Synthetic Studies on Azaspiracid: Synthesis of Key Intermediate for the Construction of the FGHI Ring System

Abstract

A highly stereoselective and convergent approach for the key intermediate of the FGHI ring system of azaspiracid is ­described. The synthesis features the desymmetrization strategy for the construction of the C27-C33 fragment, Masamune-Roush coupling conditions for the C33-C34 bond formation, and Sharpless asymmetric dihydroxylation as the key steps. One more important feature of this synthetic route is that we can synthesize other ­enantiomers of the FGHI ring system by changing asymmetric ­hydroboration conditions and valerolactone.

Key words

desymmetrization - Masamune-Roush coupling conditions - Sharpless asymmetric dihydroxylation - asymmetric hydro­boration

References and Notes

• 1 McMahon T. Silke J. Harmful Algae News  1996,  14:  2 
• 2 Satake M. Ofuji K. Naoki H. James KJ. Furey A. McMahon T. Silke J. Yasumoto T. J. Am. Chem. Soc.  1998,  120:  9967 
• 3 Nicolaou KC. Koftis TV. Vyskocil S. Petrovic G. Ling T. Yamada YMA. Tang W. Frederick MO. Angew. Chem. Int. Ed.  2004,  43:  4318 
• 4a Ofuji K. Satake M. McMahon T. Silke J. James KJ. Naoki H. Oshima Y. Yasumoto T. Nat. Toxins  1999,  7:  99 
• 4b Ofuji K. Satake M. McMahon T. James KJ. Naoki H. Oshima Y. Yasumoto T. Biosci., Biotechnol., Biochem.  2001,  65:  740 
• 5 James KJ. Sierra MD. Lehane M. Magdalena AB. Furey A. Toxicon  2003,  41:  277 
• 6a Carter RG. Weldon DJ. Org. Lett.  2000,  2:  3913 
• 6b Aiguade J. Hao J. Forsyth CJ. Tetrahedron Lett.  2001,  42:  817 
• 6c Hao J. Aiguade J. Forsyth CJ. Tetrahedron Lett.  2001,  42:  821 
• 6d Dounay AB. Forsyth CJ. Org. Lett.  2001,  3:  975 
• 6e Aiguade J. Hao J. Forsyth CJ. Org. Lett.  2001,  3:  979 
• 6f Nicolaou KC. Pihko PM. Diedrichs N. Zou N. Bernal F. Angew. Chem. Int. Ed.  2001,  40:  1262 
• 6g Carter RG. Graves DE. Tetrahedron Lett.  2001,  42:  6035 
• 6h Forsyth CJ. Hao J. Aiguade J. Angew. Chem. Int. Ed.  2001,  40:  3663 
• 6i Nicolaou KC. Qian W. Bernal F. Uesaka N. Pihko PM. Hinrichs J. Angew. Chem. Int. Ed.  2001,  40:  4068 
• 6j Carter RG. Bourland TC. Graves DE. Org. Lett.  2002,  4:  2177 
• 6k Carter RG. Graves DE. Gronemeyer MA. Tschumper GS. Org. Lett.  2002,  4:  2181 
• 6l Nicolaou KC. Li Y. Uesaka N. Koftis TV. Vyskocil S. Ling T. Govindasamy M. Qian W. Bernal F. Chen DY.-K. Angew. Chem. Int. Ed.  2003,  42:  3643 
• 6m Nicolaou KC. Chen DY.-K. Li Y. Qian W. Ling T. Vyskocil S. Koftis TV. Govindasamy M. Uesaka N. Angew. Chem. Int. Ed.  2003,  42:  3649 
• 6n Sasaki M. Iwamuro Y. Nemoto J. Oikawa M. Tetrahedron Lett.  2003,  44:  6199 
