Dihydroxylated steroid

The same dihydroxylated steroid diacid was reacted with biarylether diisonitrile building block 98 (see above) and paraformaldehyde and isopropylamine (Scheme 27). Double Ugi macrocycle 129 was the main product, but extremely large fourfold Ugi macrocycles (130 and head-head isomer) were also isolated. 

Although less effective than methyl(trifluoromethyl)dioxirane (TFDO), oxyfunctionalization of unactivated methine C-Hs with dimethyldioxirane (DDO) is feasible for various substituted steroids related to the 5/)-cholane and 5a-cholestane series to give novel mono- and dihydroxylated steroids. The reactivity and site selectivity of oxyfunctionalization is affected conspicuously by the structural and steric environments of the target methine carbon atoms. This nonenzymatic procedure may be advantageously applied to selective and short-course s)mtheses of bioactive steroids. Thus, the major reaction product of methyl... 

Ursodsoxycholic acid 3a,7p-dihydroxy-5p-cho-lan-24-oic acid, a dihydroxylated steroid carboxylic acid, one of the bile acids M, 392.58, m.p. 203 °C, [o]d -( 57° (ethanol). U. is a characteristic component of bear bile, and is also present in human bile. 

Fig. 28. Examples of regioselectivity with 5-fluorouridine and a dihydroxylated steroid (47-49).

In order to increase structural diversity and to create a polar domain in the cage-like interior of these steroid/peptide macrocycles, dihydroxylated diacid 127 was synthesized in two steps from cholic acid (126) and reacted with diisonitrile 110, paraformaldehyde, and isopropylamine to form macrocycle 128 and its head-head isomer (Scheme 26). 

The first observation of the c/x-dihydroxylation reaction with RuO was made by Sharpless et al. in 1976, who noted that E and Z-cyclododecene were oxidised by stoich. RuO /EtOAc/-78 C to the threo and erythro diols [299]. Later RuCyaq. Na(IO )/EtOAc-CH3CN/0 C was used and reaction conditions optimised for many alkenes [300] a useful paper with good practical examples discusses the scope and limitations of the procedure (Table 3.2) [301]. Later oxidations were done with stoich. RuOyaq. acetone/-70 C [302] the same reagent converted A, and A steroids to cw-diols, ketones or acids [303], while RuO /aq. Na(10 )/acetone gave diones and acids [304]. 

The development of RuO as a aT-dihydroxylation catalyst is a relatively new and potentially important area. Until recently OsO has been the reagent of choice for this, but use of the cheaper RuO may well become competitive, though stringent reaction conditions need to be used because RuO is so much more powerful an oxidant than OsO. Reactions are much faster than for OsO, but so-called flash dihydroxylations in which low temperatures are used have been developed, and are the subject of much current research. There are several reviews including mechanistic aspects [7-9] and one on the synthesis of poly oxygenated steroids [6]. The scope and limitations of the procedure have been discussed [155, 156]. 

Substitution on the steroid nucleus by fluorine leads to complicated changes in selectivity, but usually results in hydroxylation at sites remote from the fluorine substituent. Thus Sa-androstan-17-one (77) is primarily 7, 1 la-dihydroxylated by Aspergillus ochraceus, but the 12,12-difluoro derivative (78) is 7p-monohydroxylated (Scheme 14). ... 

Aspergillus giganteus (ATCC 10059) will dihydroxylate pro sterone (64) to ve the 1 la,lSP-dihy-droxy derivative (79 equation 25), which is a precursor to tire oogonial steroids. 

The cis dihydroxylation of double bonds incorporated in steroidal derivatives has received considerable attention in the past decades88 (see Houben-Weyl, Vol. 4/1 b, p 860). Depending on the steric and electronic environment, as well as on the location of the double bond in the steroidal nucleus, - or -addition can be obtained (see Table 3). 

For example, the dihydroxylation of the steroid derivative 30 using 0s04.py-ridine gave a 1 8 mixture of diastereomeric diols in favour of the unnatural isomer 32 [91].UsingDHQD-CLB,a4 l ratio in favor ofthe natural isomer 31 could be obtained (Scheme 17). 

Even greater diastereocontrol could be achieved in the asymmetric dihydroxylation of other steroid derivatives such as 33, irrespective of the stereochemistry of the adjacent chiral substituents (Scheme 18). It is noteworthy that, in these cases, (DHQD)2-PHAL is only marginally more effective than the simpler DHQD-CLB Hgand [92]. 

In 1958, Woodward and Bratcher reported a study on the cis-dihydroxylation of steroid intermediate 4.1 They attempted to use OSO4 as the oxidant, but obtained the undesired cis-diol diastereomer 5 with that reagent. Thus, they developed a two-step dihydroxylation sequence using I2, AgOAc, and HOAc followed by KOH. Not only did this procedure work remarkably well, it afforded the desired diol diastereomer 8 in which dihydroxylation had occurred on the more sterically hindered p face of 4. Thus, treatment of 4 with I2, AgOAc, and HOAc afforded a mixture of acetates 6 and 7. Basic hydrolysis of 6 and 7 with KOH in methanol then gave diol 8 in 71% yield after recrystallization. 

Ap-57 Okada, M., and Saito, Y., Steroids 6, 651 (1965). Assignment of structure to 7a, ISa-dihydroxylated product from Gibberella saubinetti on dehydroepiandrosterone. 

All known brassinosteroids have a 5a-cholestane, 5a-ergostane, or 5a-sitostane steroidal skeleton with mono- to trioxygenation on ring A and 22a-, 23a-dihydroxylation in the side chain. Ring B may be fully saturated or may contain a ketone or lactone at carbon 6 (Fig. 128.1). 

Dihydroxylation of the following steroid gives only the indicated product. Based on the mechanism of the reaction, and the stereochemistry of the product, explain why only one diol forms. 

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