Synthesis of 4,4′-biquinazoline alcohols as chiral catalysts in enantioselective alkynylation of aldehydes with phenyl acetylene

Optically active propargylic alcohols are important chiral-building blocks in asymmetric synthesis, while the asymmetric addition of a terminal alkyne to an aldehyde is one of the most important procedures to prepare these chiral-building blocks. In this work, a family of chiral 4,4′-biquinazoline alcohols has been conveniently prepared from the easily accessible (S)-2-acetoxycarboxylic acid chlorides by reaction sequences beginning with condensation and followed by key synthetic steps including chlorination, nickel(0)-mediated homocoupling, and deprotection in addition to being examined as potential ligands in the enantioselective addition of phenylacetylene to aldehydes. These chiral ligands can be combined with Ti(OiPr)4 and then used to catalyze the asymmetric addition of zinc acetylide, produced in situ by the reaction of phenylacetylene with diethylzinc, to aldehydes. The best enantiomeric excess obtained in this study was 75%.

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(S)-1-(2-Carbamoylphenylamino)-1-oxopropan-2-yl acetateC12H14N2O4Ee: 99%[α]D20=-103 (c 1, EtOH)Source of chirality: l-lactic acidAbsolute configuration: (S)

(1S)-1-[(2-Carbamoylphenyl)carbamoyl]-2-methylpropyl acetateC14H18N2O4Ee: 99%[α]D20=-120 (c 1, EtOH)Source of chirality: l-valineAbsolute configuration: (S)

(1S)-1-[(2-Carbamoylphenyl)carbamoyl]-2,2-dimethylpropyl acetateC15H20N2O4Ee: 99%[α]D20=-136 (c 1, EtOH)Source of chirality: l-tert-leucineAbsolute configuration: (S)

(1S)-2-[(2-Carbamoylphenyl)amino]-2-oxo-1-phenylethyl acetateC17H16N2O4Ee: 99%[α]D20=+60 (c 1, EtOH)Source of chirality: l-mandelic acidAbsolute configuration: (S)

(1S)-1-Benzyl-2-[(2-carbamoylphenyl)amino]-2-oxoethyl acetateC18H18N2O4Ee: 99%[α]D20=-105 (c 2.35, EtOH)Source of chirality: l-phenylalanineAbsolute configuration: (S)

(S)-2-(1-Hydroxyethyl)quinazolin-4(3H)-oneC10H10N2O2Ee: 99%[α]D20=-41 (c 2.5, EtOH)Source of chirality: l-lactic acidAbsolute configuration: (S)

2-[(1S)-1-Hydroxy-2-methylpropyl]quinazolin-4(3H)-oneC12H14N2O2Ee: 99%[α]D20=-46 (c 1, EtOH)Source of chirality: l-valineAbsolute configuration: (S)

2-[(1S)-1-Hydroxy-2,2-dimethylpropyl]quinazolin-4(3H)-oneC13H16N2O2Ee: 99%[α]D20=-33 (c 1, EtOH)Source of chirality: l-tert-leucineAbsolute configuration: (S)

2-[(S)-Hydroxy(phenyl)methyl]quinazolin-4(3H)-oneC15H12N2O2Ee: 99%[α]D20=+66 (c 1, EtOH)Source of chirality: l-mandelic acidAbsolute configuration: (S)

2-[(1S)-1-Hydroxy-2-phenylethyl]quinazolin-4(3H)-oneC16H14N2O2Ee: 99%[α]D20=-1 (c 1, AcOH)Source of chirality: l-phenylalanineAbsolute configuration: (S)

(S)-2-(1-(tert-Butyldimethylsilyloxy)ethyl)quinazolin-4(3H)-oneC16H24N2O2SiEe: 99%[α]D20=-86 (c 1, EtOH)Source of chirality: l-lactic acidAbsolute configuration: (S)

(S)-2-(1-(tert-Butyldimethylsilyloxy)-2-methylpropyl)quinazolin-4(3H)-oneC18H28N2O2SiEe: 99%[α]D20=-88 (c 1, EtOH)Source of chirality: l-valineAbsolute configuration: (S)

(S)-2-(1-(tert-Butyldimethylsilyloxy)-2,2-dimethylpropyl)quinazolin-4(3H)-oneC19H30N2O2SiEe: 99%[α]D20=-111 (c 4, EtOH)Source of chirality: l-tert-leucineAbsolute configuration: (S)

