Synthesis of the C₁-C₂₁ Southern Hemisphere of the Originally Proposed Structure of Spirastrellolide A

Abstract

A stereocontrolled synthesis of the C₁-C₂₁ [6,6]-spiro­acetal-containing domain of the originally assigned structure of spirastrellolide­ A is reported, exploiting asymmetric boron aldol methodology and an alkyne addition to a C₁₇ aldehyde. Comparison of the ¹H NMR data obtained for this synthetic fragment with that for the corresponding region of spirastrellolide suggested some stereochemical reassignment was required.

Key words

total synthesis - spiro compounds - macrolides - aldol reaction­s - asymmetric synthesis

References

• 1 Williams DE. Roberge M. Van Soest R. Andersen RJ. J. Am. Chem. Soc.  2003,  125:  5296 
• 2 Williams DE. Lapawa M. Feng X. Tarling T. Roberge M. Andersen RJ. Org. Lett.  2004,  6:  2607 
• 3a Le LH. Erlichman C. Pillon L. Thiessen JJ. Day A. Wainman N. Eisenhauer EA. Moore MJ. Invest. New Drugs  2004,  22:  159 
• 3b Honkanen RE. Golden T. Curr. Med. Chem.  2002,  9:  2055 
• For reviews on the synthesis of marine macrolides, see:
• 4a Norcross RD. Paterson I. Chem. Rev.  1995,  95:  2041 
• 4b Paterson I. Yeung K.-S. Chem. Rev.  2005,  105:  in press 
• 6a Paterson I. Gibson KR. Oballa RM. Tetrahedron Lett.  1996,  37:  8585 
• 6b Paterson I. Collett LA. Tetrahedron Lett.  2001,  42:  1187 
• 7a Evans DA. Coleman PJ. Côté B. J. Org. Chem.  1997,  62:  788 
• 7b Evans DA. Côté B. Coleman PJ. Connell BT. J. Am. Chem. Soc.  2003,  125:  10893 
• 8 Cowden CJ. Paterson I. Organic Reactions   Vol. 51:  Paquette LA. Wiley; New York: 1997.  p.1-200  
• 9a Paterson I. Wallace DJ. Velazquez SM. Tetrahedron Lett.  1994,  35:  9083 
• 9b Paterson I. Wallace DJ. Cowden CJ. Synthesis  1998,  639 
• 10 Crimmins MT. Kirincich MT. Wells SJ. Choy AL. Synth. Commun.  1998,  28:  3675 
• 12 The configuration at C₁₃ was confirmed by ¹H NMR analysis using the Kakisawa-Mosher method: Ohtani I. Kusumi T. Kashman Y. Kakisawa H. J. Am. Chem. Soc.  1991,  113:  4092 
• 13 Corey EJ. Fuchs PL. Tetrahedron Lett.  1972,  13:  3769 
• 14 Tsuji J. Synthesis  1984,  369 
• 15a Smith AB. Minbiole KP. Verhoest PR. Schelhaas M. J. Am. Chem. Soc.  2001,  123:  10942 
• 15b

  Dihydropyranone 12 was conveniently accessed via a Jacobsen hetero-Diels-Alder reaction between Danishefsky’s diene and TPSO(CH₂)₂CHO in 94% yield and 99% ee.

• 16 Paterson I. Smith JD. Ward RA. Tetrahedron  1995,  51:  9413 
• 17 Evans DA. Chapman KT. Carreira EM. J. Am. Chem. Soc.  1988,  110:  3560 
• 18a Paterson I. Anderson EA. Dalby SM. Loiseleur O. Org. Lett.  2005,  7:  4121 
• 18b Paterson I. Anderson EA. Dalby SM. Loiseleur O. Org. Lett.  2005,  7:  4125 
• For other synthetic studies towards spirastrellolide, see:
• 19a Liu J. Hsung RP. Org. Lett.  2005,  7:  2273 
• 19b Paterson I. Anderson EA. Dalby SM. Loiseleur O. Abstracts of Papers 229th National Meeting of the American Chemical Society, San Diego   ACS; Washington D.C.: 2005.  ORGN-331.
• 19c Wang C. Forsyth CJ. Abstracts of Papers 229th National Meeting of the American Chemical Society, San Diego   ACS; Washington D.C.: 2005.  ORGN-414.

5

In addition to the originally proposed structure by Professor Andersen, as reported in ref. 1, a preliminary stereochemical assignment was made by us for the C₁-C₁₁ region.

11

All new compounds gave spectroscopic data in agreement with the assigned structures. Compound 2 had [α]_D ²² = +34.5 (c 0.80, CHCl₃); ¹H NMR (500 MHz, C₆D₆): δ = 7.78-7.83 (m, 4 H, ArH), 7.22-7.29 (m, 6 H, ArH), 5.60 (dd, J = 9.9, 2.4 Hz, 1 H, H₁₅), 5.51 (dd, J = 9.9, 1.7 Hz, 1 H, H₁₆), 4.38 (m, 1 H, H₁₁), 4.22 (m, 1 H, H₉), 4.07 (m, 1 H, H₃), 4.03 (m, 1 H, H₇), 3.94 (m, 1 H, H_21eq.), 3.88 (m, 3 H, 2 × H₁, H_21ax.), 3.81 (m, 1 H, H₁₃), 3.15 (m, 1 H, H₂₀), 3.10 (s, 3 H, OMe), 2.12 (m, 1 H, H₈), 2.10 (m, 1 H, H₂), 2.09 (1H, m, H₁₀), 2.04 (m, 1 H, H₁₀), 2.02 (m, 1 H, H₁₄), 1.97 (m, 1 H, H_19ax.), 1.93 (m, 2 H, 2 × H₁₂), 1.84 (m, 1 H, H_18eq., H_19eq.), 1.82 (m, 1 H, H₂), 1.76 (m, 1 H, H₈), 1.65 (m, 1 H, H_6eq.), 1.58 (m, 1 H, H_4eq.), 1.50 (m, 1 H, H_18ax.), 1.49 (m, 2 H, 2 × H₅), 1.36 (m, 1 H, H_6ax.), 1.25 (m, 1 H, H_4ax.), 1.19 (s, 9 H, Si ^t Bu), 1.05 (s, 9 H, Si ^t Bu), 1.03 (s, 9 H, Si ^t Bu), 0.80 (d, J = 7.1 Hz, 3 H, Me₁₄), 0.26 (s, 3 H, SiMe), 0.28 (s, 3 H, SiMe), 0.24 (s, 3 H, SiMe), 0.20 (s, 3 H, SiMe); ¹³C NMR (125 MHz, C₆D₆): δ = 135.8, 135.7, 134.2, 134.1, 134.0, 129.7, 129.4, 93.0, 74.9, 71.0, 68.4, 68.3, 67.7, 67.6, 63.7, 61.5, 55.7, 46.6, 43.0, 42.5, 36.3, 34.5, 34.3, 30.8, 29.8, 27.0, 26.1, 26.0, 25.3, 19.3, 18.8, 18.2, 18.1, 17.0, -3.5, -3.7, -3.9, -4.0; HRMS (ES+): m/z [M + H]⁺ calcd for C₅₁H₈₇O₇Si₃: 895.5754; found: 895.5752.