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Synthesis of (+)-dynemicin A and analogs of wide structural variability. Establishment of the absolute configuration of natural dynemicin A

Citation

Fraley, Mark E. (1995) Synthesis of (+)-dynemicin A and analogs of wide structural variability. Establishment of the absolute configuration of natural dynemicin A. Dissertation (Ph.D.), California Institute of Technology. http://resolver.caltech.edu/CaltechETD:etd-10022007-135120

Abstract

A highly convergent synthetic route to the potent natural antitumor agent (+)-dynemicin A (1) is described. Key features of the synthesis include: (1) the condensation of the potassium enolate of menthyl acetoacetate with trans-ethyl crotonate, providing the optically pure trans-disubstituted 1,3-cyclohexanedione 38; (2) the palladium-catalyzed coupling of the enol triflate 37 with t-butyl 2-borono-4-methoxycarbanilate to furnish 35, followed by the thermolysis of the latter to afford the quinolone 34; (3) the stereoselective acetylide addition of the (Z)-enediyne bridge to an acylquinolinium intermediate derived from quinoline 60, affording the addition product 61; (4) the acetylide-mediated closure of the (Z)-enediyne bridge of ketone 65 to produce 66; (5) the carboxylation and subsequent methylation of ketone 69, providing the vinylogous carbonic acid 70; (6) the oxidation of the phenol 73 to furnish the enone 74, as well as the reductive deprotection of 75 to afford the quinone imine 77; and (7) the Diels-Alder cycloaddition reaction of the quinone imine 77 with 1,4,7-tris(trimethylsiloxy)isobenzofuran, followed by the desilylation and oxidation of the resultant adduct to complete the synthesis of 1. The preparation of structurally diverse analogs of 1 by late-stage modification of the synthetic route is detailed. The absolute configuration of natural 1 is determined to be 2S, 3S, 4S, 7R, 8R, by the comparison of circular dichroism spectra of synthetic and authentic 1.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:chemistry
Degree Grantor:California Institute of Technology
Division:Chemistry and Chemical Engineering
Major Option:Chemistry
Awards:The Herbert Newby McCoy Award, 1995
Thesis Availability:Restricted to Caltech community only
Research Advisor(s):
  • Myers, Andrew G.
Thesis Committee:
  • Myers, Andrew G. (chair)
  • Dougherty, Dennis A.
  • Carreira, Erick Moran
  • Dervan, Peter B.
  • Grubbs, Robert H.
Defense Date:14 October 1994
Record Number:CaltechETD:etd-10022007-135120
Persistent URL:http://resolver.caltech.edu/CaltechETD:etd-10022007-135120
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:3870
Collection:CaltechTHESIS
Deposited By: Imported from ETD-db
Deposited On:18 Oct 2007
Last Modified:26 Dec 2012 03:03

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