Asymmetric syntheses of pectenotoxins-4 and -8, part II: synthesis of the C20-C30 and C31-C40 subunits and fragment assembly.

Abstract

In the preceding communication,[1] the proposed synthesis plan identified the two principal pectenotoxin-4 subunits II and III (Figure 1). It was our intention to couple these fragments through the alkylation of the metalloenamine derived from hydrazone III, readily available from the coupling of advanced intermediates IV and V (transform T2), by epoxide II. However, this investigation revealed that the above bond construction was not feasible due to the decomposition of metalloeneamine III under the reaction conditions.[2] Accordingly, the objective in the present communication is the synthesis of the subunits IV and V, and the completion of the syntheses of pectenotoxin-4 (1) and pectenotoxin-8 by a revised fragment coupling strategy, where epoxide alkylation (transform T1) precedes diene formation (transform T2). The plan for the construction of the F-ring tetrahydrofuran IV was to involve a C37 hydroxy-directed epoxidation of olefin VI with a subsequent ring closure by the C32 hydroxy moiety (transform T3). Finally, the stereoselective formation of the E-ring tetrahydrofuran V from its acyclic precursor VII was based on an iodoetherification precedent provided by Bartlett and Rychnovsky (transform T4). The synthesis of the ring-E synthon V began with the known aldol adduct adduct 2 (Scheme 1).[4] Reduction of 2 (LiBH4, THF, 0 8C), and selective protection of the primary alcohol (TBSCl, Im, CH2Cl2, 100% over two steps) afforded allylic alcohol 3.[5] Acylation of 3 with the PMB-protected lactic acid 4[6] (DCC, DMAP, CH2Cl2, 52%), followed by carbonyl olefination of 5a with Tebbe reagent[7] afforded the 1,5-diene 5b. Claisen rearrangement of 5b in refluxing toluene gave the desired rearrangement product 6 in 82% yield for the two steps. Chelate-controlled reduction of the resulting ketone (Zn(BH4)2, Et2O, 78 8C, 86%, d.r. 86:14) provided the precursor for the key iodoetherification reaction. In spite of the modest selectivity that was observed for the formation of the desired tetrahydrofuran 7 (NIS, CH3CN, 40 8C, 89%, d.r. 72:28), this outcome proved sufficient to pursue the planned route. Successive radical dehalogenation of 7 (Bu3SnH, AIBN, toluene, 100%) and deprotection of the primary TBS ether (TBAF, THF, 95%) afforded alcohol 8. Oxidation with Dess± Martin reagent[8] (py, CH2Cl2, 99%), Wittig homologation (EtOC(O)CC(CH3)PPh3, THF, 65 8C; 100% E :Z> 95:5), and ester reduction (LiAlH4, Et2O, 0 8C, 92%) completed the carbon assembly of the E-ring fragment. Benzyl protection (NaH, BnBr, TBAI, THF/DMF, 94%) followed by PMB deprotection (DDQ, CH2Cl2/pH 7 buffer, 95%) gave alcohol 10. Oxidation to the methyl ketone[8] (Dess±Martin periodinane, py, CH2Cl2, 93%), and hydrazone formation (TMSCl, CH2Cl2/Me2NNH2, 100%) completed the synthesis of hydrazone 11. As summarized in Figure 1, the first stage of the synthesis of the ring-F fragment IV will be simplified to the construction of the C31±C35 phosphonium salt, the C36±C40 aldehyde, and their union through a Wittig coupling to afford the Zolefin VI. The synthesis of the C31±C35 phosphonium salt began with the known triol derivative 12 (Scheme 2).[9] Protection of the hydroxy group at C33 of 12 as a PMB ether (PMBBr, NaH, THF/DMF, 95%) followed by reductive ozonolysis (O3, EtOH, then DMS, then NaBH4, 95%) afforded alcohol 13. Transformation of 13 to the corresponding iodide (I2, Im, Ph3P, CH2Cl2, 0 8C, 89%) proceeded smoothly, but careful control of the temperature was required to access phosphonium salt 14 (Ph3P, CH3CN, 55 8C, 89%).[10] The synthesis of the aldehyde partner 17 began with protection of the hydroxy group at C37 of aldol adduct 15[11] as a base-sensitive triphenylsilyl ether (TPSCl, Im, DMAP, DMF, 0 8C, 98%; Scheme 2). Half reduction of the S-phenyl thioester[12] (Pd/C, Et3SiH, acetone, 95%), and olefination under modified Lombardo conditions[13] ([Cp2ZrCl2], Zn dust, CH2I2, THF, 0 8C, 84%) afforded olefin 16. RhodiumCOMMUNICATIONS