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Stereoselective formation and bf3-catalysed cleavage of steroidal α-epoxyketones
TetrahedronLettersNo.57, pp. 5959-W&
l!%L
STSRSOSELYCTIVS POWATION OP
Per,gmmn Frees.
meted
ie Great Britain*
ADD DP3-CATALYSED CLEAVAGB
STSSOIDAL ~RPO~S J.B. Bull
National Chemical Beeearch Laboratory, C.S.I.B.,P.O. Box 395. Pretoria, South Africa (Reoeivedin UK 14 Ootober 1966;accepted for publioM&n
25 October 196e)
The base-catalpaedepoxidationof a,S-unsaturatedketones often proceedswith a high degree of stereoeelectivity(1).
Although a variety of eteroidalu-epoxyketoneshas
been prepared in this way (2). the reaction6of A&4- and A4-6-ketoneswith alkaline hydrogen peroxide have not been reported. Choleet-S-en-4-one(I) in methanol at 2C" reacted with a slight excess of aqueous 4N potassirnn hydroxide aud 100 vol. hydrogen peroxide to give after 40 hr.. a 70x yield of 5,68-epoxy-59-cbolestan-4-one (II), r.p. lOS-lOSo, [a], + 47' [lit. (4), m.p. 102-104'1,togetherwith unreactedmaterial (4%).
(o 2.0) (3)
Careful investigation
of the reactionproduct failed to reveal the presence of any 5a,6a-epoxide. the reaction
with choleot-4-en-(i-one
(III) after 24 hr. at 20'. afforded only the
48,58-epoxy_6-ketone (IV), 00.p.136-137O.[a], - 14'
Cal, - 8.ti”] in
85% yield.
Similarly,
The identity
(o 2.0)
[lit. (S), m.p. 139-MOO,
of the eporyketones11 and IV was confirmedby
comparisonwith materials prepared using reportedmethods (4,5).
Tbe procedureoutlined
here provides a convenientstereoselectiveroute to the less accessibleepirmre in this series. The exclusiveformationof products de,rivedfrom initial S-face attack may be rationalisedin terma of favoured anti-parallelapproach (6) by the hydroperoxide anion to the teminal
position
of the cmiugated
qstem.
Thus in the case of I, the product is that the steric
formed via a B-ring pre-chair intermediate(V).
It muat be ass-d
demands of the hydroperoxide
small and that the reaction course is
anion are relatively
influenced
more by the relative energies of the transition
inhibition
of prior
B-face
attack due to the CIO-aethyl
etate
group.
conformers than by
In the event of initial
No.57
5960 c-face attack on I, the B-ring of the intermediatewould asslrmean energetically unfevourablepre-twistconformation(VI) before collapseto the epimeric epoxyketone. It was of interestto investigatethe effect of boron trifluorideon these
epoxyketonessince it is evident that the typical Lewis acid-catalysedrearrangements(7) associatedwith a-epoxyketonespossessingan a-bond capable of migration,would be inhibited. Furthermore,the degree of carboniumion characterat C5 in the co-ordinated complexwould be greatly diminishedby the adjacentcarbonylgroup, thereby suppressing the many dramaticrearrangementsassociatedwith isolated4,5- and 5,6-epoxides(8). Accordinglythe expectationwas that the favoured course of reaction in these systems would involve attack by an externalnucleophileat the position S to the carbonylgroup rather than intramolecularbond migration (7,9).
Preliminaryinvestigationsinto the
action of boron trifluorideon the epoxyketonesII and IV tend to support this view. Treatmentof II in dry benzene with freshly distilledboron trifluoride-etherete for periods of 1 min. to 24 hr. at 20' led to 6a-fluoro-5S-cholestan-5-ol-4-one (VII) (lo), m.p. 192-194',[a], + 17' (c 1.8), v:z"
3585 (OH) and 1720 aa.'l (CC).
spectrum (3) exhibitedat 6 4.64 p.p.m. a multiplet (JH6S P6c, 50; .
The n.m.r.
JH6S,H7a' lo snd
JH6S H78, 7 Hz.) and a sharp signal at 6 2.99 p.p.m. which disappearedon D20 exchange (C5&.
