Asymmetric Synthesis of Arylglycines and Their Use as Chiral Templates for the Stereocontrolled Synthesis of 7,8-Disubstituted 3-Aryl-1,2,3,4-tetrahydroisoquinolin-4-ols

Abstract

A synthetic technique for the asymmetric synthesis of arylglycines has been optimized, reaching the target amino acids in only four steps with good yields and with enantiomeric excesses higher than 99%. The key step consisted of a stereocontrolled electrophilic amination reaction of (S,S)-(+)-pseudoephedrine-based arylacetamide enolates with di-tertbutylazodicarboxylate. The arylglycines thus obtained

(S,S)-(+)-Pseudoephedrine as Chiral Auxiliary in Asymmetric Aza-Michael Reactions. Unexpected Selectivity Change when Manipulating the Structure of the Auxiliary

“…In our case, ready access to enantioenriched β-amino ketones can be accomplished from β-amino amides 2 via 1,2-addition of organolithium reagents to the pseudoephedrine amide moiety, which has previously proven to be a very appropriate group for such a transformation, giving in many cases comparable or even better results than the well-known Weinreb amides . In most of the examples reported, the addition of organolithium reagents to the carbonyl group of pseudoephedrine amides is known to be extremely fast and clean, with no presence of overaddition byproducts, and very tolerant of other functionalities present in the substrate. 10f,11a,c,12a …”

(S,S)-(+)-Pseudoephedrine as Chiral Auxiliary in Asymmetric Aza-Michael Reactions. Unexpected Selectivity Change when Manipulating the Structure of the Auxiliary

“…In our case, ready access to enantioenriched β-amino ketones can be accomplished from β-amino amides 2 via 1,2-addition of organolithium reagents to the pseudoephedrine amide moiety, which has previously proven to be a very appropriate group for such a transformation, giving in many cases comparable or even better results than the well-known Weinreb amides . In most of the examples reported, the addition of organolithium reagents to the carbonyl group of pseudoephedrine amides is known to be extremely fast and clean, with no presence of overaddition byproducts, and very tolerant of other functionalities present in the substrate. 10f,11a,c,12a …”

Syntheses of 3-Aryl Tetrahydroisoquinolines via an Intermolecular [4 + 2] Cycloaddition of Sultines with Imines

“…Examination of various sultine derivatives as masked dienes under the optimized conditions showed that the desired aza-Diels–Alder reaction proceeded to provide a range of polysubstituted THIQs 10 – 15 (Scheme ). Of note, the electron-poor dibromo THIQ 12 was prepared in a good 80% yield, highlighting the complementary nature of our methodology to those existing in the literature . The low yield of 13 was unexpected because we envisioned the transformation to follow the normal electron-demand scenario.…”

Asymmetric Synthesis of Isoquinoline Alkaloids

“…Optically active benzylamines 127 and 134 have been used by Badia's research group for the synthesis of isopavines and benzylisoquinolines and as precursors of protoberberine and the benzo[ c ]phenantridine alkaloids (Schemes −34).…”

“…In the Kaufman synthesis of (S)-(-)-salsolidine (ent-10) 86 and the 1,2-dihydroisoquinoline derivative 126b 87 (a key intermediate in the synthesis of the β-adrenergic receptor antagonist MY 336-a), the substrates were chiral benzyl alcohols 124a and 124b, respectively (Scheme 31). The treatment with N-tosylaminoacetaldehyde acetal under the Mitsunobu reaction condition produced the tosylamides Optically active benzylamines 127 and 134 have been used by Badia's research group for the synthesis of isopavines 89 and benzylisoquinolines 90 and as precursors of protoberberine 91 and the benzo[c]phenantridine 92 alkaloids (Schemes 32-34).…”

“…In another series of experiments, chiral amines 134 were oxidized by the Swern method to the corresponding aldehydes 135, which in turn were cyclized in acidic media to give diastereomerically pure 3,4cis-3-aryltetrahydroisoquinolin-4-ols 136, 91 possible precursors of protoberberine alkaloids (e.g., ophiocarpine or papaverberine). As a continuation of this line of investigation, 4-hydroxy derivatives 136 were deoxygenated to give the 3-aryl-substituted tetrahydroisoquinolines 137, which might be considered as intermediates en route to benzo[c]phenanthridines 92 (Scheme 34).…”

(S,S)-(+)-Pseudoephedrine as Chiral Auxiliary in Asymmetric Aza-Michael Reactions. Unexpected Selectivity Change when Manipulating the Structure of the Auxiliary

“…In our case, ready access to enantioenriched β-amino ketones can be accomplished from β-amino amides 2 via 1,2-addition of organolithium reagents to the pseudoephedrine amide moiety, which has previously proven to be a very appropriate group for such a transformation, giving in many cases comparable or even better results than the well-known Weinreb amides . In most of the examples reported, the addition of organolithium reagents to the carbonyl group of pseudoephedrine amides is known to be extremely fast and clean, with no presence of overaddition byproducts, and very tolerant of other functionalities present in the substrate. 10f,11a,c,12a …”

