Synthesis of (+)-carpamic acid from (+)-alanine

(+)-Carpamic acid [(2′R,5′S,6′S)-8-(5′-hydroxy-6′-methylpiperidin-2′-yl)octanoic acid, 1] was synthesized from (S)-alanine, employing intramolecular and reductive amination of acyclic amino ketone 8 as the key step to generate the piperidine ring.

Figure optionsDownload as PowerPoint slide

(3R,4S)-1-Trimethylsilyl-4-(N,N-dibenzylamino)pent-1-yn-3-olC22H29NOSi[α]D18=-24.4(c1.50,CHCl3)Source of chirality: (S)-alanineAbsolute configuration: (3R,4S)

(3R,4S)-3-Benzyloxy-4-(N,N-dibenzylamino)pent-1-yneC26H27NO[α]D26=-85.9(c1.05,CHCl3)Source of chirality: (S)-alanineAbsolute configuration: (3R,4S)

Methyl (12R,13S)-12-benzyloxy-13-(N,N-dibenzylamino)-9-oxo-10-tetradecynoateC36H43NO4[α]D23=-80.5(c1.05,CHCl3)Source of chirality: (S)-alanineAbsolute configuration: (12R,13S)

Methyl (2′R,5′R,6′S)-8-(5′-hydroxy-6′-methylpiperidin-2′-yl)octanoateC15H29NO3[α]D23=-11.3(c0.90,CHCl3)Source of chirality: (S)-alanineAbsolute configuration: (2′R,5′R,6′S)

Methyl (2′R,5′R,6′S)-8-(N-benzyloxycarbonyl-5′-hydroxy-6′-methylpiperidin-2′-yl)octanoateC23H35NO5[α]D25=-2.6(c0.60,CHCl3)Source of chirality: (S)-alanineAbsolute configuration: (2′R,5′R,6′S)

Methyl (2′R,6′S)-8-(N-benzyloxycarbonyl-6′-methyl-5′-oxopiperidin-2′-yl)octanoateC23H33NO5[α]D24=+53.7(c0.25,CHCl3)Source of chirality: (S)-alanineAbsolute configuration: (2′R,6′S)

Methyl (2′R,5′S,6′S)-8-(N-benzyloxycarbonyl-5′-hydroxy-6′-methylpiperidin-2′-yl)octanoateC23H35NO5[α]D25=-6.9(c0.35,CHCl3)Source of chirality: (S)-alanineAbsolute configuration: (2′R,5′S,6′S)

(+)-Carpamic acid (2′R,5′S,6′S)-8-(5′-hydroxy-6′-methylpiperidin-2′-yl)octanoic acidC14H27NO3[α]D24=+6.0(c0.40,MeOH)Source of chirality: (S)-alanineAbsolute configuration: (2′R,5′S,6′S)