Stereoselective Synthesis of a Key Intermediate of Sanfetrinem by Means of a Chelated Tin(IV) Enolate

Abstract

(2S)-2-Methoxycyclohexanone [(2S)-6], reacts with the 4-acetoxyazetidinone 3a in the presence of SnCl4 and a tertiary amine base (such as N,N-diisopropylethylamine) to give the ketoazetidinone 5 (a key intermediate in the synthesis of the broad-spectrum antibiotic sanfetrinem 2a) with high yield and diastereoselectivity. Low-temperature NMR studies of the reaction indicated the formation of a 1:1 chelate complex 11 between SnCl4 and (2S)-6 which, on addition of the base is transformed into the highly reactive chelated tin enolate 12. The formation of compound 11 has been confirmed by single-crystal X-ray analysis. The high diastereoselectivity observed is believed to derive from an open transition state where the chelated SnCl4 amplifies the stereochemical influence of the methoxy group. This reaction offers considerable advantages over all existing syntheses of the ketoazetidinone 5 and is currently under evaluation for inclusion in the industrial synthesis of sanfetrinem.

Condensation of β‐Diester Titanium Enolates with Carbonyl Substrates: A Combined DFT and Experimental Investigation

“…The addition of one molar equivalent of TiCl 4 to a solution of diethyl malonate in CD 2 Cl 2 at 25 8C resulted in a dramatic change of the (Figure 1c), according to previous evidence on similar enolates. [18] Quenching with a solution of DCl in D 2 O resulted in the tautomer-A C H T U N G T R E N N U N G isaA C H T U N G T R E N N U N G tion to the deuterated ester (results not shown). The coupled 13 C NMR spectrum confirmed the formation of the enolate.…”

Asymmetric Catalysis by Architectural and Functional Molecular Engineering: Practical Chemo- and Stereoselective Hydrogenation of Ketones

“…[104] This methodology was successfully applied to the asymmetric synthesis of sanfetrinem and its metabolically labile ester which has potent antibacterial activity (Scheme 56). [201,202] The key step is the hydrogenation of racemic 2-methoxycyclohexanone with an (S)-XylBINAP/ (S,S)-DPEN catalyst leading to (1R,2S)-2-methoxycyclohexanol with near-perfect stereoselectivity.…”

Obesity-linked insulin resistance in children – an emerging problem

“…Dieser Zusammenhang wurde erfolgreich bei der asymmetrischen Synthese von Sanfetrinem und seinem unter metabolischen Bedingungen labilen Ester, der starke antibakterielle Aktivität aufweist, angewendet (Schema ) 201, 202. Der Schlüsselschritt in der Synthese ist die Hydrierung von racemischem 2‐Methoxycyclohexanon mit einem ( S )‐XylBINAP/( S , S )‐DPEN‐Katalysator, die mit nahezu vollständiger Stereoselektivität zu (1 R ,2 S )‐2‐Methoxycyclohexanol führt.…”