Dihydroxyacetone side chain

The dihydroxyacetone side chain is conveniently protected by forming 17a,20 20,21-bismethylenedioxy compounds (BMD) (92). Formation of llf -ethers as by-products from 11 -hydroxycompounds (91) can be limited by using formalin with a low methanol content, or better with paraformaldehyde as a source of alcohol-free formaldehyde. ... 

The 17a- and 21-hydroxyl groups of the dihydroxyacetone side chain fail to react directly with acetone to give a 17,21-acetonide. 

When in the late 1940 s the remarkable therapeutic effects of the glucocorticoids cortisone and hydrocortisone were discovered, new raw materials had to be developed to produce these complicated molecules, and new synthetic methods devised to convert either a 20-ketopregnane or 21-acetoxy-20-ketopregnane to the dihydroxyacetone side-chain characteristic of these corticoids. This latter challenge produced some extremely useful new organic chemical reactions, many of which have wider application outside of steroids. 

Treatment of the dihydroxyacetone side-chain with acid (usually hydrochloric) can result in removal of the 17a-hydroxyl group via the following pathway ... 

The Porter-Silber reaction, diagnostic for the dihydroxyacetone side-chain, depends upon prior Mattox rearrangement. " ... 

One reaction touched upon briefly in an earlier discussion is the hydroxyla-tion of a A -20-cyano steroid with osmium tetroxide. When a 21-acetoxyl group is also present, the important dihydroxyacetone side-chain is obtained ... 

Scheme 43 Bi(0Tf)3-xH20-catalyzed cleavage of the C17-dihydroxyacetone side chain of corticosteroids...

The bismethylenedioxy group (BMD) [ (49)] represents the most suitable protecting group for the dihydroxyacetone side chain of corticosteroids. This group is stable to lead tetraacetate, brief heating with hydrochloric acid in acetic acid,108 or with sulfuric acid in methanol18 and to Jones oxidation.189... 

Dihydroxyacetone side chain of corticoids (14, 86-87). Details for the double hydroxylation of the enol silyl ether 1 are now available.2 For highest yields of 2, an excess of oxidant (3 equiv.) is required as well as excess powdered KHC03. In the absence of base, the main product is the 17-hydroxy-20-ketopregnane, formed by... 

Ethynyl groups attached to various skeletons were generally oxidized to the hydroxyacetyl functionality. The reaction was useful in the synthesis of natural products and analogues with a dihydroxyacetone side chain, e.g. adriamycin and corticosteroids. Some examples are given in Table 4.1. 

The present procedure is an efficient two-step preparation of the 17-dihydroxyacetone side chain with a 16a-methyl substituent from the l6-dehydro-17-acetyl substructure.4 The D-ring substructure of the product is of pharmaceutical importance as seen in synthetic corticoids such as betamethasone.5 The two-step conversion consists of 1) conjugate addition of a methyl group into the 16-position and 2) a novel, double hydroxylatlon of the resultant enol silyl ether. 

Acetonium-ion bridged intermediates are not peculiar to the 3,5-position, although no salts have so far been isolated from other derivatives. Pregnane-i7a,20a,2i-triols, which are normally the minor products from reduction of the corticosteroid dihydroxyacetone side chain, have been prepared from the readily available 17a,20 8,21-triols by solvolysis of... 

C(i8) methyl group, and rear attack leading to the 20/S-epimer predominates. The same conformational effect operates in 17a- and 2i-hydroxylated 20-ketones, but is overcome when the dihydroxyacetone side chain is converted into a 17,21-ortho-t ter or similar cyclic derivative (14) [577. Reduction then converts the 20-ketone exclusively into the 20a-alcohol, apparently under "product development control 757]. 

D homo-annulation of compounds with the corticosteroid dihydroxyacetone side chain proceeds with Lewis acids [21 ]] according to the mechanism described for the 21-deoxy analogues. Substitution at C(i6) results in a remarkable in-... 

The dihydroxyacetone side-chain (554) in Reichstein s S is oxidized by alkaline triphenyltetrazolium chloride to the 21-aldehyde (555) further reaction under the influence of alkali affords a salt of the 17a,20-dihydroxypregnan-21-oic acid (556).22 ... 

Androsta-l,4-diene-3,17-dione reacted selectively at C-17 with potassium acetylide to give the 17a-ethynyl-17/8-alcohol the dihydroxyacetone side-chain was then elaborated by use of known transformations, without interference from the l,4-dien-3-one system/ Ethynylation of a [16- H]- or [16- H2]-17-oxo-steroid proceeds without loss of label/ ... 

Acelonides (Isopropylidine derivatives). 2,2-Dimethoxypropane reacts with the dihydroxyacetone side chain of a corticosteroid to give a 17,21-acetonide useful for side-chain protection. " The blocking group is stable to base but can be removed by... 

Steroid ortho esters. Under add catalysis, triethyl orthoformate reacts with a steroid containing the dihydroxyacetone side chain (1) to form a protected derivative (2). Under the conditions used a A -3-keto group is not converted into the... 

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