Syntheses of 3-Aryl Tetrahydroisoquinolines via an Intermolecular [4 + 2] Cycloaddition of Sultines with Imines

“…Examination of various sultine derivatives as masked dienes under the optimized conditions showed that the desired aza-Diels–Alder reaction proceeded to provide a range of polysubstituted THIQs 10 – 15 (Scheme ). Of note, the electron-poor dibromo THIQ 12 was prepared in a good 80% yield, highlighting the complementary nature of our methodology to those existing in the literature . The low yield of 13 was unexpected because we envisioned the transformation to follow the normal electron-demand scenario.…”

Asymmetric Synthesis of Isoquinoline Alkaloids

“…Optically active benzylamines 127 and 134 have been used by Badia's research group for the synthesis of isopavines and benzylisoquinolines and as precursors of protoberberine and the benzo[ c ]phenantridine alkaloids (Schemes −34).…”

“…In the Kaufman synthesis of (S)-(-)-salsolidine (ent-10) 86 and the 1,2-dihydroisoquinoline derivative 126b 87 (a key intermediate in the synthesis of the β-adrenergic receptor antagonist MY 336-a), the substrates were chiral benzyl alcohols 124a and 124b, respectively (Scheme 31). The treatment with N-tosylaminoacetaldehyde acetal under the Mitsunobu reaction condition produced the tosylamides Optically active benzylamines 127 and 134 have been used by Badia's research group for the synthesis of isopavines 89 and benzylisoquinolines 90 and as precursors of protoberberine 91 and the benzo[c]phenantridine 92 alkaloids (Schemes 32-34).…”

“…In another series of experiments, chiral amines 134 were oxidized by the Swern method to the corresponding aldehydes 135, which in turn were cyclized in acidic media to give diastereomerically pure 3,4cis-3-aryltetrahydroisoquinolin-4-ols 136, 91 possible precursors of protoberberine alkaloids (e.g., ophiocarpine or papaverberine). As a continuation of this line of investigation, 4-hydroxy derivatives 136 were deoxygenated to give the 3-aryl-substituted tetrahydroisoquinolines 137, which might be considered as intermediates en route to benzo[c]phenanthridines 92 (Scheme 34).…”

(S,S)-(+)-Pseudoephedrine as Chiral Auxiliary in Asymmetric Aza-Michael Reactions. Unexpected Selectivity Change when Manipulating the Structure of the Auxiliary

“…In our case, ready access to enantioenriched β-amino ketones can be accomplished from β-amino amides 2 via 1,2-addition of organolithium reagents to the pseudoephedrine amide moiety, which has previously proven to be a very appropriate group for such a transformation, giving in many cases comparable or even better results than the well-known Weinreb amides . In most of the examples reported, the addition of organolithium reagents to the carbonyl group of pseudoephedrine amides is known to be extremely fast and clean, with no presence of overaddition byproducts, and very tolerant of other functionalities present in the substrate. 10f,11a,c,12a …”

Syntheses of 3-Aryl Tetrahydroisoquinolines via an Intermolecular [4 + 2] Cycloaddition of Sultines with Imines

“…Examination of various sultine derivatives as masked dienes under the optimized conditions showed that the desired aza-Diels–Alder reaction proceeded to provide a range of polysubstituted THIQs 10 – 15 (Scheme ). Of note, the electron-poor dibromo THIQ 12 was prepared in a good 80% yield, highlighting the complementary nature of our methodology to those existing in the literature . The low yield of 13 was unexpected because we envisioned the transformation to follow the normal electron-demand scenario.…”

Asymmetric Synthesis of Isoquinoline Alkaloids

“…Optically active benzylamines 127 and 134 have been used by Badia's research group for the synthesis of isopavines and benzylisoquinolines and as precursors of protoberberine and the benzo[ c ]phenantridine alkaloids (Schemes −34).…”

“…In the Kaufman synthesis of (S)-(-)-salsolidine (ent-10) 86 and the 1,2-dihydroisoquinoline derivative 126b 87 (a key intermediate in the synthesis of the β-adrenergic receptor antagonist MY 336-a), the substrates were chiral benzyl alcohols 124a and 124b, respectively (Scheme 31). The treatment with N-tosylaminoacetaldehyde acetal under the Mitsunobu reaction condition produced the tosylamides Optically active benzylamines 127 and 134 have been used by Badia's research group for the synthesis of isopavines 89 and benzylisoquinolines 90 and as precursors of protoberberine 91 and the benzo[c]phenantridine 92 alkaloids (Schemes 32-34).…”

“…In another series of experiments, chiral amines 134 were oxidized by the Swern method to the corresponding aldehydes 135, which in turn were cyclized in acidic media to give diastereomerically pure 3,4cis-3-aryltetrahydroisoquinolin-4-ols 136, 91 possible precursors of protoberberine alkaloids (e.g., ophiocarpine or papaverberine). As a continuation of this line of investigation, 4-hydroxy derivatives 136 were deoxygenated to give the 3-aryl-substituted tetrahydroisoquinolines 137, which might be considered as intermediates en route to benzo[c]phenanthridines 92 (Scheme 34).…”