Enantiocontrolled synthesis of a chiral building block via diastereoselective ring-closing metathesis

Article abstract of DOI:10.1055/s-2005-862388

An enantiocontrolled construction of a chiral building block, which had been converted into an indole alkaloid (-)-eburnamonine, has been accomplished using a diastereoselective ring-closing metathesis for the construction of the quaternary stereogenic ce

Full text of DOI:10.1055/s-2005-862388

LETTER
664
Enantiocontrolled Synthesis of a Chiral Building Block via Diastereoselective
Ring-Closing Metathesis
Enantiocontrolled
uSynthesis of
r
a
Chiral
i
Building Blo
Mck urakami, Mitsuru Shindo, Kozo Shishido*
Graduate School of Pharmaceutical Sciences, The University of Tokushima, 1-78 Sho-machi, Tokushima 770-8505, Japan
Fax +81(88)6339575; E-mail: shishido@ph.tokushima-u.ac.jp
Received 7 December 2004
The cyclohexenol 4 would be converted into 5 via the
Abstract: An enantiocontrolled construction of a chiral building
Eschenmoser fragmentation reaction4 of the correspond-
ing epoxy ketone (Scheme 1).
block, which had been converted into an indole alkaloid (–)-eburna-
monine, has been accomplished using a diastereoselective ring-
closing metathesis for the construction of the quaternary stereogen-
ic center.
The optically active alcohol 3a, the substrate for the ring-
closing metathesis, was prepared from 6-(t-butyldimeth-
ylsilyl)oxy-2-hexyn-1-ol 7.5 Iodoalumination of 7 using
Key words: ring-closing metathesis, indole alkaloid, diastereose-
lective synthesis, asymmetric induction, fragmentation reaction
sodium bis(2-methoxyethoxy)aluminum hydride (Red-
Al®) and iodine gave 8, which was subjected to the Stille
coupling6 with tri-n-butylvinylstannane in the presence of
Pd2(dba)3·CHCl3 and triphenylphosphine to provide the
In our previous communication,1 we reported a strategy
for the construction of a quaternary stereogenic center on
a cyclohexenol ring by 1,4-asymmetric induction via dia-
stereoselective ring-closing metathesis (RCM) of 1 with
reasonably high diastereomeric excess (de), the product 2
of which was converted into (–)-aspidospermine2 as
shown in Scheme 1. We report herein an alternative appli-
cation of the strategy to the enantiocontrolled synthesis of
a chiral building block 5, which has been successfully em-
ployed in the synthesis of the indole alkaloid (–)-eburna-
monine (6).3 We envisioned transforming the optically
active triene alcohol 3 with a prochiral quaternary carbon
into 4 with higher de than that for 2, simply because the
alkoxyl moiety (OR2 in 3) is closer to the prochiral center.
diene 9 in 68% yield for the 2 steps. Vinylation followed
by reductive Claisen rearrangement of the resulting 10
with tri-i-butylaluminum7 produced the 3,3-disubstituted-
1,4-pentadiene 11, whose primary hydroxyl moiety was
then protected as t-butyldiphenylsilyl (TBDPS) ether to
provide 12. Selective deprotection of the TBS ether with
1 equivalent of trimethylchlorosilane and ethanol8 gave
13. Sequential Swern oxidation and Wittig reaction pro-
duced the ester 14 in good overall yield. Katsuki–Sharp-
less asymmetric epoxidation of the allyl alcohol, prepared
from the reduction of 14 with di-i-butylaluminum hydride
OH
TBSO
OR1
a–c
d–f
HO
quant.
TMSO
R2
TBSO
R1O
7
82% de
8: R1 = H, R2 = I
OTBDPSm
2
9: R1 = H, R2 = CH=CH2
10: R1 = R2 = CH=CH2
OTBDPS
2 1
2
CO2Et
(–)-aspidospermine
R1O
OR2
g,h
i,j
RCM
de?
R1O
11: R1 = TBS, R2 = H
12: R1 = TBS, R2 = TBDPS
13: R1 = H, R2 = TBDPS
OTBDPS
OR2
OR2
14
4
3
HO
O
k,l
3: R1 = H, R2 = TBDPS
O
MeO
HO2C
H
ref. 3
N
>99% ee (MTPA)
N
OTBDPS
15
O
5
Scheme 2 Reagents and conditions: a) Red-Al®, THF, r.t., 3.5 h
then I2, EtOAc, THF, r.t., h, 77%; b) CH2=CHSnBu3,
(–)-eburnamonine (6)
Scheme 1
2
Pd2(dba)3·CHCl3, Ph3P, DMF, r.t., 14 h, 88%; c) EtOCH=CH2,
Hg(OAc)2, 50 °C, 18 h, 84%; d) i-Bu3Al, CH2Cl2, r.t., 1 h, 88%; e)
TBDPSCl, imidazole, 4-DMAP, CH2Cl2, r.t., 15 min; f) TMSCl,
EtOH, r.t., 20 min, 94% for the 2 steps; g) (COCl)2, DMSO, Et3N,
CH2Cl2, r.t., 0.5 h, 95%; h) Ph3P=CHCO2Et, benzene, 80 °C, 1.5 h,
95%; i) i-Bu2AlH, THF, r.t., 10 min, 95%; j) (+)-DIPT, (i-PrO)4Ti,
TBHP, 4 Å MS, CH2Cl2, –25 °C, 10 h; k) I2, Ph3P, imidazole, ben-
zene, r.t., 20 min; l) Zn, HOAc, 50 °C, 2 h, 76% for the 3 steps.
SYNLETT 2005, No. 4, pp 0664–0666
Advanced online publication: 22.02.2005
DOI: 10.1055/s-2005-862388; Art ID: U33404ST
© Georg Thieme Verlag Stuttgart · New York
0
4.
0
3.
2
0
0
5