(S)-2-((tert-Butyldimethylsilyloxy)(phenyl)methyl)quinazolin-4(3H)-oneC21H26N2O2SiEe: 99%[α]D20=+7 (c 1, EtOH)Source of chirality: l-mandelic acidAbsolute configuration: (S)

(S)-2-(1-(tert-Butyldimethylsilyloxy)-2-phenylethyl)quinazolin-4(3H)-oneC22H28N2O2SiEe: 99%[α]D20=-45 (c 1, EtOH)Source of chirality: l-phenylalanineAbsolute configuration: (S)

(S)-2-(1-(tert-Butyldimethylsilyloxy)ethyl)-4-chloroquinazolineC16H23ClN2OSi[α]D20=-83 (c 1, CH2Cl2)Source of chirality: l-lactic acidAbsolute configuration: (S)

(S)-2-(1-(tert-Butyldimethylsilyloxy)-2-methylpropyl)-4-chloroquinazolineC18H27ClN2OSi[α]D20=-56 (c 3, CH2Cl2)Source of chirality: l-valineAbsolute configuration: (S)

(S)-2-(1-(tert-Butyldimethylsilyloxy)-2,2-dimethylpropyl)-4-chloroquinazolineC19H29ClN2OSi[α]D20=-50 (c 0.6, CH2Cl2)Source of chirality: l-tert-leucineAbsolute configuration: (S)

(S)-2-((tert-Butyldimethylsilyloxy)(phenyl)methyl)-4-chloroquinazolineC21H25ClN2OSi[α]D20=-55 (c 1, CH2Cl2)Source of chirality: l-mandelic acidAbsolute configuration: (S)

(S)-2-(1-(tert-Butyldimethylsilyloxy)-2-phenylethyl)-4-chloroquinazolineC22H27ClN2OSi[α]D20=-1.5 (c 6.5, CH2Cl2)Source of chirality: l-phenylalanineAbsolute configuration: (S)

2,2′-Bis((S)-1-(tert-butyldimethylsilyloxy)ethyl)-4,4′-biquinazolineC32H46N4O2Si2Ee: 99%[α]D20=+70 (c 1.1, CHCl3)Source of chirality: l-lactic acidAbsolute configuration: (S)

2,2′-Bis((S)-1-(tert-butyldimethylsilyloxy)-2-methylpropyl)-4,4′-biquinazolineC36H54N4O2Si2Ee: 99%[α]D20=-49 (c 1, EtOH)Source of chirality: l-valineAbsolute configuration: (S)

(2,2′-Bis((S)-1-(tert-butyldimethylsilyloxy)-2,2-dimethylpropyl)-4,4′-biquinazolineC38H58N4O2Si2Ee: 99%[α]D20=-87 (c 1, EtOH)Source of chirality: l-tert-leucineAbsolute configuration: (S)

2,2′-Bis((S)-(tert-butyldimethylsilyloxy)(phenyl)methyl)-4,4′-biquinazolineC42H50N4O2Si2Ee: 99%[α]D20=-114 (c 1, EtOH)Source of chirality: l-mandelic acidAbsolute configuration: (S)

2,2′-Bis((S)-1-(tert-butyldimethylsilyloxy)-2-phenylethyl)-4,4′-biquinazolineC44H54N4O2Si2Ee: 99%[α]D20=+56 (c 1, EtOH)Source of chirality: l-phenylalanineAbsolute configuration: (S)

(1S,1′S)-1,1′-(4,4′-Biquinazoline-2,2′-diyl)diethanolC20H18N4O2Ee: 99%[α]D20=+83 (c 1, CHCl3)Source of chirality: l-lactic acidAbsolute configuration: (S)

(1S,1′S)-1,1′-(4,4′-Biquinazoline-2,2′-diyl)bis(2-methylpropan-1-ol)C24H26N4O2Ee: 99%[α]D20=-20 (c 1, EtOH)Source of chirality: l-valineAbsolute configuration: (S)

(1S,1′S)-1,1′-(4,4′-Biquinazoline-2,2′-diyl)bis(2,2-dimethylpropan-1-ol)C26H30N4O2Ee: 99%[α]D20=-18 (c 1, EtOH)Source of chirality: l-tert-leucineAbsolute configuration: (S)

(1S,1′S)-1,1′-(4,4′-Biquinazoline-2,2′-diyl)bis(2-phenylethanol)C32H26N4O2Ee: 99%[α]D20=-193 (c 1, CHCl3)Source of chirality: l-phenylalanineAbsolute configuration: (S)