CA1134812A - CYCLISATION SUBSTRATES, CYCLISATION PROCESS AND RELATED 11.beta.-AXIALLY-SUBSTITUTED STEROIDS - Google Patents
CYCLISATION SUBSTRATES, CYCLISATION PROCESS AND RELATED 11.beta.-AXIALLY-SUBSTITUTED STEROIDSInfo
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- CA1134812A CA1134812A CA000385867A CA385867A CA1134812A CA 1134812 A CA1134812 A CA 1134812A CA 000385867 A CA000385867 A CA 000385867A CA 385867 A CA385867 A CA 385867A CA 1134812 A CA1134812 A CA 1134812A
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Abstract
ABSTRACT OF THE DISCLOSURE
The cyclisation of compounds of the formula:
(I) wherein:
(a) R1 is H or alkyl of one to four carbon atoms;
(b) R2 is H or alkyl of one to four carbon atoms, with the proviso that R1 is H when R2 is alkyl, and with the proviso that R2 is H when R1 is alkyl;
(c) R3 is a suitable leaving group selected from the group consisting of hydroxy, alkoxy of one to four carbons, alkoxyalkoxy of two to four carbons, acyloxy of one to about seven carbon atoms, and trialkylsilyloxy of less than fifteen carbons;
(d) R4 is H, hydrocarbyl of one to fourteen carbons, carboxyacyl of two to twelve carbons, trialkylsilyl of less than fifteen carbons, or heterocyclic of five to seven atoms and four to six carbons; and (e) R5(1) and R5(2) are each H, alkyl of one to eight carbons, or an optionally esterified or etherified hydroxy group selected from the group consisting of hydroxy, alkoxy of one to four carbons, alkoxy-alkoxy of two to four carbons, carboxyacyloxy of one to seven carbons, trialkylsilyloxy of one to fifteen carbons, cycloalkoxy of four to eight carbons, or unsubstituted heterocyclic ether of five to seven members, with the proviso that at least one of R5(1) and R5(2) is hydrogen, leads to novel and biologically active compounds of the following formulae:
II III
"para" "ortho"
having R1 through R5(1) and R5(2) as defined above, with R7 being alkyl of from about one to about four carbon atoms.
The cyclisation of compounds of the formula:
(I) wherein:
(a) R1 is H or alkyl of one to four carbon atoms;
(b) R2 is H or alkyl of one to four carbon atoms, with the proviso that R1 is H when R2 is alkyl, and with the proviso that R2 is H when R1 is alkyl;
(c) R3 is a suitable leaving group selected from the group consisting of hydroxy, alkoxy of one to four carbons, alkoxyalkoxy of two to four carbons, acyloxy of one to about seven carbon atoms, and trialkylsilyloxy of less than fifteen carbons;
(d) R4 is H, hydrocarbyl of one to fourteen carbons, carboxyacyl of two to twelve carbons, trialkylsilyl of less than fifteen carbons, or heterocyclic of five to seven atoms and four to six carbons; and (e) R5(1) and R5(2) are each H, alkyl of one to eight carbons, or an optionally esterified or etherified hydroxy group selected from the group consisting of hydroxy, alkoxy of one to four carbons, alkoxy-alkoxy of two to four carbons, carboxyacyloxy of one to seven carbons, trialkylsilyloxy of one to fifteen carbons, cycloalkoxy of four to eight carbons, or unsubstituted heterocyclic ether of five to seven members, with the proviso that at least one of R5(1) and R5(2) is hydrogen, leads to novel and biologically active compounds of the following formulae:
II III
"para" "ortho"
having R1 through R5(1) and R5(2) as defined above, with R7 being alkyl of from about one to about four carbon atoms.
Description
The invention relates to the preparation of novel cyclisation substrates for steroidal compounds, and also relates to the conversion of these cyclisation substrates into novel steroidal compounds, in particular, 11~ -substituted-oxy-steroids of the oestrane series.
The known 11~ -oxy-steroids include compounds of pharmacological interest, for example, 11~ -methoxy-oestradiol, methoxy-oestrone and the corresponding ll~-ethoxy compounds, as well as the 3-ethers thereof, and are known as potent oestrogenic compounds (see Dutch Pat. 134,220).
As is also known, the introduction by chemical means of an oxygen substituent into the ll-position of a steroid is assoc-iated with substantial difficulties, both in the total synthesis and in the normal preparation. Generally, recourse is made by one skilled in the art to microbiological oxidation methods~
One such oxidation method is, for example, the method described in the Dutch Patents 121,957 and 122,324, wherein 3-oxo- ~ 5(10),9(11)_ steroids of the oestrane series are oxidized with molecular oxygen under alkaline conditions to 11~-hydroperoxy compounds, which may be converted by reduction into 11~ -hydroxy compounds. These latter compounds may, for example, be converted into some of the pharmacologically interesting 11 ~-alkoxy-A-aromatic compounds noted above (see for example U.S.
Patent No. 3,472,884 and U.S. Patent No. 3,519,654 and Dutch Patent Specification No. 134,220). The 3-oxo- ~ (10),9(11) starting material may, for example be prepared by total synthesis (see for example the U.S. Pat. 3~052~672)o It is also known in the art that the 11 ~-alkyl-l9-nor-steroids are biologically active compounds to which access by synthetic routes is difficult for those in the art For example, in 41 J. ORG. CHEM~ 531 (1976) an unsuccessful attempt is .' ~, , ~3~812 described to prepare ll-alkyl-substituted steroids by a total synthesis according to the method of Torgov. The cyclisation by the Johnson method of 2-(5~-7~-dimethyl-trideca-3~(E),7'(E)-dien-~-ynyl)3-methyl-cyclopent-2-enol to ll-methyl-steroids is described in the dissertation of T.M. Yarnell, (Stanford University, July, 1975, in DISSERTATION ABSTRACTS INTERN, B 36 (19763 no. lO at page 5054)O The 5~-methyl group in the cyclisation substrate is the "pro-C-ll" substituent. In this cyclisation, in addition to a range of other products, the 11 -methyl-steroid and the 11 -methyl-isomer were shown to be formed in approximately equal proportions. Stereo-selectivity was described as absent, and this synthesis therefore had little practical value.
Of interest also is U.S. Patent 3,778,434 to Coombs, directed to the preparation of 9 ~, ll-dimethyl-substituted estranes from the corresponding estran-17-ones.
The stereospecific cyclisation of a compound of formula 1 1 ~ j where R = CH3 into a compound of formula XXI:
3 ~ C=O
, where R = CH3 is described in 98 J.A.C.S. 1038 (1976)o Only the equatorial 11 ~ -methyl derivative is formed.
The cyclisation of a (pro)-ll-hydroxy compound also results r ~ -2-1~3~112 exclusively in the 11~ -hydroxy steroid (98 J.A.C.So 1038-1039 (1976))o Again it is mentioned that when this cyclisation is performed in the (pro)-l9-nor-series (R is H), it proves that no stereo-selectivity occurs (see T.M. Yarnell, Dissertation, Stanford University, July 1975, in 1976 DISSERTATI0~ ABSTRACTS
~ INTER, 1976, B36 no. 10, page 5054). A mixture 11~ - and 11~ - -substituted steroids in molar proportions of about 1:1 is formed.
Distantly related compounds by structure (7-substituted compounds) to those of formulae II and III
of the instant invention are disclosed in Anner et al, U. S. Patent 3,660,435 (7a-methyl-3-16a-17~ -trihydroxy -~ 1'3'5(10)-oestratienes for controlling fertility) and UOS~ Patent 3,804,866 ~3-cyclopently eth~r of 7~ ~methyl-3 16~ , 17~,~ -trihydroxy~ 1,3,5(10) oestratrienes and their 16,17-diacetates for controlling fertility)O See also UOS. Patent 3,345~570 to Anner et al (isolation of 7~ -methyl-3-oxo-~ 4-steroids from mixtures of the epimeric 7-methyl-compounds);
U.S. Patent 3,627,894 to Babcock (novel 7 ~-methylestrones); and U.S. Patent 3,928,398 to Grunwell et al (7~ -methylestr-4-ene-3 17~ -diols as antiprogestational and antifertility agents)~
A method of producing analogues of the novel steroidal compounds of the present invention is disclosed in British Pat.
1,448,873 (producing oestrone by cyclising 2-[(E)-6-aryl-3-hexenyl]-cyclopentenoles of which the hexenyl group has not been substituted). See also 95 J.A.C.S. 7501-7504 (1973).
Steroids which may be prepared according to the method of the present invention are disclosed inter alia in U.S.
Pat. 3,627,894; U.S. Pat. 3,574,197; 3,944,576; and U.S. Pats.
~ ~ -3-~'~, .
z 3,318,925/26/27/28/29.
The following stereo-selective synthesis was described in 22 Tetrahedon at 1019-1025 (1966)o H3COJ~ o~ H3CO
The main product obtained was the 6 ~-methyl compound (yield 250/~40% by weight) in addition to traces of the 6 ~-methyl compound. Since the 6 ~-methyl compounds are the most valuable, attempts were made to isomerise the 6 ~-methyl compounds to 6 ~-methyl compounds, after the A-ring had been converted to a 3-oxo- ~4-system-~H3 CH3 (IV) (V) This isomerisation occurs only in part, and the6 ~-methyl compound can only be obtained in low yield by this route. The circuitous route via the enol acetate gives higher yields (see 90 Recueil 849 (1971)).
Other distantly related art by structure includes U.S.
Pat 3,137,689 to Dorfmann et al, which teaches preparation of 6 ~-methyl-pregnenolones (anti-ovulatory activity); U.S. Pat 3,257,427 to Bowers for 6-alkyl-3-desoxy-~ 1,3,5(10) est t i substituted in the 17 position by keto or hydroxy (anti-androgenic action, low feminizing effects; for fertility control and menstral disorders): U.S. Pat. 3,082,224 to Weinstock for 16~ -~, -4-,:~
., ~ .
1~3~81Z
methyl-3,5-pregnadienes (anti-inflammatory activity) UnS~ Pat.
3,132,163 to Borrevang for corticosteroids having hemiacetal moieties at the 21 or 11, 21 positions (improved physiological activity) U.SO Pat. 3,816,481 to Douglas et al for 6~ -methyl-4-gonenes (progestational activity): and British Pat. 1,448,873 (cyclisation of (arylhexenyl)-cyclopentenols to ~ 1~3~5(10)~1 (17) gonatetraenes unsubstituted in ring C).
The present invention relates to novel cyclisation substrates of the formula:
Rl R3 R~
wherein:
(a) Rl is H or alkyl of one to four carbon atoms;
(b) R2 is H or alkyl of one to four carbon atoms, with the proviso that Rl is H when R2 is alkyl, and with the proviso that R2 is H when Rl is alkyl;
; 20 (c) R3 is a suitable leaving group selected from the ~ group consisting of hydroxy, alkoxy of one to four .-~ carbons, alkoxy of two to four carbons, : acyloxy of one to about seven carbon atoms, and trialkylsilyloxy of less than fifteen carbons;
(d) R4 is H, hydrocarbyl of one to fourteen carbons, carboxyacyl of two to twelve carbons, trialkylsilyl ; of less than fifteen carbons, or heterocyclic of ~ 30 five to seven members and four to six carbons; and '~ (e) R5(1) and R5(2) are each H, alkyl of one to eight carbons, or an optionally esterified or etherified . ,. ., ~ .
~ 5-, .
~i3~81Z
hydroxy group selected from the group consisting of hydroxy, alkoxy of one to four carbons, alkoxy-alkoxy of two to four carbons, carboxyacyloxy of one to seven carbons, trialkylsilyloxy of one to fifteen carbons, cycloalkoxy of four to eight carbons,and unsubstituted heterocyclic ether of five to seven members and from four to six carbons, with the proviso that at least one of R5(1) and R5(2) is hydrogen.
Surprisingly, it has now been found that the cyclisa-tion of a cyclisation substrate of formula (I):
R R
R ~ 3 (I) 5(1) leads stereo-selectively to axially-substituted steroid compounds of formula II and III having R4 and R5 (R5(1) or R5(2), as described above:
~ ~ 7 "para" "ortho"
which may be represented in shorthand notation by the following formula (positions indicated in small arabic numerals):
5~ R 7 R5( 1) which is more recognizable to those skilled in the art. R7 is an alkyl moiety of one to four carbon atoms ~ --6--~34812 In formula I, II, and III, most preferably Rl and R2 are H or CH3, R3 is OH, R4 is methyl, benzyl or pivaloyl, one of R5(1) and R5(2) is H and the other i5 OCH3 or trialkylsilyloxy of three to twelve carbon atoms, and R7 is CH3.
When R5(1) is the same as R5(2), the resultant com-pounds are of course identical, but when R5(1) is not R5(2), two isomers result from the cyclisation: the proportions of which are strongly influenced by the cyclisation conditions and the choice of the substituents R4, R5(1) and R5(2).
The cyclisation substrates of formula (I) are novel compounds which may be prepared in several ways each of which are known to those skilled in the art. The invention is therefore characterized by the preparation of novel compounds with the general formula (I) by steps which are in themselves known to those in the art. The invention is also characterized by the cyclisation of novel new cyclisation substrates of formula (I) to the novel and biologically active steroid compounds of formulae II and III that are axially substituted in the 11-position.
Referring to the flow Diagram below, the cyclisation substrate (I) may, for example, be prepared by condensing in Reaction (or Step) (a) an acetylide of formula (IV) with an ald-ehyde of formula (V) to give a propargyl alcohol of formula (VI).
; In step (b) the trans-allyl alcohol of formula (VIIa) is obtained i by reduction of the triple bond, and this may optionally be etherified or esterified to (VIIb), after which (VII) is hydro-lyzed in step (c) to the dioxo compound (VIII) which is condensed in step (d) to the cyclopentenone of formula (IX). When R2 is alkyl of one to four carbons, the ketone obtained is reduced to an alcohol [formula I, Rl is H, R2 is alkyl of one to four carbons and R3 is OH], or when R2 is H, it is reacted with a : . :
compound RlLi, for example methyl-lithium, ethyl-lithium, buty.l-lithium, or RlMg-halogen, where Rl is alkyl of one to four carbons, for example methyl-magnesium bromide, ethyl-magnesium iodide, to give a tertiary alcohol ~formula I, Rl is alkyl (1-4C), R2 is H, R3 is OH]. The hydroxy group (R3) is optionally further etherified or esterified.
1~348i'2 FLOW DIAGRAM
R5~JC + O~
Xl Xl HO ~' jb R4~ ~ b R~ R2~b 5~S R2~,1b (C)~
VI VI I ( b ' R4~H ) R R5~}
VIII IX
I
g_ li34~
In the Flow Diagram Rl, R2, R3, R4 and Rs have the meanings assigned aboveO M is lithium or an Mg-halogen radical, for example Mg Br, the bonds designated with "a" and "b"
represent single or double bonds, with the proviso that when "a"
represents a single bond, "b" is a double bond and vice-versa;
Xl and X2 together form an epoxy group when "a" represents a single bond: if "a" is a double bond, then Xl and X2 each represent a suitable alkylene-dichalcogen group, that is, alkylenedioxy or alkylenedithio with 2-3 carbon atoms, for example ethylene-dioxy, propylene-dithio, ethylene-dithio.
The acetylide (IV) may be prepared by allowing a precursor 4-(mrR~phenyl)butyne to react with alkyl-lithium, for example ethyl-lithium, or with magnesium shavings in the presence of an alkyl halide, for example methyl bromide or ethyl bromide, in an inert solvent, for example tetrahydrofuran at conditions well known to those in the art.
Examples of the aldehyde (V) are 7-R24,7-bis-propylene-dithioheptanal, 7-R2-4,7-bis-ethylene-dioxy-heptanal, 3-(5~-R2-
The known 11~ -oxy-steroids include compounds of pharmacological interest, for example, 11~ -methoxy-oestradiol, methoxy-oestrone and the corresponding ll~-ethoxy compounds, as well as the 3-ethers thereof, and are known as potent oestrogenic compounds (see Dutch Pat. 134,220).
As is also known, the introduction by chemical means of an oxygen substituent into the ll-position of a steroid is assoc-iated with substantial difficulties, both in the total synthesis and in the normal preparation. Generally, recourse is made by one skilled in the art to microbiological oxidation methods~
One such oxidation method is, for example, the method described in the Dutch Patents 121,957 and 122,324, wherein 3-oxo- ~ 5(10),9(11)_ steroids of the oestrane series are oxidized with molecular oxygen under alkaline conditions to 11~-hydroperoxy compounds, which may be converted by reduction into 11~ -hydroxy compounds. These latter compounds may, for example, be converted into some of the pharmacologically interesting 11 ~-alkoxy-A-aromatic compounds noted above (see for example U.S.
