Steroids total synthesis applications

The fact that the above reactions allow isolation of 4-hydroxyesters, which are often unstable and lactonize quickly, is a merit of the homoenolate chemistry. Mesylation of the hydroxy group followed by appropriate operations provides stereocontrolled routes to y-lactones and cyclopropane carboxylates [19]. Through application of such methodology steroid total synthesis has been achieved (Section 7). 

Several applications in total syntheses exemplify the value of this methodology 11-oxoequiienin methyl ether (101 Scheme 38),105 107 (+)-a-cuparenone,109 (-)-podorhizon,112 (-)-methyl jasmonate (102 Scheme 39),114 (+)-estrone methyl ether,116 and the so called (+)-A-factor (103 Scheme 40)117 were all prepared in high enantiomeric purity. Other applications constitute preparations of 2-alkylchro-man-4-ones,118 and of 3-vinylcyclopentanones, highly valuable intermediates for steroid total synthesis.106,107... 

For an application of this method in the steroid total synthesis by a tandem Claisen rearrangement-ene reaction see ref 523. 

The application of nonenzymic biogenetic-like olefinic cyclizations for the stereospecific construction of polycyclic systems, developed by W. S. Johnson and his school, represents an exciting new approach to steroid total synthesis. The synthesis of progesterone, outlined below, is based on the finding that an appositely placed acetylenic bond participates in polyolefinic cyclizations directly to produce the C/D trans-fused hydrindane system... 

During recent years, cross metathesis has found a wide range of applications in total synthesis. CM has been the key step in the syntheses of (-)-lasubine 11 [134], (+)-7a-ept-7-deoxycasuarine [135], and melithiazole C [136] to name just a few examples. It has been used for the modification of tetrapyrrolic macrocycles [137] as well as erythromycin derivatives [138], the dimerisation of steroids [139] and the synthesis of prostaglandin analogues [140]. 

The format of these Reports has remained relatively constant from year to year to facilitate the location of subject matter. However, this year two changes have occurred. Firstly, as an experiment, the information on biosynthesis is contained within the chapters dealing with the individual group of terpenoids rather than as a separate chapter. Secondly, the steroid section has been recast to minimize overlap. A report of the application of physical methods to steroids forms one chapter whilst steroid reactions and partial syntheses are reported in the second. Total synthesis will be reviewed biennially. 

Intermolecular cyclopropanation of diazoketones is an effective method in organic synthesis. Wenkert and coworkers have applied this methodology to the synthesis of a substantial number of cyclopropane adducts 2868, 2969 and 307° which are synthetic intermediates in the preparation of natural products (equations 41—43). Copper catalysts were chosen for these transformations. Another interesting application of intermolecular cyclopropanation is to be found in Daniewski s total synthesis of an aromatic steroid. Palladium(II) acetate catalysed decomposition of 4-bromo-l-diazo-2-butanone in the presence of m-methoxystyrene was used to give the cyclopropyl ketone 31 which was a key intermediate in the total synthesis (equation 44)71. 

Synthetic work in the steroid field remains an active area of research. A number of useful approaches to the steroid system, by either partial or total synthesis, have been reported during the year under review. The purpose of the present chapter is to put emphasis on original synthetic processes and sequences of general applicability. No mention will be made of particular reactions, the application of physical methods, biosynthetic studies, or microbiological reactions. 

The y, 5-double bond of a conjugated keto-diene may be selectively hydrogenated over catalysts, offering useful synthetic applications. Hydrogenation of dienone 16 affords 17 as an intermediate in the total synthesis of steroids. The disubstituted double bond is reduced more readily than the tetrasubstituted double bond in a nonpolar solvent to prevent participation of the carbonyl groups ... 

Almost 10 years after and independent of Inhoffens pioneering research, Karl Miescher (1892-1974) and George Anner from Ciba AG in Basel published in 1948 the first total synthesis of enantiopure (+)-oestrone. [32] Their approach was based on earlier work from Robert Robinson (1886-1975) in Oxford and Werner Emmanuel Bachmann (1901-1951) in Ann Arbor, Michigan. As another highlight in steroid chemistry, their synthesis stands out as one of the earliest attempts to circumvent the challenging demethylation step. Key reaction sequences are a malonic ester synthesis, a Dieckmarm cychsation, a Reformatzky reaction and the application of the Arndt-Eistert reaction. Remarkable is here as well the high art of crystallisation In the first fractional crystallisation, three racemic diastereomers were separated and in the second one two. Finally, enantiopure (+)-oestrone is obtained by stereoselective crystallisation of the desired diastereomer of the ((-)-menthyloxy) acetate. 

Pd-catalyzed cyclizations of 1,3-diene monoepoxides have thoroughly been studied due to their powerful applications in the total synthesis of natural products such as steroid precursors, vitamin intermediates, or 3-lactone moieties. For example, diastereo- and re-gioselective cycloisomerization of a diestervinyloxirane leads to the 3-lactonic precursor of Cholestane (Scheme 13). 

The subsequent stage in the development of methods for total steroid synthesis, including the sixties, is characterized, on the one hand, by increased attention to the synthesis of heterocyclic steroids and, on the other hand, to efforts to develop methods for total synthesis suitable for industrial application. This problem, the performance of a stereospecific total synthesis in a small number of stages with high yields in each stage, has been solved at the present time only for estrone (Schemes 38 and 39). 

Methods of Forming and Transforming the Rings. In the total synthesis of steroids, ring closure is carried out by very diverse methods the limits of applicability of which are shown in Table 4, These methods can be divided into three main groups cyclization with the participation of aromatic rings, with the participation of nonaromatic acids and esters, and with the participation of nonaromatic carbonyl compounds. 

Intramolecular Cycloadditions.—Application of certain intramolecular reactions allows the synthetic chemist to generate complex carbon skeletons more readily than by using intermolecular processes, and to exercise considerable control over regio- and stereo-specificity. It is not surprising, therefore, that this area of endeavour has become increasingly popular in recent years. Dominant among the reactions under study has been the intramolecular [4 + 2] cycloaddition (i.e. the intramolecular variant of the Diels-Alder reaction), some examples of which have already been noted in earlier sections. The reaction has also been applied in total syntheses of steroids, ( )-cedrol, eudesmane sesquiterpenes, and norpatchoulenol. The intramolecular [3 + 2] cycloaddition, a related process, has been used by Confalone et al. in a synthesis of ( )-biotin. The key steps are... 

Several total syntheses of estrogenic hormones and, in the first place, of derivatives of equilenin have been carried out by this route. The principles of the approach to total steroid synthesis considered in this chapter generally come up against serious obstacles even in their application to estrone derivatives. Moreover, their application to the synthesis of nonaromatic steroids has generally been unsuccessful. 

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