Methylcarbapenem intermediate

Studies of the intramolecular cyclization of P-amino acids have included the use of camphor-derived oxazoline A-oxide 66 and a [3+2] cycloaddition reaction as a step in the formation of the amino acid with the required stereochemistry <00OL1053, OOEJOC1595>. A diastereoselective synthesis of a ip-methylcarbapenem intermediate utilises a cyclization of a P-amino acid <99CC2365>. 

Takasago group and Nozaki reported the synthesis of the 1-methylcarbapenem intermediate 78 by hydroformylation of the 4-vinyl / -lactam, (3BINAPHOS system followed by oxidation (Scheme 8, Table 13, entry Slightly better selectivities are... 

A similar cyclization strategy has been used for the synthesis of a key methylcarbapenem intermediate 10 [95SL915], The note worthy aspect of this work is the establishment of three contiguous chiral centers during the radical reaction. 

The same author [63] reported the synthesis of 1 (3-methylcarbapenem intermediates such as 111 (Scheme 16), employing chiral imines prepared from (S)-methyl 3-hydroxy-2-methylpropionaldehyde and p-anisidine or DAM-NH2. The reaction of diketene 98 with these imines in the presence of imidazole produced a diastereomeric mixture of P-lactams 107 and 108 in a variable ratio. These authors found that the best results in terms of chemical yield and stereoselectivity could be obtained when the [2 + 2] cycloaddition reaction was performed on imines derived from DAM-NH2 toluene as solvent and using 4-methylimidazole instead of imidazole. Under these conditions the P-lactam 108b was obtained in 49% yield and the ratio of isomers 107b/108b was 1 15. 

Considerable efforts have been devoted to the stereoselective introduction of a /(-methyl function in intermediates for the synthesis of 1 jS-methylcarbapenems. While the trimethylsilyl trifluoromethanesulfonate catalyzed reaction of a 4-acetoxyazetidinone derivative with ketene acetals shows no selectivity, ketene thioacetals lead to stereoselective formation of the a-methyl isomer108. The zirconium enolate, however, shows high /(-methyl selectivity. 

INAC reactions have also led to enantioselective syntheses of key intermediates in the synthesis of antibiotic l 3-Methylcarbapenem (724), to optically pure derivatives of tetrahydropyrano[2,3] cyclohexane (725a) to novel terahydro-isoxazolo-fused pyrano 2,3-/ quinolines (725b) and to a novel heterocyclic system, isoxazolo[3,4-d]thieno[2,3-b]pyridine (Scheme 2.229) (221). 

This asymmetric alkylation of cyclic acylimines can provide optically active precursors to carbapenems.2 Thus reaction of the 4-acetoxy-2-azetidinone 5 with the chiral 3-acyl-(4S)-ethyl-l,3-thiazolidine-2-thione 6 provides the substituted aze-tidinone 7, an intermediate in a total synthesis of (- )-l-(3-methylcarbapenem. 

Stereoselective aldol condensation. The stereoselectivity of the reaction of 1 with the ester 2 can be controlled by the choice of the metal enolate. The products are intermediates to 1-methylcarbapenems. 

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. 

Stereoselective Reformatsky reaction. The Reformatsky reaction of the chiral 2-azetidinone 1 with 3-(2-bromopropionyl)-2-oxazolidone (2a) gives essentially a 1 1 mixture of the diastereomers 3a(3 and 3aa. However, introduction of two methyl groups at C4 in 2 markedly improves the (i-diastereoselectivity, as does an increase in the temperature from 0 to 67° (reflux, THF). The highest diastereoselectivity (95 5) is observed with the derivative of 4,4-dibutyl-5,5-pentamethylene-2-oxa-zolidone. The 3p-diastereomer is a useful intermediate to lp-methylcarbapenems.1... 

U. E. Udodong and B. Fraser-Reid, Electrophilic amination as a route to deoxyamino sugars Synthesis of the key intermediate for 1-p-methylcarbapenem, J. Org. Chem. 53 2132 (1988). 

Intramolecular acid- or rhodium [II]-cataIysed carbene nitrogen-hydrogen insertion from iodonium ylide intermediates was used in an efficient synthesis of 1-/1-methylcarbapenems the cyclization products had different stereoselectivity, depending on the catalyst [11] ... 

Enantioseiective Hydrofomiylation. Enantioseiective hy-droformylation of a 4-vinyl-3-lactam, i.e., (3S,4R)-3-[(R)-l-(/er/-butyl-dimethylsilyloxy)ethyl]-4-vinyl-2-azetidinone,has been achieved by using an Rh(l)-NORPHOS catalyst system (eq 17). The optically active hydroformylation products thereby obtained are of interest as intermediates in the synthesis of 1-methylcarbapenem antibiotics. 

S-methylcarbapenems (e.g., 76). In fact, compound 73b was transformed to the known key intermediate 75 (84H29), which had already been employed by Shih et al. for the synthesis of 76 (84H29). 

Compound 82 was readily converted to the known key intermediate 75, which is useful for synthesis of l/ -methylcarbapenems (Scheme 15). Other alkylated azetidinones 81, 83, and 84 were also similarly converted to 75. 

The BINAP-Ru-catalyzed hydrogenation of the allylic alcohol 94 results in the diastereoselective formation of 95, an intermediate for 1/9-methylcarbapenems (96) possessing an improved stability toward dehydropeptidase (Scheme 28). The combined effects of tbe intermolecular asymmetric induction caused by the (/ )-Tol-BINAP-Ru catalyst (Tol-BINAP = p-tolyl analog of BINAP) and the intramolecular asymmetric induction originating from the pre-existing chiral moiety in the substrate 94 cooperate in the generation of the extremely high diastereos-electivity, /5 a = 99.9 0.1, to form the y8-methylated isomer 96 [87]. 

The synthesis involved formation of the (3-lactam 159 which was converted into its enolate and subjected to direct aldol condensation with excess of acetaldehyde to give 160 as a mixture of diastereomers in 80.9% yield. Further elaboration of the styryl group by known procedures afforded the ( )-4-acetoxy-(3-lactam 161 as intermediate of the 6P-methylcarbapenem derivative 162. 

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