura, H.;
Morimoto, M.; Nakata, T. Chem. Lett. 1996, 487.
12. (a) Nicolaou, K. C.; Duggan, M. E.; Hwang, C.-K.; Somers, P. K. J. Chem. Soc., Chem. Commun. 1985, 1359.
(b) Nicolaou, K. C.; Prasad, C. V. C.; Somers, P. K.; Hwang, C.-K. J. Am. Chem. Soc. 1989, 111, 5330. (c)
Nicolaou, K. C.; Prasad, C. V. C.; Somers, P. K.; Hwang, C.-K. J. Am. Chem. Soc. 1989, 111, 5335.
13. Nicolaou, K. C.; Nugiel, D. A.; Couladouros, E.; Hwang, C.-K. Tetrahedron 1990, 46, 4517.
.