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Stereospecific total synthesis of (+)-ε-cadinene enolic epimerization in the wittig and methyllithium reactions
TetrahedronLettersNo.3, pp. 211-214,1970.
STEREOSPECIFIC ENOLIC EPIMERIZATION
Printed in Great Britain.
Pergamon Press.
TOTaL SYNTHESIS OF (+)-e-CADINENE IN THE WITTIG AND METHYLLITHIUM
REACTIONS
Milton D. Soffer and L&le Aka Burk Department
of Chemistry,
Smith College, Northampton,
Massachusetts
01060
(Receivedin UsA 24 November 1969; received in IX for publication 17 December 1969) (-)-c-Cadinene partially
was initially
obtained in 1964 (1) as the major product of a
directed dehydrohalogenation
that time both (-)-c-cadlnene identification,
(2) and (+)-s-cadinene
have been reported
and its formula I were incorrectly
have recently
investigations
tion.
with inversion
reactions,
of alkyllithiums
reported
with ketones,
reactions
presumably products
previously,
(7,8).
course.
enolization
conditions required
at the C, Bridgehead
has been provided by reagent,
or the
In these cases the addition of III with methylene-
in the present work, Involving
followed by normal addition
IV and V in high yield, are to the best of our knowledge
lsomerizatlon
to give
the first
and the usual nucleophlllc
upon the carbonyl group take place in the same synthetic step. the need for a separate
posi-
as well as in addition reactions
The reactions
cases in the literature where both enollzation
eliminate
we
reactions with the cis-
inert to the nucleophillc
and with methyllithium
a fast reversible
(II) (1,5).
under the mildest
of configuration
carbonyl c£
do not take the normal
triphenylphosphorane
even
For
(l), the name &-cadlnene
the evidence for enolizatlon
either the isolation of an enolate, of unreacted
species.
directed toward the above sesquiterpenes
found that the Wittig and methyllithium
In Wittig reactions
recovery
definitive work
and since
(I) (3,4), without rigorous
applied to s-muurolene
octalone enol ether III (6) proceed, for these
dihydrochloride,
to occur in different botanical
several years previous to Westfelt's
In synthetic
of (-)-cadlnene
attack
The new reactions
step in the syntheses of trans-
decalins by these methods. In the case of the reaction
of III with methylenetrlphenylphosphorane 211
(91,
NO.5
212
II
I CHz
mild hydrolysis
of the resulting
for twenty-five
minutes with 0.5N hydrogen
60% overall yield
(homogeneous
olefinic enol ether IV (10) at room temperature
strong positive
series.
stable ring inversion conformation, alignment,
should show a rather
the starting negative
cis-octalone
effect
strong negative
([a]311(max) -3760; homogeneous
yield, after purification,
dihydrochloride
VIII,which
basis of its ir spectrum,
VIII
the previous
synthesis,
for (-)-e-cadinene
(1,14).
was identical with an authentic
(l),
The structure was (1) to (+)-cadinene sample (6) on the
([a]:7+37.50), m.p. and mixed m.p.
was obtained
gc, by direct treatment
(6) with excess Wittig reagent.
The ir spectrum,
groups and for no other
at low temperature
optical rotation
it in 70,%
(I) (l)), whose structure was
from that of e-muurolene conversion
(6).
ketone VI converted
indicated four vinyl protons.
The same (+)-E-cadinene
lation and preparative
Conversely,
(12).
on other grounds
is in good agreement with that reported different
group in the equatorial
by gc analysis), which is compat-
for the exocyclic methylene
by an unambiguous
(117-117.50).
