An N4-p-methoxybenzyloxadiazinone has been prepared from (1R,2S)-norephedrine through a process of reductive amination, N-nitrosation, reduction, and cyclization. The oxadiazinone was acylated and employed in the asymmetric aldol addition reaction with aromatic and aliphatic aldehydes to yield aldol adducts in isolated yields ranging from 54% to 90%. Selected aldol adducts were treated with ceric ammonium nitrate in aqueous acetonitrile to afford the desired β-hydroxycarboxylic acids through a tandem process of oxidative cleavage of the N4-p-methoxybenzyl group and acidic hydrolysis of the N3-acyl side chain. The β-hydroxycarboxylic acids were recovered in high diastereomeric purity as determined by 500 MHz 1H NMR spectroscopy and the absolute configuration was confirmed by polarimetry. The chiral auxiliary unit, the 3,4,5,6-tetrahydro-2H-1,3,4-oxadiazin-2-one (oxadiazinone), was converted into its corresponding 3,6-dihydro-2H-1,3,4-oxadiazin-2-one (oxadiazinone) through an oxidative pathway promoted by the ceric ammonium nitrate.Download high-res image (87KB)Download full-size image

•A new putative reagent tirmethylacetic p-toluenesulfinic anhydride has been prepared.•The reagent has been used to synthesize sulfinate esters.•Sulfones were prepared from Baylis-Hillman derived alcohols.•The reagent has been used to prepare a N-p-toluenesulfinylamide.A reagent combination of toluenesulfinic acid and trimethylacetyl chloride affords a putative trimethylacetic p-toluenesulfinic anhydride. This reagent has been used to prepare a series of sulfinate esters from primary and secondary alcohols. In addition, the reagent was used to convert Baylis-Hillman substrates into allylic sulfones. Attempts to use the reagent to convert amines to sulfinamides were unsuccessful. In contrast, the use of 2-pyrrolidinone afforded N-p-toluenesulfinyl pyrrolidinone in 64% yield. The use of a chiral 4-benzyl-1,3-oxazolidinone or 4-benzyl-1,3-oxazolidine-2-thione led to the isolation of S-p-tolyl p-toluenethiosulfonate.Download high-res image (115KB)Download full-size image

A series of N-substituted phthalimides have been prepared in an effort to explore synthetic variants of the Nefkens’ reagent. Three N-acylphthalimides [R = –CH3, –CH2CH3, and –C(CH3)3] were prepared and employed for the protection of a series of representative amines. In addition, an N-methanesulfonylphthalimide and N-(diethylphosphoryl)phthalimide were also prepared. It was determined that among the phthalimides that were prepared N-propanoylphthalimide was the most effective reagent for the protection reaction.Figure optionsDownload full-size imageDownload as PowerPoint slide

(1S,2S)-Pseudoephedrine and (1S,2S)-pseudonorephedrine have been converted to their corresponding hydrazines and condensed with either o-salicylaldehyde or 2-hydroxy-1-naphthaldehyde to afford a series of β-hydroxysalicylhydrazones that have been employed in the asymmetric addition of diethylzinc to 2-naphthaldehyde in up to 56% ee. In addition to this, the Ephedra hydrazines were also condensed with the o-hydroxyacetophenone derivative to form related hydrazones. The use of these corresponding hydrazones in the asymmetric addition reaction with the diethylzinc did not yield improved enantioselectivities. Finally, Enders’ hydrazine was used as a chiral scaffold for the synthesis of β-methoxysalicylhydrazones. These compounds were employed in the asymmetric addition of diethylzinc to a variety of aromatic aldehydes with enantiomeric excesses as high as 68% ee.1-((E)-(2-((1S,2S)-1-Hydroxy-1-phenyl-2-propyl-2-methylhydrazono) methyl)-2-naphtholC21H22N2O2White solid[α]D20=-29.5 (c 1.0, CHCl3)Source of chirality: (1S,2S)-pseudoephedrineAbsolute configuration: (1S,2S)2-((E)-(2-((1S,2S)-1-Hydroxy-1-phenyl-2-propyl)-2-methylhydrazono)methyl)phenolC17H20N2O2White solid[α]D20=-13.9 (c 1.0, CHCl3)Source of chirality: (1S,2S)-pseudoephedrineAbsolute configuration: (1S,2S)(1S,2S)-2-(Isopropylamino)-1-phenylpropan-1-olC12H19N2OLight yellow oil[α]D25=+53.6 (c 0.5, CHCl3)Source of chirality: (1S,2S)-pseudonorephedrineAbsolute configuration: (1S,2S)N-((1S,2S)-1-Hydroxy-1-phenylpropan-2-yl)-N-isopropylnitrous amideC12H18N2O2White solid[α]D25=+188.0 (c 0.2, CHCl3)Source of chirality: (1S,2S)-pseudonorephedrineAbsolute configuration: (1S,2S)1-((E)-(2-((1S,2S)-1-Hydroxy-1-phenylpropan-2-yl)-2-isopropylhydrazono)methyl)naphthalen-2-olC23H26N2O2Yellow liquid[α]D25=+43.4 (c 1.0, CHCl3)Source of chirality: (1S,2S) pseudonorephedrineAbsolute configuration: (1R,2S)2-((E)-(2-((1S,2S)-1-Hydroxy-1-phenylpropan-2-yl)-2-isopropylhydrazono)methyl)phenolC19H204N2O2Yellow liquid[α]D23=+17.1 (c 1.0, CHCl3)Source of chirality: (1S,2S) pseudonorephedrineAbsolute configuration: (1S,2S)(1S,2S)-2-(Benzylamino)-1-phenylpropan-1-olC16H19NOWhite solid[α]D25=+135.9 (c 1.0, CHCl3)Source of chirality: (1S,2S) pseudonorephedrineAbsolute configuration: (1S,2S)N-Benzyl-N-((1S,2S)-1-hydroxy-1-phenylpropan-2-yl)nitrous amideC16H18N2O2White solid[α]D25=+204.7 (c 1.0, CHCl3)Source of chirality: (1S,2S)-pseudonorephedrineAbsolute configuration: (1S,2S)1-((E)-(2-Benzyl-2-((1S,2S)-1-hydroxy-1-phenylpropan-2-yl)hydrazono)methyl)naphthalen-2-olC27H26N2O2White solid[α]D25=+11.5 (c 1.0, CHCl3)Source of chirality: (1S,2S)-pseudonorephedrineAbsolute configuration: (1S,2S)N-((1R,2S)-2-Hydroxy-2,3-dihydro-1H-inden-1-yl)-N-methylnitrous amideC10H12N2O2Yellow solid[α]D24=+60.4 (c 1.1, CHCl3)Source of chirality: (1R,2S)-cis-1-amino-2-indanolAbsolute configuration: (1R,2S)Methyl (1R,2S)-2-Hydroxy-2,3-dihydro-1H-inden-1-ylcarbamateC11H13NO3White solid[α]D23=+19.1 (c 1.0, CHCl3)Source of chirality: (1R,2S)-cis-1-amino-2-indanolAbsolute configuration: (1R,2S)(1R,2S)-1-(Methylamino)-2,3-dihydro-1H-inden-2-olC10H13NOOffwhite solid[α]D24=-10.2 (c 1.0, CHCl3)Source of chirality: (1R,2S)-cis-1-amino-2-indanolAbsolute configuration: (1R,2S)N-((1R,2S)-2-Hydroxy-2,3-dihydro-1H-inden-1-yl)-N-methylnitrous amideC10H12N2O2Yellow solid[α]D24=+60.4 (c 1.1, CHCl3)Source of chirality: (1R,2S)-cis-1-amino-2-indanolAbsolute configuration: (1R,2S)(1R,2S)-1-(1-Methylhydrazinyl)-2,3-dihydro-1H-inden-2-olC21H20N2O2Light brown solid[α]D23=+122.7 (c 0.2, CHCl3)Source of chirality: (1R,2S)-cis-1-amino-2-indanolAbsolute configuration: (1R,2S)2-((E)-1-(2-((1S,2S)-1-Hydroxy-1-phenylpropan-2-yl)-2-methylhydrazono)ethyl)-4-methylphenolC19H24N2O2Yellow liquid[α]D25=-371.9 (c 1.1, CHCl3)Source of chirality: (1S,2S)-pseudoephedrineAbsolute configuration: (1S,2S)2-((E)-1-(2-((1R,2S)-1-Hydroxy-1-phenyl-2-propyl)-2-methylhydrazono)ethyl)-4-methylphenolC19H24N2O2Yellow solid[α]D25=+59.6 (c 1.0, CHCl3)Source of chirality: (1R,2S)-ephedrineAbsolute configuration: (1R,2S)1-((2-((1R,2S)-1-Hydroxy-1-phenyl-2-propyl)-2-methylhydrazinyl)methyl)-2-naphtholC21H24N2O2Offwhite solid[α]D24=+123.4 (c 0.3, CHCl3)Source of chirality: (1R,2S)-ephedrineAbsolute configuration: (1R,2S)((1R,2S)-2-((E)-1-Methyl-2-(naphthalen-1-ylmethylene)hydrazinyl)-1-phenyl-1-propanolC21H22N2OWhite solid[α]D24=+169.5 (c 1.0, CHCl3)Source of chirality: (1R,2S)-ephedrineAbsolute configuration: (1R,2S)(1R,2S)-2-(1-Methyl-2-(naphthalen-1-ylmethyl)hydrazinyl)-1-phenyl-1-propanolC21H24N2OWhite solid[α]D25=+43.4 (c 1.0, CHCl3)Source of chirality: (1R,2S)-ephedrineAbsolute configuration: (1R,2S)(S,E)-2-((2-(Methoxymethyl)pyrrolidin-1-ylimino)methyl)phenolC13H18N2O2Yellow liquid[α]D23=-202.9 (c 1.1, CHCl3)Source of chirality: (S)-Enders’ hydrazine (SAMP)Absolute configuration: (S)(S,E)-1-((2-(Methoxymethyl)pyrrolidin-1-ylimino)methyl)-2-naphtholC17H20N2O2Yellow solid[α]D23=-225.6 (c 1, CHCl3)Source of chirality: (S)-Enders’ hydrazine (SAMP)Absolute configuration: (S)(S,E)-2,4-Di-tert-butyl-6-((2-(methoxymethyl)pyrrolidin-1-ylimino)methyl)phenolC21H34N2O2Yellow solid[α]D23=-126.5 (c 1, CHCl3)Source of chirality: (S)-Enders’ hydrazine (SAMP)Absolute configuration: (S)

