Parallel Kinetic Resolution of Acyclic γ-Amino-α,β-unsaturated Esters: Application to the Asymmetric Synthesis of 4-Aminopyrrolidin-2-ones

Conjugate addition of a 50:50 pseudoenantiomeric mixture of lithium (<i>R</i>)-<i>N</i>-benzyl-<i>N</i>-(α-methylbenzyl)amide and lithium (<i>S</i>)-<i>N</i>-3,4-dimethoxybenzyl-<i>N</i>-(α-methylbenzyl)amide to a range of racemic acyclic γ-amino-α,β-unsaturated esters (derived from the corresponding α-amino acids) effects their efficient parallel kinetic resolution, allowing the preparation of enantiopure β,γ-diamino esters. The β,γ-diamino ester products of these reactions are readily converted into the corresponding substituted 4-aminopyrrolidin-2-ones via <i>N</i>-debenzylation and cyclization

Parallel Kinetic Resolution of Acyclic γ-Amino-α,β-unsaturated Esters: Application to the Asymmetric Synthesis of 4-Aminopyrrolidin-2-ones

Conjugate addition of a 50:50 pseudoenantiomeric mixture of lithium (<i>R</i>)-<i>N</i>-benzyl-<i>N</i>-(α-methylbenzyl)amide and lithium (<i>S</i>)-<i>N</i>-3,4-dimethoxybenzyl-<i>N</i>-(α-methylbenzyl)amide to a range of racemic acyclic γ-amino-α,β-unsaturated esters (derived from the corresponding α-amino acids) effects their efficient parallel kinetic resolution, allowing the preparation of enantiopure β,γ-diamino esters. The β,γ-diamino ester products of these reactions are readily converted into the corresponding substituted 4-aminopyrrolidin-2-ones via <i>N</i>-debenzylation and cyclization

Absolute Configuration Assignment by Asymmetric Syntheses of the Homalium Alkaloids (−)‑(<i>R</i>,<i>R</i>,<i>R</i>)‑Hoprominol and (−)-(4′<i>S</i>,4″<i>R</i>,2‴<i>R</i>)‑Hopromalinol

The conjugate addition of lithium (<i>R</i>)-<i>N</i>-(3-chloropropyl)-<i>N</i>-(α-methylbenzyl)­amide to α,β-unsaturated esters was used as the key step in the syntheses of all possible diastereoisomers of the homalium alkaloids hoprominol and hopromalinol. Comparison of the specific rotation data for these synthetic samples with those of samples isolated from the natural source enabled the absolute configurations within these alkaloids to be confidently assigned for the first time as (−)-(<i>R</i>,<i>R</i>,<i>R</i>)-hoprominol and (−)-(4′<i>S</i>,4″<i>R</i>,2‴<i>R</i>)-hopromalinol. The asymmetric syntheses of (−)-(<i>R</i>,<i>R</i>,<i>R</i>)-hoprominol (in 10 steps and 4.0% overall yield) and (−)-(4′<i>S</i>,4″<i>R</i>,2‴<i>R</i>)-hopromalinol (in 10 steps and 9.3% overall yield), from commercially available starting materials in each case, therefore represent the first total asymmetric syntheses of these alkaloids to be reported

Asymmetric Syntheses of the Homalium Alkaloids (−)‑(<i>S</i>,<i>S</i>)‑Homaline and (−)‑(<i>R</i>,<i>R</i>)‑Hopromine

The highly diastereoselective conjugate additions of the novel lithium amide reagents lithium (<i>R</i>)-<i>N</i>-(3-chloropropyl)-<i>N</i>-(α-methylbenzyl)­amide and lithium (<i>R</i>)-<i>N</i>-(3-chloropropyl)-<i>N</i>-(α-methyl-<i>p</i>-methoxybenzyl)­amide to α,β-unsaturated esters were used as the key steps in syntheses of the homalium alkaloids (−)-(<i>S</i>,<i>S</i>)-homaline and (−)-(<i>R</i>,<i>R</i>)-hopromine. The asymmetric synthesis of (−)-(<i>S</i>,<i>S</i>)-homaline was achieved in 8 steps and 18% overall yield, and the asymmetric synthesis of (−)-(<i>R</i>,<i>R</i>)-hopromine was achieved in 9 steps and 23% overall yield, from commercially available starting materials in each case. These syntheses therefore represent by far the most efficient total asymmetric syntheses of these alkaloids reported to date. A sample of the (4′<i>R</i>,4′′<i>S</i>)-epimer of hopromine was also produced using this approach, which provided the first unambiguous confirmation of its absolute configuration and therefore that of natural (−)-(<i>R</i>,<i>R</i>)-hopromine

Asymmetric Syntheses of the Homalium Alkaloids (−)‑(<i>S</i>,<i>S</i>)‑Homaline and (−)‑(<i>R</i>,<i>R</i>)‑Hopromine

The highly diastereoselective conjugate additions of the novel lithium amide reagents lithium (<i>R</i>)-<i>N</i>-(3-chloropropyl)-<i>N</i>-(α-methylbenzyl)­amide and lithium (<i>R</i>)-<i>N</i>-(3-chloropropyl)-<i>N</i>-(α-methyl-<i>p</i>-methoxybenzyl)­amide to α,β-unsaturated esters were used as the key steps in syntheses of the homalium alkaloids (−)-(<i>S</i>,<i>S</i>)-homaline and (−)-(<i>R</i>,<i>R</i>)-hopromine. The asymmetric synthesis of (−)-(<i>S</i>,<i>S</i>)-homaline was achieved in 8 steps and 18% overall yield, and the asymmetric synthesis of (−)-(<i>R</i>,<i>R</i>)-hopromine was achieved in 9 steps and 23% overall yield, from commercially available starting materials in each case. These syntheses therefore represent by far the most efficient total asymmetric syntheses of these alkaloids reported to date. A sample of the (4′<i>R</i>,4′′<i>S</i>)-epimer of hopromine was also produced using this approach, which provided the first unambiguous confirmation of its absolute configuration and therefore that of natural (−)-(<i>R</i>,<i>R</i>)-hopromine

