Studies towards the total synthesis of methyl isosartortuoate: Enantioselective synthesis of a precursor of the macrocycle

Article abstract of DOI:10.1016/S0040-4039(00)00607-9

A concise synthesis of a precursor of dienyl cembranoids starting from geraniol is reported. All of the four chiral centers in the dienyl unit were established by Sharpless kinetic resolution, asymmetric epoxidation and dihydroxylation. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00607-9

Tetrahedron Letters 41 (2000) 4641±4644
Studies towards the total synthesis of methyl isosartortuoate:
enantioselective synthesis of a precursor of the macrocycle
Xibin Liao and Xingxiang Xu*
Shanghai Institute of Organic Chemistry, Academia sinica, 354 Fenglin Lu, Shanghai 200032, China
Received 19 January 2000; accepted 10 April 2000
Abstract
A concise synthesis of a precursor of dienyl cembranoids starting from geraniol is reported. All of the
four chiral centers in the dienyl unit were established by Sharpless kinetic resolution, asymmetric epoxi-
dation and dihydroxylation. # 2000 Elsevier Science Ltd. All rights reserved.
Methyl isosartortuoate 1 is the ®rst tetraterpenoid of this structural type isolated by Chinese
scientists from Sarcophton Tortuosum Tixier±Durivanlt collected in the South China Sea.1 A
plausible biogenesis would involve generation of the cyclohexene ring by a Diels±Alder reaction
of two cembrenes2 (the dienophile 2 and diene 3 shown in Scheme 1), even though these cem-
brenes have not been isolated. This interesting possibility as well as the unusual architectural
features of methyl isosartortuoate prompted us to initiate a research project aimed at its total
synthesis.
Our retrosynthesis is shown in Scheme 1. Although carbocyclization has been successfully
employed in several total syntheses,3 we chose to employ a [2,3] Wittig ring contraction of the 17-
membered cyclic propargyl allylic ether 5 which should lead to the 14-membered carbocyclic
nucleus 4. Herein, we describe a stereoselective synthesis of the precursor 6, in which all of the
chiral centers in the diene unit have been established.
The synthetic work ®rst focused on the construction of the chiral THF ring by two Sharpless
AE reactions followed by an intramolecular epoxide-opening process (Scheme 2). The commercially
available geraniol was ®rst converted into the secondary allylic alcohol 7,4 then Sharpless kinetic
resolution5 of 7 provided an optically active terminal epoxyalcohol 8 in 40% yield and 94% ee.
After protection of the hydroxyl group of 8 with ethyl vinyl ether, subsequent opening of the
6
.
terminal epoxide with the lithium salt of propargyl-O-THP ether in the presence of BF3 Et2O at
^78ꢀC gave 10 in 60% yield. Protection of the resulting hydroxyl group with MOM ether,
deprotection of the primary alcohol with accompanying a hydrolysis of the EE group and an
* Corresponding author.
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00607-9

4642
Scheme 1.
Schꢀeme 2. Reagents: (a) L-(+)-DIPT, 4 A MS, Ti(i-PrO)4, TBHP, ^20ꢀC(56%); (b) i, PPTS, ethyl vinyl ether; ii, BuLi,
.
^78 C, THP-O-CH2CCH, BF3 Et2O(62%); (c) i, MOMCl, i-Pr2NEt; ii, PTS, CH3OH; iii, LiAlH4 in ether,
re¯ux(68%); (d) D-(^)-DIPT, Ti(i-PrO)4, TBHP, ^20ꢀC (99%)

