[CONTRIBUTION FROM THE FRICKCHEMICAL LABORATORY, PRINCETON UNIVERSITY]
T H E RELATIONSHIP BETWEEN OPTICAL ROTATORY POWER AND CONSTITUTION OF T H E STEROLS. 11. SEYMOUR BERKSTEIN, E . JUSTIN WILSON, JR.,' A N D EVERETT S. WALLIS
Received October i7, 1941
I n the first paper 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 is now our purpose to report the results of further studies on this problem especially as applied to certain derivatives) acetates) benzoates, etc. The method which has been employed is in principle the same as previously reported, but differs from it in the one respect that the rotatory power of the derivative is calculated directly from the value of the rotatory power of the corresponding free sterol itself. The discussion which follows has been limited to a consideration of sterol acetates, benzoates, and m-dinitrobenzoates, although of course by the same principle all other types of derivatives can be calculated. Let us consider the change in rotation which occurs when cholestanol is converted to cholestanol acetate. The molecular rotation2 of cholestanol is +8920 (l),and of cholestanol acetate is +4820. The difference in molecular rotation between these two compounds is 4100. Therefore, it follows from what has been said in Part I of this series that every acetate of this type ( L e . Cs-OH/ trans) will have a molecular rotation which CIO-CHS, cis ; C6-H/C1~-CH3, is approximately 4100" less than that for the corresponding saturated sterol. This may be tested using stigmastanol, y-sitostanol and their respective acetates. Stigmastanol = +10190(1) Stigmastanol acetate = $7050 $3140
y-sitostanol = $7650(1) y-sitostanol acetate = $4120 $3530
-
Since an error in the measurement of [ a ] D of only 2.5" results in an error of about 1000" in [MID, we see that in these two cases our expectations are fully realized. This difference,however, of 4100" should not be the same when the environment cis, or a double bond a t around CBhas been changed, i.e., C6-H/C1o-CHs, C5:6. It is also to be noted that this difference would not be expected between the rotatory power of epi-cholestanol and its acetate. It is now but a simple matter to calculate the molecular rotation of the acetate of any saturated sterol of the cholestanol type by substracting 4100 from the molecular rotation of the free sterol. We have represented the value, -4100, DuPont Fellow, 1940-1941. X molecular weight (C = 12, H = 1,0 = 16). All molecular rotations have been rounded off in the last figure. All rotations recorded are for chloroform solution. 103
* [MID= [ a ] D
104
BERNSTEIN, WILSON, AND WALLIS
by the symbol Ac3Nt which signifies an acetate group at the C3 position of a sterol of the cholestanol type (C3-OH/Clo-CH3, cis or normal, and Cs-H/ CIO-CH~, trans). A general equation for the calculation of any acetate of this type then will be [MID = [ M ] D , f ~ ~Ac3~t ~~~ Application of this equation to the calculation of the molecular rotation of stigmastanol acetate gives [M]D,,~~,~f10190
- 4100 =
+6090.
This calculated value for the molecular rotation gives a specific rotation, [aID of f13.3" which compares favorably with the observed value of f15.4'. The same procedure may be applied to all other types of derivatives of sterols which may be saturated or unsaturated. In Table I are recorded the values, TABLE I DERIVATION OF CONSTANTS ~~~
~~
SUBSTANCES USED I N CALCULATING CONSTANTS, STEROL AND STEROL DERIV.
