Steroid ring system, synthesis

Formation of oxiranes on the sterically more hindered side of the steroid ring system is usually carried out via /raw -halohydrins which afford oxiranes on treatment with base (c -Halohydrins yield ketones on exposure to base). Two general methods are available for the synthesis of tm s-halohydrins (1) the reduction of a-halo ketones and (2) the addition of a hypohalous acid to unsaturated steroids. 

The selectivity for two-alkyne annulation can be increased by involving an intramolecular tethering of the carbene complex to both alkynes. This was accomplished by the synthesis of aryl-diynecarbene complexes 115 and 116 from the triynylcarbene complexes 113 and 114, respectively, and Danishefsky s diene in a Diels-Alder reaction [70a]. The diene adds chemoselectively to the triple bond next to the electrophilic carbene carbon. The thermally induced two-alkyne annulation of the complexes 115 and 116 was performed in benzene and yielded the steroid ring systems 117 and 118 (Scheme 51). This tandem Diels-Alder/two-alkyne annulation, which could also be applied in a one-pot procedure, offers new strategies for steroid synthesis in the class O—>ABCD. 

Nature often provides excellent suggestions about how to synthesize a compound. After the pathway for the biosynthesis of steroids by cationic cyclization of polyenes was determined, Professor William S. Johnson and coworkers at Stanford University used a very similar reaction to synthesize progesterone. The last part of this synthesis is outlined in the following equations. Alcohol A was prepared in 12 steps with an overall yield of 10%. It was then cyclized to form the steroid ring system. 

Although many sterols and bile acids were isolated in the nineteenth century, it was not until the twentieth century that the stmcture of the steroid nucleus was first elucidated (5). X-ray crystallographic data first suggested that the steroid nucleus was a thin, lath-shaped stmcture (6). This perhydro-l,2-cyclopentenophenanthrene ring system was eventually confirmed by the identification of the Diels hydrocarbon [549-88-2] (4) and by the total synthesis of equilenin [517-09-9] (5) (7). 

Estranes. Investigations into the total synthesis of steroids began in the 1930s shordy after the precise formula for cholesterol was estabUshed. The eadiest studies focused on equilenin (5) because of its relative stereochemical simplicity when compared to other steroid nuclei Initially, equilenin was synthesi2ed in 20 chemical steps with an overall yield of 2.7%. This synthesis helped to confirm the perhydro-l,2-cyclopentenophenanthrene ring system of... 

This chapter will deal exclusively with three-membered rings containing the hetero atoms O, S and N, and fused to the steroid skeleton. Because of the conformational requirements in steroids, not all of the usual methods of synthesis of three-membered rings are applicable to the fused ring system. For the synthesis of steroids to which an aziridine, oxirane or thiirane is attached either in the side chain or at a ring position but not directly fused to the nucleus, the methods discussed in this chapter, as well as others, are applicable. 

Finally in 2005, Hutt and Mander reported their strategy for the synthesis of nominine (Scheme 1.3) [29], The approach relies upon construction of the steroidal ABC carbocyclic ring structure followed by stepwise preparation of the fused aza-ring system. In the key sequence of the synthetic study, enone 50 was oxidized to dienone 51 with DDQ followed by Lewis acid-catalyzed intramolecular conjugate addition of the methylcarbamate to the newly formed dienone to deliver pyrrolidine 52. 

Novel steroidal pyridazines are readily prepared from ADC compounds and steroidal A2,4-dienes,163 A14,1 -dienes,164 and A16,20-dienes.165 ADC compounds are also commonly used in the protection of the steroid 5,7-diene system (see Section V,A). These Diels-Alder adducts of steroidal dienes and azo dienophiles should not be confused with the so-called azasteroids, which are also prepared from ADC compounds. Cyclic ADC compounds such as the pyrazole-3,5-diones (7), and the diazaquinones 12 and 13 readily add to dienes to give bicyclic pyridazine derivatives,166168 and these reactions have been adapted to the synthesis of 5,10-diazasteroids (106).42 Similarly, the 13,14-diaza- (107) and 13,14,16-triazasteroid (108) ring systems have been prepared.169... 

