Recent developments in the isolation and synthesis of D-homosteroids and related compounds

Both naturally occurring and synthetic D-homologs of compounds with a sterane skeleton exhibit diverse biological activity. The main sources of isolation are plants and marine organisms. The synthetic D-homosteroids are potential leads for drug discovery. This review focuses on steroids with a six-membered carbocyclic ring D and related compounds, the isolation or syntheses of which were reported between the mid-1990s and mid-2006

Miscellaneous transformations and investigations 4. Conclusions

Introduction
Steroids are biomolecules that occur widely in nature and play key roles in the functioning of the human and animal organisms.Numerous members of this family of compounds, which can also be found in plants, exhibit varied biological activities.The series by Hanson in, "Natural Product Reports" regularly discuss the reactions and partial syntheses of diverse new steroids. 1téphan has reviewed the syntheses of modified steroids having a five-membered ring D in the androstane and androstene series. 2 There is a steadily rising need to find effective drugs; one plausible way to satisfy this need is to combine two or more different molecules with different chemical and biological properties into one new, "hybrid".The features of these new entities often differ from those of the original compounds.Mehta et al. 3 and Tietze et al. 4 have reported numerous examples of the synthesis of natural products, including steroids, where this concept for the synthesis of new derivatives was utilized.Steroidal conjugates and their pharmacological applications have been discussed by Salunke et al. 5 and the use of bile acids as building blocks of supramolecular hosts has been surveyed by Tamminen and Kolehmainen. 6Another possible way to obtain new, useful steroids for medicinal chemical purposes is to modify the original sterane skeleton, for example by the enlargement of ring D. The insertion of one additional carbon atom in ring D may alter the biological properties. 7For example, the estrogen receptors recognize Dhomoestradiol (1) only poorly; the compound exhibit of three magnitude lower receptor binding affinity, then estradiol. 8On the other hand, D-homoestrone derivatives possess antioxidant properties. 9A number of attempts has been made to produce D-homosteroids.Some of the new compounds isolated exert anticancer effects. 10,11This review discusses the D-carbocyclic Dhomosteroids whose isolation, syntheses, structure determinations, biological activities and potential applications were reported between the mid-1990s and mid-2006.There are two different ways for obtaining D-homosteroids; the isolation from natural sources (Chapter 2) and the chemical synthesis and transformation of them (Chapter 3). Figure 1 shows the ring lettering, atom numbering, and the usual configurations of the stereogenic centers of the D-homosteroids on the examples of the D-homoestrane derivatives chosen (1, 2).If not shown in the formulae, the positions of the hydrogen atoms at the stereogenic centers are 5α, 8β, 9α, 14α.

D-Homosteroids isolated from natural sources
Steroid alkaloids are usually found in higher plants and in animals.The toxic tomatidine, occurring as glycosides in Licopersicon esculentum and Solanum demissum inhibit the growth of human colon (HT29) and liver (HepG2) cancer cells. 12Batrachotoxin, produced by poison-arrow frogs, is one of the most toxic non-peptide compounds. 13All recently isolated natural derivatives discussed are C-nor,D-homosteroids.Two new steroidal alkaloids, veramine (3) and neojermininaline (4), together with the known glycoalkaloid pseudojervine, have been isolated from Veratrum album L. 14 Veramine has been found to have a jervine-type skeleton, and neojermininaline a cevine-type skeleton (Fig. 2).

Syntheses and transformations of D-homosteroids
One plausible approach to the formation of D-homosteroids is the conversion of the fivemembered ring D of the naturally occurring steroids into a six-membered one.To achieve this goal, rearrangements or ring opening reactions, followed by cyclizations must be performed.An important advantage of this strategy is that the configurations of most chiral centers remain unchanged.However, the selectivities are often low or (in the case of ring-opening -ring-closure sequences) the synthetic routes involve numerous steps.

Syntheses involving rearrangements
A classical route to the synthesis of D-homosteroids is the Tiffeneau rearrangement of 17aminomethyl-17-hydroxysteroids, which results in regioisomeric D-homosteroidal ketones. 21uccessful attempts have been made meanwhile to increase the selectivity, 22 and recently rearrangements have often been applied to obtain D-homopregnanes.Epoxide ring-opening of the protected pregnene derivative 20 with phenylmagnesium bromide led to the 16-phenyl-substituted alcohol 21, rearrangement of which with perchloric acid afforded the D-homosteroid 22 (Scheme 2). 24The synthesis and crystal structure determination of its oxidized derivative, 17α-acetoxy-17β-methyl-16β-phenyl-D-homo-4,6pregnadiene-3,17a-dione (23), have also been described. 25The inhibition of sodium acetate incorporation into lipids by this type of D-homosteroids has been investigated, 26 as have their antiandrogenic effects. 27RKAT USA, Inc.