The palladium catalyzed asymmetric allylic sulfonylation reaction has been investigated employing β-hydroxy- and β-(o-diphenylphosphino)benzoyloxy (o-diphenyl phosphino)benzamides as chiral, non-racemic ligands. The bisphosphine β-benzoyloxybenzamide ligands proved to be the best ligands for this process. Competitive transition states for the (1S,2R)-norephedrine derived ligand 14 are compared and a rationale is provided for the observed enantioselectivities.(S)-2-(2-(Diphenylphosphino)benzamido)-3-phenylpropyl 2-(diphenylphosphino)benzoateC47H39NO3P2[α]D23=+4.5 (c 1.00, CHCl3)Source of chirality: l-phenylalaninolAbsolute configuration: (S)2-(Diphenylphosphino)-N-((1S,2R)-1-hydroxy-1-phenylpropan-2-yl)benzamideC28H26NO2P[α]D23=+34.9 (c 0.38, CHCl3)Source of chirality: (1S,2R)-norephedrineAbsolute configuration: (1S,2R)(1S,2R)-2-(2-(Diphenylphosphino)benzamido)-1-phenylpropyl 2-(diphenylphosphino)benzoateC47H39NO3P2[α]D23=-10.80 (c 1.00, CHCl3)Source of chirality: (1S,2R)-norephedrineAbsolute configuration: (1S,2R)(1S,2R)-2-(2-(Diphenylphosphino)benzamido)-1-phenylpropyl benzoateC35H30NO3P[α]D23=-31.0 (c 0.98, CHCl3)Source of chirality: (1S,2R)-norephedrineAbsolute configuration: (1S,2R)(1S,2R)-2-(2-(Diphenylphosphino)benzamido)-1-phenylpropyl 1-napthoateC39H32NO3P[α]D23=-10.5 (c 0.35, CHCl3)Source of chirality: (1S,2R)-norephedrineAbsolute configuration: (1S,2R)

A series of oxadiazines derived from l-phenylalanine bearing phenolic substituents have been synthesized in a multistep, one pot process. This process involves the reaction of a mixed anhydride with a β-hydrazino alcohol, methanesulfonylation of the alcohol moiety, and base induced cyclization. The resultant oxadiazines were employed in the asymmetric addition of diethylzinc to aldehydes.(S)-2-(5-Benzyl-4-isopropyl-5,6-dihydro-4H-1,3,4-oxadiazin-2-yl)phenyl acetateC21H24N2O3[α]D24=+153.0 (c 1.78, CHCl3)Source of chirality: l-phenylalaninolAbsolute configuration: (S)(S)-2-(5-Benzyl-4-isopropyl-5,6-dihydro-4H-1,3,4-oxadiazin-2-yl)-6-methylphenyl acetateC22H26N2O3[α]D24=+124.0 (c 1.31, CHCl3)Source of chirality: l-phenylalaninolAbsolute configuration: (S)(S)-2-(5-Benzyl-4-isopropyl-5,6-dihydro-4H-1,3,4-oxadiazin-2-yl)phenolC19H22N2O2[α]D23=+164.7 (c 0.16, CHCl3)Source of chirality: l-phenylalaninolAbsolute configuration: (S)(S)-2-(5-Benzyl-4-isopropyl-5,6-dihydro-4H-1,3,4-oxadiazin-2-yl)-6-methylphenolC20H25N2O2[α]D24=+157.1 (c 1.24, CHCl3)Source of chirality: l-phenylalaninolAbsolute configuration: (S)(S)-5-Benzyl-4-isopropyl-2-(2-methoxy-3-methylphenyl)-5,6-dihydro-4H-1,3,4-oxadiazineC21H26N2O2[α]D24=+179.6 (c 0.98, CHCl3)Source of chirality: l-phenylalaninolAbsolute configuration: (S)(S)-5-Benzyl-4-isopropyl-2-(1-methoxynaphthalen-2-yl)-5,6-dihydro-4H-1,3,4-oxadiazineC24H26N2O2[α]D24=+191.3 (c 1.21, CHCl3)Source of chirality: l-phenylalaninolAbsolute configuration: (S)(S)-5-Benzyl-2-(3-tert-butyl-2-methoxyphenyl)-4-isopropyl-5,6-dihydro-4H-1,3,4-oxadiazineC24H32N2O2[α]D24=+156.1 (c 1.11, CHCl3)Source of chirality: l-phenylalaninolAbsolute configuration: (S)(S)-2-(5-Benzyl-4-isopropyl-5,6-dihydro-4H-1,3,4-oxadiazin-2-yl)naphthalen-1-olC23H25N2O2[α]D24=+179.6 (c 0.98, CHCl3)Source of chirality: l-phenylalaninolAbsolute configuration: (S)(S)-2-(5-Benzyl-4-isopropyl-5,6-dihydro-4H-1,3,4-oxadiazin-2-yl)-6-tert-butylphenolC23H30N2O2[α]D24=+146.9 (c 1.03, CHCl3)Source of chirality: l-phenylalaninolAbsolute configuration: (S)

