Strategies for the construction of morphinan alkaloid AB-rings: regioselective Friedel-Crafts-type cyclisations of γ-aryl-β-benzoylamido acids with asymmetrically substituted γ-aryl rings

The regioselectivity of the Friedel-Crafts-type cyclisation of a range of γ-aryl-β-benzoylamido acids, bearing oxy substituents at the C(3)- and C(4)-positions of the γ-aryl ring, has been investigated. In all of the cases examined (with 3,4-dimethoxy, 3,4-methylenedioxy and 3-hydroxy-4-methoxy substituents) the Lewis acid promoted cyclisation proceeds with exclusive regioselectivity for attack at the C(6)-position rather than at the C(2)-position, and furnishes the corresponding N- and O-protected 3-amino-6,7-dihydroxy-1-tetralone derivatives. This inherent regioselectivity can be overturned by the regioselective introduction of chlorine as a blocking group for the C(6)-position; subsequent Lewis acid promoted cyclisation then proceeds with exclusive regioselectivity for attack at the C(2)-position to deliver the corresponding N- and O-protected 3-amino-5-chloro-7,8-dihydroxy-1-tetralone derivative. These complementary cyclisation protocols represent useful methods for the preparation of these benzo-fused carbocyclic ring systems, which are the functionalised AB-rings of a range of morphinan alkaloids.

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tert-Butyl (R,R)-3-[N-benzyl-N-(α-methylbenzyl)amino]-4-(3′,4′-dimethoxyphenyl)butanoateC31H39NO4[α]D25 = −14.0 (c 1.0, CHCl3)Absolute configuration: (R,R)Source of chirality: asymmetric synthesis

tert-Butyl (R)-3-amino-4-(3′,4′-dimethoxyphenyl)butanoateC16H25NO4[α]D25 = +1.1 (c 0.75, CHCl3)Absolute configuration: (R)Source of chirality: asymmetric synthesis

tert-Butyl (R)-3-benzamido-4-(3′,4′-dimethoxyphenyl)butanoateC23H29NO5[α]D25 = +30.3 (c 1.6, CHCl3)Absolute configuration: (R)Source of chirality: asymmetric synthesis

(R)-3-Benzamido-4-(3′,4′-dimethoxyphenyl)butanoic acidC19H21NO5[α]D25 = +39.6 (c 1.0, DMSO)Absolute configuration: (R)Source of chirality: asymmetric synthesis

(R)-3-Benzamido-6,7-dimethoxy-1-tetraloneC19H19NO4[α]D25 = −20.0 (c 0.45, CHCl3)Absolute configuration: (R)Source of chirality: asymmetric synthesis

tert-Butyl (R,R)-3-[N-benzyl-N-(α-methylbenyl)amino]-4-(3′,4′-methylenedioxyphenyl)butanoateC30H35NO4[α]D20 = −7.7 (c 0.9, CHCl3)Absolute configuration: (R,R)Source of chirality: asymmetric synthesis

tert-Butyl (R)-3-amino-4-(3′,4′-methylenedioxyphenyl)butanoateC15H21NO4[α]D25 = −1.8 (c 0.8, CHCl3)Absolute configuration: (R)Source of chirality: asymmetric synthesis

tert-Butyl (R)-3-benzamido-4-(3′,4′-methylenedioxyphenyl)butanoateC22H25NO5[α]D25 = −8.4 (c 1.0, CHCl3)Absolute configuration: (R)Source of chirality: asymmetric synthesis

(R)-3-Benzamido-4-(3′,4′-methylenedioxyphenyl)butanoic acidC18H17NO5[α]D25 = +31.4 (c 0.8, CHCl3)Absolute configuration: (R)Source of chirality: asymmetric synthesis

(R)-3-Benzamido-6,7-methylenedioxy-1-tetraloneC18H15NO4[α]D25 = −16.5 (c 0.5, CHCl3)Absolute configuration: (R)Source of chirality: asymmetric synthesis

tert-Butyl (R,R)-3-[N-benzyl-N-(α-methylbenzyl)amino]-4-(3′-benzyloxy-4′-methoxyphenyl)butanoateC37H43NO4[α]D25 = +24.1 (c 1.0, CHCl3)Absolute configuration: (R,R)Source of chirality: asymmetric synthesis

tert-Butyl (R)-3-amino-4-(3′-hydroxy-4′-methoxyphenyl)butanoateC15H23NO4[α]D25 = +2.9 (c 1.3, CHCl3)Absolute configuration: (R)Source of chirality: asymmetric synthesis

tert-Butyl (R)-3-benzamido-4-(3′-benzoyloxy-4′-methoxyphenyl)butanoateC29H31NO6[α]D25 = +2.9 (c 1.6, CHCl3)Absolute configuration: (R)Source of chirality: asymmetric synthesis

(R)-3-Benzamido-4-(3′-hydroxy-4′-methoxyphenyl)butanoic acidC18H19NO5[α]D25 = +2.9 (c 1.0, CHCl3)Absolute configuration: (R)Source of chirality: asymmetric synthesis

(R)-3-Benzamido-6-hydroxy-7-methoxy-1-tetraloneC18H17NO4[α]D25 = −10.4 (c 0.6, CHCl3)Absolute configuration: (R)Source of chirality: asymmetric synthesis

tert-Butyl (R)-3-benzamido-4-(3′,4′-dimethoxyphenyl-6′-bromo)butanoateC23H28BrNO5[α]D25 = +80.7 (c 0.3, DMSO)Absolute configuration: (R)Source of chirality: asymmetric synthesis

(R)-3-Benzamido-4-(3′,4′-dimethoxyphenyl-6′-bromo)butanoic acidC19H20BrNO5[α]D25 = +78.8 (c 0.95, DMSO)Absolute configuration: (R)Source of chirality: asymmetric synthesis

tert-Butyl (R)-3-benzamido-4-(3′,4′-dimethoxyphenyl-6′-chloro)butanoateC23H28ClNO5[α]D25 = +57.4 (c 1.0, CHCl3)Absolute configuration: (R)Source of chirality: asymmetric synthesis

tert-Butyl (R)-3-benzamido-4-(3′,4′-dimethoxyphenyl-6′-chloro)butanoic acidC19H20ClNO5[α]D25 = +74.6 (c 1.0, DMSO)Absolute configuration: (R)Source of chirality: asymmetric synthesis

(R)-3-Benzamido-5-chloro-7-methoxy-8-hydroxy-1-tetraloneC18H16ClNO4[α]D25 = −3.7 (c 0.60, DMSO)Absolute configuration: (R)Source of chirality: asymmetric synthesis