An acid-promoted novel cascade cyclization is described. Using 8 equiv of trifluoroacetic acid or a catalytic amount of Lewis acid as the promoter, structurally diverse polycyclic cyclopenta[b]indoles were obtained in moderate to excellent yield. This cascade process was extremely effective for the synthesis of 8-membered ring-fused cyclopenta[b]indole derivatives.

A novel method for synthesizing 3-arylpyrrolidine and 4-arylpiperidine derivatives through an acid-promoted skeletal rearrangement is described. Using trifluoroacetic acid as the acid promoter, an intramolecular ipso-Friedel–Crafts-type addition of phenols to allyl cations, formation of iminium cations through rearomatization of the spirocyclohexadienone units, and an intramolecular aza-Prins reaction, proceeded sequentially to afford 3-arylpyrrolidine and 4-arylpiperidine derivatives in good yield with high diastereoselectivity.

An acid-promoted novel skeletal rearrangement is described. Using trifluoroacetic acid as the acid promoter, an intramolecular ipso-Friedel–Crafts-type addition of phenols to 3-alkylidene indolenium cations, formation of iminium cations through rearomatization of the spirocyclohexadienone units, and intramolecular Pictet–Spengler reaction proceeded sequentially, producing tricyclic indole derivatives.

We developed a novel asymmetric synthetic method for multisubstituted 9,10-dihydrophenanthrenes based on the Pd-catalyzed asymmetric intramolecular Friedel–Crafts allylic alkylation of phenols, which produces 10-vinyl or 10-isopropenyl chiral 9,10-dihydrophenanthrene derivatives in high yield with up to 94% ee.

We developed a novel method for the asymmetric synthesis of highly functionalized γ-lactams through an organocatalytic aza-Michael–Michael reaction cascade using fumaric acid amide esters as multi-reactive substrates. Using chiral primary or secondary amine organocatalysts, we obtained two types of γ-lactams with three contiguous chiral centers in moderate to good yield with excellent enantioselectivity and diastereoselectivity.

A novel catalytic asymmetric synthetic method for making spirocyclohexadienones with an all-carbon quaternary spirocenter was developed based on the Pd-catalyzed intramolecular ipso-Friedel–Crafts allylic alkylation of phenols. When 5 mol % of the Pd catalyst and 12 mol % of (−)-9-NapBN (−)-3e were used, the spirocyclic adduct was obtained with up to 93% ee, albeit with low chemical yield. On the other hand, when using 6 mol% of the Trost ligand (R,R)-3k, the spirocyclic adducts were obtained in good yields with up to 89% ee (diastereoselectivity = 9.2:1).

Novel chiral hydrogen bond donor catalysts based on a 4,5-diamino-9,9′-dimethylxanthene skeleton were designed and synthesized. Among the phenylurea-amide hybrid molecules prepared from various natural/unnatural chiral amino acids, the phenylalanine-derived catalyst, and the proline-derived catalyst were successfully applied to enantioselective conjugate addition of 1,3-dicarbonyl compounds to nitroalkenes. Using 2-acetylcyclopentanone and 2-methoxycarbonylcyclopentanone as prochiral nucleophiles, asymmetric conjugate addition to β-aryl nitroalkenes proceeded with good diastereoselectivity to provide the corresponding products bearing an all-carbon quaternary stereocenter in excellent yield with up to 95% ee.

The first enantioselective total synthesis of tangutorine has been achieved, wherein a Pd-catalyzed asymmetric allylic amination using a chiral diaminophosphine oxide (DIAPHOX) preligand was the key step.

The first successful Pd-catalyzed intramolecular ipso-Friedel−Crafts allylic alkylation of phenols, which provided a new access to spiro[4.5]cyclohexadienones, is described. The present method could be applied to catalytic enantioselective construction of an all-carbon quaternary spirocenter.

Angelmarin (1), a novel anti-cancer agent, was efficiently synthesized through a highly enantioselective epoxidation and a copper cyanide-mediated esterification of the hindered alcohol as the key steps in 53% overall yield.