Using N-benzylephedrine as a model, a collection of N-arylmethylephedrine derivatives has been prepared. These derivatives were prepared by treatment of ephedrine with selected aldehydes to create oxazolidines 8a–e. Reduction of the oxazolidines with lithium aluminum hydride afforded the target β-amino alcohols 9a–e. When applied in the catalytic asymmetric addition of diethylzinc to aldehydes and diphenylphosphinoylimines, the derivatives yielded product enantioselectivities that were comparable to those of N-benzylephedrine. An N-cyclohexylmethylephedrine derivative was also prepared; this β-aminoalcohol did not perform well in the catalytic addition of diethylzinc to 2-naphthaldehyde, thus suggesting that the aromatic motif is important in terms of maintaining a reasonable level of asymmetric induction. Finally, N-benzyl-N-methyl-2-amino-1,2-diphenyl-1-ethanol, an analogue of the N-benzylephedrine derivative, was prepared. This compound yielded comparable enantioselectivities in the catalytic asymmetric addition when employed as a ligand.(4S,5R)-3,4-Dimethyl-2-(1-naphthyl)-5-phenyloxazolidineC21H21NO[α]D24=-123.9 (c 1.0, CHCl3)Source of chirality: (1R,2S)-ephedrineAbsolute configuration: (1R,2S)(4S,5R)-3,4-Dimethyl-2-(2-naphthyl)-5-phenyloxazolidineC21H21NO[α]D22=-66.7 (c 1.0, CHCl3)Source of chirality: (1R,2S)-ephedrineAbsolute configuration: (1R,2S)(4S,5R)-2-(Biphenyl-4-yl)-3,4-dimethyl-5-phenyloxazolidineC23H23NO[α]D24=-59.5 (c 1.0, CHCl3)Source of chirality: (1R,2S)-ephedrineAbsolute configuration: (1R,2S)(4S,5R)-2-(4-Fluorophenyl)-3,4-dimethyl-5-phenyloxazolidineC17H18FNO[α]D22=-32.7 (c 0.5, CHCl3)Source of chirality: (1R,2S)-ephedrineAbsolute configuration: (4S,5R)(1R,2S)-2-[Methyl(naphthalen-1-ylmethyl)amino]-1-phenylpropan-1-olC21H23NO[α]D24=-23.2 (c 1.0, CHCl3)Source of chirality: (1R,2S)-ephedrineAbsolute configuration: (1R,2S)(1R,2S)-2-[Methyl(2-naphthylmethyl)amino]-1-phenyl-1-propanolC21H23NO[α]D23.6=-43.5 (c 1.0, CHCl3)Source of chirality: (1R)-phenethylamineAbsolute configuration: (1R,2S)(1R,2S)-2-[(Biphenyl-2-ylmethyl)(methyl)amino]-1-phenylpropan-1-olC23H25NO[α]D22=+0.4 (c 1.0, CHCl3)Source of chirality: (1R,2S)-ephedrineAbsolute configuration: ((1R,2S)(1R,2S)-2-[(Biphenyl-4-ylmethyl)(methyl)amino]-1-phenylpropan-1-olC23H25NO[α]D24=-43.5 (c 1.0, CHCl3)Source of chirality: (1R,2S)-ephedrineAbsolute configuration: (1R,2S)(1R,2S)-2-[Benzyl(methyl)amino]-1,2-diphenylethanolC22H23NO[α]D23=-53.6 (c 1.2, CHCl3)Source of chirality: (1R,2S)-2-amino-1,2-diphenyl-1-ethanolAbsolute configuration: (1R,2S)(4S,5R)-2-Cyclohexyl-3,4-dimethyl-5-phenyloxazolidineC17H25NO[α]D23=-41.3 (c 0.4, CHCl3)Source of chirality: (1R,2S)-ephedrineAbsolute configuration: (1R,2S)(1R,2S)-2-[(Cyclohexylmethyl)(methyl)amino]-1-phenylpropan-1-olC17H27NO[α]D23=-17.2 (c 1.0, CHCl3)Source of chirality: (1R,2S)-ephedrineAbsolute configuration: (1R,2S)(1R,2S)-2-(Methylamino)-1,2-diphenylethanolC15H17NO[α]D23=-37.3 (c 1.0, CHCl3)Source of chirality: (1R,2S)-2-amino-1,2-diphenyl-1-ethanolAbsolute configuration: (1R,2S)(1R,2S)-2-[(4-Fluorobenzyl)(methyl)amino]-1-phenylpropan-1-olC17H20FNOWhite solid[α]D23=-22.6 (c 1.0, CHCl3)Source of chirality: (1R,2S)-ephedrineAbsolute configuration: ((1R,2S)

A commercially available collection of β-amino alcohols have been converted to their corresponding β-(o-diphenylphosphino) benzoyloxy(o-diphenylphosphino) benzamides and have been employed in the Tsuji–Trost asymmetric alkylation reaction with 1,3-diphenylpropenyl acetate. The best ligand was derived from l-tert-leucinol and when applied to the asymmetric allylic alkylation reaction, yielded the product in an enantiomeric ratio of 99.5:0.5 favoring the (S)-enantiomer.(1R,2R)-2-Hydroxy-1,2-diphenyl 2-(diphenylphosphino)benzoateC33H27O3P[α]D24=+41.9 (c 0.80, CHCl3)Source of chirality: (R,R)-hydrobenzoinAbsolute configuration: (1R,2R)(1R,2R)-1,2-Diphenylethane-1,2-diyl bis(2-(diphenylphosphino)benzoate)C52H40O4P2[α]D23=+104.4 (c 0.10, CHCl3)Source of chirality: (R,R)-hydrobenzoinAbsolute configuration: (1R,2R)(1R,2R)-2-Hydroxy-1,2-di(naphthalen-1-yl)ethyl 2-(diphenylphosphino)benzoateC41H31O3P[α]D24=+121.5 (c 0.55, CHCl3)Source of chirality: (R,R)-1,2-di(1-naphthyl)-1,2-ethanediolAbsolute configuration: (1R,2R)(1R,2R)-1,2-Di(napthalen-1-yl)ethane-1,2-diyl bis(2-(diphenylphosphino)benzoate)C60H44O4P2[α]D23=+276.0 (c 0.21, CHCl3)Source of chirality: (R,R)-(+)-1,2-di(1-naphthyl)-1,2-ethanediolAbsolute configuration: (1R,2R)(S)-2-Hydroxy-1,2,2-triphenylethyl 2-(diphenylphosphino)benzoateC39H31O3P[α]D23=-131.7 (c 0.44, CHCl3)Source of chirality: (S)-1,1,2-triphenyl-1,2-ethanediolAbsolute configuration: (S)(R)-2-Hydroxy-2-phenylethyl 2-(diphenylphosphino)benzoateC27H23O3P[α]D23=+2.22 (c 1.68, CHCl3)Source of chirality: (R)-1-phenyl-1,2-ethanediolAbsolute configuration: (R)(1R,2R)-2-Acetoxy-1,2-diphenylethyl 2-(diphenylphosphino)benzoateC35H29O4P[α]D23=+19.6 (c 0.58, CHCl3)Source of chirality: (1R,2R)-2-hydroxy-1,2-diphenyl 2-(diphenylphosphino)benzoateAbsolute configuration: (1R,2R)(S)-2-(2-(Diphenylphosphino)benzamido)-3-methylbutyl 2-(diphenylphosphino)benzoateC43H39NO3P2[α]D23=-8.1 (c 0.20, CHCl3)Source of chirality: (S)-2-amino-3-methyl-1-butanolAbsolute configuration: (S)(S)-2-(2-(Diphenylphosphino)benzamido)-2-phenylethyl 2-(diphenylphosphino)benzoateC46H37NO3P2[α]D23=-6.3 (c 0.35, CHCl3)Source of chirality: (S)-phenylglycinolAbsolute configuration: (S)(S)-2-(2-(Diphenylphosphino)benzamido)-3,3-dimethylbutyl 2-(diphenylphosphino)benzoateC44H41NO3P2[α]D23=-3.2 (c 0.40, CHCl3)Source of chirality: (S)-2-amino-3,3-dimethyl-1-butanolAbsolute configuration: (S)

Synthesis of a γ-amino acid derived from (1R,3S)-camphoric acid is described. d-(+)-Camphoric anhydride, prepared from d-(+)-camphoric acid by treatment with methanesulfonyl chloride and triethylamine, was reacted with benzyl alcohol and catalytic DMAP, and subsequently reacted in a Curtius rearrangement to afford the corresponding carbamate derivative. This derivative was converted to the desired γ-amino acid through hydrogenolysis.(1R,5S)-1,8,8-Trimethyl-3-oxabicyclo[3.2.1]octane-2,4-dione (d-camphoric acid)C10H15O3[α]D22=-0.9 (c 0.975, CHCl3)Source of chirality: (1R,5S)-camphoric acidAbsolute configuration: (1R,5S)(1R,3S)-3-(Benzyloxycarbonyl)-1,2,2-trimethylcyclopentanecarboxylic acidC17H22O4[α]D22=+28 (c 1.00, CHCl3)Source of chirality: (1R,5S)-camphoric anhydrideAbsolute configuration: (1R,3S)(1R,3S)-1,2,2-Trimethyl-3-((2-naphthylmethoxy)carbonyl)cyclopentane carboxylic acidC21H24O4[α]D22=+12 (c 0.976, CHCl3)Source of chirality: (1R,5S)-camphoric anhydrideAbsolute configuration: (1R,3S)(1S,3R)-Benzyl 3-(benzyloxycarbonylamino)-2,2,3-trimethylcyclopentanecarboxylateC24H30NO4[α]D24=+0.2 (c 0.976, CHCl3)Source of chirality: (1R,5S)-camphoric anhydrideAbsolute configuration: (1S,3R)Zwitterion of (1R,3S)-3-amino-2,2,3-trimethylcyclopentanecarboxylic acidC9H18NO2[α]D25=+51 (c 1.00, MeOH)Source of chirality: (1R,5S)-camphoric anhydrideAbsolute configuration: (1S,3R)

