Studies on the total synthesis of methyl sartortuoate construction of the 2,3,3,6-tetrasubstituted D-ring segment

Article abstract of DOI:10.1016/S0040-4039(00)00608-0

An asymmetric synthesis of the 2,3,3,6-tetrasubstituted D-ring segment of methyl sartortuoate including four stereogenic centers is described. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00608-0

Tetrahedron Letters 41 (2000) 4811±4813
Studies on the total synthesis of methyl sartortuoate
construction of the 2,3,3,6-tetrasubstituted D-ring segment
Yuan Gao, Fajun Nan and Xingxiang Xu*
Shanghai Institute of Organic Chemistry, Academia Sinica, 354 Fenglin Rd, Shanghai 200032, China
Received 17 February 2000; accepted 10 April 2000
Abstract
An asymmetric synthesis of the 2,3,3,6-tetrasubstituted D-ring segment of methyl sartortuoate including
four stereogenic centers is described. # 2000 Elsevier Science Ltd. All rights reserved.
Keywords: methyl sartortuoate; cembrenoids; Diels±Alder reaction.
Methyl sartortuoate (1) is a tetracyclic tetraterpenoid isolated from the sarcophyton tortuosum
tixier-durivault by Su et al.1 The novelty and challenge of its structure as well as the potential
bioactivity attracted our attention and led us towards the total synthesis. Bisected from the
B-ring, the molecule could be regarded as a Diels±Alder combination of two cembrenoids, i.e. the
dienophilic A ring unit and the diene C, D ring unit (Scheme 1). As part of our synthetic studies
on the 14-membered diene unit (2), we wish to describe herein the preparation of the 2,3,3,6-
tetrasubstituted D-ring segment (14).
Scheme 1.
* Corresponding author.
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00608-0

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Based on a retrosynthesis, it was thought that compound 3, as a precursor of the D-ring, could
be prepared by the coupling of an epoxy alcohol with a sulfone-stabilized allylic anion as developed
by Marshall et al.2 Therefore, di€erent epoxides and sulfones were prepared to evaluate this
approach. As shown in Scheme 2, compound 4 was obtained from geraniol in four steps, 5 from
d-mannitol in eight steps and 6 from 3-methyl-2-buten-1-ol in one step.3
Scheme 2.
The coupling of 4a with 5 was carried out following Marshall's procedure.2 Compound 4a was
treated with 1 equiv. EtMgBr prior to the addition of the lithium derivative of 5,4 and the desired
diol 7 was produced in 46% yield with 34% of the recovered starting materials. After 7 was
converted into 8, epoxidation of 8 using VO(acac)2/TBHP and treatment of the resultant epoxide
with anhydrous K2CO3 in MeOH gave a single product 9a. 1H NMR did not distinguish possible
®ve- and six-membered ring structures, but exposure of 9a to Ac2O/Py at rt yielded a diacetyl
product 9b, which suggested that 5-exo epoxide-opening had taken place using the tertiary
hydroxyl group to give the undesired tetrahydrofuran containing product (Scheme 3).
Scheme 3. Reagents and conditions: (a) 1 equiv. EtMgBr, THF/HMPA, ^78ꢀC, 15 min, then 1 equiv. BuLi, ^78ꢀC, 6
h, 46%; (b) 6% Na/Hg, Na2HPO4, THF/MeOH, ^78ꢀC±rt, 80%; (c) triphosgene, NEt3, CH2Cl2, 95%; (d) TBAF, rt,
90%; (e) (1) cat. VO(acac)2, 1 equiv. TBHP, CH2Cl2, 0ꢀC, 1 h; (2) K2CO3, MeOH, rt, 18 h, 41% for two steps; (f) Ac2O,
pyridine, rt overnight, 87%
It is well known that nucleophilic epoxide-opening reactions can be accelerated by Lewis-acid
catalysis. In order to raise the coupling eciency, we attempted to ®nd an approach which could
change Marshall's intramolecular catalysis into an intermolecular process. After examination of
various reagents, triethylsilyl was chosen to protect the hydroxyl group of 4b, and the coupling
of 4c and 6 was executed by using n-BuLi as the base and BF3Et2O as the Lewis acid at ^78ꢀC.
The desired product 10 was obtained in 91% yield without recovery of the starting materials.
After desulfonylation and protection of the tertiary hydroxyl group, selective allylic oxidation5
with SeO2/TBHP a€orded the allylic alcohol 11. Sharpless AE of 11 smoothly produced the
required epoxy alcohol 12 in 92% yield, then selective desilylation and treatment with Ti(OPri)4
in re¯uxing benzene gave the desired tetrasubstituted D-ring segment 14 in 85% yield.6
Alternatively, the TES ether was removed ®rst, then Sharpless AE a€orded the same compound
14 in 82% yield7 (Scheme 4).