LETTER
Enantiocontrolled Synthesis of a Chiral Building Block
665
(DIBALH), provided the epoxyalcohol 15 with >99% ee
(from the MTPA ester). Iodination followed by reduction
with zinc in acetic acid produced the alcohol 3 (R1 = H,
R2 = TBDPS) in 72% yield for the 4 steps (Scheme 2).
TBSO
d
a–c
major diastereomer of
4a: R1 = H, R2 = TBDPS
CHO
17
TBSO
TBSO
e,f
With the triene substrate 3 in hand, we next examined the
RCM reaction using the Grubbs’ ruthenium carbene com-
plex 16 as a catalyst. Treatment of 3a–f9 in CH2Cl2 solu-
tion (0.02 M) with 5 mol% or 10 mol% of 16 at room
temperature gave the cyclized products 4a–f with good
OMe
OH
18
19
Scheme 3 Reagents and conditions: a) TBSCl, imidazole, 4-
DMAP, CH2Cl2, r.t., 40 min, 91%; b) n-Bu4NF, HOAc, THF, r.t., 6 h,
diastereoselectivity. The best selectivity was realized with 71%; c) Dess–Martin periodinane, CH2Cl2, r.t., 7 h, 90%; d)
Ph3P+CH2OMeCl–, t-BuOK, THF, r.t., 12 h; e) p-TsOH·H2O, THF,
r.t., 10 h; f) NaBH4, THF, r.t., 1 h, 62% for the 3 steps.
3d as the substrate to afford 4d (R1 = H, R2 = Bz), after
hydrolysis. In all cases, fortunately, the diastereomers
could be separated by simple column chromatography
(Table 1).
ing enone gave the epoxy ketone 20 as an inseparable
mixture of diastereoisomers, which was, after catalytic
hydrogenation, exposed to the conditions of the Eschen-
moser fragmentation reaction with 2,4,6-trimethylphenyl-
sulfonylhydrazine in ethanol at 0 °C12 to produce the
acetylenic aldehyde 21 in 76% yield. Deprotection and si-
multaneous acetalization was realized by brief treatment
of 21 with p-toluenesulfonic acid in methanol to give the
acetal 22. Finally, the acetylenic moiety was cleaved by
using ruthenium trichloride and sodium metaperiodate13
to produce the carboxylic acid 5, whose spectral proper-
ties were identical with those reported for compound 5
(Scheme 4).
Table 1 Ring-Closing Metathesis
PCy
3 Ph
Cl
Ru
Cl
PCy3
16
3a–f
4a–f
CH2Cl2, r.t., 48 h
Run R1 R2
16 (mol%)
Yield (%), (based dr
on recovered 3)
a
b
c
d
e
f
TMS
TBDPS 10
70 (90)a
27 (45)a
31 (70)a
30 (71)a
81 (98)
68 (88)
83:17
TMS
TMS
TMS
Bn
Ac
5
5
5
5
5
87:13
89:11
91:9
PNBz
Bz
O
O
c,d
a,b
4a
OTBDPS
TBDPS
83:17
82:18
20
MOM TBDPS
O
MeO
CHO
a After cleavage of TMS ether (R1 = H).
e,f
R
OTBDPS
21
22: R =
5: R = CO2H
C CH
To determine the absolute configuration at the newly
