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Synlett 2011(12): 1774-1778  
DOI: 10.1055/s-0030-1260822
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Synthesis of Two Diastereomers of Iriomoteolide-1a via a Tunable Four-Module Coupling Approach Using Ring-Closing Metathesis as the Key Step

Yuanxin Liua, Gaofeng Fengb, Jian Wanga, Jinlong Wua, Wei-Min Dai*a,b
a Laboratory of Asymmetric Catalysis and Synthesis, Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. of China
Fax: +86(571)87953128; e-Mail: chdai@zju.edu.cn;
b Center for Cancer Research and Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong SAR, P. R. of China
Fax: +85223581594; e-Mail: chdai@ust.hk;
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Publication History

Received 24 March 2011
Publication Date:
28 June 2011 (online)

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Abstract

A tunable four-module coupling approach has been established for assembling the 20-membered macrolactone core related to the proposed structure of iriomoteolide-1a by using ring-closing metathesis as the key step. Two C1-C6 (2E)-diene acid fragments with (4R,5S)- and (4S,5R)-stereogenic centers, respectively, were synthesized via anti-selective aldol reaction and E-selective conjugate addition of Me2CuLi with an alkynoic ester in the presence of TMSCl. The ring-closing metathesis reaction was carried out in the presence of 10 mol% Grubbs second-generation initiator at room temperature to give exclusively the (6E)-cycloalkenes. Our four-module coupling strategy enables efficient synthesis of two diastereomers of the proposed iriomoteolide-1a with opposite chirality at C4 and C5.

Key words

iriomoteolide - macrolide - modular synthesis - ring-closing metathesis - stereoisomers

    References and Notes

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10

Characterization Data for (2 Z ,4 R ,5 S )-Diene Acid 3a
A pale yellow oil. [α]D ²0 -72.2 (c 2.85, CHCl3). R f  = 0.28 (17% EtOAc-PE). IR (film): 2957, 2925, 2858, 1695, 1632, 1254, 1184, 1084 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 5.78 (d, J = 0.8 Hz, 1 H), 5.74 (ddd, J = 17.6, 10.0, 7.0 Hz, 1 H), 5.20-5.14 (m, 2 H), 4.03 (dd, J = 7.6, 7.6, 1 H), 3.65 (quin, J = 7.2 Hz, 1 H), 1.84 (d, J = 1.2 Hz, 3 H), 0.97 (d, J = 6.8 Hz, 3 H), 0.87 (s, 9 H), 0.06 (s, 3 H), 0.03 (s, 3 H); CO2H not observed. ¹³C NMR (100 MHz, CDCl3): δ = 169.5, 159.4, 139.4, 119.2, 116.6, 77.2, 41.2, 25.7 (3¥), 20.4, 18.2, 14.7, -4.1, -5.0. HRMS (+TOF EI): m/z [M+] calcd for C15H28O3Si: 284.1808; found: 284.1812.
Characterization Data for (2 E ,4 R ,5 S )-Diene Acid 3b
A pale yellow oil. [α]D ²0 -5.3 (c 3.90, CHCl3). R f  = 0.26 (17% EtOAc-PE). IR (film): 2958, 2925, 2858, 1693, 1643, 1253, 1087 cm-¹. ¹H NMR (500 MHz, CDCl3): δ = 5.73 (s, 1 H), 5.69 (ddd, J = 17.5, 10.0, 7.0 Hz, 1 H), 5.15 (d, J = 17.5 Hz, 1 H), 5.12 (d, J = 11.0 Hz, 1 H), 4.04 (dd, J = 7.0, 7.0 Hz, 1 H), 2.33 (quin, J = 7.0 Hz, 1 H), 2.17 (s, 3 H), 1.00 (d, J = 7.0 Hz, 3 H), 0.86 (s, 9 H), 0.02 (s, 3 H), 0.00 (s, 3 H); CO2H not observed. ¹³C NMR (125 MHz, CDCl3): δ = 172.3, 164.8, 139.5, 116.6, 116.0, 76.9, 50.6, 25.7 (3¥), 18.1, 17.4, 14.9, -4.1, -5.1. HRMS (+TOF EI): m/z [M+] calcd for C15H28O3Si: 284.1808; found: 284.1812.
Characterization Data for (2 E ,4 S ,5 R )-Diene Acid 3c A pale yellow oil. [α]D ²0 +4.5 (c 1.65, CHCl3). Other spectroscopic data are identical to those of 3b.

11

We obtained an analogous byproduct to 19 from global desilylation of 14 in 27% yield but its structure (compound 26 in Scheme 6 in ref. 3i) was wrongly assigned due to error in its ¹H NMR analysis. A corrected structure based on the newly obtained ¹H NMR and other spectroscopic data is found in Supporting Information of this article.

12

Desilylation of an analogous substrate to 14 under the pyridine-buffered HF˙pyridine conditions was reported in ref. 3d without migration of the C11 double bond.

13

Representative Procedure for the RCM Reaction To a stirred solution of 17 (13.8 mg, 2.6¥10-² mmol) in dry CH2Cl2 (25 mL) at r.t. was added Grubbs second-generation initiator (2.4 mg, 2.8¥10-³ mmol) followed by stirring at the same temperature for 1.5 h. The reaction mixture was condensed under reduced pressure, and the residue was purified by flash column (silica gel, 35-45% EtOAc in PE) to afford (2E,4R,5S)-20 (8.9 mg, 68%).
Characterization Data for (2 E ,4 R ,5 S )-20 A pale yellow oil. [α]D ²0 +9.5 (c 0.16, CHCl3); R f  = 0.39 (60% EtOAc-PE). IR (film): 3444 (br), 2969, 2936, 1693, 1651, 1455, 1372, 1218, 1009 cm-¹. HRMS (+TOF ESI): m/z [M + Na+] calcd for C29H46O7Na: 529.3141; found: 529.3141. For ¹H NMR and ¹³C NMR spectra, see in Supporting Information.
Characterization Data for (2 E ,4 S ,5 R )-23
A pale yellow oil. [α]D ²0 -24.7 (c 1.33, CHCl3); R f  = 0.39 (60% EtOAc-PE). IR (film): 3446 (br), 2926, 1688, 1635, 1456, 1372, 1232, 1163, 1009 cm-¹. HRMS (+TOF EI): m/z [M+] calcd for C29H46O7: 506.3244; found: 506.3235. For ¹H NMR and ¹³C NMR, see Supporting Information.

14

Yang and co-workers reported in ref. 2d that (2E,4R,5S)-20 exits as a 5:1 equilibrating mixture with its keto form in CDCl3. However, we did not observe this phenomenon for our sample. For comparison of the ¹H NMR and ¹³C NMR spectra, see Figures S1 and S2 of Supporting Information. The ¹³C NMR signal for the hemiacetal carbon (C13) of their sample is observed at δ = 96.8 ppm as compared with 99.7 (natural iriomoteolide-1a), 99.5 (our sample 20), and 99.7 (our sample 23) ppm, suggesting that their sample might be a 13R-epimer.