Synthesis of Optically Active Nine‐Membered Ring Lactams by a Zwitterionic Aza‐Claisen Reaction

Abstract

The ketene-Claisen reaction was first described by D. Bellui in 1978 as an intermolecular variant of the [3.3] sigmatropic rearrangement of allyl and thioallyl ethers."I Recently, it was reported that allyl sulfides, in particular, can be rearranged under very mild conditions chemoselectively with the expected 1,3-chirality transfer from the C-S to a C-C bond. Furthermore, excellent 1,2-asymmetric induction was found when an optically active C -0 functionality was located x to the nascent C-C bond.[*] The reaction was also employed in the syntheses of medium-sized rings (7-13 ring atoms).[31 Until now the rearrangement was restricted to activated ketenes like chloroalkyl-and dichloroketene. Ally1 amines have been used in ketene-Claisen reactions only rarely. The few reported cases focused on conformationally fixed bicyclic systems or amines bearing an unhindered terminal olefinic unit.[41 Here, we report on the synthesis of optically active[51 hexahydroazoninones by a zwitterionic aza-Claisen reaction with complete 1,3-chirality transfer from chiral allyl amines.f5IAs starting compounds we used the ally1 amines 3, 6, and 9. The proline methyl ester 2 was synthesized from L-( -)-proline (1) by Clarke-Eschweiler methylationr6I and subsequent esterification (Scheme I).['] In a one-pot reaction 2 was reduced with diisobutylaluminum hydride (DIBAH) in situ to give the aldehyde; Horner olefination provided amino ester 3. Amino esters 6 and 9 were prepared by analogous sequences starting from truns-and cis-4-hydroxy-~-proline (4) and (7), respectively. Prior to the one-pot reduction/chain extension reaction, the free O H group was protected as a terr-butyldimethylsilyl (TBDMS) ether in 5 and S.rsl The diastereomeric purity of amino esters 3, 6, and 9 was determined by 'H and I3C N M R spectroscopy (see Table I) and by HPLC analysis. ['] Special two-phase conditions were developed for the Claisen rearrangement of ally1 amines 3, 6, and 9. A slurry of the amine and solid potassium carbonate in anhydrous chloroform at 0 "C was treated with acetyl chloride and 20 to 30 mol YO of trimethylaluminium. The corresponding partially hydrogenated azoninones 14, 15, and 16 were isolated in 65 to 84% yield (Scheme 2). In considering the reaction mechanism it seemed reasonable to assume that the acyl ammonium salt 10 forms initially. This intermediate could be attacked either by the nucleophilic halide ion in a von Braun type S, reaction["] generating the chlorides 11 and/or 12, or by a base (e.g. the chloride ion) which could deprotonate the a-position of the activated carbony1 group. The resulting zwitterionic intermediate 13 could then undergo 1) Acyl ammonium-salt 10 was detected in the reaction mixture at low temperatures by 'H and I3C N M R spectroscopy.2) Halides of type 11 and 12 were isolated in products of the rearrangement. Apparently the reaction path taken is determined by the bulk of the alkyl substituent on acyl ammonium salt 10: N-benzylated amino esters underwent the von Braun reaction to yield amides 11 and 12, whe...

An Enzyme-Labile Linker Group for Organic Syntheses on Solid Supports

“…[1] In the majority of the cases combinatorial syntheses are carried out on solid supports. Once the desired compounds are constructed they have to be released from the supports selectively and without attack on the synthesized structures through cleavage of a suitable anchor group (linker).…”

“…Treatment of the resulting immobilized nucleoside 15 with lipase RB 001-05 There is currently much interest in the preparation of new polyoxo(peroxo)metalates for homogeneous catalysis [1] and heterogeneous systems [2] in order to understand the chemistry of surface species and the nature of the catalytically active sites of transition metal containing molecular sieves or other materials. While studying oxidation reactions with mesoporous materials, [1m] which are potentially interesting catalysts and/or catalyst supports, [3] we became interested in comparing anionic or neutral oxoperoxo complexes with those that can be formed on silica and/or alumina.…”

“…[4] Furthermore, silica (BET specific surface area 263 m 2 g À1 ) and molybdenum± (or tungsten ± ) oxoperoxo species interact in aqueous acidic medium to form surface peroxo species with characteristic IR bands n Ä O±O near 870 cm À1 (n Ä O±O is expected to be in the range of 845 ± 885 cm À1 ). [1] These observations suggest that it might be possible to synthesize oxoperoxoheterosiloxanes involving the various functionalities on the silica surface (i.e., lone at pH 6.5 initiated the fragmentation of the linker and released the DMTr-protected thymidine 16 from the solid support under gentle conditions (Scheme 4).…”

Ungewöhnliche Diastereoselektivität beim Aufbau von Neunringlactamen und konformationskontrollierte transanulare Reaktion zu optisch aktiven Indolizidinonen

“…[1,2] Der streng geordnete sesselförmige Übergangszustand [3] der [3,3]-sigmatropen Umlagerung ermöglichte stets einen vollständigen 1,3-Chiralitätstransfer von einem chiralen (E)-Allylamin zum entsprechenden g,d-ungesättigten Lactam. [1,3] Darüber hinaus konnte in den meisten Fällen eine hohe Diastereoselektivität erzielt werden, [2,3] die mit einer (Z)-Enolatgeometrie im hypothetischen zwitterionischen Intermediat zu erklären war. Die auf diesem Wege erhaltenen Azoninone konnten in regio-und diastereoselektiven transanularen Reaktionen in Indolizidinone überführt werden.…”

“…Die Aldehyde trans-4 epimerisierten beim Aufbewahren bei Raumtemperatur (RT) allmählich, so daû nach der Diastereomerentrennung auch die cis-Vinylpyrrolidine cis-5 erhalten werden konnten. [12] Die Vinylpyrrolidine 5 wurden unter Standardbedingungen [1,2] in Chloroform in Gegenwart von Trimethylaluminium mit Chloracetylchlorid umgesetzt (Schema 2). Sowohl die Schema 2.…”