Patent No. 3,472,884 and U.S. Patent No. 3,519,654 and Dutch Patent Specification No. 134,220). The 3-oxo- ~ (10),9(11) starting material may, for example be prepared by total synthesis (see for example the U.S. Pat. 3~052~672)o It is also known in the art that the 11 ~-alkyl-l9-nor-steroids are biologically active compounds to which access by synthetic routes is difficult for those in the art For example, in 41 J. ORG. CHEM~ 531 (1976) an unsuccessful attempt is .' ~, , ~3~812 described to prepare ll-alkyl-substituted steroids by a total synthesis according to the method of Torgov. The cyclisation by the Johnson method of 2-(5~-7~-dimethyl-trideca-3~(E),7'(E)-dien-~-ynyl)3-methyl-cyclopent-2-enol to ll-methyl-steroids is described in the dissertation of T.M. Yarnell, (Stanford University, July, 1975, in DISSERTATION ABSTRACTS INTERN, B 36 (19763 no. lO at page 5054)O The 5~-methyl group in the cyclisation substrate is the "pro-C-ll" substituent. In this cyclisation, in addition to a range of other products, the 11 -methyl-steroid and the 11 -methyl-isomer were shown to be formed in approximately equal proportions. Stereo-selectivity was described as absent, and this synthesis therefore had little practical value.
Of interest also is U.S. Patent 3,778,434 to Coombs, directed to the preparation of 9 ~, ll-dimethyl-substituted estranes from the corresponding estran-17-ones.
The stereospecific cyclisation of a compound of formula 1 1 ~ j where R = CH3 into a compound of formula XXI:
3 ~ C=O
, where R = CH3 is described in 98 J.A.C.S. 1038 (1976)o Only the equatorial 11 ~ -methyl derivative is formed.
The cyclisation of a (pro)-ll-hydroxy compound also results r ~ -2-1~3~112 exclusively in the 11~ -hydroxy steroid (98 J.A.C.So 1038-1039 (1976))o Again it is mentioned that when this cyclisation is performed in the (pro)-l9-nor-series (R is H), it proves that no stereo-selectivity occurs (see T.M. Yarnell, Dissertation, Stanford University, July 1975, in 1976 DISSERTATI0~ ABSTRACTS
~ INTER, 1976, B36 no. 10, page 5054). A mixture 11~ - and 11~ - -substituted steroids in molar proportions of about 1:1 is formed.
Distantly related compounds by structure (7-substituted compounds) to those of formulae II and III
of the instant invention are disclosed in Anner et al, U. S. Patent 3,660,435 (7a-methyl-3-16a-17~ -trihydroxy -~ 1'3'5(10)-oestratienes for controlling fertility) and UOS~ Patent 3,804,866 ~3-cyclopently eth~r of 7~ ~methyl-3 16~ , 17~,~ -trihydroxy~ 1,3,5(10) oestratrienes and their 16,17-diacetates for controlling fertility)O See also UOS. Patent 3,345~570 to Anner et al (isolation of 7~ -methyl-3-oxo-~ 4-steroids from mixtures of the epimeric 7-methyl-compounds);
U.S. Patent 3,627,894 to Babcock (novel 7 ~-methylestrones); and U.S. Patent 3,928,398 to Grunwell et al (7~ -methylestr-4-ene-3 17~ -diols as antiprogestational and antifertility agents)~
A method of producing analogues of the novel steroidal compounds of the present invention is disclosed in British Pat.
1,448,873 (producing oestrone by cyclising 2-[(E)-6-aryl-3-hexenyl]-cyclopentenoles of which the hexenyl group has not been substituted). See also 95 J.A.C.S. 7501-7504 (1973).
Steroids which may be prepared according to the method of the present invention are disclosed inter alia in U.S.
Pat. 3,627,894; U.S. Pat. 3,574,197; 3,944,576; and U.S. Pats.
~ ~ -3-~'~, .
z 3,318,925/26/27/28/29.
The following stereo-selective synthesis was described in 22 Tetrahedon at 1019-1025 (1966)o H3COJ~ o~ H3CO
The main product obtained was the 6 ~-methyl compound (yield 250/~40% by weight) in addition to traces of the 6 ~-methyl compound. Since the 6 ~-methyl compounds are the most valuable, attempts were made to isomerise the 6 ~-methyl compounds to 6 ~-methyl compounds, after the A-ring had been converted to a 3-oxo- ~4-system-~H3 CH3 (IV) (V) This isomerisation occurs only in part, and the6 ~-methyl compound can only be obtained in low yield by this route. The circuitous route via the enol acetate gives higher yields (see 90 Recueil 849 (1971)).
Other distantly related art by structure includes U.S.
Pat 3,137,689 to Dorfmann et al, which teaches preparation of 6 ~-methyl-pregnenolones (anti-ovulatory activity); U.S. Pat 3,257,427 to Bowers for 6-alkyl-3-desoxy-~ 1,3,5(10) est t i substituted in the 17 position by keto or hydroxy (anti-androgenic action, low feminizing effects; for fertility control and menstral disorders): U.S. Pat. 3,082,224 to Weinstock for 16~ -~, -4-,:~
., ~ .
1~3~81Z
methyl-3,5-pregnadienes (anti-inflammatory activity) UnS~ Pat.
3,132,163 to Borrevang for corticosteroids having hemiacetal moieties at the 21 or 11, 21 positions (improved physiological activity) U.SO Pat. 3,816,481 to Douglas et al for 6~ -methyl-4-gonenes (progestational activity): and British Pat. 1,448,873 (cyclisation of (arylhexenyl)-cyclopentenols to ~ 1~3~5(10)~1 (17) gonatetraenes unsubstituted in ring C).
The present invention relates to novel cyclisation substrates of the formula:
Rl R3 R~
wherein:
(a) Rl is H or alkyl of one to four carbon atoms;
(b) R2 is H or alkyl of one to four carbon atoms, with the proviso that Rl is H when R2 is alkyl, and with the proviso that R2 is H when Rl is alkyl;
; 20 (c) R3 is a suitable leaving group selected from the ~ group consisting of hydroxy, alkoxy of one to four .-~ carbons, alkoxy of two to four carbons, : acyloxy of one to about seven carbon atoms, and trialkylsilyloxy of less than fifteen carbons;
(d) R4 is H, hydrocarbyl of one to fourteen carbons, carboxyacyl of two to twelve carbons, trialkylsilyl ; of less than fifteen carbons, or heterocyclic of ~ 30 five to seven members and four to six carbons; and '~ (e) R5(1) and R5(2) are each H, alkyl of one to eight carbons, or an optionally esterified or etherified . ,. ., ~ .
~ 5-, .
~i3~81Z
hydroxy group selected from the group consisting of hydroxy, alkoxy of one to four carbons, alkoxy-alkoxy of two to four carbons, carboxyacyloxy of one to seven carbons, trialkylsilyloxy of one to fifteen carbons, cycloalkoxy of four to eight carbons,and unsubstituted heterocyclic ether of five to seven members and from four to six carbons, with the proviso that at least one of R5(1) and R5(2) is hydrogen.
Surprisingly, it has now been found that the cyclisa-tion of a cyclisation substrate of formula (I):
R R
R ~ 3 (I) 5(1) leads stereo-selectively to axially-substituted steroid compounds of formula II and III having R4 and R5 (R5(1) or R5(2), as described above:
~ ~ 7 "para" "ortho"
which may be represented in shorthand notation by the following formula (positions indicated in small arabic numerals):
5~ R 7 R5( 1) which is more recognizable to those skilled in the art. R7 is an alkyl moiety of one to four carbon atoms ~ --6--~34812 In formula I, II, and III, most preferably Rl and R2 are H or CH3, R3 is OH, R4 is methyl, benzyl or pivaloyl, one of R5(1) and R5(2) is H and the other i5 OCH3 or trialkylsilyloxy of three to twelve carbon atoms, and R7 is CH3.
When R5(1) is the same as R5(2), the resultant com-pounds are of course identical, but when R5(1) is not R5(2), two isomers result from the cyclisation: the proportions of which are strongly influenced by the cyclisation conditions and the choice of the substituents R4, R5(1) and R5(2).
The cyclisation substrates of formula (I) are novel compounds which may be prepared in several ways each of which are known to those skilled in the art. The invention is therefore characterized by the preparation of novel compounds with the general formula (I) by steps which are in themselves known to those in the art. The invention is also characterized by the cyclisation of novel new cyclisation substrates of formula (I) to the novel and biologically active steroid compounds of formulae II and III that are axially substituted in the 11-position.
Referring to the flow Diagram below, the cyclisation substrate (I) may, for example, be prepared by condensing in Reaction (or Step) (a) an acetylide of formula (IV) with an ald-ehyde of formula (V) to give a propargyl alcohol of formula (VI).
; In step (b) the trans-allyl alcohol of formula (VIIa) is obtained i by reduction of the triple bond, and this may optionally be etherified or esterified to (VIIb), after which (VII) is hydro-lyzed in step (c) to the dioxo compound (VIII) which is condensed in step (d) to the cyclopentenone of formula (IX). When R2 is alkyl of one to four carbons, the ketone obtained is reduced to an alcohol [formula I, Rl is H, R2 is alkyl of one to four carbons and R3 is OH], or when R2 is H, it is reacted with a : . :
compound RlLi, for example methyl-lithium, ethyl-lithium, buty.l-lithium, or RlMg-halogen, where Rl is alkyl of one to four carbons, for example methyl-magnesium bromide, ethyl-magnesium iodide, to give a tertiary alcohol ~formula I, Rl is alkyl (1-4C), R2 is H, R3 is OH]. The hydroxy group (R3) is optionally further etherified or esterified.
1~348i'2 FLOW DIAGRAM
R5~JC + O~
Xl Xl HO ~' jb R4~ ~ b R~ R2~b 5~S R2~,1b (C)~
VI VI I ( b ' R4~H ) R R5~}
VIII IX
I
g_ li34~
In the Flow Diagram Rl, R2, R3, R4 and Rs have the meanings assigned aboveO M is lithium or an Mg-halogen radical, for example Mg Br, the bonds designated with "a" and "b"
represent single or double bonds, with the proviso that when "a"
represents a single bond, "b" is a double bond and vice-versa;
Xl and X2 together form an epoxy group when "a" represents a single bond: if "a" is a double bond, then Xl and X2 each represent a suitable alkylene-dichalcogen group, that is, alkylenedioxy or alkylenedithio with 2-3 carbon atoms, for example ethylene-dioxy, propylene-dithio, ethylene-dithio.
The acetylide (IV) may be prepared by allowing a precursor 4-(mrR~phenyl)butyne to react with alkyl-lithium, for example ethyl-lithium, or with magnesium shavings in the presence of an alkyl halide, for example methyl bromide or ethyl bromide, in an inert solvent, for example tetrahydrofuran at conditions well known to those in the art.
Examples of the aldehyde (V) are 7-R24,7-bis-propylene-dithioheptanal, 7-R2-4,7-bis-ethylene-dioxy-heptanal, 3-(5~-R2-
2'-furyl)-propanal, 7-R2-4,7-bis-ethylene-dithioheptanal.
The reduction of the propargyl alcohol (VI) to the alkyl alcohol (VII) with the desired (E)-configuration may be achieved with a metal hydride, for example lithium aluminium hydride.
The cyclisation substrate (I) obtained is cyclised with a Lewis acid under conditions specified below to give a tetracyclic compound with an axial R40-substituent.
The following comments can be made with reference to the substituents Rl to R6 inclusive.
Either Rl or R2 is usually methyl or ethyl, preferably methyl, while the other substituent is H. R3 as a suitable j "leaving" group known to those skilled in the art is usually ,, .
1~3~8i2 alkoxy of one to four carbons, for example methoxy otherwise (1) alkoxyalkoxy of two to four carbons, for example methoxy-methc,xy or l'-ethoxyethoxy; (2) carboxyacyloxy of one to seven carbons for example acetoxy propionyloxy butyroxy pivaloyl-oxy valeryloxy benzoyloxy or (3) trialkylsilyloxy of less than fifteen carbons for example trimethylsilyloxy.
R4 is hydrogen, a hydrocarbyl (hydrocarbon) group of one to fourteen carbons or carboxyacyl group of two to twelve carbonsor a trialkylsilyl or an unsubstituted heterocyclic of five to seven members and four to six carbons. Examples of hydrocarbyl groups are (1) alkyl, such as methyl or ethyl;
(2) aryl such as phenyl or tolyl (3) aralkyl such as benzyl, p-phenyl-benzyl, naphthyl-methyl or (4) cyclo-alkyl such as cyclopentyl or cyclohexyl. Examples of carboxyacyl-groups are acetyl~ benzoyl, pivaloyl, decanoyl. An example of a trial-kylsilyl group is trimethylsilyl. A preferable heterocyclic group is tetrahydropyranyl. Examples of suitable heterocyclic groups are the following unsubstituted heterocycles: pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyrrolidine, pyridine, pyrimidine, and purine.
; If the allyl alcohol (VII) is hydrolyzed ~step (c) 3 and cyclodehydrated ~step td)~ without first protecting the hydroxy or equivalent group in the "pro-Cll" position, then allowance must be made for the possibility that the "pro-Cll"
OH group can be modified during these reactions. Hydrolysis of the furyl ring (Xl and X2 are epoxy) with methanol/sulphuric acid leads for example to a di-oxo compound (VIII) in which R4 is CH3. This does not necessarily constitute a drawback, but the reaction conditions are generally not optimal for a good yield. If a certain substituent R40 is desired in the cyclisation substrate (I)~ then it is better first to modify the ~3481Z
"pro-Cll" hydroxy group in the (compound (VII), for example by converting it into a benzyloxy group with benzylchloride/KOH
in tetrahydrofuran, or into a methoxy group with CH3I/NaH in dimethyl sulphoxide, after wllich the hydrolysis and cyclodehydra-tion can be performed.
The hydrolysis may be performed with an acid, for example with H2SO4 in methanol or with H2SO4/HOAc or with CH3I/CH3 CN/H2O under conditions known to those in the art. The cyclodehydration is achieved with alcoholic alkali, for example with KOH in ethanol or with trimethylbenzylammonium hydroxide.
It will be recognized by those skilled in the art that R4 may optionally be modified after each of the reaction steps (c), (d) and (e).
( 5(1) 5(2) ) P y hydroxy, or in the alternative, optionally esterified or etherif-ied hydroxy of less than fifteen carbons, for example (1) hydro-carbyloxy of one to eight carbons such as methoxy, ethoxy, cyclopentoxy, cyclohexenyloxy, benzyloxy, (2) ~-alkoxyalkoxy of ~ -two to four carbons, such as methoxymethoxy l-ethoxyethoxy: (3) trimethylsilyloxy or tetrahydropyranyloxy, and (4) carboxyacyloxy of one to seven carbon atoms, such as acetoxy, pivaloyloxy or benzoyloxy.
If R5 is an oxy-group, then the posi-tions 2, 4 and 6 of the phenyl nucleus are activated in the cyclisation. Due to steric factors, position 4 takes no part in the reaction and two products may therefore be formed as indicated above by the formulae (II) and (III). As previously noted, the ratio of formation of these two products can be changed considerably by a suitable choice of R4 and R5.
If for example, R4 is methyl and R5 is methoxy or 1~3~81Z
trimethyl-silyloxy, then much more "para" product is formed than "ort:ho" product, the proportions of the two products being about
The reduction of the propargyl alcohol (VI) to the alkyl alcohol (VII) with the desired (E)-configuration may be achieved with a metal hydride, for example lithium aluminium hydride.
The cyclisation substrate (I) obtained is cyclised with a Lewis acid under conditions specified below to give a tetracyclic compound with an axial R40-substituent.
The following comments can be made with reference to the substituents Rl to R6 inclusive.
Either Rl or R2 is usually methyl or ethyl, preferably methyl, while the other substituent is H. R3 as a suitable j "leaving" group known to those skilled in the art is usually ,, .
1~3~8i2 alkoxy of one to four carbons, for example methoxy otherwise (1) alkoxyalkoxy of two to four carbons, for example methoxy-methc,xy or l'-ethoxyethoxy; (2) carboxyacyloxy of one to seven carbons for example acetoxy propionyloxy butyroxy pivaloyl-oxy valeryloxy benzoyloxy or (3) trialkylsilyloxy of less than fifteen carbons for example trimethylsilyloxy.
