Andrew W. Bridge

Total synthesis of (R,R)-crinan via regiospecific and stereoselective palladium catalysed cyclisation

Abstract The synthesis of (R,R)-crinan from (S)-1-cyclohexenylethan-1-ol is described. The key palladium catalysed step involves a regiospecific 6-exo trig cyclisation which proceeds with 20:1 stereoselectivity for the trans-ring junction over the cis-ring fusion. The ring junction stereochemistry is sensitive to solvent, phosphine and small amounts of water.

Sequential and cascade 1,3-dipolar cycloaddition-palladium catalysed carbonylation-cyclisation reactions. Diastereospecific and homochiral processes

Abstract Combinations of imine a azomethine ylide a cycloaddition cascades with Pd(0) catalysed cyclisation -carbonylation forming 5- and 6-membered lactams in sequential reactions are described and both diastereospecific and homochiral examples are provided. The azomethine ylides can be generated either via thermal 1,2-prototropy or metal ion catalysis at ambient temperature. The former sequence has been combined with the Pd(0) catalysed cascade into a one-pot protocol.

RP 70676: A potent systematically available inhibitor of acyl-CoA:cholesterol O-acyl transferase (ACAT)

Abstract RP 70676 (3d) is a potent inhibitor of ACAT. It is an effective hypocholesterolaemic agent in the cholesterol-fed rabbit, and reduces the accumulation of both cholesterol and cholesterol ester in rabbit aorta and thoracic artery. The compound is readily bioavailable in rabbits with significant levels of parent compound present in plasma up to 6 hours after an oral dose.

Rearrangement of a steroidal α-hydroxyacetal: a convenient new method for the introduction of a 5α-methyl group into the steroid nucleus

Both 5-hydroxy-3β-methoxy-5α-cholestane-6-spiro-2′-(1′,3′-dioxolane)(2) and its 5β-epimer (3) undergo cleavage of the acetal ring with skeletal rearrangement to give 5-(2-hydroxyethoxy)-3β-methoxy-4aα-methyl-A-homo-B-nor-5β-cholestan-4aβ-ol (5) upon treatment with MeMgl in refluxing toluene; in a second rearrangement the A-homo-B-norsteroid (5) is smoothly converted into 3β-methoxy-5-methyl-5α-cholestan-6-one (7).

Neighbouring group participation in the cleavage of steroidal α-hydroxyacetals

Both 6,6-ethylenedioxy-5-hydroxy-3β-methoxy-5α-cholestane 13 and its 5β-epimer 17 undergo cleavage of the acetal ring with skeletal rearrangement to give 5-(2-hydroxyethoxy)-3β-methoxy-4aα-methyl-4a-homo-7-nor-5β-cholestan-4aβ-ol 19 upon treatment with MeMgl in refluxing toluene; in a second rearrangement the 4a-homo-7-norsteroid 19 is smoothly converted into 3β-methoxy-5-methyl-5α-cholestan-6-one 25.

Synthesis of 1,3-disubstituted-pyrrolo[2,1-a]isoquinoline-2-carboxylic acids, esters and amides

A number of 1,3-disubstituted pyrrolo [2,1-a] isoquinoline-2-carboxylic esters have been prepared using a variety of independent routes. The corresponding acids and a range of amides were subsequently synthesised. The primary amides were found to differ significantly from those reported to arise from the reaction between the anion of an isoquinoline Reissert compound and an α,β-unsaturated nitrile. Re-investigation has established that the latter reaction does not produce primary amides. The true nature of the products as 2-acyl-3-aminopyrrolo[2,1-a]isoquinolines was established using X-ray crystallography.

Preparation and cleavage reactions of some steroidal epoxides

The steroidal epoxides (12), (13), (28), and (34) have been prepared and their reactions investigated. Attempts to prepare the epoxides (12) and (13) by the action of dimethylsulphonium methylide or dimethylsulphoxonium methylide on the ketone (1) gave instead the rearranged product (2) and its methyl ether (3). Compound (2) has also been obtained by base-catalysed isomerisation of the spiro-epoxide (13). Lewis acid-catalysed rearrangement of the epoxides (12), (28), and (34) into the A-homo-B-norsteroids (16), (29), and (43) respectively is described.