Synthesis of the J ring segment of gambieric acid

Article abstract of DOI:10.1016/S0040-4039(01)00530-5

The J ring segment 2 of gambieric acid was synthesized stereoselectively by the coupling between the cyclic ether component 3 and the alkenyl iodide 4. The tetrahydropyran 3 was stereoselectively synthesized by the 6-endo-cyclization of a hydroxyepoxide prepared from deoxy-D-ribose. The side chain moiety 4 was prepared by the stereoselective hydrostannation of an internal alkyne.

Full text of DOI:10.1016/S0040-4039(01)00530-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 3649–3651
Synthesis of the J ring segment of gambieric acid
Isao Kadota,a Hiroyoshi Takamurab and Yoshinori Yamamotob,*
aResearch Center for Organic Resources and Material Chemistry, Institute for Chemical Reaction Science, Tohoku University,
Sendai 980-8578, Japan
bDepartment of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan
Received 13 March 2001; accepted 21 March 2001
Abstract—The J ring segment 2 of gambieric acid was synthesized stereoselectively by the coupling between the cyclic ether
component 3 and the alkenyl iodide 4. The tetrahydropyran 3 was stereoselectively synthesized by the 6-endo-cyclization of a
hydroxyepoxide prepared from deoxy-D-ribose. The side chain moiety 4 was prepared by the stereoselective hydrostannation of
an internal alkyne. © 2001 Elsevier Science Ltd. All rights reserved.
In the preceding paper,1 we described the stereoselective
synthesis of the A ring segment of gambieric acid (1).
We now report the synthesis of the J ring segment of 1.
tion of the TBS protective group of 6 (97%) followed
by the acid catalyzed 6-endo-cyclization of the resulting
hydroxyepoxide 7 afforded the tetrahydropyran 8 as
Me
H
H
Me Me
H
F
O
O
C
H
O Me
OH
H
HO
HO
E
B
D
O
G
O
Me
H
O
H
H
O H
H
H
H
A
H
H O
I
O
H
H
J
H
HO2C
Me O
Me
Me
H
Me
Gambieric acid A (1)
OH
Scheme 1 describes our synthetic strategy. The target
molecule 2 is broken down to the alcohol 3 and the
vinylic iodide 4. The tetrahydropyran ring of 3 can be
constructed by the stereoselective 6-endo cyclization of
a hydroxyepoxide. The olefin 4 can be prepared by
the stereoselective hydrostannation of an internal
alkyne.
the sole product in 78% yield.3 Hydrogenation of the
unsaturated ester 8 gave 9 in 95% yield. The ester 9 was
reduced with LiAlH4 to give the diol 10 in 91% yield.
Protection of 10 using BnBr/KH gave the bis-benzyl
ether 11 in 90% yield. The benzylidene acetal of 11 was
cleaved by acidic treatment to give the diol 12 in 91%
yield. Protection of 12 with TBSCl gave the bis-silyl
ether 13 in 96% yield. Selective deprotection of the
primary silyloxy group of 13 was carried out using a
catalytic amount of CSA in CH2Cl2–MeOH to give the
alcohol 3 in 92% yield.
A Wittig reaction of the aldehyde 5, prepared from
deoxy-
-ribose by the known procedure,2 gave the a,b-
D
unsaturated ester 6 in 89% yield (Scheme 2). Deprotec-
H
H
H
H
BnO
OTBS
BnO
OTBS
OH
+
OTBDPS
OTBDPS
BnO
BnO
I
O
O
Me
H
Me
H
4
3
2
Scheme 1. Retrosynthesis of the J ring segment 2.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00530-5

