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NAME AND ADDRESS DATE
NORTHWESTERN UNIVERSITY
TRICYCLIC INTERMEDIATES FOR
THE SYNTHESIS OF STEROIDS
A DISSERTATION
SUBMITTED TO THE GRADUATE SCHOOL
IN PARTIAL FULFILLMENT OF THE REQUIREMENTS
for the degree
DOCTOR OF PHILOSOPHY
FIELD OF CHEMISTRY
by
CAMERON KIRBY LYON
EVANSTON, ILLINOIS
SEPTEMBER, 1951
1952
ProQuest Number: 10101693
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ACKNOWLEDGEMENT
The author is deeply indebted to Professor Byron
Riegel for his guidance and encouragement throughout
this work*
The author also wishes to thank the Research
Corporation for financing a Research Assistantship
under which much of this work was done.
TABLE OF CONTENTS
INTRODUCTION .......................................... 1
HISTORICAL
I. The building of the D-ring onto an ABC-
tricyclic intermediate............. • • . 4
II- The building of the A-ring onto a BCD-
tricyclic intermediate • ................ 14
III- The condensation of two suitable fragments
to form the ABCD-tetracyclic nucleus • • • 23
DISCUSSION ..................................... 28
EXPERIMENTAL
I. Preparation of 2-methyl-l-vinylcyclohexene
2-Methylcyclohexanol .................... 45
2-Methylcyclohexanone • • • • • • • • • • • 45
2-Methyl-l-ethynylcyclohexanol ........... 46
2-Methyl-l-vinylcyclohexanol ......... 46
2-Methyl-l-ethynylcyelohexene.......... 48
2-Methyl-l-vinylcyclohexene............... 48
A- Dehydration of 2-methyl-1-vinyleyelo-
hexanol............................ 48
B. T^rdrogenation of 2-methyl-l-ethynyl-
cyclohexene........................ 49
C. Dehydration of (2-methyl-l-cyclo-
hexenyl)-methylcarbinol ........... 49
II. Attempted Diela-Alder condensations with
5-methyr^l-vinylcyclbhexene
With maleic anhydride...................... 50
With benzoquinone - • • • • • • 51
With 2-carbomethoxybenzoquinone........... 53
III* Preparation of 1-vinylcyclohexene
1-Ethynyleyclohexanol ........... . . . . . 53
1-Acetylcyclohexene
A. Rearrangement of 1-ethynylcyclo-
h e x a nol............................ 54
B. By the Darzens reaction........... 54
1-Cyclohexenylmethylcarbinol 54
1-Vinylcyclohexene 55
IV* Diels-Alder condensation products of
T^vinylcyclohexeney and their further
transformations
4a-Carbomethoxy-l,4-diketo-A^*®a( -
decahydrophenanthrene » . . . . ......... 56
4a-Carbomethoxy-l» 4-dike to- £ra' ' -
dodecahydrophenanthrene . ............... 56
1.4-Diketo-A^*8a(9)-decahydrophenanthrene . 59
Reduction of 1,4-diketo-(£?*8av9)-deca
hydrophenanthrene with zinc and acetic acid 60
4a-Carbomethoxy-l,4-diketoperhydro-
phenanthrene.........• * .............. 61
(B/C cis)-1,4-Diketo-^-dodecahydro
phenanthrene . . . . . .......... . . . . . 62
1.4-Diketoperhydrophenanthren e .......... 62
(B/c trans)-1,4-Diketo--dodecahydro
phenanthrene ............................... 63
2-Succinyl-^-octalin-l-carboxylic acid • . 64
Dehydrogenation of 2-auccinyl-A^-octalin-
1-carboxylic acid.......................... 65
1>4-Dihydroxy-4b,5,6,7,8,8a,9,10-octahydro-
phenanthrene ............................ 66
Acid isomerization of l,4-diketo-^&(9)-
dodecahydrophenanthrenea ................. 67
Acid isomerization of 1,4-diketo- ,8a(9).
decahydrophenanthrene ...................... 68
Isomerization of (B/C cis)-1,4-diketo-
^8a(9)-dodecahydrophenanthrene to the
(B/C trans)-isomer........................ 68
Ethylene ketal of (B/c cis)-1»4-diketo-
^8a\9)-dodecahydrophenanthrene . . . . . . 69
Ethylene ketal of (B/c trans)-Is4-diketo-
^8a\9)-dodecahydrophenanthrene . . . . . . 70
Ethylene ketal of 4a-carbomethoxy-l,4-
diketo-A8a(-dodecahydrophenanthrene . . ♦ 70
Attempted decarboxylation of the mono-
ethylene ketal of 4a-carbomethoxy-1,4-
diketo-A8a(^)-dodecahydrophenanthrene . . . 71
V* Preparation of l-methyl-4-methoxy-2-vinyl-
cyclohexene
4-Methoxycyclohexanol...................... 71
4-Methoxycyclohexanone.................... 72
l-Methyl-4-methoxycyclohexanol . . . . . . 72
1-Methyl-4-methoxycyclohexene . . . . . . . 72
Attempted preparation of l-methyl-4-methoxy-
2-acetylcyclohexene . . . . . . . ......... 73
VI* Preparation of 2-carbomethoxybenzoquinone
Gentiaic Acid • . . • ..................... 74
Methyl gentiaate .......................... 75
2-Carbomethoxybenzoquinone 76
S UMMARY.............................................. 77
BIBLIOGRAPHY.......................................... 78
VITA.................................................. 82
INTRODUCTION
The steroids are naturally occurring compounds, all
of which contain the characteristic tetracyclic nucleus of
1,2-cyclopentenophenanthrene. Members of this class of
compounds are present in all living cells except those of
a few primitive bacteria. The steroid compounds, which
include the bile acids, cholesterol and many of the
hormones, are extremely important physiologically.
Investigations on the structures of the steroids were
begun in 1903 by Windaus and in 1912 by Wieland. Finally
in 1932, based on the degradation studies of Windaus,
Wieland and a number of others, the dehydrogenation work
of Diels (1927), and the X-ray crystallographic studies
of Bernal (1932), the accepted structure of the steroid
nucleus was proposed by Rosenheim and King and also by
Wieland and Dane.
There has been great interest in the total synthesis
of these steroids since their structures have become known
Total synthesis, besides constituting a final proof of
structure, is of importance because the supply of some of
the steroid hormones from natural sources falls far short
of the demand, and the production from these sources is
very costly.
That the total synthesis of steroids is a challenging
and difficult task may be seen by examining the structures
of three of the steroid hormones: equilenin (I), estrone (
2
and androsterone (III)*
0 0
II ii
H0- H0-
I II
CHgOH
0 C=0
OH
HO 0 =
III IV
These are arranged in order of increasing complexity*
There are two asymmetric carbons in equilenin and there
fore four possible isomers. Estrone has four asymmetric
carbons, so could have sixteen isomeric forms. There are
128 isomeric forms of androsterone since it has seven
asymmetric carbons.
The difficulty of synthesizing these compounds is
increased by the presence of angular methyl groups at the
ring fusions. Equilenin and estrone have one angular
methyl group, while androsterone has two.
As would be expected, the first total synthesis of
a naturally occurring steroid was that of equilenin (I).
This was accomplished by Bachman, Cole and Wilds^ in 1939*
