Asymmetric synthesis of 4-formyl-1-(ω-haloalkyl)-β-lactams and their transformation to functionalized piperazines and 1,4-diazepanes

A nitrilase-mediated entry to 4-carboxymethyl-β-lactams from chemically prepared 4-(cyanomethyl)azetidin-2-ones

“…of methoxy-, benzyloxy-or phenoxyacetyl chloride 5a-c in the presence of an excess of triethylamine as a base. [42][43][44][45] The optically pure b-lactams 6a-c were prepared in 85-89% yield and with high diastereomeric ratios of (90/10)-(95/5), favoring the expected relative cis-conguration as conrmed by the 1 H NMR (CDCl 3 ) spectra. Indeed, the vicinal coupling constants between the protons on the 3-and 4-position of the b-lactam rings in compounds 6a-c ranged between 5.0 and 5.5 Hz (CDCl 3 ), indicating a cis-relationship according to literature values.…”

“…Indeed, the vicinal coupling constants between the protons on the 3-and 4-position of the b-lactam rings in compounds 6a-c ranged between 5.0 and 5.5 Hz (CDCl 3 ), indicating a cis-relationship according to literature values. 44,46 Next, b-lactams 6a-c were easily converted into the corresponding 4-hydroxymethyl-b-lactam key intermediates 7a-c in 82-96% yield via a three-step approach, including (i) p-toluenesulphonic acid-mediated hydrolysis in a THF/water mixture (1/1) under reux conditions for 4-6 hours, 42,44,45,47 (ii) subsequent oxidation using sodium periodate in the presence of sodium bicarbonate and stirring in dichloromethane for 2-16 hours at room temperature, [43][44][45]47 and (iii) selective reduction by means of two molar equiv. of sodium borohydride in methanol under reux for 1-2 hours.…”

“…of sodium borohydride in methanol under reux for 1-2 hours. 44,45 In the following steps, modications in the hydroxymethyl side chain attached to the 4-position of novel b-lactams 7a-c were performed in order to install the nitrile functionality. At rst, the hydroxyl group was converted into a better leaving group in order to create a more reactive compound, sensitive to nucleophilic substitution reactions (Scheme 2).…”

Recent progress toward the asymmetric synthesis of carbon-substituted piperazine pharmacophores and oxidative related heterocycles

“…The asymmetric synthesis of 4-formyl-1-(ω-haloalkyl)-β-lactams 84 ( Scheme 13 ) and their transformation into functionalized homochiral piperazines were reported by the group of De Kimpe in Belgium. 44 The synthesis of chiral 4-formyl-1-(ω-haloalkyl)-β-lactams was performed by means of a slightly modified four-step literature procedure as shown in Scheme 13 . ( R )-Glyceraldehyde acetonide 82 was condensed with 2-chloroethylamine ( in situ prepared from the corresponding hydrohalide salt using 3 equiv.…”

“…The latter azetidin-2-one 83 could be easily converted to the requisite (3 R , 4 R )-4-formyl-β-lactam 84 by consecutive hydrolysis and oxidation ( Scheme 13 ). 44 …”