[GQNTRIBUTIOX FROX T H E S T E R L I N G CIIEM1ST;SY
LABORATORY, PALE
U N I V E R S I T Y , A??D T H E
M E D I C A L R E S E A R C H LABORATORY, P E O V I D E S C E C O L L E G E ]
STRUCTURE AND OPTICAL ROTATORY POWER OF POLYNUCLEAR NATURAL PRODUCTS. 11. KETO- AND HYDROXY-STEROIDS' WILLIAM M. STOKES
LYD
WERXER BERGMANN
Received Narch 31, 1962
In a previous communication (1) certain relationships between the structure and optical activity of steroid hydrocarbons were discussed on the basis of some simple generalizations derivable from the theory of optical rotatory power (2). The present communication deals with the correlation of the structures and optical activities of some oxygenated steroids. KETOSTEROIDS
The attachment of a ketonic oxygen to the steroid nucleus produces an increment of optical rotation. The averaged values for such increments have been tabulated by Barton and Klyne (3), and they are in part reproduced in Table I.2 The signs of the increments for keto groups on rings A and C are positive, and negative for those on rings B and D-homo. It appears certain that these regularities are analogous to those found among mono-unsaturated steroid hydrocarbons (l), and that the alternation of the sign of rotation is due to the symmetry of the molecule. (See composite Figures I and 11.) Thus the carbon atoms
surrounding a %-keto group are a mirror image of those surrounding the 6-keto group, and t,he 3- and 7-keto groups bear the same relationship to each other. Such pairs may therefore be expected to show reversed signs of rotation. The 11- and 12-keto groups with their adjacent carbon atoms can be superimposed upon the 2- and 1-ketones respectively and also upon the 4- and 3-ketones. The atoms surrounding the l7a-keto group in D-homosteroids mirror those about the This paper is dedicated to Professor Adolf Windaus, Gottingen, on the occasion of his 75th birthday. The material presented in this and a. previous paper (1) constitutes part of a dissertation submitted by William M. Stokes in partial fulfillment of the requirements for the Ph.D. degree, Yale University, 1952. 2 Unless stated otherwise the rotations referred to in this paper were measured in chloro. form for the Na, line. 1194 f
ROTATION VS STRUCTURE OF NATURAL PRODUCTS.
1195
I1
12-keto group; and the 11- and 12-ketones are likewise reflexions of the 7- and 6ketones respectively. I n these cases reversed signs of rotation are observed. Clearly defined mirror image conformations are observed in ketosteroids of the allo-series in Pc-hich the keto group is adjacent to an asymmetric center with an angular hydrogen atom or methyl group. A steroid ketone belongs to the dextrofamily when, with the keto groups turned upward and to the left of the angular carbon atom, the angular hydrogen atom or methyl group projects forward, i.e. occupies the @-position.(See Figures I11 and IV.)
dextrorotatory I11
dext.rorotatory IV
TABLE I CONTRIBUTIONS TO MOLECULAR ROTATION OF KETOGROUPSIN STEROIDS" SERIES
1
5-allo
POSmION
PING
1
A A A A B
2 3 4 6 5-allo and combined
D-homo a
*
5-normal
II
7 11 12 17
-227 +79
B C
270 +248
D
17s
- 152
D
+
c
Data according t o Barton and Klyne (3). Data according to references (4) and (5). HYDROXYSTEROIDS
Steroids which are hydroxylated at secondary, cyclic carbon atoms exist as epimeric pairs. Many of such pairs, which are distinguished by the indices a and p, have been prepared, and their conformations have been well established. The atoms surrounding the a-hydroxylated center of asymmetry mirror the corresponding atoms of the p-epimer. I n the absence of very large and overshadowing vicinal effects one may therefore expect that on a cyclic, secondary carbon atom the displacement of a hydrogen by an a- or p-oriented hydroxyl group will bring about rotational increments of opposite sign. The data presented in Table I1 show that this is indeed the rule. As a first approximation these increments may be regarded as the sum of two factors. The first represents the vicinal effects, similar in magnitude in both
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W. 31. STOKES AND W. BERGMANN
epimers, and the second, the contribution of the new asymmetric center, which is of similar magnitude but of opposite sign in the two epimers. If the average vicinal effect is represented by A, and the average contribution of the new center as B, the increments are equal t o A B for the /?-epimer, and A - B for the a-epimer. The data given in Table I1 show that the observed values for B fall into the following two classes. (a) Small values (C-2 and C-3) when the hydroxylated center is flanked by two methylene groups. As has been pointed out in the previous communication (l), such centers possess a relatively high degree of symmetry, which accounts for the small value of their contributions. (b) Large values (C-4 ,-6 ,-7 ,-11,-12 and C-17) when the hydroxylated center is adjacent to a tertiary or quaternary carbon atom. In this class the highly asymmetric surroundings, composed of a hydroxyl group, a hydrogen atom, a methylene group, and a tertiary or quaternary carbon atom, endow the center with considerable optical activity. Mirror image conformations of such centers are found in many of the known steroid alcohols. The signs of their contributions depend on whether the conformation belongs to the d- or the I- family, where the d-family is defined as the one in which the contribution of the /?-epimer is dextrorotatory. The observed values for the various epimers are shown in Table 11. In the composite figures V and VI the conformation of six @-hydroxylated asymmetric centers are analyzed through the application of Marker’s rule (10). According to Marker’s table, the ordinal numbers of the substituents surrounding the centers increase in the following order:
+
C -CH2--
