Total asymmetric syntheses of (1S,2S)-norcoronamic acid, and of (1R,2R)- and (1S,2S)-coronamic acids from the diastereoselective cyclization of 2-(N-benzylideneamino)-4-chlorobutyronitriles

Abstract

(3R)-2-(N-Benzylideneamino)-4-chloro-3-methylbutyronitrile 3, prepared from the commercially available methyl (2S)-3-hydroxy-2-methyl propionate 5 (96% ee), readily underwent potassium carbonate induced cyclization to provide, after acid hydrolysis (6 N HCl) and chromatography, the (1S,2S)-norcoronamic acid 1a with 88% diastereoselectivity and > 95% enantiomeric excess. From (2R)-2-(hydroxymethyl)butyl acetate 23 (> 88% ee) obtained by enzymatic enantioselective hydrolysis with lipase PS, was prepared the (3S)-2-(N-benzylideneamino)-3-(chloromethyl)valeronitrile 29, which after base-induced cyclization (K2CO3) and acid (6 N HCl) or basic (0.8 N NaOH) hydrolysis led to the non-natural (1R,2R)-coronamic acid 18 (> 88% ee). Also from this same acetate (2R)-23 was prepared the (3R)-3-(chloromethyl)-2-[(diphenylmethylene)amino]pentanenitrile 37, which provided the (1S,2S)-coronamic acid 17 (> 88% ee) after base-induced cyclization (K2CO3 or LDA) and acid hydrolysis (6 N HCl). It is noteworthy that these short synthetic sequences, which do not require any expensive chiral auxiliary or optically active precursors, do not alter the enantiomeric purity of the stereogenic centers of these 2,3-methanoamino acids. However, the E diastereoselectivity of these cyclizations was not improved by using bulky N-(diphenylmethylene)amino substituent, contrary to results of some molecular mechanic calculations (MAD).

Synthetic Approaches to Coronafacic Acid, Coronamic Acid, and Coronatine

“…64 Salaün and co-workers applied their general method for the construction of (E)-2-alkyl ACCs to the synthesis of (+)-5, using enzymatic resolution (Scheme 25). 65 Scheme 25 Salaün's enzymatic resolution based synthesis of (+)-5…”

“…In a follow-up to their previous asymmetric synthesis, 65 Salaün and co-workers reported a racemic, palladium-catalysed allylation strategy for the synthesis of (±)-5 (Scheme 27). 68 Scheme 27 Salaün's synthesis of (±)-5 featuring a palladium-catalysed cyclisation Di-electrophile 185 generated 186 in high yield and as a single diastereomer via a highly stereoselective cyclisation.…”

Titanium-Mediated Diastereoselective Formation of (E)- or (Z)-2-Substituted 1-Vinylcyclopropanols: Scope and Limitation, Applications

“…Chromatography of the residue on silica gel (eluent pentane/diethyl ether, 9:1) gave 2.99 g (11.68 mmol, 73% yield) of (Z)-2-(2-tert-butyldimethylsiloxyethyl)-1-(prop-1-enyl)cyclopropanol as a colourless oil. (E)-1-Amino-2-ethylcyclopropanecarboxylic Acid (Coronamic Acid) (62): [53,65] 1,3-Propanedithiol (440 mg, 4.4 mmol, 4 equiv.) and triethylamine (610 mg, 4.4 mmol) were added to a solution of the azidocyclopropane (E)-61 (180 mg, 1.1 mmol) in methanol (3 mL).…”

“…The combined organic phases were dried with MgSO 4 and concentrated in vacuo to give 99 mg (77% overall yield from (E)-61) of the amino acid (E)-62 (coronamic acid), with spectral and analytical data in total agreement with reported data. [65] (E)-1-Azido-2-ethyl-1-(prop-1-enyl)cyclopropane (64a): By the procedure used to obtain the azidocyclopropane (E)-61, cyclopropyl mesylate (Z)-56a (650 mg, 3.19 mmol) was treated with Pd(dba) 2 (92 mg, 0.16 mmol, 0.05 equiv. ), PPh 3 (100 mg, 0.38 mmol, 0.06 equiv.)…”

Ring‐Closing Strategy Utilizing Nitrile α‐Anions: Chiral Synthesis of (+)‐Norchrysanthemic Acid and Expeditious Asymmetric Total Synthesis of (+)‐Grandisol

“…31–32). Moreover, limited effort has been invested in an enantioselective version with nitrile α‐anions . Our object in this report is a couple of chiral syntheses of small cycloalkanes utilizing characteristic properties of nitrile α‐anions as the key strategy.…”