A series of enantiomerically and diastereomerically enriched N-sulfonylaziridines have been prepared by a single-pot process from (1R,2S)- and (1S,2R)-norephedrine and (1S,2S)-pseudonorephedrine. The cyclization process involved N-sulfonylation of the Ephedra alkaloid followed by O-sulfonylation with methanesulfonyl chloride. The bis(sulfonyl)Ephedra derivatives were treated with either hydrazine or sodium hydroxide to afford the N-sulfonylaziridines.(2S,3S)-2-Methyl-1-(methanesulfonyl)-3-phenylaziridineC10H14NO2SColorless oil[α]D25=-95.2 (c 0.99, CH2Cl2)Source of chirality: (1R,2S)-norephedrineAbsolute configuration: (2S,3S)N-((1R,2S)-1-Hydroxy-1-phenyl-2-propyl)-p-toluenesulfonamideC16H20NO3SWhite solid[α]D24=-2.3 (c 1.0, CH2Cl2)Source of chirality: (1R,2S)-norephedrineAbsolute configuration: (1R,2S)(1R,2S)-2-(p-Toluenesulfonamido)-1-phenylpropyl methanesulfonateC17H25N2O5S2White solid[α]D25=-68.7 (c 1.0, CH2Cl2)Source of chirality: (1R,2S)-norephedrineAbsolute configuration: (1R,2S)(2S,3S)-2-Methyl-3-phenyl-1-toluenesulfonylaziridineC16H18NO2SColorless oil[α]D26=+66.2 (c 1.06, CHCl3)Source of chirality: (1R,2S)-norephedrineAbsolute configuration: (2S,3S)(2S,3S)-2-Methyl-1-(o-nitrobenzenesulfonyl)-3-phenylaziridineC15H15N2O4SColorless oil[α]D24=-93.5 (c 0.77, CH2Cl2).Source of chirality: (1R,2S)-norephedrineAbsolute configuration: (2S,3S)(2S,3R)-2-Methyl-3-phenyl-1-toluenesulonylaziridineC16H17NO2SColorless oil[α]D26=-35.2 (c 0.71, CHCl3)Source of chirality: (1S,2S)-pseudonorephedrineAbsolute configuration: (2S,3R)(2S,3R)-2-Methyl-1-(o-nitrobenzenesulfonyl)-3-phenylaziridineC15H15N2O4SColorless oil[α]D24=-129.1 (c 1.0, CH2Cl2)Source of chirality: (1S,2S)-pseudonorephedrineAbsolute configuration: (2S,3R)1-(7,7-Dimethyl-2-oxobicyclo[2.2.1]-1-heptyl)-N-((1R,2S)-1-hydroxy-1-phenyl-2-propyl) methanesulfonamideC19H28NO4SColorless oil[α]D24=+4.3 (c 1.15 CHCl3)Source of chirality: (1R,2S)-norephedrineAbsolute configuration: (1R,2S)1-(7,7-Dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)-N-((1S,2R)-1-hydroxy-1-phenyl-2-propyl)methanesulfonamideC19H28NO4SColorless oil[α]D24=+27.1 (c 1.10, CHCl3)Source of chirality: (1S,2R)-norephedrineAbsolute configuration: (1S,2R)7,7-Dimethyl-1-(((2S,3S)-2-methyl-3-phenylaziridin-1-ylsulfonyl)methyl)bicyclo [2.2.1]heptan-2-oneC19H26NO3SColorless oil[α]D24=+118.5 (c 1.03, CHCl3)Source of chirality: (1R,2S)-norephedrineAbsolute configuration: (2S,3S)7,7-Dimethyl-1-(((2R,3R)-2-methyl-3-phenylaziridin-1-ylsulfonyl)methyl)bicyclo [2.2.1]heptan-2-oneC19H26NO3SColorless oil[α]D24=-79.0 (c 0.91, CHCl3)Source of chirality: (1R,2S)-norephedrineAbsolute configuration: (2R,3R)

An investigation of the impact of oxygenated side chains in Ephedra compounds on the catalytic asymmetric addition of diethylzinc to aldehydes has been conducted. (1R,2S)-Ephedrine and (1S,2S)-pseudoephedrine were alkylated with either alkyl halides or β-alkoxyalkyl halides to afford a series of ligands 9a–h and 10a–h. These compounds were employed in the enantioselective addition of diethylzinc to a variety of aldehydes. It was determined that the presence of oxygen could have a negative effect in terms of obtaining high levels of enantiomeric discrimination, but the effect is diminished with higher levels of substitution near the oxygen.(1R,2S)-2-Butyl(methyl)amino)-1-phenylpropan-1-olC14H24NO[α]D25=-184 (c 0.71, CHCl3)Source of chirality: (1R,2S)-ephedrineAbsolute configuration: (1R,2S)(1S,2S)-2-Butyl(methyl)amino)-1-phenylpropan-1-olC14H24NO[α]D25=-84 (c 0.85, CHCl3)Source of chirality: (1S,2S)-pseudoephedrineAbsolute configuration: (1S,2S)(1R,2S)-2-((2-Methoxyethyl)(methyl)amino)-1-phenylpropan-1-olC13H22NO2[α]D25=-196 (c 0.71, CHCl3)Source of chirality: (1R,2S)-ephedrineAbsolute configuration: (1R,2S)(1S,2S)-2-((2-Methoxyethyl)(methyl)amino)-1-phenylpropan-1-olC13H22NO2[α]D25=-553 (c 0.107, CHCl3)Source of chirality: (1S,2S)-pseudoephedrineAbsolute configuration: (1S,2S)(1R,2S)-2-(Isobutyl(methyl)amino)-1-phenylpropan-1-olC14H24NO[α]D25=-165 (c 0.83, CHCl3)Source of chirality: (1R,2S)-ephedrineAbsolute configuration: (1R,2S)(1S,2S)-2-(Isobutyl(methyl)amino)-1-phenylpropan-1-olC14H24NO[α]D25=-136 (c 0.61, CHCl3)Source of chirality: (1S,2S)-pseudoephedrineAbsolute configuration: (1S,2S)(1R,2S)-2-((2-Ethylbutyl)(methyl)amino)-1-phenylpropan-1-olC16H28NO[α]D25=-225 (c 0.61, CHCl3)Source of chirality: (1R,2S)-ephedrineAbsolute configuration: (1R,2S)(1S,2S)-2-((2-Ethylbutyl)(methyl)amino)-1-phenylpropan-1-olC16H28NO[α]D25=-166 (c 0.55, CHCl3)Source of chirality: (1S,2S)-pseudoephedrineAbsolute configuration: (1S,2S)(1R,2S)-2-((2,2-Dimethoxyethyl)(methyl)amino)-1-phenylpropan-1-olC14H24NO3[α]D25=-337 (c 0.40, CHCl3)Source of chirality: (1R,2S)-ephedrineAbsolute configuration: (1R,2S)(1S,2S)-2-((2,2-Dimethoxyethyl)(methyl)amino)-1-phenylpropan-1-olC14H24NO3[α]D25=-45.6 (c 1.13, CHCl3)Source of chirality: (1S,2S)-pseudoephedrineAbsolute configuration: (1S,2S)(1R,2S)-2-((2,2-Diethoxyethyl)(methyl)amino)-1-phenylpropan-1-olC16H28NO3[α]D25=-170 (c 0.81, CHCl3)Source of chirality: (1R,2S)-ephedrineAbsolute configuration: (1R,2S)(1S,2S)-2-((2,2-Diethoxyethyl)(methyl)amino)-1-phenylpropan-1-olC16H28NO3[α]D25=-138 (c 0.65, CHCl3)Source of chirality: (1S,2S)-pseudoephedrineAbsolute configuration: (1S,2S)(1R,2S)-2-((Cyclopentylmethyl)(methyl)amino)-1-phenylpropan-1-olC16H26NO[α]D25=-211 (c 0.65, CHCl3)Source of chirality: (1R,2S)-ephedrineAbsolute configuration: (1R,2S)(1S,2S)-2-((Cyclopentylmethyl)(methyl)amino)-1-phenylpropan-1-olC16H26NO[α]D25=-173 (c 0.52, CHCl3)Source of chirality: (1S,2S)-pseudoephedrineAbsolute configuration: (1S,2S)(1R,2S)-2-(((1,3-Dioxolan-2-yl)methyl)(methyl)amino)-1-phenylpropan-1-olC14H24NO[α]D25=-126 (c 1.15, CHCl3)Source of chirality: (1R,2S)-ephedrineAbsolute configuration: (1R,2S)(1R,2S)-2-(((1,3-Dioxolan-2-yl)methyl)(methyl)amino)-1-phenylpropan-1-olC14H24NO[α]D25=-51 (c 1.08, CHCl3)Source of chirality: (1R,2S)-ephedrineAbsolute configuration: (1R,2S)