R4 is hydrogen, a hydrocarbyl (hydrocarbon) group of one to fourteen carbons or carboxyacyl group of two to twelve carbonsor a trialkylsilyl or an unsubstituted heterocyclic of five to seven members and four to six carbons. Examples of hydrocarbyl groups are (1) alkyl, such as methyl or ethyl;
(2) aryl such as phenyl or tolyl (3) aralkyl such as benzyl, p-phenyl-benzyl, naphthyl-methyl or (4) cyclo-alkyl such as cyclopentyl or cyclohexyl. Examples of carboxyacyl-groups are acetyl~ benzoyl, pivaloyl, decanoyl. An example of a trial-kylsilyl group is trimethylsilyl. A preferable heterocyclic group is tetrahydropyranyl. Examples of suitable heterocyclic groups are the following unsubstituted heterocycles: pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyrrolidine, pyridine, pyrimidine, and purine.
; If the allyl alcohol (VII) is hydrolyzed ~step (c) 3 and cyclodehydrated ~step td)~ without first protecting the hydroxy or equivalent group in the "pro-Cll" position, then allowance must be made for the possibility that the "pro-Cll"
OH group can be modified during these reactions. Hydrolysis of the furyl ring (Xl and X2 are epoxy) with methanol/sulphuric acid leads for example to a di-oxo compound (VIII) in which R4 is CH3. This does not necessarily constitute a drawback, but the reaction conditions are generally not optimal for a good yield. If a certain substituent R40 is desired in the cyclisation substrate (I)~ then it is better first to modify the ~3481Z
"pro-Cll" hydroxy group in the (compound (VII), for example by converting it into a benzyloxy group with benzylchloride/KOH
in tetrahydrofuran, or into a methoxy group with CH3I/NaH in dimethyl sulphoxide, after wllich the hydrolysis and cyclodehydra-tion can be performed.
The hydrolysis may be performed with an acid, for example with H2SO4 in methanol or with H2SO4/HOAc or with CH3I/CH3 CN/H2O under conditions known to those in the art. The cyclodehydration is achieved with alcoholic alkali, for example with KOH in ethanol or with trimethylbenzylammonium hydroxide.
It will be recognized by those skilled in the art that R4 may optionally be modified after each of the reaction steps (c), (d) and (e).
( 5(1) 5(2) ) P y hydroxy, or in the alternative, optionally esterified or etherif-ied hydroxy of less than fifteen carbons, for example (1) hydro-carbyloxy of one to eight carbons such as methoxy, ethoxy, cyclopentoxy, cyclohexenyloxy, benzyloxy, (2) ~-alkoxyalkoxy of ~ -two to four carbons, such as methoxymethoxy l-ethoxyethoxy: (3) trimethylsilyloxy or tetrahydropyranyloxy, and (4) carboxyacyloxy of one to seven carbon atoms, such as acetoxy, pivaloyloxy or benzoyloxy.
If R5 is an oxy-group, then the posi-tions 2, 4 and 6 of the phenyl nucleus are activated in the cyclisation. Due to steric factors, position 4 takes no part in the reaction and two products may therefore be formed as indicated above by the formulae (II) and (III). As previously noted, the ratio of formation of these two products can be changed considerably by a suitable choice of R4 and R5.
If for example, R4 is methyl and R5 is methoxy or 1~3~81Z
trimethyl-silyloxy, then much more "para" product is formed than "ort:ho" product, the proportions of the two products being about
3:1 by weight. If R4 is benzyl or pivaloyl, the ratio becomes much more favourable (10:1 or more) with respect to the "para"
product, which is of importance since the "para" product leads to the desirable natural steroids.
If use is made as starting material of a butyne (IV) with R5 being a protected hydroxy group, then the protective group may be retained during the various reaction steps, but it may also be modifiedO For some reaction steps, certain pro-tective groups are preferred, while for other reaction steps yet other protective groups are preferred. For example, in the I steps (a) and (b), R5 is preferably methoxy or methoxy-methoxy.
In the steps ~c), (d) and (e), R5 may optionally be hydroxy while in the cyclisation step~ R5 is preferably a"bulky" group, if the "para" - product is of primary interestu One permissible variation in the preparation of the cyclisation substrate is that the order of the (1) reduction of the propargyl alcohol and (2) the hydrolysis and (cyclo-dehydration) may be reversed. After the condensation of (IV) with (V), the hydrolysis and cyclo-dehydration are first performed to give 2-[2'-hydroxy-6~ -R5~phenyl)-hex-3~-ynyl]-3-R2-cyclopent-2-enone, after which the oxo group in the cyclo-pentenone is temporarily protected, for example in the form of the thioketal, the hexynyl group is reduced to the (E)-hexenyl group, and the oxo group i5 deprotected, giving compound IX. The deprotection of the oxo group may, optionally, be preceded by modification of the R40 substituent, for example conversion of the OH into benzyloxy.
The cyclisation substrate contains two asymmetric centers~ namely, the carbon atom carrying the substituent Rl and 1~34B~2 the carbon atom carrying the substituent R40. The stereochem-istry of the cyclisation product proves to be governed predomi-nantly by the latter center. In the cyclisation product, the substituent R40 has surprisingly been shown to occur predominant-ly in the axial configuration. If use is made as starting mate-rial of a racemic cyclisation substrate, i.e. a product with equal amounts of the (R)-R40-substituted and the (S)-R40-substi-tuted compound, then a racemic tetracyclic product is formed, consisting of two enantiomers, while on grounds of the two asym-metric centers, four stereo-isomers would be formed in equal a-mounts if there were no optical induction. It is concluded that the asymmetric center with the substituent Rl has little or no influence on the stereochemistry of the end product because the (S)-Rl-(S)-R40-substituted cyclisation substrate gives the same R40-axially su~stituted cyclisation product as the (R)-Rl-(S)-R40-substituted cyclisation substrate. For example, both l(S)-3-methyl-2{2'-(S)-benzyloxy-6'-(m-methoxyphenylt3'(E)-hexenyl]-2-cyclopentenol and l(R)-3-methyl-2-[2'(S)-benzyloxy-6'-(m-methoxy-phenyl)-3'(E)-hexenyl]-2-cyclopentenol give the "natural" 3-20 methoxy-11~-benzyloxy-~1'3'5(1)'l3(17)-gonatetraene of formula II on cyclisation.
It has been indicated in formula I that the substituent R40 may be present in the (R)-configuration or in the (S)-confi-guration. If use is made of the racemate as starting material, and the ortho/para isomerism of the aromatic ring is ignored, the cyclisation results in a racemate of the R40-axially-substi-tuted steroid compound with formula III. If an optically active cyclisation substrate is used as starting material, for example the (S)-methoxy compound, than an optically active compound of 30 formula II is formed, that is, a "natural" ll~-methoxy-~ 1,3,5(10), 13(l7)-gonat0traene-By epoxidising the 13(17)-olefine (II,III) obtained i;! - 14 -1'1348~2 with a per-acid (for example m-chloro-perbenzoic acid) the cor-responding 13~,17~-epoxy compound below (formula X) is formed.
Opening of the epoxide ring under weakly acid conditions, prefer-ably by use of an aprotic Lewis acid, for example BF3/diethyl ether, initiates a migration of the substituent R7 from position 17 to position 13, whereby the corresponding 13~-R7-17-ketone (XI) is formed from the ~-epoxide (see Example III):
(II,III) 4 ~ 7 R40 R5(2) 1 H I ¦ R5(2) ¦ H
R5(~X ~ R5 X XI
When R5(1) is methoxy and R7 is methyl, the 3-methyl ether of ll~-methoxy-oestrone is obtained in this way.
In a corresponding fashion, the antipode can be conver-ted into the ent-3-R5-11~-OR4-13~-R7-~1'3'5(10)-gonatrien-17-one.
The internal condensation of the dioxo compound VIII
(step (d)) may be brought about in the usual way, for example with alkaline ethanol or with trimethylbenzyl-ammonium hydroxide.
In the cyclisation Reaction (step e), an effective a-mount of an aprotic or a protic Lewis acid is used and the reac-tion is performed in a non-nucleophilic protic or aprotic solvent.
Examples of suitable solvents are formic acid, acetic acid, tri-fluoro-acetic acid, trifluoro-ethanol, benzene, saturated hydro-carbons such as pentane, hexane, cyclohexane, and halogenated hydrocarbons such as dichloromethane.
Examples of protic Lewis acids are carboxylic acids ` with a pK (20C) of less than about 4, and preferably less than about 2, such as, for example, trifluoro-acetic acid, trichloro-`:
: ~!
~ '' 113~81Z
acetic acid, formic acid.
Examples of aprotic Lewis acids are stannic chloride, titanium tetrachloride, zinc chloride, zinc bromide, boron tri-fluoride. Aprotic Lewis acids are preferably used, in an amount of about 0.1 to about 10 moles per mole cyclisation substrate, and preferably about 0.5 to about 5 moles per mole. Stannic chloride is preferable.
The cyclisation reaction is usually carried out at a temperature below ~oom temperature (about 20-22C) and above -150C preferably at a temperature between about +10C and about -100C.
The mixtures of "ortho"- and "para"- products ("ortho"
means A-aromatic steroid substituted in position 1, "para" means A-aromatic steroid substitu~ed in position 3) of compound II-III
obtained in the cyclisation step (e) may be separated in the usual way known to those in the art, for example, by chromato-graphy or by crystallization. Racemates of intermediate or final products may be resolved to give the optical antipodes in the usual way.
As to the reaction steps (a) - (f) the following addi-tional information can be given:
Reaction step (a) is usually carried out at a temper-ature between about -100C and about 0C, preferably between about -75C and about -25C. The solvent is usually an etheric solvent, such as diethyl ether, tetrahydrofuran and mixtures thereof. A preferred solvent is an 1:1 mixture of diethyl ether and tetrahydrofuran.
Reaction step (b) is usually carried out at a temper-ature between about 30C and 70C preferably between 40 and 60C.
30 The solvent is an etheric solvent such as tetrahydrofuran, dioxan or diethyl ether. A preferred solvent is tetrahydrofuran. [cf.J.
Org.Chem. 39,969 ~1974)].
Reaction step (c) is usually carried out at a temper-~ . , . ~ , ~ i - 16 -.. ...
~3a~81;~
ature between about 20C and 80C, preferably between about 50C
and 60C. The solvent may be an etheric solvent, such as dimeth-oxyethane, or a mixture of water and an alcohol, such as ethanol.
An 1:2 mixture of water and ethanol containing between 5 and 10 mmol HCl per liter, is very suited.
Reaction step (d) is usually carried out between about 60C and 80C, preferably at about 80C. The solvent is the same as used in step (c). An 1:2 mixture of water and ethanol con-taining between 5 and 10 mmol NaOH or an equivalent amount of KOH
or trimethylbenzyl-ammoniumhydroxide is very suited.
Reaction step (e): The reduction of the ketone to an alcohol is carried out with a complex metallic hydride, such as lithiumaluminiumhydride, di-isobutyl-aluminium-hydride, sodium-di-isobutylboronhydride, at a temperature between about -50C and 0C, preferably between about -25C and 0C. The reaction of the ketone with a compound Rl Li or RlMghalogen is usually carried out at a temperature between -70C and 0C, preferably between -70C and 20C. The solvent is usually an etheric solvent, pre-ferably diethyl ether.
The reaction steps (a), (e), and (f) are preferably carried out in an inert atmosphere (nitrogen or argon blanket).
Cyclisation reaction step (f): When using a protic solvent, preferably a protic Lewis acid is used. A protic sol- `, vent, such as formic acid, trifluoro-acetic acid, trifluoro-ethanol, may also serve as protic Lewis acid. An aprotic solvent may be combined with either a protic Lewis acid or an aprotic Lewis acid.
Although the invention has been described with refer-ence to the specific embodiments above numerous variations and modifications will become evident to those skilled in the art, without departing from the scope and spirit of the invention as described above, defined in the appended claims, and as shown in 1~3~81Z
the following Examples:
Example I
(a) Preparation of 4,7-bis-(propylene-dithio)-heptanal ethylene a ta Precursor of Compound V
About 160 ml of a 2N solution of butyl-lithium in hex-ane was added dropwise over a period of about 10 minutes to a solution of 41.80 g (157 mmol) 2,2'-ethylene-bis-t_-dithiane) in 1000 ml tetrahydrofuran at about -40C under nitrogen. The mix-10 ture was stirred at a temperature between about -20C and about -30C for about 4 hours. A solution of 28.8 g (160 mmol) 3-brom~
propanal ethylene acetal in 120 ml tetrahydrofuran was then added dropwise to the orange-colored solution over a period of about 30 minutes. The whole was stirred for 2 hours at about -20C and another 16 or 80 hours at room temperature (20-25C).
40 ml water was 510wly added dropwise at about 0C. The volume was reduced to about 100 ml by evaporation under reduced press-ure, the mixture was diluted with 500 m.l water and extracted with methylene chloride. The combined organic layers were washed with 20 water until neutral. After drying over sodium sulphate and fil-tering, the filtrate was evaporated to dryness under reduced pressure. The residue (59.0 g) was filtered through about 120 g neutral washed aluminium oxide with 500 ml toluene. After remov-~- al of toluene by evaporation, 39.0 g product was obtained.
, (b) Preparation of 4,7-bis-(ProPYlene-dithio)-heptanal `~ (formula V R = H X = X = propylene-dithio).
2 ' 1 2 250 ml 0.5N hydrochloric acid was added with stirring ~'~ to a solution of 25.62 g (70 mmol) 4,7-bis-(propylene-dithio)-heptanal ethylene acetal in 25 ml methylene chloride under nitro-30 gen. The mixture was stirred in an oil bath at about 110C for about 5 hours. After cooling to room temperature, the mixture ` was extracted with methylene chloride. The organic layers were t - 18 -' ~348~2 washed with water until neutral. After drying over sodium sul-phate and filtering, the filtrate was evaporated to dryness under reduced pressure. The product obtained (22.5 g) was used imme-diately in the following step.
(c) Step (a): Preparation of dl-l-(m-methoxyphenyl)-8,11-bis-(propylene-dithio)-3-undecyn-5-ol (formula VI, R2 = H, R5 = methoxy, Xl = X2 = propylene-dithio) A solution of 8.76 g (80 mmol) ethyl bromide in about 40 ml tetrahydrofuran was added dropwise over a period of about 1 hour to 1.92 g (80 mmol) magnesium shavings in 30 ml tetrahydro-furan under nitrogen. The whole was stirred for another 15 min-utes or so, giving a clear solution to which was added dropwise over a period of about 30 minutes a solution of 12.8 g (80 mmol)
product, which is of importance since the "para" product leads to the desirable natural steroids.
If use is made as starting material of a butyne (IV) with R5 being a protected hydroxy group, then the protective group may be retained during the various reaction steps, but it may also be modifiedO For some reaction steps, certain pro-tective groups are preferred, while for other reaction steps yet other protective groups are preferred. For example, in the I steps (a) and (b), R5 is preferably methoxy or methoxy-methoxy.
In the steps ~c), (d) and (e), R5 may optionally be hydroxy while in the cyclisation step~ R5 is preferably a"bulky" group, if the "para" - product is of primary interestu One permissible variation in the preparation of the cyclisation substrate is that the order of the (1) reduction of the propargyl alcohol and (2) the hydrolysis and (cyclo-dehydration) may be reversed. After the condensation of (IV) with (V), the hydrolysis and cyclo-dehydration are first performed to give 2-[2'-hydroxy-6~ -R5~phenyl)-hex-3~-ynyl]-3-R2-cyclopent-2-enone, after which the oxo group in the cyclo-pentenone is temporarily protected, for example in the form of the thioketal, the hexynyl group is reduced to the (E)-hexenyl group, and the oxo group i5 deprotected, giving compound IX. The deprotection of the oxo group may, optionally, be preceded by modification of the R40 substituent, for example conversion of the OH into benzyloxy.
The cyclisation substrate contains two asymmetric centers~ namely, the carbon atom carrying the substituent Rl and 1~34B~2 the carbon atom carrying the substituent R40. The stereochem-istry of the cyclisation product proves to be governed predomi-nantly by the latter center. In the cyclisation product, the substituent R40 has surprisingly been shown to occur predominant-ly in the axial configuration. If use is made as starting mate-rial of a racemic cyclisation substrate, i.e. a product with equal amounts of the (R)-R40-substituted and the (S)-R40-substi-tuted compound, then a racemic tetracyclic product is formed, consisting of two enantiomers, while on grounds of the two asym-metric centers, four stereo-isomers would be formed in equal a-mounts if there were no optical induction. It is concluded that the asymmetric center with the substituent Rl has little or no influence on the stereochemistry of the end product because the (S)-Rl-(S)-R40-substituted cyclisation substrate gives the same R40-axially su~stituted cyclisation product as the (R)-Rl-(S)-R40-substituted cyclisation substrate. For example, both l(S)-3-methyl-2{2'-(S)-benzyloxy-6'-(m-methoxyphenylt3'(E)-hexenyl]-2-cyclopentenol and l(R)-3-methyl-2-[2'(S)-benzyloxy-6'-(m-methoxy-phenyl)-3'(E)-hexenyl]-2-cyclopentenol give the "natural" 3-20 methoxy-11~-benzyloxy-~1'3'5(1)'l3(17)-gonatetraene of formula II on cyclisation.