Cholestanol (1) and acetate (8).. . . . . . . . . . . . Cholestanol (1) and benzoate (8b). . . . . . . . . . Stigmastanol (1) and m-dinitrobenzoate (9). Cholesterol (1) and acetate (IO). . . . . . . . . . . . . p-Sistosterol (1) and benzoate (11). . . . . . . . . . 6-Sistosterol (1) and m-dinitrobenzoate (11) Ergosterol (I) and acetate (12). . .,. ,. , . . 7-Dehydrocholesterol (1) and benzoate (8a) , , , ,
W'DDeriv. - [%terol VALUE O F CONSTANT
SYMBOL FOR CONSTANT'
-4100 0
-2260 -3500 +7800 +8630
+11820 +17660
~
* Legend: Ac = acetate; Bz = benzoate; DNBz = m-dinitrobenzoate. Subscripts: 3 = Cs of sterol molecule; N = cis or normal configuration a t Cs to CIO-CHa; t = trans configuration of Cs-H to Clo--CHa; D = double bond (numerical subscripts with this letter indicate positions). and symbols for the various constants used in our calculations of the rotations of sterol derivatives. -4general equation for the calculation of any sterol derivative will be
+
[M]Dderivative = [MIDsterol Constant (symbol and value, Table I). Since there is now available an observed and a calculated value for the rotation of a sterol (l),two calculated values for the rotation of a sterol derivative are possible. These values for several acetates, benzoates, and m-dinitrobenzoates are recorded in Table 11. In general the agreement between the observed and calculated values is excellent. In Table I11 are listed a number of compounds which have a double bond either at the C*:M(a-position) or the C14:16 ((3-position), and whose optical rotations have been calculated by use of the following deriva. constants have been pretive constants, AcSNt,Bz3Nt, and D N B z ~ N ~These viously used for the calculation of the rotatory powers of derivatives of saturated
105
OPTICAL ROTATORY POWER OF STEROLS
sterols (see Table 11). The results in Table I11 indicate that a- and p-stenol derivatives may be calculated successfully with these constants by assuming a negligible interaction between these double bonds and the C3 region of asymm e t r ~ . . ~It should be pointed out in 'this connection, however, that nothing definite can be said a t this time in regard to &(double bond a t C S : ~and ) y(double bond a t Cy:*) stenol derivatives, since the number of such compounds known is too few to warrant a trustworthy conclusicn. But a survey of the values of their rotatory power does indicate that 6- and y-double bonds do influence appreciably the C3 region of asymmetry. OBSERVED COMPOUND
TABLE I1 CALCULATED ROTATIONS
AND
I
Stigmastanol acetate. . . . . . . . . . . . . . . r-sitostanol acetate. . . . . . . . . . . . . . . . Ergostanol acetate. . . . . . . . . . . . . . . . . al-Sitostanol acetate. . . . . . . . . . . . . . ., Ergostanol m-dinitrobenzoate.. . . . . Stigmasterol acetate. . . . . . . . . . . . . . . @-Sitosterolacetate. . . . . . . . . . . . . . . . Brassicasterol acetate. . . . . . . . . . . . . . 22,23-Dihydrobrassicasterolacetate 7-Sitosterol acetate. . . . . . . . . . . . . . . . 22,23-Dihydrobrassicasterol
OBS. [ulD(CHCls)
CALC. [elD(CI-ICla)
DI.[
CALC.
(CHCla)
:USING OBS. [MID (1) OF STEROL)
(USING CALC'D [MI, (1) OF STEROL)
+13.3 $7.8 $4.8 $15.6 +6.6 -51.3 -40.5 -64.7 -40.8 -46.2
$13.4 $8.2 $7.5 +8.6
-19.0 (17) -19.6 (18) -28.0 (9)
-21.3 -18.8 -27.5
-19.7 -16.4 -26.0
-17.1 -21.5 -74.8 -71.0 -54.0 -68.0 -71.5 -88.3
-16.6 -18.4 -71.7 -79.3 -58.3 -67.9
-15.3 -20.1 -75.7 -67.2 -47.8
$15.4 +9.0 +6.8 $39.4 +13.5 -55.6 -41.0 -65.0 -45.5 -46.1
(13) (14) (15) (av.) (2b) (9) (av.) (16) (11) (9) (17) (14)
(17) (17) (19) (20) (20) (21) (22) (23)
-
-38.2 -60.3 -45.8 -47.8
-
By the use of these data which have been recorded, it is of interest to examine the results of the application of this methodof calculation of the optical rotation of sterols and their derivatives to recent experimental results which have appeared in the literature. I n their studies on the sitosterol complex Wallis and his collaborators (2) reported the isolation in a pure state of two new compounds which they a t that time named a1- and cY2-sitosterol respectively. Hydrogenation of al-sitosterol gave a saturated compound which they named cdtostanol. I n Part I (1) of this series calculations of these derivatives were made on the assumption that the influence of the double bonds a t C~:14and C14:la on the Ca center of asymmetry was not negligible. This assumption appears t o be unnecessary.
106
BERNSTEIN, WILSON, AND WALLIS
Its acetate was also prepared and a specific rotation in chloroform, +39.4", was recorded. I n Table I1 is listed the calculated value of this acetate, using the observed molecular rotation of the free alcohol itself. I n this instance a complete disagreement between the observed and calculated values is to be noted. Therefore, we are forced to one of three conclusions: (a) the method of calculation does not hold; (b) the reported rotatory power either of the free saturated alcohol or of its acetate is wrong; (c) the proposed structure of the compound itself and consequently of its acetate is incorrect. We are inclined to believe that the last conclusion is the most probable. Indeed, in our opinion if the use of the constants in Table I leads to calculated values which are in appreciable disagreement with those reported for molecules of the supposedly TABLE I11 CALCULATED ROTATIONS OF UNSATURATED STEROLS COMPOUND
OBS.
