Diastereoselective ring-closing metathesis for the construction of a quaternary carbon stereogenic center

Article abstract of DOI:10.1016/S0040-4039(02)00162-4

A diastereoselective ring-closing metathesis of the trienes 1 leading to the formation of a quaternary carbon stereogenic center on the cyclohexenes 2 has been developed.

Full text of DOI:10.1016/S0040-4039(02)00162-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 2047–2049
Diastereoselective ring-closing metathesis for the construction of
a quaternary carbon stereogenic center†
Yu-ichi Fukuda, Hiroyuki Sasaki, Mitsuru Shindo and Kozo Shishido*
Institute for Medicinal Resources, University of Tokushima, 1-78 Sho-machi, Tokushima 770-8505, Japan
Received 12 December 2001; revised 15 January 2002; accepted 18 January 2002
Abstract—A diastereoselective ring-closing metathesis of the trienes 1 leading to the formation of a quaternary carbon stereogenic
center on the cyclohexenes 2 has been developed. © 2002 Elsevier Science Ltd. All rights reserved.
Carbonꢀcarbon bond forming reactions leading to ring
closure are of great interest in organic synthesis.
Among these, the ring-closing metathesis (RCM)1 has
been studied extensively by many groups for the last
decade. In particular, the development of a new genera-
tion of versatile catalysts, i.e. Grubbs’ ruthenium car-
bene complexes 32 and 4,3 has accelerated the
application of RCM to the synthesis of natural and
unnatural products. However, only a few reports deal
with the diastereoselective introduction of a quaternary
carbon stereogenic center on the prochiral carbon dur-
ing RCM via asymmetric induction.4 In this paper we
Scheme 1.
describe an unprecedented methodology for the
diastereoselective construction of a quaternary carbon
stereogenic center, which contains all four carbon sub-
stituents, on the cyclohexene 2 via 1,4-asymmetric
induction employing the RCM of the trienes 1 (Scheme
1).
alcohol 7 as a mixture of the E and Z isomers. Sequen-
tial vinyl ether formation and reductive Claisen
rearrangement6 gave the alkenyl ether 8 in good overall
yield. Exposure of
8
to Grieco’s dehydration
conditions7 produced cleanly the 1,4-diene 9, the silyl
ether of which was deprotected with tetra-n-butylam-
monium fluoride to give the alcohol 10. Swern oxida-
tion followed by reaction with vinyllithium provided
the desired trienol 12a in good overall yield. Two other
trienols 13a and 14a were similarly prepared by reac-
tion of the corresponding Grignard reagents with 5.
These were converted by the conventional manner into
the corresponding benzyl, trimethylsilyl, and MOM
ethers and benzoate, respectively (Scheme 2).
As the substrates, we chose three basic compounds 12,
13 and 14, since the expected products could be useful
as chiral building blocks for the synthesis of natural
products with a quaternary stereogenic center. Starting
from the amide 5, which was derived from g-butylolac-
tone according to the literature procedure,5 we pre-
pared a variety of racemic trienes 12a–d, 13a–d and
14a–d, in order to evaluate the diastereoselectivity. A
Grignard reaction followed by a Horner–Emmons reac-
tion of the resulting methyl ketone 6 and reduction with
diisobutylaluminum hydride (Dibal) provided the allyl
With the triene substrates in hand, the ruthenium car-
bene complex-catalyzed RCM reaction was examined
using 3 as a catalyst. Treatment of 12b–e, 13b–e and
14b–e in CH2Cl2 solution (0.02 M) with 10 mol% of 3
at room temperature gave the cyclized products 15–17,8
which were obtained, after hydrolysis (except in the
case of benzyl ethers, series b), with slight to good
Keywords: metathesis; cyclization; asymmetric induction; quaternary
carbon; diastereoselection.
* Corresponding author. Tel./fax: +81 88 633 7287; e-mail: shishido@
ph2.tokushima-u.ac.jp
†
Dedicated to Professor Kunio Ogasawara on the occasion of his
retirement at Tohoku University.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00162-4