It has been indicated in formula I that the substituent R40 may be present in the (R)-configuration or in the (S)-confi-guration. If use is made of the racemate as starting material, and the ortho/para isomerism of the aromatic ring is ignored, the cyclisation results in a racemate of the R40-axially-substi-tuted steroid compound with formula III. If an optically active cyclisation substrate is used as starting material, for example the (S)-methoxy compound, than an optically active compound of 30 formula II is formed, that is, a "natural" ll~-methoxy-~ 1,3,5(10), 13(l7)-gonat0traene-By epoxidising the 13(17)-olefine (II,III) obtained i;! - 14 -1'1348~2 with a per-acid (for example m-chloro-perbenzoic acid) the cor-responding 13~,17~-epoxy compound below (formula X) is formed.
Opening of the epoxide ring under weakly acid conditions, prefer-ably by use of an aprotic Lewis acid, for example BF3/diethyl ether, initiates a migration of the substituent R7 from position 17 to position 13, whereby the corresponding 13~-R7-17-ketone (XI) is formed from the ~-epoxide (see Example III):
(II,III) 4 ~ 7 R40 R5(2) 1 H I ¦ R5(2) ¦ H
R5(~X ~ R5 X XI
When R5(1) is methoxy and R7 is methyl, the 3-methyl ether of ll~-methoxy-oestrone is obtained in this way.
In a corresponding fashion, the antipode can be conver-ted into the ent-3-R5-11~-OR4-13~-R7-~1'3'5(10)-gonatrien-17-one.
The internal condensation of the dioxo compound VIII
(step (d)) may be brought about in the usual way, for example with alkaline ethanol or with trimethylbenzyl-ammonium hydroxide.
In the cyclisation Reaction (step e), an effective a-mount of an aprotic or a protic Lewis acid is used and the reac-tion is performed in a non-nucleophilic protic or aprotic solvent.
Examples of suitable solvents are formic acid, acetic acid, tri-fluoro-acetic acid, trifluoro-ethanol, benzene, saturated hydro-carbons such as pentane, hexane, cyclohexane, and halogenated hydrocarbons such as dichloromethane.
Examples of protic Lewis acids are carboxylic acids ` with a pK (20C) of less than about 4, and preferably less than about 2, such as, for example, trifluoro-acetic acid, trichloro-`:
: ~!
~ '' 113~81Z
acetic acid, formic acid.
Examples of aprotic Lewis acids are stannic chloride, titanium tetrachloride, zinc chloride, zinc bromide, boron tri-fluoride. Aprotic Lewis acids are preferably used, in an amount of about 0.1 to about 10 moles per mole cyclisation substrate, and preferably about 0.5 to about 5 moles per mole. Stannic chloride is preferable.
The cyclisation reaction is usually carried out at a temperature below ~oom temperature (about 20-22C) and above -150C preferably at a temperature between about +10C and about -100C.
The mixtures of "ortho"- and "para"- products ("ortho"
means A-aromatic steroid substituted in position 1, "para" means A-aromatic steroid substitu~ed in position 3) of compound II-III
obtained in the cyclisation step (e) may be separated in the usual way known to those in the art, for example, by chromato-graphy or by crystallization. Racemates of intermediate or final products may be resolved to give the optical antipodes in the usual way.
As to the reaction steps (a) - (f) the following addi-tional information can be given:
Reaction step (a) is usually carried out at a temper-ature between about -100C and about 0C, preferably between about -75C and about -25C. The solvent is usually an etheric solvent, such as diethyl ether, tetrahydrofuran and mixtures thereof. A preferred solvent is an 1:1 mixture of diethyl ether and tetrahydrofuran.
Reaction step (b) is usually carried out at a temper-ature between about 30C and 70C preferably between 40 and 60C.
30 The solvent is an etheric solvent such as tetrahydrofuran, dioxan or diethyl ether. A preferred solvent is tetrahydrofuran. [cf.J.
Org.Chem. 39,969 ~1974)].
Reaction step (c) is usually carried out at a temper-~ . , . ~ , ~ i - 16 -.. ...
~3a~81;~
ature between about 20C and 80C, preferably between about 50C
and 60C. The solvent may be an etheric solvent, such as dimeth-oxyethane, or a mixture of water and an alcohol, such as ethanol.
An 1:2 mixture of water and ethanol containing between 5 and 10 mmol HCl per liter, is very suited.
Reaction step (d) is usually carried out between about 60C and 80C, preferably at about 80C. The solvent is the same as used in step (c). An 1:2 mixture of water and ethanol con-taining between 5 and 10 mmol NaOH or an equivalent amount of KOH
or trimethylbenzyl-ammoniumhydroxide is very suited.
Reaction step (e): The reduction of the ketone to an alcohol is carried out with a complex metallic hydride, such as lithiumaluminiumhydride, di-isobutyl-aluminium-hydride, sodium-di-isobutylboronhydride, at a temperature between about -50C and 0C, preferably between about -25C and 0C. The reaction of the ketone with a compound Rl Li or RlMghalogen is usually carried out at a temperature between -70C and 0C, preferably between -70C and 20C. The solvent is usually an etheric solvent, pre-ferably diethyl ether.
The reaction steps (a), (e), and (f) are preferably carried out in an inert atmosphere (nitrogen or argon blanket).
Cyclisation reaction step (f): When using a protic solvent, preferably a protic Lewis acid is used. A protic sol- `, vent, such as formic acid, trifluoro-acetic acid, trifluoro-ethanol, may also serve as protic Lewis acid. An aprotic solvent may be combined with either a protic Lewis acid or an aprotic Lewis acid.
Although the invention has been described with refer-ence to the specific embodiments above numerous variations and modifications will become evident to those skilled in the art, without departing from the scope and spirit of the invention as described above, defined in the appended claims, and as shown in 1~3~81Z
the following Examples:
Example I
(a) Preparation of 4,7-bis-(propylene-dithio)-heptanal ethylene a ta Precursor of Compound V
About 160 ml of a 2N solution of butyl-lithium in hex-ane was added dropwise over a period of about 10 minutes to a solution of 41.80 g (157 mmol) 2,2'-ethylene-bis-t_-dithiane) in 1000 ml tetrahydrofuran at about -40C under nitrogen. The mix-10 ture was stirred at a temperature between about -20C and about -30C for about 4 hours. A solution of 28.8 g (160 mmol) 3-brom~
propanal ethylene acetal in 120 ml tetrahydrofuran was then added dropwise to the orange-colored solution over a period of about 30 minutes. The whole was stirred for 2 hours at about -20C and another 16 or 80 hours at room temperature (20-25C).
40 ml water was 510wly added dropwise at about 0C. The volume was reduced to about 100 ml by evaporation under reduced press-ure, the mixture was diluted with 500 m.l water and extracted with methylene chloride. The combined organic layers were washed with 20 water until neutral. After drying over sodium sulphate and fil-tering, the filtrate was evaporated to dryness under reduced pressure. The residue (59.0 g) was filtered through about 120 g neutral washed aluminium oxide with 500 ml toluene. After remov-~- al of toluene by evaporation, 39.0 g product was obtained.
, (b) Preparation of 4,7-bis-(ProPYlene-dithio)-heptanal `~ (formula V R = H X = X = propylene-dithio).
2 ' 1 2 250 ml 0.5N hydrochloric acid was added with stirring ~'~ to a solution of 25.62 g (70 mmol) 4,7-bis-(propylene-dithio)-heptanal ethylene acetal in 25 ml methylene chloride under nitro-30 gen. The mixture was stirred in an oil bath at about 110C for about 5 hours. After cooling to room temperature, the mixture ` was extracted with methylene chloride. The organic layers were t - 18 -' ~348~2 washed with water until neutral. After drying over sodium sul-phate and filtering, the filtrate was evaporated to dryness under reduced pressure. The product obtained (22.5 g) was used imme-diately in the following step.
(c) Step (a): Preparation of dl-l-(m-methoxyphenyl)-8,11-bis-(propylene-dithio)-3-undecyn-5-ol (formula VI, R2 = H, R5 = methoxy, Xl = X2 = propylene-dithio) A solution of 8.76 g (80 mmol) ethyl bromide in about 40 ml tetrahydrofuran was added dropwise over a period of about 1 hour to 1.92 g (80 mmol) magnesium shavings in 30 ml tetrahydro-furan under nitrogen. The whole was stirred for another 15 min-utes or so, giving a clear solution to which was added dropwise over a period of about 30 minutes a solution of 12.8 g (80 mmol)
4-(m-methoxyphenyl)-1-butyne in about 20 ml tetrahydrofuran. The reaction mixture was then stirred at about 50C for about 1 1/2 hours. After cooling to 5C, a solution of 22.50 g (70 mmol) 4,7-bis(propylene-dithio)-heptanal in 50 ml tetrahydrofuran was added dropwise over a 20 minute period and the whole was stirred ' at room temperature for about 2 hours. About 30 ml of 6N hydro-chloric acid was then added at about 0C and the whole was evap-- orated to a bulk of about 50 ml under reduced pressure. The mix-ture was diluted with about 200 ml water and extracted with methylene chloride. The organic layers were washed with water until neutral. After drying over sodium sulphate and filtering, the filtrate was evaporated to dryness under reduced pressure.
The residue was filtered through 150 g silica gel with 1 liter hexane/acetone 9:1 and give 26.3 g product.
(d) steP (b): Preparation of dl-(~)-l-(m-methoxyphenyl)-8,11-bis-(propYlene-dithio)-3-undecen-5-ol (formula VIIIa, R2 = H, R5 = methoxy, Xl = X2 = propylene-dithio) A solution of 8.20 g (17 mmol) dl-l-(m-methoxyphenyl)-8,11-bis-(propylene-dithio)-3-undecyn-5-ol in 40 ml tetrahydro-~13~312 furan was added dropwise over a period of approximately 20 min-utes to a suspension of 1.26 g (33 mmol) lithium aluminium hy-dride in 72 ml tetrahydrofuran under nitrogen, and the whole was then stirred in a water bath at about 60C for about 3 hours.
After cooling to about 0C, the following consecutive additions were cautiously made dropwise to the suspension: 1:26 ml water, 1.26 ml 15% sodium hydroxide solution and about 3.5 ml water.
Sodium sulphate (5 g) was added and the whole was filtered. The filtrate was evaporated to dryness under reduced pressure. Yield 10 8.20 g product.
(e) dl-(E)-l-(m-methoxyphenyl)-8,11-bis-(propylene-dithio)-3-undecen-5-ol, 5-benzyl ether (formula VIIb, R2 = H, R5 = methoxy, Xl = X2 = propylene-dithio, R,l = benzYl).
16.0 g (296 mmol) powered potassium hydroxide and 16.0 ml (171 mmol) benzyl chloride were added consecutively to a solu-tion of 8.20 g (17 mmol) dl-(E)-l-tm-methoxyphenyl)-8,11-bis-(propylene-dithio)-3-undecen-5-ol in about 82 ml tetrahydrofuran under nitrogen, and the resultant mixture was stirred at room 20 temperature for about 16 hours. After filtering, the filtrate was evaporated to dryness under vacuum. The residue was filtered through 100 g silica gel with toluene/ethylacetate 98:2 (600 ml), giving 8.78 g product.
(f) dl-2-[(E)-6-(m-methoxyPhenyl)-2-benzyloxy-3-hexen-yl3-2-cyclopentenone (Step (c) + SteP (d)).
(formula IX, R2 = H, R4 = benzyl, R5 = methoxy).
~; 13.00 g (130 mmol) calcium carbonate was added under nitrogen to a solution of 5.65 g (9.84 mmol) dl-(E)-l-(m-methoxy-phenyl)-8,11-bis-(propylene-dithio)-3-undecen-5-ol-5 benzyl ether 30 in about 110 ml methyl cyanide-water 4:1. About 25 ml (400 mmol) methyl iodide was then added dropwise during a period of about 30 minutes, and the whole was stirred for a further about 5 hour s in ~ - 20 -~13a~8~Z
a water-bath at about 5C. After filtering, the filtrate was poured into 400 ml water and extracted with methylene chloride.
The methylene chloride layer was evaporated to dryness under re-duced pressure. The residue was filtered through about 50 g silica gel with toluene/ethyl acetate (about 200 ml). The pro-duct (2.55 g) obtained by evaporation to dryness under reduced pressure, was stirred in about 250 ml 0.lN ethanolic potassium hydroxide solution in an oil bath at about 80C for 2 hours.
After cooling, the reaction mixture was poured into about 500 ml water and extracted with methylene chloride. The methylene chlor-ide layer was washed with water and evaporated to dryness under reduced pressure. The residue (2.40 g) was filtered through 50 g silica gel with 250 ml toluene/ethyl acetate 9:1 giving 1.35 g product.
(q) Step (e): dl-l-methvl-2-~(E)-6-(m-methoxYphenYl)-2-benzyloxy-3-hexenyl]-2-cycloPenteno:l (formula I, R = methyl; R = H R~ = OH: R4 = benzyl: R = meth-2 ' 5 oxY ) -6.0 ml 2M methyl-lithium in ether was added dropwise at about 0C under nitrogen to a solution of 1.08 g (2.87 mmol) dl-2-[(E)-6-(m-methoxy-phenyl)-2-benzyloxy-3-hexenyl]-2-cyclopent-enone of step I(f) in about 40 ml absolute ether. The reaction mixture was stirred for a f,urther about 30 minutes at about 0C, poured into about 50 ml ice-water and extracted with ether. The ether layers were washed with water until neutral. After drying over sodium sulphate and filtering, the filtrate was evaporated to dryness under reduced pressure. Yield: 1.12 g product.
(oil) NMR (in CDC13 + C5D5N): ~ 1.25 and 1.29 (s, CH3 at C-l), 3~78 (s, CH30), 3.9 (m, H-C-O), 4.20 and 4.50 (2 x d, J = 12, Ar CH2O), 5.15-5.85 (m, olefinic protons).
~3~8iZ
Example II: Cyclisation (Step (f)) dl-3-methoxy-11~-benzYloxY-7 th 1 ~l~3~5(lo)~l3(l7)-qonatetraene mula II, R = methoxy R4 = benzyl, R7 = methyl).
A solution of 1.12 g dl-1-methyl-2-~(E)-6-(m-methoxy-phenyl)-2-benzyloxy-3-hexenyl]-2-cyclopentenol of Example I in 2 ml methylene chloride was added dropwise over a 30 minute period to a solution of 1.02 ml (9.0 mmol) stannic chloride in 30 ml methylene chloride at about -75C under a nitrogen atmosphere.
The whole was stirred for a further about 45 minutes at about -75C, after which 30 ml of about 20% methanolic potassium hydrox-ide solution was added dropwise to the reaction mixture over a period of about 15 minutes. The reaction mixture was poured in-to 100 ml water and extracted with methylene chloride. The meth-ylene chloride layers were washed with water until neutral and evaporated to dryness under reduced pressure. The residue (1.05 g) was chromatographed on 30 g silica gel with toluene/ethyl acetate 99:1, giving 0.52 g product in the form of an oil. NMR
(in CDC13): S 1.60 (s,17 - CH3), 3.76 (s, CH30), 4.15-4.5 (m, 11~-H + Ar CH20).
ExamPle III: Preparation of dl-3-methoxy-llB-benzYloxv~
(1)-oestratrien-17-one (SteP (q) + SteP (h)) (formula XI. R4 = benzvl, R5 = methoxy. R7 = methyl)-A solution of 173 mg m-chloro-perbenzoic acid (content 70%, 0.70 mmol) in 10 ml methylene chloride was added dropwise at 0C to a solution of 187 mg (0.50 mmol) dl-3-methoxy-11~-benzyl-oxy-17-methyl- ~1'3~5(10)'13(17)-gonatetraene in 20 ml methylene chloride and the resultant mixture was stirred for a further about 2.5 hours at about 0C.
The reaction mixture was vigorously stirred with 12.5 ml saturated sodium bicarbonate solution for about 15 minutes.
The organic layer was separated and dried over anhydrous potas-sium carbonate. The solution, containing the 13~,17~-epoxide, li3~81Z
was filtered and mixed with 1 ml boron trifluoride etherate.