Diphenylphosphinobenzoic acid was treated with 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC), DMAP, and with either one of two equivalents of (1R,2S)-norephedrine and (1S,2S)-pseudonorephedrine. This process yielded a series of β-hydroxy and β-(diphosphino) benzoyloxy(diphosphino)benzamides that were employed in the Tsuji–Trost asymmetric allylic alkylation process. It was determined that the diastereomeric geometry of the norephedrine series was superior to that of the pseudonorephedrine-based ligands. In addition, it was determined that the norephedrine-based β-(o-diphosphino)benzoyloxy(o-diphosphino)benzamide afforded the best enantiomeric ratio (94:6) favoring the (S)-enantiomer.2-(Diphenylphosphino)-N-(1R,2S)-1-hydroxy-1-hydroxy-1-phenyl-2-propyl)benzamideC28H25NO2P[α]D23=-15.6 (c 0.10, CHCl3)Source of chirality: (1R,2S)-norephedrineAbsolute configuration: (1R,2S)2-(Diphenylphosphino)-N-(1S,2S)-1-hydroxy-1-hydroxy-1-phenyl-2-propyl)benzamideC28H25NO2P[α]D24=+11.3 (c 0.10, CHCl3)Source of chirality: (1S,2S)-pseudo norephedrineAbsolute configuration: (1S,2S)(1R,2S)-2-(2-Diphenylphosphino)benzamido)-1-phenylpropyl 2-(diphenylphosphino)benzoateC47H39NO3P2[α]D23=+7.8 (c 0.10, CHCl3)Source of chirality: (1R,2S)-norephedrineAbsolute configuration: (1R,2S)(1S,2S)-2-(2-Diphenylphosphino)benzamido)-1-phenylpropyl 2-(diphenylphosphino)benzoateC47H39NO3P2[α]D23=-16.9 (c 0.10, CHCl3)Source of chirality: (1S,2S)-pseudonorephedrineAbsolute configuration: (1S,2S)

N-Pyridylmethyl-substituted Ephedra derivatives were synthesized by either direct alkylation or reductive alkylation of (1R,2S)-norephedrine, (1S,2S)-pseudo norephedrine, and (1R,2S)-ephedrine. These derivatives were then employed in asymmetric addition reactions with diethylzinc and aldehydes and diphenylphosphinoylimines. The use of the diastereomers from the Ephedra family allowed for a systematic evaluation of the contribution of the N-pyridylmethyl.(1S,2S)-2-(Benzylamino)-1-phenylpropan-1-olC16H19NO[α]D24=+128.9 (c 1, CH2Cl2)Source of chirality: (1S,2S)-pseudonorephedrineAbsolute configuration: (1S,2S)(1S,2S)-1-Phenyl-2-(pyridin-2-ylmethylamino)propan-1-olC15H18N2O[α]D25=+92.1 (c 1, CH2Cl2)Source of chirality: (1S,2S)-pseudonorephedrineAbsolute configuration: (1S,2S)(1S,2S)-2-((6-Methylpyridin-2-yl)methylamino)-1-phenyl-1-propanolC16H21N2Owhite solid[α]D25=+112.5 (c 1, CH2Cl2)Source of chirality: (1S,2S)-pseudonorephedrineAbsolute configuration: (1S,2S)(1R,2S)-2-((6-Methylpyridin-2-yl)methylamino)-1-phenyl-1-propanolC16H20N2O[α]D25=+12.8 (c 1, CH2Cl2)Source of chirality: (1R,2S)-norephedrineAbsolute configuration: (1R,2S)(1S,2S)-1-Phenyl-2-(quinolin-2-ylmethylamino)-1-propanolC19H20N2O[α]D25=+132.5 (c 1, CH2Cl2)Source of chirality: (1S,2S)-pseudonorephedrineAbsolute configuration: (1S,2S)(1R,2S)-1-Phenyl-2-(quinolin-2-ylmethylamino)-1-propanolC19H20N2O[α]D25=+34.9 (c 1, CH2Cl2)Source of chirality: (1R,2S)-norephedrineAbsolute configuration: (1R,2S)(1S,2S)-2-(Benzyl(methyl)amino)-1-phenyl-1-propanolC17H21NO[α]D23=+110.7 (c 1, CH2Cl2)Source of chirality: (1S,2S)-pseudoephedrineAbsolute configuration: (1S,2S)-ephedrine(1S,2S)-2-(Methyl(pyridin-2-ylmethyl)amino)-1-phenyl-1-propanolC16H20NO2[α]D23.2=+98.2 (c 1.0, CH2Cl2)Source of chirality: (1S,2S)-pseudoephedrineAbsolute configuration: (1S,2S)(1R,2S)-2-(Dibenzylamino)-1-phenylpropan-1-olC23H25NO[α]D24.4=-40.4 (c 1.38, CHCl3)Source of chirality: (1R,2S)-ephedrineAbsolute configuration: (1R,2S)(R)-1-(Naphthalen-2-yl)propan-1-olC13H14O[α]D24.4=-40.4 (c 1.38, CHCl3)Source of chirality: (1R,2S)-ephedrineAbsolute configuration: (R)(1R,2S)-2-(Methyl(pyridin-3-ylmethyl)amino)-1-phenylpropan-1-olC16H20NO2[α]D23.2=+98.2 (c 1.0, CH2Cl2)Source of chirality: (1R,2S)-ephedrineAbsolute configuration: (1R,2S)(R,E)-1-Phenylpent-1-en-3-olC11H14O[α]D25=+4.8 (c 1.0, CHCl3)Source of chirality: (1R,2S)-ephedrineAbsolute configuration: (R)(R)-P,P-Diphenyl-N-(1-phenylpropyl)phosphinic amideC21H22NOP[α]D24=+20.4 (c 0.6, CHCl3)Source of chirality: (1R,2S)-N-benzylephedrineAbsolute configuration: (1R,2S)-ephedrine(R)-1-(Benzyloxy)butan-2-olC11H16O2[α]D25=+0.3 (c 1.7, CHCl3)Source of chirality: (1R,2S)-ephedrineAbsolute configuration: (1R,2S)(1R,2S)-2-(Benzyl(methyl)amino)-1-phenylpropan-1-olC17H21NO[α]D23=-22.2 (c 1.03, CH2Cl2)Source of chirality: (1R,2S)-N-benzylephedrineAbsolute configuration: (1R,2S)-ephedrine(R)-N-(1-(4-Chlorophenyl)propyl)-P,P-diphenylphosphinic amideC21H21ClNOP[α]D23=+45.3 (c 0.4, CHCl3)Source of chirality: (1R,2S)-ephedrineAbsolute configuration: (1R,2S)(R)-N-(1-(4-Fluorophenyl)propyl)-P,P-diphenylphosphinic amideC21H21FNOP[α]D24.0=+19.0 (c 1.0, CHCl3)Source of chirality: (1R,2S)-ephedrineAbsolute configuration: (1R,2S)(R)-N-(1-(4-Methoxyphenyl)propyl)-P,P-diphenylphosphinic amideC22H24NO2P[α]D25=+35.6 (c 0.9, CHCl3)Source of chirality: (1R,2S)-N-benzylephedrineAbsolute configuration: (1R,2S)

