THE RELATIONSHIP BETWEEN OPTICAL ROTATORY POWER AND

May 1, 2002 - SEYMOUR BERNSTEIN, ELIJAH M. HICKS Jr., DAVID M. CLARK, and EVERETT S. WALLIS. J. Org. Chem. , 1946, 11 (6), pp 646–656...
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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![ethyl 3-acetoxy-12keto-9-cholenate

a

7. Methyl 3 - a c e t o x y - l l ~ hydroxy cholanate

a

8. Methyl 3-acetoxy-12ketocholanate

a

9. Methyl-3-acetoxy-11ketoetiocholanate

a!

H. “Pregnane” compounds 1. Allopregnan-01-3-one-20

-2. Pregnan-01-3-one-20 3. 20-Methylpregnanediol3,20

BEF.

SOLVE&

6

B

B B

I

1

6“o

a

194 176-178

B a

142-143 148-149

+101.6 +113.8

6

168-171 190-201

+16.5 f23.0

A.A A.A.(?)

55 55

144 141-142

$79.8 +94.5

A.A. A.A.

54 54

116.5 99

+86.5 +123.7

A.A. A.A.

55

fi

a!

I

-~

I. “Pregnane” derivatives 1. Allopregnanol-3-one-20 acetate

a

2. Pregnanol-3-one-20 acetate

a

J. Unmturated “pregnane” compounds 1. Ahs-Pregnenol-3-one-20

B B

B a

2. 20-Methyl-A17: 20-pregnenol-3

B a

189-190 148-152 141-142 164-165.5

1

$30 +54.5

55

A A

56 57 I

$14.7 +45.4

654

BEFWSTEIN, HICKS, JR., CLARK, AND WALLIS

TABLE V-Concluded 0 COXPOUND

SOLVENP BEF.

CONFIGUBA. TION

br.P”C

B

149-150 147

$22 $57.2

58 57

164 221

+4.2 $12.6

59 66

172 182-183

$88.6

K. Unsaturated “pregnane” derivatives 1. Ab-Pregnenoloneacetate

a

L. “Androstane” compounds 1. Androstanediol-3,17 (a)

B a

2. Androstan-01-3-one-17

$103.5

61 62

193-195 203-205

-66.5 -35.5

M M

63 63

222-225 2047206

-16.5 $4.5

H H

63 63

124-125 150-151

-45 -21.7

M M

63 63

CY

148 221

f10.9 0

A A

64 65

B

182-183

-49.4

A

m.p. 65 rot. 66

a

208-209

-54

A

B

168-169 171-172 173-174.5

(f3.9

64 67 24

193-194 230

+19

$1

68 68

a

3. 3-Hydroxy-~-homoandro stanone-(17a)

a

4. 3,17-Dihydroxy-17aminoethylandroetane

a

M. “Androstane” derivatives 1. 3-Acetoxy-~ -homoandrostanone (17a)

-M M

B

B B

B a

N. Unsaturated “androstane” compounds 1. Dehydroandrosterone 2. A~-Androstenedio1-3,17

B

(4 0. Unsaturated “androstane” derivatives 1. Dehydroandrosterone acetate

a

P. “Cardiac aglucon” derivative A~0:S2-3-Acetoxy-21-hydroxynorallocholenic acid lactone @ C = chloroform. A = alcohol. A.A. = absolute alcohol. B = benzene. Ac = acetone. D = dioxane. M = methyl alcohol. H = 1 N acetic acid.

B a

ROTATORY POWER OF STEROLS.

