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Stereoselective synthesis of trisubstituted olefins
Tetrtiedron Letten
No.
16, pp 1389 - 1392, 1973.
STEREOSELECTIVE
Per-
Praar.
Printed In Great Fkitain.
SYNTHESIS OF TRISUGSTITLTTED OLEFINS
D. A. Evans,' 6. C. Andrews, T. T. Fujfmoto, D. Wells Contribution No. 3117 from the Department of Chemistry University of California, Los Angeles, California 90024 (Received ia USA 26 Jan-
1973; reoeiti
In UK for publioatien 12 Ikeah 1973)
In the preceeding cotnaunication the application of allylic sulfoxides to a general synThe purpose of this disclosure is to demonstrate
thesis of allylic alcohols was described.2 the applicability of sulfoxide-stabilized
allylic carbanions to the synthesis of trisubstituted
olefinic allylic alcohols. The two general olefin trisubstitution
patterns of interest in this study were of :he type
?t, and ~lt_,both of which are corenon structural components in polyisoprenoid
For
substances.
both practical and theoretical considerations we were particularly interested in the effects of ally1 substitution on olefin geometries resulting from [2,3] sigmatropic rearrangement and subsequent cleavage4 of sulfoxides 2 and 5.
To answerthese
questions, the sulfoxfde-stabilized
allylic carbanions derived from 1 and i5 were treated with a variety of alkyl and allylic
1. base
-
2.
(Meo),P
Ph
R
-
R-X
A, R, = alkyl, G R,=H,
R, =H
R,=alkyl H
1. base
H
2. R-X R
& R, = alkyl, R1 =Cl+, 35, R,=CH,,
1389
R, zalkyl
no. 16
1390 halides affording the a-alkylated I-alkylation
with trimethyl phosphite-methanol smarized
derivatives ,2 and 5 tn addition to the products derived fran
(cf. Table for a:y ratios).6 -
The resulting sulfoxides were transformed -in situ
into the allylic alcohols 3;, 35 and $t, 65 respectively.
As
in the Table, the alkylation of 1 and 12with a variety of alkyl halides followed by
rearrangement of the resulting sulfoxides 2 and 2 affords in all cases a predominance of the trans-trisubstituted
olefins z$ and $$.7 Scheme
I . . ..“_..-._-..I
J5
L
2,
R=OH
%R=l
2
3
$
R=H,OH
&,R=O Application of this olefin sequence to the synthesis of the sesquiterpene nuciferal (!Ob,3a is illustrated in Scheme I. and trimethylphosphonoacetate in THF (4P,
The cinnamate ester z,* prepared from e-methylacetophenone
in 64% yield,' was smoothly reduced to the alcohol !a_with LiAlH4
2 hr) in 90% yield (bp llO", 1 mm Hg).
Conversion of 8~ to the iodide !b was
accomplished routinely with methyl iodide-triphenyl phosphite. lo
Alkylation of the allylic
anion derived from 1,with gb afforded 9, as well as some y-alkylated material
(u:y = 2).
Cleav-
age of 9 with trimethyl phosphite-methanol yielded the trans-a;iyiic alcohol JCla,in 43% yield uncontaminated by the cis-isomer as evidenced by nmr analysis.
’
Manganese dioxide oxida-
tion of _.._ 10a afforded (+) nuciferal (lcb) in 99% yield.13 Alkylation of l_with other alkyl and allylic halides and subsequent cleavage to the allylic alcohols5 3t, 3c afforded the transisomers in greater than 95% isomeric purity. The resul.ts of our &$-on the alkylation of 1 .. 15 and subsequent rearrangement to __ 3t, __ 3c are not in canplete accord with those reported by Grieco. To gain information on the relative proportion of cis and trans-allylic alcohols derived from the rearrangement of allylic sulfoxides of the general type 5_,the synthesis of geraniol 13: and nerol ___ 13c outlined in Scheme II was carried out. Alkylation of the anion derived from 4 with 11 l6 afforded the a-alkylated product !,2 as well as the L-isomer (5:~ = 2.3). -7 In situ CleaVage
of 12 at room temperature resulted in a 90:10 ratio of geraniol 13t and nerol 13c in
55% yield.
The relatively high degree of selectivity observed in the
___ ..,I.” rearrangement of 12 is -_
Iio.
1391
16
lJ
3
R,=H,
R,=cH,OH
b,
R, =CH,OH,
R, = H
surprising in view of other published work on \;,3] sigmatropic rearrangements leading to At this time the intimate details that govern
olefins having a similar substitution pattern.
the allylic olefin geometry are unknown since the relative rates of the rearrangement and cleav. age steps have not been determined. Table. Alkylation-Rearrangement -._I.,..
