Progress toward the Total Synthesis of Azaspiracid: Construction of the ABC Ring System

1. Progress toward the Total Synthesis of Azaspiracid: Construction of the ABC Ring System Rich G. Carter, T. Campbell Bourland and Melissa A. Gronemeyer Department of Chemistry Oregon State University Corvallis, OR 97331 E-mail: rich.carter@oregonstate.edu Group Web page: http://www.onid.orst.edu/~carteric/ Figure 2. Reported locations of isolation in Ireland of the azaspiracids. Figure 1. Photo of Mytilus edulis.1 Introduction. A new class of toxins in shellfish, the azaspiracids (Figures 1 and 2), has been recently observed in mussels harvested in the surrounding waters of Europe. Azaspiracid (1) and its related structures, azaspiracid 2-5 (2-5), have been shown to induce serious injury to the digestive tracts, liver, pancreas, thymus and spleen in mice (Figure 3).2 In addition to their significant biological properties, the azaspiracids represent a daunting synthetic challenge as the parent structure 1 possesses twenty stereocenters and three separate spirocyclic linkages. For these reasons, the azaspiracids have garnered significant recent attention in both the biological and synthetic communities.2-5 This poster discloses the successful construction of the C1-C17 portion of azaspiracid including the crucial C10, C13 transoidal bisspirocyclic array. discover that the predominate product was the cisoidal bisspirocycle 30.6 It would appear from these observations that the cisoidal bisspirocycle 30 is the result of kinetic control while the transoidal bisspirocycle AB can be accessed under thermodynamic conditions. Scheme 2. Fragment A. i. TBDPSCl, DMAP, Et3N, CH2Cl2; ii. TPAP, NMO, mol. sieves, CH2Cl2; Ph3P=CHCO2Me, 80% (two steps); iii. DIBAL-H, CH2Cl2, -78 to 0°C, 99%; iv. TPAP, NMO, mol. sieves, CH2Cl2, 88%; v. 10, Et2O, -78°C to -20°C, 93%; vi. (-)-DIPT, Ti(Oi-Pr)4, TBHP, CH2Cl2, mol. sieves, -20°C, > 95% e.e. at 57% conversion; vii. TESOTf, 2,6-lutidine, CH2Cl2, -78°C, 85%, viii. n-BuLi, CeCl3 (1.3 equiv.), THF; 13, 63%; ix. Lindlar's Catalyst, H2, quinoline, 1-octene / hexanes (1:9), 81%; x. Et3N•HF, HF, MeOH, CH2Cl2, 65%. 1 R1 = R2 = R4 = H, R3 = Me 2 R1 = R4 = H, R2 = R3 = Me 3 R1 = R2 = R3 = R4 = H 4 R1 = OH, R2 = R3 = R4 = H 5 R1 = R2 = R3 = H, R4 = OH ation of the alkyne 14 initially proved problematic; however, the addition of 1-octene as a co-solvent suppressed any overreduction of the C8,9 olefin. Synthesis of the aldehyde fragment B began from known Evans’ alkylation product 16 (Scheme 3). Direct Sharpless dihydroxylation of the substrate containing the oxazolidinone yielded a disappointing 1.5:1 ratio (at C16) of lactone products. The selectivity in the dihydroxylation could be improved to 3:1 by replacement of the Evans auxiliary with a benzyl ester. Based on published3a,3e and unpublished work from our laboratory, this substitution appears to be a general remedy for poor diastereoselectivity in dihydroxylations on similar systems. Removal of the pivaloate protecting group from 21 was best accomplished using LiBH4 in the presence of a small amount of sat. aq. NH4Cl. Use of H2O as an additive or alternate reduction conditions (DIBAL-H) proved inferior. Figure 3. The Azaspiracids. Strategy. Due to the structural complexity and size of azaspiracid, it is imperative that any synthetic approach towards 1 be highly convergent (Scheme 1). Our strategy disconnects the target into two major subunits AB and CDE. Further disconnections at C12,13 