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Scheme 4. Reagents and conditions: (a) 1 equiv. BuLi, 1 equiv. BF3Et2O, THF, ^78ꢀC, 2 h, 92%; (b) (1) 6% Na/Hg,
Na2HPO4, THF/MeOH, ^78ꢀC±rt; (2) MOMCl, DIPEA, CH2Cl2, 0ꢀC±rt, overnight; (3) 0.5 equiv. SeO2, 3 equiv.
TBHP, CH2Cl2, 10ꢀC, 3 h, 25% for three steps; (c) cat. d-(^)-DIPT, Ti(OiPr)4, CH2Cl2, 1 equiv. TBHP, ^25ꢀC, 92%;
(d) PPTS, MeOH/H2O, overnight, 95%; (e) Ti(OiPr)4, benzene, re¯ux, 1 h, 89%; (f) 1.2 equiv. d-(^)-DIPT, 1.1 equiv.
Ti(OiPr)4, CH2Cl2, 1.2 equiv. TBHP, ^25ꢀC, overnight, 82%
In conclusion, we have successfully constructed the 2,3,3,6-tetrasubstituted D-ring segment 14
of methyl sartortuoate and established four stereogenic centers. Further work towards the 14-
membered diene unit 2 is underway in this laboratory.
Acknowledgements
We are grateful to the Academy of Sciences and National Natural Science Foundation of
China for their ®nancial support (No. 29572079).
References
1. Su, J.; Long, K.; Pang, T.; He, C.; Jon, C. J. Am. Chem. Soc. 1986, 108, 177. Su, J.; Long, K.; Pang, T.; Zeng, L.;
Zheng, L.; Zheng, Q.; Lin, X. Scientia Sinica, Ser. B. 1988, 31, 1172.
2. Marshall, J. A.; Jenson, T. M.; Deho€, B. S. J. Org. Chem. 1987, 52, 3860. Marshall, J. A.; Andrews, R. C. J. Org.
Chem. 1985, 50, 1602.
3. Terrao, T.; Shiraishi, M.; Kato, K. Synthesis 1979, 467. Mulzer, J.; Angermann, A. Tetrahedron Lett. 1983, 24,
2843. Kanai, T.; Kanagawa, Y.; Ishii, Y. J. Org. Chem. 1990, 55, 3274.
4. For the segments 5a and 5b, ees exceed 90%.
5. Umbreit, M. A.; Sharpless, K. B. J. Am. Chem. Soc. 1977, 5526.
6. Morgans, D. J.; Sharpless, K. B. J. Am. Chem. Soc. 1981, 103, 462.
7. Evens, D. A.; Bender, S. L.; Morrid, J. J. Am. Chem. Soc. 1988, 110, 2506. Data for 14: H NMR ꢀ (300 MHz,
1
CDCl3), 7.72 (m, 4H), 7.47 (m, 6H), 5.41 (t, J=6.3 Hz, 1H), 4.76 (d, J=7.4 Hz, 1H), 4.72 (d, J=7.4 Hz, 1H), 4.23
(d, J=6.3 Hz, 2H), 3.78 (d, J=10.7 Hz, 1H), 3.29±3.45 (m, 5H), 3.18 (d, J=10.7 Hz, 1H), 1.58±1.91 (m, 6H), 1.45
(s, 3H), 1.25±1.45 (m, 2H), 1.30 (s, 3H), 1.10 (s, 3H), 1.05 (s, 9H).