A family of N-alkylnorephedrine and N-alkylpseudonorephedrine derived ligands were prepared and applied in the asymmetric alkylation of benzaldehyde using diethylzinc. The absolute configuration of the addition product was directed primarily by the benzylic position of the Ephedra alkaloid, while the magnitude of the enantiomeric ratio was heavily influenced by the nitrogen substituent. However, sterically demanding substituents at the nitrogen position caused the enantioselectivity to be the same for the two diastereomeric systems. Among the ligands that were prepared, it was determined that the N-cyclooctylpseudonorephedrine derivative 7b yielded the highest enantiomeric ratios (87.5:12.5 to 91.0:9.0) when applied in the catalytic asymmetric addition of diethylzinc to aldehydes.(1R,2S)-2-(n-Octylamino)-1-phenylpropan-1-olC17H29NO[α]D25=+15.1 (c 012, CHCl3)Source of chirality: (1R,2S)-norephedrineAbsolute configuration: (1R,2S)(1R,2S)-2-(Benzylamino)-1-phenyl-1-propanolC12H19NO[α]D25=+10.3 (c 1.28, CHCl3)Source of chirality: (1S,2R)-norephedrineAbsolute configuration: (1R,2S)(1R,2S)-2-(Naphthalen-1′-ylmethylamino)-1-phenylpropan-1-olC20H21NO[α]D26=-28.2 (c 0.59, CHCl3)Source of chirality: (1R,2S)-norephedrineAbsolute configuration: (1R,2S)(1R,2S)-2-(Naphthalen-2′-ylmethylamino)-1-phenylpropan-1-olC20H21NO[α]D25=-11.4 (c 0.64, CHCl3)Source of chirality: (1R,2S)-norephedrineAbsolute configuration: (1R,2S)(1R,2S)-2-(Anthracen-9′-ylmethylamino)-1-phenylpropan-1-olC24H23NO[α]D25=-71.5 (c 0.55, CHCl3)Source of chirality: (1R,2S)-norephedrineAbsolute configuration: (1R,2S)2-{[(1R,2S)-1-Hydroxyl-1-phenylpropan-2-ylamino]methyl}phenolC16H19NO2[α]D25=+11.2 (c 0.57, CHCl3)Source of chirality: (1R,2S)-norephedrineAbsolute configuration: (1R,2S)(1R,2S)-2-(2′-Methoxybenzylamino)-1-phenylpropan-1-olC17H21NO2[α]D25=-17.6 (c 0.62, CHCl3)Source of chirality: (1R,2S)-norephedrineAbsolute configuration: (1R,2S)(1R,2S)-2-(3′-Methoxybenzylamino)-1-phenylpropan-1-olC17H21NO2[α]D25=-11.9 (c 0.63, CHCl3)Source of chirality: (1R,2S)-norephedrineAbsolute configuration: (1R,2S)(1R,2S)-2-(3′,4′-Dimethoxybenzylamino)-1-phenylpropan-1-olC18H24NO3[α]D25=-11.2 (c 0.60, CHCl3)Source of chirality: (1R,2S)-norephedrineAbsolute configuration: (1R,2S)(1R,2S)-2-(2′-Ethylbenzylamino)-1-phenylpropan-1-olC18H23NO[α]D25=-22.2 (c 0.43, CHCl3)Source of chirality: (1R,2S)-norephedrineAbsolute configuration: (1R,2S)(1R,2S)-2-(o-Biphenylmethylamino)-1-phenylpropan-1-olC22H23NO[α]D25=-12.7 (c 0.51, CHCl3)Source of chirality: (1R,2S)-norephedrineAbsolute configuration: (1R,2S)(1R,2S)-2-(p-Biphenylmethylamino)-1-phenylpropan-1-olC22H23NO[α]D25=-22.9 (c 0.61, CHCl3)Source of chirality: (1R,2S)-norephedrineAbsolute configuration: (1R,2S)(1R,2S)-1-Phenyl-2-(2′,4′,6′-trimethylbenzylamino)propan-1-olC19H25NO[α]D25=-32.7 (c 0.61, CHCl3)Source of chirality: (1R,2S)-norephedrineAbsolute configuration: (1R,2S)(1R,2S)-2-(3′,5′-Di-tert-butyl-2′-methoxybenzylamino)-1-phenylpropan-1-olC25H37NO2[α]D25=+1.7 (c 0.56, CHCl3)Source of chirality: (1R,2S)-norephedrineAbsolute configuration: (1R,2S)(1R,2S)-2-(2′-(Benzyloxy)-3′,5′-di-tert-butyl-2′-methoxybenzylamino)-1-phenylpropan-1-olC31H41NO2[α]D25=-2.7 (c 0.61, CHCl3)Source of chirality: (1R,2S)-norephedrineAbsolute configuration: (1R,2S)(1R,2S)-2-(3,5-Dibromobenzylamino)-1-phenylpropan-1-olC16H17NOBr2[α]D25=-5.4 (c 0.81, CHCl3)Source of chirality: (1R,2S)-norephedrineAbsolute configuration: (1R,2S)(1R,2S)-2-(Pentan-3′-ylamino)-1-phenylpropan-1- olC14H23NO[α]D25=-8.8 (c 0.61, CHCl3)Source of chirality: (1R,2S)-norephedrineAbsolute configuration: (1R,2S)(1R,2S)-2-Cyclohexylamino-1-phenyl-1-propanolC15H23NO[α]D25=+8.1 (c 0.60, CHCl3)Source of chirality: (1R,2S)-norephedrineAbsolute configuration: (1R,2S)(1R,2S)-2-(2,3-Dihydro-1H-inden-2-ylamino)-1-phenylpropan-1-olC18H21NO[α]D25=-22.2 (c 0.18, CHCl3)Source of chirality: (1R,2S)-norephedrineAbsolute configuration: (1R,2S)(1R,2S)-2-(Cyclooctylamino)-1-phenylpropan-1-olC17H27NO[α]D25=+27.7 (c 0.10, CHCl3)Source of chirality: (1R,2S)-norephedrineAbsolute configuration: (1R,2S)(1R,2S)-2-(Cyclopentylamino)-1-phenylpropan-1-olC14H21NO[α]D25=-2.8 (c 0.70, CHCl3)Source of chirality: (1R,2S)-norephedrineAbsolute configuration: (1R,2S)(1S,2S)-2-(2′-Methoxybenzylamino)-1-phenylpropan-1-olC17H21NO2[α]D25=+87.1 (c 0.64, CHCl3)Source of chirality: (1S,2S)-norephedrineAbsolute configuration: (1S,2S)(1S,2S)-2-(Cyclooctylamino)-1-phenylpropan-1-olC17H27NO[α]D25=+84.8 (c 0.91, CHCl3)Source of chirality: (1S,2S)-norephedrineAbsolute configuration: (1S,2S)(1R,2S)-2-(Cyclopentylamino)-1-phenylpropan-1-olC14H21NO[α]D25=+133.9 (c 0.66, CHCl3)Source of chirality: (1S,2S)-norephedrineAbsolute configuration: (1S,2S)(1R,2S)-1-Phenyl-2-(tritylamino)propan-1-olC28H27NO[α]D25=+74.5 (c 0.64, CHCl3)Source of chirality: (1R,2S)-norephedrineAbsolute configuration: (1R,2S)(1S,2S)-1-Phenyl-2-(tritylamino)propan-1-olC28H27NO[α]D25=-0.2 (c 0.72, CHCl3)Source of chirality: (1S,2S)-norephedrineAbsolute configuration: (1S,2S)(1S,2S)-1-Phenyl-2-(1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylideneamino)-1-propanolC19H30NO[α]D25=+90.3 (c 1.0, CHCl3)Source of chirality: (1S,2S)-norephedrine, d-camphorAbsolute configuration: (1S,2S)(1S,2S)-1-Phenyl-2-(1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylamino)-1-propanolC19H29NO[α]D25=+144.4 (c 1.0, CHCl3)Source of chirality: (1S,2S)-norephedrine, d-camphorAbsolute configuration: (1S,2S)

The stereochemical outcome of the asymmetric addition of diethylzinc to aldehydes catalyzed by (R,R)-hydrobenzoin can be influenced by the absence or presence of Ti(O-iPr)4. The enantiomeric ratios obtained in the absence of Ti(O-iPr)4 favor the (S)-enantiomer, whereas the ratios obtained from the use of Ti(O-iPr)4 favor the formation of the (R)-enantiomer. The formation of the opposite enantiomers is attributed to the different transition states mediated by either zinc or titanium.(S)-1-(2′-Naphthyl)-1-propanolC13H14O[α]D24=-32.3 (c 1.11, CHCl3)Source of chirality: (1R,2R)-hydrobenzoinAbsolute configuration: (S)(S)-1-(1′-Naphthyl)-1-propanolC13H14O[α]D24=-41.7 (c 0.57, CHCl3)Source of chirality: (1R,2R)-hydrobenzoinAbsolute configuration: (S)(S)-1-Phenyl-1-penten-3-olC11H14O[α]D24=-5.25 (c 0.45, CHCl3)Source of chirality: (1R,2R)-hydrobenzoinAbsolute configuration: (S)(S)-1-(4-Methoxyphenyl)-1-propanolC10H14O2[α]D24=-23.4 (c 0.30, CHCl3)Source of chirality: (1R,2R)-hydrobenzoinAbsolute configuration: (S)(S)-1-Phenyl-1-propanolC9H12O[α]D24=-36.1 (c 0.30, CHCl3)Source of chirality: (1R,2R)-hydrobenzoinAbsolute configuration: (S)