Homogeneous chiral nickel-bisphosphine complexes catalyze the asymmetric hydrogenation of α-amino-β-keto ester hydrochlorides through dynamic kinetic resolution to efficiently afford anti-β-hydroxy-α-amino esters with high diastereo- and enantioselectivities.

A Pd-catalyzed asymmetric allylic alkylation of 2-substituted cycloalkenyl carbonates using a chiral diaminophosphine oxide is described. Asymmetric allylic substitution of various cyclic substrates proceeded using 5 mol % of Pd catalyst, 10 mol % of (S,RP)-Ph-DIAPHOX 1, 10 mol % of LiOAc, and N,O-bis(trimethylsilyl)acetamide (BSA), to afford the corresponding products in excellent yields with up to 92% ee.(1R)-2-Phenyl-2-cyclohexen-1-yl malonic acid dibenzyl esterC29H28O4Ee = 86%[α]D24=-35.4 (c 0.32, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (R)(1R)-2-Phenyl-2-cyclopenten-1-yl malonic acid dibenzyl esterC28H26O4Ee = 89%[α]D19=-43.2 (c 0.87, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (R)

The asymmetric hydrogenation of α-amino-β-keto esters using ruthenium (Ru) anti-selectively proceeds via a dynamic kinetic resolution to afford anti-β-hydroxy-α-amino acids with high enantiomeric purities, which are important chiral building blocks for the synthesis of medicines and natural products. A mechanistic investigation has revealed that the Ru-catalyzed asymmetric hydrogenation takes place via the hydrogenation of the double bond in the enol tautomer of the substrate.Benzyl (2S,3S)-2-benzoylamino-3-hydroxy-4-methyl-pentanoateC20H23NO4Ee = 100%[α]D23=+33.9 (c 1.00, CHCl3)Source of chirality: BINAPAbsolute configuration: (2S,3S)Benzyl (2S,3S)-2-benzoylamino-3-cyclobutyl-3-hydroxy-propionateC21H23NO4Ee = 100%[α]D23=+22.3 (c 1.00, CHCl3)Source of chirality: BINAPAbsolute configuration: (2S,3S)Benzyl (2S,3S)-2-benzoylamino-3-cyclopentyl-3-hydroxy-propionateC22H25NO4Ee = 100%[α]D24=+20.5 (c 1.00, CHCl3)Source of chirality: BINAPAbsolute configuration: (2S,3S)Benzyl (2S,3S)-2-benzoylamino-3-cyclohexyl-3-hydroxy-propionateC23H27NO4Ee = 100%[α]D25=+14.8 (c 1.10, CHCl3)Source of chirality: BINAPAbsolute configuration: (2S,3S)Benzyl (2S,3S)-2-benzoylamino-3-cycloheptyl-3-hydroxy-propionateC24H29NO4Ee = 100%[α]D25=+12.9 (c 1.00, CHCl3)Source of chirality: BINAPAbsolute configuration: (2S,3S)Benzyl (2S,3S)-2-benzoylamino-3-hydroxy-pentanoateC19H21NO4Ee = 100%[α]D22=+36.2 (c 1.00, CHCl3)Source of chirality: BINAPAbsolute configuration: (2S,3S)Benzyl (2S,3S)-2-benzoylamino-3-hydroxy-hexanoateC20H23NO4Ee = 100%[α]D22=-18.3 (c 0.96, CHCl3)Source of chirality: MeO-BIPHEPAbsolute configuration: (2S,3S)Benzyl (2S,3S)-2-benzoylamino-3-hydroxy-4,4-dimethyl-pentanoateC21H25NO4Ee = 79%[α]D22=+23.9 (c 1.00, CHCl3)Source of chirality: BINAPAbsolute configuration: (2S,3S)Methyl (2S,3S)-2-benzoylamino-3-cyclohexyl-3-hydroxy-propionateC17H23NO4Ee = 96%[α]D26=+35.5 (c 1.07, CHCl3)Source of chirality: BINAPAbsolute configuration: (2S,3S)