2048
Y. Fukuda et al. / Tetrahedron Letters 43 (2002) 2047–2049
RO
TBDPSO
RO
RO
O
O
OH
ii, iii
iv, v
i
Me
OH
N
5
6: R=TBDPS
7
8
MeO
RO
R2O
OHC
x
vi, vii
viii
ix
R1
13a-e: R1=Et,
R2=H, Bn, TMS, MOM, Bz
14a-e: R1=Ph,
12a: R1=Me, R2=H
11
9: R=TBDPS
10: R=H
12b: R1=Me, R2=Bn
12c: R1=Me, R2=TMS
12d: R1=Me, R2=MOM
12e: R1=Me, R2=Bz
R2=H, Bn, TMS, MOM. Bz
Scheme 2. Reagents and conditions: (i) MeMgI, Et2O, rt, 87%; (ii) (EtO)2P(O)CH2CO2Et, NaH, DME, 50°C, quant.; (iii)
DIBAL-H, THF, 0°C, 96%; (iv) EtOCHꢁCH2, Hg(OAc)2, rt, 94%; (v) Dibal, CH2Cl2, rt, quant.; (vi) o-nitrophenyl selenocyanate,
nBu3P, THF, rt, quant.; (vii) H2O2, THF, rt, 84%; (viii) nBu4NF, THF, rt, 95%; (ix) (COCl)2, DMSO, Et3N, CH2Cl2, rt; (x)
n
(CH2ꢁCH)4Sn, BuLi, Et2O, −78°C, 71% (two steps).
diastereoselectivity (Table 1). The best result was real-
ized with 13b as the substrate to afford the cyclo-
hexenol 16 in 84% yield with 72% de (entry 6). When
the substituent (R1) on the prochiral carbon is phenyl,
the diastereomeric excesses are uniformly lower (entries
9–12). Although the trienols, 12a, 13a and 14a, gave no
cyclized products with catalyst 3,9 in the presence of
catalyst 4 (5 mol%), reactions proceeded rapidly (within
1 h) to give 15, 16 and 17 in 78, 75 and 92% yield,
respectively. However, no diastereoselectivity was
observed at all.
of the optically active substrate 21. A Wittig reaction of
11 followed by reduction with Dibal provided the allyl
alcohol 18, which was exposed to the conditions of the
Katsuki–Sharpless asymmetric epoxidation10 providing
the epoxy alcohol 19. After mesylation, reduction with
sodium naphthalenide11 gave the trienol 20, the enan-
tiomeric excess of which was determined to be >99% by
MTPA analysis. The absolute configuration was con-
firmed to be R by the Mosher–Kusumi method.12 The
optically pure TMS ether 21 was treated with 3 to give
22,8 which was sequentially hydrolyzed and oxidized to
produce the enone 23, [h]D +70. Since the specific
rotation, [h]D −113 (85% ee), of the authentic material
with the R configuration has been reported,13 the abso-
lute configuration of our synthetic material was estab-
lished to be S. Thus, it was revealed that the quaternary
stereogenic center with the S-configuration can be gen-
erated from the tertiary C–O chirality with the R-
configuration. This finding seems to be quite useful in
clarifying the mechanism of the asymmetric induction
(Scheme 3).
To determine the stereochemistry at a newly generated
quaternary stereogenic center, we carried out the RCM
Table 1. RCM reaction of the trienes 12–14 in CH2Cl2
solution (0.02 M) in the presence of 3 (10 mol%) at room
temperature
HO
1) RCM
R1O
2) hydrolysis
R2
R2
15: R2=Me; 16: R2=Et
12-14
17: R2=Ph
Entry
Substrate
R1
R2
Yield (%)
drb
1
2
3
4
5
6
7
8
12b
12c
12d
12e
13b
13c
13d
13e
14b
14c
14d
14e
Bn
Me
Me
Me
Me
Et
Et
Et
Et
Ph
Ph
Ph
Ph
78a
69
61
90
80a
84
69
85
87a
55
88
85
71:29a,c
74:26c
64:36c
64:36c
85:15a
86:14
77:23
71:29
56:44a
61:39
62:38
62:38
TMS
MOM
Bz
Bn
TMS
MOM
Bz
9
Bn
10
11
12
TMS
MOM
Bz
Scheme 3. Reagents and conditions: (i) Ph3PꢁCHCO2Et, ben-
zene, reflux, 88%; (ii) Dibal, THF, 0°C, quant.; (iii)
D-(−)-
diisopropyl tartrate, Ti(OiPr)4, TBHP, CH2Cl2, −23°C, 82%;
(iv) MsCl, Et3N, CH2Cl2, rt, quant.; (v) Na, naphthalene,
THF, 0°C, 60%; (vi) TMSCl, Et3N, CH2Cl2, rt, quant.; (vii) 3,
THF, rt; (viii) 1N HCl, THF, rt, 69% (two steps); (ix) MnO2,
acetone, rt, 75%.
a These data are for the benzyl ether.
b Determined by 1H NMR.
c The relative stereochemistry of the major diastereomer was deter-
mined to be (1RS,4SR) in comparison (1H NMR) with optically
active 15 derived from 22.

Y. Fukuda et al. / Tetrahedron Letters 43 (2002) 2047–2049
2049
In summary, we have developed a novel methodology
for the diastereoselective construction of a quaternary
carbon stereogenic center on the prochiral carbon via
1,4-asymmetric induction during the RCM. The cyclo-
hexene derivatives generated by this reaction would be
versatile and flexible chiral building blocks for the
synthesis of biologically significant natural products.
Investigations into a possible mechanism of asymmetric
induction and further optimization, extension and
application of the methodology are currently underway
in our laboratories.
J. Chem. 2000, 78, 868–883; (c) Schmidt, B.; Wildemann,
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unsuccessful.
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