In order to study heterocyclic steroid analogues, such as the 7,11-dithiaazasteroid analogues, Fravolini developed the synthesis of new heterocyclic ring systems tri- and tetracyclic 2,1-benzothiazines <82JHC1045>. Intermediate 137 was prepared from 1-methyl-4-oxo-lH-2, -bcnzothiazinc-4(3f/)-onc 2,2-dioxide 37 and thioglycolic acid and could be converted into 6-methyl-4-oxo-3,4-dihydro-2//,6//-thiopyrano[3,2-c][2,l]benzothiazine 5,5-dioxide 138 by cyclization with polyphosphoric acid. The reaction of 138 with dimethyl... 

Strategies based on two consecutive specific reactions or the so-called "tandem methodologies" very useful for the synthesis of polycyclic compounds. Classical examples of such a strategy are the "Robinson annulation" which involves the "tandem Michael/aldol condensation" [32] and the "tandem cyclobutene electrocyclic opening/Diels-Alder addition" [33] so useful in the synthesis of steroids. To cite a few new methodologies developed more recently we may refer to the stereoselective "tandem Mannich/Michael reaction" for the synthesis of piperidine alkaloids [34], the "tandem cycloaddition/radical cyclisation" [35] which allows a quick assembly of a variety of ring systems in a completely intramolecular manner or the "tandem anionic cyclisation approach" of polycarbocyclic compounds [36]. 

This annulation process was of considerable value in early approaches to steroid synthesis. The structural relationship of the bicyclic product obtained here to the male sex hormone testosterone is immediately apparent. Further, the non-conjugated carbonyl is now activating the adjacent carbon that subsequently features in building up the third ring system. 

Allyl sulfoxide -> sulfenate rearrangement.2 A key step in a stereoselective first synthesis of withaferin A (3), a steroid antitumor agent, is the production of the desired A/B ring system by an allyl sulfoxide-> sulfenate rearrangement in the presence of trimethyl phosphite (equation I). 

Pinhey utilized the decarboxylative rearrangement of 2 to the nor-alkyl pyridyl sulfide 3, oxidation to the corresponding sulfoxide and thermal elimination sequence in a simple transformation of podocarpic acid 4 into useful synthons 5 (for example, in vitamin D3 synthesis) for steroid CD-ring systems, as shown in Scheme l.8... 

An efficient synthesis of 1,4-oxazepines has been developed based on iodine-sodium bicarbonate-promoted intramolecular cyclisation of the enamides 237, which were derived in turn from the p-formyl enamides 236 by sodium borohydride reduction. Reductive removal of the iodo-substituent in 238 was readily achieved using sodium sulfite. The R1 and R2 groups were part of a ring system, for example a steroid system [01SC3281],... 

Under conditions not favoring dehydration alternative hydrolytic pathways predominate.233 Thus, if the carbinolamine derived from compound (101) is treated with aqueous base, the main product is the octalone (102).234 This annelation clearly has great potential in synthesis, and it has already been exploited in, for example, the construction of the AB ring system of steroids (Stork and McMurry235 see also Ohashi236). 

In addition to cationic cyclizations, other conditions for the cyclization of polyenes and of ene-ynes to steroids have been investigated. Oxidative free-radical cyclizations of polyenes produce steroid nuclei with exquisite stereocontrol. For example, treatment of (259) and (260) with Mn(III) and Cu(II) afford the D-homo-5a-androstane-3-ones (261) and (262), respectively, in approximately 30% yield. In this cyclization, seven asymmetric centers are established in one chemical step (226,227). Another intramolecular cyclization reaction of iodo-ene poly-ynes was reported using a carbopaUadation cascade terminated by carbonylation. This carbometalation—carbonylation cascade using CO at 111 kPa (1.1 atm) at 70°C converted an acycHc iodo—tetra-yne (263) to a D-homo-steroid nucleus (264) [162878-44-6] in approximately 80% yield in one chemical step (228). Intramolecular aimulations between two alkynes and a chromium or tungsten carbene complex have been examined for the formation of a variety of different fiised-ring systems. A tandem Diels-Alder—two-alkyne annulation of a triynylcarbene complex demonstrated the feasibiHty of this strategy for the synthesis of steroid nuclei. Complex (265) was prepared in two steps from commercially available materials. Treatment of (265) with Danishefsky s diene in CH CN at room temperature under an atmosphere of carbon monoxide (101.3 kPa = 1 atm), followed by heating the reaction mixture to 110°C, provided (266) in 62% yield (TBS = tert — butyldimethylsilyl). In a second experiment, a sequential Diels-Alder—two-alkyne annulation of triynylcarbene complex (267) afforded a nonaromatic steroid nucleus (269) in approximately 50% overall yield from the acycHc precursors (229). 

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