Scheme 2. Preparation of 4. a) 9-BBN, THF, RT; then 3m NaOH, 30%
aqueous H2O2, RT, 100%; b) PivCl, py, DMAP, CH2Cl2, RT, 100%;
c) BF3·OEt2, Me2S, CH2Cl2, À308C, 92%; d) Dess–Martin periodinane,
CH2Cl2, RT, 94%; e) 6a or 6b (2.0 equiv), Ph3SnH, Et3B, benzene, RT,
90% (from 6a), 83% (from 6b); f) Burgess reagent, benzene, RT,
92%. 9-BBN=9-borabicyclo[3.3.1]nonane, DMAP=4-dimethylamino-
pyridine, MOM=methoxymethyl, py=pyridine.
reaction of the involved boron enolate with a bulky aldehyde
proceeds efficiently under mild conditions to afford the
coupling products. Indeed, the reaction of 5 and 6a with
triphenyltin hydride and triethyl borane in benzene was
carried out at room temperature to afford 8 as the single
product (90%). The reaction of 5 with 6b under the same
conditions also provided 8 (83%) as the single product. It
should be noted that this coupling reaction proceeded without
the b-elimination reaction of the siloxy group, a reaction that
often occurs in such a cyclopentenone system. The dehydra-
tion of 8 with the Burgess reagent[13] successfully afforded the
desired enone 4 in 92% yield.
Considerable attention has been given to the formation of
eight-membered carbocyclic rings by RCM because of its
potential utility.[14] However, to the best of our knowledge, the
number of natural product syntheses that employ RCM to
form an eight-membered carbocyclic ring is limited.[14a,c,d,i] We
also found that there are only two natural product syntheses
that utilize RCM to form a trisubstituted double bond in an
eight-membered carbocyclic ring.[14a,c] Moreover, the con-
struction of the ophiobolin skeleton by RCM has not been
reported to date. Nonetheless, among the various preparation
methods for eight-membered carbocyclic rings, RCM is the
most straightforward approach. Therefore, we decided to
examine the RCM of 12, which was prepared from 4
(Scheme 3).
Scheme 3. Total synthesis of (+)-ophiobolin A (1). a) H2, Raney Ni,
MeOH/THF=1:1, RT, 82%, d.r.=41:1; b) MeLi, Et2O, À78 to 08C,
98%, d.r.=1:0; c) (COCl)2, DMSO, CH2Cl2, À788C; then Et3N, RT,
98%; d) Ph3P+MeBrÀ, tBuOK, THF, 08C, 99%; e) PPTS, EtOH, RT,
quant.; f) IBX, DMSO, RT; g) MeLi, Et2O, 08C; h) Dess–Martin period-
inane, CH2Cl2, RT, 78% (over 3 steps); i) TMSCl, imidazole, DMF, RT,
quant; j) Comins reagent, KHMDS, THF, À788C; k) Pd(PPh3)4, Et3N,
CO (1 atm), MeOH/toluene=20:1, 508C; l) DIBAL-H, hexane, À788C,
47% (over 3 steps); m) PivCl, py, DMAP, CH2Cl2, RT; n) TBAF, THF,
RT; o) TBSCl, DIPEA, DMAP, CH2Cl2, 08C; p) BnBr, NaH, DMF, 08C;
q) DIBAL-H, hexane, À788C, 76% (over 5 steps); r) Hoveyda–
Grubbs II, 1,4-benzoquinone, toluene, 1108C; s) BnBr, NaH, 08C;
t) PPTS, EtOH, RT, 68% (over 3 steps); u) (COCl)2, DMSO, CH2Cl2,
À788C; then Et3N, RT; v) (CH3)2CHPPh3+IÀ, nBuLi, RT; w) Li, naphtha-
lene, THF, À308C; x) (COCl)2, DMSO, CH2Cl2, À788C; then Et3N, RT,
49% (over 4 steps). DIBAL-H=diisobutylaluminum hydride, DIPEA=
diisopropylethylamine, DMF=N,N-dimethylformamide, DMSO=di-
methyl sulfoxide, IBX=ortho-iodoxybenzoic acid, KHMDS=potassium
hexamethyldisilazide, PPTS=pyridinium para-toluenesulfonate,
TBAF=tetrabutylammonium fluoride, TMS=trimethylsilyl.
then subjected to the reaction with methyllithium, followed
by oxidation with Dess–Martin periodinane, and the reaction
of the products with TMSCl to afford ketone 11. The reaction
of 11 with Comins reagent[17] afforded the enol triflate, the
following palladium-mediated carbonylation and the reduc-
tion with DIBAL-H gave 12.
The RCM of 12 was first attempted with Grubbs II
catalyst[18] in toluene or dichloroethane under reflux; how-
ever, the desired product was not obtained. Use of the
Hoveyda–Grubbs II catalyst[18] or the modified Grubbs II
catalyst,[19] which was reported to be effective for hindered
alkenes, gave the same results. We found that in all RCM
reactions most of the starting material remained and a small
Hydrogenation of 4 with Raney Ni in a mixed solvent
(MeOH/THF = 1:1) afforded 9 with high selectivity and
yield.[15] The reaction of methyllithium with ketone 9 occurred
as predicted from the less-hindered b face with concomitant
removal of the pivaloyl group to afford the desired diol as the
single isomer. The subsequent Swern oxidation, Wittig
reaction, and removal of the TBS group afforded 10.
Unfortunately, the Swern oxidation of 10 caused dehydration
of the tertiary alcohol. However, the oxidation with IBX[16]
proceeded without dehydration to afford the lactol, which was
Angew. Chem. Int. Ed. 2011, 50, 9452 –9455
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
9453