A convenient synthesis of δ,γ-unsaturated amino acids has been developed. After a mixture of (R)-tert-butanesulfinamide and glyoxylic acid with molecular sieves in CH2Cl2 was stirred for 42 h at room temperature, allylboronic acid pinacol ester was added to the mixture to give (R)-2-((R)-tert-butanesulfinamido)pent-4-enoic acid with high diastereoselectivity. The corresponding reaction of (Z)-crotylboronic acid pinacol ester produced no product; however, that of (E)-crotylboronic acid pinacol ester produced (2R,3S)-2-((R)-tert-butylsulfinamido)-3-methylpent-4-enoic acid with excellent diastereoselectivity.(2R,RS)-2-(tert-Butylsulfinamido)pent-4-enoic acidC9H17NO3S[α]D23=-32.6 (c 1.0, CHCl3)Source of chirality: (R)-tert-butanesulfinamideAbsolute configuration: (2R,RS)(2R,3S,RS)-2-(tert-Butylsulfinamido)-3-methylpent-4-enoic acidC10H19NO3S[α]D23=-78.5 (c 1.0, CHCl3).Source of chirality: (R)-tert-butanesulfinamideAbsolute configuration: (2R,3S,RS)(2S,3R,SS)-2-(tert-Butylsulfinamido)-3-methylpent-4-enoic acidC10H19NO3S[α]D30=+74.1 (c 1.0, CHCl3)Source of chirality: (S)-tert-butanesulfinamideAbsolute configuration: (2S,3R,SS)(2R,3S,RS)-2-(tert-Butylsulfinamido)-3-propylpent-4-enoic acidC12H23NO3S[α]D29=-37.9 (c 1.0, CHCl3)Source of chirality: (R)-tert-butanesulfinamideAbsolute configuration: (2R,3S,RS)(2S,3R,SS)-2-(tert-Butylsulfinamido)-3-propylpent-4-enoic acidC12H23NO3S[α]D29=+37.8 (c 1.3, CHCl3)Source of chirality: (S)-tert-butanesulfinamideAbsolute configuration: (2S,3R,SS)(2R,RS)-2-(tert-Butylsulfinamido)-4-methylpent-4-enoic acidC10H19NO3S[α]D28=-33.9 (c 1.1, CHCl3)Source of chirality: (R)-tert-butanesulfinamideAbsolute configuration: (2R,RS)(R)-2-Aminopent-4-enoic acidC5H9NO2[α]D25=+23.7 (c 0.11, H2O, 94% ee)Source of chirality: (R)-tert-butanesulfinamideAbsolute configuration: (R)(2S,3R)-2-Amino-3-methylpent-4-enoic acidC6H11NO2[α]D26=+16.9 (c 0.61, H2O)Source of chirality: (S)-tert-butanesulfinamideAbsolute configuration: (2S,3R)(2S,3R)-2-Amino-3-propylpent-4-enoic acidC8H14NO2[α]D25=-3.2 (c 0.62, MeOH).Source of chirality: (S)-tert-butanesulfinamideAbsolute configuration: (2S,3R)(R)-2-Amino-4-methylpent-4-enoic acidC6H11NO2[α]D18=+40.7 (c 0.39, H2O)Source of chirality: (R)-tert-butanesulfinamideAbsolute configuration: (R)(S)-2-Amino-4-hydroxy-4-methylpentanoic acidC6H13NO3[α]D31=-11.4 (c 0.51, MeOH)Source of chirality: (S)-tert-butanesulfinamideAbsolute configuration: (S)

The enantioselective synthesis of (R)-(−)-actisonitrile 1 has been achieved via O-alkylation of (4R,αS)-4-hydroxymethyl-3-(α-methylbenzyl)oxazolidin-2-one (αS)-4 with 1-iodohexadecane in the presence of CsOH in DMF. Under these reaction conditions, the O-alkylation was much faster than the intramolecular acyl transfer of (αS)-4.Diethyl (S)-(α-methylbenzyl)aminomalonateC15H21NO4[α]D27=-58.0 (c 1.0, CHCl3)Source of chirality: (S)-(α-methylbenzyl)amineAbsolute configuration: (S)(S)-2-(α-Methylbenzyl)amino-1,3-propanediolC11H17NO2[α]D27=-58.0 (c 1.0, CHCl3)Source of chirality: (S)-(α-methylbenzyl)amineAbsolute configuration: (S)(4R,αS)-4-Hydroxymethyl-3-(α-methylbenzyl)oxazolidin-2-oneC12H15NO3[α]D24=-99.1 (c 1.0, CHCl3)Source of chirality: (S)-(α-methylbenzyl)amineAbsolute configuration: (4R,αS)(4R,αS)-4-(Hexadecyloxymethyl)-3-(α-methylbenzyl)oxazolidin-2-oneC28H47NO3[α]D25=-49.2] (c 0.6, CHCl3).Source of chirality: (S)-(α-methylbenzyl)amineAbsolute configuration: (4R,αS)(4R,αR)-4-(Hexadecyloxymethyl)-3-(α-methylbenzyl)oxazolidin-2-oneC28H47NO3[α]D28=-10.3 (c 0.43, MeOH)Source of chirality: (R)-(α-methylbenzyl)amineAbsolute configuration: (4R,αR)(R)-4-(Hexadecyloxymethyl)oxazolidin-2-oneC20H39NO3[α]D30=+24.7 (c 1.0, CHCl3)Source of chirality: (S)-(α-methylbenzyl)amineAbsolute configuration: (R)(S)-2-Amino-3-(hexadecyloxy)propan-1-olC19H41NO2[α]D29=-3.2 (c 1.0, MeOH)Source of chirality: (S)-(α-methylbenzyl)amineAbsolute configuration: (S)(S)-N-(1-(Hexadecyloxy)-3-hydroxypropan-2-yl)formamideC20H41NO3[α]D26=-13.4 (c 0.62, CHCl3)Source of chirality: (S)-(α-methylbenzyl)amineAbsolute configuration: (S)(R)-2-Formamido-3-(hexadecyloxy)propyl acetateC22H43NO4[α]D30=-4.1 (c 0.65, CHCl3)Source of chirality: (R)-(α-methylbenzyl)amineAbsolute configuration: (S)(R)-3-(Hexadecyloxy)-2-isocyanopropyl acetate, (R)-(−)-actisonitrileC22H41NO3[α]D31=-15.1 (c 0.3, CHCl3)Source of chirality: (R)-(α-methylbenzyl)amineAbsolute configuration: (R)(2R,αR)-3-(Hexadecyloxy)-2-[3-(α-methylbenzyl)ureido]propyl acetateC30H52N2O4[α]D34=-42.6 (c 0.10, CHCl3)Source of chirality: (R)-(α-methylbenzyl)amine (for two chiral centers)Absolute configuration: (2R,αR)(2R,αS)-3-(Hexadecyloxy)-2-(3-α-methylbenzyl)ureidopropyl acetateC30H52N2O4[α]D33=+5.1 (c 0.06, CHCl3)Source of chirality: (R)- and (S)-(α-methylbenzyl)amines (for two chiral centers)Absolute configuration: (2R,αS)

Two reaction pathways and their diastereoselectivity-determining steps of the asymmetric desymmetrization of (R)-2-(α-methylbenzyl)amino-1,3-propanediol 1 with 2-chloroethyl chloroformate (CCF) and with N,N′-disuccinimidyl carbonate giving (4S,αR)-4-hydroxymethyl-3-α-methylbenzyl-2-oxazolidinones (4S)-3 and its (4R,αR)-diastereomer (4R)-3 were investigated. The reaction of serinol 1 and CCF to give the corresponding carbonates was not a diastereoselectivity-determining step. The carbonates gave (R)-5-(α-methylbenzyl)amino-1,3-dioxan-2-one 4 after addition of DBU, and an intramolecular acyl transfer of 4 was found to be a diastereoselectivity-determining step to give (4S)-3. Conversely, the reaction of serinol 1 and N,N′-disuccinimidyl carbonate afforded directly the opposite diastereomer (4R)-3 but not via the intermediate 4. Thus, their diastereoselectivities depended on the acylating reagent.

