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Effect of symmetry on C19 N.M.R. shifts in steroids
Tetrahedron Letters No. 18, pp. 1161-1166, Printed in Great Britain.
EFFECTOFSYUETET
CU Cl9
1963.
1I.Y.B.
Pergamon Press Ltd.
s.Ex?m
111 m(l)
by E. R. Malinouaki, M. S. Manhas, 0. 8. Mllller ad Ajay K. Boae Department of Chemirtry aud Chemical eagiaeering Stevens Institute of Technology, Kobohen, New Jareey, 8.S.A. (Received 1 May 1963) Several investigators (2,3) have obaetved additivfty relations for chemical shifta of angular methyl protons of steroida.
In tlmae ltudiea
"replacement conatanta"(3) are aarigned to various aubatituent greapa of the molecule. When added together these replacement constanta accurately predict the variation in chemical shift of angular methyl protons upon the introduction of rubstituent groupa into the parent molecule.
Tba re-
placement constant for a given aubatituent group varies according to fta position in the molecule.
In thia c-nication
significance of structural awetry
we wish to point cut the
on such additivity ralatioua.
We have investigated the Cl9 methyl proton lhifta of a large Iumber of steroid derivatives (see Table I). Keaaurersnta were ude
with a
Varien Dp-60 Sigh Resolution N. t4. a. Spectroaeter on corpmnd8
dkaolVed
in deuterated chloroform. Valuer for the replacement constants of variow groups in different positions of the steroid nucleus were determined by a method of least squares and are listed iu Table 11. As ahown in Tabla I. in almost all cases the predicted chemical ahifta using valuea in Table II are in excellent agreament with the experimental result. the experimental error being ? 0.01 to 0.02 p.p.r.
Upon studying the variations in the valuaa for cboleatane (tr~na AD)
derivativea we find that the replecament constants for braine
the 2oi, 4&and
6~poeitiona
are identical. Again, the replae-t
1161
ie
Cholcstane 3oLUeH3/5-O& 3/&w3-kato2k-Br,3d-OH2fl-Br,3d-OU2&-C1,3-keto2,&X,3-k&o2d-Br,3-keto2fi-Br,3-keto3j4-CH,'I-keto3#-OAc,7-keto3-k&o,%-Cl3-keto,6P-Br3-keto,7-keto2a-C1,2/-C1,3-keto?uC*Br,f-keto,43C-Br2d-Br,3-keto,S&-Cl2d-Br,3-keto,6/-Br2,4-Br.3-keto,Sd-Cl3,d-OAc.6&Br,7-keto3,4-OAc,6;/-Br,7-keto3-keto.5&-Br.6fl-Br2+Cl.J-keto,Sx-Br.6/-BrZ&Br,3-keto,51L-Br,6/-Br-
A/B-trPM
Capound
9.19 9.17 9.01 9.13 8.92 8.91 8.83 8.91 8.79 8.94 8.93 8.773 8.73' 8.75 8.73 8.82 8.6g3 8.67" 8.53' 8.85 8.70 8.42 8.32' 8.39
9.23
9.23
9.20 9.18 9.18 9.00 9.10 8.93 8.91 8.80 8.92 8.75 8.95 8.95 8.76 8.75 8.77 8.71 8.84 8.68 8.67 8.51 8.87 8.70 8.43 8.34 8.35
___
9.09 8.98 8.70 8.90 8.63
Methyl cholanate 3-k&o3-keto,7-keto3-keto,l2-kcto3-keto,7-keto,l2-keto-
9.0gb 8.97b 8.74' 8.91 8.64
___ 8.97 8.92 8.87
a Value for corresponding cholestane derivative. b Value for corresponding coprostane derivative. c Value obtained by adding shift for 7- or 3-keto group in the cholestane series to the yvalue of the Cl9 - methyl signal in coprostan-3-one.