After shaking vigorously for 1 minute, the red reaction mixture was washed with 25 ml 10% potassium carbonate solution. The organic layer was separated and dried over anhydrous potassium carbonate. Evaporation to dryness yielded 190 mg residue, which was purified by chromatography on 10 g silica gel with hexane/
ethyl acetate 9:1, followed by 8:2. In this way, 90 mg of pure product was obtained; oil NMR (in CDC13): o 1.12 (s, 13-CH3), 3.73 (s, CH30), 4.35 (q, ll~-H), 4.30 and 4.60 (2 x d, J = J =
10 ArCH20 ) Example IV: (a) Preparation of dl-(E)-l-(m-methoxyphenyl)-8,11-bis-(1,3-propylene-dithio)-3-undecen-5-ol, 5-methyl ether (formula VIIb, R2 = H, R~ = methyl, R5 = methoxy, Xl = ~2-Propylene-dithio ,.
1.00 g (20.8 mmol) sodium hydride (50% suspension in oil was added under nitrogen to a solution of 4.24 g (8.7 mmol) dl-(E)-l-m-methoxyphenyl)-8,11-bis-(propylene-dithio)-3-undecen-
The residue was filtered through 150 g silica gel with 1 liter hexane/acetone 9:1 and give 26.3 g product.
(d) steP (b): Preparation of dl-(~)-l-(m-methoxyphenyl)-8,11-bis-(propYlene-dithio)-3-undecen-5-ol (formula VIIIa, R2 = H, R5 = methoxy, Xl = X2 = propylene-dithio) A solution of 8.20 g (17 mmol) dl-l-(m-methoxyphenyl)-8,11-bis-(propylene-dithio)-3-undecyn-5-ol in 40 ml tetrahydro-~13~312 furan was added dropwise over a period of approximately 20 min-utes to a suspension of 1.26 g (33 mmol) lithium aluminium hy-dride in 72 ml tetrahydrofuran under nitrogen, and the whole was then stirred in a water bath at about 60C for about 3 hours.
After cooling to about 0C, the following consecutive additions were cautiously made dropwise to the suspension: 1:26 ml water, 1.26 ml 15% sodium hydroxide solution and about 3.5 ml water.
Sodium sulphate (5 g) was added and the whole was filtered. The filtrate was evaporated to dryness under reduced pressure. Yield 10 8.20 g product.
(e) dl-(E)-l-(m-methoxyphenyl)-8,11-bis-(propylene-dithio)-3-undecen-5-ol, 5-benzyl ether (formula VIIb, R2 = H, R5 = methoxy, Xl = X2 = propylene-dithio, R,l = benzYl).
16.0 g (296 mmol) powered potassium hydroxide and 16.0 ml (171 mmol) benzyl chloride were added consecutively to a solu-tion of 8.20 g (17 mmol) dl-(E)-l-tm-methoxyphenyl)-8,11-bis-(propylene-dithio)-3-undecen-5-ol in about 82 ml tetrahydrofuran under nitrogen, and the resultant mixture was stirred at room 20 temperature for about 16 hours. After filtering, the filtrate was evaporated to dryness under vacuum. The residue was filtered through 100 g silica gel with toluene/ethylacetate 98:2 (600 ml), giving 8.78 g product.
(f) dl-2-[(E)-6-(m-methoxyPhenyl)-2-benzyloxy-3-hexen-yl3-2-cyclopentenone (Step (c) + SteP (d)).
(formula IX, R2 = H, R4 = benzyl, R5 = methoxy).
~; 13.00 g (130 mmol) calcium carbonate was added under nitrogen to a solution of 5.65 g (9.84 mmol) dl-(E)-l-(m-methoxy-phenyl)-8,11-bis-(propylene-dithio)-3-undecen-5-ol-5 benzyl ether 30 in about 110 ml methyl cyanide-water 4:1. About 25 ml (400 mmol) methyl iodide was then added dropwise during a period of about 30 minutes, and the whole was stirred for a further about 5 hour s in ~ - 20 -~13a~8~Z
a water-bath at about 5C. After filtering, the filtrate was poured into 400 ml water and extracted with methylene chloride.
The methylene chloride layer was evaporated to dryness under re-duced pressure. The residue was filtered through about 50 g silica gel with toluene/ethyl acetate (about 200 ml). The pro-duct (2.55 g) obtained by evaporation to dryness under reduced pressure, was stirred in about 250 ml 0.lN ethanolic potassium hydroxide solution in an oil bath at about 80C for 2 hours.
After cooling, the reaction mixture was poured into about 500 ml water and extracted with methylene chloride. The methylene chlor-ide layer was washed with water and evaporated to dryness under reduced pressure. The residue (2.40 g) was filtered through 50 g silica gel with 250 ml toluene/ethyl acetate 9:1 giving 1.35 g product.
(q) Step (e): dl-l-methvl-2-~(E)-6-(m-methoxYphenYl)-2-benzyloxy-3-hexenyl]-2-cycloPenteno:l (formula I, R = methyl; R = H R~ = OH: R4 = benzyl: R = meth-2 ' 5 oxY ) -6.0 ml 2M methyl-lithium in ether was added dropwise at about 0C under nitrogen to a solution of 1.08 g (2.87 mmol) dl-2-[(E)-6-(m-methoxy-phenyl)-2-benzyloxy-3-hexenyl]-2-cyclopent-enone of step I(f) in about 40 ml absolute ether. The reaction mixture was stirred for a f,urther about 30 minutes at about 0C, poured into about 50 ml ice-water and extracted with ether. The ether layers were washed with water until neutral. After drying over sodium sulphate and filtering, the filtrate was evaporated to dryness under reduced pressure. Yield: 1.12 g product.
(oil) NMR (in CDC13 + C5D5N): ~ 1.25 and 1.29 (s, CH3 at C-l), 3~78 (s, CH30), 3.9 (m, H-C-O), 4.20 and 4.50 (2 x d, J = 12, Ar CH2O), 5.15-5.85 (m, olefinic protons).
~3~8iZ
Example II: Cyclisation (Step (f)) dl-3-methoxy-11~-benzYloxY-7 th 1 ~l~3~5(lo)~l3(l7)-qonatetraene mula II, R = methoxy R4 = benzyl, R7 = methyl).
A solution of 1.12 g dl-1-methyl-2-~(E)-6-(m-methoxy-phenyl)-2-benzyloxy-3-hexenyl]-2-cyclopentenol of Example I in 2 ml methylene chloride was added dropwise over a 30 minute period to a solution of 1.02 ml (9.0 mmol) stannic chloride in 30 ml methylene chloride at about -75C under a nitrogen atmosphere.
The whole was stirred for a further about 45 minutes at about -75C, after which 30 ml of about 20% methanolic potassium hydrox-ide solution was added dropwise to the reaction mixture over a period of about 15 minutes. The reaction mixture was poured in-to 100 ml water and extracted with methylene chloride. The meth-ylene chloride layers were washed with water until neutral and evaporated to dryness under reduced pressure. The residue (1.05 g) was chromatographed on 30 g silica gel with toluene/ethyl acetate 99:1, giving 0.52 g product in the form of an oil. NMR
(in CDC13): S 1.60 (s,17 - CH3), 3.76 (s, CH30), 4.15-4.5 (m, 11~-H + Ar CH20).
ExamPle III: Preparation of dl-3-methoxy-llB-benzYloxv~
(1)-oestratrien-17-one (SteP (q) + SteP (h)) (formula XI. R4 = benzvl, R5 = methoxy. R7 = methyl)-A solution of 173 mg m-chloro-perbenzoic acid (content 70%, 0.70 mmol) in 10 ml methylene chloride was added dropwise at 0C to a solution of 187 mg (0.50 mmol) dl-3-methoxy-11~-benzyl-oxy-17-methyl- ~1'3~5(10)'13(17)-gonatetraene in 20 ml methylene chloride and the resultant mixture was stirred for a further about 2.5 hours at about 0C.
The reaction mixture was vigorously stirred with 12.5 ml saturated sodium bicarbonate solution for about 15 minutes.
The organic layer was separated and dried over anhydrous potas-sium carbonate. The solution, containing the 13~,17~-epoxide, li3~81Z
was filtered and mixed with 1 ml boron trifluoride etherate.
After shaking vigorously for 1 minute, the red reaction mixture was washed with 25 ml 10% potassium carbonate solution. The organic layer was separated and dried over anhydrous potassium carbonate. Evaporation to dryness yielded 190 mg residue, which was purified by chromatography on 10 g silica gel with hexane/
ethyl acetate 9:1, followed by 8:2. In this way, 90 mg of pure product was obtained; oil NMR (in CDC13): o 1.12 (s, 13-CH3), 3.73 (s, CH30), 4.35 (q, ll~-H), 4.30 and 4.60 (2 x d, J = J =
10 ArCH20 ) Example IV: (a) Preparation of dl-(E)-l-(m-methoxyphenyl)-8,11-bis-(1,3-propylene-dithio)-3-undecen-5-ol, 5-methyl ether (formula VIIb, R2 = H, R~ = methyl, R5 = methoxy, Xl = ~2-Propylene-dithio ,.
1.00 g (20.8 mmol) sodium hydride (50% suspension in oil was added under nitrogen to a solution of 4.24 g (8.7 mmol) dl-(E)-l-m-methoxyphenyl)-8,11-bis-(propylene-dithio)-3-undecen-
5-ol in about 15 ml tetrahydrofuran and 50 ml dimethyl sulphox-ide. After stirring for about 5 minutes at room temperature 1.00 ml (15.5 mmol) methyl iodide was added. The reaction mixture was stirred for a further about 60 minutes at room temperature after which it was poured into 500 ml ice-water and extracted with methylene chloride. The methylene chloride layers were washed with water. After drying over sodium sulphate, the methylene chloride solution was evaporated to dryness under reduced press-ure. Yield: 4.5 g product.
(b) dl-2-~(E)-6'-m-methoxyPhenyl)-2'-methoxy-3'-hexenyll-2-cyclo-pentenone (Step (c) + Step (d)).
In an exact way analogous to that described in example I(f), 4.5 9 dl-(E)-l-(_-methoxyphenyl)-8,11-bis-(1,3-propylene-dithio)-3-undecen-5-ol 5-methyl ether was converted into 0.4 g product.
1~348:12 (c) Step (e) dl-l-methyl-2-[(E)-6'-(m-methoxyphenyl)-2'-methoxy-3'-hexenyl~-2-cyclopentenol (formula I, R1 = methyl, R2 = H, R3 = OH, R~_= methyl, R5 _ methoxy).
In an exact way analogous to that described in example I(g), 0.4 g dl-(E)-l-(_-methoxyphenyl)-8,11-bis-(1,3-propylene-dithio)-3-undecen-5-ol 5-methyl ether was converted into 0.4 g product (oil). NMR (in CDC13 + C5D5~): S 1.25 and 1.29 (s, CH3 at C-1), 3.16 (s, aliphatic CH30) 3.75 (s, aromatic CH30), 3.65 (m, H-C-OCH3), 5.1-5.8 (m, olefinic protons).
Example V: Cyclisation (Step (f)) Preparation of dl-3, 11~-dimethoxy-17-methyl-~ 1,3,5(10),13(17)_ qonatetraene (formula II R~ = methyl, R5 = methoxy, R7 = methyl).
In an exact way analogous to that described in example II, 0.4 g dl-1-methyl-2-~(E)-6'-(_ -methoxyphenyl)-2'-methoxy-3'-hexenyl]-2-cyclopentenol was cyclised to 0.2 g product (oil).
NMR (in CDC13): ~ 1.62 (s, 17-CH3), 3.20 (s, 11~-OCH3), 3.75 (3-OCH3), 4.15 (q, lla-h).
Examp]e VI
(a) dl-3-methyl-2-[6-(m-methoxyphenyl)-2-hydroxy-3-hexynyl]-2-cyclopentenone A solution of 10.00 g (33.6 mmol) dl-l-(m-methoxyphen-yl)-7-(5-methyl-2-furyl)-3-heptyn-5-ol in 20 ml acetic acid, a-bout 10 ml water and 0.40 ml about 20% sulphuric acid was stirred under nitrogen in an oil-bath at 90C for about 24 hours. After cooling, the mixture was poured into 200 ml water and extracted with methylene chloride. The methylene chloride layer was washed with water and evaporated to dryness under reduced pressure. The residue (10.60 g) was dissolved in 500 ml of about O.lN ethanolic potassium hydroxide solution and stirred under nitrogen in an oil-bath at about 80C for about 1 hour. After cooling, the mixture . . .
, ~13'~81Z
was poured into 1000 ml water and extracted with methylene chlor- !
ide. The methylene chloride layer was washed with water and evaporated to dryness under reduced pressure. Yield: 9.85 g.
_ (b) dl-3-methyl-2-[6-(m-methoxyphenyl)-2-hydroxy-3-hexynyll-2-cyclopentenone ethylene dithioketal A solution of about 9.85 g (33 mmol) dl-3-methyl-2-[6-(m-methoxyphenyl)-2-hydroxy-3-hexynyl]-2-cyclopentenone in about 50 ml methanol, about 1.50 ml boron trifluoride etherate and about 5.0 ml ethane-dithiol was refluxed under nitrogen for about 3 hours. After cooling, the reaction mixture was poured into about 500 ml water and extracted with methylen~ chloride.
The methylene chloride layer was washed with water and evaporated to dryness under reduced pressure. The residue was filtered through 130 g neutral washed aluminium oxide with hexane/methyl-ene chloride 9:1 (700 ml), giving 9.20 g product.
(c) dl-3-methyl-2-[(E)-6-(m-methoxyphenyl)-2-benzyloxy-3-hexenyll-2-cyclopentenone ethylene dithioketal.
A solution of about 9.20 g (24.6 mmol) dl-3-methyl-2-[6-(m-methoxy-phenyl)-2-hydroxy-3-hexynyl]-2-cyclopentenone ethyl-ene dithioketal in 53 ml tetrahydrofuran was added dropwise overa period of about 20 minutes to a suspension of 1.86 g (40 mmol) lithium aluminium hydride in about 80 ml tetrahydrofuran under a nitrogen atmosphere. The mixture was stirred in a water bath at about 60C for about 4 hours. After cooling to about 0C, the following consecutive dropwise additions were cautiously made to the suspension: 1.86 ml water, 1.86 ml 15% sodium hydroxide solu-tion and 5.50 ml water. Sodium sulphate (5 g) was added and the whole was filtered. The filtrate was evaporated to dryness under reduced pressure and the residue (7.35 g) was dissolved in about 100 ml tetrahydrofuran. The following consecutive additions were made to this solution under nitrogen: 20.0 g (370 mmol) powdered potassium hydroxide and 20.0 ml (214 mmol) benzyl chloride. The ~3~81Z
whole was then stirred for about 16 hours at room temperature.
After filtering, the filtrate was evaporated to dryness under reduced preqsure. The residue was filtered through about 100 g silica gel with hexane/acetone 9:1 by weight (500 ml) giving 8.70 g product.
(d) dl-3-methyl-2-[(E)-6-(m-methoxyphenyl-2-benzyl-oxy-3-hexenyl~-2-cyclopentenone (formula IX, R2 = CH3~, R~ = ~enzyl, R5 = methoxy) About 10.0 (100 ml) calcium carbonate was added under nitrogen to a solution of 8.70 g (18.6 mmol) dl-3-methyl-2-[(E)-
(b) dl-2-~(E)-6'-m-methoxyPhenyl)-2'-methoxy-3'-hexenyll-2-cyclo-pentenone (Step (c) + Step (d)).
In an exact way analogous to that described in example I(f), 4.5 9 dl-(E)-l-(_-methoxyphenyl)-8,11-bis-(1,3-propylene-dithio)-3-undecen-5-ol 5-methyl ether was converted into 0.4 g product.
1~348:12 (c) Step (e) dl-l-methyl-2-[(E)-6'-(m-methoxyphenyl)-2'-methoxy-3'-hexenyl~-2-cyclopentenol (formula I, R1 = methyl, R2 = H, R3 = OH, R~_= methyl, R5 _ methoxy).
In an exact way analogous to that described in example I(g), 0.4 g dl-(E)-l-(_-methoxyphenyl)-8,11-bis-(1,3-propylene-dithio)-3-undecen-5-ol 5-methyl ether was converted into 0.4 g product (oil). NMR (in CDC13 + C5D5~): S 1.25 and 1.29 (s, CH3 at C-1), 3.16 (s, aliphatic CH30) 3.75 (s, aromatic CH30), 3.65 (m, H-C-OCH3), 5.1-5.8 (m, olefinic protons).
Example V: Cyclisation (Step (f)) Preparation of dl-3, 11~-dimethoxy-17-methyl-~ 1,3,5(10),13(17)_ qonatetraene (formula II R~ = methyl, R5 = methoxy, R7 = methyl).
In an exact way analogous to that described in example II, 0.4 g dl-1-methyl-2-~(E)-6'-(_ -methoxyphenyl)-2'-methoxy-3'-hexenyl]-2-cyclopentenol was cyclised to 0.2 g product (oil).