A series of tridentate β-hydroxysalicylhydrazone ligands have been prepared from (1R,2S)-ephedrine and (1R,2S)-norephedrine and tested in the catalytic asymmetric addition of diethylzinc to aldehydes. The isolated chemical yields of the addition products ranged from 50% to 84%. The reactions exhibited very good enantioselectivity with enantiomeric ratios ranging from 89:11 to 96:4.2-[(E)-(2-((1R,2S)-1-Hydroxy-1-phenyl-2-propyl)-2-methylhydrazono)methyl]phenolC17H20N2O2Yellow oil[α]D26=+233.6 (c 0.62, CHCl3)Source of chirality:(1R,2S)-ephedrineAbsolute Configuration:(1R,2S)(1R,2S)-2-[(E)-2-Benzylidene-1-methylhydrazinyl]-1-phenylpropan-1-olC17H20N2OWhite solid, Mp = 51–53 °C[α]D26=+140.2 (c 0.71, CHCl3)Source of chirality:(1R,2S)-ephedrineAbsolute Configuration:(1R,2S)2-[(E)-(2-((1R,2S)-1-Hydroxy-1-phenyl-2-propyl)-2-methylhydrazono)methyl]-6-methyl phenolC18H22N2O2Clear oil[α]D25=+219.7 (c 0.72, CHCl3)Source of chirality:(1R,2S)-ephedrineAbsolute Configuration:(1R,2S)2-tert-Butyl-6-((E)-(2-((1R,2S)-1-hydroxy-1-phenyl-2-propyl)-2-methylhydrazono)methyl)phenolC21H28N2O2Yellow solid, Mp = 100–101 °C[α]D25=+191.9 (c 0.62, CHCl3)Source of chirality:(1R,2S)-ephedrineAbsolute Configuration:(1R,2S)2,4-Di-tert-butyl-6-((E)-(2-((1R,2S)-1-hydroxy-1-phenyl-2-propyl)-2-methylhydrazono)methyl)phenolC25H36N2O2Clear oil[α]D25=+111.3 (c 0.80, CHCl3)Source of chirality:(1R,2S)-ephedrineAbsolute Configuration:(1R,2S)2-((E)-(2-((1R,2S)-1-Hydroxy-1-phenyl-2-propyl)-2-methylhydrazono)methyl)-4-nitrophenolC25H35NO2Orange solid, Mp = 147–149 °C[α]D25=+180.4 (c 0.60, CHCl3)Source of chirality: (1R,2S)-ephedrineAbsolute Configuration: (1R,2S)2-((E)-(2-((1R,2S)-1-Hydroxy-1-phenyl-2-propyl)-2-methylhydrazono)methyl)-4-methoxyphenolC18H22N2O3Clear oil[α]D25=+175.8 (c 0.59, CHCl3)Source of chirality: (1R,2S)-ephedrineAbsolute Configuration: (1R,2S)1-((E)-(2-((1R,2S)-1-Hydroxy-1-phenyl-2-propyl)-2-methylhydrazono)methyl)naphthalen-2-olC21H22N2O2Dark yellow solid, Mp = 123–125 °C[α]D25=+192.8 (c 0.63, CHCl3)Source of chirality: (1R,2S)-ephedrineAbsolute Configuration: (1R,2S)2-((E)-(2-((1R,2S)-1-Hydroxy-1-phenyl-2-propyl)-2-isopropylhydrazono)methyl)phenolC19H24N2O2Yellow oil[α]D25=+314.4 (c 0.70, CHCl3)Source of chirality: (1R,2S)-norephedrineAbsolute Configuration: (1R,2S)1-((E)-(2-((1R,2S)-1-Hydroxy-1-phenyl-2-propyl)-2-isopropylhydrazono)methyl)naphthalene-2-olC23H26N2O2Yellow oil[α]D25=+196.6 (c 0.63, CHCl3)Source of chirality: (1R,2S)-norephedrineAbsolute Configuration: (1R,2S)

A series of oxazolidines have been prepared by reaction of either (1R,2S)-ephedrine or (1S,2S)-pseudoephedrine with salicylaldehyde derivatives. The resultant oxazolidines were used as catalytic ligands in the addition of diethylzinc to a variety of aromatic and aliphatic aldehydes. It was determined that the (1R,2S)-ephedrine based oxazolidine derivative 9 gave the highest enantioselectivities.(2′S,4′S,5′R)-2-(3′,4′-Dimethyl-5′-phenyl-oxazolidin-2′-yl)-phenolC17H19NO2White solid[α]D26=−32.3 (c 0.62, CHCl3)Source of chirality: (1R,2S)-ephedrineAbsolute Configuration: (2′S,4′S,5′R)(2′S,4′S,5′S)-2-(3′,4′-Dimethyl-5′-phenyl-oxazolidin-2′-yl)-phenolC17H19NO2White solid[α]D26=+71.6 (c 0.64, CHCl3)Source of chirality: (1S,2S)-pseudoephedrineAbsolute Configuration: (2′S,4′S,5′S)(2′R,4′S,5′R)-2-tert-Butyl-6-(3′,4′-dimethyl-5′-phenyl-oxazolidin-2′-yl)-phenolC21H27NO2White solid[α]D26=12.0 (c 0.64, CHCl3)Source of chirality: (1R,2S)-ephedrineAbsolute Configuration: (2′R,4′S,5′R)(2′S,4′S,5′S)-2-tert-Butyl-6-(3′,4′-dimethyl-5′-phenyl-oxazolidin-2′-yl)-phenolC21H27NO2White solid[α]D26=−188.6 (c 0.64, CHCl3)Source of chirality: (1S,2S)-pseudoephedrineAbsolute Configuration: (2′S,4′S,5′S)(2′R,4′S,5′R)-2,4-Di-tert-butyl-6-(3′,4′-dimethyl-5′-phenyl-oxazolidin-2′-yl)-phenolC25H35NO2White solid[α]D26=−22.6 (c 0.60, CHCl3)Source of chirality: (1R,2S)-ephedrineAbsolute Configuration: (2′R,4′S,5′R)(2′S,4′S,5′S)-2,4-Di-tert-butyl-6-(3′,4′-dimethyl-5′-phenyl-oxazolidin-2′-yl)-phenolC25H35NO2Yellow oil[α]D26=40.0 (c 0.65, CHCl3)Source of chirality: (1S,2S)-pseudoephedrineAbsolute Configuration: (2′S,4′S,5′S)

An l-phenylalanine derived oxadiazinanone bearing an isopropyl group at the N4-position was prepared and acylated with either hydrocinnamoyl or propanoyl chloride. These oxadiazinanones were utilized in titanium-mediated asymmetric aldol reactions with aromatic and aliphatic aldehydes. The diastereoselectivities observed from these reactions ranged from fair to very good and suggested that the N4-isopropyl-l-phenylalanine based oxadiazinanones are conformationally and configurationally stable at the N4-nitrogen.(S)-2-N-Isopropylamino-3-phenyl-1-propanolC12H19NO[α]D25=+6.6 (c 0.38, CHCl3)Source of chirality: l-phenylalanineAbsolute configuration: (S)(S)-2-N-Isopropylhydrazino-3-phenyl-1-propanolC12H20N2O[α]D25=+7.5 (c 0.36, CHCl3)Source of chirality: l-phenylalanineAbsolute configuration: (S)(4R,5S)-5-Benzyl-4-isopropyl-2H-1,3,4-oxadiazinan-2-oneC13H18N2O2[α]D25=+24.7 (c 0.36, CHCl3)Source of chirality: l-phenylalanineAbsolute configuration: (4R,5S)(4R,5S)-5-Benzyl-4-isopropyl-3-(3-phenylpropanoyl)-2H-1,3,4-oxadiazin-2-oneC22H26N2O3[α]D25=-61.6 (c 0.30, CHCl3)Source of chirality: l-phenylalanineAbsolute configuration: (4R,5S)(2′S,3′S,4R,5S)-5-Benzyl-3-[2-benzyl-3-hydroxy-3-phenylpropanoyl]-4-isopropyl-2H-1,3,4-oxadiazinan-2-oneC29H32N2O4[α]D29=-130.9 (c 1.39, CHCl3)Source of chirality: l-phenylalanineAbsolute configuration: (2′S,3′S,4R,5S)(2′S,3′S,4R,5S)-5-Benzyl-3-[2-benzyl-3-hydroxy-3-(4-chlorophenyl)propanoyl]-4-isopropyl-2H-1,3,4-oxadiazinan-2-oneC29H31N2O4Cl[α]D29=-125.5 (c 0.58, CHCl3)Source of chirality: l-phenylalanineAbsolute configuration: (2′S,3′S,4R,5S)(2′S,3′S,4R,5S)-5-Benzyl-3-[2-benzyl-3-hydroxy-3-(2-naphthyl)propanoyl]-4-isopropyl-2H-1,3,4-oxadiazinan-2-oneC33H34N2O4[α]D29=-81.9 (c 0.74, CHCl3)Source of chirality: l-phenylalanineAbsolute configuration: (2′S,3′S,4R,5S)(2′S,3′S,4R,5S)-5-Benzyl-3-[2-benzyl-3-hydroxy-4,4-dimethylpentanoyl]-4-isopropyl-2H-1,3,4-oxadiazinan-2-oneC27H36N2O4[α]D29=-180.1 (c 0.67, CHCl3)Source of chirality: l-phenylalanineAbsolute configuration: (2′S,3′S,4R,5S)(2′S,3′S,4R,5S)-5-Benzyl-3-(2-benzyl-4-benzyloxy-3-hydroxybutanoyl)-4-isopropyl-2H-1,3,4-oxadiazinan-2-oneC31H36N2O5[α]D25=-103.5 (c 0.28, CHCl3)Source of chirality: l-phenylalanineAbsolute configuration: (2′S,3′S,4R,5S)(4R,5S)-5-Benzyl-4-isopropyl-3-propanoyl-2H-1,3,4-oxadiazinan-2-oneC16H22N2O3[α]D29=-167.5 (c 5.5, CHCl3)Source of chirality: l-phenylalanineAbsolute configuration: (4R,5S)(2′S,3′S,4R,5S)-5-Benzyl-3-(3-hydroxy-2-methyl-3-phenylpropanoyl)-4-isopropyl-2H-1,3,4-oxadiazinan-2-oneC23H28N2O4[α]D29=-92.2 (c 1.39, CHCl3)Source of chirality: l-phenylalanineAbsolute configuration: (2′S,3′S,4R,5S)(2S,3S)-Methyl 3-hydroxy-2-methyl-3-phenylpropanoateC10H14O3[α]D29=-11.6 (c 0.74, CHCl3)Source of chirality: l-phenylalanineAbsolute configuration: (2S,3S)