required
to (+)-E-cadinene
showing intense absorption
but is markedly
cis isomer in its -
Cotton effect
(9) of the methylene
from its nmr data which
unsaturation,
([c~]~~e(m~x)+865~)
enol ether III showed a relatively weak but clear
Further Wittig treatment
confirmed
The corresponding
in
ketone VI (II),
Cotton effect
with the isopropyl
ible only with the cis stereochemistry
evident
in 95% ethanol produced
the methylene
by gc analysis),
which was shown by its relatively to belong to the trans-decalone
chloride
in 79% yield after distil-
(9) of the (+)-trans-diketone
The product,
on admixture with that from
showed a single peak on the gas chromatopram
and was
NO.3
213
converted, as before, to (+)-cadinene dihydrochloride. In separate experiments, epimerization at C, took place when the cis-octalone III was treated with excess methyllithium. In this case the resulting crude enol ether methyl carbinol (V) (15) obtained in quantitative yield, was directly hydrolized by repeated extraction from ether with aqueous sodium bisulfite. When the regenerated hydroxyketone (16)
was
again allowed to react with excess methyl-
lithium and the resulting crude dial (17) was treated with hydrogen chloride under specific conditions (-23O) for the retention of the bridgehead stereochemistry (l), the only crystalline
product obtained was (+)-cadinene dihydrochlorlde.
No muurolene dihydrochloride could be detected, even with the sensitive techniques of Westfelt (1) which are specifically effective in the presence of cadinene dihydrochloride. The above reactions, taken together with the stereospecific syntheses of the starting ketones III and VIII, provide new variations in the total stereospecific synthesis of (+)-cadinene dihydrochloride (6,18),
and the first total synthesis
of (+)-e-cadinene. The synthesis of the latter provides additional support for the revised structure I (1) of this sesquiterpene. Acknowledgment. We wish to thank Dr. L. Westfelt, for a reference sample of muurolene dihydrochloride, and Drs. G. E. Gunay and M. K. Logahi for their aid In certain phases of this work, and to acknowledge gratefully grants from the Sloan Foundation and from the National Science Foundation.
REFERENCES AND FOOTNOTES L. Westfelt, Acta Chem. Stand. g, 572 (1964); 2, 2852 (1966). 2. E. von Rudloff and K. W. Hefendehl, Can. J. Chem. e, 2015 (1966). The inordinately high value stated, [CL];=-1620, should perhaps read 16.20 (cf. ref. 13). E. von Rudloff and E. W. Underhill, Phytoohemlstry !, 11 (1965). 3. 4. R. Vlahov, M. Holub, I. Ognjanov and V. Herout, Collection Czech. Chem. Commun. 2, 808 (1967). [C,A. 2, S704h 5. V. Herout and D. I. Dimitrov, Chem. Listy 4&, 432 (1952) (1953)]; V. Herout and F. zantz Collection Czech. Chem. Commun. &_& 118 (1954); V. Sikora, V, Herout and F.G, a. 2, 2181 (1958). 1.
214
No.3
6. M. D. Soffer, G. E. Gfinay, 0. Korman and M. B. Adams, Tetrahedron
Letters
389 (1963)~ M. D. Soffer and G. E. Gi_inay,w. 1355 (1965). 7. U. Schoellkopf, Doctoral Dissertation, Universltat Tublngen, 1956 ["Organic Reactions," 2, 349 (1965)1. 8. H. W. B. Reed, J. Chem. Sot, 1931 (1954). For analogous reactions with Grignard reagents
see C. D. Gutsche,
Prentice Hall, New Jersey,
"The Chemistry
of Carbonyl Compounds,"
1967, pp. 71-99.
9. R. Greenwald, M. Chaykovski and E. J. Corey, J. Org. Chem. g,
1128 (1963).
The reagent was prepared with a slight excess of methyltriphenylphosphonium bromide
over the sodium hydride used to insure the absence of any carbanion
base during the reaction 10, Found for the methylene
with the ketone. enol ether IV:
uz4
(cm-') 3080 (m), 1660 (m),
1189 (s, enol ether), 890 (s), 1715 (VW, trace of unreacted ketone). uCCl* (cm-') 3080 11. Found for the methylene ketone VI: c, 81.51~ H, 10.86. (m) 1715 (s), 1650 (m), 895 (s); nmr (Varian A-60-A, Internal TMS) 4.6~ (2H, doublet, (3H) [both doublets 12. C. Djerassi,
terminal methylene),
6, doK:leld
from
0.92 (3H) and 0.68
(J = 6.5 Hz) isopropyl group].