NMR (in CDC13): ~ 1.62 (s, 17-CH3), 3.20 (s, 11~-OCH3), 3.75 (3-OCH3), 4.15 (q, lla-h).
Examp]e VI
(a) dl-3-methyl-2-[6-(m-methoxyphenyl)-2-hydroxy-3-hexynyl]-2-cyclopentenone A solution of 10.00 g (33.6 mmol) dl-l-(m-methoxyphen-yl)-7-(5-methyl-2-furyl)-3-heptyn-5-ol in 20 ml acetic acid, a-bout 10 ml water and 0.40 ml about 20% sulphuric acid was stirred under nitrogen in an oil-bath at 90C for about 24 hours. After cooling, the mixture was poured into 200 ml water and extracted with methylene chloride. The methylene chloride layer was washed with water and evaporated to dryness under reduced pressure. The residue (10.60 g) was dissolved in 500 ml of about O.lN ethanolic potassium hydroxide solution and stirred under nitrogen in an oil-bath at about 80C for about 1 hour. After cooling, the mixture . . .
, ~13'~81Z
was poured into 1000 ml water and extracted with methylene chlor- !
ide. The methylene chloride layer was washed with water and evaporated to dryness under reduced pressure. Yield: 9.85 g.
_ (b) dl-3-methyl-2-[6-(m-methoxyphenyl)-2-hydroxy-3-hexynyll-2-cyclopentenone ethylene dithioketal A solution of about 9.85 g (33 mmol) dl-3-methyl-2-[6-(m-methoxyphenyl)-2-hydroxy-3-hexynyl]-2-cyclopentenone in about 50 ml methanol, about 1.50 ml boron trifluoride etherate and about 5.0 ml ethane-dithiol was refluxed under nitrogen for about 3 hours. After cooling, the reaction mixture was poured into about 500 ml water and extracted with methylen~ chloride.
The methylene chloride layer was washed with water and evaporated to dryness under reduced pressure. The residue was filtered through 130 g neutral washed aluminium oxide with hexane/methyl-ene chloride 9:1 (700 ml), giving 9.20 g product.
(c) dl-3-methyl-2-[(E)-6-(m-methoxyphenyl)-2-benzyloxy-3-hexenyll-2-cyclopentenone ethylene dithioketal.
A solution of about 9.20 g (24.6 mmol) dl-3-methyl-2-[6-(m-methoxy-phenyl)-2-hydroxy-3-hexynyl]-2-cyclopentenone ethyl-ene dithioketal in 53 ml tetrahydrofuran was added dropwise overa period of about 20 minutes to a suspension of 1.86 g (40 mmol) lithium aluminium hydride in about 80 ml tetrahydrofuran under a nitrogen atmosphere. The mixture was stirred in a water bath at about 60C for about 4 hours. After cooling to about 0C, the following consecutive dropwise additions were cautiously made to the suspension: 1.86 ml water, 1.86 ml 15% sodium hydroxide solu-tion and 5.50 ml water. Sodium sulphate (5 g) was added and the whole was filtered. The filtrate was evaporated to dryness under reduced pressure and the residue (7.35 g) was dissolved in about 100 ml tetrahydrofuran. The following consecutive additions were made to this solution under nitrogen: 20.0 g (370 mmol) powdered potassium hydroxide and 20.0 ml (214 mmol) benzyl chloride. The ~3~81Z
whole was then stirred for about 16 hours at room temperature.
After filtering, the filtrate was evaporated to dryness under reduced preqsure. The residue was filtered through about 100 g silica gel with hexane/acetone 9:1 by weight (500 ml) giving 8.70 g product.
(d) dl-3-methyl-2-[(E)-6-(m-methoxyphenyl-2-benzyl-oxy-3-hexenyl~-2-cyclopentenone (formula IX, R2 = CH3~, R~ = ~enzyl, R5 = methoxy) About 10.0 (100 ml) calcium carbonate was added under nitrogen to a solution of 8.70 g (18.6 mmol) dl-3-methyl-2-[(E)-
6-(m-methoxyphenyl)-2-benzyloxy-3-hexenyl]-2-cyclopentenone ethyl-ene dithioketal in about 100 ml methyl cyanide/water 4:1 by weight. About 12.5 ml (200 mmol) methyl iodide was then added dropwise with vigorous stirring during a period of about 1 hour and the whole was stirred for a further about 5 hours in a water-bath at about 50C. After filtering, the filtrate was poured in-to about 500 ml water and extracted with methylene chloride. The methylene chloride layer was washed with water and evaporated to dryness under reduced pressure. The residue was filtered through 90 g silica gel with hexane/ethyl acetate 95:5 by weight (500 ml), giving 3.60 g product.
Example VII
dl-3-methoxy~ -benzyloxy-17-methyl- ~1'3'5(10)'13(17)-qonate-traene (formula II, R~ = benzyl, R5 = methoxy, R = methvl) ;~ A solution of dl-3-methyl-2-[(E)-6-(m-methoxyphenyl)-2-benzyloxy-3-hexenyl~-2-cyclopentenone of Example VI (1.50 g, 3.86 mmol) in 15 ml ether was added dropwise over a period of about 15 minutes to a suspension of 0.37 g (9.7 mmol) lithium aluminium hydride in about 30 ml ether at about -5C under nitro-gen. The mixture was stirred for a further about 30 minutes at about 0C. The following consecutive dropwise additions were ~ ~ ! - 26 -~13~2 then cautiously made: about 0.37 ml water, 0.37 ml 15% sodium hydroxide solution and about 1.10 ml water. Sodium sulphate (1 g) was added and the suspension was filtered. The filtrate was evaporated to dryness under reduced pressure. The residue (1.50 g) was dissolved in 4.5 ml methylene chloride and added dropwise over a period of 30 minutes to a solution of 1.36 ml (12 mmol) stannic chloride in 13 ml methylene chloride at about -75C un-der nitrogen. The whole was stirred for a further about 30 min-utes at about -75C. 20 ml 20% methanolic potassium hydroxide 10 was then added dropwise to the reaction mixture during an approx-imate 15 minute period. The reaction mixture was poured into approximately 100 ml water and extracted with methylene chloride.
The methylene chloride layers were washed with water and evap-orated to dryness under reduced pressure. The residue (1.40 g) was chromatographed on 45 g silica gel with hexane/ethylacetate 95:5 ~200 ml), giving 0.43 g product, which was identical with the product of Example II.
Example VIII
dl-3-methoxy-11~-benzyloxv-17-ethyl /'\ 1'3'5(10)'13(17)-gonatetra-20 ene (formula II, R~ = benzyl, R5 = methoxy, R7 = ethvl).
Dl-2-[(E)-6-(m -methoxyphenyl-2-benzyloxy-3-hexenyl~-2-cyclopentone was converted with ethyl-lithium into dl-l-ethyl-2-[(E)-6-(_-methoxy-phenyl)-2-benzyloxy-3-hexenyl]-2-cyclopentenol in the exact way described in example I(g).
A solution of 0.30 g (0.74 mmol) dl-1-ethyl-2-[(E)-6-(m-methoxyphenyl)-2-benzyloxy-3-hexenyl]-2-cyclopentenol in 3 ml nitro-ethane was added dropwise over a period of about 10 minutes to a solution of 0.34 g (1.5 mmol) zinc bromide in 15 ml nitro-30 ethane at about -20C under nitrogen. The reaction mixture was stirred at about -20C for a further approximately 3 hours after which about 30 ml 10,~ sodium hydroxide solution was added. The reaction mixture was poured into 50 ml water and extracted with . ~
, 113~31Z
methylene chloride. The methylene chloride layer was washed with water and evaporated to dryness under reduced pressure. The residue was filtered through 9 g silica gel with hexane/ethyl acetate 95:5 (20 ml), giving 140 mg product. M.p. 90-92C.
Example IX
(a) 4,7-bis-ethylene-dithio heptanoic acid n-propyl ester (precursor of compound V) A solution of 12.0 g (80 mmol) of 3,2-furoyl propienic acid, 20 ml (22.4 g, 0.24 mol) ethane dithiol and ~0 ml borol trifluoride etherate in 160 ml n-propanol was refluxed for about 22 hours. The reaction mixture was cooled, diluted with ether, and washed with 2N sodium hydroxide solution. The organic layer was dried on water free potassium carbonate and evaporated to dryness. The residue was chromatographed through 400 g silica gel with hexane/ethyl acetate 8:2, giving 22.5 g product (colorless oil).
(b~ 4,7-bis-ethYlene-dithio-hePtanal (formula V, R~ = H, Xl = X =
ethvlene-dithio).
A solution of the n-propyl ester of Example IX(a) (21.1 g, 60 mmol) in 120 ml dry toluene was cooled to -78C under ni-trogen. While stirring, 50 ml 1.2 M diisobutyl aluminium hydride in toluene was added dropwise in about 30 minutes. 10 Minutes later, 10 ml water was added. The reaction mixture was brought to room temperature and filtered through HYFL0*. The filtrate was dried on watex-free sodium sulfate and evaporated to dryness.
The residue was chromatographed through 200 g silica gel with hexane/ethyl acetate 8:2, giving 13.4 g product (colorless oil);
(c) SteP (a) dl-l-(m-methoxyphenyl-8,11-bis-(ethylene-dithio)-3-undecyn-5-ol (formula VI, R = H; R = methoxy, Xl = X2 = ethylene-dithio) A solution of 8.0 g (50 mmol) 4-(m-methoxyphenyl)-1-butyne was cooled to about 10C under nitrogen. A solution of * Trademark 113~81Z
n-butyl-lithium in hexane (1.6 M) was added dropwise until the color changed to a light yellow (about 33 ml). The solution thus obtained was stirred for about 30 minutes at about 0C and was subsequently cooled to about -15C. A solution of 12.8 g (43.6 mmol) 4,7-bis-(ethylene-dithio)-heptanal in 75 ml tetra-hydrofuran was added slowly and the whole was then stirred for about 1 hour at about -10C. The reaction mixture was poured into water and extracted with ether. The extracts were dried over anhydrous sodium sulphate and evaporated to dryness. The residue was chromatographed on 300 g silica gel with hexane/
ethyl acetate 8:2, giving about 17.6 g product.
(d) dl-(E)-l-(m-methoxyPhenyl)-8,11-bis-(ethYlene-dithio) -3-undecen-5-ol (formula VIIa, R2 ~ H; R5 = methoxY; Xl = X2 - ethylene-dithio).
The compound obtained in example IX(c) was reduced in an exact way analogous to that described in example I(d). The product was obtained as a colorless oil in quantitative yield.
(e) dl-(E)-l-(m-methoxYPhenYl)-5-PivalovloxY-8~ll-bi (ethylene-dithio)-3-undecene (formula VIIb, R = H; R = methoxy; X = X = ethvlene-dithio;
_~ = pivalovl) The compound obtained in example IX(d) (18.2 g, 40 mmol) was dissolved in 200 ml dry pyridine. The solution was cooled under a nitrogen atmosphere to about 0C, after which about 10 ml pivaloyl chloride (about 2 eq.) was added dropwise with stirring.
The resultant mixture was stirred for about 2 hours at about 0C
and subsequently for about 16 hours at room temperature, after which water was added and the whole was extracted with ether.
The ether extracts were washed with 2N hydrochloric acid, satu-rated sodium bicarbonate solution, and water, and finally driedover anhydrous MgS04. The solvent was removed by evaporation and the residue was chromatographed on about 300 g silica gel .
~ ~ - 29 -with hexane/ethyl acetate 9:1. 20.1 g product was obtained.
(f) dl-2-r(E)-~-(m-methoxyphenyl)-2-pivaloyloxy-3-h nyll-2-cyclopentenone (formula IX, R2 = H, R1 = pivaloyl, R5 = methoxy) The compound obtained in example IX(e) (4.3 g, 8 mmol) was hydrolysed in a way analogous to that described in example I(f). The crude product was purified by chromatography on 70 g silica gel with he~ane/ethyl acetate 8:2. The keto-aldehyde (1.74 g) obtained in this way was dissolved in 175 ml 96% ethanol and mixed with 1.75 ml 40% trimethylbenzyl-ammonium hydroxide -("Triton s"*). The mixture was heated at 60C for 30 minutes, cooled, and further worked up as described in example I(f). In this way, 1.40 g product was obtained in the form of a light yellow oil.
(g) dl-l-methYl-2-~(E)-6-(m-methoxy~henvl)-2-pivaloyl-oxy-3-hexenyl]-2-cvcloPentenol (formula I, Rl = methyl: R2 = H, R3 = OH, R~_- Pivaloyl, R5 _ methoxY ) The compound obtained in example IX(f) (1.40 g, 3.8 mmol) was dissolved in about 70 ml dry ether. The solution was cooled under nitrogen to about -70C after which 1.9 ml 2 M
methyl-lithium (3.8 mM) in ether was added dropwise. The reac-tion mixture was stirred for 30 minutes at about -70C and then poured into water. The organic layer was separated and dried over anhydrous sodium sulphate. Removal of solvent by evapora-tion gave 1.44 g product (oil). NMR (in CDC13 + C5D5N), ~ 1.13 (s, t-C4H~COO), 1.25 and 1.29 (s, CH3 at C-l), 3.75 (s, CH30), 5.1-5.8 (m, olefinic protons + H-C-O).
Example X: Cyclisation dl-3-methoxY-llB-PivaloYloxy-l7-methyl-~l~3J5(lo)~
13(17)-qonatetraene (formula II, R5 = methoxy, R4 = pivaloyl, R7 = methyl) * Trademark `, ~3~81Z
The product from Example IX (g) (1.44 g, 3.7 mmol) was cyclised in a way analogous to that described in Example II. The crude product was purified by chromatography on 40 g silica gel with hexane/ethyl acetate 9:1. In this way, 0.69 g pure product was obtained. M.p. 91-92C.
Example XI
dl-3,11~-dihydroxy ~ 1~3'5'(1)-oestratriene-17-one-3-methyl ether The product of Example X (0.69 g, 1.9 mmol) was con-verted in the corresponding 13~,17~-epoxide in an exact way anal-10 ogous to that described in Example III. The epoxide (m.p. 101- 4 105C) was treated with lithium aluminium hydride (0.07 g, 1.9 mmol) at -40C to convert the pivaloyloxy group into a hemi-- acetal group. The product thus obtained (m.p. 152C) was reacted with boron trifluoride etherate in toluene, exactly as described in Example III. Chromatographic purification gave 0.20 g pro-duct, m.p. 95-100C.
Example XII
(a) dl-(E)-l-(m-methoxyphenyl)-8,11-bis-(ethylene-dithio) -3-undecen-5-ol-5-benzoate 20 (formula VIIb, R2 = H; R5 = methoxy, Xl = X2 = ethylene-dithio, R~ = benzoyl).
In an exact way analogous to that described in Example IX (e), 2.3 g dl-(E)-l-(m-methoxyphenyl)-8,11-bis-(ethylene- di-thio)-3-undecen-5-ol was reacted with 1.3 ml benzoyl chloride to give the desired product (2.57 g).
(b) dl-2-[(E)-6-(m-methoxyphenyl)-2-benzoyloxy-3-hexen-yll-2-cyclopentenone (formula IX, R2 = H, R4 = benzoyl, R5 = methoxy) The product from Example XII(a) (2.57 g, 4.6 mmol) was 30 stripped of the thioketal group in a way analogous to that de-scribed in example I(f). The resultant keto-aldehyde (1.0 g) was cyclodehydrated in an exact way analogous to that of Example ' ~
~13~
IX(f), giving 0.66 g of the desired product.
_ (c) dl-l-methyl-2-t(E)-6-(m-methoxyphenyl)-2-benzoyl-oxy-3-hexenyll-2-cyclopentenol (formula I, Rl = methyl, R2 = H, R3 = OH, R~ = benzoYl, R5_ meth xy~
The product from Example XII(b) (0.66 g, 1.7 mmol) was converted into the desired product in quantitative yield in an exact way analogous to that of Example IX(g) (oil), NMR (in CDC13 ~ C5D5N): ~ 1.32 (s, CH3 at C-l), 3.78 (s, CH30) 5.3-6.0 (m, olefinic protons + H-C-O).
Example XIII
dl-3-methoxy~ benzoyloxy-17-methyl-~ 1~3'5(10)'13(17)-qonate-traene (formula II, R1 = benzoyl, R5 = methoxy; R7 = methyl) The product from Example XII(c) (0.68 g, 1.67 mmol) was cyclised in a way analogous to that of Example II. The crude product was purified by chromatography on 20 g silica gel with hexane/ethyl acetate 9:1, giving 169 mg pure product, melting point 133C (decomposition).
