Stereoselective Access to γ‐Nitro Carboxylates, Precursors for Highly Functionalized γ‐Lactams

Abstract

A straightforward synthesis of the enantiomerically pure nitro derivatives 31 and epi-32, which are particularly useful intermediates for the synthesis of highly functionalized g-lactams, is presented. ()-(R)-3-Hydroxy-3-phenylpropanoic acid (20) and its ethyl ester 25 were prepared from ()-l-mandelic acid (21). Condensation of 20 with pivalaldehyde furnished the novel enantiomerically pure 1,3-dioxan-4-one 17, the absolute configuration of which was established by X-ray crystal-structure analysis. Treating the lithium enolate of 17 with the nitro alkene 18 led, in a Michael-type addition, to a 1 : 1 mixture of two diastereoisomeric products. The stereocontrol of the addition was limited to the novel stereogenic center next to the lactone function. When the lithium enolate of 25 was treated with 18, the same selectivity was observed but with a lower chemical yield. Very facile separation of the isomers was achieved later in the synthetic sequence, when one isomer cyclized selectively to the nitro lactone 31, while the other one was isolated as hydroxy ester epi-32. The relative configuration of racemic epi-32 could be established by X-ray crystal-structure analysis.Introduction. ± In the course of our investigations on the total synthesis of caesalpinine A (1; Scheme 1) [1], a cyclic spermidine alkaloid [2], we were interested in finding an easy access to the lactam 2. The nitro ester 3 was assumed to be a useful precursor to 2, as it should undergo lactamization as soon as the NO 2 group is reduced. In 1979, Fra¬ter had found that b-hydroxybutyrate 4 can be alkylated with high diastereoselectivity, when its corresponding enolate is treated with alkyl bromides (Scheme 2) [3]. Seebach and co-workers applied this method for nitro alkenes 5 as alkylating agents [4]. Subsequent hydrogenation of the NO 2 groups afforded the corresponding g-lactams through spontaneous cyclization of the in situ formed amino esters. The configuration of the novel stereogenic center in the a-position to the ester was in agreement with the findings of Fra¬ter. The stereoselectivity can be explained by

Convenient preparations of 2‐alkyl‐5‐oxopyrrolidine‐3‐carboxylic acids

“…A plethora of synthetic methods towards pyrrolidinones exists in the literature [3]. According to our retrosynthetic plan, the preparation of these model compounds could be achieved by reduction of the nitro compounds 5, which in turn are the Michael addition products of the anion of 3 to a conjugated ester like 4.…”

Asymmetric Synthesis of Both Antipodes of β-Hydroxy Nitriles and β-Hydroxy Carboxylic Acids via Enzymatic Reduction or Sequential Reduction/Hydrolysis

“…23,62,63 The absolute configurations of the product β-hydroxy carboxylic acids were determined by comparison of the sign of specific rotation data with those in the literature. 23,64 "Two-Step-One-Pot" Process. The reaction was carried out as follows: D-glucose (400 mg), D-glucose dehydrogenase (10 mg), NADPH (10 mg), and carbonyl reductase CMCR (10 mg) were mixed in a potassium phosphate buffer (50 mL, 100 mM, pH 7.0).…”

“…The organic extract was dried over sodium sulfate and evaporated under reduced pressure to give crude product, which was purified by preparative TLC. The product ( S )-3-hydroxy-3-phenylpropanoic acid ( 3a -( S )) was obtained as a white crystalline solid (71 mg, 90% yield), which was identified by comparison of 1 H and 13 C NMR with literature data. ,, The absolute configurations of the product β-hydroxy carboxylic acids were determined by comparison of the sign of specific rotation data with those in the literature. , …”

Asymmetric Reduction of β‐Ketonitriles with a Recombinant Carbonyl Reductase and Enzymatic Transformation to Optically Pure β‐Hydroxy Carboxylic Acids.

“…1,9,10 The absolute configurations of the product alcohols were determined by comparison of the sign of specific rotation data with those in the literature. 1,11…”

“…H NMR (CDCl 3 ) (ppm) 2.66 (d, J = 6.0 Hz, 2H, CH 2 ), 3.45 (br, 1H, OH), 4.93 (t, J = 8.0 Hz, 1H, CH), 7.29-7.37 (m, 5H, aromatic); 13 C NMR (CDCl 3 ) (ppm) 27.7 (CH 2 ), 69.5 (CH), 117.5 (CN), 125.4 (CH), 128.5 (CH), 128.7 (CH), 140.9 (C); [α]22 D +44.7 (c 2.50, CH 3 OH); lit 11. [α]22 D +50.4 (c 4.945, CH 3 OH).…”