[a], (CHCla)
CALC'D [ a ] D C H C l s ) (USING
OBS. [MID(1) OF STEBOL)
a-Cholestenol acetate. . . . , . . . a-Ergostenol acetate. . . . . . . . . p-Ergostenol acetate, . , , , , , , I ,
+9.5 (8a, 24) (av.)
'I
a-Stigmastenol acetate.. . , . . , Zymosterol acetate. , . . . , . . . . . Ergostadiene, 8:14,22:23-01-3 acetate?. . , . . . . . , . . . . . . . . , , p-Cholestenol benzoate. , . . . . . a-Cholestenol benzoate.. . . . . . p-Ergostenol benzoate.. . . . . . . a-Stigmastenol benzoate. . . , . a-Spinasterol benzoate. , , . . , . I Zymosterol benzoate. . . . , . . . . I ~
1 ~
1
'
or-Spinasterol m-dinitrobenzoate. . . . . . . . , , . . . . . . . . .
~
+3.0 +15.9 $10.0 +15.5 +34.0
(15a) (15b) (15e) (26) (8b, 22, 24, 27) (av.)
-20.0 +32.2 +7.5 f18.3 +11.0 +2.3 +36.4 f44.1
( 1 5 ~28) , (8a) (av.) (8) (av.) (29) (26) (30) (22, 31) (24)
-3.5 (30) (CHCla?)
CALC'D [aID CHCls) (USING IALC'D [MIr, (1) OF STEBOL)
+8.9 +3.8
+5.2
+9.0
+17.0
+13.7 +34.0
+11.2 -
-27.3 +26.8 +16.1 +16.0 +20.0 0 $38.1
-9.1 $23.1
-3.7
$1.8
f17.8 -
steroid type, then it is questionable whether such compounds are truly steroid in nature. If this conclusion be accepted, then it follows that another tool besides selenium dehydrogenation is available for indicating the presence of a cyclopentanoperhydrophenanthrene nucleus. Attention is now called to certain experimental results reported by Fernholz and his collaborators (3). I n the course of their studies on the sterol, campesterol, they reported the preparation and rotations of several derivatives. A proposed structure for this sterol was also given. I n Table IV are recorded both the calculated values for the specific rotations of these derivatives, assuming the structure proposed by them, and the observed rotatory powers. These values are in excellent agreement. Similar calculations have been made for the two sponge sterols, clionasterol
107
OPTICAL ROTATORY POWER OF STEROLS
CzsH600(one double bond) and poriferasterol, C29H480 (two double bonds), and their derivatives, recently described by Valentine and Bergmann (4). These values are recorded in Table V. Our calculations indicate that in both of these compounds one double bond is a t the c6:Bposition and in poriferasterol it appears to us that the second double bond may not be placed a t c7:8,C8:9, c8:14,or CIM, positions. Certain results of Mazur ( 5 ) are of special interest from this point of view. This investigator has recently reported the isolation of a sterol from a fresh TABLE IV ROTATIONS OF CAMPESTEROL DERIVATIVES OBS. [alD(CHCld
comouND
~
Campesterol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Campesterol acetate. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Campesterol benzoate. . . . . . . . . . . . . . . . . . . . . . . . . . . . . Campesterol m-dinitrobenzoate . . . . . . . . . . . . . . . . . . . . Campestanol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Campestanol acetate. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Campestanol m-dinitrobenzoate. . . . . . . . . . . . . . . . . . . . i-Campesteryl methyl ether. . . . . . . . . . . . . . . . . . . . . . . .
CALC’D [aID(CHCls) (ASSUMING STRUCTURE OF FEBNHOLZ AND CO-WORKERS)
-33.0 -35.5 -10.2 (av.) - 7 . 2 (av.) +31.0 +18.3 +22. $62.
