Highly Selective Addition of Chiral, Sulfonimidoyl Substituted Bis(allyl)titanium Complexes to N-Sulfonyl α-Imino Esters:  Asymmetric Synthesis of γ,δ-Unsaturated α-Amino Acids Bearing a Chiral, Electron-Withdrawing Nucleofuge at the δ-Position

Abstract

Selective addition of the chiral, sulfonimidoyl substituted bis(allyl)titanium complexes 5a-d, which are configurationally labile in regard to the Calpha-atoms, to N-toluenesulfonyl (Ts)-, N-2-trimethylsilylethanesulfonyl (SES)-, and N-tert-butylsulfonyl (Bus) alpha-imino ester (9a-c) in the presence of Ti(OiPr)(4) and ClTi(OiPr)(3) afforded with high regio- and diastereoselectivities in good yields the (syn, E)-configured beta-alkyl-gamma,delta-unsaturated alpha-amino acid derivatives 2a-g, which carry a chiral, electron-withdrawing nucleofuge at the delta-position and a cyclohexyl, an isopropyl, a phenyl, and a methyl group at the beta-position. Addition of the cyclic bis(allyl)titanium complex 14 to N-Bus alpha-imino ester 9c afforded with similar high regio- and diastereoselectivities the (E)- and (Z)-configured amino acid derivatives (E)-8 and (Z)-8. Reaction of complexes 5a-d with alpha-imino esters 9a-c in the presence of Ti(OiPr)(4) occurs stepwise to give first the mono(allyl)titanium complexes containing 2a-g as ligands, which react in the presence of ClTi(OiPr)(3) with a second molecule of 9a-c with formation of two molecules of 2a-g. Formation of (S,R,E)-configured homoallylic amines 2a-g entails Si,Re,E processes of alpha-imino esters 9a-c with the (R,R)-configured bis(allyl)titanium complexes (R,R)-5a-d and (R)-configured mono(allyl)titanium complexes (R)-17a-d, both of which are most likely in rapid equilibrium with their (S,S)-diastereomers and (S)-diastereomers, respectively. Interestingly, in the reaction of 5a-d with aldehydes, the (S,S)-configured complexes (S,S)-5a-d are the ones which react faster. Reaction of the N-titanated amino acid derivatives Ti-2a and Ti-2b with N-Ts alpha-imino ester 9a led to the highly diastereoselective formation of imidazolidinones 15a and 15b, respectively. Cleavage of the sulfonamide group of the N-Bus amino acid derivative 2d with CF(3)SO(3)H gave quantitatively the sulfonimidoyl functionalized amino acid H-2d. A Ni-catalyzed cross-coupling reaction of the amino acid derivative 2e with ZnPh(2) led to a substitution of the sulfonimidoyl group by a phenyl group and furnished the enantiomerically pure protected alpha-amino acid Bus-1. Two new N-sulfonyl alpha-imino esters, the SES and the Bus alpha-imino esters 9b and 9c, respectively, have been synthesized from the corresponding sulfonamides by the Kresze method in medium to good yields. The N-SES alpha-imino ester 9b and the N-Bus alpha-imino ester 9c should find many synthetic applications, in particular, in cases where the N-Ts alpha-imino ester 9a had been used before.

Vinyl and Bromo‐Vinyl Sulfoximine Synthesis via Reactive Sulfonimidoyl Bromide Intermediates

“…Based on our experimental results and the literature, [29][30][31][32][33][34] we propose a plausible mechanism as shown in Scheme 6. In the first step, DBDMH oxidatively brominates thiophenol A to give intermediate B, which subsequently couples with the sulfonamide under basic conditions to form sulfenamide C. Compound C then undergoes two consecutive bromination-oxidation steps to furnish aza-dibromosulfonium species E, which upon hydrolysis delivers isolable sulfonimidoyl bromide F. A SET between F and the thiophenolate anion generates radical anion G, which, via homolytic cleavage, furnishes radical H along with a bromide anion.…”

Vinyl and Bromo‐Vinyl Sulfoximine Synthesis via Reactive Sulfonimidoyl Bromide Intermediates

“…Based on our experimental results and the literature, [29][30][31][32][33][34] we propose a plausible mechanism as shown in Scheme 6. In the first step, DBDMH oxidatively brominates thiophenol A to give intermediate B, which subsequently couples with the sulfonamide under basic conditions to form sulfenamide C. Compound C then undergoes two consecutive bromination-oxidation steps to furnish aza-dibromosulfonium species E, which upon hydrolysis delivers isolable sulfonimidoyl bromide F. A SET between F and the thiophenolate anion generates radical anion G, which, via homolytic cleavage, furnishes radical H along with a bromide anion.…”