9.08 8.97 8.92 8.88
Coprostane 3-keto3-keto,Irfi -Br26-Br,3-keto.44 -Br-
A/B-cis
9.01a 8.93a
5&-Andrortane 3-keto,17p -CA+ 24-Br,3-keto,17$-OAc-
8.99 8.90
8.26 8.18 8.62
(cont.1
Qppm, r(ppm) obs. talc.
Cholestane (cont.) 2~-Br,3-keto.5d-C1,6,8--Cl- 8.273 2/-Br,3-keto,W-Br,6,9-Br8.1a3 3,4-CAc,6k-Br.$.4 -Br,7-keto- 8.68
A/B-tran8
Compound
Chemical Shifts of Cl9 Methyl Protons
TABLE I
No.
18
1163
Effect of symmetry on Cl9 N.M.R. shifts in steroids
constants for bromine in the 2 4 and 4(1 positions are equal to each ir other.
Furthermore, the replacement constant for a ketone in position 3
is identical to that for a ketone in position 7.
Such equivalence in the
trans A/B series provides us with information concerning the conformations of rings A and B (see Fig. 11. Theories of diamagnetic bond anisotropy predict that chemical shift is, among other things, a function of bond angles and interatomic distances. The effect of a substituent group on chemical shift will be dependent upon the exact location and structural orientation of the substituent group relative to the proton in question. From sylmDetryconsiderations relative to the freely rotating protons of the Cl9 methyl group we have come to the conclusion that there is An operation here a rule reminiscent of Freudenberg's (41 "Rule of Shift" for optical rotation:
the same change in substituents at analogous posi-
tions (vis-a-vis the methyl group under study) will produce the same rc-placement constant. Therefore, for the trans A/B compounds listed in Table I, ring A must be symmetrical with respect to a plane passing through C3 and CIO; furthermore, rings A and B must be symmetrical relative to a plane passing through CS and Cl,,. Such syraaetryis, of course, predicted on the basis of conformational analysis.
If the A/B ring junction is c&,
then the syPlnetrybetween rings
A and B relative '30Cl9 is destroyed (see Fig. 2) and equivalence between groups in the two rings is not to be expected. There will, however, be equivalence between the 2- and 4- positions with respect to C19.
The
values in Table II are in full accord with these symmetry considerations.
We can uee some of the data in Table I for testing the rule of shift.
Thus. the introduction of a bromine in the Z&-position produces
No.18
Effect of symmetry on Cl9 N.M.R. shifts in steroids
1164
TABLE II Replacement Consta..rsfor Cl9 Methyl Protons SubstLtuent
truu
R19 (pen)
A/B-steroids .09 .20 24 :os 25 132 .03 .05 .05 .23
2ot-a 2/3- or .3)8-a SoC-cl 2&-, 40(- or b&-Br 2p- or b,&Br 50GBr 3Q(-on 3p-OR 3/s-Ac 3- or 7-k&to
cia
A/B-Steroid8
2',&- or 4/#-Br
.05 .ll .27 .07
3-keto 7-kcto 12-keto
Figure
1
tha .-
shift in 17P-~c~torJrmdr~t~n-3-~~
choinic
mid
ltamwba-em tha .-
"
3-kato group
derivatives the A rhg
.. in chola#tan-3-one.
disposition im the ‘BPC as Ln copro-
tke diaposftion of the B ring v4-a-via in cholutenr.
c.ue.a tb
l
It will k -
aiit
In
tb
C19-uthyl
im
moticed that the introduction of a
in the c 19-methyl aigna1 in copro8tanc
No.18
1165
Effect of symmetry on Cl9 N.M.R. shifts in steroids
and methyl cholenete. Again, the ehift for introducing the 7-keto group in methyl 3-ketocholenate or mthyl
3,12-diketocholenate ti 0.27 p.p.I.,
which is very close to the shift of 0.23 p.p.n. observed on introducing e 7-keto group in e cholestane derivative. The cull
verietioa in thee
two
values may indicate slightly varying emountr of di8tortion in the ring systems under comparlon.