-33.1 -37.8 -10.7 -7.7
-
+l8.9
TABLE V ROTATIONS OF SPONQESTEROLS COMPOUND
1
Poriferastanol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Poriferastanone. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Poriferastanol acetate. . . . . . . . . . . . . . . . . . . . . . . . . . . . . Poriferastanol m-dinitrobenzoate. . . . . . . . . . . . . . . . . . . Poriferasterol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Poriferasterol acetate. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Poriferast&-ol benzoate. . . . . . . . . . . . . . . . . . . . . . . . . . . . Poriferasterol m-dinitrobenzoate. . . . . . . . . . . . . . . . . . . Clionasterol (assumed to be dihydroporiferasterol) . . Clionasterol acetate. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clionasterol benzoate.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clionasterol m-dinitrobenzoate. . . . . . . . . . . . . . . . . . . . .
OBS.
[.ID (CHCh)
+24.7 $46.7 +16.3 +17.1 -49.7 -53.0 -22.0 -22.1 -37. -41.9 -16.8 -14.0
1
DI.[
CALC’D
(CHCh)
+41.5 +13.5 +13.1 -52.8 -24.6 -19.6 -33.8 -41.3 -14.5 -11.0
water sponge to which he assigned the structure 5,6-dihydrostigmasterol. From the physical constants reported he has stated that he is of the opinion that clionasterol is identical with 5,6-dihydrostigmasterol. It appears to us that this latter statement can be questioned. In Table VI1 we have recorded the melting points of Mazur’s compound together with those of a compound prepared by Marker and Wittle (6) and described by them as 5,6-dihydrostigmasterol. The bad agreement in these values clearly indicates non-identity. I n Table VI11 are recorded the calculated values for the optical rotations of 5,6-dihydro-
108
BERNSTEIN, WILSON, AiSD WALLIS
stigmasterol and its various derivatives together with those values recorded for these compounds reported by Mazur. Unfortunately similar values for the compound described by Marker and Wittle were not recorded and hence are not available. In our opinion the disagreement between the observed and calculated values is so striking that it may be safely concluded that the compound described by RIazur is not 5,6-dihydrostigmasterol. On the contrary the TABLE VI PREDICTED
ROTATIONS OF
DERIVATIVES
CY-ANHYDRO-UZARIGENIN
PREDICTED [aID( C H C l a )
a-ANHYDRO-UZARIGENIN DERIVATIVE
Acetate. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Benzoate. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . m-Dinitrobenzoate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
-52.7 -21.0 -16.1
TABLE VI1 DIHYDROSTIGMASTEROL
I M A R K E ~ , ~ II f b ~ I
COMPOUND
I
U Z U R , Y.P.,
5,6-Dihydrostigrnasterol., , , . . , . , . , . , , , , , . , , , , . . . . I 5,6-Dihydrostigmasterol acetate. . . . . . . . . . . . . . . . . . : j ~
187 122
j
OC.
136.5-137 137
~~~
TABLE VI11 ROTATIONS OF DIHYDROSTIGMASTEROL DERIVATIVES
DI.[
OBS.
COMPOUND
5,6-Dihydrostigmasterol.. . . . . . . . . . . . . . . . . . . . . . . . . . 5,6-Dihydrostigmasterol acetate. . . . . . . . . . . . . . . . . . . 5,6-DihydrostigmasteroI benzoate. . . . . . . . . . . . . . . . . . 5,6-Dihydrostigmasterol m-dinitrobeneoate. ........
1
CHCls
[ah (CHCla)
CALC'D
-41.8 -47.6 -17.1 -18.3
f10.6 +0.6 +8.5 +3.5
TABLE IX ROTATIONS OF MAZUR'S STEROL MAZUB'S STEROL DERIVATIVE
Acetate. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
~
OBS. [a]= (CHCla)
I1
c.4Lc'D [alD( C H C l a ) (ASSUMING DOUBLE C6:e POSITION)
BONE AT
-45.6
OPTICAL ROTATORY POWER OF STEROLS
109
Another illustration of the use of this method may be of interest. In a recent paper by Ruzicka and eo-workers (7) evidence is presented to 21-dioxynorcholadienic acid establish that a-anhydro-uzarigenin and A5:e,20:22-3, lactone are identical.
