Synthetic studies towards gambierol. Part 1: Synthesis of the AB ring segment

Article abstract of DOI:10.1016/S0040-4039(01)01204-7

The AB ring segment of gambierol (1) was synthesized from 2-deoxy-D-ribose in 23 steps. The key steps were Brown's asymmetric allylboration of the aldehyde 5 and the intramolecular hetero-Michael reaction of 7.

Full text of DOI:10.1016/S0040-4039(01)01204-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 6195–6197
Synthetic studies towards gambierol. Part 1: Synthesis of the AB
ring segment
Isao Kadota,a Choul-Hong Park,b Kumi Satob 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 1 January 2001; revised 15 June 2001; accepted 6 July 2001
Abstract—The AB ring segment of gambierol (1) was synthesized from 2-deoxy-D-ribose in 23 steps. The key steps were Brown’s
asymmetric allylboration of the aldehyde 5 and the intramolecular hetero-Michael reaction of 7. © 2001 Elsevier Science Ltd. All
rights reserved.
Gambierol (1), which has a 6,6,6,6,7,6,6,7-polycyclic
ether skeleton including 18 stereocenters and a triene
side chain, was isolated from the cultured cells of
Gambierdiscus toxicus by Yasumoto in 1993.1 The com-
pound shows significant toxicity against mice (LD50 50
mg/kg), and the symptoms resemble those caused by
ciguatoxins inferring the possibility that it is also impli-
cated in ciguatera poisoning.2 In the course of our
Scheme 1.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01204-7

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I. Kadota et al. / Tetrahedron Letters 42 (2001) 6195–6197
synthetic effort towards gambierol, we synthesized the
AB ring segment in 1998,3 based on the absolute
stereochemistry proposed by Yasumoto and co-work-
ers in 1993.1 However, later on in 1999, they revised
the absolute stereochemistry;2 it is now believed to be
the opposite to that reported in 1993. Accordingly,
we undertook to synthesize the AB ring segment hav-
ing the correct absolute stereochemistry. Scheme 1
illustrates our new synthetic strategy for the conver-
gent synthesis of 1. The polycyclic ether framework
of 1 would be constructed from 2 via oxidation of
the CꢀC triple bond to an a-diketone, selective
removal of the TBS protective groups, and subse-
quent reductive cyclization of the resulting hydroxy
ketone.4 Retrosynthetic disassembly of the alkyne 2
based on a retro-acetylide–triflate coupling furnished
the AB ring segment 3 and the EFGH ring segment
4.5 In this paper, we wish to report the stereocon-
trolled synthesis of the natural AB ring segment 3 as
part of the total synthetic study of 1.
tection of the hydroxy group of 9 with TIPSOTf
followed by reduction of the ester group of 10 with
LiAlH4 gave the alcohol 11 in 94% yield. One carbon
elongation of the hydroxymethyl group of 11 was
achieved in the following way. Swern oxidation and
subsequent Wittig reaction of the resulting aldehyde
with Ph3PꢁCH2 gave the corresponding one carbon
elongated olefin, which was converted to the alcohol
12 through hydroboration in 85% yield. Benzyl pro-
tection of the hydroxy group of 12 followed by
removal of the benzylidene acetal using catalytic CSA
in MeOH furnished the diol 13 in 99% yield. Protec-
tion of 13 as a bis TBS ether followed by selective
deprotection of the primary silyloxy group gave 14 in
76% yield. Swern oxidation, Wittig reaction, and
hydroboration afforded the alcohol 15 in 72% yield.
Conversion of 15 to the alkyne 17 was performed by
oxidation with SO3·py/DMSO/Et3N, reaction with
CBr4/PPh3, followed by treatment of the resulting
dibromoolefin 16 with n-BuLi.10,11 The yield of 17
from 15 was 96%.
Protection of the known starting material 56 with
TBSCl followed by ozonolysis gave the aldehyde 6 in
99% yield (Scheme 2). Brown’s asymmetric allylbora-
tion of 6 using allyldiisopinocampheylborane derived
from (+)-pinene afforded the homoallylic alcohol 7 as
the sole product in 92% yield.7,8 Deprotection of the
silyloxy group of 7 using TBAF and ozonolysis fol-
lowed by Wittig reaction gave the a,b-unsaturated
ester 8 in 94% yield. The cyclization precursor 8 was
then subjected to an intramolecular hetero-Michael
reaction. Thus, treatment of 8 with 20 mol% of DBU
in refluxing toluene gave a 12:1 mixture of the desired
bicyclic compound 9 and its diastereoisomer in 78%
combined yield.9 The stereochemistry of the major
product 9 was unambiguously confirmed by NOE
experiments on the corresponding acetate derivative
as shown in Fig. 1.
In conclusion, the synthesis of the AB ring segment,
having absolute stereochemistry corresponding to nat-
ural gambierol 1, was achieved from 2-deoxy-D-
ribose. Brown’s asymmetric allylboration and the
intramolecular hetero-Michael reaction were success-
fully applied to the construction of the A ring moi-
ety.
We next examined the chain elongation and introduc-
tion of an alkynyl group as shown in Scheme 3. Pro-
Figure 1. Observed NOEs are shown by arrows.
Scheme 2. (a) (i) TBSOTf, 2,6-lutidine, CH2Cl2, 40°C, 100%; (ii) O3, CH2Cl2–MeOH, −78°C, then PPh3, −78°C to rt, 99% (two
d
steps); (b) Ipc2B-allyl, ether, −78°C; H2O2, NaOH, rt, 92%; (c) (i) TBAF, THF, rt, 100%; (ii) O3, CH2Cl2–MeOH, −78°C, then
PPh3, −78°C to rt, 99%; (iii) Ph3PꢁCHCO2Me, CH2Cl2, rt, 95%; (d) DBU, toluene, 110°C, 78% (92:8).

