Total synthesis of 6-epi-sarsolilide A

Article abstract of DOI:10.1016/S0040-4039(99)02126-7

This paper describes an asymmetric synthesis of 6-epi-sarsolilide A. The 11-membered carbocycle and seven-membered lactone were established by an intramolecular HWE reaction and iodolactonization. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(99)02126-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 941–943
Total synthesis of 6-epi-sarsolilide A
Jiazhong Zhang and Xingxiang Xu ∗
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
Received 30 September 1999; accepted 10 November 1999
Abstract
This paper describes an asymmetric synthesis of 6-epi-sarsolilide A. The 11-membered carbocycle and seven-
membered lactone were established by an intramolecular HWE reaction and iodolactonization. © 2000 Elsevier
Science Ltd. All rights reserved.
Keywords: sarsolilide A; intramolecular HWE reaction; total synthesis.
Sarsolilide A 11 has been isolated from the marine Sarcophyton solidun Tixier-Durivault (Alcyoni-
idae). Due to the scarcity of the natural material, its absolute stereochemistry and biological activity are
not known. The unique structure of sarsolilide A make it of synthetic interest.
In a preliminary report2 we have described the synthesis of compound 2 containing three of the
necessary chiral centers. However, experiments showed that it was very troublesome to convert 2 into
the required precursor 3 for macrocyclization because of the presence of the C6–OH. So we changed our
plan and attempted to firstly establish the 11-membered carbocycle from compound 7, and then construct
the last chiral center by iodolactonization. However, the results revealed that the chiral center created
by iodolactonization was different from sarsolilide A 1, as communicated herein. The synthetic route is
shown in Scheme 1.
The synthesis commenced with compound 4.2 Selective desilylation3 and then protection of the two
hydroxyl groups gave carbonate 54 in 86% yield. Cleavage of the TBDPS ether followed by iodination
produced iodide 6 in 92% yield. The compound 6 was treated with three phosphonate reagents5 and then
hydrolysis6 of the acetal with Amberlyst-15 afforded the corresponding precursors for intramolecular
HWE reaction, that is 7, 8 and 9 in 73%, 64% and 60% yield, respectively (two steps).
∗
Corresponding author. E-mail: xuxx@pub.sioc.ac.cn (X. Xu)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02126-7
tetl 16054

942
Scheme 1. Reagents and conditions: (a) LiAlH4, Et2O, rt, overnight; (b) triphosgene, pyridine, CH2Cl2, −78°C→0°C; (c)
Bu4NF, THF, rt, 1 h; (d) I2, Ph3P, imidazole, THF:CH3CN (3:1), rt; (e) (i) (RO)2P(O)CH2COOMe, NaH, DMSO, rt, 30 min;
(ii), 6, DMSO, 50°C, 4 h; (f) Amberlyst-15, acetone–H2O, rt, 2 h; (g) NaH, DME, rt, 20 h; (h) NaOH, THF–H2O, reflux,
overnight; (i) I2, NaHCO3, CH3CN, rt, 1 h; (j) Bu3SnH, AIBN, benzene, reflux, 30 min; (k) Dess–Martin oxid., CH2Cl2, rt, 30
min; (l) CH2I2, Zn, TiCl4, THF, rt, 30 min
In our efforts at macrocyclization, exposure of the phosphono ester aldehyde 7 to NaH in DME at room
temperature provided a mixture of cyclized products enriched in the undesired E-olefin in a 50% total
yield (2:1 ratio of E:Z).7 Examining the phenyl phosphonate aldehyde 88 in the macrocyclization, showed
that this reaction exhibited a surprising trend, and provided a mixture of product enriched in the desired
Z-olefin in a 30% total yield (3:8 ratio of E:Z). We also had the occasion to examine the trifluoromethyl
phosphonate aldehyde 9; a variety of conditions for the cyclization of 9 were tried, but the results were
disappointing and almost no product was obtained.
