M. Nakada et al.
by altering the hydrolysis conditions were unsuccessful.
Therefore, we considered kinetic resolution to improve the
ee value. In general, the hydrolysis of half-esters does not
occur in the PLE-catalyzed enantioselective hydrolysis of s-
symmetric prochiral diesters. However, we found that half-
ester 10c (89% ee) underwent PLE-catalyzed hydrolysis
when compound 10c (89% ee) was gradually added to a sus-
pension of PLE in potassium phosphate buffer (pH 8.0) by
using a syringe pump, thus leading to the kinetic resolution
of compound 10c. Thus, 88% of ester 10c (96% ee) was ob-
tained by using this procedure.
Subsequently, we prepared compound 7 from 10c as out-
lined in Scheme 2. Ester 10c was converted into alkyl iodide
7 by using standard procedures in a 15-step sequence that
began with the conversion of compound 10c into its corre-
sponding acid chloride, which was reduced with NaBH4 to
afford compound 11. Alcohol 11 was protected as a MOM
ether, followed by reduction with LiAlH4 and acetylation to
afford compound 12. Compound 12 was subjected to ozonol-
ysis, followed by reductive work-up to afford the corre-
sponding alcohol. The obtained alcohol was protected as an
ethoxyethyl ether, followed by removal of the acetyl group,
Parrikh–Doering oxidation, a Horner–Wadsworth–Emmons
reaction, and DIBAL-H reduction to give compound 13.
Treatment of compound 13 with lithium chloride and meth-
A
ACHTUNGTRENsNUNG ulfonyl chloride afforded the corresponding allylic chlo-
AHCTUNGTRENNUNG
the allyltrimethylsilane. Subsequent removal of the ethox-
yethyl group and conversion of the resultant alcohol into
the corresponding iodide furnished fragment 7.
Fragment 8 (Scheme 2) was prepared from known com-
pound 8a[12] as follows: Iodolactonization[13] of compound
8a efficiently afforded compound 8b, which was converted
into the corresponding trifluoroacetate, followed by removal
of the trifluoroacetate by using diethylamine to give alcohol
8c. The protection of compound 8c as a TBDPS ether final-
ly afforded compound 8.[14] Treatment of compound 7 with
tBuLi generated the corresponding organolithium inter-
mediate, which was treated with compound 8 to generate 6
as a mixture of two diastereomers (d.r.=1:1).
Intramolecular Hosomi–Sakurai reaction of compound 6:
Then, we examined the intramolecular Hosomi–Sakurai re-
action of compound 6 to construct the complex spirocyclic
CD ring (Table 2). Treatment of 6 with TiCl4 or TiACHTUNGTRENNUNG(OiPr)4
did not yield compound 14, probably because of unsuitable
acidity (Table 2, entries 1 and 2). However, treatment with
TiCl
31, and 40% yield, respectively (Table 2, entry 3). The use
of the less-acidic TiCl2A(OiPr)2 provided an unexpected C15
epi diastereomer (14d) in 57% yield, and treatment with
TiCl(OiPr)3 afforded compound 14d as the sole product in
3ACHTUNGTRENUN(NG OiPr) afforded compounds 14a, 14b, and 14c in 29,
CTHUNGTRENNUNG
AHCTUNGTRENNUNG
84% yield (Table 2, entries 4 and 5). The structure of com-
pound 14d was confirmed by X-ray crystallography
(Figure 2). Treatment of 6 with BF3·OEt2 afforded the de-
sired compound (14a) as the major product in 45% yield
(Table 2, entry 6). Various Lewis acids were investigated to
improve the yield of compound 14a (Table 2, entries 7–
10),[15] but only fruitless results were obtained. Moreover,
neither reaction temperature nor quantity of Lewis acid al-
tered the selectivity.
The observed stereoselectivity in the formation of com-
pounds 14a–14c may be explained by the proposed transi-
tion states shown in Figure 3. Among the four possible tran-
sition states, only TS1–TS3 were considered because the
other possible transition state (not shown) generated severe
steric strain between the allylsilane group and the C15
methyl group. Transition state TS1, which would afford com-
pound 14a, is ideal, because the reaction of allylsilane at the
C14 position may circumvent the steric strain between the
allylsilane and the THF ring. On the other hand, the steric
strain in transition states TS2 and TS3 may be relatively
large, because the allylsilane group is located on the THF
ring. However, transition states TS2 and TS3 could be stabi-
lized by secondary orbital interactions,[16] which arise from
Scheme 2. Preparation of compound 6: a) PLE, KPB 8, 308C, 7 days,
88% yield, 96% ee; b) (COCl)2, DMF (cat.), CH2Cl2, 08C to RT;
c) NaBH4, MeOH, THF, À308C to RT, 86% yield (2 steps); d) MOMCl,
DIPEA, NaI, CH2Cl2, reflux, 99% yield; e) LiAlH4, Et2O, RT; f) Ac2O,
Py, DMAP, CH2Cl2, RT, quantitative yield (2 steps); g) O3, MeOH,
À788C, then NaBH4, À78 to 08C, 94% yield; h) ethyl vinyl ether, PPTS,
CH2Cl2, RT, 96% yield; i) K2CO3, MeOH, RT, quantitative yield;
j) SO3·Py,
DMSO,
Et3N,
0 8C,
98%
yield;
k) tBuOK,
(EtO)2P(O)CH2CO2Et, THF, À788C to RT, quantitative yield;
l) DIBAL-H, CH2Cl2, À788C, 99% yield; m) MsCl, 2,6-lutidine, LiCl,
DMF, 08C, 98% yield; n) Me3SiSiMe3, MeLi, Et2O/HMPA (4:1), À608C,
88% yield; o) PPTS, EtOH, RT, quantitative yield; p) PPh3, imidazole,
I2, benzene, RT, 94% yield; q) NCS, NaHCO3, NaI, EtOAc/H2O (2:1),
RT, 92% yield (>30:1); r) CF3CO2Na, DMF, 908C, then Et2NH, RT,
63% yield; s) TBDPSCl, imidazole, CH2Cl2, RT, 97% yield; t) compound
7, tBuLi, Et2O, À788C, 15 min, then compound 8, À788C, 2 h, 84% yield,
d.r.=1:1. MOMCl=methoxymethyl chloride, DIPEA=N,N-diisoprop
ACHTUNGERTNyNUNG l-
ACHTUNGTRENNUNGethylamine, Py=pyridine, DMAP=4-dimethylaminopyridine, PPTS=
pyridinium para-toluenesulfonate, DIBAL-H=diisobutylaluminium hy-
dride, MsCl=methanesulfonyl chloride, HMPA=hexamethylphosphor-
ACHTUNGTRENNUNG
5478
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 5476 – 5486