Asymmetric allylic aminations with aromatic amine nucleophiles using Pd–DIAPHOX catalyst systems are described. The asymmetric allylic aminations of various allylic carbonates proceeded using 2–5 mol % of the catalyst and BSA, providing the corresponding N-aryl chiral allylic amines in up to 99% ee for cyclic substrates, and in up to 97% ee for acyclic substrates.(6S)-6-(4-Methoxy-phenylamino)-cyclohex-1-enecarboxylic acid methyl esterC15H19NO3Ee = 94%[α]D20=-98.2 (c 0.62, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (S)(1S)-(4-Methoxy-phenyl)-2-phenyl-cyclohex-2-enyl)-amineC19H21NOEe = 97%[α]D23=-165.4 (c 0.14, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (S)(1R)-(1,3-Diphenyl-allyl)-(4-methoxy-phenyl)-amineC22H21NOEe = 97%[α]D22=-56.2 (c 0.80, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (R)

The synthesis of novel P-stereogenic phenylphosphonamides 3 and 11 via an intramolecular nucleophilic substitution of P-stereogenic phosphoramide 8 is described. These compounds were used as chiral Lewis basic catalysts for the asymmetric allylation of benzaldehyde, providing the corresponding homoallylic alcohol derivatives in up to 54% ee.We succeeded in the synthesis of novel P-stereogenic phenylphosphonamides, which could be utilized as chiral Lewis basic catalysts for asymmetric allylation of benzaldehyde using allyltrichlorosilane.(1S,4aR)-(4a-Oxo-4-phenyl-1,2,3,4,4a,9-hexahydro-4,9a-diaza-4aλ5-phospha-fluoren-1-ylmethyl)-phenyl-amineC23H24N3OPEe = 100%[α]D23=+335.3 (c 0.25, CHCl3)Source of chirality: (S)-aspartic acidAbsolute configuration: (S,RP)(1S,4aR)-N-(4a-Oxo-4-phenyl-1,2,3,4,4a,9-hexahydro-4,9a-diaza-4aλ5-phospha-fluoren-1-ylmethyl)-N-phenyl-benzamideC30H28N3O2PEe = 100%[α]D23=+68.8 (c 0.83, CHCl3)Source of chirality: (S)-aspartic acidAbsolute configuration: (S,RP)

Rhodium-catalyzed asymmetric hydrogenation of α-amino-β-keto ester hydrochlorides through dynamic kinetic resolution is described. The hydrogenation proceeds with the catalyst derived from a Rh complex and a chiral ferrocenylphosphine under hydrogen in the presence of sodium acetate in acetic acid to afford anti-β-hydroxy-α-amino acid esters with 58–83% ee in a diastereomeric ratio of 92:8–97:3.(2S,3S)-Methyl 2-benzoylamino-3-hydroxy-3-phenylpropionateC17H17NO4Ee = 90%[α]D25=+127.8 (c 0.93, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2S,3S)(2S,3S)-Ethyl 3-benzo[1,3]dioxol-5-yl-2-benzoylamino-3-hydroxypropionateC19H19NO6Ee = 80%[α]D25=+96.1 (c 0.21, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2S,3S)(2S,3S)-Methyl 2-benzoylamino-3-(4-benzyloxyphenyl)-3-hydroxypropionateC24H23NO5Ee = 93%[α]D25=+105.4 (c 0.97, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2S,3S)(2S,3S)-Methyl 2-benzoylamino-3-(4-bromophenyl)-3-hydroxypropionateC17H16BrNO4Ee = 75%[α]D25=+97.0 (c 0.99, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2S,3S)(2S,3S)-Ethyl 2-benzoylamino-3-hydroxy-3-thiophen-2-yl-propionateC16H17NO4SEe = 79%[α]D25=+63.6 (c 1.16, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2S,3S)(2S,3S)-Methyl2-benzoylamino-3-furan-2-yl-3-hydroxypropionateC15H15NO5Ee = 88%[α]D25=+88.9 (c 0.97, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2S,3S)

