[CONTRIBUTION FROM
THE
FRICKCHEMICAL LABORATORY, PRINCETON UNIVERSITY ]
THE RELATIONSHIP BETWEEN OPTICAL ROTATORY POWER AND CONSTITUTION OF THE STEROLS. I11 SEYMOUR BERNSTEIN: ELIJAH M. HICKS, JR.,*DAVID M. CLARK, EVERETT S . WALLIS
AND
Received February 21, 1946
In the previous two papers of this series (1) the application of the modern theories of optical rotatory power to steroids was discussed, and a method of calculation of the rotatory power of these compounds was developed. It was shown, for example, that a-steroids of the cholestanol type will always have a molecular rotation greater by 2540" (CHCla),in the positive direction, than the corresponding 8-form. In the coprostanol series the a-form will always be higher by 2680". It is our purpose in this paper to present evidence which shows that configurations can be assigned to diastereoisomers at the Cs position of many other steroids from a knowledge of their optical rotatory powers. By these additional correlations, the validity of the assumptions made in our calculations (1)becomes more firmly established. In this connection we have amplified the work of Callow and Young (2) who made a study of the relationship between optical rotatory power and the constitution of steroids. Among other things, these investigators pointed out that in fifteen out of eighteen cases an increase in the dextrorotatory power results group from the 8- t o the a-position. We have from inversion of the listed in Table V eighty-two pairs of compounds epimeric at the CSposition with their melting points and, where known (fifty-seven pairs), optical rotatory powers. An analysis of these optical data has been made in Tables 11, 111,and IV and allows the following conclusion to be made : The Cs a-form of any steroid will have a higher positive rotatory power (sodium D light) than the corresponding 8-form regardless of the solvent used. We would like to point out that the only exceptions t o this rule may be in its application to A&%tenols in solvents other than chloroform. In fifty-one out of fifty-four cases (A6:6-stenolsin alcohol are excluded) the a-form has the higher positive rotatory power. This fact corroborates, then, the basic assumptions made by us in calculating the rotatory powers of steroids. We are of the opinion that the three exceptions are in error which may be ascribed to the purity of the compounds involved or that an error was made in the determination of their rotations. Moreover, the chemist now has an additional method for assigning configurations to Cp-diastereomers purely on the basis of optical rotatory power. We have also made a thorough study of the melting point relationship of a and @-diastereoisomers. Previous work on this subject may be found in the literature. Ruzicka, Wirz, and Meyer (3) have assumed on the basis of a-cholestanol 1
2
Present address:-Lederle Laboratories, Inc., Pearl River, N. Y. Present address:-duPont and Company, Richmond, Virginia.
646
ROTATORY POWER OF STEROLS.
647
III
having a higher melting point than j3-cholestanol that the same melting point relationship would hold for the corresponding chlorides. Also Reindel,,and TABLE I (MELTINGPOINT) CLASS OF COKPOUND ~~
~~~~~~~~
~~~~~~
~
~
Saturated sterols. . . . . . . . . . SaturatJed sterol derivativ
7
0
2
6
Unsaturated sterols. . . . . . . . . . . . . . . . . . . . . . . . . Unsaturated sterol derivatives
5 1
16
-
7
Bile acids. . . . . . . Bile acid methyl esters. . . . . . . . . . . . . . . . . . . . . Derivatives of bile acids or methyl ester . . . .I
3 2
3 3
4
4
“Pregnane” compounds. . . . . . . . . . . . . . . . . . . . . “Pregnane” derivatives. . . . . . . . . . . . . . . . . . . . . I Unsaturated “pregnane” compounds . . . . . . . . Unsaturated “pregnane” derivatives . . . . . . . .
I
2
j
1 0
1 2 1
“Androstane” compounds.. . . . . . . . . . . . . . . . . . “Androstane” derivatives. . . . . . . . . . . . . . . . . . .
3
1
1
0
Unsaturated “androstane” compounds . . . . . . Unsaturated i‘androstanel’ derivatives . . . . . .
2 1
0 0
“Cardiac aglucon’’ derivative . . . . . . . . . . . . . .
1
0
,I
0
1
--
TABLE I1 (ROTATIONS: CHCla)
-
NO. OF C a - E P n r p R s I N WEICE a - P O HAS A HIGHER POSITIVE [ a ]
CLASS OP COMPODND
~
NO. OF C a - E P m B S I N WHICH @-FORM HAS HIGHEB POSITIVE [ab
Saturat,ed sterols. ........................... Saturat#edsterol derivatives.. . . . . . . . . . . . . . . .
3 2
Unsaturated sterols. ........................ Unsaturated sterol derivatives.. . . . . . . . . . . . . .
10
Bile acids. .................... . . . . . . . . . . . . . . Bile acid derivatives. . . . . . . . . .
2 1
0 0
“Cardiac aglucon” derivative
1
0
1
7
Niederlander (4)have made a comparison between the melting points of a large number of saturated stereoisomers. In both the cholestane and coprostane series, the member of an epimeric pair that gives an insoluble digitonide (Le., @-form)nearly always has the lower melting point.