Example XIV
(a~ dl-(E)-l-(m-methoxyphenyl)-8,11-bis-(ethylene-dithio)-3-unde-cen-5-ol-5-~-naphthylmethyl ether I (formula VII b, R2 = H, R5 = methoxv: Xl _ 2 = ethylene-dithio, R4 = ~-naphthYlmethyl) A solution of 2.3 g (5 mmol) dl-(E)-l-(m-methoxyphenyl)-8,11-bis-(ethylene-dithio)-3-undecen-5-ol in 10 ml dry tetra-hydrofuran was mixed with 1 ml hexamethylphosphoric acid triamide and 0.48 g sodium hydride (50% suspension in mineral oil, 10 m-mol). The mixture was heated at about 50C for about 30 minutes, after which 1.77 g (10 mmol) ~-choromethyl-naphthalene was added dropwise. The mixture was stirred for about 4 hours at about 50C, after which waterand ether were added. The organic layer :!
11~481Z
was separated, dried over anhydrous sodium sulphate and evaporat-ed to dryness. The residue was chromatographed on 40 g silica gel with hexane/ethyl acetate about 9:1 by weight. 2.58 g pro-duct was obtained in the form of a colorless oil.
(b) dl-2-[(E)-6-(m-methoxyphenyl)-2-~-naphthylmethyloxy)-3-hexen-yll-2-cvclopentenone (formula IX, R2 = H, R4 = ~-naphthylmethyl, R5 = methoxy) The thioketal group in the product from Example XIV(a) (2.58 g, 4.3 mmol) was removed in an exact way analogous to that described in Example I(f). The resultant keto-aldehyde (1.06 g) was cyclo-dehydrated in a way analogous to that of Example IX(f), giving 0.60 g pure product.
(c) dl-l-methyl-2-[(E)-6-(m-methoxyphenyl-2-(~-naphthylmethyloxy)-3-hexenyll-2-cyclopentenol (formula I, Rl = methyl, R2 = E~, R3 = OH, R,l =a-naphthylmethyl;
R5 = methoxv The compound immediately preceding (0.60 g, 1.4 mmol~
was converted into the desired product (0.63 g) in an exact way -analogous to that of Example IX(g). Oil, NMR (in CDC13 + C5D51ir):
~ 1.15 and 1.22 (s, CH3 at C-l), 3.66 (s, CH30), 3.92 (m, H-C-O), 4.75 (q, J=12, ArCH20), 5.2-5. (m, olefinic protons).
Example XV
dl-3-methoxy-11~ naPhthYlmethyloxy-17-methyl- ~1~3~4(10)~13(17)_ qonatetraene (formula II, R1 = ~-naphthylmethyl, R5 = methoxy, R7 = methyl) The product from Example XIV(c) (0.63 g, 1.4 mmol) was cyclised in an exact way analogous to that of Example II. The desired product was isolated by chromatography on silica gel with hexane/ethyl acetate 99:1. Yield: 180 mg oil, NMR (in CDC13):
30 1.6 (s, 17-CH3), 3.73 (s, CH30), 4.70 and 4.95 (2 x d, J = 12, ArCH20) 4.43 (q, J=2, 11~ H).
~ - 33 -~34191Z
Example XVI
dl-l-methyl-2-[(E)-6-(m-methoxyphenyl)-2-trimethylsilyloxy-3-hexenvll-2-cyclopentenol (formula I, Rl - methyl, R2 = H; R3 = OH, R~ = trimethylsilyl;
R5 - methoxy) Starting from dl-(E)-l-(m-methoxyphenyl)-8,11-bis-(ethylene-dithio)-3-undecen-5-ol and trimethylsilyl chloride, the title cyclopentenol was prepared in an exact way analogous to that described in Example XIV.
Example XVII
dl-3-methoxy-11~-trimethylsilyloxy-17-methyl-~ 1,3,5(10),13(17)_ qonatetraene (formula II, R~ = trimethylsilyl; R5 = methoxy; R7 - methyl) The product from Example XVI was cyclised to the title gonatetraene in an exact way analogous to that described in Ex-ample II.
Example XVIII
l dl-l-methYl-2-[~E)-6-(m-methoxYPhenYl)-2-(p-PhenYl-benzYloxY)-3-hexenyll-2-cyclopentenol (formula I, Rl = methyl; R2 = H; R~ = OH; R~ = p-phenylbenzyl;
R5 = methoxy Starting from dl-(E)-l-(m-methoxyphenyl)-8,11-bis-(ethylene-dithio)-3-undecen-5-ol and p-phenylbenzyl chloride, the desired cyclopentenol (I) was obtained in an exact way analogous to that-described in Example XIV. Oil, NMR (in CDC13 + C5D5N) ~.25 and 1.30 (s, CH3 at C-l), 3.76 (s, CH30), 3.83 (m, H-C-O), 4.25 and 4.48 (2 x d, J = 12, ArCH20), 5.2-5.9 (m, olefinic pro-tons).
Example XIX
dl-3-methoxY-ll~-p-~henylbenzyloxy-17-methyl-~ 1,3,5(10),13(17)_ aonatetraene (formula II, R~ = p-Phenylbenzyl; R5 = methoxy, R7 = methyl) The product from Example XVIII was cyclised to the title 113~81Z
gonatetraene in a way analogous to that of Example II.
Oil, NMR (in CDC13): ~ 1.65 (s, 17-CH3), 3.74 (s, CH30), 4.40 (q, J=2, ll~H), 4.40 and 4.56 (2 x d, J=12, ArCH20).
It should be noted that the ll~-substituted 17-alkyl-a l'3'5(10)'13(17)-gonatetraenes obtained in the cyclisation and the 13~,17~-epoxy derivatives thereof are novel compounds. These compounds have hormonal properties and are furthermore of impor-tance for the synthesis of known ll~-substituted steroids.
This application is a division of application Serial No. 314,202 which was filed on October 25, 1978.
Example VII
dl-3-methoxy~ -benzyloxy-17-methyl- ~1'3'5(10)'13(17)-qonate-traene (formula II, R~ = benzyl, R5 = methoxy, R = methvl) ;~ A solution of dl-3-methyl-2-[(E)-6-(m-methoxyphenyl)-2-benzyloxy-3-hexenyl~-2-cyclopentenone of Example VI (1.50 g, 3.86 mmol) in 15 ml ether was added dropwise over a period of about 15 minutes to a suspension of 0.37 g (9.7 mmol) lithium aluminium hydride in about 30 ml ether at about -5C under nitro-gen. The mixture was stirred for a further about 30 minutes at about 0C. The following consecutive dropwise additions were ~ ~ ! - 26 -~13~2 then cautiously made: about 0.37 ml water, 0.37 ml 15% sodium hydroxide solution and about 1.10 ml water. Sodium sulphate (1 g) was added and the suspension was filtered. The filtrate was evaporated to dryness under reduced pressure. The residue (1.50 g) was dissolved in 4.5 ml methylene chloride and added dropwise over a period of 30 minutes to a solution of 1.36 ml (12 mmol) stannic chloride in 13 ml methylene chloride at about -75C un-der nitrogen. The whole was stirred for a further about 30 min-utes at about -75C. 20 ml 20% methanolic potassium hydroxide 10 was then added dropwise to the reaction mixture during an approx-imate 15 minute period. The reaction mixture was poured into approximately 100 ml water and extracted with methylene chloride.
The methylene chloride layers were washed with water and evap-orated to dryness under reduced pressure. The residue (1.40 g) was chromatographed on 45 g silica gel with hexane/ethylacetate 95:5 ~200 ml), giving 0.43 g product, which was identical with the product of Example II.
Example VIII
dl-3-methoxy-11~-benzyloxv-17-ethyl /'\ 1'3'5(10)'13(17)-gonatetra-20 ene (formula II, R~ = benzyl, R5 = methoxy, R7 = ethvl).
Dl-2-[(E)-6-(m -methoxyphenyl-2-benzyloxy-3-hexenyl~-2-cyclopentone was converted with ethyl-lithium into dl-l-ethyl-2-[(E)-6-(_-methoxy-phenyl)-2-benzyloxy-3-hexenyl]-2-cyclopentenol in the exact way described in example I(g).
A solution of 0.30 g (0.74 mmol) dl-1-ethyl-2-[(E)-6-(m-methoxyphenyl)-2-benzyloxy-3-hexenyl]-2-cyclopentenol in 3 ml nitro-ethane was added dropwise over a period of about 10 minutes to a solution of 0.34 g (1.5 mmol) zinc bromide in 15 ml nitro-30 ethane at about -20C under nitrogen. The reaction mixture was stirred at about -20C for a further approximately 3 hours after which about 30 ml 10,~ sodium hydroxide solution was added. The reaction mixture was poured into 50 ml water and extracted with . ~
, 113~31Z
methylene chloride. The methylene chloride layer was washed with water and evaporated to dryness under reduced pressure. The residue was filtered through 9 g silica gel with hexane/ethyl acetate 95:5 (20 ml), giving 140 mg product. M.p. 90-92C.
Example IX
(a) 4,7-bis-ethylene-dithio heptanoic acid n-propyl ester (precursor of compound V) A solution of 12.0 g (80 mmol) of 3,2-furoyl propienic acid, 20 ml (22.4 g, 0.24 mol) ethane dithiol and ~0 ml borol trifluoride etherate in 160 ml n-propanol was refluxed for about 22 hours. The reaction mixture was cooled, diluted with ether, and washed with 2N sodium hydroxide solution. The organic layer was dried on water free potassium carbonate and evaporated to dryness. The residue was chromatographed through 400 g silica gel with hexane/ethyl acetate 8:2, giving 22.5 g product (colorless oil).
(b~ 4,7-bis-ethYlene-dithio-hePtanal (formula V, R~ = H, Xl = X =
ethvlene-dithio).
A solution of the n-propyl ester of Example IX(a) (21.1 g, 60 mmol) in 120 ml dry toluene was cooled to -78C under ni-trogen. While stirring, 50 ml 1.2 M diisobutyl aluminium hydride in toluene was added dropwise in about 30 minutes. 10 Minutes later, 10 ml water was added. The reaction mixture was brought to room temperature and filtered through HYFL0*. The filtrate was dried on watex-free sodium sulfate and evaporated to dryness.
The residue was chromatographed through 200 g silica gel with hexane/ethyl acetate 8:2, giving 13.4 g product (colorless oil);
(c) SteP (a) dl-l-(m-methoxyphenyl-8,11-bis-(ethylene-dithio)-3-undecyn-5-ol (formula VI, R = H; R = methoxy, Xl = X2 = ethylene-dithio) A solution of 8.0 g (50 mmol) 4-(m-methoxyphenyl)-1-butyne was cooled to about 10C under nitrogen. A solution of * Trademark 113~81Z
n-butyl-lithium in hexane (1.6 M) was added dropwise until the color changed to a light yellow (about 33 ml). The solution thus obtained was stirred for about 30 minutes at about 0C and was subsequently cooled to about -15C. A solution of 12.8 g (43.6 mmol) 4,7-bis-(ethylene-dithio)-heptanal in 75 ml tetra-hydrofuran was added slowly and the whole was then stirred for about 1 hour at about -10C. The reaction mixture was poured into water and extracted with ether. The extracts were dried over anhydrous sodium sulphate and evaporated to dryness. The residue was chromatographed on 300 g silica gel with hexane/
ethyl acetate 8:2, giving about 17.6 g product.
(d) dl-(E)-l-(m-methoxyPhenyl)-8,11-bis-(ethYlene-dithio) -3-undecen-5-ol (formula VIIa, R2 ~ H; R5 = methoxY; Xl = X2 - ethylene-dithio).
The compound obtained in example IX(c) was reduced in an exact way analogous to that described in example I(d). The product was obtained as a colorless oil in quantitative yield.
(e) dl-(E)-l-(m-methoxYPhenYl)-5-PivalovloxY-8~ll-bi (ethylene-dithio)-3-undecene (formula VIIb, R = H; R = methoxy; X = X = ethvlene-dithio;
_~ = pivalovl) The compound obtained in example IX(d) (18.2 g, 40 mmol) was dissolved in 200 ml dry pyridine. The solution was cooled under a nitrogen atmosphere to about 0C, after which about 10 ml pivaloyl chloride (about 2 eq.) was added dropwise with stirring.
The resultant mixture was stirred for about 2 hours at about 0C
and subsequently for about 16 hours at room temperature, after which water was added and the whole was extracted with ether.
The ether extracts were washed with 2N hydrochloric acid, satu-rated sodium bicarbonate solution, and water, and finally driedover anhydrous MgS04. The solvent was removed by evaporation and the residue was chromatographed on about 300 g silica gel .
~ ~ - 29 -with hexane/ethyl acetate 9:1. 20.1 g product was obtained.
(f) dl-2-r(E)-~-(m-methoxyphenyl)-2-pivaloyloxy-3-h nyll-2-cyclopentenone (formula IX, R2 = H, R1 = pivaloyl, R5 = methoxy) The compound obtained in example IX(e) (4.3 g, 8 mmol) was hydrolysed in a way analogous to that described in example I(f). The crude product was purified by chromatography on 70 g silica gel with he~ane/ethyl acetate 8:2. The keto-aldehyde (1.74 g) obtained in this way was dissolved in 175 ml 96% ethanol and mixed with 1.75 ml 40% trimethylbenzyl-ammonium hydroxide -("Triton s"*). The mixture was heated at 60C for 30 minutes, cooled, and further worked up as described in example I(f). In this way, 1.40 g product was obtained in the form of a light yellow oil.
(g) dl-l-methYl-2-~(E)-6-(m-methoxy~henvl)-2-pivaloyl-oxy-3-hexenyl]-2-cvcloPentenol (formula I, Rl = methyl: R2 = H, R3 = OH, R~_- Pivaloyl, R5 _ methoxY ) The compound obtained in example IX(f) (1.40 g, 3.8 mmol) was dissolved in about 70 ml dry ether. The solution was cooled under nitrogen to about -70C after which 1.9 ml 2 M
methyl-lithium (3.8 mM) in ether was added dropwise. The reac-tion mixture was stirred for 30 minutes at about -70C and then poured into water. The organic layer was separated and dried over anhydrous sodium sulphate. Removal of solvent by evapora-tion gave 1.44 g product (oil). NMR (in CDC13 + C5D5N), ~ 1.13 (s, t-C4H~COO), 1.25 and 1.29 (s, CH3 at C-l), 3.75 (s, CH30), 5.1-5.8 (m, olefinic protons + H-C-O).
Example X: Cyclisation dl-3-methoxY-llB-PivaloYloxy-l7-methyl-~l~3J5(lo)~
13(17)-qonatetraene (formula II, R5 = methoxy, R4 = pivaloyl, R7 = methyl) * Trademark `, ~3~81Z
The product from Example IX (g) (1.44 g, 3.7 mmol) was cyclised in a way analogous to that described in Example II. The crude product was purified by chromatography on 40 g silica gel with hexane/ethyl acetate 9:1. In this way, 0.69 g pure product was obtained. M.p. 91-92C.
Example XI
dl-3,11~-dihydroxy ~ 1~3'5'(1)-oestratriene-17-one-3-methyl ether The product of Example X (0.69 g, 1.9 mmol) was con-verted in the corresponding 13~,17~-epoxide in an exact way anal-10 ogous to that described in Example III. The epoxide (m.p. 101- 4 105C) was treated with lithium aluminium hydride (0.07 g, 1.9 mmol) at -40C to convert the pivaloyloxy group into a hemi-- acetal group. The product thus obtained (m.p. 152C) was reacted with boron trifluoride etherate in toluene, exactly as described in Example III. Chromatographic purification gave 0.20 g pro-duct, m.p. 95-100C.
Example XII
(a) dl-(E)-l-(m-methoxyphenyl)-8,11-bis-(ethylene-dithio) -3-undecen-5-ol-5-benzoate 20 (formula VIIb, R2 = H; R5 = methoxy, Xl = X2 = ethylene-dithio, R~ = benzoyl).
In an exact way analogous to that described in Example IX (e), 2.3 g dl-(E)-l-(m-methoxyphenyl)-8,11-bis-(ethylene- di-thio)-3-undecen-5-ol was reacted with 1.3 ml benzoyl chloride to give the desired product (2.57 g).
(b) dl-2-[(E)-6-(m-methoxyphenyl)-2-benzoyloxy-3-hexen-yll-2-cyclopentenone (formula IX, R2 = H, R4 = benzoyl, R5 = methoxy) The product from Example XII(a) (2.57 g, 4.6 mmol) was 30 stripped of the thioketal group in a way analogous to that de-scribed in example I(f). The resultant keto-aldehyde (1.0 g) was cyclodehydrated in an exact way analogous to that of Example ' ~
~13~
IX(f), giving 0.66 g of the desired product.
