(3R)-Chiral Control of 3-Alkyl-3-hydroxy-β-lactams via Addition Reaction of Imines to Enolates of 1,3-Dioxolan-4-ones

Abstract

A method is described for the chiral construction of (3R)-3-alkyl-3-hydroxy-beta-lactams in a versatile and predictable manner. This protocol follows Seebach's synthetic principle of self-regeneration of stereocenters and has been applied to addition reactions among a selected number of imines and (2S)-chiral enolates of 1,3-dioxolan-4-ones. These reagents are easily available from the acetalization of (S)-alpha-hydroxy acids (lactic, mandelic, isovaleric, malic) and pivalaldehyde or pinacolone. In several cases, the addition of the enolate to the imine, the cyclization, and the removal of the auxiliary center occur in a one-step sequence, affording the corresponding beta-lactams as (3R,4S)-Z and (3R,4R)-E diastereomeric mixtures with high enantiomeric excesses. Four N-unsubstituted (3R,4S)-3-hydroxy-3-methyl-beta-lactams bearing 2-furyl (4e), phenylethenyl (4h), methoxycarbonyl (4i), and 2-thienyl (4l) substituents at C4 were obtained as major diastereomers and were purified by crystallization. The simultaneous presence of these substituents at C3 and C4 make these beta-lactams useful intermediates for the synthesis of new taxoids with interesting structural modifications at the isoserine moiety.

Conformational Flexibility and Absolute Stereochemistry of (3R)‐3‐hydroxy‐4‐aryl‐β‐lactams Investigated by Chiroptical Properties and TD‐DFT Calculations

“…2): (3R,4R)-3-hydroxy-3-methyl-1,4-diphenylazetidin-2-one (trans-1; C 16 H 15 NO 2 , MW: 253.30), (3R,4S)-3-hydroxy-1,3,4-triphenylazetidin-2-one (cis-2; C 21 H 17 NO 2 , MW: 315.17), (3R,4R)-3-hydroxy-1,4-diphenyl-3-(propan-2-yl)azetidin-2-one (trans-3; C 18 H 19 NO 2 , MW: 281.35) and its (3R,4S)-diastereomer (cis-3), (3R,4R)-3-hydroxy-3-methyl-4-(thiophen-2-yl)azetidin-2-one (cis-4; C 8 H 9 NO 2 S, MW: 183.23), (3R,4S)-4-(furan-2-yl)-3-hydroxy-3-methylazetidin-2-one (cis-5; C 8 H 9 NO 3 , MW: 167.16), and (3R,4R)-3-hydroxy-3-phenyl-4-(thiophen-2-yl)azetidin-2-one (cis-6; C 13 H 11 NO 2 S, MW: 245.30). [16][17][18][19]36 The ultraviolet (UV) and ECD spectra of trans-1 (concentration: 0.4 mM; pathlength: 0.1 cm; range: 350-200 nm), trans-3 (3.5 mM; 0.01 cm; 350-200 nm), cis-3 (3.5 mM; 0.01 cm; 350-220 nm), and cis-4 (5.5 mM; 0.01 cm; 300-190 nm) were recorded in 2-propanol (Sigma-Aldrich, Milan, Italy) on a Jasco (Tokyo, Japan) J-720 spectropolarimeter at room temperature. Experimental [a] D values were also already reported and are summarized in Table 1.…”

“…[11][12][13][14][15] A series of (3R)-3-hydroxy-4-aryl-b-lactam derivatives (Figs. 1, 2) was previously synthesized for this purpose [16][17][18][19] through the synthetic method of self-regeneration of stereocenters, 20 consisting in addition reactions of arylimines to lithium enolates of (2S,5S)-dioxolan-4-ones, which allowed full control of stereochemistry at C3. Stereochemical characterization is therefore crucial in the employment of these b-lactam derivatives as chiral intermediates.…”

“…10 Moreover, their employment as precursors for the asymmetric synthesis of a variety of compounds of medicinal interest, such as proteinogenic and nonproteinogenic amino acids for peptides and peptidomimetics, taxanes, statines, and norstatines, is well documented in literature under the name of b-lactam synthon method. 1, 2) was previously synthesized for this purpose [16][17][18][19] through the synthetic method of self-regeneration of stereocenters, 20 consisting in addition reactions of arylimines to lithium enolates of (2S,5S)-dioxolan-4-ones, which allowed full control of stereochemistry at C3. 1, 2) was previously synthesized for this purpose [16][17][18][19] through the synthetic method of self-regeneration of stereocenters, 20 consisting in addition reactions of arylimines to lithium enolates of (2S,5S)-dioxolan-4-ones, which allowed full control of stereochemistry at C3.…”

Chiral Glycolate Equivalents for the Asymmetric Synthesis of α-Hydroxycarbonyl Compounds

“…These pioneering methods have been applied widely in organic synthesis; including in the preparation oflactams by the addition reactions of 1,3-dioxalan-4-one derived enolates to imines; 18 in performing key transformations towards the synthesis of the natural products such as eremantholide A 19 and the antitumour pyrrolizidine alkaloid indicine N-oxide 20 and achieving an enantioselective synthesis of asymmetric benzoins. 21 These methods have likewise underpinned research into diastereoselective radical reactions 22 and synthetic approaches to natural products.…”

Crystal Structure of (2S,5R)-2-(tert-Butyl)-5-phenyl-5-(cyclopentyl-1-ol)-1,3-dioxolan-4-one

“…1,2 Our recent drug candidate, 9α-(3-azabicyclo [3,3,1]nonanyl)-2′-cyclopentyl-2′-hydroxy-2′-phenylacetate, is a potent selective M1 antagonist. It is composed of a tertiary hydroxy acid as a key component, like the majority of muscarinic receptor antagonists.…”