Stephan D. Gero

Stereoselectivity in radical reactions of 2′-deoxynucleosides. A synthesis of an isostere of 3′-azido-3′-deoxythymidine-5′-monophosphate (AZT-5′ monophosphate)

Abstract The bulky t-butyldiphenylsilyl group, attached to the 3′-hydroxyl of the uronic acid from thymidine, permits a stereoselective formation of a carbon-carbon bond using the 4′ carbon radical. Taking advantage of this stereoselectivity an isostere of 3′-azido-3′-deoxythymidine-5′-monophosphate (AZT 5′-monophosphate) has been synthesised.

Preparation of six membered carbocycles by aryl-tellurium mediated free-radical cyclisation

Abstract Radical cyclisation of various telluro-compounds was examined. Olefins conjugated to an electron withdrawing group, ( 7, 8, 9, 10, and 11 ) gave high yields of the corresponding six membered products. Non-activated olefin 23 gave the corresponding thiopyridyl derivative 24 as the only product. The photolysis, using oxime 18 as radicophile for the cylisation, proceeded slowly at room temperature, and gave only a low yield of products 19 and 20 .

Chiral synthesis of 3,4-disubstituted 2-azetidinones from (R,R)-(+)-tartaric acid

Abstract A novel route Is described for the enantioselective synthesis of 2-azetidinones 24 and 25 from (R,R)-(+)-tartaric acid. Monomethylation, monobenzylation of 2 and the use of site specific pig liver esterase (PLE) to produce 6 and 7 are the key steps in the sequence.

Radical decarboxylative alkylation of tartaric acid

Abstract New derivatives of L-(+)-tartaric acid have been synthesized from the monomethyl-2,3-O-isopropylidene (R,R)-(+)-tartrate by visible light photolysis of its N-hydroxy-2-thiopyridone ester derivative in presence of activated alkenes. The carbon radical generated at the dioxolane ring adds stereoselectively to olefins to give the addition products with retention of configuration.

Stereospecificity in radical carbon–carbon bond formation reactions based on tartaric acid

Radical decarboxylative addition to activated alkenes, using the thiohydroxamic ester method, of a suitably protected derivative of (+)-L-tartaric acid leads to overall substitution of the carboxy group with essentially complete retention of configuration.

Total synthesis of (–)-ovalicin and analogues from L-quebrachitol

We describe here the first chiral total synthesis of (–)-ovalicin and the synthesis of several related analogues, from the naturally occurring cyclitol L-quebrachitol.

Synthesis of trans-(3S,4S)-dibenzyloxycyclopentanone

The 1-cyano-1-thiophenylcyclopentone derivative 1, obtained from (R,R)-(+)-tartaric acid, has been converted into a number of derivatives including the important trans-(3S,4S)-dibenzyloxycyclopentanone 2 in 45% overall yield.

Enantioselective synthesis of inositols as intermediates for the preparation of deoxy-inositol phosphates from D-galactose

Abstract Optically pure 6-deoxy-inososes, 6-deoxy-inositols and 6-deoxy-inositol-1,4,5-trisphosphates were synthesized from D-galactose by the carbohydrate-inosose Ferrier rearrangement. 6-Deoxy-inositolphosphates exhibit a tight binding to the Ins-P 3 -receptor making such compounds an interesting tool for studying the intracellular signalling. It is now well established that receptor stimulated hydrolysis of inositol phospholipids is a common mechanism for transmembrane signalling when cells respond to external stimuli such as hormones, neurotransmitters, antigens, light, growth factors and insulin 1 . It was also shown that phosphatidylinositol-4,5-bisphosphate [(Ptd)Ins(4,5)P 2 ] is a major inositol lipid hydrolysed by activated phospholipase C, resulting into the simultaneous generation of two “second messengers”, D- myo -inositol-1,4,5-trisphosphate [Ins(1,4,5)P 3 ] and diacylglycerol (DG) 2 . Ins(1,4,5)P 3 triggers the mobilization of Ca ++ from intracellular stores and DG stimulates protein phosphorylation via the activation of protein kinase C 3,4 . In addition (Ptd)Ins(4,5)P 2 contains a high percentage of arachidonic acid in the sn-2 position, which is released for lipoxygenase and cyclooxygenase pathways. These “second messengers” and their metabolites control and modulate vital physiological processes by their independent, additive and synergestic effects. 5 Therefore, it is conceivable that inhibitors of the key enzymes of the phosphoinositide cascade could be of medicinal interest and could be also useful tools to elucidate the individual role of the inositol metabolites in regulation of cell functions. 6,7 In view of difficulties in the isolation of inositol phosphate metabolites from natural sources and the need for structural analogues, several synthetic studies have been reported 8 . However, these have employed mostly the optically inactive myo inositol as a logical and cheap starting material. The crucial role of the phosphate esters at positions 1, 3, 4, and 5 of the myo inositol nucleus in the “second messengers” Ins(1,4,5)P 3 and Ins(1,3,4,5)P 4 is well established. For analogue synthesis, modifications of the centers C-1, C-3, C-4 and C-5 or alteration of the hydroxyl functions at neighboring carbons (C-2 or C-6), not involved at first glance in cellular processes, seemed justified. With these considerations in mind we have initiated a synthetic program aimed to proxide access to the hitherto unknown partially protected 6-deoxy-cyclitols 8 and 9, appropriate precursors of a variety of chiral deoxy-inositol phosphates 9 . Our approach to the deoxy-inositols 8 and 9 has been envisaged from the chiral deoxy-inososes 6 and 7 which could be obtained by mercury(II) mediated carbohydrate-inosose Ferrier rearrangement 10 from hex-5- ene -pyranoside 5. Olefin 5 was readily prepared in a four steps sequence from methyl-β-D-galactopyranoside 1 in 60% overall yield 11 . Treatment of 1 with 1,1-dimethoxycyclohexane in DMF in presence of sulfuric acid afforded acetal 2 in 90% yield. The latter was selectively brominated with triphenylphosphine-carbontetrabromide, leading to 3 (m.p. 122–123°C). Benzylation of 3 by a phase transfer process (powdered KOH, benzyltriethylammonium chloride, benzyl bromide in CH 2 Cl 2 ) furnished benzyl ether 4 (m.p. 94–95°C,[ α ] rmD 20 + 46). Access to olefin 5 (m.p. 61–62°C, [ α ] rmD 20 − 55) was achieved by two methods. Initially the bromo compound 4 was dehydrobrominated with sodium hydride in DMF (3h, 100°C) giving 5 in 90% yield 12. An alternative route for the

The use of radical decarboxylation in the preparation of 1-methylcarbapenem antibiotic precursors from D-glucosamine

Abstract The stereocontrolled synthesis of optically active 1-methylcarbapenams has been performed by radical cyclization and radical decarboxylation. 1,3,4-Trisubstituted-2-azetidinones, prepared by the Staudinger reaction with D -glucosamine as chiral auxiliary and sorbic acid were used as starting materials.

Novel (4 + 1) fragment combination approach to chiral cyclopentanoids from tartaric acid

A chiral cyclopentanoid building block 29 has been synthesized in “one pot” cyclization process from epoxides 22 - 25 (which are readily accessible from (R,R)-(+) tartaric acid) with the carbanion derived from phenylthioacetonitrile (PhS-CH2-CN).