"Optical Rotatory Dispersion,"
McGraw-Hill,
New York, 1960,
pp. 178-190; R. Howe and F. J. McQuillin, -J. Chem. Sot. 1194 (1958). from 1111 s2 1.5039~ [a]E0+60 (CHCl,); uiz24 (cm-')
13. Found for (+)-E-cadinene 3075
(m), 1790 (w), 1648 (s), 1188 (m), 1140 (m), 1085, 1075 (m, doublet),
893 (vs); ~2; 3075 (m), 1785 (w), 1648 (s), 1188 (m), 1138 (m), 1080, 1072 (m, doublet), 890 (vs), 817 (m), 652 (m), 638 (s)i nmr (CDCl,, 6) 4.58 (4H multiplet,
terminal methylene),
Hz) isopropyl
0.91 (3H) and 0.70 (3H)[both doublets (J=6.5
group]; homogeneous
by gc analysis, retention
time 19 min. at
155", lo ft. x 0,125 in. 25% Carbowax 20M/firebrlck, He 0.17 ml.,/sec. For (+)-e-cadinene from VIII: r$" 1.5033; [a]z" +lO" (CHCl,); ir, nmr and gc as above.
Reportedr
[a]ge +5.6O
[a1g2 -15.9" (1). 14. J. Pliva, M. Ho&k,
Reported
(9).
Reported
for (-)-c-cadinene
for (+)-c-muurolene:
V. Herout and F. Sorm,
r15' 1.5049;
"Die Terpene,"
ng2 1.5032;
[a];" +50.7" (1).
I, Berlin , 1960.
carbinol V: uzzi4 (cm-') 3615 (m, sharp), 1660 (m), 1188 (s, enol ether), 1718 (VW, trace of unreacted ketone). uCC1, (cm-") 3615 (m, sharp), 1715 (as). 16. Found for the hydroxyketoner 15. Found for the enol ether methyl
17. Found for the dial:
,p4
max
(cm-y3610
(ma),
1714 (VW, trace of unreacted
ketone). 18. For a synthesis
of the racemic
Rao and S. Dev, Tetrahedron
dihydrochlorlde,
22, 1977 (1966).
see M. V. R. K. Rao, G. S. K.
STEREOSPECIFIC ENOLIC EPIMERIZATION
Printed in Great Britain.
Pergamon Press.
TOTaL SYNTHESIS OF (+)-e-CADINENE IN THE WITTIG AND METHYLLITHIUM
REACTIONS
Milton D. Soffer and L&le Aka Burk Department
of Chemistry,
Smith College, Northampton,
Massachusetts
01060
(Receivedin UsA 24 November 1969; received in IX for publication 17 December 1969) (-)-c-Cadinene partially
was initially
obtained in 1964 (1) as the major product of a
directed dehydrohalogenation
that time both (-)-c-cadlnene identification,
(2) and (+)-s-cadinene
have been reported
and its formula I were incorrectly
have recently
investigations
tion.
with inversion
reactions,
of alkyllithiums
reported
with ketones,
reactions
presumably products
previously,
(7,8).
course.
enolization
conditions required
at the C, Bridgehead
has been provided by reagent,
or the
In these cases the addition of III with methylene-
in the present work, Involving
followed by normal addition
IV and V in high yield, are to the best of our knowledge
lsomerizatlon
to give
the first
and the usual nucleophlllc
upon the carbonyl group take place in the same synthetic step. the need for a separate
posi-
as well as in addition reactions
The reactions
cases in the literature where both enollzation
eliminate
we
reactions with the cis-
inert to the nucleophillc
and with methyllithium
a fast reversible
(II) (1,5).
under the mildest
of configuration
carbonyl c£
do not take the normal
triphenylphosphorane
even
For
(l), the name &-cadlnene
the evidence for enolizatlon
either the isolation of an enolate, of unreacted
species.