• 6o Carter RG. Bourland TC. Zhou X.-T. Gronemeyer MA. Tetrahedron  2003,  59:  8963 
• 6p Ishikawa Y. Nishiyama S. Tetrahedron Lett.  2004,  45:  351 
• 6q Ishikawa Y. Nishiyama S. Heterocycles  2004,  63:  539 
• 6r Ishikawa Y. Nishiyama S. Heterocycles  2004,  63:  885 
• 6s Nicolaou KC. Koftis TV. Vyskocil S. Petrovic G. Ling T. Yamada YMA. Tang W. Frederick MO. Angew. Chem. Int. Ed.  2004,  43:  4318 
• 6t Nicolaou KC. Vyskocil S. Koftis TV. Yamada YMA. Ling T. Chen DY.-K. Tang W. Petrovic G. Frederick MO. Li Y. Satake M. Angew. Chem. Int. Ed.  2004,  43:  4312 
• 6u Zhou X.-T. Carter RG. Chem. Commun.  2005,  2138 
• 6v Geisler LK. Nguyen S. Forsyth CJ. Org. Lett.  2004,  6:  4159 
• 6w Nicolaou KC. Pihko PM. Bernal F. Frederick MO. Qian W. Uesaka N. Diedrichs N. Hinrichs J. Koftis TV. Loizidou E. Petrovic G. Rodriquez M. Sarlah D. Zou N. J. Am. Chem. Soc.  2006,  128:  2244 
• 6x Nicolaou KC. Chen DY.-K. Li Y. Uesaka N. Petrovic G. Koftis TV. Bernal F. Frederick MO. Govindasamy M. Ling T. Pihko PM. Tang W. Vyskocil S. J. Am. Chem. Soc.  2006,  128:  2258 
• 6y Nicolaou KC. Koftis TV. Vyskocil S. Petrovic G. Tang W. Frederick MO. Chen DY.-K. Li Y. Ling T. Yamada YMA. J. Am. Chem. Soc.  2006,  128:  2859 
• 6z Nguyen S. Xu J. Forsyth CJ. Tetrahedron  2006,  62:  5338 
• 7 Blanchette MA. Choy W. Davis JT. Essenfeld AP. Masamune S. Roush WR. Sakai T. Tetrahedron Lett.  1984,  25:  2183 
• 8a Kolb HC. VanNieuwenhze MS. Sharpless KB. Chem. Rev.  1994,  94:  2483 
• 8b Bennai YL. Sharpless KB. Tetrahedron Lett.  1993,  34:  2079 
• 8c Walsh PJ. Sharpless KB. Synlett  1993,  605 
• 9a Yadav JS. Rao CS. Chandrasekhar S. Ramarao AV. Tetrahedron Lett.  1995,  36:  7717 
• 9b Yadav JS. Abraham S. Reddy MM. Sabitha G. Sankar AR. Kunwar AC. Tetrahedron Lett.  2001,  42:  4713 
• 9c Yadav JS. Abraham S. Reddy MM. Sabitha G. Sankar AR. Kunwar AC. Tetrahedron Lett.  2002,  43:  3453 
• 9d Yadav JS. Ahmed MdM. Tetrahedron Lett.  2002,  43:  7147 
• 9e Yadav JS. Reddy KB. Sabitha G. Tetrahedron Lett.  2004,  45:  6475 
• 9f Yadav JS. Srinivas R. Sathiah K. Tetrahedron Lett.  2006,  47:  1603 
• 9g Yadav JS. Venkatram Reddy P. Chandraiah L. Tetrahedron Lett.  2007,  48:  145 
• 10 Rossi R. Carpita A. Chini M. Tetrahedron  1985,  41:  627 
• 11a Yadav JS. Prahlad V. Chander MC. J. Chem. Soc., Chem. Commun.  1993,  137 
• 11b Takano KS. Samizu K. Sugihara T. Ogasawara K. J. Chem. Soc., Chem. Commun.  1989,  1344 
• 12a Frigerio M. Santagostino M. Sputore S. J. Org. Chem.  1999,  64:  4537 
• 12b Dess DB. Martin JC. J. Org. Chem.  1983,  48:  4155 
• 12c Dess DB. Martin JC. J. Am. Chem. Soc.  1991,  113:  7277 