_ (c) dl-l-methyl-2-t(E)-6-(m-methoxyphenyl)-2-benzoyl-oxy-3-hexenyll-2-cyclopentenol (formula I, Rl = methyl, R2 = H, R3 = OH, R~ = benzoYl, R5_ meth xy~
The product from Example XII(b) (0.66 g, 1.7 mmol) was converted into the desired product in quantitative yield in an exact way analogous to that of Example IX(g) (oil), NMR (in CDC13 ~ C5D5N): ~ 1.32 (s, CH3 at C-l), 3.78 (s, CH30) 5.3-6.0 (m, olefinic protons + H-C-O).
Example XIII
dl-3-methoxy~ benzoyloxy-17-methyl-~ 1~3'5(10)'13(17)-qonate-traene (formula II, R1 = benzoyl, R5 = methoxy; R7 = methyl) The product from Example XII(c) (0.68 g, 1.67 mmol) was cyclised in a way analogous to that of Example II. The crude product was purified by chromatography on 20 g silica gel with hexane/ethyl acetate 9:1, giving 169 mg pure product, melting point 133C (decomposition).
Example XIV
(a~ dl-(E)-l-(m-methoxyphenyl)-8,11-bis-(ethylene-dithio)-3-unde-cen-5-ol-5-~-naphthylmethyl ether I (formula VII b, R2 = H, R5 = methoxv: Xl _ 2 = ethylene-dithio, R4 = ~-naphthYlmethyl) A solution of 2.3 g (5 mmol) dl-(E)-l-(m-methoxyphenyl)-8,11-bis-(ethylene-dithio)-3-undecen-5-ol in 10 ml dry tetra-hydrofuran was mixed with 1 ml hexamethylphosphoric acid triamide and 0.48 g sodium hydride (50% suspension in mineral oil, 10 m-mol). The mixture was heated at about 50C for about 30 minutes, after which 1.77 g (10 mmol) ~-choromethyl-naphthalene was added dropwise. The mixture was stirred for about 4 hours at about 50C, after which waterand ether were added. The organic layer :!
11~481Z
was separated, dried over anhydrous sodium sulphate and evaporat-ed to dryness. The residue was chromatographed on 40 g silica gel with hexane/ethyl acetate about 9:1 by weight. 2.58 g pro-duct was obtained in the form of a colorless oil.
(b) dl-2-[(E)-6-(m-methoxyphenyl)-2-~-naphthylmethyloxy)-3-hexen-yll-2-cvclopentenone (formula IX, R2 = H, R4 = ~-naphthylmethyl, R5 = methoxy) The thioketal group in the product from Example XIV(a) (2.58 g, 4.3 mmol) was removed in an exact way analogous to that described in Example I(f). The resultant keto-aldehyde (1.06 g) was cyclo-dehydrated in a way analogous to that of Example IX(f), giving 0.60 g pure product.
(c) dl-l-methyl-2-[(E)-6-(m-methoxyphenyl-2-(~-naphthylmethyloxy)-3-hexenyll-2-cyclopentenol (formula I, Rl = methyl, R2 = E~, R3 = OH, R,l =a-naphthylmethyl;
R5 = methoxv The compound immediately preceding (0.60 g, 1.4 mmol~
was converted into the desired product (0.63 g) in an exact way -analogous to that of Example IX(g). Oil, NMR (in CDC13 + C5D51ir):
~ 1.15 and 1.22 (s, CH3 at C-l), 3.66 (s, CH30), 3.92 (m, H-C-O), 4.75 (q, J=12, ArCH20), 5.2-5. (m, olefinic protons).
Example XV
dl-3-methoxy-11~ naPhthYlmethyloxy-17-methyl- ~1~3~4(10)~13(17)_ qonatetraene (formula II, R1 = ~-naphthylmethyl, R5 = methoxy, R7 = methyl) The product from Example XIV(c) (0.63 g, 1.4 mmol) was cyclised in an exact way analogous to that of Example II. The desired product was isolated by chromatography on silica gel with hexane/ethyl acetate 99:1. Yield: 180 mg oil, NMR (in CDC13):
30 1.6 (s, 17-CH3), 3.73 (s, CH30), 4.70 and 4.95 (2 x d, J = 12, ArCH20) 4.43 (q, J=2, 11~ H).
~ - 33 -~34191Z
Example XVI
dl-l-methyl-2-[(E)-6-(m-methoxyphenyl)-2-trimethylsilyloxy-3-hexenvll-2-cyclopentenol (formula I, Rl - methyl, R2 = H; R3 = OH, R~ = trimethylsilyl;
R5 - methoxy) Starting from dl-(E)-l-(m-methoxyphenyl)-8,11-bis-(ethylene-dithio)-3-undecen-5-ol and trimethylsilyl chloride, the title cyclopentenol was prepared in an exact way analogous to that described in Example XIV.
Example XVII
dl-3-methoxy-11~-trimethylsilyloxy-17-methyl-~ 1,3,5(10),13(17)_ qonatetraene (formula II, R~ = trimethylsilyl; R5 = methoxy; R7 - methyl) The product from Example XVI was cyclised to the title gonatetraene in an exact way analogous to that described in Ex-ample II.
Example XVIII
l dl-l-methYl-2-[~E)-6-(m-methoxYPhenYl)-2-(p-PhenYl-benzYloxY)-3-hexenyll-2-cyclopentenol (formula I, Rl = methyl; R2 = H; R~ = OH; R~ = p-phenylbenzyl;
R5 = methoxy Starting from dl-(E)-l-(m-methoxyphenyl)-8,11-bis-(ethylene-dithio)-3-undecen-5-ol and p-phenylbenzyl chloride, the desired cyclopentenol (I) was obtained in an exact way analogous to that-described in Example XIV. Oil, NMR (in CDC13 + C5D5N) ~.25 and 1.30 (s, CH3 at C-l), 3.76 (s, CH30), 3.83 (m, H-C-O), 4.25 and 4.48 (2 x d, J = 12, ArCH20), 5.2-5.9 (m, olefinic pro-tons).
Example XIX
dl-3-methoxY-ll~-p-~henylbenzyloxy-17-methyl-~ 1,3,5(10),13(17)_ aonatetraene (formula II, R~ = p-Phenylbenzyl; R5 = methoxy, R7 = methyl) The product from Example XVIII was cyclised to the title 113~81Z
gonatetraene in a way analogous to that of Example II.
Oil, NMR (in CDC13): ~ 1.65 (s, 17-CH3), 3.74 (s, CH30), 4.40 (q, J=2, ll~H), 4.40 and 4.56 (2 x d, J=12, ArCH20).
It should be noted that the ll~-substituted 17-alkyl-a l'3'5(10)'13(17)-gonatetraenes obtained in the cyclisation and the 13~,17~-epoxy derivatives thereof are novel compounds. These compounds have hormonal properties and are furthermore of impor-tance for the synthesis of known ll~-substituted steroids.
This application is a division of application Serial No. 314,202 which was filed on October 25, 1978.
Claims (27)
1. A method of preparing compounds of the formulae:
II III
from the compound:
I
wherein:
(a) R1 is H or alkyl of one to four carbon atoms;
(b) R2 is H or alkyl of one to four carbon atoms, with the proviso that R1 is H when R2 is alkyl, and with the proviso that R2 is H when R2 is alkyl;
(c) R3 is a suitable leaving group selected from the group consisting of hydroxy, alkoxy of one to four carbons, alkoxyalkoxy of two to four carbons, acyloxy of one to about seven carbons, and trialkylsilyloxy of less than fifteen carbons;
(d) R4 is H, hydrocarbyl of one to fourteen carbons, carboxyacyl of two to twelve carbons, trialkylsilyl of less than fifteen carbons, or heterocyclic of five to seven members and four to six carbons;
(e) R5(1) and R5(2) are each H, alkyl of one to eight carbons, or an optionally esterified or etherified hydroxy group selected from the group consisting of hydroxy, alkoxy of one to four atoms, alkoxy-alkoxy of two to four carbons, carboxyacyloxy of one to seven carbons, trialkylsilyloxy of one to fifteen carbons, cycloalkoxy of four to eight carbons, and unsubstituted heterocyclic ether of five to seven members and from four to six carbons, with the proviso that at least one of R5(1) and R5(2) is hydrogen; and (f) R7 is alkyl of one to about four carbon atoms;
which comprises the step of:
cyclising compound I in a suitable solvent with an effective amount of one or more of the acids consisting of the suitable protic and suitable aprotic Lewis acids at a tempera-ture below about room temperature and above about -150°C.
II III
from the compound:
I
wherein:
(a) R1 is H or alkyl of one to four carbon atoms;
(b) R2 is H or alkyl of one to four carbon atoms, with the proviso that R1 is H when R2 is alkyl, and with the proviso that R2 is H when R2 is alkyl;
(c) R3 is a suitable leaving group selected from the group consisting of hydroxy, alkoxy of one to four carbons, alkoxyalkoxy of two to four carbons, acyloxy of one to about seven carbons, and trialkylsilyloxy of less than fifteen carbons;
(d) R4 is H, hydrocarbyl of one to fourteen carbons, carboxyacyl of two to twelve carbons, trialkylsilyl of less than fifteen carbons, or heterocyclic of five to seven members and four to six carbons;
(e) R5(1) and R5(2) are each H, alkyl of one to eight carbons, or an optionally esterified or etherified hydroxy group selected from the group consisting of hydroxy, alkoxy of one to four atoms, alkoxy-alkoxy of two to four carbons, carboxyacyloxy of one to seven carbons, trialkylsilyloxy of one to fifteen carbons, cycloalkoxy of four to eight carbons, and unsubstituted heterocyclic ether of five to seven members and from four to six carbons, with the proviso that at least one of R5(1) and R5(2) is hydrogen; and (f) R7 is alkyl of one to about four carbon atoms;
which comprises the step of:
cyclising compound I in a suitable solvent with an effective amount of one or more of the acids consisting of the suitable protic and suitable aprotic Lewis acids at a tempera-ture below about room temperature and above about -150°C.
2. The method of claim 1 wherein the cyclisation takes place from about +10°C to about -100°C.
3. The method of claim 1 wherein an aprotic Lewis acid is used.
4. The method of claim 3 wherein the amount of Lewis acid employed is from about 0.5 to about 5 moles per mole of compound (III).
5. The method of claim 1 wherein a protic Lewis acid is used.
6. The method of claim 5 wherein the protic Lewis acid employed has a pK (20°C) of less than about 2.
7. The method according to claim 1, wherein in compounds I, II and III, R4 is methyl.
8. The method according to claim 1, wherein in compounds I, II and III, one of R5(1) and R5(2) is methoxy.
9. The method according to claim 1, wherein in compounds I, II and III, R7 is CH3 or ethyl.
10. The method according to claim 1, wherein in compounds I, II and III, R4 is benzyl, one of R5(1) and R5(2) is methoxy and R7 is methyl.
11. The method according to claim 1, wherein in compounds I, II and III, R4 is methyl, one of R5(1) and R5(2) is benzyl and R7 is methyl.
12. The method according to claim 1, wherein in compounds I, II and III, R4 is benzyl, one of R5(1) and R5(2) is methoxy and R7 is ethyl.
13. The method according to claim 1, wherein in compounds I, II and III, R4 is pivaloyl, one of R5(1) and R5(2) is methoxy and R7 is methyl.
14. The method according to claim 1, wherein in compounds I, II and III, R4 is benzoyl, one of R5(1) and R5(2) is methoxy and R7 is methyl.
15. The method according to claim 1, wherein in compounds I, II and III, R4 is trimethylsilyl, one of R5(1) and R5(2) is methoxy and R7 is methyl.
16. The method according to claim 1, wherein in compounds I, II and III, R4 is p-phenylbenzyl, one of R5(1) and R5(2) is methoxy and R7 is methyl.
17. A compound of the formula:
(II, III) wherein:
(a) R4 is H, hydrocarbyl of one to fourteen carbons;
carboxylacyl of two to twelve carbons, trialkylsilyl of less than fifteen carbons, or heterocyclic of five to seven members and four to six carbons;
(b) R5(1) and R5(2) are each H, alkyl of one to eight carbons, or an optionally esterified or etherified hydroxy group selected from the group consisting of hydroxy, alkoxy of one to four carbons, alkoxy-alkoxy bf two to four carbons, carboxy-acyloxy of one to seven carbons, trialkylsilyloxy of one to fifteen carbons, cycloalkoxy of four to eight carbons, and un-substituted heterocyclic ether of five to seven members and four to six carbons with the proviso that at least one of R5(1) and R5(2) is H; and (c) R7 is an alkyl of one to about four carbon atoms, whenever produced by the method of claim 1 or its obvious chemical equivalents.
(II, III) wherein:
(a) R4 is H, hydrocarbyl of one to fourteen carbons;
carboxylacyl of two to twelve carbons, trialkylsilyl of less than fifteen carbons, or heterocyclic of five to seven members and four to six carbons;
(b) R5(1) and R5(2) are each H, alkyl of one to eight carbons, or an optionally esterified or etherified hydroxy group selected from the group consisting of hydroxy, alkoxy of one to four carbons, alkoxy-alkoxy bf two to four carbons, carboxy-acyloxy of one to seven carbons, trialkylsilyloxy of one to fifteen carbons, cycloalkoxy of four to eight carbons, and un-substituted heterocyclic ether of five to seven members and four to six carbons with the proviso that at least one of R5(1) and R5(2) is H; and (c) R7 is an alkyl of one to about four carbon atoms, whenever produced by the method of claim 1 or its obvious chemical equivalents.
18. The compound of claim 17, wherein R4 is methyl, whenever produced by the method of claim 7 or its obvious chemical equi-valents.
19. The compound of claim 17, wherein one of R5(1) and R5(2) is methoxy, whenever produced by the method of claim 8 or its obvious chemical equivalents.
20. The compound of claim 17, wherein R7 is CH3 or ethyl, whenever produced by the method of claim 9 or its obvious chemic-al equivalents.
21. The compound of claim 17 wherein R4 is benzyl, one of R5(1) and R5(2) is methoxy and R7 is methyl, whenever produced by the method of claim 10 or its obvious chemical equivalents.
22. The compound of claim 17 wherein R4 is methyl, one of R5(1) and R5(2) is benzyl and R6 is methyl, whenever produced by the method of claim 11 or its obvious chemical equivalents.
23. The compound of claim 17 wherein R4 is benzyl, one of R5(1) and R5(2) is methoxy and R7 is ethyl, whenever produced by the method of claim 12 or its obvious chemical equivalents.
24. The compound of claim 17 wherein R4 is pivaloyl, one of R5(1) and R5(2) is methoxy and R7 is methyl, whenever produced by the method of claim 13 or its obvious chemical equivalents.
25. The compound of claim 17 wherein R4 is benzoyl, one of R5(1) and R5(2) is methoxy, and R7 is methyl, whenever produced by the method of claim 14 or its obvious chemical equivalents.
26. The compound of claim 17 wherein R4 is trimethylsilyl, one of R5)1) and R5(2) is methoxy and R7 is methyl, whenever produced by the method of claim 15 or its obvious chemical equi-valents.
27. The compound of claim 17 wherein R4 is ?-phenylbenzyl, one of R5(1) and R5(2) is methoxy and R7 is methyl, whenever produced by the method of claim 16 or its obvious chemical equi-valents.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000385867A CA1134812A (en) | 1977-10-25 | 1981-09-14 | CYCLISATION SUBSTRATES, CYCLISATION PROCESS AND RELATED 11.beta.-AXIALLY-SUBSTITUTED STEROIDS |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| NL77.11667 | 1977-10-25 | ||
| NL7711667A NL7711667A (en) | 1977-10-25 | 1977-10-25 | PROCESS FOR PREPARING CYCLIZATION SUBSTRATES FOR STEROID LINKS AND STEROID LINKS THEREOF. |
| CA314,202A CA1123444A (en) | 1977-10-25 | 1978-10-25 | CYCLISATION SUBSTRATES, CYCLISATION PROCESS AND RELATED 11.beta.-AXIALLY-SUBSTITUTED STEROIDS |
| CA000385867A CA1134812A (en) | 1977-10-25 | 1981-09-14 | CYCLISATION SUBSTRATES, CYCLISATION PROCESS AND RELATED 11.beta.-AXIALLY-SUBSTITUTED STEROIDS |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1134812A true CA1134812A (en) | 1982-11-02 |
Family
ID=27165933
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000385867A Expired CA1134812A (en) | 1977-10-25 | 1981-09-14 | CYCLISATION SUBSTRATES, CYCLISATION PROCESS AND RELATED 11.beta.-AXIALLY-SUBSTITUTED STEROIDS |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1134812A (en) |
-
1981
- 1981-09-14 CA CA000385867A patent/CA1134812A/en not_active Expired
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