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E-selective reduction of the alkyne a€orded the desired allylic alcohol 11. Sharpless asymmetric
epoxidation5 of 11 gave the epoxide 12 which rapidly underwent a Lewis acid catalyzed ring-
opening7 in situ to furnish the necessary 2,5-disubstituted THF compound 13 in 99% yield.
However, our results showed that the diastereoselectivity was not good in the second AE reaction
based on HPLC (2,5-con®guration of the tetrahydrofuran ring ꢁ1.35:1, trans:cis). When the
secondary hydroxyl was protected as the ethyl vinyl ether, the diastereoselectivity increased to 95%.
With tetrahydrofuran 13 in hand, the chain extension in both directions was explored (Scheme 3).
Protection of the vicinal diol gave the corresponding acetonide,13 on the right hand side, the benzyl
group was then removed with lithium naphthalenide.8 Treatment of the allylic alcohol with 2
equiv. of triphosgene9 a€orded the chloride 14 in 80% yield. This chloride was again homologated
to the acetylene 15 in 70% yield via coupling with TIPS-protected propargylmagnesium bromide10
in the presence of CuI followed by ¯uoride cleavage of the silyl protecting group. Treatment of the
acetylene 15 with n-BuLi at ^78ꢀC, followed by addition of paraformaldehyde yielded the alcohol
16. The acetonide was removed smoothly with HOAc:H2O (4:1). Oxidative cleavage of the
resulting diol using silica gel-supported metaperiodate11 produced an aldehyde which, without
puri®cation, underwent ole®nation with carbethoxyethylidenetriphenylphosphorane to give the
unsaturated ester 17 (E:Z=1.3:1).
Sharpless asymmetric dihydroxylation12 of the ester 17 and protection of the resultant diol gave
the acetonide 614 in 78% yield for two steps, with 80% diastereoselectivity. The macrocyclization
of 6 and further synthetic studies directed towards the cembranoid diene 3 are now undergoing in
our laboratory.
Scheme 3. Reagents and conditions: (a) i, PPTS, dimethoxypropane; ii, lithium naphthalenide, ^20ꢀC; iii, triphosgene,
Et3N, ^78ꢀC(75%); (b) i, TIPS^CH2CCMgBr, CuI, ^20ꢀC; ii, Bu4NF, THF (70%); (c) n-BuLi, CH2O(88%); (d) i,
HOAc/H2O(4:1); ii, NaIO4; iii, toluene, Ph3PˆC(CH3)CO2Et(63%); (e) i, K2CO3, K3Fe(CN)6, NaHCO3,
K2OsO2(OH)4, (DHQ)2-PHAL, 0ꢀC, H2O/t-BuOH=1:1; ii, PPTS, dimethoxypropane(78%)

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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.
2. Su, J.; Long, K.; Pang, T.; Zeng, L., Zheng, Q.; Lin, X. Scientia Sinica, Ser. B. 1988, 31, 1172.
3. For a review of cembranoid synthesis, see: Tius, M. A. Chem Rev. 1988, 88, 719.
4. Terrao, T.; Shiraishi, M.; Kato, K. Synthesis 1979, 467.
5. Gao, Y.; Hunson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.; Sharpless, K. B. J. Am. Chem. Soc. 1987, 109,
5765.
6. Yamaguchi, M.; Hirao, I. Tetrahedron Lett. 1983, 391.
7. Doherty, A. M.; Ley, S. V. Tetrahedron Lett. 1986, 105.
8. Liu, H.; Yip, J. Tetrahedron Lett. 1997, 2253.
9. Goren, Z.; Heey, M. J.; Mobashery, S. J. Org. Chem. 1991, 56, 7186.
10. Marshall, J. A.; Jenson, T. M.; Deho€, B. S. J. Org. Chem. 1987, 52, 3860.
11. Zhong, Y.; Shing, T. K. M. J. Org. Chem. 1997, 62, 2622.
12. Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem Rev. 1994, 94, 2483.
25
13. The corresponding acetonide 130: Data for 130: ‰ꢀŠD =^15.9 (c 1.3, CHCl3) H NMR ꢁ (300 MHz, CDCl3), 7.31
(m, 5H), 5.41 (t, J=7Hz, 1H), 4.74 (d, J=7.51Hz, 2H), 4.50 (s, 2H), 4.03 (m, 5H), 3.77 (m, 2H), 3.37 (s, 3H), 2.22
(m, 2H), 2.06 (m, 2H), 1.73 (m, 2H), 1.70 (s, 3H), 1.43 (s, 3H), 1.37 (s, 3H), 1.28 (s, 3H).
14. Data for 6: 1H NMR ꢁ ( 300 MHz, CDCl3), 6.75 (d, J=8Hz, 1H), 4.77 (m, 2H), 4.70 (m, 1H), 4.24 (s, 2H), 4.19 (q,
2H), 3.95 (m, 1H), 3.82 (m,1H), 3.39 (s, 3H), 2.42 (m, 2H), 2.17 (m, 1H), 2.05 (m, 1H), 1.85 (s, 3H), 1.42 (s, 3H),
1.29 (m, 16H), 1.09 (s, 3H).
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