Steroidal intermediates, asymmetric

During the past three years, we have had excellent success in achieving some asymmetric syntheses O). We have focused attention specifically on faithful transfer of chirality from the sulfur atom of some a-carbonyl a,3-ethylenic sulfoxides to the 3-carbon atom during organometalllc 3-addition reactions. This type of high asymmetric induction in forming carbon-carbon bonds has led to successful preparation of several classes of optically active synthetic intermediates such as 3-methylalkanoic acids and 3-methylcycloalkanones. In addition, this asymmetric methodology has been applied successfully to preparation of more complex, enantiomerically pure molecules such as steroids and steroid intermediates. 

Acetoxy-l,7-octadiene (40) is converted into l,7-octadien-3-one (124) by hydrolysis and oxidation. The most useful application of this enone 124 is bisannulation to form two fused six-membered ketonesfl 13], The Michael addition of 2-methyl-1,3-cyclopentanedione (125) to 124 and asymmetric aldol condensation using (5)-phenylalanine afford the optically active diketone 126. The terminal alkene is oxidi2ed with PdCl2-CuCl2-02 to give the methyl ketone 127 in 77% yield. Finally, reduction of the double bond and aldol condensation produce the important intermediate 128 of steroid synthesis in optically pure form[114]. 

An asymmetric synthesis of estrone begins with an asymmetric Michael addition of lithium enolate (178) to the scalemic sulfoxide (179). Direct treatment of the cmde Michael adduct with y /i7-chloroperbenzoic acid to oxidize the sulfoxide to a sulfone, followed by reductive removal of the bromine affords (180, X = a and PH R = H) in over 90% yield. Similarly to the conversion of (175) to (176), base-catalyzed epimerization of (180) produces an 85% isolated yield of (181, X = /5H R = H). C8 and C14 of (181) have the same relative and absolute stereochemistry as that of the naturally occurring steroids. Methylation of (181) provides (182). A (CH2)2CuLi-induced reductive cleavage of sulfone (182) followed by stereoselective alkylation of the resultant enolate with an allyl bromide yields (183). Ozonolysis of (183) produces (184) (wherein the aldehydric oxygen is by isopropyUdene) in 68% yield. Compound (184) is the optically active form of Ziegler s intermediate (176), and is converted to (+)-estrone in 6.3% overall yield and >95% enantiomeric excess (200). 

Octonol is an intermediate for the production of several optically active pharmaceuticals, such as steroids and vitamins. The asymmetric reduction of 2-octanone to (5)-2-octonol by baker s yeast was inhibited severely by substrate and product concentration of 10 him and 6 mM respectively. Whole-cell biotransformation of 2-octanone in a water-ra-dodecane biphasic system yielded a high product concentration of 106him with 89% ee in 96h [37],... 

Johnson et al.3 used this reagent for reduction of 2, an intermediate in a synthesis of 1 la-hydroxy steroids. The desired enantiomer (3) was obtained with an optical yield of 97%. Asymmetric reduction of a similar intermediate had been effected pre-... 

Further breakthroughs in enantioselectivity were achieved in the 1970s and 1980s. For example, 1971 saw the discovery of the Hajos-Parrish-Eder-Sauer-Wiechert reaction, i.e. the proline (l)-catalyzed intramolecular asymmetric aldol cyclodehydration of the achiral trione 11 to the unsaturated Wieland-Miescher ketone 12 (Scheme 1.3) [12, 13]. Ketone 12 is an important intermediate in steroid synthesis. 

A wide variety of tandem, triple [12], and even quadruple [13, 14] cyclizations can be performed with multiply unsaturated 1,3-dicarbonyl compounds as shown in Eq. (1) [14] this provide intermediates for steroid and terpene syntheses. High levels of asymmetric induction can be achieved with phenylmenthyl acetoacetate... 

The products of this highly efficient asymmetric synthesis are important intermediates in natural product chemistry, e.g., the total synthesis of steroids and prostaglandins. 

