Olivanic acid analogues. Part 6. Biomimetic synthesis of (±)-PS-5, (±)-6-Epi-PS-5, and (±)-benzyl MM22381

Abstract

Michael addition of thiols t o 6-substituted azabicyclo[3.2.0] hept-2-ene-2-carboxylates, followed by reintroduction of the double bond with iodobenzene dichloride-pyridine under anhydrous conditions, provides a biomimetic strategy for the synthesis of 3-alkylthio-substituted olivanic acids (carbapenems) and their derivatives. This is illustrated by syntheses of representatives of the PS-5 and M M22381 series of antibacterial natural products.Paper 9/05476F

Correlation of biological activity in β-lactam antibiotics with Woodward and Cohen structural parameters—a Cambridge database study

“…8 (compound 8) and Fig. 9(b) (19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30). Compound 19 has a normal c distance (3.75 A) and a somewhat high h value (0.21 A) for a monocyclic p-lactam.…”

Olivanic acid analogues. Part 9. Allylic oxidative functionalisation of substituted azetidinones: synthesis of some 4-acyloxy-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylates

“…Addition of ethanethiol to the A2-double bond gave a single adduct. 21,22 This is assigned as the 2~-carboxy,3~-sulphide isomer 31 (66%) on steric grounds, a product of trans-addition. Decarbonylation of aldehyde 31 using Wilkinson's catalyst gave22 the 6P-methyl derivative 32 as an oil (82%).…”

“…-Aldehyde 25 (0.040 g) in D M F (1 ml) was stirred with ethanethiol (0.006 g) in the presence of potassium carbonate (0.001 g) for 5 min. 21 The mixture was diluted with ethyl acetate (10 ml), washed well with brine ( x 3), dried and evaporated. The residue was chromatographed on silica gel, eluting with ethyl acetate-hexane (1 : 1) to give the adduct 31, a single isomer, as a gum (0.030 g, 66%) (Found: M', 512.1235.…”

Olivanic acid analogues. Part 5. Synthesis of 3-alkylthio and 3-alkylsulphinyl analogues via Michael addition of thiols to 3-unsubstituted 1-azabicyclo[3.2.0]hept-2-ene-2-carboxylates. X-Ray molecular structure of (2RS,3RS,5SR)-benzyl 3-ethylthio-7-oxo-1-azabicyclo[3.2.0]heptane-2-carboxylate and (2RS,3SR,5SR,6RS,1′RS)- and (2RS,3SR,5RS,6SR,1′SR)-benzyl 3-chloro-6-(1-hydroxyethyl)-7-oxo-3-[(SR)-phenylsulphinyl]-1-azabicyclo[3.2.0]heptane-2-carboxylate

“…Thus, reaction of compound (4) in dimethylformamide (DMF) in the presence of potassium carbonate and ethanethiol gave a separable mixture of the isomeric products (5) (4979, (6) (673, and (7) (26%).$ The major products (5) and (7) were those resulting from trans-addition of thiol to the double bond. Isomer (7) was converted into isomer (6) in the presence of 1,8-diazabicyclo[5.4.OJundec-7-ene (DBU), suggesting that the presence of compound (6) in the reaction mixture is the consequence of a base-catalysed epimerisation of product (7). This observation, together with the characteristic lower field 'H NMR shift of the 2-proton in compounds (5) and (6) having the 'natural' stereochemistry (as designated in penicillins) compared with compound (7) with the 'unnatural' configuration, allowed the assignments of stereo- chemistry to be made as shown.'…”

“…Addition of acetamidoethanethiol to compound (13) resulted in a separable mixture of all three isomers (17) (16%), (18) (36%), and (19) (14%). In another series the p-bromophenacyl ester of the cis-subsituted bicyclic fl-lactam, compound (20), 6 gave adducts (21), (22), and (23) in an overall yield of 56%. Little indication of addition to the C-6 side-chain double bond was apparent.…”