d'
v
C=
CH
CH2
CO
I
\ /
I
0
Ho\/\
A5:692022-3 ,21-dioxynorcholadienic acid lactone
If a-anhydro-uzarigenin has one of its double bonds a t the C6:6 position, then one is able to calculate the optical rotation of several derivatives with the aid of the appropriate constants in Table I. Since these constants are characteristic for such a structure @-OH at C3,and double bond at cS:6), agreement between the calculated and observed values would substantiate fairly conclusively the presence of such a structure. We have calculated the rotations of a-anhydrouzarigenin acetate, benzoate, and m-dinitrobenzoate, assuming the above men,21-dioxynorcholadienic tioned identity of a-anhydro-uzarigenin and A5:6'20:22-3 acid lactone, and the specific rotation, -49.1" (CHCl,), reported by Ruzicka and co-workers (7) to be correct. The rotations of these derivatives of a-anhydrouzarigenin are not known. Therefore our calculated values (Table VI) are to be considered as predictions. SUMMARY
1. A simple method for the calculation of the optical rotatory power of steroid derivatives has been developed. 2. Application of this method as a structural tool has been made. PRINCETON, N. J. REFERENCES (1) BERNSTEIN, KAUZMANN, AND WALLIS,J . Org. Chem., 6,319 (1941). (2) (a) WALLISAND FERNHOLZ, J . Am. Chem. SOC.,68, 2446 (1936). (b) BERNSTEIN AND WALLIS,J . Am. Chem. SOC.,61, 2308 (1939). (3) FERNHOLZ AND MACPHILLAMY, J . Am. Chem. SOC.,63, 1155 (1941); FERNHOLZ AND RUIGH,J . Am. Chem. SOC.,63, 1157 (1941). (4) VALEXTINE AND BERGMANN, J. Org. Chem., 6, 452 (1941). (5) MAZCR, J . Am. Chem. Soc., 63, 2442 (1941). (6) MARKER AND WITTLE,J. Am. Chem. SOC., 69,2704 (1937). (7) RIJZICKA, PLATTNER, AND FURST,Helv. Chim. Acta, 24,716 (1941). et al., J . Chem. Soc., ( 8 ) (a) SCHENCR et al., Ber., 69, 2696 (1936). (b) HEATH-BROWN 1940, 1482. (9) FERNHOLZ AND STAVELY, J . Am. Chem. Soc., 61, 142 (1939). (10) SANDQVIST AND GORTON, Ber., 63, 1759 (1930); JAEGER, Rec. truv. chim., 26,334 (1906); PAGEAND RUDY,Biochem. Z . , 220, 304 (1930). (11) WALLISAND CHAKRAVORTY, J . Org.Chem., 2, 335 (1937).
110
BERNSTEIN, WILSON, .4ND WALLIS
(12) HEILBRON et al., J. Chem. SOC.,1938, 874; BILLSAND HONEYWELL, J. B i d . Chem., 80, 15 (1928). (13) BERNSTEIN AND WALLIS, J. Org. Chem., 2, 341 (1937). (14) ANDERSON AND SHRINER, J. Am. Chem. SOC.,48, 2976,2986, (1936). (15) (a) REINDEL et al., Ann., 462, 34 (1927). (b) REINDELAND WALTER,Ann., 460, 212 Ann., 460, 225 (1928). (d) HARTAND HEYL, (1928). (c) WINDAUSAND BRUNKEN, J. Am. Chem. SOC.,63, 1413 (1931). (e) HARTAND EMERSON, J. Am. Chem. SOC., 64, 1070 (1932). (16) SANDQVIST AND GORTON, Ber., 63, 1935 (1930). (17) FERNHOLZ AND RUIGH,J. Am. Chem. SOC., 62, 3346 (1940). (18) ICHIBA, Sci. Papers Inst. Phys. Chem. Research (Tokyo),28, 112 (1935). (19) WINDAUSAND LAKGER, Ann., 608, 105 (1933). (20) WUNDERLICH, 2. physiol. Chem., 241, 116 (1936). (21) WINDAUSAND RYGH,Nachr. Ges. Wiss.Gottingen, 311 (1928). (22) WIELANDAND ASANO,Ann., 473, 300 (1929). (23) CALLOW, Biochem. J., 26, 79 (1931). (24) (a) REINDEL AND WEICKMANN, Ann., 476, 86 (1929). (b) REINDELAND WEICKMANN, Ann., 482, 120 (1930). AND HEYL,J. Am. Chem. Soc., 66, 2663 (1934). (25) LARSEN (26) FERNHOLZ A N D RUIGH,J. Am. Chem. SOC., 62, 2341 (1940). (27) HAUSSLER AND BRAUCHLI, Helv. Chim. Acta, 12, 187 (1929). (28) REINDEL A N D DETZEL, Ann., 476, 78 (1929). (29) HEILBRON AND WILKINSON,J. Chem. Soc., 1932,1708. (30) HARTAND HEYL,J. B i d . Chem., 96, 311 (1932). (31) WIELANDAND COUGH, Ann. 482, 36 (1930).