648
BERNSTEIN, HICKS, JR., CLARK, AND WALLIS
However, Marker et al. ( 5 ) have pointed out in A6:6-stenolsthat the /?-formhas the higher melting point. Landenburg, Chakravorty, and Wallis (6) have also noted that application of the assumption that the a-forms have higher melting TABLE I11
Saturated sterols. ........................... Unsaturated sterols
NO. OF Ct-EPraaSXS IN WHICH &FORM HAS HlGaEB POSITIVE [ab
NO. OF CrEPraaSBS IN WHICH a-FOXY HAS HIGHEB POSITIVE [ab
CLASS OF COMPOUND
1
..................
Bile acids.. .................................
I
0
0
1
3
0
~~~
“Pregnane” compounds. .................... “Pregnane” derivatives. ....................
1 0
I
I
Unsaturated “pregnane” compounds (As:c). . Unsaturated “pregnane” compounds Unsaturated “pregnane” derivatives (A6:S). .
1
“Androstane” compounds.. ................. Unsaturated “androstane” derivatives (A6:‘).
1
I
0 0 0
I 0
2
TABLE IV
CLASS OF COXPOUND
NO. OF C a - s p ~ s n s IN WHICH a - F O p Y HAS HIGBBP POSITIVE [ajD
NO. OF Ca-EPIXEXS IN WHICH P-FOXX HAS BIGHEP POSITIVE [a]D
Unsaturated sterols
1 (B)
0
Bile acid methyl ester.. ...............
1 (D) 2 (Ac)
0 0
Bile acid methyl ester derivatives.. . . . “Androstane” compounds. . . . . . . . . . . . . “Androstane” derivatives. ............
0
2 (MI
1 (H)
0 0
1 (MI
0
Ac = acetone; B = benzene; D = dioxane; H = 1 N acetic acid; M = methyl alcohol.
points than the corresponding &forms leads to confusion in assigning configurations to the 3-cholorocholestanone-6’s. An analysis of the melting point data in Table V has been made in Table I, and the following conclusions can be made: 1. The Cs a-form of an unsubstituted saturated sterol will have a higher melting point than the corresponding8-form.
ROTATORY POWER OF STEROLS.
649
I11
TABLE V CS COMPOUND
CONFIGmuL-
SOLVENTO
M.P."C
REP.
TION
A. Saturated Sterols 1. Cholestanol
2. Stigmastanol
B B ff
B 01
6. Bisnorcoprostanol
B ff
7. 24-Ethylcoprostanol
B CY
B. Saturated Sterol Derivatives 1. Cholestanyl acetate
B U
2. Stigmastanyl acetate
B CY
3. Ergostanyl acetate
B cy
4. Coprostanyl acetate
+23.8 +26.0
C C
9 10
141 205
+15.3 +14.6
C C
11 12
101-102 116-118
+23.6 +31.6
C C
13 13
117-118 153-154
(-1-29.2
182-184
CY
5. Norcoprostanol
136-137 203
CY
B
4. Coprostanol
7 8 7 8
140-141
ff
3. Ergostanol
+34
C A C A
B
B ff
+23 +29 +32.2
4 14
126-127 134-135
4 4
127 137
15 15
109-110 95.5-96
(+11.5
C)
16 17
129-129.5 88
+15.4 +28.0
C C
9 10
143-144 144
+6.3 +20.6
C C
11
88-89 87-88
(+43.8
18 14
122-123 93-94
(+48.2
14
12
~~
5. Norcoprostanyl acetate 6. Bisnorcoprostanyl
--
105-104 93-94
acetate 7. 24:-Ethylcoprostanyl acetate
4
4 4
--
B
89
15
ff
94
15
650
BERNSTEIN, HICKS, JR., CLARE, AND WAUIS TABLE V-Continued G COMPODND
8. Coprostanyl benzoate C. Unsaturated sterols 1. Allocholesterol 2. Allo-@-sitosterol
CONPIGOBA. TION
M.P."C
B a
114-1 15 85-86
B
132
a
84
B
158 138
a
3. Cholesterol
B a
147-149 140.5
[a].
SOLVE&
PBF.
19 20 +43.7 +120.8
B B
21 21 22 22
-38.8 -31.0
-34 -37.5
C A C A
23 24 7 24
4. @-Sitosterol
136-137 135
(-36.6
C)
25 5
5. Stigmasterol
168-170 151
(- 51.0
C)
26 5
142-143.5 124-126
- 113.6
C C
27 28
6. 7-Dehydrocholesterol
B a
7. Allodehydrocholesterol
B a
8. Zymosterol
B a ~
115-116 93-94
+10
+80
C C
29 29
108-110 160-162
$49 55
C C
30 31
128-129 183
+ +50 +56
C C
30 31
165-166 203-204
+22.0 f36.2
C C
32 33
- 12 4-28.7 av.
c (2)
34
C
35
C)
36 35
~-
9. Dihydrozymosterol
B a
10. Ergosterol-D
B a
11. Neoergosterol
152 177
12. 22-Dihydroneo-
150 167
ergosterol
-70.5
(f28.8
-
D Unsaturated sterol derivatives 1. Allocholesteryl acetate
B a
85 82.5
21 21
ROTATORY POWER OF STEROLS.
