Abstract:
This thesis describes efforts directed towards the enantioselective total synthesis of the dimeric pyranonaphthoquinone crisamicin A 18. The synthetic approach utilizes a double stereoselective reduction, Suzuki-Miyaura homocoupling of 405 and Hauser-Kraus annulation between enone 407 and cyanophthalide 406 as key steps. Initial work focused on the preparation of novel enone 407 for use in the key Hauser- Kraus annulation with cyanophthalide 406. Enone 407 was prepared from the natural sugar D-mannitol 433. Key steps include use of a magnesium in methanol mediated reductive cleavage to prepare the r,β-unsaturated ester 409, and a Sharpless asymmetric dihydroxylation-lactonization sequence to produce cis-lactone 443. Protection-deprotectionoxidation sequences gave lactone aldehyde 408 and Horner-Wadsworth-Emmons olefination of 408 gave enone 407. With enone 407 in hand, attention focused on the synthesis of nanaomycin D 8 in which the viability of enone 407 to undergo successful Hauser-Kraus annulation to produce annulation product 412 was investigated. Further elaboration of 412 gave 470 that comprises the entire carbon framework of the natural product nanaomycin D 8 thus completing its formal synthesis. The synthesis of 470 also provided a model study that delivered the foundation for the total synthesis of crisamicin A 18. The Hauser-Kraus annulation methodology was next applied to the synthesis of the dimer crisamicin A 18. After successful Hauser-Kraus annulation of cyanophthalide 406 with enone 407, triflate 405 was synthesized. The Suzuki-Miyaura homocoupling of 405 afforded dimer 536. Double deprotection of 536 gave diol 537 that upon cyclization underwent methanolysis to give dimeric naphthopyran 540 after double stereoselective reduction. All attempts to prepare bis-lactone 539 from both 537 and 540 were unsuccessful. Attention then focused on a modified route that involved the late stage Suzuki- Miyaura homocoupling of triflate 543. Suzuki-Miyaura homocoupling of 543 produced dimer 539 thus achieving the enantioselective synthesis of the carbon framework of crisamicin A 18. The enantioselective synthesis of dimeric pyranonaphthoquinone 552, 5,5'-di-epi-10,10'- O,O'-dimethylcrisamicin A was effected by oxidative demethylation of dimer 539 Disappointingly, the subsequent demethylation of 552 was unsuccessful and completion of the synthesis of crisamicin A 18 was not realized.