I11

655

2. Application of this rule to other steroids is unwarranted. 3. The rule is most likely reversed for A5:5-stenolsand for certain derivatives of unsaturated sterols. REFERENCES (1) BERNSTEIN,KAUZMANN, AND WALLIS, J. Org. Chem., 6 , 319 (1941). BEENSTEIN, WILSON, AND WALLIS, J . org. Chem., 7,103 (1942). (2) CALLOW AND YOUNG, PTOC. Roy. Soc. (London),A 167, 194 (1936). (3) RUZICKA, WIRZ,AND MEYER,Helv. Chim. Acta, 18, 998 (1935). Ann., 622, 218 (1936). (4) REINDELAND NIEDERLANDER, (5) M A R ~ EetR al., J. Am. Chem. SOC.,69, 2714 (1937). (6) LADENBURG, CHAHRAVORTY, AND WALLIS, J. Am. Chem. SOC., 61, 3483 (1939). (7) BARNETT et al., J. Chem. SOC.,1390 (1940). (8) DUTCHER AND WINTERSTEINER,J. Am. Chem. ~ o c . ,61, 1992 (1939). (9) BERNSTEIN AND WALLIS, J . org. Chem., 2, 341 (1937). (10) DALMER et al., Ber., 68, 1814 (1935). (11) WINDAUS AND BRUNKEN, Ann. 460,225 (1928). (12) WINDAUS et al., Ann., 477, 268 (1929). (13) WINDAUS, Ber., 49, 1724 (1916). AND GOLDBERG, Helv. Chim. Acta, 18,668 (1935). (14) RUZICKA (15) MARKER AND WITTLE,J. Am. Chem. SOC., 69, 2704 (1937). (16) HEATH-BROWN et al., J . Chem. Soc., 1482 (1940). et al., Helv. Chim. Acta, 17, 1407 (1934). (17) RUZICKA (18) D O R ~AND E GARDNER, Proc. Roy. Soc. (London),B 80,227 (1908). (19) BONDZYNSKI, Ber., 29, 476 (1896). (20) D O ~ AND E GARDNER, J . Chem. SOC.,1625 (1908). (21) SCHOENHEIMER AND EVANS,J. Biol. Chem., 114, 567 (1936). J. Am. Chem. SOC.,69,2708 (1937). (22) MARKERAND OAKWOOD, (23) SANDQVIST AND GORTON, Ber., 63, 1759 (1930). (24) RUZICKA AND GOLDBERG, Helv. Chim. Acta, 19, 1407 (1936). (25) WALLISAND CHAKRAVORTY, J. Org. Chem., 2 , 335 (1937). (26) SANDQVIST AND GORTON, Ber., 63, 1935 (1930). et al., Ann., 620, 98 (1935). (27) WINDAUS (28) WINDAUS AND NAGGATZ, Ann., 642, 204 (1939). (29) WINDAUSAND KAUFMANN, Ann., 644,218 (1939). Ann., 648,19 (1941). (30) WIELAND,ROTH,AND BENEND, (31) WIBLAND AND BENEND, Ber., 76, 1708 (1942). (32) WINDAUS AND ANHAGEN, Ann., 473, 185 (1929). (33) WINDAUS et al., Ann., 448, 91 (1931). (34) WINDAUS AND BORGEAUD, Ann., 480,235 (1928). (35) WINDAUSAND DEPPE,Ber., 70, 76 (1937). (36) WINDAUS AND LANGER, Ann., 608, 105 (1933). (37) SCHENCK et al., Ber., 69, 2696 (1936). AND WALLIS, J. Org. Chem., 6,319 (1941); J . Org. (38) Calculated by method of BERNSTEIN Chem., 7, 103 (1942). (39) L E T T R Ber., ~ , 70,450 (1937). unpublished. (40) BERGAND BERNSTEIN, (41) INHOFFEN, Ann., 497, 130 (1932). (42) FERNHOLZ AND CHAKRAVORTY, Ber., 67,2021 (1934). (43) CAI,LOW AND YOUNG, Proc. Roy. SOC.(London),A 167, 194 (1936). (44) WIELANDet al., 2. physiol. Chem., 216, 15 (1933). (45) KYOGOKU, 2. physiol. Chem., 246, 99 (1937). (46) KIMURA, 2. physiol. Chem., 248,280 (1937).

656

BERNSTEIN, EICKS, JB., CLARK, AND WALLJ.S

(47) WINDAUSAND BOFINE,Ann., 495, 278 (1923). AND REICESTEIN,Helv. Chim. Acta, 26,878 (1942). (48) PRESS (49) LARDON AND REICESTEIN,Helv. Chim. Acta, 36,705 (1943). (50) LARDON AND REICESTEIN,Helv. Chim. Acta, 26,607 (1943). GRANDJEAN, AND REICESTEIN, Helv. Chim. Acta, 26,598 (1943). (51) PRESS, AND REICHSTEIN, Helv. Chim. Acta, 26, 586 (1943). (52)LARDON (53) REICESTEIN AND SORICIN, Helv. Chim. Acta, 26, 797 (1942). (54) FLEISCHER et al., J. Am. Chem. SOC., 60,79 (1938). (65) BUTENANDT AND MULLER,Ber., 71, 191 (1938). (56) BUTENANDT AND WESTPEAL, Ber., 69,443 (1936). AND HEUSNER,Ber., 72, 1119 (1939). (57) BVTENANDT (58) WETTSTEIN, Helv. Chim. Acta, 23,1371 (1940). et al., Ber., 68, 2097 (1935). (59) BUTENANDT AND TSCHERNINO, 2.physiol. Chem., a54,224 (1935). (60) BUTENANDT (61) WALLISAND FERNHOLZ, J . Am. Chem. Soc., 67, 1511 (1935). (62) RUZICKAet al., Helv. Chim. Acta, 17, 1395 (1934). AND MONNIER, Helv. Chim. Acta, 23, 376 (1940). (63) GOLDBERG (64) BUTENANDT et al., 2.physiol. Chem., 237, 57 (1935). (65) BUTENANDT AND HANIBCH, Ber., 68,1859 (1935). (66) RUZICKA et al., Helv. Chim. Acta, 20, 541 (1937). AND WETTSTEIN, Helv. Chim. Acta, 18,986 (1935). (67) RUZICKA RUZICKA, AND FURST, Helv. Chim. Acta, a8,2274 (1943). (68) PLATTNEB,