651
I11
TABEL V-Continued Cs COMPOUND
2. Allo-B-sitosteryl acetate 3. Cholesteryl acetate
CONFIGUBATION
M.P.OC
B
88
a
92
6. '7-Dehydrocholesterylacetate
23 24
125-126 66
(-41.0
25 5
143-144 98
(-55.6
cy
26 5
B
130
B
a
114-115
CY
7. Allodehydrocholesterylacetate 8. Zymosteryl acetate
109 96
B a
10. Ergosteryl-D acetate 11. Neoergosteryl acetate
-77.6 (calc'd) - 35 -56.0
+126.3
106-108 83-85
B CY
9. Dihydrosymosteryl acetate
22 22 (-42.0
a
5. Stigmasteryl acetate
PEP.
114.7-115.6 85
B a
4. 6-Sitosteryl acetate
SOLVENT0
C
m.p. 37
rot. 38
C
28
C C
29 29
C)
30 31
128-129 85-87
f31.5 f40
C C
30 31
ff
173-174 150
f20.7 +40.6
C C
33 33
B
122-123
-8
C
m.p. 34
98
$27.2
C
118 83
-3.1 f24.6
C C
36 35
-17.0
C
40
-29
C
7
-53.2
C
27
$48.5
C
28
-78.5
C
29
C
29
C
41
C
35
B a
B
rot. 39 cy
12. 22-Dihydroneoergosteryl acetate
ff
13. Cholesteryl benzoate
B
B
148-50 and 177 99.5
a
14. '7-Dehydrocholesteryl benzoate
13940 and 183 118-119
B a
15. Allodehydrocholesteryl m-dinitrobenzoate
154(180185) 150(180185)
B a
16. Neoergosteryl m-dinitrobenzoate
a
1
218-220 204
+I59
- 13 +21.2
652
BERNSTEIN, HICKS, JR., CLARK, AND WALLIS
TABLE V-Continued 0 CO~OUND
17. Neoergosteryl methyl ether
Y.P.'C
bID
94 74
-5 +18.4
C C
35 35
a
179 188
$25.1 $33.6
A A
8 8
B
218
$17.2
C
a
208-210
$23.3
C
m.p. 42 rot. 43 m.p. 44 rot. 43
P
226 205-207
CONFIOUPlr TION
B a
SOLVENP REP.
E. Bile Acids 1. 3-Hydroxycholanic acid 2. 3-Hydroxyallocholanic acid
3. 3-Hydroxynorallocholank acid
P
a
I
($21.0 -10.1 (calc'd) 17
4. 3-Hydroxybisnorallocholanic acid
+
220 5. 3-Hydroxy-12-ketocholanic acid
218-220 164165
+90.5 +110.2
6. Hyodesoxycholic acid
189-190 196-197
+5.1 +8.4
7. 3-Hydroxy-11-cholenic acid
ca. 128
165-166
I
I
1
+27.8 $33.2
-C)
42 10
C
38
C
10
A.A. A.A.
45 45
A A
-l
1
0)
46 m.p. 47 rot. 46
D D (?)
48 48
A)
44
C)
44
C)
42 10
~
F. Bile acid methyl esters 1. Methyl 3-hydroxyallocholanate
151 164
(f18.4 (+17.7
1
1
2. Methyl 3-hydroxynorallocholanate
156 169-170
3. Methyl 3-hydroxy-llp, lab-oxidocholanate
114-115 96-98
+27.1 $35.7
Ac Ac
48 48
4. Methyl 3-hydroxy-11ketoetiocholanate
172-175 155-158
f72.1
Ac
49 49
5. Methyl 3-hydroxy-11etiocholenate
131-133 122-124
$70.7 +77.7
Ac Ac
50 50
-19.5 (calc'd)
C
38
C
10
G. Derivatives of bile acids 01 methyl esters 1. 3-Acetoxybisnorallocholanic acid
225-227
($21.0
$2
ROTATORY POWER OF STEROLS.
653
III
TABLE V-Continued ca COYPOVND
CONFIGUPA, TION
2. Methyl 3-acetoxynorallocholanate
a
3. Methyl 3-acetoxy, llfi, 12,9-oxido-cholanate 4. Methyl 3-acetoxy-11ketocholanate
-163 189-190
(+26.0
C)
42 10
a
150-152 140-142
+31.2 +52.8
Ac Ac
48 48
Is a
173-174 132-133
$56.4 $67.1
Ac Ac
51 52
$62.5 +87.7
Ac
192-193 149-150
$73.9 +102.5
Ac Ac
51 52
139-140 146-148
$50.0 +70.7
Ac AC
51 52
184-186 153.5-154.5
$77.9 $104.8
Ac Ac
51 53
129-131 147-149
+71.8 +98.1
Ac Ac
49 49
$90.5 +87.7
A.A. A.A.
54 54
A.A. A.A.
55 55
fi
B
5. Methyl 3-acetoxy-11etiocholenate
99-100 70-72
6. h