The position of the proton eignal of the Clg methyl group8 depondr largely on substituents in the A, B end C ringa, and very little on the substituents in the D ring. Therefore,
for a c
A/B or e
A/B etrroid
substituted in the A ring, the chemical lhift of the Cl9 methyl group can be directly obtained from the corresponding coproetane or choleatane derivative which differs only in the D ring subetitution. Replec-t
con-
stants for substituents in ring B of either -cir or trans A/B steroida ten be obtained from the more aveileble cholestene derivativee. The date in Table I indeed show that this is true. Furthermore, by taking note of the equfvelence of poeitionr 2, 4, 6 and of 3 and 7 in 8 trans A/B steroid, it ie poerible to predict the chemical ehift of Cl9 methyl protons in e wide variety of Heroida the values in Table II.
wing
Deviations from sdditivity would indicate devie-
tion from the normal conformation of the ring systems. The qumtitetive Correlations die-ussed here should also be useful for uarining
ring
systems other than steroids.
We are thankful to Edward R. Townley for preparing pounds studied by us.
l
ime of the CQ-
This investigation wee rupported in pert by reeeereh
grant O-13290 from the National Science Foundation end reeesrch great CY5079 from the National Cancer Institute. U. S. Public Eeelth Service, for which greteful acknowledgement ie ude.
1166
Effect of symmetry on Cl9 N.M.R. shifts in steroids
NO.18
REFERENCES
(1) Baeed in pert on a paper preeented in August, 1962 before the Second International Sympooium on the Chemistry of Natural Product8 in Prague.
(2) J. N. Shoolery end M. T. Rogere, J. Amer. Chea. Sot.
80. 5121 (1958). =
(3) J. Jacqueey, J. Lehn and J. Levisaller, Bull. Sot. chin. France 2444 (1961), end references cited therein.
(4) K. R-eudenberg, W. Kuhn and I. Bumann, Ber. -=
63, 2380 (1930).
EFFECTOFSYUETET
CU Cl9
1963.
1I.Y.B.
Pergamon Press Ltd.
s.Ex?m
111 m(l)
by E. R. Malinouaki, M. S. Manhas, 0. 8. Mllller ad Ajay K. Boae Department of Chemirtry aud Chemical eagiaeering Stevens Institute of Technology, Kobohen, New Jareey, 8.S.A. (Received 1 May 1963) Several investigators (2,3) have obaetved additivfty relations for chemical shifta of angular methyl protons of steroida.
In tlmae ltudiea
"replacement conatanta"(3) are aarigned to various aubatituent greapa of the molecule. When added together these replacement constanta accurately predict the variation in chemical shift of angular methyl protons upon the introduction of rubstituent groupa into the parent molecule.
Tba re-
placement constant for a given aubatituent group varies according to fta position in the molecule.
In thia c-nication
significance of structural awetry
we wish to point cut the
on such additivity ralatioua.
We have investigated the Cl9 methyl proton lhifta of a large Iumber of steroid derivatives (see Table I). Keaaurersnta were ude
with a
Varien Dp-60 Sigh Resolution N. t4. a. Spectroaeter on corpmnd8
dkaolVed
in deuterated chloroform. Valuer for the replacement constants of variow groups in different positions of the steroid nucleus were determined by a method of least squares and are listed iu Table 11. As ahown in Tabla I. in almost all cases the predicted chemical ahifta using valuea in Table II are in excellent agreament with the experimental result. the experimental error being ? 0.01 to 0.02 p.p.r.