A camphor-based oxadiazinone was prepared by reaction of the N-nitroimine of d-camphor with (1R,2S)-norephedrine; the reduction of the resultant imine; N-nitrosation of the amine; reduction to the corresponding hydrazine and cyclization. The conformational behaviour of oxadiazinone 7 was modeled in the gas and solution phases using the semiempirical AM1 method and density functional theory. Application of the oxadiazinone in the titanium mediated asymmetric aldol reaction provided the highly diastereoselective formation of the expected syn-adducts 8a–d as evidenced by single crystal X-ray diffraction analysis. Attempts to remove the oxadiazinone auxiliary using acidic or basic conditions failed to yield the expected β-hydroxyacid in significant yield.(5S,6R,1′R,2′R,4′R)-3,4,5,6-Tetrahydro-5-methyl-4-(1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)-6-phenyl-2H-1,3,4-oxadiazin-2-oneC20H28N2O2[α]D = −10.9 (c 0.47, MeOH)Source of chirality: (1R,2S)-norephedrine, d-camphorAbsolute configuration: (5S,6R,1′R,2′R,4′R)(5S,6R,1′R,2′R,4′R)-3,4,5,6-Tetrahydro-5-methyl-4-(1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)6-phenyl-3-propionyl-2H-1,3,4-oxadiazin-2-oneC23H32N2O3[α]D = −139 (c 1.02, MeOH)Source of chirality: (1R,2S)-norephedrine, d-camphorAbsolute configuration: (5S,6R,1′R,2′R,4′R)(5S,6R,1′R,2′R,4′R, 2″S,3″S)-3,4,5,6-Tetrahydro-3-(3-hydroxy-2-methyl-3-phenylpropionyl)-5-methyl-6-phenyl-4-(1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)-2H-1,3,4-oxadiazin-2-oneC30H39N2O4[α]D = −129 (c 0.47, MeOH)Source of chirality: (1R,2S)-norephedrine, d-camphorAbsolute configuration: (5S,6R,1′R,2′R,4′R,2″S,3″S)(5S,6R,1′R,2′R,4′R,2″S,3″S)-3-[3-(4-Chlorophenyl)-3-hydroxy-2-methylpropionyl]-3,4,5,6-tetrahydro-5-methyl-4-(1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)-6-phenyl-2H-1,3,4-oxadiazin-2-oneC30H38ClN2O4[α]D = −113 (c 0.65, MeOH)Source of chirality: (1R,2S)-norephedrine, d-camphorAbsolute configuration: (5S,6R,1′R,2′R,4′R,2″S,3″S)(5S,6R,1′R,2′R,4′R,2″S,3″S)-3,4,5,6-Tetrahydro-3-(3-hydroxy-2-methyl-3-naphthalen-2-yl-propionyl)-5-methyl-(1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)-6-phenyl-4-2H-1,3,4-oxadiazin-2-oneC34H41N2O4[α]D = −122(c 1.33, MeOH)Source of chirality: (1R,2S)-norephedrine, d-camphorAbsolute configuration: (5S,6R,1′R,2′R,4′R,2″S,3″S)(5S,6R,1′R,2′R,4′R,2″S,3″S)-3,4,5,6-Tetrahydro-3-(3-hydroxy-2,4,4-trimethyl-pentanoyl)-5-methyl-6-phenyl-4-(1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)-2H-1,3,4-oxadiazin-2-oneC28H43N2O4[α]D = −135 (c 1.77, MeOH)Source of chirality: (1R,2S)-norephedrine, d-camphorAbsolute configuration: (5S,6R,1′R,2′R,4′R,2″S,3″S)

An N3-(p-methoxyphenoxy)acetyloxazolidine-2-thione has been synthesized and employed in glycolate asymmetric aldol addition reactions with aromatic and aliphatic aldehydes. It was determined that the titanium tetrachloride medicated aldol reaction afforded diastereoselectivities that ranged from 75:25 to 94:6 when the reaction was conducted at −78 °C. The absolute stereochemistry of the aldol adducts was determined by 1H NMR spectroscopy and X-ray crystallography. The 1H NMR spectra of the aldol adducts contained a signal (the α-proton of the glycolate position of the aldol side chain) that was highly deshielded due to conformational restriction about the N(3)-(p-methoxyphenoxy)acetyl side chain and the oxazolidine-2-thione auxiliary.(S)-4-Benzyl-3-[(p-methoxyphenoxy)acetyl]oxazolidine-2-thioneC19H19NO4S[α]D23 = +85.0 (c 1.02, CHCl3)Source of chirality: l-phenylalaninolAbsolute configuration: (S)(2S,3R)-4-Benzyl-3-[(3-hydroxy-2-(p-methoxyphenoxy)-3-phenylpropanoyl]oxazolidine-2-thioneC26H25NO5S[α]D23 = +148 (c 1.00, CHCl3)Source of chirality: l-phenylalaninolAbsolute configuration: (2S,3R)(2S,3R)-4-Benzyl-3-[(p-chlorophenyl)-3-hydroxy-2-(p-methoxyphenoxy)propanoyl]oxazolidine-2-thioneC26H24NClO5S[α]D23 = +124 (c 1.00, CHCl3)Source of chirality: l-phenylalaninolAbsolute configuration: (2S,3R)(2S,3R)-4-Benzyl-3-[(p-bromophenyl)-3-hydroxy-2-(p-methoxyphenoxy)propanoyl]oxazolidine-2-thioneC26H25NBrO5S[α]D23 = +148 (c 1.00, CHCl3)Source of chirality: l-phenylalaninolAbsolute configuration: (2S,3R)(2S,3R)-4-Benzyl-3-[(o-fluorophenyl)-3-hydroxy-2-(p-methoxyphenoxy)propanoyl]oxazolidine-2-thioneC26H24NFO5S[α]D23 = +16 (c 1.00, CHCl3)Source of chirality: l-phenylalaninolAbsolute configuration: (2S,3R)(2S,3R)-4-Benzyl-3-[(3-hydroxy-2-(p-methoxyphenoxy)-3-(m-nitrophenyl)propanoyl]oxazolidine-2-thioneC26H24N2O7S[α]D23 = +85 (c 1.10, CHCl3)Source of chirality: l-phenylalaninolAbsolute configuration: (2S,3R)(2S,3R)-4-Benzyl-3-[(3-hydroxy-2-(p-methoxyphenoxy)-3-(2-naphthyl)propanoyl]oxazolidine-2-thioneC30H27NO5S[α]D23 = +166 (c 1.00, CHCl3)Source of chirality: l-phenylalaninolAbsolute configuration: (2S,3R)(2S,3R,E)-1-[(S)-4-Benzyl-(3-hydroxy-2-(p-methoxyphenoxy)-5-phenyl-4-pentenoyl)oxazolidine-2-thioneC28H27NO5S[α]D23 = +205 (c 1.00, CHCl3)Source of chirality: l-phenylalaninolAbsolute configuration: (2S,3R)(2S,3R)-4-Benzyl-3-(3-hydroxy-2-(p-methoxyphenoxy)-4,4-dimethylpentanoyl)oxazolidine-2-thioneC24H29NO5S[α]D23 = +76 (c 1.50, CHCl3)Source of chirality: l-phenylalaninolAbsolute configuration: (2S,3R)(2S,3R)-4-Benzyl-3-[(3-hydroxy-2-(p-methoxyphenoxy)-5-methylhexanoyl)]oxazolidine-2-thioneC24H29NO5S[α]D23 = +9.4 (c 1.10, CHCl3)Source of chirality: l-phenylalaninolAbsolute configuration: (2S,3R)Methyl 3-hydroxy-2-(p-methoxyphenoxy)-3-phenylpropanoateC17H18O5[α]D23 = +146 (c 0.50, CHCl3)Source of chirality: l-phenylalaninolAbsolute configuration: (2S,3R)