Subsequently, hydrolysis of the methyl ester of compound 10 was accompanied by the deprotection
of the carbonate and iodolactonization was in situ performed. On treatment with a large excess of iodine
at room temperature9 for prolonged periods, lactone 12 was obtained in only 30% overall yield (two
steps).10 The most efficient iodolactonization condition was I2–CH3CN, resulting in reaction completed
in 1 h, to give 12 in 32% yield. Reduction of the iodide 12 with tributyltin hydride and oxidation of the
resulting alcohol by Dess–Martin reagent gave compound 13 in 45% yield (two steps).

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Finally, methylenation of ketone 13 by the mild CH2I2–Zn–TiCl4 system11 yielded the target 14.
1
However, it was notable that there was a remarkable difference on comparison of the H NMR of
compound 14 with that of sarsolilide A 112 in the chemical shifts of C11–H and C6–CH3 (compound
14: C11–H, δ 3.63; C6–CH3, δ 1.52; sarsolilide A 1: C11–H, δ 3.01; C6–CH3, δ 1.40). Consequently,
it appears that the final chiral center created at the C6-position is different from sarsolilide A 1.
To confirm the assignment of the C6-configuration, the iodide 12 was studied by 1H NMR, TOCOSY,
DQCOSY and NOESY spectra. The C5 proton position was identified through the correlation of the
C3–C4–C5 protons in the TOCOSY and DQCOSY spectra. The observed intense correlation between
C5–H and C11–H in the NOESY experiment indicated that the configuration of C6 was different from
that in the natural product.
In summary, we have achieved the first enantioselective synthesis of 6-epi-sarsolilide A.
Acknowledgements
We are grateful to the Academy of Sciences and the National Natural Science Foundation of China for
their financial support (Grant No. 29732061).
References
1. Zhang, M.; Long, K. H.; Huang, S. H.; Shi, K. L.; Thomas, C. W. J. Nat. Prod. 1992, 55, 1672–1675.
2. Zhang, J.; Xu, X. Tetrahedron Lett. 1998, 39, 6525–6528.
3. Erik F. J. de Vries; Brussee, J.; Arne Van der Gen J. Org. Chem. 1994, 59, 7133–7137.
4. Burk, R. M.; Roof, M. B. Tetrahedron Lett. 1993, 34, 395–398.
5. Marshall, J. A.; DeHoff, B. S. J. Am. Chem. Soc. 1986, 27, 4873–4876.
6. Mandal, A. K.; Shrotri, P. Y.; Ghogare, A. D. Synthesis 1986, 221–222.
7. The E- and Z-isomers of the ester-substituted double bond could be separated by column chromatography (3:1
petroleum:ethyl acetate), their configurations were readily identified by the chemical shifts of the characteristic vinylic
hydrogen in 1H NMR (E-olefin: δ 6.93 for C3–H; Z-olefin δ 5.79 for C3–H). Selected data for the Z-isomer 10:
[α]D15=+217.9 (c 0.53, CHCl3); 1H NMR (400 MHz, CDCl3) δ 5.79 (t, 1H, J=8.3 Hz), 5.61 (s, 1H), 5.24 (d, 1H, J=1.9 Hz),
5.19 (d, 1H, J=9.6 Hz), 4.48 (t, 1H, J=3.1 Hz), 3.77 (s, 3H), 3.00–2.94 (m, 1H), 2.72–2.67 (m, 1H), 2.57 (dd, 1H, J=2.6,
9.6 Hz), 2.48–2.43 (m, 1H), 2.32–2.09 (m, 7H), 2.00–1.92 (m, 1H), 1.87–1.73 (m, 2H), 1.04 (d, 3H, J=6.8 Hz), 1.03 (d, 3H,
J=6.8 Hz). Selected data for the E-isomer: [α]D15=+174.4 (c 0.20, CHCl3); 1H NMR (300 MHz, CDCl3) δ 6.93 (dd, 1H,
J=6.7, 9.1 Hz), 5.52 (s, 1H), 5.16 (d, 1H, J=10.2 Hz), 5.13 (s, 1H), 4.56–4.54 (m, 1H), 3.75 (s, 3H), 2.95 (dd, 1H, J=2.6,
10.2 Hz), 2,72–2.45 (m, 4H), 2.38–2.18 (m, 5H), 2.11–1.98 (m, 3H), 1.85–1.75 (m, 1H), 1.03 (d, 3H, J=6.9 Hz), 1.01 (d,
3H, J=6.9 Hz).