R-X
Sulfoxide
of Allylic Sulfoxides Alkylation' Conditions
i
CH31 n-C6H131
-50°,10 min -30°,2 hr
i
(CH3)2C=CHCH2Br
1 4
1
4
a:y b Ratio 10
(75)
g7:3
2.5
3t,3c
42
g6:4
GUI“, 2 hr
2.0
-- _- {
46
g6:4
s!?
-20°, 6 hr
2.0
E!
43
>g5:<5
CH31
-6O“,20 min
2.6
-50°, 5 hr
2.4
4
'ZH5' (CH3)2C=CCH2Br
-
I!.
-40°, 2 hr
f
1.1
-8O, 10 min-
2.3
a Carried out according to the procedure described in ref. 2. lationwereisolated tion.
ROH, Yield%'
d %trans:%cis
and characterized.
6t,6c ..,_ ..,5 (:) ( 35 13t,13c -..,_ se_
55(70)
e
;;:27 g3:7 go:10
b Products derived from g-alky-
The -a:y-ratios were determined either by nmr or isola-
2 Figures in parenthesis refer to glc or nmr yields relative to an internal standard;
other figures refer to isolated yields based on sulfoxide _lr
5.
comparison with authentic samples of cis and trans-isomers.
e No cis-isomer as evidenced by
nmr analysis.
d Determined by glc by
f The halide was added to the anion at -30' and the temp was raised to -8“.
Acknowledgement. We wish to thank the U. S. Public Health Service, the National Science FounQ_..___-..._ _____ dation and the Petroleum Research Fund adninfstered by the American Chemical Society for thefr support of this research.
1392
References _________I
7.
Camille and Henry Dreyfus Teacher-Scholar
2.
D. A. Evans, 6. C. Andrews, T. T. Fujimoto, 0. Wells, Tetrahedron E.,
recipient, A. P. Sloan Fellow, 1972-1974.
3.
For examples of terpenes containing the 3t substructural unit see: (a) T. Sakai, K. Nishimura, Y. Hirose, -*+-. 8;;1 Chem Brieger, Tetrahedron m.,
Sot
0000. (1972).
Japan, 3_8 381 (1965); (b) 6.
2123 (1963); (c) R. A. Flath, R. E. Lundin, R. Teranishi, fbid.,
295 (1966); (d) W. H. Nutting, H. Rapoport, L. Machlis, -J. Amer. m.
x.,
gc, 6434
(1968). 4.
D. A. Evans, 6. C. Andrews,
9_4_, 3672 (1972).
m.,
5.
P. Bickart, F. W. Carson, J. Jacobus, E. G. Miller, K. Mislow, c.,
6.
The alkylation and sulfoxide cleavage conditions used in this study were those reported in
90 __, 4869 (1968).
7.
Satisfactory
8.
M. A. Psarrea, C. Sandris, 6. Tsatsas, --Bull Sot. Chim. France, 2145 (1961).
9.
W. S. Wadsworth, Jr., W. D. Ennnons, J. Amer. Chem. z.,
the preceeding communication, ref 2. spectra and elemental analyses have been obtained for all new compounds re-
ported herein.
s.,
83, 1733 (1960).
10.
S. R. Landauer, H. N. Rydon, J. m.
2224 (1953).
11.
The cis-isomer is a naturally occurring compound whose nmr spectrum has been published, ref 3a.
12.
For the determination of trisubstituted olefin geometries of this type see: Bhalerao, H. Rapoport, Tetrahedron m., m.
m.,
J_. m.
m.
s.,
g,
U. T.
4835 (1971); H. C. Kretschnmr, W. F. Enaan,
41, (1970); K. C. Chan, R. A. Jewell, W. H. Nutting, H. Rapoport, J.
33, 3382 (1968).
13.
The ir, nmr and mass spectra of !CJJ are identical to those published for nuciferal, ret 3a.
14.
Authentic samples of the cis-isomers 3: (R=C6H13, CH3) were prepared by Corey's procedure:
15.
P. A. Grieco, Chem. Cornnun., 702 (1972).
E. J. Corey, H. Yamamoto, J_. Amer. Chem. s.,
92, 226 (1970).
This worker reports no y-alkylation;
found this side reaction unavoidable under his reaction conditions. use of n-butyllithium 16.
we have
Also, the reported
leads to lower yields, ref 2.
Prepared by a modification of Julia's procedure where HI was substituted for H8r. M. Julia, S. Julia, R. Guegan, Bull Sot. Chim. France., 1072 (1960).
17.
V. Rautenstrauch, Helv. Chim. m, Patrick, Tetrahedron m.,
54, 739 (1971); J. E. Baldwin, J. DeBernardis, J. E.