directed toward the above sesquiterpenes
found that the Wittig and methyllithium
In Wittig reactions
recovery
definitive work
and since
(I) (3,4), without rigorous
applied to s-muurolene
octalone enol ether III (6) proceed, for these
dihydrochloride,
to occur in different botanical
several years previous to Westfelt's
In synthetic
of (-)-cadlnene
attack
The new reactions
step in the syntheses of trans-
decalins by these methods. In the case of the reaction
of III with methylenetrlphenylphosphorane 211
(91,
NO.5
212
II
I CHz
mild hydrolysis
of the resulting
for twenty-five
minutes with 0.5N hydrogen
60% overall yield
(homogeneous
olefinic enol ether IV (10) at room temperature
strong positive
series.
stable ring inversion conformation, alignment,
should show a rather
the starting negative
cis-octalone
effect
strong negative
([a]311(max) -3760; homogeneous
yield, after purification,
dihydrochloride
VIII,which
basis of its ir spectrum,
VIII
the previous
synthesis,
for (-)-e-cadinene
(1,14).
was identical with an authentic
(l),
The structure was (1) to (+)-cadinene sample (6) on the
([a]:7+37.50), m.p. and mixed m.p.
was obtained
gc, by direct treatment
(6) with excess Wittig reagent.
The ir spectrum,
groups and for no other
at low temperature
optical rotation
it in 70,%
(I) (l)), whose structure was
from that of e-muurolene conversion
(6).
ketone VI converted
indicated four vinyl protons.
The same (+)-E-cadinene
lation and preparative
Conversely,
(12).
on other grounds
is in good agreement with that reported different
group in the equatorial
by gc analysis), which is compat-
for the exocyclic methylene
by an unambiguous
(117-117.50).
required
to (+)-E-cadinene
showing intense absorption
but is markedly
cis isomer in its -
Cotton effect
(9) of the methylene
from its nmr data which
unsaturation,
([c~]~~e(m~x)+865~)
enol ether III showed a relatively weak but clear
Further Wittig treatment
confirmed
The corresponding
in
ketone VI (II),
Cotton effect
with the isopropyl
ible only with the cis stereochemistry
evident
in 95% ethanol produced
the methylene
by gc analysis),
which was shown by its relatively to belong to the trans-decalone
chloride
in 79% yield after distil-
(9) of the (+)-trans-diketone
The product,
on admixture with that from
showed a single peak on the gas chromatopram
and was
NO.3
213
converted, as before, to (+)-cadinene dihydrochloride. In separate experiments, epimerization at C, took place when the cis-octalone III was treated with excess methyllithium. In this case the resulting crude enol ether methyl carbinol (V) (15) obtained in quantitative yield, was directly hydrolized by repeated extraction from ether with aqueous sodium bisulfite. When the regenerated hydroxyketone (16)
was
again allowed to react with excess methyl-
lithium and the resulting crude dial (17) was treated with hydrogen chloride under specific conditions (-23O) for the retention of the bridgehead stereochemistry (l), the only crystalline
product obtained was (+)-cadinene dihydrochlorlde.
No muurolene dihydrochloride could be detected, even with the sensitive techniques of Westfelt (1) which are specifically effective in the presence of cadinene dihydrochloride. The above reactions, taken together with the stereospecific syntheses of the starting ketones III and VIII, provide new variations in the total stereospecific synthesis of (+)-cadinene dihydrochloride (6,18),
and the first total synthesis
of (+)-e-cadinene. The synthesis of the latter provides additional support for the revised structure I (1) of this sesquiterpene. Acknowledgment. We wish to thank Dr. L. Westfelt, for a reference sample of muurolene dihydrochloride, and Drs. G. E. Gunay and M. K. Logahi for their aid In certain phases of this work, and to acknowledge gratefully grants from the Sloan Foundation and from the National Science Foundation.
REFERENCES AND FOOTNOTES L. Westfelt, Acta Chem. Stand. g, 572 (1964); 2, 2852 (1966). 2. E. von Rudloff and K. W. Hefendehl, Can. J. Chem. e, 2015 (1966). The inordinately high value stated, [CL];=-1620, should perhaps read 16.20 (cf. ref. 13). E. von Rudloff and E. W. Underhill, Phytoohemlstry !, 11 (1965). 3. 4. R. Vlahov, M. Holub, I. Ognjanov and V. Herout, Collection Czech. Chem. Commun. 2, 808 (1967). [C,A. 2, S704h 5. V. Herout and D. I. Dimitrov, Chem. Listy 4&, 432 (1952) (1953)]; V. Herout and F. zantz Collection Czech. Chem. Commun. &_& 118 (1954); V. Sikora, V, Herout and F.G, a. 2, 2181 (1958). 1.