as well as C25,26 and C34,35 lead back to five readily available fragments: A - E. The C12,13 linkage has already been constructed using a Julia coupling strategy between sulfone A and aldehyde B in good yield. In addition, we have already constructed significant portions of four of the five fragments. The C34,35 linkage should be available via a matched, chelation-controlled lithio imine addition to the requisite a-oxy aldehyde D. The C25,26 alkene CDE will be available from a Wittig olefination. Scheme 5. Synthesis of ABC Ring System. Scheme 3. Fragment B. i. LDA, THF, -78°C then B; ii. TPAP, NMO, CH2Cl2, mol. sieves 60% (over 2 steps); iii. 5% Na / Hg, Na2HPO4, MeOH, THF, -10°C; iv. CSA, PhMe / t-BuOH, 80% over 2 steps, 3:5 ratio (AB:30); v. CSA, PhMe / t-BuOH (1:1), 92%, 3:5 ratio (AB:30). i. BnOLi, PMBOH, THF, 99%; ii. AD mix , NaHCO3, t-BuOH, H2O; iii. TIPSOTf, 2,6-lutidine, CH2Cl2, -78°C, 66% overall yield from 17 (3:1 d.s.); iv. LiBH4, MeOH, THF, 0°C, 99%; v. PivCl, Et3N, DMAP, CH2Cl2, 66%; vi. NaH, BnBr, DMF, -50°C to -10°C; vii. TBAF, THF, 79% (over 2 steps); viii. TESCl, DMAP, Et3N, CH2Cl2, 95%; ix. LiBH4, sat. aq. NH4Cl, THF, 0°C to r.t., 99%; x. TPAP, NMO, CH2Cl2, mol. sieves, 87%. Conclusion. The successful construction of the ABC ring system of azaspiracid has been accomplished. Bisspiroketal AB contains a key handle for further elaboration using the C16 benzyloxy moiety. This handle should allow for the necessary functionalization to access the target 1. In addition, the synthesis of compounds 25 and 27 should provide access to fragments C and E. Further progress toward the total synthesis of azaspiracid will reported in due course. Acknowledgement. The authors thank the National Institutes of Health (GM 63723) and Oregon State University for support of this work. References. 1. This photograph was taken by Keith Hiscock. For more information see: http://www.marlin.ac.uk/demo/Mytedu.htm. 2. (a) MacMahon, T.; Silke, J. Harmful Algae News 1996, 14, 2. (b) Satake, M.; Ofuji, K.; Naoki, H.; James, K. J.; Furey, A.; McMahon, T.; Silke, J.; Yasumoto, T. J. Am. Chem. Soc.1998, 120, 9967. (c) Ofuji, K.; Satake, M.; McMahon, T.; Silke, J.; James, K. J.; Naoki, H.; Oshima, Y.; Yasumoto, T. Nat. Toxins 1999, 7, 99. (d) Ofuji, K.; Satake, M.; McMahon, T.; James, K. J.; Naoki, H.; Oshima, Y.; Yasumoto, T. Biosci. Biotechnol. Biochem.2001, 65, 740. (e) Ito, E.; Satake, M.; Ofuji, K.; Kurita, N.; McMahon, T.; James, K.; Yasumoto, T. Toxicon. 2000, 38, 917. 3. (a) Carter, R. G.; Weldon, D. J. Org. Lett. 2000, 2, 3913. (b) Carter, R. G.; Weldon, D. J. Bourland, T. C. 221st National ACS Meeting, San Diego, ORGN-479. (c) Carter, R. G.; Graves, D. E. Tetrahedron Lett.2001, 42, 6035. (d) Carter, R. G.; Bourland, T. C.; Graves, D. E. Org. Lett. 2002, 4, 2177. (e) Carter, R. G.; Graves, D. E.;  Gronemeyer, M. A., Tschumper, G. S. Org. Lett. 2002, 4, 2181. 4. (a) Forsyth, C. J.; Hao, J.; Aiguade, J. Angew. Chem. Int. Ed.2001, 40, 3662. (b) Nicolaou, K. C.; Pihko, P. M.; Diedrichs, N.; Zou, N., Bernal,F. Angew. Chem. Int. Ed.2001, 40, 1262. (c) Dounay, A. B.; Forsyth, C. J. Org. Lett.2001, 3, 975. (d) Aiguade, J.; Hao, J.; Forsyth C. J. Org. Lett.2001, 3, 979. (e) Aiguade, J.; Hao, J.; Forsyth, C. J. Tetrahedron Lett. 2001, 42, 817. (f) Hao, J.; Aiguade, J.; Forsyth, C. J. Tetrahedron Lett. 2001, 42, 821. (g) Buszek, K. R. 221st National ACS Meeting, San Diego, ORGN-5701. 