Synthetic studies towards gambierol. Part 2: Synthesis of the EFGH ring segment

Article abstract of DOI:10.1016/S0040-4039(01)01205-9

The EFGH ring segment of gambierol was synthesized from 2-deoxy-D-ribose in 40 steps. The present synthesis includes a SmI₂-mediated reductive cyclization and a Pd-catalyzed coupling of enol triflate with a zinc bis-homoenolate as key steps.

Full text of DOI:10.1016/S0040-4039(01)01205-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 6199–6202
Synthetic studies towards gambierol. Part 2: Synthesis of the
EFGH ring segment
Isao Kadota,a Chie Kadowaki,b Hiroyoshi Takamurab and Yoshinori Yamamotob,*
aResearch Center for Sustainable Materials Engineering, Institute of Multidisciplinary Research for Advanced Materials,
Tohoku University, Sendai 980-8578, Japan
bDepartment of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan
Received 24 May 2001; accepted 5 July 2001
Abstract—The EFGH ring segment of gambierol was synthesized from 2-deoxy-D-ribose in 40 steps. The present synthesis
includes a SmI2-mediated reductive cyclization and a Pd-catalyzed coupling of enol triflate with a zinc bis-homoenolate as key
steps. © 2001 Elsevier Science Ltd. All rights reserved.
In the preceding paper, we described the synthesis of
the AB ring segment of gambierol.1 We next examined
the synthesis of the EFGH ring segment.2
by the Nakata protocol.7 Thus, treatment of the alcohol
9 with ethyl propiolate and 4-methylmorphorine gave
the acrylate 10, which was then subjected to the SmI2-
mediated reductive cyclization to give the bicycle 11 as
a single stereoisomer in 97% yield.
Scheme 1 describes the synthesis of the EF ring seg-
ment. The starting material 1,3 derived from 2-deoxy-
D-
ribose, was converted into
2 in 67% yield by
Construction of the EFGH ring system is illustrated in
Scheme 2. Protection of the hydroxy group of 11 with
TMS-imidazole followed by reduction of the ester with
LiAlH4 gave the alcohol 12 in quantitative yield. Swern
oxidation of 12 followed by Wittig reaction gave the
enol ether 13 in 64% yield. After hydrolysis, the result-
ing aldehyde was oxidized to the corresponding
hydroxy carboxylic acid, which was allowed to cyclize
under Yamaguchi conditions to give 14 in 74% yield.8
Treatment of the lactone 14 with PhNTf2 and KHMDS
gave the corresponding ketene acetal triflate,9 which
was allowed to react with IZn(CH2)3CO2Et in the pres-
ence of Pd(PPh3)4 to afford 15 in 87% yield.10–12 Unfor-
tunately, hydroboration of the enol ether 15 gave the
undesired stereoisomer 16 as the sole product, although
the yield was quantitative. Stereoisomerization of 16
was performed by the following steps; Dess–Martin
oxidation13 of 16 followed by treatment with DBU gave
17 in 64% yield, and then reduction of the ketone 17
with NaBH4 gave the desired alcohol 18 as a single
stereoisomer in 98% yield. Hydrolysis of the ester fol-
lowed by Yamaguchi lactonization gave the EFGH ring
segment 19 in 76% yield.14 The stereochemistry of 19
was unambiguously confirmed by 1H NMR analysis
and NOE experiments as illustrated in Fig. 1.
hydrogenation, Swern oxidation, methylation, hydroly-
sis, and Yamaguchi lactonization.4 The lactone 2 was
treated with PhNTf2 and KHMDS to give the corre-
sponding enol triflate,5 which was subjected to the
palladium-catalyzed carbonylation to give 3 in 90%
yield.6 DIBALH reduction of the ester 3 followed by
MPM protection gave 4 in 99% yield. Hydroboration
of the enol ether 4 with BH3·SMe2 gave a 3:2 mixture of
the desired alcohol 5 and its stereoisomer 6 in 89%
yield. Protection of 5 with MPMCl, hydrolysis of the
benzylidene acetal, protection of the resulting diol as a
bis-TBS ether, and selective removal of the primary
TBS group afforded 7 in 57% yield. One carbon elonga-
tion of the hydroxymethyl group of 7 was achieved by
Swern oxidation and subsequent Wittig reaction of the
resulting aldehyde followed by hydroboration to give
alcohol 8 in 77% yield. Swern oxidation followed by the
addition of MeMgBr to the resulting aldehyde gave the
corresponding methyl carbinol, which was oxidized
under Swern conditions, giving the methyl ketone 9
upon desilylation, in 66% yield. Construction of the F
ring including 1,3-diaxial methyl groups was carried out
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01205-9