The stereoselective synthesis of (3R,5R)-5-hydroxypiperazic acid, a component of naturally occurring antibiotic cyclodepsipeptides, and its diastereomer was achieved via the use of Lewis acid-promoted diastereoselective Strecker synthesis as a key step, in which an interesting stereochemical reversal of diastereoselectivity by the choice of Lewis acid catalyst was observed.(R)-1-Benzoyl-5-(tert-butyldimethylsiloxy)-1,4,5,6-tetrahydropyridazine[α]D25=-26.7 (c 1.43, CHCl3)Source of chirality: ethyl (R)-4-chloro-3-hydroxybutyrate(3R,5R)-1-Benzoyl-5-(tert-butyldimethylsiloxy)-hexahydropyridazine-3-carbonitrile[α]D25=+15.8 (c 0.85, CHCl3)Source of chirality: ethyl (R)-4-chloro-3-hydroxybutyrate(3S,5R)-1-Benzoyl-5-(tert-butyldimethylsiloxy)-hexahydropyridazine-3-carbonitrile[α]D24=-26.7 (c 1.19, CHCl3)Source of chirality: ethyl (R)-4-chloro-3-hydroxybutyrate(3R,5R)-1-tert-Butoxycarbonyl-5-hydroxypiperazic acid methyl ester[α]D25=+7.0 (c 1.00, CHCl3)Source of chirality: ethyl (R)-4-chloro-3-hydroxybutyrate(3R,5S)-1-tert-Butoxycarbonyl-5-hydroxypiperazic acid methyl ester[α]D26=+1.96 (c 1.00, CHCl3)Source of chirality: ethyl (R)-4-chloro-3-hydroxybutyrate(S)-1-Benzoyl-5-(tert-butyldimethylsiloxy)-1,4,5,6-tetrahydropyridazine[α]D25=+26.7 (c 1.43, CHCl3)Source of chirality: (S)-malic acid(3S,5S)-1-Benzoyl-5-(tert-butyldimethylsiloxy)-hexahydropyridazine-3-carbonitrile[α]D25=-13.0 (c 0.89, CHCl3)Source of chirality: (S)-malic acid(3R,5S)-1-Benzoyl-5-(tert-butyldimethylsiloxy)- hexahydropyridazine-3-carbonitrile[α]D24=+26.1 (c 2.10, CHCl3)Source of chirality: (S)-malic acid

The highly efficient synthesis of (R)- and (S)-piperazic acids, components of naturally occurring antibiotic cyclodepsipeptides, was achieved in 80% overall yield by the use of a proline-catalyzed asymmetric α-hydrazination as the key step.(R)-5-Bromo-2-N,N′-dibenzyloxy carbonyhydrazino-1-pentanolC21H25BrN2O5Ee = >99%[α]D22=-10.7 (c 1.04, CHCl3)Source of chirality:asymmetric synthesisAbsolute configuration:(2R)(S)-5-Bromo-2-N,N′-dibenzyloxy carbonyhydrazino-1-pentanolC21H25BrN2O5Ee = >99%[α]D22=+12.4 (c 1.03, CHCl3)Source of chirality:asymmetric synthesisAbsolute configuration:(2S)(R)-5-Bromo-2-N,N′-di-tert-butyl carbonyhydrazino-1-pentanolC15H29BrN2O5Ee = 80%[α]D23=-8.0 (c 1.00, CHCl3)Source of chirality:asymmetric synthesisAbsolute configuration:(2R)(R)-2-(N,N′-Dibenzyloxycarbonylhydrazino)-5-bromo-1-(tert-butyldimethylsiloxy)pentaneC27H39BrN2O5SiEe = >99%[α]D22=+12.3 (c 0.95, MeOH)Source of chirality:asymmetric synthesisAbsolute configuration:(2R)(S)-2-(N,N′-Dibenzyloxycarbonylhydrazino)-5-bromo-1-(tert-butyldimethylsiloxy)pentaneC27H39BrN2O5SiEe = >99%[α]D22=-12.2 (c 1.13, MeOH)Source of chirality:asymmetric synthesisAbsolute configuration:(2S)(R)-1,2-Dibenzyloxycarbonyl-3-(tert-butyldimethyl siloxymethyl)tetrahydropyridazineC27H38N2O5SiEe = >99%[α]D22=+17.5 (c 1.10, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (R)(S)-1,2-Dibenzyloxycarbonyl-3-(tert-butyldimethyl siloxymethyl)tetrahydropyridazineC27H38N2O5SiEe = >99%[α]D22=-16.7 (c. 1.16 CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (S)(R)-1,2-Dibenzyloxycarbonyl-3-hydroxymethyltetrahydropyridazineC21H24N2O5Ee = >99%[α]D22=-11.0 (c 1.48, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (R)(S)-1,2-Dibenzyloxycarbonyl-3-hydroxymethyltetrahydropyridazineC21H24N2O5Ee = >99%[α]D22=+12.6 (c 1.03 CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (S)(R)-1,2-Dibenzyloxycarbonylpiperazic acidC21H22N2O6Ee = 98%[α]D22=+20.0 (c 0.975, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (R)(S)-1,2-Dibenzyloxycarbonylpiperazic acidC21H22N2O6Ee = 98%[α]D22=-19.6 (c 1.04 CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (S)(R)-Piperazic acid trifluoroacetic acid saltC7H11F3N2O4Ee = >99%[α]D22=-10.5 (c 0.96, MeOH)Source of chirality: asymmetric synthesisAbsolute configuration: (R)(S)-Piperazic acid trifluoroacetic acid saltC7H11F3N2O4Ee = >99%[α]D22=+11.1 (c 0.98 MeOH)Source of chirality: asymmetric synthesisAbsolute configuration: (S)

