3-Acetyl-p-lactam

P-Lactams. Diketene can function as an equivalent to acetylketene, CH3C0CH=C=0, to provide 3-acetyl-p-lactams by [2 + 2]cycloaddition with imines.1 A stereoselective cycloaddition of this type can furnish a useful precursor (2) to lp-methylcarbapenems. Thus reaction of diketene with the chiral imine 1, prepared in a few steps from the readily available methyl (S)-3-hydroxy-2-meth-ylpropionate (Aldrich), can provide the desired 3,4-frpreviously developed for synthesis of the antibacterial carbapenem 4. 

An alternative route [53] that provided the azetidine-2,3-dione 93 in better yield was the cycloaddition reaction between 90 and the Schiff base. 75 promoted by phenyl dichlorophosphate reagent followed by oxidative hydrolysis of the in situ generated p-lactam 92. In this way the P-lactam 93 was obtained in 90% overall yield from 90. Conversion of 93 into the 3-acetyl-P-lactam 97 was achieved in three steps according to our procedure [54]. Namely, the a-keto-P-lactam 93 was treated with nitroethane in the presence of base. 

The utility of diketene 98 in P-lactam chemistry has also been shown by Simig and coworkers [64] to synthesize 3-acetyl P-lactams of type 116 suitable for further elaborations to ( ) thienamycin (Scheme 17). In such an approach, diketene was reacted with diethyl substituted aminomalonates 113, followed by ring closure of the resulting products 114 by treatment with sodium ethoxide in the presence of iodine. Ketalization of 115 and subsequent deethoxycarbon-ylation of 116 provided a mixture of cis and trans isomers of 117 which could be separated by column chromatography. Completion of the synthesis to the ( ) thienamycin precursor 8 could be achieved by established methods. A variant of the diketene method as source of acetylketene has been developed by Sato and Kaneko starting from a-aminoalkyl l,3-dioxin-4-ones [65]. 

In 2000, the group of Banik et al. reported the enantiospecific synthesis of 3-hydroxy-2-azetidinones by microwave assisted Staudinger reaction [51]. Chiral imines, derived from chiral aldehydes and achiral amines, reacted with methoxy- or acet-oxy-acetyl chloride to afford a single, optically pure c/s-p-lactam, (Scheme 7). 

A collection of 4-(C-galactosyl)- and 4-(C-ribosyl)-p-lactams featuring different substituents at C-3 and N-l has been prepared by combining in a one-pot procedure a formyl C-glycoside, a primary amine, and a substituted acetyl chloride in the presence of a base (Scheme 28), [90],... 

The synthesis of the azetidin-2-one nucleus, via the classical annulation of acetyl-chlorides with imines, requires more than stoichiometric amounts of Uiethylamine (about 3 equivalent), which cannot be recovered and reused. In addition, the procedure needs a large amount of organic solvents (VOCs) and, as a consequence, causes a large amount of waste. To overcome these difficulties, the possible ytterbium (III) triflate-catalysed stereoselective synthesis of P-lactams via [2+2] cyclocondensation in ionic liquids has been investigated by Su et al. (Scheme 16.4) [93]. 

The reaction between tri-O-acetyl-D-glucal 7 and chlorosulfonyl isocyanate has been studied in the past, but neither formation of a cycloadduct nor of a rearranged product has been observed. Isocyanate acted only as acid catalyst causing decomposition of sugar material. On the other hand, [2+2]cycloaddition of active isocyanates to dihydro-2H-pyran and to its derivatives has been widely investigated, under a variety of conditions. The reaction of tosyl isocyanate with dihydro-2H-pyran 1 at low temperature (0 ) led to the formation of bicyclic p-lactam 2. Elevation of the cyclization temperature resulted in the rearrangement of the four-membered ring to the open-chain amide 3 (Scheme 4). 

In the reaction of diketene with A-di-p-anisylmethyl substituted imine mixtures of the two 3-acetyl-/3-lactams are formed in a ratio of 7 1... 

