Studies Toward Elucidating the Stereochemical Structure of Iriomoteolide 1a

Abstract

A diastereomer of iriomoteolide 1a has been synthesized as part of our effort to identify the so far unknown stereochemical structure of the natural product. The synthetic route features a lithium acetylide-chloroformate coupling, the ring-closing metathesis to form the macrocyclic diolide, and a SmI₂-mediated intramolecular reductive allylation for formation of the cyclic hemiketal.

iriomoteolide - natural products - total synthesis - antitumor agent - reductive allylation - misassignment

References

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

2a Liu Y. Wang J. Li H. Wu J. Feng G. Dai W.-M. Synlett  2010,  2184 

2b Paterson I. Rubenbauer P. Synlett  2010,  571 

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

2d Xie J. Ma Y. Horne DA. Org. Lett.  2009,  11:  5082 

2e Wang S.-Y. Chen Y.-J. Loh T.-P. Synthesis  2009,  3557 

2f Ye Z. Deng L. Qian S. Zhao G. Synlett  2009,  2469 

2g Chin Y.-J. Wang S.-Y. Loh T.-P. Org. Lett.  2009,  11:  3674 

2h Xie J. Horne DA. Tetrahedron Lett.  2009,  50:  4485 

2i Ghosh AK. Yuan H. Tetrahedron Lett.  2009,  50:  1416 

2j Fang L. Xue H. Yang J. Org. Lett.  2008,  10:  4645 

3a Xie J. Ma Y. Horne DA. Tetrahedron  2011,  67:  7485 

3b Ghosh AL. Yuan H. Org. Lett.  2010,  12:  3120 

3c Xie J. Ma Y. Horne DA. Chem. Commun.  2010,  46:  4770 

For a recent synthesis of the proposed iriomoteolide 1b:

3d Ye Z. Gao T. Zhao G. Tetrahedron  2011,  67:  5979 

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

5a Liu Y. Feng G. Wang J. Wu J. Dai W.-M. Synlett  2011,  1774 

5b

The spectra reported by Dai and co-workers for macrolide 2 are different from ours. In particular, a chemical shift of δ = 96.8 ppm was observed for 2 at C13 (and δ = 97.0 ppm for 6) in our hands, but δ = 99.5 ppm by Dai and co-workers and δ = 99.7 ppm for the natural product. It is not clear what is the source of this discrepancy.

6

Supporting Information of ref. 1.

7

Fang, L.; Yang, J. unpublished results.

8 Zhang D. Bleasdale C. Golding BT. Watson WP. Chem. Commun.  2000,  1141 

9 Marshall JA. J. Org. Chem.  2007,  72:  8153 

10 Evans DA. Bartroli J. Shih TL. J. Am. Chem. Soc.  1981,  103:  2127 

11a Levin JI. Turos E. Weinreb SM. Synth. Commun.  1982,  12:  989 

11b Basha A. Lipton M. Weinreb SM. Tetrahedron Lett.  1977,  18:  4171 

12a Miwa K. Aoyama T. Shioiri T. Synlett  1994,  107 

For a recent review, see:

12b Habrant D. Rauhala V. Koskinen AMP. Chem. Soc. Rev.  2010,  39:  2007 

For two reviews of the Mitsunobu reaction, see:

13a Mitsunobu O. Synthesis  1981,  1 

13b Kumara Swamy KC. Bhuvan Kumar NN. Balaraman E. Pavan Kumar KVP. Chem. Rev.  2009,  109:  2551 

14 Scholl M. Ding S. Lee CW. Grubbs RH. Org. Lett.  1999,  1:  953 

15 Finkelstein H. Ber. Dtsch. Chem. Ges.  1910,  43:  1528 

16 Heumann LV. Keck GE. Org. Lett.  2007,  9:  1951 

17a Gaffney BL. Jones RA. Tetrahedron Lett.  1982,  23:  2257 

17b Coleman RS. Li J. Navarro A. Angew. Chem. Int. Ed.  2001,  40:  1736 

18

Characterization Data for Compound 6
[α]_D -11.07 (c 0.6, CHCl₃). IR (thin film): 2967, 2928, 2854, 1661 1638, 1427, 1013, 871 cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 5.72 (s, 1 H), 5.72-5.70 (m, 2 H), 5.62-5.57 (m, 1 H), 5.45 (dd, J = 16.2, 9.1 Hz, 1 H), 4.87 (s, 1 H), 4.85-4.80 (m, 1 H), 4.83 (s, 1 H), 3.77 (t, J = 9.1 Hz, 1 H), 3.64 (dd, J = 11.9, 2.4 Hz, 1 H), 3.61-3.53 (m, 1 H), 3.03 (s, 1 H), 2.50-2.46 (m, 1 H), 2.44-2.35 (m, 1 H), 2.33 (d, J = 8.1 Hz, 1 H), 2.25 (dd, J = 13.6, 10.3 Hz, 1 H), 2.17-2.11 (m, 3 H), 2.08 (s, 3 H), 2.06-1.98 (m, 1 H), 1.93-1.88 (m, 1 H), 1.84-1.79 (m, 1 H), 1.51-1.45 (m, 1 H), 1.28 (d, J = 6.8 Hz, 3 H), 1.15 (s, 3 H), 1.17-1.11 (m, 1 H), 1.07 (d, J = 6.3 Hz, 3 H), 1.02 (d, J = 7.1 Hz, 3 H), 0.85 (d, J = 6.8 Hz, 3 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 168.1, 162.6, 141.2, 139.0, 135.0, 128.0, 120.7, 115.7, 111.3, 97.0, 79.9, 75.8, 75.7, 73.7, 72.4, 48.4, 45.9, 43.8, 38.0, 37.0, 36.2, 35.4, 33.6, 23.2, 21.5, 20.4, 17.7, 16.9, 15.9. ESI-HRMS: m/z calcd for C₂₉H₄₆O₇Na⁺
[M + Na⁺]: 529.3141; found: 529.3152.