AbstractImproved stereoselective syntheses of the target compounds (+)-valiolamine 1 and (+)-valienamine 2 starting from naturally abundant (–)-shikimic acid are described. A common key intermediate compound 7 was first synthesized from (–)-shikimic acid in 9 steps. The compound 7 was then converted to (+)-valiolamine 1 in 3 steps, and was also converted to (+)-valienamine 2 in 4 steps. In summary, (+)-valiolamine 1 and (+)-valienamine 2 were synthesized from (–)-shikimic acid in 12 (or 13) steps in 40% and 39% overall yields, respectively. The present syntheses are more practical and might be important for the potential industrial preparations of pharmaceutically valuable (+)-valiolamine 1 and (+)-valienamine 2.

A green and highly stereoselective method for the synthesis of cis or trans-1,3-disubstituted-tetrahydro-β-carbolines has been developed using water as the solvent. A mixture of cis and trans-1,3-disubstituted-tetrahydro-β-carboline hydrochlorides can be converted to a single cis or trans isomer via a crystallization-induced asymmetric transformation process. It is possible to get both isomers using this method by incorporating different additives in water. This method has advantages such as environmental friendliness, high stereoselectivity, suitability for industrialization, and non-toxicity.

A stereoselective synthesis of the pharmaceutically useful pseudo-aminosugar (+)-valienamine 1 is described. Epoxide 2 was first prepared via four steps in 79.7% overall yield starting from the naturally abundant (−)-shikimic acid. Epoxide 2 was then converted into the vicinal dihydroxyl compound 3 in 96% yield via a highly regio- and stereoselective water-mediated epoxide opening. Compound 3 was transformed into compound 4 in 86% yield over two steps via ester-reduction and benzylation of the three hydroxyl groups. Compound 4 was converted into azido compound 5 in 90% yield via an SN2-type nucleophilic substitution of the OMs leaving group with sodium azide. Ruthenium-catalyzed stereoselective dihydroxylation of compound 5 afforded dihydroxyl compound 6 in 91% yield. Compound 6 was transformed into compound 7 in 92% yield via selective mono-acetylation of the less-hindered hydroxyl group. Dehydration of tertiary alcohol 7 via an acid-mediated elimination furnished olefinic compound 8 in 85% yield. Finally, compound 8 was converted into the title compound 1 in 91% yield over two steps via deprotection and Lindlar-catalyst-promoted highly selective hydrogenation of the azido group (N3) in the presence of a double bond. (+)-Valienamine 1 was thus synthesized starting from the naturally abundant (−)-shikimic acid via 13 steps in 38.3% total yield.(1S,2S,3S,4R)-1-Amino-5-hydroxymethyl-2,3,4-trihydroxycyclohex-5-ene [(+)-valienamine]C7H13NO4[α]D20 = +88.9 (c 0.35, H2O)Source of chirality: (−)-Shikimic acidAbsolute configuration: (1S,2S,3S,4R)(3S,4R,5R)-Ethyl 5-O-(methanesulfonyl)shikimateC10H16O7S[α]D20 = −34.1 (c 1.00, CH3OH)Source of chirality: (−)-Shikimic acidAbsolute configuration: (3S,4R,5R)(3S,4R,5R)-1-Benzoyloxymethyl-3,4-dibenzoyloxy-5-methanesulfonyloxy-cyclohex-1-eneC29H26O9S[α]D20 = +85.1 (c 0.80, CHCl3)Source of chirality: (−)-Shikimic acidAbsolute configuration: (3S,4R,5R)(3S,4S,5S)-5-Azido-1-benzoyloxymethyl-3,4-dibenzoyloxycyclohex-1-eneC28H23N3O6[α]D20 = +76.6 (c 1.30, CHCl3)Source of chirality: (−)-Shikimic acidAbsolute configuration: (3S,4S,5S)(1S,2S,3S,4S,5S)-1-Azido-5-benzoyloxymethyl-2,3-dibenzoyloxy-4,5-dihydroxycyclohexaneC28H25N3O8[α]D20 = −7.65 (c 1.00, CH3OH)Source of chirality: (−)-Shikimic acidAbsolute configuration: (1S,2S,3S,4S,5S)(1S,2S,3R,4S,5S)-4-Acetoxy-1-azido-5-benzoyloxymethyl-2,3-dibenzoyloxy-5-hydroxycyclohexaneC30H27N3O9[α]D20 = +21.2 (c 1.00, CH3OH)Source of chirality: (−)-Shikimic acidAbsolute configuration: (1S,2S,3R,4S,5S)(1S,2S,3S,4R)-4-Acetoxy-1-azido-5-benzoyloxymethyl-2,3-dibenzoyloxycyclohex-5-eneC30H25N3O8[α]D20 = +71.8 (c 1.00, CH3OH)Source of chirality: (−)-Shikimic acidAbsolute configuration: (1S,2S,3S,4R)