The total synthesis of nocardicin A and its analogues has received considerable attention. One of the first approaches 11,14) made use of the classical keten-imine reaction for construction of the P-lactam ring. Reaction of phthalimido-acetyl chloride with the thioimidate (13) in the presence of triethylamine gave the P-lactam (14). Removal of the sulphvu grouping and deprotection afforded 3-ANA, which could be acylated with the appropriate side-chain acid to give nocardicins D, E and G. Reaction of nocardicin D with hydroxylamine produced nocardicin A. Alternative routes 15,16) utilise triazines such as (15) to provide a source of the imines of type (16). This sequence also removes the necessity of a desulphurisation step. 

Racemic compounds separated using alkylated CF6 as the selector in GC includes P-lactams, trifluoroacetyl derivatized amino acids, and tartaric acid esters [47]. Hydrogen bonding is of critical importance for enantiomeric separations in GC. On permethylated CF6, a-(trifluoromethyl)benzyl alcohol was baseline separated, whereas esters of this alcohol were less retained and no separation was observed (Table 3). Furthermore, no separation was observed for native a-methylbenzyl alcohol, which is a weaker hydrogen bond donor than a-(trifluoromethyl)benzyl alcohol. Likewise, enantiomers of A-acetylated amino acids were poorly separated or not separated, whereas A-trifluoroacetylated amino acids are very well separated [47]. 

Nitrogen-, Sulfur- and Selenium-containing Compounds.- 2,3.4-Tri-O-acetyl-P-D-arabinopyranosyl azide, 5 the azido orthoester 15, the diazirine 16, episulfide 17, selenourea 18, a-D-ribopyranosylamine l,3-(cyclic carbonate), lactams 19a/b and 20, the 6-nitro-7-methylthioheptitol 21,2-acetamido-2-deoxy-P-D-glycopyranosyl nitromethane (3-... 

When W-aceCyl-protected sugar amines were under investigation the A -acetyl group was observed to undergo transformation to the O-benzyl imidate in competition with OH benzylation (eq 3). It appears for best yields at least 1 equiv of reagent per OH and NAc group is needed, and subsequent hydrolysis and reacetylation of the amine are necessary to obtain are the originally desired material. Similar problems were encountered with the morpholine derived lactams (eq 4), where mixed products were obtained, but with p-lactams with yV-amide protection (eq 5), t -benzylation with benzyl trichloroacetimidate proceeded smoothly. BTCA has recently been used to convert diketopiperazines into their bis-benzyl imino ethers. ... 

METHOXYCARBONYL-1,1,6-TRIMETHYL-1,4,4a,5,6,7,8,8a-OCTAHYDRO-2,3-BENZOPYRONE, an intramolecular Diels-Alder reaction is responsible for the diastereoselectivity. The stereoselective 1,4-functionalization of 1,3-dienes is exemplified by a two-step process leading to cis- and trans-1-ACETOXY-4-(DICARBOMETHOXYMETHYL)-2-CYCLOHEXENE. The effectiveness of a silyl hydride in providing a means for erythro-directed reduction of a p-keto amide is applied in a route to ERYTHRO-1 -(3-HYDROXY-2-METHYL-3-PHENYL-PROPANOYLJPIPERIDINE. This is followed by an asymmetric synthesis based on a chiral bicyclic lactam leading to (R)-4-ETHYL-4-ALLYL-2-CYCLOHEXEN-1-ONE. The stereoselectivity with which acetoxy migration can operate to an adjacent radical center is reflected in the one-step reaction that gives rise to 1,3,4,6-TETRA-O-ACETYL-2-DEOXY-a-D-GLUCOPYRANOSE. 

Raney nickel) of the potassium salt of D-xy/o-5-hexulosonic acid oxime produces a mixture of 5-amino-5-deoxy-L-idonic and -D-glu-conic acid in the ratio of 2 1, which is converted into the methyl ester hydrochloride. Upon treatment with alkali, spontaneous cyclization to the pair of 1,5-lactams occurs. 5-Amino-5-deoxy-L-idono-l,5-lactam and 5-amino-5-deoxy-D-glucono-l,5-lactam were separated by recrystallization. The optical rotatory dispersion curves of both compounds were discussed. A new type of lactam, namely, 2-enamino-N,N -bis[(p-methoxycarbonyl)phenyl]-4-(D-gaiacfo-penta-acetoxypentyl)-4-butanelactam was prepared by tbe reaction of 5,6,7,8,9-penta-0-acetyl-3,4-dideoxy-D-ga/ocfo-nonulos- rcns-3-en-l-onic acid with methyl p-aminobenzoate. 

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