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At this stage, conservation of the limited stock of tricyclic enone (96) was important, so the model bicyclic enone (123) was employed to assess the annulation sequence.

5.2.1 Synthesis of tricyclic model compounds

Annulation of the bicyclic model compound (123) was effected with methyl vinyl ketone to give the tricyclic enone (130) as follows:

Scheme 14 (123)

-But

(iv)J (129) (130)

0).

(iii) 0 (127) l(ii) HOHC (128) + Conditions (i) Li/NH.

(ii) NaOMe, HCC^Et, benzene (iii) H2C=CHCOCH3, Et3N

The bicyclic enone (123) was reduced to the trans bicyclic ketone (127) in high yield using lithium in liquid ammonia. The stereochemistry was assumed (see page 67). Formylation to the hydroxymethylene ketone (128) again occurred in good yield (88%). The regiochemistry of addition was assumed to be as indicated, in view of the overwhelming supporting evidence in the literature (see section 3.3.1). Addition of the Q -hydroxymethylene ketone (128) to methyl vinyl ketone was accomplished in 83% yield to give a yellow oil. The n.m.r. spectrum of t£e product (129) indicated two peaks at 6 9.67 and 9.45, in a 7:1 ratio, which were assigned as the the aldehyde proton of the two stereoisomers of (129).

Cyclisation of the adduct (129) employing the conditions as previously established, surprisingly gave a very poor yield (17%) of the tricyclic enone (130).

Further chromatography of the reaction mixture led to the isolation of two other products in substantial amounts, which were identified as hydroxy ketone intermediates (131) (m.p.201-202°C) and (132)

(m.p.291.5-293.5°C). Significantly two hydroxy ketones were also isolated in small amounts from cyclisation of the model Michael adduct (122) to the bicyclic enone

(123) (see scheme 12).

The stereochemistry of both the hydroxy ketones (131) and (132) was uncertain. However, dehydration of (131) readily occurred in refluxing benzene in the presence of para-toluenesulphonic acid to give the tricyclic enone (130) (by i.r.,t.I.e.,mixed m.p.) in 64% yield. This provided an overall yield of 34% for the cyclisation of the adduct (129) to the tricyclic enone (130). Dehydration of the hydroxy ketone (13Z) gave an enone which was not identical to the tricyclic enone

(130) by t.l.c.

This may be explained by considering the reaction of the a -hydroxymethylene ketone (128) with methyl vinyl ketone. The Michael adduct formed by equatorial addition of the annulating reagent could cyclise to give the hydroxy ketones (131a) and (131b), as indicated below. Both of these hydroxy ketones would be expected to undergo dehydration to the tricyclic enone (130). However, the Michael adduct formed by axial addition of methyl vinyl ketone to the d-hydroxymethylene ketone (128) could cyclise to give the hydroxy ketone (132) only. Dehydration of this hydroxy ketone would be expected to give the stereoisomeric enone (133).

0 31Q)

But

(132)

Bu1-

(133)

The occurrence of similar f} -hydroxy ketone intermediates from the cyclisation of Michael adducts have been reported in the literature**^' . These intermediates have been dehydrated to the corresponding

enones either by treatment of the hydroxy ketone with potassium hydroxide (8%) in ethanol at 20°C,^ or by heating under reflux with an aqueous solution of hydrochloric acid (3 M)^.

5.2.2 Synthesis of linear anthrasteroid analogues of 19-nortestosterone

The series of reactions described previously (scheme 14) were used for the synthesis of the linear anthrasteroid analogue of 19-nortestosterone (26) as outlined (scheme 15).

Scheme 15 (96) H H (1 36) (iv)j (137) L _ (i).

(iiDJ

(iii) hohc H H ( v ) (l3SQ) (138) Conditions (i) Li/NH3

(ii) HCC^Et; NaOMe; benzene (iii) H2C=CHCOCH3, Et3N

(iv) KOH (1% w/w), water, methanol (1:1 v/v) (v) pTsOH; benzene, reflux

The tricyclic enone (96) was reduced using lithium in liquid ammonia to give the saturated ketone (134) in 60% yield. The stereochemistry of the reduction was assumed to give the trans fused ring junction (see page 67). Formylation of the tricyclic ketone (134) gave the CT-hydroxymethylene ketone (135a) in 93% yield. The regiochemistry of this reaction was assumed to be as indicated, in view of the supporting body of evidence in the literature (see section 3.3.1). The n.m.r. of the product (135a) indicated peaks at 6 14.3 and 8.55, corresponding to the vinylic and hydroxyl protons of the hydroxymethylene moeity.

In contrast to the bicyclic hydroxymethylene ketone (87) (scheme 7) analogue, other signals indicating the presence of the regioisomeric tricyclic hydroxymethylene ketone (135b) were absent.

CHOH (135 b)

Michael addition of the tricyclic hydroxymethylene ketone (135a) to methyl vinyl ketone gave the adduct

(136) in 79% yield.

Cyclisation of the Michael adduct (136) to the enone (137) was achieved, but in only 20% yield. Further chromatography of the reaction mixture led to the isolation of a hydroxy ketone (138), which was obtained in 39% yield, as a solid (m.p. 214-216°C). This hydroxy ketone was dehydrated by heating under reflux with p-toluenesulphonic acid in benzene to give the tetracyclic enone (137) (by i.r.,mixed m.p.^H n.m.r.).

This provided an overall yield for the cyclisation of (136) to the tetracyclic enone (137) of 43%.

The cyclisation of the Michael adduct (136) closely resembles the cyclisation of the adduct (129) in the model system (scheme 14). However, only one j3“hyd°roxy ketone intermediate (138) was recovered in a significant amount from the cyclisation of the Michael adduct (136).

The final step in the synthesis of the target compound (26), involving removal of the t-butyl group to reveal the alcohol group, proved problematic. Initial attempts to cleave the t-butyl ether by heating with

. 15

dilute hydrochloric acid gave a poor yield (47%) of -151-

product (26). This prompted the use of the tricyclic butyl ether (96) as a model system, to assess the three different sets of reaction conditions considered to effect cleavage of the t-butyl ether group.

OH

0

(96) (139)

Hydrolysis of the t-butyl ether group of (96) with 15 o

aqueous alcoholic hydrochloric acid at 80 C gave the alcohol (139) in only 48% yield. A better yield (56%) was achieved when the t-butyl ether (96) was treated with the chlorotrimethylsilane/sodium iodide

97 98

reagent ' at room temperature. However, the best yield (74%) of (139) was obtained by stirring the t-butyl ether (96) in trifluoroacetic acid overnight at 9 9 ambient temperature, followed by alkaline hydrolysis Hydrolysis of the t-butyl ether of the tetracyclic compound (137) was similarly accomplished using trifluoroacetic acid to give the tetracyclic

alcohol(26) in good (73%) yield.

OH

H H Me T

H H

(

26

)

Thus the target linear anthrasteroid analogue (26) of 19-nortestosterone has been synthesised in 15 steps in

an overall yield of 2% from

2-methyl-1,3-cyclopentanedione (32).

5.3 LINEAR ANTHRASTEROID ANALOGUES OF ESTRADIOL

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