Synthesis of Carbacephems from Serine

Abstract

Carbacephems have been synthesized from D-serine by two routes involving construction first of the six-membered ring followed by cyclization to give the bicyclic β-lactam. In one route, alkylation of a lactim ether was accomplished with Ni(Acac) 2 as a catalyst. The desired R stereochemistry at the carbon corresponding to C-6 of the cephem was obtained by stereospecific hydrogenation of a vinylogous carbamate. The second route involved a stereospecific Michael cyclization to give the same C-6 stereochemistry. Closure of a piperidyl β-amino acid intermediate common to both routes was accomplished using a modified Mukaiyama reagent found to be superior in our system to the traditional reagent. The resulting carbacephem core was stereospecifically substituted at C-7 with an ethyl or amino functionality. The ethylated intermediate was transformed into a stable enol triflate useful for the further elaboration of biologically important carbacephems.

Total synthesis of (±)-halichlorine, (±)-pinnaic acid, and (±)-tauropinnaic acid

“…To this end, amino ester 21 was converted to the corresponding amino acid by treatment with trif luoroacetic acid. ␤-lactam formation was effected in good yield by using modified Mukaiyama reagent 24 (34). Acetate cleavage pro- † Danishefsky and coworkers found, after some experimentation, that the trifluoroacetate group was suitable for this application (4, 5).…”

Synthesis of fused N-heterocycles utilizing the heterocyclic enamine protocol

“…Melting points are uncorrected. 1 H NMR and 13 C NMR spectra were obtained on a Bruker 300 spectrometer. IR spectra were obtained on a HITACHI-260-50 spectrometer as liquid films or KBr discs.…”

“…Since the late 1970s, heterocyclic enamines have been investigated by Kishi, 2 Danishefsky, 3-5 Rapoport 6 and others in the synthesis of saxitoxin, camptothecin, mitomycins and alkaloids. [7][8][9][10][11][12] And recently, exo-cyclic enaminoesters have been employed in the the synthesis of carbacephems 13 , a new class of β-lactam antibiotics. One of the most noticeable features of heterocyclic secondary enamines 1 is their ambident bisnucleophilicity; nucleophilic reaction can occur at the enaminic carbon and/or the secondary amino nitrogen.…”

2-Bromo-N-n-propyl-pyridinium-1,1,1-trifluoromethanesulfonate

“…Mukaiyama's reagent has low solubility in CH 2 Cl 2 . Due to these concerns, modified Mukaiyama's reagents possessing non nucleophilic counterions, such as tetrafluoroborate, hexachloroantimonate, 14 and triflate, 15 have been developed, providing higher yields in ester and peptide syntheses compared with the classical Mukaiyama's reagent.…”