353 (1970).
No.
16, pp 1389 - 1392, 1973.
STEREOSELECTIVE
Per-
Praar.
Printed In Great Fkitain.
SYNTHESIS OF TRISUGSTITLTTED OLEFINS
D. A. Evans,' 6. C. Andrews, T. T. Fujfmoto, D. Wells Contribution No. 3117 from the Department of Chemistry University of California, Los Angeles, California 90024 (Received ia USA 26 Jan-
1973; reoeiti
In UK for publioatien 12 Ikeah 1973)
In the preceeding cotnaunication the application of allylic sulfoxides to a general synThe purpose of this disclosure is to demonstrate
thesis of allylic alcohols was described.2 the applicability of sulfoxide-stabilized
allylic carbanions to the synthesis of trisubstituted
olefinic allylic alcohols. The two general olefin trisubstitution
patterns of interest in this study were of :he type
?t, and ~lt_,both of which are corenon structural components in polyisoprenoid
For
substances.
both practical and theoretical considerations we were particularly interested in the effects of ally1 substitution on olefin geometries resulting from [2,3] sigmatropic rearrangement and subsequent cleavage4 of sulfoxides 2 and 5.
To answerthese
questions, the sulfoxfde-stabilized
allylic carbanions derived from 1 and i5 were treated with a variety of alkyl and allylic
1. base
-
2.
(Meo),P
Ph
R
-
R-X
A, R, = alkyl, G R,=H,
R, =H
R,=alkyl H
1. base
H
2. R-X R
& R, = alkyl, R1 =Cl+, 35, R,=CH,,
1389
R, zalkyl
no. 16
1390 halides affording the a-alkylated I-alkylation
with trimethyl phosphite-methanol smarized
derivatives ,2 and 5 tn addition to the products derived fran
(cf. Table for a:y ratios).6 -
The resulting sulfoxides were transformed -in situ
into the allylic alcohols 3;, 35 and $t, 65 respectively.
As
in the Table, the alkylation of 1 and 12with a variety of alkyl halides followed by
rearrangement of the resulting sulfoxides 2 and 2 affords in all cases a predominance of the trans-trisubstituted
olefins z$ and $$.7 Scheme
I . . ..“_..-._-..I
J5
L
2,
R=OH
%R=l
2
3
$
R=H,OH
&,R=O Application of this olefin sequence to the synthesis of the sesquiterpene nuciferal (!Ob,3a is illustrated in Scheme I. and trimethylphosphonoacetate in THF (4P,
The cinnamate ester z,* prepared from e-methylacetophenone
in 64% yield,' was smoothly reduced to the alcohol !a_with LiAlH4
2 hr) in 90% yield (bp llO", 1 mm Hg).
Conversion of 8~ to the iodide !b was
accomplished routinely with methyl iodide-triphenyl phosphite. lo
Alkylation of the allylic
anion derived from 1,with gb afforded 9, as well as some y-alkylated material
(u:y = 2).
Cleav-
age of 9 with trimethyl phosphite-methanol yielded the trans-a;iyiic alcohol JCla,in 43% yield uncontaminated by the cis-isomer as evidenced by nmr analysis.
’
Manganese dioxide oxida-
tion of _.._ 10a afforded (+) nuciferal (lcb) in 99% yield.13 Alkylation of l_with other alkyl and allylic halides and subsequent cleavage to the allylic alcohols5 3t, 3c afforded the transisomers in greater than 95% isomeric purity. The resul.ts of our &$-on the alkylation of 1 .. 15 and subsequent rearrangement to __ 3t, __ 3c are not in canplete accord with those reported by Grieco. To gain information on the relative proportion of cis and trans-allylic alcohols derived from the rearrangement of allylic sulfoxides of the general type 5_,the synthesis of geraniol 13: and nerol ___ 13c outlined in Scheme II was carried out. Alkylation of the anion derived from 4 with 11 l6 afforded the a-alkylated product !,2 as well as the L-isomer (5:~ = 2.3). -7 In situ CleaVage
of 12 at room temperature resulted in a 90:10 ratio of geraniol 13t and nerol 13c in
55% yield.
The relatively high degree of selectivity observed in the
___ ..,I.” rearrangement of 12 is -_
Iio.
1391
16
lJ
3
R,=H,
R,=cH,OH
b,
R, =CH,OH,
R, = H
surprising in view of other published work on \;,3] sigmatropic rearrangements leading to At this time the intimate details that govern
olefins having a similar substitution pattern.
the allylic olefin geometry are unknown since the relative rates of the rearrangement and cleav. age steps have not been determined. Table. Alkylation-Rearrangement -._I.,..