(3S,4R)-3,4-Dimethyl-(S)-glutamine, a common component of cyclodepsipeptides, papuamide A and callipeltin A, was stereoselectively prepared from (S)-pyroglutamic acid. The stereostructure of natural dimethylglutamine was unambiguously confirmed to be (2S,3S,4R) by comparison of the CD and NMR spectra of the synthetic 3,4-dimethylpyroglutamic acid with the hydrolysate of callipeltin A.(3S,4R)-3,4-Dimethyl-(S)-glutamine was stereoselectively prepared from (S)-pyroglutamic acid. The stereostructure of natural dimethylglutamine was unambiguously confirmed to be (2S,3S,4R) by comparison of the CD and NMR spectra of the synthetic 3,4-dimethylpyroglutamic acid with the hydrolysate of callipeltin A.(2R,5S,6S)-6-Methyl-2-phenyl-1-aza-3-oxabicyclo[3.3.0]octan-8-oneC13H15NO2E.e.=100%[α]D22=+227.9 (c 0.64, CHCl3)Source of chirality: (S)-pyroglutamic acidAbsolute configuration: (2R,5S,6S)(2R,5S,6S,7S)-6,7-Dimethyl-2-phenyl-1-aza-3-oxabicyclo[3.3.0]octan-8-oneC14H17NO2E.e.=100%[α]D22=+151.8 (c 0.75, CHCl3)Source of chirality: (S)-pyroglutamic acidAbsolute configuration: (2R,5S,6S,7S)(2R,5S,6S,7R)-6,7-Dimethyl-2-phenyl-1-aza-3-oxabicyclo[3.3.0]octan-8-oneC14H17NO2E.e.=100%[α]D22=+154.4 (c 0.42, CHCl3)Source of chirality: (S)-pyroglutamic acidAbsolute configuration: (2R,5S,6S,7R)(3R,4S,5S)-3,4-Dimethyl-5-hydroxymethylpyrrolidin-2-oneC7H13NO2E.e.=100%[α]D24=+88.0 (c 0.48, CHCl3)Source of chirality: (S)-pyroglutamic acidAbsolute configuration: (3R,4S,5S)(3R,4S,5S)-3,4-Dimethyl-5-t-butyldimethylsiloxymethylpyrrolidin-2-oneC13H27NO2Si[α]D27=+54.3 (c 0.64, CHCl3)Source of chirality: (S)-pyroglutamic acidAbsolute configuration: (3R,4S,5S)(3R,4S,5S)-N-t-Butoxycarbonyl-3,4-dimethyl-5-t-butyldimethylsiloxymethylpyrrolidin-2-oneC18H35NO4Si[α]D27=−46.7 (c 1.12, CHCl3)Source of chirality: (S)-pyroglutamic acidAbsolute configuration: (3R,4S,5S)(3R,4S,5S)-N-t-Butoxycarbonyl-3,4-dimethyl-5-hydroxymethylpyrrolidin-2-oneC12H21NO4[α]D24=−47.8 (c 1.37, CHCl3)Source of chirality: (S)-pyroglutamic acidAbsolute configuration: (3R,4S,5S)(2R,3S,4S)-4-t-Butoxycarbonylamino-2,3-dimethyl-5-hydroxypentamideC12H24N2O4[α]D27=−27.7 (c 0.55, CHCl3)Source of chirality: (S)-pyroglutamic acidAbsolute configuration: (2R,3S,4S)(3S,4R)-N-t-Butoxycarbonyl-3,4-dimethyl-(S)-glutamineC12H22N2O5E.e.=100%[α]D21=+15.0 (c 0.56, CH3OH)Source of chirality: (S)-pyroglutamic acidAbsolute configuration: (2S,3S,4R)(3S,4R)-3,4-Dimethyl-(S)-pyroglutamic acidC7H11NO3E.e.=100%[α]D26=+43.4 (c 0.83, CH3OH)Source of chirality: (S)-pyroglutamic acidAbsolute configuration: (2S,3S,4R)

