Synthesis of novel cinchona-amino acid hybrid organocatalysts for asymmetric catalysis

Three novel subclasses of cinchonidine derivatives coupled to diverse amino acids were prepared in very good overall yield and tested in a benchmark organocatalytic aldol reaction, between acetone and aromatic aldehydes. These subclasses are a family of amino acid-cinchonidine (subclass A), N-formamides-cinchonidine (subclass B) and dipeptide-cinchonidine (subclass C) hybrids. Our main goal, besides obtaining very good yields and enantioselectivities, was to understand the influence of the amino acid side chain residues on the enantioselectivity of the asymmetric aldol reactions. Different amino acid tethered cinchonidine hybrids were compared and their catalytic behaviour was evaluated, allowing good enantioselectivities to be achieved, 92% ee in one case. Other reactions such as Biginelli, Michael addition and ketimine hydrosilylation reactions were screened with these ligands, but the outcome was less successful.

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(8S,9S,αS)-9-l-Phenylalanylamide(9-deoxy)-epi-cinchonidineC28H32N4O[α]D28 = +2.1 (c 1.05, MeOH)Source of chirality: chiral poolAbsolute configuration: (8S,9S,αS)

(8S,9S)-9-Glycinylnamide(9-deoxy)-epi-cinchonidineC21H26N4O[α]D28 = +15.9 (c 1.04, MeOH)Source of chirality: chiral poolAbsolute configuration: (8S,9S)

(8S,9S,αS)-9-l-Valinylamide(9-deoxy)-epi-cinchonidineC24H32N4O[α]D27 = +13.7 (c 1.36, MeOH)Source of chirality: chiral poolAbsolute configuration: (8S,9S,αS)

(8S,9S,αS,βR)-9-l-Isoleucinylamide(9-deoxy)-epi-cinchonidineC25H34N4O[α]D25 = +17.8 (c 1.11, MeOH)Source of chirality: chiral poolAbsolute configuration: (8S,9S,αS,βR)

(8S,9S,αS)-9-l-Leucinylamide(9-deoxy)-epi-cinchonidineC25H34N4O[α]D25 = +12.4 (c 1.16, MeOH)Source of chirality: chiral poolAbsolute configuration: (8S,9S,αS)

(8S,9S,αS)-9-(N-Methyl)-l-phenylalaninylamide(9-deoxy)-epi-cinchonidineC29H34N4O[α]D24 = +17.4 (c 1.03, MeOH)Source of chirality: chiral poolAbsolute configuration: (8S,9S,αS)

(8S,9S,αS)-9-l-Tyrosinylamide(9-deoxy)-epi-cinchonidineC28H32N4O2[α]D24 = −0.7 (c 0.92, MeOH)Source of chirality: chiral poolAbsolute configuration: (8S,9S,αS)

(8S,9S,αS)-9-(N-Formyl)-l-phenylalanylamide(9-deoxy)-epi-cinchonidineC29H32N4O2[α]D24 = −16.1 (c 1.28, MeOH)Source of chirality: chiral poolAbsolute configuration: (8S,9S,αS)

(8S,9S)-9-(N-Formyl)glicinylamide(9-deoxy)-epi-cinchonidineC22H26N4O2[α]D23 = −8.6 (c 1.09, MeOH)Source of chirality: chiral poolAbsolute configuration: (8S,9S)

(8S,9S,αS)-9-(N-Formyl)-l-valinylamide(9-deoxy)-epi-cinchonidineC25H32N4O2[α]D23 = −9.4 (c 1.23, MeOH)Source of chirality: chiral poolAbsolute configuration: (8S,9S,αS)

(8S,9S,αS,βR)-9-(N-Formyl)-l-isoleucinylamide(9-deoxy)-epi-cinchonidineC26H34N4O2[α]D23 = −6.8 (c 1.24, MeOH)Source of chirality: chiral poolAbsolute configuration: (8S,9S,αS,βR)

(8S,9S,αS)-9-(N-Formyl)-l-leucinylamide(9-deoxy)-epi-cinchonidineC26H34N4O2[α]D24 = +29.8 (c 1.8, MeOH)Source of chirality: chiral poolAbsolute configuration: (8S,9S,αS)

(8S,9S,αS)-9-(N-Formyl)-l-prolinylamide(9-deoxy)-epi-cinchonidineC25H30N4O2[α]D24 = +65.2 (c 1.01, MeOH)Source of chirality: chiral poolAbsolute configuration: (8S,9S,αS)

(8S,9S,αS)-9-(N-Formyl)amino(9-deoxy)-epi-cinchonidineC20H23N3O[α]D23 = −28.5 (c 1.15, MeOH)Source of chirality: chiral poolAbsolute configuration: (8S,9S,αS)

(8S,9S,αS,α′S)-9-(l-Phenylalanyl-l-phenylalanineamide)-(9-deoxy)-epi-cinchonidineC37H41N5O2[α]D24 = +24.6 (c 1.4, MeOH)Source of chirality: chiral poolAbsolute configuration: (8S,9S,αS,α′S)

(8S,9S,αS,α′S)-9-(l-Prolinyl-l-phenylalanineamide)-(9-deoxy)-epi-cinchonidineC33H39N5O2[α]D23 = −40.4 (c 1, MeOH)Source of chirality: chiral poolAbsolute configuration: (8S,9S,αS,α′S)

(8S,9S,αS,α′S)-9-(l-Valinyl-l-phenylalanineamide)-(9-deoxy)-epi-cinchonidineC33H41N5O2[α]D24 = −17.9 (c 1.28, MeOH)Source of chirality: chiral poolAbsolute configuration: (8S,9S,αS,α′S)

(8S,9S,αS,α′S)-9-(l-Methioninyl-l-phenylalanineamide)-(9-deoxy)-epi-cinchonidineC33H41N5O2S[α]D24 = −19.6 (c 1.13, MeOH)Source of chirality: chiral poolAbsolute configuration: (8S,9S,αS,α′S)

(8S,9S,αR)-9-(Glycinyl-l-phenylalanineamide)-(9-deoxy)-epi-cinchonidineC30H35N5O2[α]D24 = −14.5 (c 1.3, MeOH)Source of chirality: chiral poolAbsolute configuration: (8S,9S,αR)