generated quaternary stereogenic center, we carried out
the 5-step transformation of the major diastereomer of 4a
(R1 = H, R2 = TBDPS)10 into compound 19, whose abso-
lute structure has been firmly established by our group.2
Sequential protection of the alcohol moiety as the TBS
ether, selective deprotection with tetra-n-butylammonium
fluoride and acetic acid11 and Dess–Martin oxidation gave
the aldehyde 17. The Wittig reaction afforded the enol
ether 18, which was hydrolyzed, and the resulting alde-
hyde was reduced with sodium borohydride to provide the
alcohol 19, whose spectral properties and the sign of
Scheme 4 Reagents and conditions: a) MnO2, acetone, r.t., 8 h,
97%; b) 30% H2O2, 5% NaOH, MeOH, r.t., 1 h, 99%; c) H2, 10% Pd-
C, MeOH, r.t., 10 min, 89%; d) 2,4,6-trimethylphenylsulfonylhydra-
zine, EtOH, 0 °C, 40 min, 76%; e) p-TsOH·H2O, MeOH, r.t., 1.5 h,
82%; f) RuCl3·nH2O, NaIO4, MeCN, CCl4, H2O, r.t., 5 min, 88%.
In summary, an enantiocontrolled synthesis of the chiral
building block for the indole alkaloid (–)-eburnamonine
has been accomplished using a diastereoselective ring-
closing metathesis for the construction of a quaternary
carbon stereogenic center and the Eschenmoser fragmen-
tation reaction as the key reaction steps. The present meth-
odology developed here can also be applied to the
synthesis of natural products with quaternary asymmetric
carbons.
26
26
optical rotation {[a]D –102.6 (c 0.4, CHCl3); lit.2 [a]D
–110.5 (c 1.3, CHCl3)} are identical with those for the
authentic material; thus the absolute configuration was
determined to be S and the diastereoselectivity of the
RCM reaction of 3 proved to be the same as for the homol-
ogous substrate 12 (Scheme 3).
Acknowledgment
For the transformation directed toward the key intermedi-
ate 5, we used the optically pure (1S,4S)-4a as starting ma-
terial because of its easy accessibility. Oxidation with
manganese dioxide followed by epoxidation of the result-
This work was supported financially by a Grant-in-Aid of Scientific
Research (A) (No.16209001) from the Japan Society for the Promo-
tion of Science.
Synlett 2005, No. 4, 664–666 © Thieme Stuttgart · New York

666
Y. Murakami et al.
LETTER
(9) The trienes 3a,e,f were prepared from 3 (R1 = H,
References
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Synlett 2005, No. 4, 664–666 © Thieme Stuttgart · New York