COMMUNICATION
in the presence of the C16 methylene group; 2) regio- and
diastereoselective dihydroxylation of the endocyclic C12=
C13 double bond in (E)-8 in the presence of the C16 exocy-
clic methylene group; and 3) regioselective oxidation of the
C13 hydroxy group in the 12,13-diol. We envisaged that the
relatively low reactivity of the 1,1-disubstituted double bond
in RCM[14] might provide the basis for our required regiose-
lectivity in the ring formation. In contrast, selective dihy-
droxylation of 1,2-disubstituted alkenes over 1,1-disubstitut-
ed counterparts is very rare.[11b] We expected that the sub-
stituents and ring conformation may be helpful for “shield-
ing” the C16 methylene group during AD after inspecting
the crystal structure of 1.[2c]
Scheme 3 shows the synthesis of the diene alcohol 6. The
chiral iodide 9 was obtained from methyl (S)-lactate in 92%
overall yield through protection of the hydroxy group as the
TBDPS ether, reduction of the ester moiety by BH3·SMe2,
and conversion of the hydroxy group into the iodide in the
presence of I2, PPh3, and imidazole. It was then transformed
into the aldehyde 11 in 72% overall yield in four steps:
1) alkylation of methyl acetoacetate with 9; 2) enantioselec-
tive hydrogenation of the b-ketone ester;[15] 3) TES ether
formation; and 4) controlled DIBAL-H reduction of the
ester moiety. On the other hand, the chiral iodide 10 was
prepared by a modified procedure from methyl (R)-(À)-3-
hydroxy-2-methylpropionate (Roche ester) in 76% overall
yield by tosylation, partial ester reduction, Wittig-type meth-
ylenation, and iodide replacement of the tosylate. Addition
of the alkyllithium prepared from 10 with the aldehyde 11
gave, after DMP oxidation, the ketone 12. The latter was
treated with the Nystedꢂs reagent 13[16] to directly afford the
diene alcohol 6 (76%) as the major product along with the
TES ether 14 (16%), suggesting that the TES ether 14 un-
derwent partial cleavage under the Lewis acidic conditions.
Upon exposure to TFA/H2O/THF (1:4:100, RT, 2.5 h), the
TES ether 14 was converted into the alcohol 6 in 90% yield.
We obtained the acid fragment 7 through a nine-step se-
quence by using the SmI2-mediated enantioselective reduc-
tive coupling of the (1S,2R)-N-methylephedrine-derived
crotonate with aldehydes to secure the cis stereochemistry
at C7/C8 on the tetrahydrofuran ring.[8b] As shown in
Scheme 4, the alcohol 6 and the acid 7 were condensed to
give the seco ester, which was then treated with Grubbs
second-generation initiator Ib (5 mol%) in CH2Cl2 at reflux
for 4 h, affording the macrolactones (E)-8 (63%) and (Z)-8
(23%) (entry 2, Table 1). We were pleased to achieving high
regioselectivity in the RCM reaction without affecting the
C16 methylene group. To improve the E/Z ratio, the RCM
reaction was carried out in different solvents. A remarkable
solvent effect was found; by using Ib only the seco ester was
Scheme 3. Synthesis of the alcohol fragment 6. a) 4-Toluenesulfonyl chlo-
ride (TsCl), 4-dimethylaminopyridine (DMAP), Et3N, CH2Cl2, RT, 12 h,
98%; b) i) diisobutylaluminum hydride (DIBAL-H), PhMe, À908C, 1 h;
ii) nBuLi, MeP+Ph3BrÀ, THF, 08C, 0.5 h, 83% (2 steps); c) LiI, Et2O,
reflux, 4 h, 94%; d) TBDPSCl, imidazole, THF, RT, 2 h, 99%;
e) i) BH3·SMe2, THF, reflux, 2 h; ii) I2/PPh3/imidazole (4:2:4), THF,
reflux, 1 h, 93% (2 steps); f) methyl acetoacetate, NaH, nBuLi, THF/hex-
amethylphosphoric triamide (HMPA) (3:1), 08C; 9, RT, 4 h, 59% (82%
based on reacted starting material (brsm)); g) [RuBr2{(R)-BINAP}]
(BINAP=2,2’-bis(diphenylphosphino)-1,1’-binaphthyl), MeOH, 608C,
6 h, 90%; h) triethylsilyl trifluoromethanesulfonate (TESOTf), 2,6-luti-
dine, CH2Cl2, 08C, 0.5 h, 99%; i) DIBAL-H, CH2Cl2, À788C, 1 h, 99%;
j) 10, tBuLi, pentane/Et2O (3:2), À788C, 0.5 h and À208C, 0.5 h, then 11,
À788C, 2 h, 70% (82% brsm); k) Dess–Martin periodinane (DMP),
NaHCO3, RT, 2 h, 87%; l) 13, TiCl4, THF, reflux, 0.5 h, 76% 6, 16% 14;
m) trifluoroacetic acid (TFA)/H2O/THF (1:4:100), RT, 2.5 h, 90%.
Scheme 4. Synthesis of macrolactones (E)-8 and (Z)-8 by RCM. a) 1-(3-
Dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride
(EDCI),
DMAP, RT, 16 h, 91%; b) 5 mol% Ib, CH2Cl2, reflux, 4 h, 63% (E)-8,
23% (Z)-8. Mes=2,4,6-trimethylphenyl.
Chem. Eur. J. 2010, 16, 11530 – 11534
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
11531