Optisch aktive Alkohole aus 1,3‐Dioxan‐4‐onen: eine praktikable Variante der enantioselektiven Synthese unter nucleophiler Substitution an Acetal‐Zentren

Abstract

Secondary alcohols in enantiomcric excesses above 90% are accessible from 2-substituted 6-methyl-I ,3-dioxan-4-ones lSchmie 4 ) . The dioxanones are prepared from aldehydes and readily available (R)or (S)-3-hydroxybutanoic acid. Treatment of the dioxanones with ailyl nucleophiles or triisopropoxy(inethyl)titanium in the presence of [CI,TiX] yields the corresponding 3-alkoxy acids in diastcreoselectivities 2 95%. The 'chiral auxiliary' is removed from the alkoxy acids by treatnieiit with LiN(i-Pr), to give the secondary alcohols with 2 90% ee. &/tran.c -Mixtures (9 : I ) or the dioxanones furnish products or the samc configurational purity as those obtained from pure cis-isomers. In comparison with other variants of eiiantioseleclive syntheses with nucleophilic substitution at acetal centers, the following advantages of the dioxanone method are noteworthy: i) ( R ) -and (S)-3hydroxybutanoic acids are both readily available; ii) reactions are not sensitive to changes in conditions; iii) the 'chiral auxiliary' is removed simply by base elimination, no oxidation is required; ic) no chromatographic purification steps are necessary. The overall reaction described here is an enantioselective nucleophilic addition to aldehydes with concomitant dehydration or enantiomerically pure 3-hydroxybutanoic to crotonic acid.Einleitung und Problemstellung. -Uber die Herstellung von optisch aktiven Alkoholen durch nucleophile Substitution an Acetal-Zentren wurde in jungster Zeit von verschiedenen Arbeitsgruppen berichtet [ 1-28]. Bei dicser Methode wird ein Aldehyd oder ein Keton im ersten Schritt mit einem enantiomerenreinen Diol in ein cyclisches Acetal iibergefuhrt. Anschliessend erfolgt eine diastereoselektive Lewis -Siiure induzierte Substitution am Acetal-Zentrum zuin Substitutionsprodukt, aus welchem der optisch aktive Alkohol freigesetzt wird. Der Vorteil dieser Methode liegt in der grossen Variationsmoglichkeit der verwendbaren Nucleophile: Allylsilane, Silylacetylene, Silyl-cyanide, a -Silylketone, Silyl-enol-ether, Silyl-ether, Silyl-keten-acetale, Alkyl-Grignard-und Alkyl-Lithium-Reagenzien, Alkyl-trihalogenotitan und Dialkyl-cuprate. Falls Ketone umgesetzt werden, konnen die entsprechenden Acetale mit Et,SiH/TiC14 oder Aluminiumhydriden geiiffnet werden. D a bei dieser Methode der chirale Hilfsstoff verloren geht, hangt ihre Anwendung vor allem von dessen Zugiinglichkeit oder Preis ab. Mit den von 2,3-Butandiol abgeleiteten Acetalen 1 (Schema I ) sind die Selektivitaten meist ungeniigend ( 2 90% ds) und die Spaltung der resultierenden a-Alkoxy-alkohole schwierig [2-51. Mit ') Vorlaufige Mitteilung, s. (261. ' ) ' ) Teil der Dissertation (Nr. X142) von R. I., ETH Zurich, 1986. Diplomarbeit von G . S . , ETH Zurich, 1985. PHB mehreren Tonnen pro Jahr industriell produziert4). PHB ist neben Glykogen das meist verbreitete Reservematerial von Mikroorganismen [35]. Durch Erhitzen von PHB in 1,2-Dichlorethan/EtOH (oder MeOH) unter Zusatz einer katalytischen Menge H,SO, wird der monomere (R)-konfigurierte Ethyl-(oder Methyl-)E...

Tetrahydrolipstatin: Degradation products produced by human carboxyl‐ester lipase

“…Tests with a mixture of 1 and degradation products thereof showed that the hydroxy acids formed are stabilized in the mixture [7] and rearrange at room temperature only after weeks to the corresponding 8-lactones, and that the hydroxy acids of the mixture in MeOH/Et,O give the corresponding methyl esters in nearly quantitative yield on addition of diazomethane in Et,O. To elucidate the configuration of the degradation products, the relative HPLC retention time(s) (tR) of the isolated diazomethane-quenched metabolite(s) of 1 were compared with that of the independently synthesized stable methyl 8-hydroxycarboxylates 2b and 3b. Products with inverted configuration at C(a) or C (8) were not anticipated because under harsher conditions than those used for the workup of the incubation with HCEL (CL Exper. Part), we never observed compounds arising from epimerization at one or both these centers [7].…”

“…Both isomers 2b and 4 proved to be stable below room temperature for months; in solution (MeCN/H,O 6 :4,MeOH,or MeCN) at room temperature, the isomers were fairly stable, and equilibrium by 1,3-shift of the amino-acid side chain was not attained within a month. For the synthesis of the 3-epimer 3b, we initially followed the protocol developed by Seebach and coworkers for the epimerization of ethyl 3-hydroxybutyrate [8]. Tosylation of the regioisomer mixture 2b/4 provided N-(formylamino)-tosylates 5a/6a as the main products together with isocyano-tosylates 7, by-products which were formed by dehydration of the desired tosylates 5a/6a (Scheme 2).…”

(+)-Sorangicin A: evolution of a viable synthetic strategy

“…Silylation of (+)- 11 , followed by condensation with (+)- 12 , promoted by TMSOTf, 62 furnished dioxanone (+)- 71 ; Petasis-Tebbe olefination 63 then provided enol ether (+)- 72 in 79% yield over the three steps without purification (Scheme 21). Exposure of (+)- 72 to our optimized Lewis acid (Me 2 AlCl) protocol, to trigger the Petasis-Ferrier rearrangement, pleasingly furnished tetrahydropyranone (+)- 73 in 70% yield as a single diastereomer.…”

(2S,4R,5S)-2,4-Dimethyl-5-hexanolide: Ants of Different SpeciesCamponotus Can Distinguish the Absolute Configuration of Their Trail Pheromone

“…For the synthesis of the anti isomers of 3, we started with the enantiomers of ethyl 3-hydroxybutanoate, which were converted to 10 and ent-10 using Seebachs procedure [7] followed by enolate methylation to 11, which was isolated in an anti/ syn diastereoselectivity of 95:5. The syn product could be removed by recrystallization from pentane, which is more effective than the column chromatographic procedure described in the literature.…”