13

Analytical Data for Compound 18: Liquid; [α]_D ²⁵ -20.18 (c = 2.0, CHCl₃). IR (Neat): 2958, 2172, 1671, 1613, 1513, 1462, 1427, 1249, 1172, 1110, 1036, 843 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 0.13 (s, 9 H), 0.85 (d, J = 6.7 Hz, 3 H), 0.89 (m, 1 H), 0.94 (d, J = 6.6 Hz, 3 H), 0.98 (d, J = 6.2 Hz, 3 H), 1.04 (s, 9 H), 1.49-1.61 (m, 1 H), 1.64-1.78 (m, 2 H), 2.14-2.45 (m, 6 H), 2.55-2.65 (m, 1 H), 3.25-3.32 (m, 1 H), 3.37 (dd, J = 6.4, 9.8 Hz, 1 H), 3.45-3.52 (m, 1 H), 3.76 (s, 3 H), 4.33 (q, J = 11.3, 16.6 Hz, 2 H), 6.06 (d, J = 15.8 Hz, 1 H), 6.66-6.78 (m, 1 H), 6.75 (d, J = 8.6 Hz, 2 H), 7.09 (d, J = 8.6 Hz, 2 H), 7.29-7.42 (m, 6 H), 7.59-7.65 (m, 4 H). ¹³C NMR (100 MHz, CDCl₃): δ = 0.1, 15.6, 18.1, 19.2, 19.5, 26.8, 26.9, 28.8, 33.3, 33.5, 34.5, 36.4, 45.6, 55.1, 68.7, 71.6, 81.2, 86.2, 105.2, 113.6, 127.5, 129.2, 129.5, 130.5, 132.1, 133.8, 135.5, 144.7, 159.0, 199.4. HRMS (ESI): m/z [M + NH₄]⁺ calcd for C₄₄H₆₂O₄Si₂: 728.4530; found: 728.4501.

14

Analytical Data for Compound 19: Liquid; [α]_D ²⁵ -2.584 (c = 0.6, CHCl₃). IR (Neat): 2958, 2931, 2172, 1714, 1610, 1513, 1462, 1374, 1301, 1249, 1169, 1082, 1034, 844, 758, 703, cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 0.12 (s, 9 H), 0.85 (d, J = 6.7 Hz, 3 H), 0.97 (d, J = 4.5 Hz, 6 H), 1.05 (s, 9 H), 1.30-1.39 (m, 1 H), 1.36 (s, 3 H), 1.40 (s, 3 H), 1.48-1.62 (m, 2 H), 1.68-1.90 (m, 3 H), 2.12-2.27 (m, 3 H), 2.35 (dd, J = 6.0, 18.1 Hz, 1 H), 2.74 (dd, J = 6.0, 18.1 Hz, 1 H), 3.29-3.47 (m, 2 H), 3.48-3.58 (m, 1 H), 3.76 (s, 3 H), 3.85 (d, J = 7.5 Hz, 1 H), 3.96-4.10 (m, 1 H), 4.24 (d, J = 11.3 Hz, 1 H), 4.37 (d, J = 11.3 Hz, 1 H), 6.74 (d, J = 9.0 Hz, 2 H), 7.08 (d, J = 8.3 Hz, 2 H), 7.64 (m, 6 H), 7.60-7.68 (d, J = 6.7 Hz, 4 H). ¹³C NMR (100 MHz, CDCl₃): δ = 0.1, 15.8, 18.4, 19.2, 19.4, 26.2, 26.6, 26.8, 27.3, 33.2, 33.4, 35.3, 35.8, 44.0, 55.2, 68.7, 71.7, 75.3, 79.6, 85.5, 86.2, 105.1, 109.9, 113.6, 127.5, 129.1, 129.4, 131.0, 133.9, 135.6, 158.9, 208.9. HRMS (ESI): m/z [M + Na]⁺ calcd for C₄₇H₆₈O₆Si₂: 807.4452; found: 807.4474.