214
No.3
6. M. D. Soffer, G. E. Gfinay, 0. Korman and M. B. Adams, Tetrahedron
Letters
389 (1963)~ M. D. Soffer and G. E. Gi_inay,w. 1355 (1965). 7. U. Schoellkopf, Doctoral Dissertation, Universltat Tublngen, 1956 ["Organic Reactions," 2, 349 (1965)1. 8. H. W. B. Reed, J. Chem. Sot, 1931 (1954). For analogous reactions with Grignard reagents
see C. D. Gutsche,
Prentice Hall, New Jersey,
"The Chemistry
of Carbonyl Compounds,"
1967, pp. 71-99.
9. R. Greenwald, M. Chaykovski and E. J. Corey, J. Org. Chem. g,
1128 (1963).
The reagent was prepared with a slight excess of methyltriphenylphosphonium bromide
over the sodium hydride used to insure the absence of any carbanion
base during the reaction 10, Found for the methylene
with the ketone. enol ether IV:
uz4
(cm-') 3080 (m), 1660 (m),
1189 (s, enol ether), 890 (s), 1715 (VW, trace of unreacted ketone). uCCl* (cm-') 3080 11. Found for the methylene ketone VI: c, 81.51~ H, 10.86. (m) 1715 (s), 1650 (m), 895 (s); nmr (Varian A-60-A, Internal TMS) 4.6~ (2H, doublet, (3H) [both doublets 12. C. Djerassi,
terminal methylene),
6, doK:leld
from
0.92 (3H) and 0.68
(J = 6.5 Hz) isopropyl group].
"Optical Rotatory Dispersion,"
McGraw-Hill,
New York, 1960,
pp. 178-190; R. Howe and F. J. McQuillin, -J. Chem. Sot. 1194 (1958). from 1111 s2 1.5039~ [a]E0+60 (CHCl,); uiz24 (cm-')
13. Found for (+)-E-cadinene 3075
(m), 1790 (w), 1648 (s), 1188 (m), 1140 (m), 1085, 1075 (m, doublet),
893 (vs); ~2; 3075 (m), 1785 (w), 1648 (s), 1188 (m), 1138 (m), 1080, 1072 (m, doublet), 890 (vs), 817 (m), 652 (m), 638 (s)i nmr (CDCl,, 6) 4.58 (4H multiplet,
terminal methylene),
Hz) isopropyl
0.91 (3H) and 0.70 (3H)[both doublets (J=6.5
group]; homogeneous
by gc analysis, retention
time 19 min. at
155", lo ft. x 0,125 in. 25% Carbowax 20M/firebrlck, He 0.17 ml.,/sec. For (+)-e-cadinene from VIII: r$" 1.5033; [a]z" +lO" (CHCl,); ir, nmr and gc as above.
Reportedr
[a]ge +5.6O
[a1g2 -15.9" (1). 14. J. Pliva, M. Ho&k,
Reported
(9).
Reported
for (-)-c-cadinene
for (+)-c-muurolene:
V. Herout and F. Sorm,
r15' 1.5049;
"Die Terpene,"
ng2 1.5032;
[a];" +50.7" (1).
I, Berlin , 1960.
carbinol V: uzzi4 (cm-') 3615 (m, sharp), 1660 (m), 1188 (s, enol ether), 1718 (VW, trace of unreacted ketone). uCC1, (cm-") 3615 (m, sharp), 1715 (as). 16. Found for the hydroxyketoner 15. Found for the enol ether methyl
17. Found for the dial:
,p4
max
(cm-y3610
(ma),
1714 (VW, trace of unreacted
ketone). 18. For a synthesis
of the racemic
Rao and S. Dev, Tetrahedron
dihydrochlorlde,
22, 1977 (1966).
see M. V. R. K. Rao, G. S. K.