Asymmetric Synthesis of Unsaturated, Fused Bicyclic Proline Analogues through Amino Alkylation of Cyclic Bis(allylsulfoximine)titanium Complexes and Migratory Cyclization of δ-Amino Alkenyl Aminosulfoxonium Salts

“…To rationalize the E / Z -stereoselectivities of the reaction of 6 with 5 in dependence of the ring size, the two Si,Re chairlike six-membered cyclic transition state models TS - 1 and TS - 2 are proposed for the transfer of the first allylic moiety. Similar transition state models have been put forward previously to rationalize the stereochemistry of the reaction of similar acyclic bis(allylsulfoximine)titanium complexes with 5 . In TS - 1 and TS - 2 the imino ester and the sulfoximine group are coordinated through their N-atoms to the Ti-atom, and the tert -butylsulfonyl and the ester group both occupy pseudoaxial positions.…”

“…The absolute configuration of ent - E - 4d had already been established by X-ray crystal structure analysis . A X-ray crystal structure analysis of Z - 4c showed it to have the absolute configuration depicted in Figure .…”

Functionalized Chiral Vinyl Aminosulfoxonium Salts: Asymmetric Synthesis and Application to the Synthesis of Enantiopure Unsaturated Prolines, β,γ-Dehydro Amino Acids, and Cyclopentanoid Keto Aminosulfoxonium Ylides

“…3 , 4-Dehydro Prolines. Treatment of the sulfonimidoyl-substituted bis(allyl)titanium(IV) complexes 3a − e , which were prepared from the corresponding enantiomerically pure allyl sulfoximines E - 2a − e through titanation following lithiation, with the N -Bus imino ester 4 19 afforded the corresponding functionalized vinyl sulfoximines 5a − e , respectively, with high regio- and diastereoselectivities in good yields as described previously (Scheme ) . The α-imino ester 4 was prepared from sulfonamide 6 , using a modified version of our previously reported procedure, which allowed an increase of the yield by 30% to 93%.…”

“…Stereo-Complementary Aminoalkylation of Sulfonimidoyl-Substituted Mono( a llyl)titanium Complexes. We had previously shown that the bis(allyl)titanium complexes 28a − d , which are derived from the corresponding cyclic allyl sulfoximines 27a − d through lithiation and titanation with ClTi(O i Pr) 3 , react with the α-imino ester 4 with high regio- and diastereoselectivities at the γ-position to give E-syn - and Z-syn -configured functionalized vinyl sulfoximines E -29a − d and Z -29a − d , respectively, both with very high diastereoselectivities in ratios of 1.4:1, 5:1, 1:3, and 1:12, respectively (Scheme ) .…”

Vinyl and Bromo‐Vinyl Sulfoximine Synthesis via Reactive Sulfonimidoyl Bromide Intermediates

“…Based on our experimental results and the literature, [29][30][31][32][33][34] we propose a plausible mechanism as shown in Scheme 6. In the first step, DBDMH oxidatively brominates thiophenol A to give intermediate B, which subsequently couples with the sulfonamide under basic conditions to form sulfenamide C. Compound C then undergoes two consecutive bromination-oxidation steps to furnish aza-dibromosulfonium species E, which upon hydrolysis delivers isolable sulfonimidoyl bromide F. A SET between F and the thiophenolate anion generates radical anion G, which, via homolytic cleavage, furnishes radical H along with a bromide anion.…”

Asymmetric Synthesis of Unsaturated, Fused Bicyclic Proline Analogues through Amino Alkylation of Cyclic Bis(allylsulfoximine)titanium Complexes and Migratory Cyclization of δ-Amino Alkenyl Aminosulfoxonium Salts

“…To rationalize the E / Z -stereoselectivities of the reaction of 6 with 5 in dependence of the ring size, the two Si,Re chairlike six-membered cyclic transition state models TS - 1 and TS - 2 are proposed for the transfer of the first allylic moiety. Similar transition state models have been put forward previously to rationalize the stereochemistry of the reaction of similar acyclic bis(allylsulfoximine)titanium complexes with 5 . In TS - 1 and TS - 2 the imino ester and the sulfoximine group are coordinated through their N-atoms to the Ti-atom, and the tert -butylsulfonyl and the ester group both occupy pseudoaxial positions.…”

“…The absolute configuration of ent - E - 4d had already been established by X-ray crystal structure analysis . A X-ray crystal structure analysis of Z - 4c showed it to have the absolute configuration depicted in Figure .…”

Functionalized Chiral Vinyl Aminosulfoxonium Salts: Asymmetric Synthesis and Application to the Synthesis of Enantiopure Unsaturated Prolines, β,γ-Dehydro Amino Acids, and Cyclopentanoid Keto Aminosulfoxonium Ylides

