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

Yuanxin Liu; Gaofeng Feng; Jian Wang; Jinlong Wu; Wei-Min Dai

doi:10.1055/s-0030-1260822

LETTER

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

Yuanxin Liu^a, Gaofeng Feng^b, Jian Wang^a, Jinlong Wu^a, 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;

Abstract

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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

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References

References and Notes

For isolation and proposed structures of iriomoteolide-1a, -1b, and -1c, see:

1a Tsuda M. Oguchi K. Iwamoto R. Okamoto Y. Kobayashi J. Fukushi E. Kawabata J. Ozawa T. Masuda A. Kitaya Y. Omasa K. J. Org. Chem. 2007, 72: 4469

1b Tsuda T. Oguchi K. Iwamoto R. Okamoto Y. Fukushi E. Kawabata J. Ozawa T. Masuda A. J. Nat. Prod. 2007, 70: 1661

For total synthesis of the proposed structures and stereomers of iriomoteolide-1a and -1b, see:

2a Xie J. Ma Y. Horne DA. Chem. Commun. 2010, 46: 4770

2b Li S. Chen Z. Xu Z. Ye T. Chem. Commun. 2010, 46: 4773

2c Ghosh AK. Yuan H. Org. Lett. 2010, 12: 3120

2d Fang L. Yang J. Yang F. Org. Lett. 2010, 12: 3124

For synthesis of fragments of iriomoteolide-1a, see:

3a Fang L. Xue H. Yang J. Org. Lett. 2008, 10: 4645

3b Ghosh AK. Yuan H. Tetrahedron Lett. 2009, 50: 1416

3c Xie J. Horne DA. Tetrahedron Lett. 2009, 50: 4485

3d Xie J. Ma Y. Horne DA. Org. Lett. 2009, 11: 5082

3e Ye Z. Deng L. Qian S. Zhao G. Synlett 2009, 2469

3f Chin Y.-J. Wang S.-Y. Loh T.-P. Org. Lett. 2009, 11: 3674

3g Wang S.-Y. Chin Y.-J. Loh T.-P. Synthesis 2009, 3557

3h Paterson I. Rubenbauer P. Synlett 2010, 571

3i Liu Y. Wang J. Li H. Wu J. Feng G. Dai W.-M. Synlett 2010, 2184

For our three-module coupling approach in the synthesis of butenoilde stereomers, see:

4a Dai W.-M. Shi L. Li Y. Tetrahedron: Asymmetry 2008, 19: 1549

4b Wang Y. Dai W.-M. Tetrahedron 2010, 66: 187

For selected reviews on use of RCM in total synthesis, see:

5a Nicolaou KC. Bulger PG. Sarlah D. Angew. Chem. Int. Ed. 2005, 44: 4490

5b Gradillas A. Pérez-Castells J. Angew. Chem. Int. Ed. 2006, 45: 6086

5c Hoveyda AH. Malcolmson SJ. Meek SJ. Zhugralin AR. Angew. Chem. Int. Ed. 2010, 49: 34

For our previous total synthesis using RCM strategy, see:

6a Jin J. Chen Y. Wu J. Dai W.-M. Org. Lett. 2007, 9: 2585

6b Dai W.-M. Chen Y. Jin J. Wu J. Lou J. He Q. Synlett 2008, 1737

6c Sun L. Feng G. Guan Y. Liu Y. Wu J. Dai W.-M. Synlett 2009, 2361

6d Li H. Wu J. Luo J. Dai W.-M. Chem. Eur. J. 2010, 16: 11530

6e Wu D. Li H. Jin J. Wu J. Dai W.-M. Synlett 2011, 895

7 For a review on B-alkyl Suzuki-Miyaura coupling, see: Chemler SR. Trauner D. Danishefsky SJ. Angew. Chem. Int. Ed. 2001, 40: 4544

8a Abiko A. Liu J.-F. Masamune S. J. Am. Chem. Soc. 1997, 119: 2586

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9 Corey EJ. Fuchs PL. Tetrahedron Lett. 1972, 13: 3769

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.

Supplementary Material

Supporting Information