8. Ando, K. J. Org. Chem. 1998, 62, 1934–1939.
9. Chamberlin, A. R.; Dezube, M.; Dussault, P.; McMills, M. C. J. Am. Chem. Soc. 1983, 105, 5819–5825.
10. Selected data for 12: [α]D20=+32.0 (c 0.19, CHCl3); 1H NMR (600 MHz, CDCl3) δ 6.34 (dd, 1H, J=5.4, 9.0 Hz), 5.44 (d,
1H, J=10.2 Hz), 4.05 (d, 1H, J=11.1 Hz), 4.01 (br s, 1H), 3.40 (d, 1H, J=11.1 Hz), 3.17 (dd, 1H, J=5.1, 10.2 Hz), 2.93
(dd, 1H, J=5.4, 13.8 Hz), 2.83 (dd, 1H, J=5.4, 13.2 Hz), 2.70 (s, 1H), 2.34–2.16 (m, 6H), 2.06–1.96 (m, 4H), 1.90 (dt, 1H,
J=2.4, 11.2 Hz), 1.69–1.63 (m, 1H), 1.08 (d, 3H, J=6.9 Hz), 1.05 (d, 3H, J=6.9 Hz).
11. (a) Hibino, J.; Okazoe, T.; Takai, K.; Nozaki, H. Tetrahedron Lett. 1985, 45, 5579–5580; (b) Lombardo, L. Tetrahedron
Lett. 1982, 23, 4293–4296.
12. Selected data for 14: 1H NMR (600 MHz, CDCl3) δ 6.32 (dd, 1H, J=9.0, 6.0 Hz), 5.16 (d, 1H, J=10.2 Hz), 4.94 (s, 1H),
4.63 (s, 1H), 3.63 (dd, 1H, J=2.4, 10.2 Hz), 2.82 (dt, 1H, J=3.6, 13.6 Hz), 2.66–2.59 (m, 1H), 2.43–2.36 (m, 2H), 2.33–2.15
(m, 5H), 1.99 (dd, 1H, J=5.1, 13.2 Hz), 1.78 (ddd, 1H, J=2.4, 8.4, 13.2 Hz), 1.67 (ddd, 1H, J=9.3, 11.1, 13.2 Hz), 1.52 (s,
3H), 1.07 (d, 3H, J=6.9 Hz), 1.05 (d, 3H, J=6.9 Hz); HRMS found 316.2043; calcd: 316.2039. Selected data for sarsolilide
A 1: 1H NMR (400 MHz, CDCl3) δ 6.29 (dd, 1H, J=9.0, 6.0 Hz), 5.18 (d, 1H, J=10.3 Hz), 4.89 (d, 1H, J=1.9 Hz), 4.64 (d,
1H, J=1.9 Hz), 3.01 (d, 1H, J=10.3 Hz), 2.91 (m 1H), 2.63–2.43 (m, 2H), 2.40 (m, 2H), 2.35 (m, 1H), 2.20 (m, 1H), 2.07
(m, 2H), 1.97 (m, 2H), 1.78 (m, 2H), 1.60 (br s, 1H, OH), 1.40 (s, 3H), 1.04 (d, 3H, J=6.8 Hz), 1.04 (d, 3H, J=6.8 Hz).