Until quite recently the isolation of optically active seienoxides has been limited to those contained in steroids (isolated as diastereoisomeis). < The difficulty in obtaining these compounds was attributed to the racemization through the achiral hydrated intermediates. Simple optically active sel enoxides (S-11% ee) were first prepared by kinetic resolution. Direct oxidation of selenides to seienoxides was first reported using optically active oxaziridine derivatives under anhydrous conditions, but the extent of the asymmetric induction was somewhat unsatisfactory with methyl phenyl selenide as substrate (8-9% Recently much improved enantiomeric excesses (45-73%) were achieved with new oxaziridine reagents such as (70). An attempt at the asymmetric oxidation of more bulky selenides was independently carried out using Bu OCl in the presence of (-)-2-octanol (equation 55), but resulted in unsatisfactory enantioselectivities (ee 1%). Much better results were obtained by the oxidation of p-oxyalkyl aryl selenides (ee 18-40% equation 56) 27 gjyj selenides (ee 1-28%) using... 

Asymmetrically synthesized c/d intermediates with the natural configuration continue to provide intermediates for steroid synthesis. Thus the alkylation of (-H)-(18)with m-methoxyphenacylbromide (19)gave (14)inhigh yield in contrast to the low yields in this type of alkylation obtained with (20). The action of trimethyl orthoformate on (14) gave the extremely sensitive compound (15) which cyclized with toluene-p-sulphonic acid in benzene to yield (22), High-pressure hydrogenation... 

Ruthenium hydrogenation of estrone, estradiol, or related steroids 7 gives 3 )3-hydroxy-5 a,10 a-estranes 8 as the major products [equation (e)]. Reaction proceeds through a 3-keto intermediate and the stereochemistry of the product at all three new asymmetric centers follows the pattern of cfr-rear attack. ... 

The asymmetric synthesis of optically active 6-thiaoestrogens has been described. This work followed previously reported total synthetic schemes in which the asymmetric conversion was effected with 8,14-seco-intermediates. In addition, the synthesis of variously modified 6-thia-steroids by the classical route has also been reported. ... 

In contrast, Michael additions of a,a-disubstituted lithium enolates proceed, apparently via the chelated form of enone sulfoxides (Figure 5.2), with almost complete jt-facial diastereoselectivity [104]. This methodology has been used in the asymmetric synthesis of the pheromone, (-)-methyl jasmonate (121), from cyclopentenone sulfoxide (98b) [105] via the intermediate (120), which was formed in at least 98% enantiomeric purity upon asymmetric Michael addition of bis a-silylated a-lithioacetate to (98b). Addition of the a-bromo enolate (122) to enantiomerically pure (98a) and oxidation gives the product sulfone (123), with almost complete asymmetric -induction with respect to the sulfoxide. Sulfone (123) was then converted into the steroidal sex hormone, (+)-oestradiol (124) (Scheme 5.42) [106]. 

In this context, it is well worth citing the classic example of the L-proline-catalyzed intramolecular asymmetric aldol reaction, involving cyclodehydration of achiral triketone 1 to yield the unsaturated Wieland-Miescher diketone 2 (Scheme 8.1) [7, 8]. In early papers, it was reported that in the presence of 20 mol% of L-proline, the diketone 2, an important intermediate in steroid synthesis, is obtained in high yield and in approximately 70-90% enantiomeric excess (e.e.). 

Below we discuss methods for the formation of the C10—C9—C8—Ci4—C13 centers of asymmetry which, together with the C5 center, represent the main asymmetrical backbone of the steroid molecule (137) (the formation of the C5 center was developed within the framework of partial synthesis and is therefore not considered). Moreover, at the end of the section we also consider methods for the resolution of racemic end products and intermediates of total synthesis into their optical antipodes. 

It is possible to represent the formulas of the unnatural Z-enantiomers in the mirror projection (297) . however, it is more striking to illustrate them with changed symbols for the a - and -bonds (298). In this book, the structural formulas illustrating compounds with asymmetric carbon atoms not separated into optical antipodes arbitrarily represent one enantiomer (generally the cZ-enantiomer), but they everywhere refer to the racemic dl > compounds. The prefix dl is omitted in the text and all steroids and intermediates must be regarded as racemates unless otherwise specified. As a rule, the steroid numbering of the carbon atoms is used to describe intermediates it must therefore be borne in mind that the attachment of a numerical subscript to a carbon atom (Cg, C21, etc.) always means... 

In 2010, Zhou et al. " demonstrated the utility of RuCl2-SDPs/DPEN-catalyzed asymmetric hydrogenation of racemic ketone 112 via DKR in the enantioselective synthesis of alcohol (1R,25)-114, a chiral key intermediate of non-steroidal glucocorticoid modulator 115. The chiral... 

---