Asymmetrische Synthesen via metallierte chirale Hydrazone. Enantioselektive Alkylierung von cyclischen Ketonen und Aldehyden1

Abstract

Aldehyde und cyclische Ketone werden mit (S)-l-Amino-2-(methoxymethyl)pyrrolidin (13) (SAMP) in die entsprechenden chiralen SAMP-Hydrazone 1 iibergefiihrt, die mit Lithiumdiisopropylamid in Tetrahydrofuran in a-Stellung metalliert werden konnen. Die resultierenden chiralen ,,Azaenolate" 2 werden bei -95 "C zu Produkthydrazonen 3 alkyliert, die durch Ozonolyse bzw. Hydrolyse iiber Methoiodide 15 zu optisch aktiven, a-chiralen Carbonylverbindungen 5 gespalten werden. Die Methode gestattet die enantioselektive Alkylierung von Aldehyden und cyclischen Ketonen in chemischen Gesamtausbeuten von 51 -80% und in hoher bis zu volliger Enantioselektivitat. Die chirale Hilfsverbindung ,,SAMP" wird unter Verwendung des ,,chiralen pools" in 4 Stufen aus (S)-Prolin (12) uber 9,lO und 11 bzw. in 6 Stufen iiber 9 , 6 , 7 , 8 und 11 hergestellt. Es wird gezeigt, d& a-chirale Aldehyde mit dem BH, . THF-Komplex racemisierungsfrei zu p-chiralen Alkoholen 16 reduziert werden konnen. Eine ,,synthon-kontrollierte Enantioselektivitat" wird am Beispiel der enantioselektiven Synthese von (R)-und (S)-2-Methylbutanal(51, 5 1') demonstriert. Asymmetric Synthesis via Metalated Chiral Hydrazones. Enantioselective Alkylation of Cyclic Ketones and Aldehydes l . 3Aldehydes and cyclic ketones are converted with (S)-l-amino-2-(methoxymethyl)pyrrolidine (13) (SAMP) to the corresponding chiral SAMP-hydrazones 1, which can be metalated in a-position by lithium diisopropylamide in tetrahydrofuran. The resulting chiral ,,azaenolates" 2 are alkylated at -95 "C to product hydrazones 3, which are cleaved to optically active a-chiral carbonyl compounds 5 by ozonolysis or hydrolysis oiu methoiodides 15. The method allows the enantioselective alkylation of aldehydes and cyclic ketones in overall chemical yields of 51 -80% and in high, up to complete enantioselectivity. The chiral auxiliary ,,SAMP" is prepared using the ,,chiral pool" in 4 steps from (S)-proline (12) oiu 9, 10 and ll or in 6 steps oiu 9, 6, 7, 8 and l l . It is shown that a-chiral aldehydes can be reduced with BH, . THF-complex to bchiral alcohols 16 without racemization. A ,,synthon-controlled enantioselectivity" is demonstrated in the case of the enantioselective synthesis of (R)-and (S)-2-methylbutanal(51, 51').Da die biologische Aktiviut von Enantiomeren in der Regel verschieden ist, wird man in der modernen Wirkstoffsynthese mehr und mehr Wege beschreiten miissen, die zu enantiomerenreinen Produkten fiihren3). Eine chiral okonomische4) Ldsung hierzu bietet die asymmetrische Syntheses). Obwohl in den letzten 7 -8 Jahren enorme Fortschritte erzielt wurden5fs h,i), gilt die

Asymmetric synthesis of long chain α-methyl-β-thiotrifluoromethyl ketones employing the SAMP-/RAMP-hydrazone alkylation methodology

“…48 The absolute configuration was assigned by an analogy with previous results obtained with b-sulfenylated ketones, as well as for the model currently accepted for the relative topicity of electrophilic attack onto lithium azaenolates derived from SAMP-hydrazones. 34,49 Therefore, the newly created stereogenic center has an (R)-configuration, whereas the pyrrolidine stereogenic center maintained the original configuration of the starting non-methylated hydrazones. Similarly, the alkylation product with the (S) configuration at the new stereogenic center can be obtained from the RAMP-hydrazone.…”

Aldehyde N,N‐Dialkylhydrazones as Neutral Acyl Anion Equivalents: Umpolung of the Imine Reactivity

“…[95] Additionally, the method developed for the cleavage of N,N-dimethylhydrazones 191 by MMPP proved to be also suitable for the cleavage of SAMP-hydrazones 195, [91,92b,89b] which afforded optically enriched nitriles (S)-193 in excellent yields (Scheme 31). Thanks to the mild conditions required, both transformations were found to proceed without racemization, in spite of the sensibility of the stereogenic centers of the products.…”

Stereoselective Synthesis of α‐Branched Amines by Nucleophilic Addition of Unstabilized Carbanions to Imines

“…The method most commonly used for the preparation of imines derived from aldehydes and anilines [9], primary amines, or hydrazines [10] consists in mixing a nucleophilic amine with the corresponding carbonyl derivative under Dean-Stark conditions or in the presence of a dehydrating agent, such as magnesium sulfate or molecular sieves. For example, the preparation of the imine derived from benzaldehyde and o-anisidine is accomplished by stirring both reagents in benzene in the presence of molecular sieves (Scheme 1.3).…”