EXPERIMENTAL STUDIES IN THE STEROIDS. PART I. A STUDY OF NEW METHODS FOR THE DEGRADATION OF THE SIDE-CHAIN IN CERTAIN BILE ACIDS. PART II. ANOVEL METHOD FOR THE PREPARATION OF STEROL-DICHLORIDES. PART III. THE PREPARATION OF SOME NEW STEROL-OXIDES

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EXPERIMENTAL STUDIES IN THE STEROIDS. PART I. A STUDY OF NEW METHODS FOR THE DEGRADATION OF THE SIDE-CHAIN IN CERTAIN BILE ACIDS. PART II. ANOVEL METHOD FOR THE PREPARATION OF STEROL-DICHLORIDES. PART III. THE PREPARATION OF SOME NEW STEROL-OXIDES

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EXPERIMENTAL STUDIES IN TEE STEROIDS

Part I. A Study of New Methods for the Degrada­ tion of the Side-ohain in Certain Bile Aoids. Part II. A Novel Method for the Preparation of Sterol Dichlorides; Part III.. The Preparation of Some New Sterol Oxides.

fcy Carl John Berg .11

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A Dissertation ^ presented to the f Faculty of Princeton University ,\r in Candidacy for the D6{p?ee of Dootor of Philosophy'

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Recommended for acceptance by the Department of Chemistry June, 1942

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ACKNOWLEDGEMENT This dissertation was carried out under the direction of Professor Everett S. Wallis, to whom I am deeply indebted for continual aid and en­ couragement • I am also indebted to Dr. Purnendu Nath Chakravorty, Rockefeller Foundation assistant in organic chemistry, for advice and assistance; to Trinity College for the H. E. Russell Fellowship held by me during the first two years of my studies in Princeton; to the Rockefeller Founda­ tion for a grant-in-aid which made the work pos­ sible; and to Merck and Company of Rahway, N. J. for the microanalyses reported in the descrip­ tion of the results of these experimental studies.

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INTRODUCTION The steroids oomprise a group of naturally ooourring com­ pounds all of which contain the oyolopentanoperhydrophenanthrene nuoleus.

The variations on this basic struoture are

very numerous, as is illustrated by the following examples of types of these compounds:

Cholesterol A sterol

Desoxyoholio acid A bile acid

Progesterone A sex hormone

Corticosterone An adrenal cortex hormone

Sarsapogenin A sapogenin

Strophantidin A heart poison

Of the known classes of this family the sterols and bile acids are the most generally available, and the hormone

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E. substances physiologically are of the most importance.

This

faot has led to many attempts to convert the one into the other by laboratory methods.

These attempts have been made,

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notably, from two directions:

(a) the total or partial re­

moval of the side chain present in these oompounds; and (b) the removal and introduction of groups into the nuclear sys­ tem. The experimental work presented in this thesis touches on all of these aspects of the problem.

In Part I there are

described certain experimental results obtained in a study of new methods for the degradation of the side chain in desoxyoholio acid.

Part II contains a description of a novel

method for the preparation of certain sterol diohlorides and certain chemical properties of these compounds.

In Part

III a description of a method for the preparation of new sterol oxides is given, together with the results of some experiments designed to introduce an hydroxyl or keto group into certain portions of the steroid molecule known to be responsible for adrenal cortex activity.

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3.

PART ONE! The systematic removal of carbon atoms from bile acid side chains dates from the work of Wieland, Sohlichting, and (1 ) Jaoobio Employing the method of Barbier these investiga(1)

Wieland, Sohliohting, and Jacobi, H. S. 161, 80 (1926).

tors were able to carry out systematically the follCAving reactions:

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\A-J Noroholanio acid This process was then repeated to give bisnorcholanic acid* (I).

In their hands the next step led to the formation of

etio-oholanio acid (II) when chromic acid was used as an oxidant.

On working up the mother liquors, they also ob­

tained small amounts of etiooholanone (III) and pregnanone (IV).

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II.

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III

IV

Since their work was carried out previous to the dis­ covery of the hormones, a number of years elapsed before suf­ ficient interest was aroused for either repetition or ex­ tension of these investigations.

The eluoidation of the

structure of the hormones, however, stimulated anew active interest in this field, with the result that every known bile acid has been systematically studied from this point of view. This is shown by the fact that from 1935 to 1940 fourteen (2 ) describing investigations of this type have appapers (S)

Dalmer, von Werder, Honigmann, and Heyns, Ber. 68, 1814 (1935). 3-hydroxy-allooholanic acid to ancErosterone • Reindel and Niederlander, Ber. 68, 1969 (1935). Lithocholio acid to bisnor-lithooholic acid. Marker, Kamm, McGinty, Jones, Wittle, Oakwood, and Crooks, J. A. C. S. 59, 768, 1367 (1937). 3-ohloro aliocholanic acid to epi-allopregnanolone. Morsmann, Steiger, and Reichstein, Helv.