Corticoid side chain

Acylated Corticoids. The corticoid side-chain of (30) was converted iato the cycHc ortho ester (96) by reaction with a lower alkyl ortho ester RC(OR )2 iu benzene solution ia the presence of i ra-toluenesulfonic acid (88). Acid hydrolysis of the product at room temperature led to the formation of the 17-monoesters (97) ia nearly quantitative yield. The 17-monoesters (97) underwent acyl migration to the 21-monoesters (98) on careful heating with. In this way, prednisolone 17a,21-methylorthovalerate was converted quantitatively iato prednisolone 17-valerate, which is a very active antiinflammatory agent (89). The iatermediate ortho esters also are active. Thus, 17a,21-(l -methoxy)-pentyhdenedioxy-l,4-pregnadiene-liP-ol-3,20-dione [(96), R = CH3, R = C Hg] is at least 70 times more potent than prednisolone (89). The above conversions... 

A third variation of this strategy has been appHed to an enantioselective total synthesis of cortisone. From an appropriately functionalized, scalemic hydrindan that possessed an 11-oxo-group and a masked corticoid side-chain, (+)-cortisol was produced in an 11-step total synthesis (213). 

Oxidation of the 3-hydroxy-A systenli with manganese dioxide in refluxing benzene affords a moderate yield of the corresponding 4,6-dien-3-one. These vigorous conditions also suffice to cleave the corticoid side chain (17a,21-dihydroxy-20-ketones) to give 17-keto steroids. ... 

Corticoid side chain.5 The final step in a recent total synthesis of cortisone (2) employed a novel double hydroxylation of an enol silyl ether (1) for construction of the side chain. Thus treatment of 1 with 3 equiv. of the peracid and KHC03 in CH2C12 at 0° results in hydroxylation at both Cl7 and C,. 

Double Hydroxylation Reaction for Construction of Corticoid Side Chain Synthesis of 16a-Methylcortexolone. 

W P Schneider and A V McIntosh, U S Patent 2,769,824 (1957) [C A 51, 8822e (1957)] The use of NMO in catalytic Os04 reactions was first disclosed in this patent during work to introduce the corticoid side chain (an a-ketol) in a steroid... 

In order to synthesize 17-a-hydroxyaldosterone 2a,12 a side chain protection was needed. Otherwise the 18-carbon radical tended to furnish a methylene group and open the 13-17 bond in ring D. A convenient protection for the corticoid side chain is the A/.v-ketal derived from formaldehyde. Thus Msmethyl-enedioxy-1-dehydrohydrocortisone 21 was converted to its nitrite and photolyzed in the usual way. The only product (60 % isolated yield) was the desired isomer 22. When this was treated with nitrous acid, an unusual sequence of reactions took place. The normal nitrosation intermediate underwent ring closure to 24 followed by oxonium ion formation 25 as indicated. The oxonium ion 25 then opened one of the adjacent methylenedioxy groups (25 -> 26) which on hydration with water afforded the isolated product 27. Acetylation of 27 with acetic anhydride and acid catalysis gave the triacetate 28 in 80 % overall yield from the oxime 22. Mild alkaline hydrolysis... 

DOUBLE HYDROXYLATION REACTION FOR CONSTRUCTION OF THE CORTICOID SIDE CHAIN 16a-METHYLCORTEXOLONE (Pregn-4-ene-3,20-dione, 17,21-dlhydroxy-16-methyl-, (16a)-( )-)... 

DOUBLE HYDROXYLATION REACTION FOR CONSTRUCTION OF THE CORTICOID SIDE CHAIN ... 

Synthesis of pregnane and corticoid side chains.6 The 17a-ethynylcarbinol acetate (1) is reduced by zinc dust in refluxing diglyme, a process which is accompanied by rearrangement and elimination, to give the allenyl steroid (2) in 86 % yield. The desired corticoid side chain (3) can be formed from (2) by reaction with osmium tetroxide-... 

The isomerization of 17-a-ethynyl-17j8-hydroxy-steroids (22) to the 17(20)-en-21-al compounds (23) is catalysed in high yield by [(C6Hs)3SiO]3VO. This rearrangement, which probably proceeds via the intermediacy of a vanadate ester, affords a new entry into the preparation of the corticoid side chain from 17-keto-steroids and compares favourably with earlier related routes. 

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