(2R,3R)- and (2S,3S)-3-Hydroxyleucines, components of cyclodepsipeptides, papuamides and polyoxypeptins, were efficiently synthesized along with their diastereomers from the corresponding β-keto-α-amino acid ester through dynamic kinetic resolution using RuCl2(binap)-catalyzed hydrogenation.(2R,3R)- and (2S,3S)-3-Hydroxyleucines, which are components of cyclodepsipeptides, papuamides and polyoxypeptins, were efficiently synthesized along with their diastereomers from the corresponding β-keto-α-amino acid ester through dynamic kinetic resolution using RuCl2(binap)-catalyzed hydrogenation.Methyl (2R,3S)-2-benzoylamino-3-hydroxy-4-methylpentanoateC14H19NO4E.e.=99%[α]D24=−27.8 (c 0.85, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2R,3S)(4R,5R)-4-Methoxycarbonyl-5-(1-methylethyl)-1-phenyl-1,3-oxazolineC14H17NO3E.e.=97%[α]D24=−97.5 (c 0.90, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (4R,5R)(2R,3R)-3-HydroxyleucineC6H13NO3E.e.=97%[α]D26=−21.6 (c 1.15, H2O)Source of chirality: asymmetric synthesisAbsolute configuration: (2R,3R)(2S,3R)-3-HydroxyleucineC6H13NO3E.e.=98%[α]D26=−4.3 (c 1.10, H2O)Source of chirality: asymmetric synthesisAbsolute configuration: (2S,3R)

An acid-promoted novel skeletal rearrangement is described. Using trifluoroacetic acid as the acid promoter, an intramolecular ipso-Friedel–Crafts-type addition of phenols to 3-alkylidene indolenium cations, formation of iminium cations through rearomatization of the spirocyclohexadienone units, and intramolecular Pictet–Spengler reaction proceeded sequentially, producing tricyclic indole derivatives.

Angelmarin (1), a novel anti-cancer agent, was efficiently synthesized through a highly enantioselective epoxidation and a copper cyanide-mediated esterification of the hindered alcohol as the key steps in 53% overall yield.

Homogeneous chiral nickel-bisphosphine complexes catalyze the asymmetric hydrogenation of α-amino-β-keto ester hydrochlorides through dynamic kinetic resolution to efficiently afford anti-β-hydroxy-α-amino esters with high diastereo- and enantioselectivities.