Asymmetric Synthesis of (−)-Martinellic Acid

A high-yielding total asymmetric synthesis of (−)-martinellic acid is reported. The conjugate addition of lithium (<i>R</i>)-<i>N</i>-allyl-<i>N</i>-(α-methyl-4-methoxybenzyl)amide to <i>tert</i>-butyl (<i>E</i>)-3-[2′-(<i>N</i>,<i>N</i>-diallylamino)-5′-bromophenyl]propenoate and alkylation of the resultant β-amino ester have been used as the key steps to install the C(9b) and C(3a) stereogenic centers, respectively, and a highly diastereoselective Wittig reaction/intramolecular Michael addition was then used to create the C(4) stereogenic center within this tricyclic molecular architecture

Asymmetric Synthesis of (−)-Martinellic Acid

A high-yielding total asymmetric synthesis of (−)-martinellic acid is reported. The conjugate addition of lithium (<i>R</i>)-<i>N</i>-allyl-<i>N</i>-(α-methyl-4-methoxybenzyl)amide to <i>tert</i>-butyl (<i>E</i>)-3-[2′-(<i>N</i>,<i>N</i>-diallylamino)-5′-bromophenyl]propenoate and alkylation of the resultant β-amino ester have been used as the key steps to install the C(9b) and C(3a) stereogenic centers, respectively, and a highly diastereoselective Wittig reaction/intramolecular Michael addition was then used to create the C(4) stereogenic center within this tricyclic molecular architecture

4.1.1 Key elements of personal skills

Conjugate addition of lithium (<i>S</i>)-<i>N</i>-allyl-<i>N</i>-(α-methyl-<i>p</i>-methoxybenzyl)amide to methyl (<i>E</i>,<i>E</i>)-hepta-2,5-dienoate furnished the corresponding β-amino ester. <i>N</i>-Protecting group manipulation, ring-closing metathesis, and ester hydrolysis gave enantiopure [<i>N</i>(1′)-<i>tert</i>-butoxycarbonyl-1,2,3,6-tetrahydropyridin-2′-yl]ethanoic acid. Subsequent iodolactonization gave a bicyclic iodolactone scaffold. This key intermediate was elaborated to (+)-pseudodistomin D [in >99% ee and 7% yield over 16 steps from methyl (<i>E</i>,<i>E</i>)-hepta-2,5-dienoate]

Probing Competitive and Co-operative Hydroxyl and Ammonium Hydrogen-Bonding Directed Epoxidations

The diastereoselectivities and rates of epoxidation (upon treatment with Cl₃CCO₂H then <i>m</i>-CPBA) of a range of <i>cis</i>- and <i>trans</i>-4-aminocycloalk-2-en-1-ol derivatives (containing five-, six-, and seven-membered rings) have been investigated. In all cases where the two potential directing groups can promote epoxidation on opposite faces of the ring scaffold, evidence of competitive epoxidation pathways, promoted by hydrogen-bonding to either the in situ formed ammonium moiety or the hydroxyl group, was observed. In contrast to the relative directing group abilities already established for the six-membered ring system (NHBn ≫ OH > NBn₂), an <i>N</i>,<i>N</i>-dibenzylammonium moiety appeared more proficient than a hydroxyl group at directing the stereochemical course of the epoxidation reaction in a five- or seven-membered system. In the former case, this was rationalized by the drive to minimize torsional strain in the transition state being coupled with assistance from hydrogen-bonding to the ammonium moiety. In the latter case, this was ascribed to the steric bulk of the ammonium moiety disfavoring conformations in which hydrogen-bonding to the hydroxyl group results in direction of the epoxidation to the <i>syn</i> face. In cases where the two potential directing groups can promote epoxidation on the same face of the ring scaffold, an enhancement of epoxidation diastereoselectivity was not observed, while introduction of a second, allylic heteroatom to the substrate results in diminishment of the rate of epoxidation in all cases. Presumably, reduction of the nucleophilicity of the olefin by the second, inductively electron-withdrawing heteroatom is the dominant factor, and any assistance to the epoxidation reaction by the potential to form hydrogen-bonds to two directing groups rather than one is clearly unable to overwhelm it

Ammonium-Directed Olefinic Epoxidation: Kinetic and Mechanistic Insights

The ammonium-directed olefinic epoxidations of a range of differentially N-substituted cyclic allylic and homoallylic amines (derived from cyclopentene, cyclohexene, and cycloheptene) have been investigated, and the reaction kinetics have been analyzed. The results of these studies suggest that both the ring size and the identity of the substituents on nitrogen are important in determining both the overall rate and the stereochemical outcome of the epoxidation reaction. In general, secondary amines or tertiary amines with nonsterically demanding substituents on nitrogen are superior to tertiary amines with sterically demanding substituents on nitrogen in their ability to promote the oxidation reaction. Furthermore, in all cases examined, the ability of the (in situ formed) ammonium substituent to direct the stereochemical course of the epoxidation reaction is either comparable or superior to that of the analogous hydroxyl substituent. Much slower rates of ring-opening of the intermediate epoxides are observed in cyclopentene-derived and cycloheptene-derived allylic amines as compared with their cyclohexene-derived allylic and homoallylic amine counterparts, allowing for isolation of these intermediates in both of the former cases