15

Analytical Data for Compound 20: Viscous liquid; [α]_D ²⁵ -21.804 (c = 0.6, CHCl₃). IR (KBr): 794, 1071, 1248, 1513, 2172, 2958 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 0.12 (s, 9 H), 0.78-0.86 (d, J = 6.7 Hz, 3 H), 0.87-0.93 (d, J = 6.7 Hz, 3 H), 0.94-1.00 (d, J = 6.0 Hz, 3 H), 1.04 (s, 10 H), 1.21-1.39 (m, 1 H), 1.33 (s, 3 H), 1.35 (s, 3 H), 1.40-1.88 (m, 7 H), 1.99-2.10 (dd, J = 6.7, 16.6 Hz, 1 H), 2.12-2.22 (dd, J = 5.2, 16.6 Hz, 1 H), 3.31-3.40 (dd, J = 6.7, 9.8 Hz, 1 H), 3.42-3.56 (m, 3 H), 3.58-3.65 (dd, J = 3.7, 8.3 Hz, 1 H), 3.73 (s, 3 H), 4.01-4.14 (m, 1 H), 4.24-4.32 (d, J = 10.5 Hz, 1 H), 4.34-4.42 (d, J = 11.3 Hz, 1 H), 4.48-4.56 (d, J = 12.0 Hz, 1 H), 4.58-4.65 (d, J = 11.3 Hz, 1 H), 6.64-6.71 (d, J = 8.3 Hz, 2 H), 7.03-7.10 (d, J = 8.3 Hz, 2 H), 7.17-7.27 (m, 5 H), 7.29-7.41 (m, 6 H), 7.59-7.68 (d, J = 7.5 Hz, 4 H). ¹³C NMR (75 MHz, CDCl₃): δ = 0.1, 15.7, 18.5, 18.8, 19.2, 26.8, 27.0, 27.5, 27.7, 28.8, 33.4, 33.7, 35.8, 36.1, 37.1, 55.1, 68.7, 72.2, 72.4, 74.0, 75.9, 79.9, 80.0, 82.9, 85.7, 99.9, 105.8, 108.2, 113.5, 127.3, 127.5, 127.7, 128.2, 129.0, 129.4, 131.2, 133.9, 135.5, 138.5, 158.8. HRMS (ESI): m/z [M + Na]⁺ calcd for C₅₄H₇₆O₆Si₂: 899.5078; found: 899.5051.

16

Analytical Data for Compound 21: Viscous liquid; [α]_D ²⁵ -15.098 (c = 0.25, CHCl₃). IR (Neat): 3310, 2950, 2885, 2097, 1736, 1612, 1513, 1463, 1362, 1247, 1081, 837, 773, 632 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 0.01 (s, 3 H), 0.02 (s, 3 H), 0.06 (s, 3 H), 0.07 (s, 3 H), 0.74 (d, J = 6.5 Hz, 3 H), 0.88 (s, 9 H), 0.92 (s, 9 H), 0.94 (d, J = 6.5 Hz, 3 H), 0.97 (d, J = 6.5 Hz, 3 H), 0.85-1.08 (m, 3 H), 1.40-1.55 (m, 2 H), 1.66-1.91 (m, 4 H), 1.94-2.06 (m, 1 H), 2.07-2.17 (m, 2 H), 2.90 (dd, J = 7.3, 11.7 Hz, 1 H), 3.08-3.17 (m, 1 H), 3.33-3.41 (m, 1 H), 3.52-3.58 (m, 1 H), 3.67-3.75 (m, 1 H), 3.79 (s, 3 H), 3.93 (dd, J = 3.6, 10.2 Hz, 1 H), 4.25 (d, J = 10.2 Hz, 1 H), 4.51 (d, J = 10.9 Hz, 1 H), 4.62 (d, J = 11.7 Hz, 1 H), 4.69 (d, J = 12.4 Hz, 1 H), 6.79 (d, J = 8.7 Hz, 2 H), 7.17 (d, J = 8.7 Hz, 2 H), 7.23-7.31 (m, 5 H). ¹³C NMR (75 MHz, CDCl₃): δ = -4.7, -4.5, -4.2, -3.1, 16.6, 17.9, 18.9, 19.2, 25.6, 25.9, 26.7, 28.7, 31.3, 31.4, 35.2, 38.6, 55.2, 57.4, 69.3, 70.4, 71.7, 71.9, 75.7, 77.8, 80.3, 83.0, 113.5, 120.4, 127.0, 127.3, 128.1, 128.7, 131.5, 139.5, 158.8. HRMS (ESI): m/z [M + Na]⁺ calcd for C₄₄H₇₃N₃O₅Si₂: 802.4986; found: 802.4968.