R-X
Sulfoxide
of Allylic Sulfoxides Alkylation' Conditions
i
CH31 n-C6H131
-50°,10 min -30°,2 hr
i
(CH3)2C=CHCH2Br
1 4
1
4
a:y b Ratio 10
(75)
g7:3
2.5
3t,3c
42
g6:4
GUI“, 2 hr
2.0
-- _- {
46
g6:4
s!?
-20°, 6 hr
2.0
E!
43
>g5:<5
CH31
-6O“,20 min
2.6
-50°, 5 hr
2.4
4
'ZH5' (CH3)2C=CCH2Br
-
I!.
-40°, 2 hr
f
1.1
-8O, 10 min-
2.3
a Carried out according to the procedure described in ref. 2. lationwereisolated tion.
ROH, Yield%'
d %trans:%cis
and characterized.
6t,6c ..,_ ..,5 (:) ( 35 13t,13c -..,_ se_
55(70)
e
;;:27 g3:7 go:10
b Products derived from g-alky-
The -a:y-ratios were determined either by nmr or isola-
2 Figures in parenthesis refer to glc or nmr yields relative to an internal standard;
other figures refer to isolated yields based on sulfoxide _lr
5.
comparison with authentic samples of cis and trans-isomers.
e No cis-isomer as evidenced by
nmr analysis.
d Determined by glc by
f The halide was added to the anion at -30' and the temp was raised to -8“.
Acknowledgement. We wish to thank the U. S. Public Health Service, the National Science FounQ_..___-..._ _____ dation and the Petroleum Research Fund adninfstered by the American Chemical Society for thefr support of this research.
1392
References _________I
7.
Camille and Henry Dreyfus Teacher-Scholar
2.
D. A. Evans, 6. C. Andrews, T. T. Fujimoto, 0. Wells, Tetrahedron E.,
recipient, A. P. Sloan Fellow, 1972-1974.
3.
For examples of terpenes containing the 3t substructural unit see: (a) T. Sakai, K. Nishimura, Y. Hirose, -*+-. 8;;1 Chem Brieger, Tetrahedron m.,
Sot
0000. (1972).
Japan, 3_8 381 (1965); (b) 6.
2123 (1963); (c) R. A. Flath, R. E. Lundin, R. Teranishi, fbid.,
295 (1966); (d) W. H. Nutting, H. Rapoport, L. Machlis, -J. Amer. m.
x.,
gc, 6434
(1968). 4.
D. A. Evans, 6. C. Andrews,
9_4_, 3672 (1972).
m.,
5.
P. Bickart, F. W. Carson, J. Jacobus, E. G. Miller, K. Mislow, c.,
6.
The alkylation and sulfoxide cleavage conditions used in this study were those reported in
90 __, 4869 (1968).
7.
Satisfactory
8.
M. A. Psarrea, C. Sandris, 6. Tsatsas, --Bull Sot. Chim. France, 2145 (1961).
9.
W. S. Wadsworth, Jr., W. D. Ennnons, J. Amer. Chem. z.,
the preceeding communication, ref 2. spectra and elemental analyses have been obtained for all new compounds re-
ported herein.
s.,
83, 1733 (1960).
10.
S. R. Landauer, H. N. Rydon, J. m.
2224 (1953).
11.
The cis-isomer is a naturally occurring compound whose nmr spectrum has been published, ref 3a.
12.
For the determination of trisubstituted olefin geometries of this type see: Bhalerao, H. Rapoport, Tetrahedron m., m.
m.,
J_. m.
m.
s.,
g,
U. T.
4835 (1971); H. C. Kretschnmr, W. F. Enaan,
41, (1970); K. C. Chan, R. A. Jewell, W. H. Nutting, H. Rapoport, J.
33, 3382 (1968).
13.
The ir, nmr and mass spectra of !CJJ are identical to those published for nuciferal, ret 3a.
14.
Authentic samples of the cis-isomers 3: (R=C6H13, CH3) were prepared by Corey's procedure:
15.
P. A. Grieco, Chem. Cornnun., 702 (1972).
E. J. Corey, H. Yamamoto, J_. Amer. Chem. s.,
92, 226 (1970).
This worker reports no y-alkylation;
found this side reaction unavoidable under his reaction conditions. use of n-butyllithium 16.
we have
Also, the reported
leads to lower yields, ref 2.
Prepared by a modification of Julia's procedure where HI was substituted for H8r. M. Julia, S. Julia, R. Guegan, Bull Sot. Chim. France., 1072 (1960).
17.
V. Rautenstrauch, Helv. Chim. m, Patrick, Tetrahedron m.,
54, 739 (1971); J. E. Baldwin, J. DeBernardis, J. E.
353 (1970).