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The development of an efficient manufacturing route to 2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetic acid methyl ester SB-235349, a key intermediate in the synthesis of lotrafiban is described. The synthesis starts with 2-nitrobenzyl alcohol which is mesylated, reacted with methylamine and then dimethylacetylene dicarboxylate followed by reduction of the nitro group. Treatment of the resultant aniline with acid gives an intermediate quinazoline which rearranges on treatment with base to give a 1,4-benzodiazapine. Reduction of the exocyclic double bond affords SB-235349. The process can be run without isolation of any of the intermediates and has been used to prepare several tons of SB-235349.

During the scale-up of a chemical process to produce phase II supplies of the chiral compound Lotrafiban, partial racemisation occurred to produce drug substance of unacceptable chiral purity. A new route capable of producing several hundred kilograms of Lotrafiban of high chiral purity had to be rapidly identified and scaled up. The strategy adopted was to employ an enzymic resolution as the final step, thus introducing the chirality under very mild conditions to prevent any racemisation. This was achieved using an immobilised form of the Candida antarctica B lipase in water at 30 °C. The biotransformation was demonstrated to be a robust, reliable, and an economic way to introduce the chirality into the Lotrafiban molecule.

A new condensation of 3-alkenamides with benzaldehyde in acidic media, notably polyphosphoric acid, leads to gamma-lactam rings with high regio- and stereocontrol. One such gamma-lactam was shown to undergo a novel and stereocontrolled ring-expansion to a delta-lactam.

delta-Lactams have been synthesized with excellent stereocontrol of substituents by condensing 3-alkenamides with aryl aldehydes in polyphosphoric ester. The scope of the condensation of 3-alkenamides with aryl aldehydes in several phosphate media is examined, and a rationale is proposed regarding gamma-lactam versus delta-lactam formation.

A new synthesis of lotrafiban SB-214857-A is reported. The key steps are the preparation of racemic (4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-2-yl)-acetic acid methyl ester from 2-nitrobenzyl alcohol, a resolution using an immobilised lipase enzyme and a palladium-catalysed aminocarbonylation reaction.

(I) C 12 H 13 NO, P2 1 /c, a=14.589, b=8.330, c=8.186 A, β=103.17°, R=0.055. (II) C 19 H 19 NO, P2 1 2 1 2 1 , a=9.100, b=9.678, c=17.360 A, R=0.049. (III) C 13 H 15 NO, P2 1 /n, a=8.121, b=16.257, c=8.686 A, β=107.65 °, R=0.046.

delta-Lactams have been synthesized with excellent stereocontrol of substituents by condensing 3-alkenamides with aryl aldehydes in polyphosphoric ester. The scope of the condensation of 3-alkenamides with aryl aldehydes in several phosphate media is examined, and a rationale is proposed regarding gamma-lactam versus delta-lactam formation.

Transannular hydrogen bonding stabilizes a left-handed double helical conformation in the tryptophan-derived tetraazacyclooctadecane 1 both in solution and the solid state, whereas the analogous tryptamine-derived macrocycle 2 shows less tendency towards intramolecular hydrogen bonding and does not exist as a helix in the crystal. Azamacrocycles 1 and 2 are synthesized by a novel method and their secondary structure analysed by NMR spectroscopy, circular dichroism and X-ray diffraction. Molecular modelling does not account for the conformational differences between 1 and 2.

(I) C 12 H 13 NO, P2 1 /c, a=14.589, b=8.330, c=8.186 A, β=103.17°, R=0.055. (II) C 19 H 19 NO, P2 1 2 1 2 1 , a=9.100, b=9.678, c=17.360 A, R=0.049. (III) C 13 H 15 NO, P2 1 /n, a=8.121, b=16.257, c=8.686 A, β=107.65 °, R=0.046.

Treatment of an unsaturated 2,3-epoxy alcohol with SnBr 4 leads to a stereoselective formation of a cyclopropane ring, and an α-ketol unit as part of a subsequent ring expansion.

gamma-Lactams and delta-lactams have been synthesized stereoselectively by condensing 3-alkenamides with benzaldehyde in acidic media.

[reaction: see text] Tryptophan-derived azoninoindole imines select partners of the same chirality for dimerization to helical macrocycles.

Transannular hydrogen bonding stabilizes a left-handed double helical conformation in the tryptophan-derived tetraazacyclooctadecane 1 both in solution and the solid state, whereas the analogous tryptamine-derived macrocycle 2 shows less tendency towards intramolecular hydrogen bonding and does not exist as a helix in the crystal. Azamacrocycles 1 and 2 are synthesized by a novel method and their secondary structure analysed by NMR spectroscopy, circular dichroism and X-ray diffraction. Molecular modelling does not account for the conformational differences between 1 and 2.

A convergent regiospecific route to the aklavinone (II) ring system is described.