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I. Kadota et al. / Tetrahedron Letters 42 (2001) 6199–6202
H
H
H
H
O
Ph
O
Ph
O
Ph
a
b
MeO2C
O
O
O
HO
O
O
Me
Me
c
O
MeO2C
3
1
2
H
H
H
O
Ph
O
Ph
O
Ph
H
H
d
HO
HO
MPMO
+
O
O
O
H
O
O
O
H
Me
e
Me
Me
MPMO
H
H
MPMO
5
6
4
H
H
OTBS
OH
OTBS
OH
H
H
g
f
MPMO
MPMO
MPMO
MPMO
MPMO
OH
O
H
O
H
O
Me
h
O
Me
Me
MPMO
H
7
8
9
H
H
H
O
F
O
H
H
CO2Et
CO2Et
i
MPMO
MPMO
MPMO
MPMO
E
OH
O
H
O
H
Me Me
Me
O
11
10
Scheme 1. (a) (i) H2, 5% Pd–C, EtOAc, 98%; (ii) (COCl)2, DMSO, CH2Cl2, −78°C, then Et3N, −78°C to rt; (iii) Me3Al, CH2Cl2,
−20°C, 70% (two steps); (iv) LiOH, THF/H2O, rt, 100%; (v) 2,4,6-trichlorobenzoyl chloride, Et3N, THF, rt, then DMAP, benzene,
rt, 98%; (b) (i) PhNTf2, KHMDS, HMPA, THF, −78°C; (ii) CO, Et3N, Pd(PPh3)4, MeOH, rt, 90% (two steps); (c) (i) DIBALH,
CH2Cl2, −78°C, 99%; (ii) MPMCl, KH, THF, 0°C to rt, 100%; (d) BH3·SMe2, THF, 0°C to rt, then 30% H2O2, 3N NaOH, 0°C,
53% for 5, 36% for 6; (e) (i) MPMCl, KH, THF, 0°C to rt, 77%; (ii) CSA, CH2Cl2/MeOH, rt, 84%; (iii) TBSOTf, 2,6-lutidine,
CH2Cl2, 0°C to rt, 96%; (iv) CSA, CH2Cl2/MeOH, 0°C, 91%; (f) (i) (COCl)2, DMSO, CH2Cl2, −78°C, then Et3N, −78°C to rt,
95%; (ii) Ph3P+CH3Br−, NaHMDS, THF, 0 to rt, 96%; (iii) (c-Hex)2BH, 0°C, then H2O2, 3N NaOH, 0°C, 84%; (g) (i) (COCl)2,
DMSO, CH2Cl2, −78°C, then Et3N, −78°C to rt, 86%; (ii) MeMgI, ether, 0°C; (iii) (COCl)2, DMSO, CH2Cl2, −78°C, then Et3N,
−78°C to rt, 89% (two steps); (iv) TBAF, THF, rt, 86%; (h) ethyl propiolate, 4-methylmorphorine, CH2Cl2, rt, 100%; (i) SmI2,
MeOH, THF, 0°C, 97%.
We should mention the difficulties we encountered on
introducing the two bridgehead methyl groups of the
EFGH ring segment. We attempted to install a
methyl group by the reaction of an acetal with
organometals such as Me2Zn15 and Me3Al16 in the
presence of a variety of Lewis acids, but all attempts
resulted in failure. Finally, the SmI2 and palladium
methods enabled us to synthesize the EFGH ring seg-
ment, relatively easily.
In conclusion, the synthesis of the EFGH ring seg-
ment of gambierol was achieved in 40 steps from
2-deoxy-D-ribose in 1.9% total yield. The SmI2-medi-
ated reductive cyclization was successfully applied to
the construction of the EF ring bearing two 1,3-diax-
ial methyl groups. The palladium-catalyzed coupling
of enol triflate and zinc bis-homoenolate was very
effective and efficient for synthesizing the GH ring
moiety. Further studies toward the total synthesis of
gambierol are now in progress in our laboratories.
3%
H
H
H
Acknowledgements
H
O
O
O
MPMO
MPMO
O
O
Me
Me
H
This work was financially supported by the Hayashi
Memorial Foundation for Female Natural Scientists
and the Grant-in-Aid for Scientific Research from
the Ministry of Education, Science and Culture of
Japan.
H
19
4%
16%
13%
Figure 1. Observed NOEs are shown by arrows.