5. Nicolaou and co-workers recently reported an alternate solution to the C10, C13 bisspiroketal involving substitution of the C8,9 alkene with a C9 hydroxyl function. Nicolaou, K. C.; Qian, W.; Bernal, F.; Uesaka, N.; Pihko, P. M.; Hinrichs, J. Angew. Chem. Int. Ed.2001, 40, 4068. 6. Further warming of the reaction to room temperature for an additional 48 h, resulted in the previously observed (3:5 ratio of 30:AB) equilibrium mixture. The synthesis of fragments C and E could be simplified by the observation that both fragments may arise from a common subunit 24 (Scheme 4). This lactone has been previously prepared by several other laboratories using a route similar to the approach outlined below. Subsequent reduction to the hemi-acetal followed by formation of the dithiane yielded the alcohol 25. The required conversion of 25 to the aldehyde C should be available using standard methods. Treatment of the previously mentioned lactone 24 with MeLi provided the hemiketal in good yield. Conversion to the keto azide 27 could be accomplished via the corresponding tosylate 26. Reduction / imine formation of 27 is currently under investigation. Scheme 4. Fragment C and E. i. DHP, PPTS, CH2Cl2, 99%; ii. DIBAL-H, CH2Cl2, -78°C, 98%; iii. TPAP, NMO, 4 Å mol. sieves, CH2Cl2; iv. EtCO2Et, LDA, THF, -78°C, 85%; v. PTSA, PhH, Dean-Stark Trap, reflux, 85%; vi. 5% Rh/Al2O3, H2, Et2O, -30°C, 90%, 6:1 d.s.; vii. DIBAL-H, CH2Cl2, -60°C, 95%; viii. HS(CH2)3SH, BF3Et2O, CH2Cl2, 72%; ix. MeLi, -78°C, Et2O, 85%; x. TsCl, Et3N, CH2Cl2, 72%; ii. NaN3, DMF, 0°C to r.t., 80%. Synthesis of ABC Ring System. With access to both fragments A and B, coupling of the two subunits was explored. Based on prior work from our laboratory,3c a Julia coupling approach has proven reliable (Scheme 5). The corresponding hydroxysulfone adduct was prone to spirocyclization at C10; however, this problem could be easily circumvented by immediate oxidation of the crude Julia adduct to the stable keto sulfone 28. Based on experimental and computational work, we have begun to map out the controlling influences in bisspirocyclization.3b-e While substitution at C17 has proven to be detrimental to obtaining the correct stereochemical bisspirocyclic array, C16 substitution does allow access to the natural stereochemical configurations at C10 and C13.3e The desired product AB was isolated in a 3:5 (AB:30) ratio with its C13 cisoidal epimer 30 using our standard [CSA (0.04 M) t-BuOH/PhMe (1:1)] conditions. In addition, we were gratified to observe that the cisoidal product 30 could be equilibrated to the transoidal species AB by resubmission to the reaction conditions in an identical [3:5 ratio (AB:30), 92% yield] equilibrium ratio. With one equilibration cycle, a 50% overall yield of the desired transoidal bisspirocycle AB could be obtained. In order to further study the nature of the bisspiroketalization, bisspirocyclization with the ketone 29 was performed at lower temperatures (-10 to 4°C, 21 h) and reduced molarity of the acid catalyst (0.003 M) under otherwise identical reaction conditions (1:1 t-BuOH / PhMe). We were intrigued to Scheme 1. Retrosynthetic Strategy. Synthesis of Fragments. Our approach toward fragment A employed a key kinetic resolution strategy for the incorporation of the C6 stereogenic center (Scheme 2). First generation approaches from our laboratory toward this stereocenter utilized a Corey chiral auxiliary, allenyl borane approach;3a however, the level of enantioselectivity (80%) and other logistical issues rendered that strategy inferior. Semihydrogen-