17

Analytical data for Compound 22: Liquid; [α]_D ²⁵ -47.136 (c = 1.1, CHCl₃). IR (Neat): 3417, 2119, 1618, 1389, 1204, 772 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 0.95 (d, J = 6.5 Hz, 3 H), 1.06 (d, J = 6.5 Hz, 3 H), 1.09 (d, J = 6.5 Hz, 3 H), 1.23-1.36 (m, 2 H), 1.45-1.71 (m, 3 H), 1.74-2.05 (m, 3 H), 2.18 (dd, J = 2.1, 5.8 Hz, 2 H), 2.61 (m, 1 H), 2.68 (d, J = 5.8 Hz, 2 H), 3.07-3.21 (m, 2 H), 3.40 (m, 1 H), 3.64-3.71 (m, 1 H), 3.74 (s, 0.5 H), 3.85 (s, 0.5 H), 4.07-4.15 (m, 1 H), 4.52 (d, J = 11.7 Hz, 1 H), 4.68 (d, J = 11.7 Hz, 1 H), 7.27-7.41 (m, 5 H). ¹³C NMR (75 MHz, CDCl₃): δ = 17.0, 17.8, 19.7, 25.9, 28.8, 31.4, 36.2, 37.0, 44.3, 44.5, 57.6, 68.3, 69.7, 71.9, 73.8, 78.6, 82.5, 127.9, 128.2, 128.5, 137.8, 213.9. HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₄H₃₅N₃O₄: 452.2525; found: 452.2512.

18

Analytical data for Compound 5 (Major Diastereomer): Liquid; [α]_D ²⁵ -18.801 (c = 0.6, CHCl₃). IR (Neat): 3418, 2925, 2097, 1665, 1622, 1553, 1527, 1383, 1111, 616 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 0.92 (d, J = 7.1 Hz, 3 H), 0.99 (d, J = 6.2 Hz, 3 H), 1.01 (d, J = 7.1 Hz, 3 H), 1.39 (s, 1 H), 1.54-1.73 (m, 3 H), 1.77-2.05 (m, 4 H), 2.07-2.23 (m, 4 H), 2.55 (d, J = 7.1 Hz, 1 H), 3.07 (dd, J = 6.2, 11.6 Hz, 1 H), 3.18 (s, 3 H), 3.24 (dd, J = 6.2, 11.6 Hz, 1 H), 3.85-3.91 (m, 1 H), 3.95 (dd, J = 3.5, 6.2 Hz, 1 H), 4.37-4.44 (m, 1 H), 4.65 (d, J = 11.6 Hz, 1 H), 4.77 (d, J = 11.6 Hz, 1 H), 7.27-7.40 (m, 5 H). ¹³C NMR (100 MHz, CDCl₃): δ = 16.3, 18.8, 19.2, 26.2, 28.7, 32.1, 32.4, 36.9, 37.0, 43.3, 47.7, 57.5, 69.6, 72.4, 72.5, 76.2, 82.8, 83.2, 111.2, 127.6, 127.9, 128.3, 138.5. HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₅H₃₇N₃O₄: 466.2681; found: 466.2680.