Stereo- and Regiocontrolled Syntheses of Exomethylenic Cyclohexane β-Amino Acid Derivatives

Cyclohexane analogues of the antifungal icofungipen [(1R,2S)-2-amino-4-methylenecyclopentanecarboxylic acid] were selectively synthesized from unsaturated bicyclic β-lactams by transformation of the ring olefinic bond through three different regio- and stereocontrolled hydroxylation techniques, followed by hydroxy group oxidation and oxo-methylene interconversion with a phosphorane. Starting from an enantiomerically pure bicyclic β-lactam obtained by enzymatic resolution of the racemic compound, an enantiodivergent procedure led to the preparation of both dextro- and levorotatory cyclohexane analogues of icofungipen.


Results and Discussion
A convenient and simple novel regio-and stereocontrolled synthetic procedure for the access to cyclohexane analogues of icofungipen is described, with an exomethylene group in different positions. Cyclohexene β-amino acids were subjected to regio-and stereoselective hydroxylation, oxidation and oxo-methylene interconversion as illustrated in the retrosynthetic scheme (Scheme 1).
The above experiments (27→29 and 28→29) with the racemates led us to suppose that both enantiomers of 29 could be obtained by starting from an enantiomerically pure bicyclic lactam. For this purpose, therefore, enantiomerically pure β-lactam (+)-30 (ee = 99%) was prepared by CAL-B-catalyzed ring-opening of racemic lactam (±)-30 (Scheme 9) [24]. A modification of an earlier-described method [23] was next used: oxidation of hydroxylated amino esters (±)-25 and (±)-26 with PCC in CH2Cl2 at room temperature led to the corresponding cis and trans keto esters (±)-27 and (±)-28 [23]. Although cis-keto aminocarboxylate (±)-27 afforded the Wittig product on treatment with methyltriphenylphosphonium bromide/t-BuOK in tetrahydrofurane due to the presence of the active hydrogen isomerization occurred at C-2 under alkaline conditions and gave the thermodynamically more stable (±)-29 (only the relative stereochemistry is shown), in which the amino and carboxylate functions are in a trans relationship; trans amino ester (±)-28 reacted with the phosphonium salt in the presence of t-BuOK to yield (±)-29 stereoisomer with the ester and carbamate in the trans arrangement (Scheme 7). The isomerization of cis-(±)-27 at C-2 during the Wittig reaction with methyltriphenylphosponium bromide/t-BuOK in THF to give (±)-29 through trans amino ester (±)-28 is depicted in Scheme 8.
The above experiments (27→29 and 28→29) with the racemates led us to suppose that both enantiomers of 29 could be obtained by starting from an enantiomerically pure bicyclic lactam. For this purpose, therefore, enantiomerically pure β-lactam (+)-30 (ee = 99%) was prepared by CAL-B-catalyzed ring-opening of racemic lactam (±)-30 (Scheme 9) [24]. A modification of an earlier-described method [23] was next used: oxidation of hydroxylated amino esters (±)-25 and (±)-26 with PCC in CH2Cl2 at room temperature led to the corresponding cis and trans keto esters (±)-27 and (±)-28 [23]. Although cis-keto aminocarboxylate (±)-27 afforded the Wittig product on treatment with methyltriphenylphosphonium bromide/t-BuOK in tetrahydrofurane due to the presence of the active hydrogen isomerization occurred at C-2 under alkaline conditions and gave the thermodynamically more stable (±)-29 (only the relative stereochemistry is shown), in which the amino and carboxylate functions are in a trans relationship; trans amino ester (±)-28 reacted with the phosphonium salt in the presence of t-BuOK to yield (±)-29 stereoisomer with the ester and carbamate in the trans arrangement (Scheme 7). The isomerization of cis-(±)-27 at C-2 during the Wittig reaction with methyltriphenylphosponium bromide/t-BuOK in THF to give (±)-29 through trans amino ester (±)-28 is depicted in Scheme 8.

General Procedure for the Methylenation of Oxo Esters
To a solution of methyltriphenylphosphonium bromide (2 mmol) in THF (15 mL), t-BuOK (1 equiv.) was added and the solution was stirred for 15 min at 20 °C. The β-aminooxocarboxylate (1 equiv.) was then added and the mixture was further stirred at this temperature. After 6 h, water (15 mL) was added, and the mixture was extracted with CH2Cl2 (2 × 15 mL). The organic layer was dried (Na2SO4) and concentrated, and the crude product was purified by column chromatography on silica gel (n-hexane/EtOAc 9:1).

General Procedure for the Methylenation of Oxo Esters
To a solution of methyltriphenylphosphonium bromide (2 mmol) in THF (15 mL), t-BuOK (1 equiv.) was added and the solution was stirred for 15 min at 20˝C. The β-aminooxocarboxylate (1 equiv.) was then added and the mixture was further stirred at this temperature. After 6 h, water (15 mL) was added, and the mixture was extracted with CH 2 Cl 2 (2ˆ15 mL). The organic layer was dried (Na 2 SO 4 ) and concentrated, and the crude product was purified by column chromatography on silica gel (n-hexane/EtOAc 9:1).

Conclusions
Cyclohexane β-amino esters with an extracyclic methylene at position 3, 4 or 5 have been regio-and stereoselectively synthetized from 2-aminocyclohexenecarboxylic acid regioisomers by transformation of the ring olefinic bond via three different regio-and stereocontrolled hydroxylation procedures, followed by deoxygenation through oxo-methylene interconversion via Wittig reactions. An enantiodivergent route starting from a bicyclic β-lactam enantiomer permitted the synthesis of both enantiomers of a cyclohexane icofungipen analogue.