3650
I. Kadota et al. / Tetrahedron Letters 42 (2001) 3649–3651
H
H
H
O
Ph
O
Ph
O
Ph
a
b
O
O
O
O
O
O
OHC
MeO2C
MeO2C
OTBS
OTBS
OH
5
6
7
H
H
H
H
O
HO
O
Ph
HO
Ph
c
d
e
O
O
MeO2C
O
MeO2C
BnO
O
Me
H
Me
H
8
9
H
H
H
H
H
H
HO
O
Ph
O
Ph
f
g
O
HO
O
BnO
O
O
Me
10
Me
11
H
H
H
H
BnO
OH
OH
BnO
OTBS
OTBS
h
i
3
BnO
BnO
O
O
Me
H
Me
13
H
12
Scheme 2. (a) Ph3PꢀCHCO2Me, cat. PhCO2H, benzene, rt, 89%; (b) TBAF, THF, rt, 97%; (c) cat. PPTS, CH2Cl2, rt, 78%; (d)
H2, cat. 5% Pd–C, MeOH, rt, 95%; (e) LiAlH4, ether, 0°C, 91%; (f) BnBr, KH, THF, 0°C, 90%; (g) cat. CSA, CH2Cl2–MeOH,
rt, 91%; (h) TBSCl, imidazole, DMF, 70°C, 96%; (i) cat. CSA, CH2Cl2–MeOH, 0°C, 92%.
Scheme 3 summarizes the preparation of the side chain
moiety 4. Protection of the chiral alcohol 14 with
TBDPSCl gave 15 in quantitative yield. Reduction of
the ester 15 with DIBALH gave the aldehyde 16 in 96%
yield. Dibromomethylenation of 16 was carried out
with CBr4/PPh3 to give 17 in 90% yield. Treatment of
17 with n-BuLi followed by trapping with MeI gave the
internal alkyne 18 in 84% yield.4 Regio- and stereoselec-
tive hydrostannation of 18 was performed by using
palladium catalyst to give the vinylsyannane 19,5 which
was treated with iodine to give the vinyliodide 4 in 56%
yield.
Next, we examined the SN2 alkylation of the triflate 20
prepared from 3 with the vinylmetals derived from 4
according to the reported procedure (Scheme 4).6 How-
ever, the desired coupling product 2 was not obtained
from these reactions. The less nucleophilic reagents 21
acted as a base to decompose the reactive triflate 20.
An alternative synthetic route to 2, based on the addi-
tion of 21 to an aldehyde followed by Barton reduc-
tion,7 is described in Scheme 5. The alcohol 3 was
converted to the aldehyde 22 by Swern oxidation. Reac-
tion of 22 with the vinyllithium reagent 21 afforded the
a
b
OH
OTBDPS
OTBDPS
MeO2C
MeO2C
OHC
14
15
16
Br
d
e
c
OTBDPS
OTBDPS
Br
17
18
f
OTBDPS
OTBDPS
Bu3Sn
I
19
4
Scheme 3. (a) TBDPSCl, imidazole, DMF, rt, 100%.; (b) DIBALH, CH2Cl2, −90°C, 96%.; (c) CBr4, PPh3, CH2Cl2, 0°C, 90%; (d)
n-BuLi, THF, −78°C; MeI, −78°C to rt, 84%; (e) Bu3SnH, cat. PdCl2(PPh3)2, CH2Cl2, rt; (f) I2, benzene, rt, 56% from 18.

I. Kadota et al. / Tetrahedron Letters 42 (2001) 3649–3651
3651
H
H
H
OTBDPS
H
H
H
M
BnO
OTBS
OTf
BnO
OTBS
21
BnO
OTBDPS
BnO
O
O
Me
20
Me
M = Li, Cu
2
Scheme 4.
H
H
H
H
H
BnO
OTBS
BnO
OTBS
OH
a
b
3
BnO
OTBDPS
BnO
O
CHO
O
Me
22
Me
H
23
H
H
BnO
OTBS
d
c
2
OTBDPS
BnO
O
Me
H
O
SMe
24
S
Scheme 5. (a) (COCl)2, DMSO, CH2Cl2, −78°C; Et3N, −78°C to rt, 89%; (b) 4, t-BuLi, ether, −78°C, 76%; (c) CS2, KH, ether,
rt; MeI, rt, 98%; (d) Bu3SnH, cat. AIBN, benzene, reflux, 25%.
addition product 23 as a mixture of diastereoisomers in
76% yield. Treatment of 23 with CS2/KH, followed by
the reaction with MeI gave the xanthate 24 in 98%
yield. Hydrogenolysis of 24 was carried out with
Bu3SnH and a catalytic amount of AIBN in refluxing
benzene to give 2 in 25% yield.8
References
1. Kadota, I.; Oguro, N.; Yamamoto, Y. Tetrahedron Lett.
2001, 42, 3645–3647.
2. Nicolaou, K. C.; Nugiel, D. A.; Couladouros, E.; Hwang,
C.-K. Tetrahedron 1990, 46, 4517–4552.
3. Nicolaou, K. C.; Prasad, C. V. C.; Somers, P. K.; Hwang,
C.-K. J. Am. Chem. Soc. 1989, 111, 5330–5334.
4. Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 3769–
3772.
In conclusion, we have reported the synthesis of the
A and J ring segments of gambieric acid in this and
the preceding paper. Further studies toward the total
synthesis of gambieric acid are in progress in our
laboratories.
5. Zhang, H. X.; Guibe´, F.; Balavoine, G. J. Org. Chem.
1990, 55, 1857–1867.
6. (a) Kotsuki, H.; Kadota, I.; Ochi, M. Tetrahedron Lett.
1989, 30, 1281–1284; (b) Kotsuki, H.; Kadota, I.; Ochi, M.
Tetrahedron Lett. 1990, 31, 4609–4612.
Acknowledgements
7. Martin, S. F.; Daniel, D.; Cherney, R. J.; Liras, S. J. Org.
Chem. 1992, 57, 2523–2525.
8. The reaction gave the olefinic isomers 25 (22%) and the
dithiocarbonates 26 (14%) as by-products. Similar rear-
rangement in the hydrogenolysis of allylic xanthates has
been reported, see Ref. 7.
This work was financially supported by the Grant-in-
Aid for Scientific Research from the Ministry of Educa-
tion, Science and Culture of Japan.
H
H
H
H
BnO
OTBS
BnO
OTBS
OTBDPS
OTBDPS
SMe
BnO
BnO
O
O
Me
H
Me
H
S
25 (22%)
26 (14%)
O
.
.