Diastereomeric monosubstituted [2.2]paracyclophane-based N,O-ligands, which unite the planar and central chiral elements, were optimized for the enantioselective diethylzinc addition to aldehydes. (S)-1-{(Sp)-[2.2]Paracyclophan-4-yl}methyl-2-pyrrolidine-α,α-diphenylmethanol (Sp,S)-3 catalyzed the addition to give (R)-1-phenyl-1-propanol in a high yield and with a good enantioselectivity (91% ee).(S)-2-Hydroxymethyl-1-{(Sp)-[2.2]paracyclophane-4-carbonyl}pyrrolidineC22H25NO2Ee >98%[α]D24=+3.3 (c 0.7, CHCl3)Source of chirality:(S)-prolinolAbsolute configuration:(Sp,S)(S)-2-Hydroxymethyl-1-{(Rp)-[2.2]paracyclophane-4-carbonyl}pyrrolidineC22H25NO2Ee >98%[α]D24=-119 (c 0.8, CHCl3)Source of chirality:(S)-prolinolAbsolute configuration:(Rp,S)(S)-2-(1-Hydroxy-1-methyl)ethyl-1-{(Sp)-[2.2]paracyclophane-4-carbonyl}pyrrolidineC24H29NO2Ee >98%[α]D23=-22.0 (c 1.2, CHCl3)Source of chirality:(S)-1-methyl-1-(pyrrolidin-4-yl)ethanolAbsolute configuration:(Sp,S)(S)-2-(1-Hydroxy-1-methyl)ethyl-1-{(Rp)-[2.2]paracyclophane-4-carbonyl}pyrrolidineC24H29NO2Ee >98%[α]D24=-145 (c 1.3, CHCl3)Source of chirality:(S)-1-methyl-1-(pyrrolidin-4-yl)ethanolAbsolute configuration:(Rp,S)(S)-2-(1,1-Diphenyl-1-hydroxy)methyl-1-{(Sp)-[2.2]paracyclophane-4-carbonyl}pyrrolidineC34H35NO2Ee >98%[α]D25=-7.1 (c 1.0, CHCl3)Source of chirality:(S)-α,α-diphenyl-2-pyrolidinemethanolAbsolute configuration:(Sp,S)(S)-2-(1,1-Diphenyl-1-hydroxy)methyl-1-{(Rp)-[2.2]paracyclophane-4-carbonyl}pyrrolidineC34H35NO2Ee >98%[α]D26=-70.9 (c 1.4, CHCl3)Source of chirality:(S)-α,α-diphenyl-2-pyrolidinemethanolAbsolute configuration:(Rp,S)(S)-[1-{(Sp)-[2.2]Paracyclophan-4-yl}methylpyrrolidin-2-yl]methanolC22H27NOEe >98%[α]D28=+27.6 (c 0.6, CHCl3)Source of chirality:(S)-prolinolAbsolute configuration:(Sp,S)(S)-[1-{(Rp)-[2.2]Paracyclophan-4-yl}methylpyrrolidin-2-yl]methanolC22H27NOEe >98%[α]D24=-93.4 (c 0.5, CHCl3)Source of chirality:(S)-prolinolAbsolute configuration:(Rp,S)(S)-1-Methyl-1-[1-{(Sp)-[2.2]paracyclophan-4-yl}methylpyrrolidin-2-yl]ethanolC24H31NOEe >98%[α]D27=+32.7 (c 0.3, CHCl3)Source of chirality:(S)-1-methyl-1-(pyrrolidin-4-yl)ethanolAbsolute configuration:(Sp,S)(S)-1-Methyl-1-[1-{(Rp)-[2.2]paracyclophan-4-yl}methyl-2-pyrrolidin-2-yl]ethanolC24H31NOEe >98%[α]D27=-85.1 (c 0.8, CHCl3)Source of chirality:(S)-1-methyl-1-(pyrrolidin-4-yl)ethanolAbsolute configuration:(Rp,S)(S)-1-{(Sp)-[2.2]Paracyclophan-4-yl}methyl-2-pyrrolidine-α,α-diphenylmethanolC34H35NO2Ee >98%[α]D25=-17.9 (c 0.8, CHCl3)Source of chirality: (S)-α,α-diphenyl-2-pyrolidinemethanolAbsolute configuration: (Sp,S)(S)-1-{(Rp)-[2.2]Paracyclophan-4-yl}methyl-2-pyrrolidine-α,α-diphenylmethanolC34H35NO2Ee >98%[α]D25=-59.8 (c 0.4, CHCl3)Source of chirality: (S)-α,α-diphenyl-2-pyrolidinemethanolAbsolute configuration: (Rp,S)N-(2-Hydroxymethyl-2,2-diphenyl)ethyl-N-methyl-(Sp)-[2.2]paracyclophane-4-carboxamideC32H31NO2Ee >98%[α]D23=+28.8 (c 0.5, CHCl3)Source of chirality: (S)-prolinolAbsolute configuration: (Sp)2-{N-Methyl-N-(Sp)-[2.2]paracyclophanylmethyl}amino-1,1-diphenylethanolC32H33NOEe >98%[α]D26=+24.9 (c 0.5, CHCl3)Source of chirality: (S)-prolinolAbsolute configuration: (Sp)