“…3 , 4-Dehydro Prolines. Treatment of the sulfonimidoyl-substituted bis(allyl)titanium(IV) complexes 3a − e , which were prepared from the corresponding enantiomerically pure allyl sulfoximines E - 2a − e through titanation following lithiation, with the N -Bus imino ester 4 19 afforded the corresponding functionalized vinyl sulfoximines 5a − e , respectively, with high regio- and diastereoselectivities in good yields as described previously (Scheme ) . The α-imino ester 4 was prepared from sulfonamide 6 , using a modified version of our previously reported procedure, which allowed an increase of the yield by 30% to 93%.…”

“…Stereo-Complementary Aminoalkylation of Sulfonimidoyl-Substituted Mono( a llyl)titanium Complexes. We had previously shown that the bis(allyl)titanium complexes 28a − d , which are derived from the corresponding cyclic allyl sulfoximines 27a − d through lithiation and titanation with ClTi(O i Pr) 3 , react with the α-imino ester 4 with high regio- and diastereoselectivities at the γ-position to give E-syn - and Z-syn -configured functionalized vinyl sulfoximines E -29a − d and Z -29a − d , respectively, both with very high diastereoselectivities in ratios of 1.4:1, 5:1, 1:3, and 1:12, respectively (Scheme ) .…”

Vinyl and Bromo‐Vinyl Sulfoximine Synthesis via Reactive Sulfonimidoyl Bromide Intermediates

“…Based on our experimental results and the literature, [29][30][31][32][33][34] we propose a plausible mechanism as shown in Scheme 6. In the first step, DBDMH oxidatively brominates thiophenol A to give intermediate B, which subsequently couples with the sulfonamide under basic conditions to form sulfenamide C. Compound C then undergoes two consecutive bromination-oxidation steps to furnish aza-dibromosulfonium species E, which upon hydrolysis delivers isolable sulfonimidoyl bromide F. A SET between F and the thiophenolate anion generates radical anion G, which, via homolytic cleavage, furnishes radical H along with a bromide anion.…”

Asymmetric Synthesis of Unsaturated, Fused Bicyclic Proline Analogues through Amino Alkylation of Cyclic Bis(allylsulfoximine)titanium Complexes and Migratory Cyclization of δ-Amino Alkenyl Aminosulfoxonium Salts

“…To rationalize the E / Z -stereoselectivities of the reaction of 6 with 5 in dependence of the ring size, the two Si,Re chairlike six-membered cyclic transition state models TS - 1 and TS - 2 are proposed for the transfer of the first allylic moiety. Similar transition state models have been put forward previously to rationalize the stereochemistry of the reaction of similar acyclic bis(allylsulfoximine)titanium complexes with 5 . In TS - 1 and TS - 2 the imino ester and the sulfoximine group are coordinated through their N-atoms to the Ti-atom, and the tert -butylsulfonyl and the ester group both occupy pseudoaxial positions.…”

“…The absolute configuration of ent - E - 4d had already been established by X-ray crystal structure analysis . A X-ray crystal structure analysis of Z - 4c showed it to have the absolute configuration depicted in Figure .…”

Functionalized Chiral Vinyl Aminosulfoxonium Salts: Asymmetric Synthesis and Application to the Synthesis of Enantiopure Unsaturated Prolines, β,γ-Dehydro Amino Acids, and Cyclopentanoid Keto Aminosulfoxonium Ylides

“…3 , 4-Dehydro Prolines. Treatment of the sulfonimidoyl-substituted bis(allyl)titanium(IV) complexes 3a − e , which were prepared from the corresponding enantiomerically pure allyl sulfoximines E - 2a − e through titanation following lithiation, with the N -Bus imino ester 4 19 afforded the corresponding functionalized vinyl sulfoximines 5a − e , respectively, with high regio- and diastereoselectivities in good yields as described previously (Scheme ) . The α-imino ester 4 was prepared from sulfonamide 6 , using a modified version of our previously reported procedure, which allowed an increase of the yield by 30% to 93%.…”

“…Stereo-Complementary Aminoalkylation of Sulfonimidoyl-Substituted Mono( a llyl)titanium Complexes. We had previously shown that the bis(allyl)titanium complexes 28a − d , which are derived from the corresponding cyclic allyl sulfoximines 27a − d through lithiation and titanation with ClTi(O i Pr) 3 , react with the α-imino ester 4 with high regio- and diastereoselectivities at the γ-position to give E-syn - and Z-syn -configured functionalized vinyl sulfoximines E -29a − d and Z -29a − d , respectively, both with very high diastereoselectivities in ratios of 1.4:1, 5:1, 1:3, and 1:12, respectively (Scheme ) .…”