When the reactionwas followedby t.l.c., startingmaterial was completely
consumed after co. 25 min. and the product was obtained in nearly quantitativeyields. Similar treatmentof IV affordedonly 4a-fluoro-56-cholestsn-5-ol-6-one (VIII), m.p. 83-85', [a], - 46'
(c 1.8).
vzf3
3485 (OH) snd 1704 cm.-' (CC), in 80% yield.
The n.m.r. signal of the 46-protonappearedat 6 4.23 p.p.m. as a multiplet (Jl14S F4a, 50 , - 3 8x,)while that of the C5-OH proton was a sharp signal at and JH4S,H3a - '848,838 6 4.02 p.p.m. The structuralassignmentsof the products VII and VIII follow from the spectroscopicdate and are in accordencewith mechanisticexpectations.
No.57
5961
$I”,7 1
-
@
I
0
co o* It
Ill
I b
I
5962
No.57
1.
H.E. Zimmerman,L. Singer and B.S. Thayagarajan,J. Amer. Chm. Sot., ii, 108 (1959).
2.
Steroid Reactions (Ed., C. Djerassi),Ch. 14, Holden-DayInc., San Francisco (1963).
3.
Rotationswere measured in Cl-Xl3at 20°. and n.m.r. spectrawere recorded in CDC13 on a Varian HA-100 instrument. D. Lavie, Y. Kaehman and E. Glotter,Tetrahedron,22, 1103 (1966). S. Greenfield,E. Glotter,D. Lavie and Y. Kashman,J. Chem. SOC (Cl, 1460 (1967). J. Valls and E. Toromanoff,BUZZ. Sot. Chim. France, 758 (1961). D.J. Collins,J. Chem. Sot., 3919 (1959); J.M. Coxon, H.P. Hartshorn and D.N. Kirk, Tetmhedron, 22, 2531 (1964).
8.
J.M. Coxon, K.P. Bartshom, C.N. Muir and K.E. Eichards,TetrahedronLetters, No. 38 PIIII-' 3725 (1967) and previous papers in this series.
9.
10.
P.J. May, (Mrs.)F.A. Nice and G.B. Phillips,J. Cbm. SOC. fC/, 2210 (1966). The compoundsVII and VIII gave satisfactoryelementalanalyses and mass spectra.
l!%L
STSRSOSELYCTIVS POWATION OP
Per,gmmn Frees.
meted
ie Great Britain*
ADD DP3-CATALYSED CLEAVAGB
STSSOIDAL ~RPO~S J.B. Bull
National Chemical Beeearch Laboratory, C.S.I.B.,P.O. Box 395. Pretoria, South Africa (Reoeivedin UK 14 Ootober 1966;accepted for publioM&n
25 October 196e)
The base-catalpaedepoxidationof a,S-unsaturatedketones often proceedswith a high degree of stereoeelectivity(1).
Although a variety of eteroidalu-epoxyketoneshas
been prepared in this way (2). the reaction6of A&4- and A4-6-ketoneswith alkaline hydrogen peroxide have not been reported. Choleet-S-en-4-one(I) in methanol at 2C" reacted with a slight excess of aqueous 4N potassirnn hydroxide aud 100 vol. hydrogen peroxide to give after 40 hr.. a 70x yield of 5,68-epoxy-59-cbolestan-4-one (II), r.p. lOS-lOSo, [a], + 47' [lit. (4), m.p. 102-104'1,togetherwith unreactedmaterial (4%).
(o 2.0) (3)
Careful investigation
of the reactionproduct failed to reveal the presence of any 5a,6a-epoxide. the reaction
with choleot-4-en-(i-one
(III) after 24 hr. at 20'. afforded only the
48,58-epoxy_6-ketone (IV), 00.p.136-137O.[a], - 14'
Cal, - 8.ti”] in
85% yield.
Similarly,
The identity
(o 2.0)
[lit. (S), m.p. 139-MOO,
of the eporyketones11 and IV was confirmedby
comparisonwith materials prepared using reportedmethods (4,5).
Tbe procedureoutlined
here provides a convenientstereoselectiveroute to the less accessibleepirmre in this series. The exclusiveformationof products de,rivedfrom initial S-face attack may be rationalisedin terma of favoured anti-parallelapproach (6) by the hydroperoxide anion to the teminal
position
of the cmiugated
qstem.
