Asymmetric synthesis of tetrahydrolipstatin and valilactone

The highly diastereoselective aldol reaction between acyl complexes of the iron chiral auxiliary [(η5-C5H5)Fe(CO)(PPh3)] and β-hydroxy aldehydes (obtained via a Noyori asymmetric hydrogenation), followed by a tandem oxidative decomplexation–cyclisation process gives access to β-substituted and α,β-disubstituted β-lactones in high ee. This methodology has been employed in the asymmetric syntheses of tetrahydrolipstatin and valilactone.

Graphical abstractStereoselective aldol reaction of a homochiral iron octanoyl complex, followed by tandem oxidative decomplexation–cyclisation facilitated the asymmetric syntheses of tetrahydrolipstatin and valilactone.Figure optionsDownload full-size imageDownload as PowerPoint slide

(S)-Carbonyl(cyclopentadienyl)[(R)-3-hydroxy-4,4-dimethylpentanoyl](triphenylphosphino)ironC31H34FeO3P[α]D25=+82.4 (c 0.2 in CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (SFe,3R)

(R)-Carbonyl(cyclopentadienyl)[(2R,3S)-2-methyl-3-hydroxy-4,4-dimethylpentanoyl](triphenylphosphino)ironC32H36FeO3P[α]D25=-210 (c 0.5 in CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (RFe,2R,3S)

(R)-Carbonyl(cyclopentadienyl)[(2R,3R)-2-methyl-3-hydroxy-4,4-dimethylpentanoyl](triphenylphosphino)ironC32H36FeO3P[α]D20=-129 (c 0.25 in CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (RFe,2R,3R)

(R)-4-tert-Butyloxetan-2-oneC7H12O2[α]D25=-12.6 (c 0.7 in CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (R)

(3R,4S)-3-Methyl-4-tert-butyloxetan-2-oneC8H14O2[α]D25=+33.1 (c 0.3 in CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3R,4S)

(3R,4R)-3-Methyl-4-tert-butyloxetan-2-oneC8H14O2[α]D25=+11.5 (c 0.7 in CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3R,4R)

(R)-N-α-Methylbenzyl (R)-3-hydroxy-4,4-dimethylpentanamideC15H23NO2[α]D20=+94.6 (c 0.5 in CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3R,R)

Methyl (S)-3-hydroxytetradecanoateC15H30O3[α]D20=+17.9 (c 1.3 in CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (S)

Methyl (S)-3-benzyloxytetradecanoateC22H36O3[α]D20=+6.85 (c 1.1 in CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (S)

(S)-3-Benzyloxytetradecan-1-olC21H36O2[α]D20=+32.3 (c 1.45 in CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (S)

(S)-3-BenzyloxytetradecanalC21H34O2[α]D20=+32.3 (c 1.45 in CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (S)

(S)-Carbonyl(cyclopentadienyl)octanoyl(triphenylphosphino)ironC32H36FeO2P[α]D20=+123.2 (c 1.0 in CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (S)

(3S,4S,2′S)-3-Hexyl-4-(2′-hydroxytridec-1′-yl)oxetan-2-oneC22H42O3[α]D20=-14.8 (c 0.7 in CH2Cl2)Source of chirality: asymmetric synthesisAbsolute configuration: (3S,4S,2′S)

(2S,2′S,3′S)-1-(3′-Hexyl-4′-oxooxetan-2′-yl)tridecan-2-yl (S)-N-formyl-leucinateC29H53NO5[α]D20=-31.8 (c 0.37 in CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2S,2′S,3′S,2″S)

Methyl (S)-3-hydroxyoctanoateC9H18O3[α]D20=+22.5 (c 1.1 in CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (S)

Methyl (S)-3-benzyloxyoctanoateC16H24O3[α]D20=+7.11 (c 1.2 in CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (S)

(S)-3-BenzyloxyoctanalC15H22O2[α]D20=+14.1 (c 1.0 in CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (S)

(3S,4S,2′S)-3-Hexyl-4-(2′-benzyloxyhept-1′-yl)oxetan-2-oneC23H36O3[α]D20=-2.45 (c 1.0 in CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3S,4S,2′S)

(3S,4S,2′S)-3-Hexyl-4-(2′-hydroxyhept-1′-yl)oxetan-2-oneC16H30O3[α]D20=-17.0 (c 1.0 in CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3S,4S,2′S)

(2S,2′S,3′S)-1-(3′-Hexyl-4′-oxooxetan-2′-yl)heptan-2-yl (S)-N-formyl-valinateC22H39NO5[α]D20=-31.5 (c 0.5 in CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2S,2′S,3′S,2″S)