I. Kadota et al. / Tetrahedron Letters 42 (2001) 6195–6197
6197
Scheme 3. (a) TIPSOTf, 2,6-lutidine, DMF, 60°C, 98%; (b) LiAlH4, ether, 0°C, 96%; (c) (i) (COCl)2, DMSO, CH2Cl2, −78°C, then
Et3N, −78°C to rt; (ii) Ph3P+CH3Br−, NaHMDS, THF, 0°C, 90% (two steps); (iii) (c-Hex)2BH, 0°C, then 30% H2O2, 3N NaOH,
0°C to rt, 94%; (d) (i) BnBr, KH, THF, 60°C; (ii) CSA, MeOH, rt, 99% (two steps); (e) (i) TBSOTf, 2,6-lutidine, CH2Cl2, rt; (ii)
CSA, MeOH–CH2Cl2, rt, 76% (two steps); (f) (i) (COCl)2, DMSO, CH2Cl2, −78°C, then Et3N, −78°C to rt; (ii) Ph3P+CH3Br−,
NaHMDS, THF, 40°C, 97% (two steps); (iii) BH3·SMe2, 0°C, then 30% H2O2, 3N NaOH, 0°C to rt, 74%; (g) (i) SO3·py, DMSO,
Et3N, CH2Cl2, 0°C; (ii) CBr4, PPh3, CH2Cl2, 0°C, 97% (two steps); (h) n-BuLi, THF, −78°C, 99%.
7. Racherla, U. S.; Brown, H. C. J. Org. Chem. 1991, 56,
401–404.
Acknowledgements
8. The reaction with allylmagnesium bromide in THF gave
a 3:1 mixture of diastereoisomers. See Ref. 3.
9. For a recent example of the synthesis of cyclic ethers via
the intramolecular hetero-Michael reaction, see: Betan-
cort, J. M.; Mart´ın, V. S.; Padro´n, J. M.; Palazo´n, J. M.;
Ram´ırez, M. A.; Soler, M. A. J. Org. Chem. 1997, 62,
4570–4583 and references cited therein.
This work was financially supported by the Grant-in-
Aid for Scientific Research from the Ministry of Educa-
tion, Science and Culture of Japan.
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11. Compound 17: colorless oil; [h]2D4 +49.0 (c 0.50, CHCl3);
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;
(300 MHz, CDCl3): l 7.35–7.22 (m, 5H), 4.48 (s, 2H),
3.91 (s, 1H), 3.83 (m, 1H), 3.76 (dd, J=12.1, 4.2 Hz, 1H),
3.46 (m, 3H), 2.45 (dd, J=16.3, 2.8 Hz, 1H), 2.45 (dd,
J=16.3, 2.8 Hz, 1H), 2.10 (d, J=16.2 Hz, 1H), 1.90 (t,
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3H), 1.10–0.95 (s, 21H), 0.85 (s, 9H), 0.08 (s, 3H), 0.05 (s,
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.