Thus in the case of I, the product is that the steric
formed via a B-ring pre-chair intermediate(V).
It muat be ass-d
demands of the hydroperoxide
small and that the reaction course is
anion are relatively
influenced
more by the relative energies of the transition
inhibition
of prior
B-face
attack due to the CIO-aethyl
etate
group.
conformers than by
In the event of initial
No.57
5960 c-face attack on I, the B-ring of the intermediatewould asslrmean energetically unfevourablepre-twistconformation(VI) before collapseto the epimeric epoxyketone. It was of interestto investigatethe effect of boron trifluorideon these
epoxyketonessince it is evident that the typical Lewis acid-catalysedrearrangements(7) associatedwith a-epoxyketonespossessingan a-bond capable of migration,would be inhibited. Furthermore,the degree of carboniumion characterat C5 in the co-ordinated complexwould be greatly diminishedby the adjacentcarbonylgroup, thereby suppressing the many dramaticrearrangementsassociatedwith isolated4,5- and 5,6-epoxides(8). Accordinglythe expectationwas that the favoured course of reaction in these systems would involve attack by an externalnucleophileat the position S to the carbonylgroup rather than intramolecularbond migration (7,9).
Preliminaryinvestigationsinto the
action of boron trifluorideon the epoxyketonesII and IV tend to support this view. Treatmentof II in dry benzene with freshly distilledboron trifluoride-etherete for periods of 1 min. to 24 hr. at 20' led to 6a-fluoro-5S-cholestan-5-ol-4-one (VII) (lo), m.p. 192-194',[a], + 17' (c 1.8), v:z"
3585 (OH) and 1720 aa.'l (CC).
spectrum (3) exhibitedat 6 4.64 p.p.m. a multiplet (JH6S P6c, 50; .
The n.m.r.
JH6S,H7a' lo snd
JH6S H78, 7 Hz.) and a sharp signal at 6 2.99 p.p.m. which disappearedon D20 exchange (C5&.
When the reactionwas followedby t.l.c., startingmaterial was completely
consumed after co. 25 min. and the product was obtained in nearly quantitativeyields. Similar treatmentof IV affordedonly 4a-fluoro-56-cholestsn-5-ol-6-one (VIII), m.p. 83-85', [a], - 46'
(c 1.8).
vzf3
3485 (OH) snd 1704 cm.-' (CC), in 80% yield.
The n.m.r. signal of the 46-protonappearedat 6 4.23 p.p.m. as a multiplet (Jl14S F4a, 50 , - 3 8x,)while that of the C5-OH proton was a sharp signal at and JH4S,H3a - '848,838 6 4.02 p.p.m. The structuralassignmentsof the products VII and VIII follow from the spectroscopicdate and are in accordencewith mechanisticexpectations.
No.57
5961
$I”,7 1
-
@
I
0
co o* It
Ill
I b
I
5962
No.57
1.
H.E. Zimmerman,L. Singer and B.S. Thayagarajan,J. Amer. Chm. Sot., ii, 108 (1959).
2.
Steroid Reactions (Ed., C. Djerassi),Ch. 14, Holden-DayInc., San Francisco (1963).
3.
Rotationswere measured in Cl-Xl3at 20°. and n.m.r. spectrawere recorded in CDC13 on a Varian HA-100 instrument. D. Lavie, Y. Kaehman and E. Glotter,Tetrahedron,22, 1103 (1966). S. Greenfield,E. Glotter,D. Lavie and Y. Kashman,J. Chem. SOC (Cl, 1460 (1967). J. Valls and E. Toromanoff,BUZZ. Sot. Chim. France, 758 (1961). D.J. Collins,J. Chem. Sot., 3919 (1959); J.M. Coxon, H.P. Hartshorn and D.N. Kirk, Tetmhedron, 22, 2531 (1964).
8.
J.M. Coxon, K.P. Bartshom, C.N. Muir and K.E. Eichards,TetrahedronLetters, No. 38 PIIII-' 3725 (1967) and previous papers in this series.
9.
10.
P.J. May, (Mrs.)F.A. Nice and G.B. Phillips,J. Cbm. SOC. fC/, 2210 (1966). The compoundsVII and VIII gave satisfactoryelementalanalyses and mass spectra.