Both enantiomers of cytoxazone, (−)-1 and (+)-1, were synthesized using the Petasis reaction of dl-glyceraldehyde 2, 4-methoxyphenylboronic acid 3 and (R)-1-(1-naphthyl)ethylamine 7, following formation of an oxazolidin-2-one ring.(4R,5R)-5-Hydroxymethyl-4-(4-methoxyphenyl)-3-[(R)-1-(1-naphthyl)ethyl]oxazolidin-2-oneC23H24NO4Ee >98%[α]D30=-104.9 (c = 1.7, CHCl3)Source of chirality: (R)-1-(1-naphthyl)ethylamineAbsolute configuration: (4R,5R,1′R)(4S,5R)-5-Hydroxymethyl-4-(4-methoxyphenyl)-3-[(R)-1-(1-naphthyl)ethyl]oxazolidin-2-oneC23H24NO4Ee >98%[α]D30=+7.4 (c = 1.4, CHCl3)Source of chirality: (R)-1-(1-naphthyl)ethylamineAbsolute configuration: (4S,5S,1′R)

Mono-O-acylation of (R)-2-(α-methylbenzyl)amino-1,3-propanediol 1 with 4-nitrobenzoyl chloride and DMAP in dichloromethane at room temperature gave crystals of optically active (2S,αR)-3-hydroxy-2-(α-methylbenzyl)aminopropyl 4-nitrobenzoate hydrochloride [(2S)-2a·HCl] in 33% yield by fractional crystallization. Optically active oxazolidinones, aziridines, and serinol derivatives were synthesized from the benzoate (2S)-2a.Graphic(2S,αR)-3-Hydroxy-2-(α-methylbenzyl)aminopropyl 4-nitrobenzoate hydrochlorideC18H20N2O5·HClE.e. >98%[α]D21=−15.4 (c 1.0, DMSO)Source of chirality: (R)-(α-methylbenzyl)amineAbsolute configuration: (2S,αR)(2S,αR)-3-Hydroxy-2-(α-methylbenzyl)aminopropyl 4-nitrobenzoateC18H20N2O5E.e. >98%[α]D21=−14.4 (c 1.0, CHCl3)Source of chirality: (R)-(α-methylbenzyl)amineAbsolute configuration: (2S,αR)(2S,αR)-3-Hydroxy-2-(α-methylbenzyl)aminopropyl benzoate hydrochlorideC18H21NO3·HClE.e. >98%[α]D21=−12.1 (c 1.0, MeOH)Source of chirality: (R)-(α-methylbenzyl)amineAbsolute configuration: (2S,αR)(2S,αR)-3-Hydroxy-2-(α-methylbenzyl)aminopropyl benzoate hydrobromideC18H21NO3·HBrE.e. >98%[α]D21=−6.5 (c 1.0, MeOH)Source of chirality: (R)-(α-methylbenzyl)amineAbsolute configuration: (2S,αR)(2S,αR)-3-Hydroxy-2-(α-methylbenzyl)aminopropyl benzoateC18H21NO3E.e. >98%[α]D21=−11.3 (c 0.3, CHCl3)Source of chirality: (R)-(α-methylbenzyl)amineAbsolute configuration: (2S,αR)(2R,αR)-3-Hydroxy-2-(α-methylbenzyl)aminopropyl 4-nitrobenzoateC18H20N2O5E.e. >98%[α]D21=+46.6 (c 1.0, CHCl3)Source of chirality: (R)-(α-methylbenzyl)amineAbsolute configuration: (2R,αR)(αR)-2-(α-Methylbenzyl)amino-1,3-propyl di-4-nitrobenzoateC25H23N3O8E.e. >98%[α]D21=−3.2 (c 0.3, CHCl3)Source of chirality: (R)-(α-methylbenzyl)amineAbsolute configuration: (αR)(αR)-2-(α-Methylbenzyl)amino-1,3-propyl dibenzoateC25H25NO4E.e. >98%[α]D21=−18.6 (c 0.5, CHCl3)Source of chirality: (R)-(α-methylbenzyl)amineAbsolute configuration: (2S,αR)(4S,αR)-(3-α-Methylbenzyl-2-oxazolidinon-4-yl)methyl 4-nitrobenzoateC19H18N2O6E.e. >98%[α]D26=−51.5 (c 1.1, CHCl3).Source of chirality: (R)-(α-methylbenzyl)amineAbsolute configuration: (4S,αR)(4S,αR)-4-Hydroxymethyl-3-α-methylbenzyl-2-oxazolidinoneC12H15NO3E.e. >98%[α]D26=+102.1 (c 1.0, CHCl3)Source of chirality: (R)-(α-methylbenzyl)amineAbsolute configuration: (4S,αR)(2S,αR)-1-α-Methylbenzyl-2-aziridinyl)methyl 4-nitrobenzoateC18H18N2O4E.e. >98%[α]D28=+31.4 (c 1.1, CHCl3)Source of chirality: (R)-(α-methylbenzyl)amineAbsolute configuration: (2S,αR)(2R,αR)-3-(tert-Butyldimethylsilyl)oxy-2-(N-α-methylbenzyl)aminopropyl 4-nitrobenzoateC24H34N2O5SiE.e. >98%[α]D26=−0.8 (c 1.0, CHCl3)Source of chirality: (R)-(α-methylbenzyl)amineAbsolute configuration: (2R,αR)(2R,αR)-3-(tert-Butyldimethylsilyl)oxy-2-(N-α-methylbenzyl)amino-1-propanolC17H31NO2SiE.e. >98%[α]D26=−0.3 (c 0.46, CHCl3)Source of chirality: (R)-(α-methylbenzyl)amineAbsolute configuration: (2R,αR)