Efforts directed towards an asymmetric total synthesis of the antitumor antibiotic Fredericamycin A and a study of the Diels-Alder reactions of a carvone-derived diene

Morrison, Christopher F. (2001) Efforts directed towards an asymmetric total synthesis of the antitumor antibiotic Fredericamycin A and a study of the Diels-Alder reactions of a carvone-derived diene. Doctoral (PhD) thesis, Memorial University of Newfoundland.

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Abstract

Since its discovery in 1981, the antitumor antibiotic Fredericamycin A (1) has been the subject of extensive synthetic efforts focused mainly on construction of its 1,3-cyclopentanedione subunit. Six total syntheses of 1 in racemic form have been reported. An asymmetric synthesis of 1 was accomplished only very recently. We have devised a potentially enantioselective route to 1 relying on precedents set in our laboratory for the construction of spiro-1,3-cycIopentanediones and their reduction in an enantioselective manner by Baker's yeast. Reduction of 2’3'-dihydro-7'-methoxy-5'- methyIspiro(cyclopentane-2.1’-(1H)indene)-1,3-dione (132) with Baker's yeast furnished (2R,3R)-2’3’-dihydro-3-hydroxy-7’-methoxy-5’-methyIspiro(cycIopentane-2.1’-(1H)indene)-1-one (142). The absolute stereochemistry of 142 was determined through derivatization as camphorsulfonyl ester 143. which was diastereomerically pure and crystalline. On the basis of the absolute stereochemistry of 142, it was determined that ethyl 3,4,6-trimethoxy-2-[1,3]dithiolan-2-ylbenzoate (144) would be the required A ring synthon to lead to the natural enantiomer of 1. The A ring synthon 144 was to be annulated to the CDEF synthon employing a tandem Michael-CIaisen sequence. In a model reaction, deprotonated ethyl 2-[1.3]dithioIan-2-ylbenzoate (114a) reacted smoothly in a tandem Michael-CIaisen process with (2R*,3S*)-2'.3’-dihydro-7’-methoxy- 5’-methyl-3-(trimethylsilyl)oxyspiro([4]cyclopentene-2,1’-(1H)indene)-1-one (135) to furnish (2R*.3S*.3aS*)-4-[1.3]dithiolan-2-y1-2.2’.3.3’.3a.4-hexahydro-9-hydroxy-7’- methoxy-5'-methyl-3-(trimethylsilyl)oxyspiro((1H)-benz[f]indene-2.1'-(1H)-indene)-1-one (136) in 85% yield. -- Unfortunately, all attempts to convert N,N-diethyl-2-[1,3]dithiolan-2-y1-3,4,6-trimethoxybenzamide (147) to ester 144, either directly or indirectly, were unsuccessful. However, the synthesis of ethyl 2-[1,3]dithiolan-2-y1-5,6-dimethoxybenzoate (245) was achieved. Deprotonation of 245, followed by addition to a Michael acceptor, did not yield the expected tandem Michael-CIaisen product, but unsymmetrically substituted phthalic thiothionoanhydride 250. This unexpected elimination of ethene was circumvented by conversion of the dithiolane to a dithiane moiety. Deprotonated ethyl 2-[1,3]dithian-2-y1-5,6-dimethoxybenzoate (258) reacted smoothly with both 4-((tert-butyldimethylsilyl)oxy)spiro[4.5]dec-2-en-1-one (119) and (2R*,3R*)-3-acetoxy-2’.3’-dihydrospiro([4]cyclopentene-2,1’-[1H]indene)-1-one (249) to furnish the expected tandem Michael-CIaisen adducts in excellent overall yield. -- Singlet oxygen often exhibits unusual facial selectivity in the Diels-Alder reaction, presumably due to the formation of a perepoxide intermediate. Our investigations into this unusual facial selectivity are presented, including attempts to extend this unusual facial selectivity to other dienophiles, such as N-phenylmaleimide, 4-phenyl-1.2.4-triazoline-3,5-dione (276), and tetracyanoethene.

Item Type: Thesis (Doctoral (PhD))
URI: http://research.library.mun.ca/id/eprint/1317
Item ID: 1317
Additional Information: Bibliography: leaves 245-257.
Department(s): Science, Faculty of > Chemistry
Date: 2001
Date Type: Submission
Library of Congress Subject Heading: Antineoplastic antibiotics--Synthesis; Diels-Alder reaction

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