I. Kadota et al. / Tetrahedron Letters 42 (2001) 6199–6202
6201
H
H
H
H
O
OH
OTMS
O
H
H
OMe
b
a
MPMO
MPMO
MPMO
MPMO
11
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H
O
H
Me Me
Me Me
13
12
c
H
H
H
H
O
CO2Et
O
H
H
H
d
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MPMO
MPMO
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O
O
O
H
O
Me Me
Me Me
MPMO
H
15
14
e
H
H
H
H
H
O
OH CO2Et
O
O
CO2Et
H
f
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MPMO
MPMO
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O
O
H
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H
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H
Me Me
H
MPMO
17
16
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O
H
H
H
H
H
H
H
H
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O
F
O
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H
H
h
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MPMO
MPMO
MPMO
E
G
O
H
O
O
H
O
H
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Me Me
18
19
Scheme 2. (a) (i) TMS-imidazole, CH2Cl2, rt; (ii) LiAlH4, ether, 0°C, 100% (two steps). (b) (i) SO3·py, DMSO, Et3N, CH2Cl2, rt,
87%; (ii) Ph3P+CH2OMeCl−, NaHMDS, THF, −78°C to rt, 74%; (c) (i) CSA, CH3CN/H2O, rt, 83%; (ii) NaClO2, 2-methyl-2-
butene, NaH2PO4, t-BuOH/H2O, rt; (iii) 2,4,6-trichlorobenzoyl chloride, Et3N, THF, rt, then DMAP, benzene, rt, 89% (two
steps); (d) (i) PhNTf2, KHMDS, HMPA, THF, −78°C; (ii) IZn(CH2)3CO2Et, Pd(PPh3)4, benzene, rt, 87% (two steps); (e)
BH3·SMe2, THF, 0°C, then 30% H2O2, satd NaHCO3, 94%; (f) (i) Dess–Martin periodinane, NaHCO3, CH2Cl2, rt; (ii) DBU,
toluene, rt, 64% (two steps); (g) NaBH4, CH2Cl2/MeOH, −78°C, 98%; (h) (i) LiOH, THF/H2O, 40°C; (ii) 2,4,6-trichlorobenzoyl
chloride, Et3N, THF, rt, then DMAP, benzene, rt, 76% (two steps).
Yamaguchi, M. Bull. Chem. Soc. Jpn. 1979, 52, 1989–
1993.
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CH2Cl2, 2:1); Rf=0.26 (hexane/EtOAc, 1:1); [h]2D5=−
31.2 (c 0.99, CHCl3); IR (KBr) 2941, 1755, 1514, 1109
cm−1 1H NMR (300 MHz, CDCl3): l 7.22 (d, J=8.6
;
Hz, 2H), 7.19 (d, J=8.6 Hz, 2H), 6.86 (d, J=8.6 Hz,
2H), 6.83 (d, J=8.6 Hz, 2H), 4.47 (s, 2H), 4.43 (d,
J=11.8 Hz, 1H), 4.36 (d, J=11.8 Hz, 1H), 4.13 (ddd,
J=10.4, 10.4, 5.1 Hz, 1H), 4.00 (bs, 1H), 3.80 (s, 3H),
3.79 (s, 3H), 3.68 (bs, 1H), 3.61 (ddd, J=9.3, 9.3, 3.3
Hz, 1H), 3.42 (dd, J=9.8, 5.0 Hz, 1H), 3.29 (dd, J=
8. Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.;

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I. Kadota et al. / Tetrahedron Letters 42 (2001) 6199–6202
9.7, 6.3 Hz, 1H), 3.19 (dd, J=11.8, 3.3 Hz, 1H), 3.13
34.4, 30.7, 25.4, 23.3, 20.6, 17.0, 16.6; HRMS (EI)
calcd for C27H37O8 (M−C8H9O) 489.2488, found
489.2499.
(dd, J=13.2, 3.5 Hz, 1H), 2.68 (dd, J=13.5, 7.0 Hz,
1H), 2.55 (dd, J=13.6, 13.6 Hz, 1H), 2.32–1.45 (m,
12H), 1.47 (s, 3H), 1.29 (s, 3H); 13C NMR (75 MHz,
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l 174.4, 159.1, 159.0, 130.6, 130.5, 129.2,
G. Tetrahedron 1987, 28, 6339–6342.
128.9, 113.7, 113.7, 88.8, 79.7, 78.2, 77.8, 76.4,
75.8, 73.0, 72.4, 71.9, 70.4, 70.1, 55.2, 53.4, 36.0,
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.