Scheme 11
Intramolecular Lewis-acid-catalyzed cyclizations of the steroid aryliminium salts 46 obtained from the secoestrone aldehyde 36 yielded either the tetrahydroquinoline derivatives of estrone 3methyl ether 47 or the N-arylamino-D-homosteroids 48, depending on the nature of the substituent on the aniline moiety.][44] ARKAT USA, Inc.A similar tendency could be observed in the 13α-estrone series.Earlier investigations revealed that the conformations of rings C and D are strongly influenced by the substitution pattern on ring D. 37 An X-ray crystallographic investigation showed the chair conformations of both rings C and D of a 16α-fluoro-17aα-arylamino-D-homoestrone derivative. 45he cyclization of iminium salts of a D-secopregnene aldehyde led to a 16β-arylamino-17αaminomethyl-17β-fluoro-D-homosteroid as a side-product. 46n a novel one-pot fragmentation-cyclization, 17β-hydroxy-17α-substituted 16-oximino derivatives in the androstane and estrane (50) series have been converted into a new type of Dhomosteroid derivatives (51; Scheme 13). 47The inhibitory effects of D-homo compounds of this type in the androstane series toward aromatase, 3β-and 17β-hydroxysteroid dehydrogenase, and 17α-hydroxylase/C17, 20 lyase (P450c17) have been investigated. 48

Total synthetic approaches
The classical Torgov method made possible the industrial-scale total synthesis of estrones. 49This reaction sequence can also be used to obtain D-homoestrones. 50A short, flexible, efficient method has been developed by Sarabèr and de Groot for the synthesis of 17-substituted steroid skeletons and D-homosteroid skeletons through the use of a ZnBr 2 -catalyzed coupling of a silyl enol ether-containing ring D precursor (53) with a Torgov-type reagent (52), followed by acidcatalyzed cyclization of the adducts (54), to furnish steroid and D-homosteroid skeletons (55; Scheme 14). 51,52

Scheme 14
In another approach by the de Groot group, an efficient procedure has been developed for the synthesis of C,D-cis-coupled steroid and D-homosteroid skeletons.A Mukaiyama reaction with transfer of the silyl group of the starting silyl enol ether 56 to the enol of the adduct, followed by the addition of vinyl magnesium bromide to the unprotected carbonyl group, leads to adducts 58, which have been cyclized with ZnBr 2 to 59.The synthesis of functionalized steroid skeletons in overall yields of about 50% can be achieved in four steps in this way (Scheme 15). 52,53On the basis of Mukaiyama chemistry, a further efficient procedure has been developed to obtain C,Dcis annelated D-homosteroids. 54

Scheme 17
The D-homosteroid 74 has been synthesized by Tietze and Petersen, by two successive Heck reactions, starting from enantiopure 71 and a bromoarene 70 containing a (Z)-bromovinyl group.
The first intermolecular Pd-catalyzed reaction led in a highly regio-and diastereoselective way to 73, which afforded 74 with an unnatural B/C cis-junction in a second intramolecular Heck reaction (Scheme 18). 57ew, biomimetic, intramolecular methodology for the preparation of racemic Dhomosteroids has been described by Zoretic et al. 58 The polyene 77 has been cyclized to the tetracycle 78 in a radical process.After removal of the ethoxycarbonyl functional group on C-4 and conversion of the angular cyano group on C-

Miscellaneous transformations and investigations
A review has been published on the synthesis of 8-azasteroids, including D-homo derivatives. 59ransformations of unsaturated derivatives of equilenin (80) and D-homoequilenin (81) have been performed (Figure 7).

Figure 7
The properties and reactions of B-nor-8-iso analogs of D-homoestrone have been investigated. 61An NMR study has been performed on the stereo-structure and intramolecular dynamics of D-homoandrostenes and a B-nor-8-iso-D-homoestrone derivative. 62The crystal structures of two steroid 19,B-dinor-8,10-iso analogs 63 and of two 6-oxa-D-homo-8-isoestra derivatives 64 have been published.An investigation has been made on the phosphorescence of enaminocarbonyl-8-azasteroids (including D-homo derivatives). 65The results of CI-MS investigations on 17-substituted estra-and 17a-substituted-D-homoestra-derivatives have been reported. 66Computational studies have shown that derivatives of tetrahydrochrisene (82) can be successfully docked into the second binding site of ERα and ERβ (Figure 8). 67

Figure 8
The metabolism of desogestrel has been studied in vivo after the administration of single oral doses to rats and dogs.In dogs, 17a-keto-D-homosteroids have been found among the metabolites of the progestogen. 68

Conclusions
The pharmacological potential of natural D-homosteroids, which occur widely in various plants and marine organisms, is a driving force for the isolation of new derivatives and their structureelucidation.The considerable amount of recent partial and total synthetic work, directed to the Figure 1