Anthony David Baxter

Application of the Michaelis–Arbusov reaction to the synthesis of internucleoside 3′-S-phosphorothiolate inkages

The 5′-O-monomethoxytrityl-3′-S-(aryldisulfanyl)-3′-deoxythymidines 7 and 8 have been prepared by the reaction of 5′-O-monomethoxytrityl-3′-thiothymidine with the appropriate arenesulfenyl chloride. These disulfides undergo a Michaelis–Arbusov reaction with simple trialkyl phosphites to yield 5′-O-monomethoxytrityl-3′-thiothymidin-3′-yl O,O-dialkyl phosphorothiolates. More interestingly, 3′-deoxy-3′-S-(2, 4-dinitrophenylsulfanyl)-5′-O-monomethoxytritylthymidine 8 reacts with a variety of thymidin-5′-yl dialkyl phosphites to give dithymidine phosphorothiolate triesters with the phosphorothiolate group protected with either a methyl or a 2-cyanoethyl group.3′-O-(tert-Butyldimethylsilyl)thymidin-5′-yl triethylammoniumphosphonate 17 is converted into the corresponding bis-(O-trimethylsilyl) phosphite by treatment with bis(trimethylsilyl)trifluoroacetamide. in situ Reaction of this phosphate with disulfide 8 gives, after work-up, the dithymidine phosphorothiolate diester directly. Methylation of compound 17 with methyl chloromethanoate, followed by silylation and subsequent reaction with disulfide 8, gives the methyl-protected dithymidine phosphorothiolate triester.

Synthesis and use of 7-substituted norbornadienes for the preparation of prostaglandins and prostanoids

Syntheses of 7-substituted norbornadienes from 7-t-butoxy- and 7-halogeno-norbornadienes are described. Rearrangement of the products in the presence of peracetic acid gives bicyclic aldehydes (2) in equilibrium with enol ethers (3) which are hydrolysed to hydroxycyclopentenylacetaldehydes (4), and converted into key intermediates for the synthesis of prostaglandins and their analogues. Syntheses of prostaglandin J analogues with n-hexyl and phenyl groups replacing the ω-side-chain are described.

Synthesis of (±)-prostaglandin I2 methyl ester and its 15-epimer from 2-(cyclopent-2-enyl)-1-(2-oxocyclopentyl)ethanol derivatives

The threo-2-(cyclopent-2-enyl)-1-(2-oxocyclopentyl)ethanol derivatives (2) and (3) have been converted into (±)-prostaglandin I2 methyl ester and its 15-epimer. The route involved halogenoetherification, hydrodehalogenation, Baeyer–Villiger oxidation, and methanolysis, to give the 5-hydroxyprostaglandin I1 derivatives (17) and (18). These hydroxy esters were mesylated, the 11- and 15-hydroxy groups were deprotected, and the resulting 15-epimeric alcohols were separated. The final elimination, accomplished by means of neat 1,8-diazabicyclo[5.4.0]undec-7-ene, gave the required Δ5-olefin with a high degree of regioselectivity, and was stereospecifically trans, giving the required Z-configuration (25).

Synthesis of 12,13-didehydroprostaglandin J2 methyl ester

A new class of prostanoid has been synthesized. The carboxylic acid ester (3) is an analogue of prostaglandin J2 and contains an allene moiety at C12. The novel compound (3) is available from 7-chloronorbornadiene (5) in a route which has two key steps. The first is the reaction of (5) with an alkynyl Grignard reagent to give the dienyne (7). The second is the regioselective epoxidation of the dienyne (7), rearrangement of the epoxide (8) to give the aldehyde (9), followed by an oxa-Cope rearrangement; the derived enol (10) was hydrolysed to give the useful prostaglandin synthon (14) directly.

Stereochemistry of the aldol reaction between [4-t-butyldimethylsilyloxy-5-(3-t-butyldimethylsilyloxyoct-1-enyl)cyclopent-2-enyl]ethanal and cyclopentanone enolates; a key step in the total synthesis of prostacyclin

Reactions of lithium, boron, zirconium, and tin enolates derived from cyclopentanone with [4-t-butyldimethylsilyloxy-5-(3-t-butyldimethylsilyloxyoct-1-enyl)cyclopent-2-enyl]ethanal (6) gave mainly the 5R, 6R, and 5S, 6S(prostaglandin numbering), threo-adducts, regardless of the nature of the enolate; the highest yield of threo-products (83% of a total yield of 93%) was obtained with lithium enolate in pentane at –78 °C. In contrast, the ratio of 5R,6R to 5S,6S products was significantly affected by the nature of the enolate, ranging from ca. 1:1.3 with a boron enolate to ca. 1:3 with a tin enolate, and ca. 1:4 with a lithium enolate.