ENANTIOSELECTIVE TOTAL SYNTHESIS OF (-)-CHLOROTHRICOLIDE VIA THE TANDEM INTERMOLECULAR AND INTRAMOLECULAR DIELS-ALDER REACTION OF A HEXAENOATE INTERMEDIATE

An enantioselective total synthesis of (-)-chlorothricolide (1) has be en completed via a route involving the tandem inter- and intramolecula r Diels-Alder (IMDA) reaction of hexaenoate 19 and the chiral dienophi le (R)-12. This reaction, which establishes seven asymmetric centers i n a single operation, is feasible only by virtue of the high diastereo facial and exo selectivity of dienophile 12. The C(9)-trimethylsilyl s teric directing group of 19 also plays a key role by controlling the s tereochemical course of the IMDA reaction leading to the bottom half o ctahydronaphthalene unit. Hexaenoate 19 was prepared in 32% overall yi eld by a 10-step sequence starting from the known acetylenic ketone 33 . Key steps include the asymmetric reduction of 33 using Alpine Borane (up to 94% eel, the Suzuki cross coupling of a-iodo vinylsilane 20 wi th vinylboronic acid 21, and the Homer-type olefination of aldehyde 41 with dienylic phosphonate 22. The key tandem inter-intramolecular Die ls-Alder reaction was performed by heating a mixture of 19 and (R)-12 (2 equiv) in toluene at 120 degrees C, which provided the targeted dou ble cycloadduct 44 in 40-45% yield, along with 19% of other cycloadduc t isomers and 25-20% of the IMDA adduct 24 with an (E,E,E)-C(16)--C(21 ) triene. The latter compound was recycled by treatment with additiona l (R)-12 in trichloroethylene at 125 degrees C. The yield of 44 from h exaenoate 19 was 55-59% after one recycle of (E,E,E)-24. Elaboration o f 44 to (-)-chlorothricolide was accomplished by a 9-step sequence in 26% overall yield, key steps of which included the construction of the spirotetronate subunit of 51 via the Dieckmann cyclization of 50, dep rotection of the two allyl units with Pd(0) catalysis, and the BOP-Q-m ediated macrolactonization of seco acid 52. The vinyl trimethylsilane substituent was removed in the final step of the synthesis by treatmen t with EtSH and BF3.Et2O. Because an authentic sample of chlorothricol ide was not available, synthetic (-)-chlorothricolide was treated with CH2N2 to give 24-O-methyl chlorothricolide methyl ester (59) [[alpha] D-25 -29.3 degrees (c = 0.95, CHCl3), mp 228.5-229 degrees C; lit.(1a) [alpha]D-20 - 30 degrees (c = 1, CHCl3), lit.(1a) mp 230 degrees C)] which proved identical in all respects (except optical rotation and mp ) with an authentic sample of racemic 59 provided by Professor Yoshii.