Alain Commerçon

Improved protection and esterification of a precursor of the taxotere® and taxol side chains

Abstract (4S,5R)-N-BOC-2,2-dimethyl-4-phenyl-5-oxazolidinecarboxylic acid 8 was prepared and efficiently esterified by conveniently protected baccatins 9a,b . Smooth deprotection in formic acid gave the N-deprotected intermediates of Taxotere® and taxol. This protocol did not generate any epimerization at C-2′ and constitutes a pratical method to prepare Taxotere®, taxol and analogs.

A practical access to chiral phenylisoserinates, preparation of Taxotere® analogs

Abstract A practical diastereoselective synthesis of phenylisoserine methyl esters 8a-c is described using α-methyl-benzylamine as the chiral template of a Staudinger reaction. Optically pure diastereoisomers 6a-c were easily recovered by crystallization. After opening of these intermediate azetidinones by hydrochloric acid and methanol, regioselective cleavage of the chiral auxiliary was achieved by hydrogenation over palladium. Phenylisoserinates 8b,c were used to prepare analogs of Taxotere®.

2-Monosubstituted-1,3-oxazolidines as improved protective groups of N-boc-phenylisoserine in docetaxel preparation

Abstract A new route for semisynthetic docetaxel, 1, is described using 2-monosubstituted-4-phenyl-1,3-oxazolidine-5-carboxylic acids in esterification of 7,10-O-diTroc-10-desacetylbaccatin III (4). Subsequent deprotection of esters 10(+10′) afforded title compound 1 without removal of the Boc group.

Constrained analogs of KCVFM with improved inhibitory properties against farnesyl transferase

Abstract Constrained analogs of KCVFM, reported thus far as one of the most active peptidic inhibitors of farnesyl transferase, have been synthesized. Replacement of Val-Phe with Val-Tic and (N-Me)Val-Tic led to dramatically more active analogs possessing favored extended conformations. Based on molecular modelling studies the design and synthesis of various conformational probes to be substituted for Val and Phe led to a good correlation between the ratio of extended conformers and biological activity.

Diastereoselective chlorocyclofunctionalization of n-allylic trichloroacetamides : synthesis of an analogue and potential precursor of RP49532

Abstract Treatment of (E)-N-cinnamyl trichloroacetamide with hypochlorous acid yielded trans -dihydro-oxazine 8 which was easily hydrolyzed to (±)- erythro -β-chloro-γ-hydroxy- γ-phenyl-propanamine 2 . Applied to the imidazole series, this chlorocyclization gave 15 , a potential intermediate in the synthesis of RP49532.

Expeditious semisynthesis of docetaxel using 2-trichloromethyl-1,3-oxazolidine as side-chain protection

Chloral reacts with phenylisoserine and N-Boc-phenylisoserine methyl esters to give N-unprotected 2-trichloromethyl-1,3-oxazolidines 4+4′. The corresponding oxazolidinecarboxylic acids 5+5′ were esterified by 10-desacetyl-7,10-diTroc-baccatin III. Concomitant deprotection of the Troc and 2-trichloromethylmethylene groups was achieved under reducing conditions (Zn, AcOH). The recovered product 7 was acylated with di-tert-butyldicarbonate to give docetaxel 1.

PREPARATION OF 7-MODIFIED DOCETAXEL ANALOGS USING ELECTROCHEMISTRY

The electrochemical reduction of 7α-iodo docetaxel at E-1.3V vs. SCE in methanol in the presence of lithium chloride and hydrochloric acid leads predominantly to 7-deoxy-docetaxel 9. When the electroreduction is conducted at E-1.7V vs. SCE in the presence of sodium acetate and acetic acid, the cyclopropanol-containing taxoid 10 is formed in good yield. Electrochemical reduction of 7-deoxy-docetaxel at C-10 is also reported. All these docetaxel analogs retain biological activity.

Direct access to 2-debenzoyl taxoids by electrochemistry, synthesis of 2-modified docetaxel analogs

Abstract A new route to semisynthetic 2-modified docetaxel analogs is described using electrochemical cleavage of the 2-benzoate as the key reaction. Subsequent reacylation at C-2 followed by sequential deprotections afforded the title analogs. Biological results of selected 2-docetaxel analogs are presented.

A diastereoselective synthesis of girolline

Girolline (RP 49532, 1), a new antitumour agent, was prepared in the racemic series using an oxidation-reduction sequence starting from (±)-erythro-β-chloro-γ-hydroxy- 1-triphenylmethyl-1H-4-imidazolepropanamine 3. The heterocyclic amino function was introduced via the coupling reaction of 9 with an aryldiazonium salt, followed by the reduction-deprotection of the 2-arylazo derivative 10.

Enantioselective synthesis of girolline

Abstract Girolline (RP 49532) is efficiently and enantioselectively synthesized from the aldol reaction of (R)-3-chloroacetyl-4-isopropyl-1,3-oxazolidin-2-one 2 and 1-triphenylmethylimidazole-4-carboxaldehyde 3 followed by reaction with aqueous ammonia and reduction with borane. The last steps use the 2-arylazo procedure.