Upon studying the variations in the valuaa for cboleatane (tr~na AD)
derivativea we find that the replecament constants for braine
the 2oi, 4&and
6~poeitiona
are identical. Again, the replae-t
1161
ie
Cholcstane 3oLUeH3/5-O& 3/&w3-kato2k-Br,3d-OH2fl-Br,3d-OU2&-C1,3-keto2,&X,3-k&o2d-Br,3-keto2fi-Br,3-keto3j4-CH,'I-keto3#-OAc,7-keto3-k&o,%-Cl3-keto,6P-Br3-keto,7-keto2a-C1,2/-C1,3-keto?uC*Br,f-keto,43C-Br2d-Br,3-keto,S&-Cl2d-Br,3-keto,6/-Br2,4-Br.3-keto,Sd-Cl3,d-OAc.6&Br,7-keto3,4-OAc,6;/-Br,7-keto3-keto.5&-Br.6fl-Br2+Cl.J-keto,Sx-Br.6/-BrZ&Br,3-keto,51L-Br,6/-Br-
A/B-trPM
Capound
9.19 9.17 9.01 9.13 8.92 8.91 8.83 8.91 8.79 8.94 8.93 8.773 8.73' 8.75 8.73 8.82 8.6g3 8.67" 8.53' 8.85 8.70 8.42 8.32' 8.39
9.23
9.23
9.20 9.18 9.18 9.00 9.10 8.93 8.91 8.80 8.92 8.75 8.95 8.95 8.76 8.75 8.77 8.71 8.84 8.68 8.67 8.51 8.87 8.70 8.43 8.34 8.35
___
9.09 8.98 8.70 8.90 8.63
Methyl cholanate 3-k&o3-keto,7-keto3-keto,l2-kcto3-keto,7-keto,l2-keto-
9.0gb 8.97b 8.74' 8.91 8.64
___ 8.97 8.92 8.87
a Value for corresponding cholestane derivative. b Value for corresponding coprostane derivative. c Value obtained by adding shift for 7- or 3-keto group in the cholestane series to the yvalue of the Cl9 - methyl signal in coprostan-3-one.
9.08 8.97 8.92 8.88
Coprostane 3-keto3-keto,Irfi -Br26-Br,3-keto.44 -Br-
A/B-cis
9.01a 8.93a
5&-Andrortane 3-keto,17p -CA+ 24-Br,3-keto,17$-OAc-
8.99 8.90
8.26 8.18 8.62
(cont.1
Qppm, r(ppm) obs. talc.
Cholestane (cont.) 2~-Br,3-keto.5d-C1,6,8--Cl- 8.273 2/-Br,3-keto,W-Br,6,9-Br8.1a3 3,4-CAc,6k-Br.$.4 -Br,7-keto- 8.68
A/B-tran8
Compound
Chemical Shifts of Cl9 Methyl Protons
TABLE I
No.
18
1163
Effect of symmetry on Cl9 N.M.R. shifts in steroids
constants for bromine in the 2 4 and 4(1 positions are equal to each ir other.
Furthermore, the replacement constant for a ketone in position 3
is identical to that for a ketone in position 7.
Such equivalence in the
trans A/B series provides us with information concerning the conformations of rings A and B (see Fig. 11. Theories of diamagnetic bond anisotropy predict that chemical shift is, among other things, a function of bond angles and interatomic distances. The effect of a substituent group on chemical shift will be dependent upon the exact location and structural orientation of the substituent group relative to the proton in question. From sylmDetryconsiderations relative to the freely rotating protons of the Cl9 methyl group we have come to the conclusion that there is An operation here a rule reminiscent of Freudenberg's (41 "Rule of Shift" for optical rotation:
the same change in substituents at analogous posi-
tions (vis-a-vis the methyl group under study) will produce the same rc-placement constant. Therefore, for the trans A/B compounds listed in Table I, ring A must be symmetrical with respect to a plane passing through C3 and CIO; furthermore, rings A and B must be symmetrical relative to a plane passing through CS and Cl,,. Such syraaetryis, of course, predicted on the basis of conformational analysis.
