studies in synthesis of 6-oxasteroids

Abstract

Thesis Title Studies in: (I) Synthesis of 6-Oxasteroids and (II) Ultraviolet Spectra of 1,2-Dicyano Esters and Related Compounds

The thesis is divided into three parts:

Part I: Synthesis of 6-Oxasteroids

Chapter I: A review of the synthesis of oxasteroids. Chapter II: Investigations towards the total synthesis of 6-oxasteroids, resulting in the synthesis of 17-acetoxy-3-methoxy-6-oxa-7,7-dimethylestra-1,3,5(10),8,14-pentaene (J).

Key Experimental Details:

Condensation of 7-methoxychroman-4-one with glyoxylic acid in the presence of sodium hydroxide gave a mixture of:

1-oxo-4-oxa-6-methoxy-2-tetrylideneacetic acid (2a) 1-oxo-4-oxa-6-methoxy-1,4-dihydro-2-naphthylacetic acid (3a) Ratio: 1:3

Structures confirmed by UV and IR spectra and catalytic hydrogenation of methyl esters (2b and 3b) to the same saturated ester: methyl 1-oxo-4-oxa-6-methoxy-1,2,3,4-tetrahydro-2-naphthylacetate. Michael condensation of acid (2a) with ?-methylacetoacetonitrile (4) in the presence of sodium hydroxide, followed by esterification, afforded: 1-methoxycarbonyl-2-cyano-2-methyl-3-oxo-7-methoxy-9-oxa-1,2,3,9,10,10a-hexahydrophenanthrene (5) in very low yield. Alternative approach: Using 7-methoxy-2,2-dimethylchroman-4-one (6).

Condensation with glyoxylic acid and esterification gave methyl 1-oxo-3,3-dimethyl-4-oxa-6-methoxy-2-tetrylideneacetate (7) and related compounds in poor yields. Attempts at Michael condensation failed.

Successful Route:

Chromanone (6) condensed with vinylmagnesium bromide ? 7-methoxy-2,2-dimethyl-4-vinylchroman-4-ol Converted to 3-methoxy-6-oxa-7,7-dimethyl-8,14-secoestra-1,3,5(10),9(11)-tetraene-14,17-dione by condensation with 2-methylcyclopentane-1,3-dione. Sodium borohydride reduction ? hydroxy compound ? acetylation and cyclization ? pentaene derivative (J). By-products characterized; one identified as 5-methoxy-6-oxa-7,7-dimethyl-9,14-oxido-8,14-secoestra-1,5(10)-trien-17-one using UV, IR, and NMR spectra.

Part II: Cope-Knoevenagel Reaction

Reaction of 2-carbethoxycyclopentanone with ethyl cyanoacetate. Structure of condensation product revised from ethyl 2-carbethoxy-2-cyclopentenylcyanoacetate to ethyl 2-carbethoxycyclopentylidenecyanoacetate based on UV, IR, NMR spectra and ozonolysis. By-products characterized.

Part III: UV Spectra of 1,2-Dicyano Esters

Detailed investigation of UV spectra of several new 1,2-dicyano esters and related compounds. Observations:

Anomalous UV absorption maxima around 245 nm with low extinction coefficients, concentration-dependent. Similar anomalies in 1,1,2-tricyano compounds around 231 nm.

Studies in ethanol at different concentrations and IR spectra in chloroform and chloroform-methanol mixtures confirm keteniminization as the cause of absorption. Influence of the 2-cyano group on keteniminization demonstrated.

Appendix Contains the paper: “A Revised Structure for the Condensation Product of 2-Carbethoxycyclopentanone and Ethyl Cyanoacetate” T.R. Kasturi and A. Srinivasan, Tetrahedron, 22, 2575 (1966).