If the A/B ring junction is c&,
then the syPlnetrybetween rings
A and B relative '30Cl9 is destroyed (see Fig. 2) and equivalence between groups in the two rings is not to be expected. There will, however, be equivalence between the 2- and 4- positions with respect to C19.
The
values in Table II are in full accord with these symmetry considerations.
We can uee some of the data in Table I for testing the rule of shift.
Thus. the introduction of a bromine in the Z&-position produces
No.18
Effect of symmetry on Cl9 N.M.R. shifts in steroids
1164
TABLE II Replacement Consta..rsfor Cl9 Methyl Protons SubstLtuent
truu
R19 (pen)
A/B-steroids .09 .20 24 :os 25 132 .03 .05 .05 .23
2ot-a 2/3- or .3)8-a SoC-cl 2&-, 40(- or b&-Br 2p- or b,&Br 50GBr 3Q(-on 3p-OR 3/s-Ac 3- or 7-k&to
cia
A/B-Steroid8
2',&- or 4/#-Br
.05 .ll .27 .07
3-keto 7-kcto 12-keto
Figure
1
tha .-
shift in 17P-~c~torJrmdr~t~n-3-~~
choinic
mid
ltamwba-em tha .-
"
3-kato group
derivatives the A rhg
.. in chola#tan-3-one.
disposition im the ‘BPC as Ln copro-
tke diaposftion of the B ring v4-a-via in cholutenr.
c.ue.a tb
l
It will k -
aiit
In
tb
C19-uthyl
im
moticed that the introduction of a
in the c 19-methyl aigna1 in copro8tanc
No.18
1165
Effect of symmetry on Cl9 N.M.R. shifts in steroids
and methyl cholenete. Again, the ehift for introducing the 7-keto group in methyl 3-ketocholenate or mthyl
3,12-diketocholenate ti 0.27 p.p.I.,
which is very close to the shift of 0.23 p.p.n. observed on introducing e 7-keto group in e cholestane derivative. The cull
verietioa in thee
two
values may indicate slightly varying emountr of di8tortion in the ring systems under comparlon.
The position of the proton eignal of the Clg methyl group8 depondr largely on substituents in the A, B end C ringa, and very little on the substituents in the D ring. Therefore,
for a c
A/B or e
A/B etrroid
substituted in the A ring, the chemical lhift of the Cl9 methyl group can be directly obtained from the corresponding coproetane or choleatane derivative which differs only in the D ring subetitution. Replec-t
con-
stants for substituents in ring B of either -cir or trans A/B steroida ten be obtained from the more aveileble cholestene derivativee. The date in Table I indeed show that this is true. Furthermore, by taking note of the equfvelence of poeitionr 2, 4, 6 and of 3 and 7 in 8 trans A/B steroid, it ie poerible to predict the chemical ehift of Cl9 methyl protons in e wide variety of Heroida the values in Table II.
wing
Deviations from sdditivity would indicate devie-
tion from the normal conformation of the ring systems. The qumtitetive Correlations die-ussed here should also be useful for uarining
ring
systems other than steroids.
We are thankful to Edward R. Townley for preparing pounds studied by us.
l
ime of the CQ-
This investigation wee rupported in pert by reeeereh
grant O-13290 from the National Science Foundation end reeesrch great CY5079 from the National Cancer Institute. U. S. Public Eeelth Service, for which greteful acknowledgement ie ude.
1166
Effect of symmetry on Cl9 N.M.R. shifts in steroids
NO.18
REFERENCES
(1) Baeed in pert on a paper preeented in August, 1962 before the Second International Sympooium on the Chemistry of Natural Product8 in Prague.
(2) J. N. Shoolery end M. T. Rogere, J. Amer. Chea. Sot.
80. 5121 (1958). =
(3) J. Jacqueey, J. Lehn and J. Levisaller, Bull. Sot. chin. France 2444 (1961), end references cited therein.
(4) K. R-eudenberg, W. Kuhn and I. Bumann, Ber. -=
63, 2380 (1930).