A new stereoselective synthesis of (−)-quinic acid from the naturally abundant (−)-shikimic acid is described. Ethyl shikimate 2 was first prepared in 97% yield via esterification of (−)-shikimic acid according to a previous report. Ester 2 was then transformed into an epimeric mixture of 3,4-O-benzylidene shikimate 3, which was directly converted into compound 4 in 90% yield (over 2 steps from ester 2) via an NBS-mediated acetal ring-opening reaction. Acetylization of the hydroxyl group at the C-5 position of compound 4 gave compound 5 in 98% yield. Compound 5 was transformed into compound 6 in 91% yield via a highly stereoselective Ru-catalyzed dihydroxylation. Subsequently, compound 6 was converted into epoxide 7 in 82% yield via an intramolecular SN2 type substitution. A regioselective epoxide-opening of compound 7 by PPh3–I2 complex furnished an iodo compound 8 in 79% yield. Removal of the iodine atom in compound 8 by Pd/C-catalyzed hydrogenation produced compound 9 in 92% yield. Methanolysis of compound 9 gave methyl quinate 10 in 92% yield. Finally, hydrolysis of compound 10 afforded the targeted compound (−)-quinic acid 1 in 90% yield. The title compound (−)-quinic acid 1 was stereoselectively synthesized through 10 steps starting from (−)-shikimic acid in 38% overall yield.(1S,3R,4S,5R)-1,3,4,5-Tetrahydroxycyclohexane carboxylic acid [(−)-quinic acid]C7H12O6[α]D25 = −43.2 (c 1.80, H2O)Source of chirality: (−)-Shikimic acidAbsolute configuration: (1S,3R,4S,5R)(3S,4S,5R)-Ethyl 3-bromo-4-benzoyloxy-5-hydroxyl-cyclohex-1-ene carboxylateC16H17BrO5[α]D25 = +58.8 (c 1.32, CHCl3)Source of chirality: (−)-Shikimic acidAbsolute configuration: (3S,4S,5R)(3S,4S,5R)-Ethyl 5-acetoxy-3-bromo-4-benzoyloxy-cyclohex-1-ene carboxylateC18H19BrO6[α]D25 = +87.6 (c 1.30, CHCl3)Source of chirality: (−)-Shikimic acidAbsolute configuration: (3S,4S,5R)(1R,2R,3S,4S,5R)-Ethyl 5-acetoxy-4-benzoyloxy-3-bromo-1,2-dihydroxy-cyclohexane carboxylateC18H21BrO8[α]D25 = −11.6 (c 2.11, CHCl3)Source of chirality: (−)-Shikimic acidAbsolute configuration: (1R,2R,3S,4S,5R)(1R,2S,3S,4S,5R)-Ethyl 5-acetoxy-4-benzoyloxy-2,3-epoxy-1-hydroxy-cyclohexane carboxylateC18H20O8[α]D25 = −125 (c 1.62, CHCl3)Source of chirality: (−)-Shikimic acidAbsolute configuration: (1R,2S,3S,4S,5R)(1S,2R,3S,4R,5R)-Ethyl 5-acetoxy-4-benzoyloxy-1,3-dihydroxy-2-iodo-cyclohexane carboxylateC18H21IO8[α]D25 = −19.6 (c 1.72, CHCl3)Source of chirality: (−)-Shikimic acidAbsolute configuration: (1S,2R,3S,4R,5R)(1R,2R,3S,4S,5R)-Ethyl 5-acetoxy-4-benzoyloxy-1,2-dihydroxy-3-iodo-cyclohexane carboxylateC18H21IO8[α]D25 = −6.5 (c 1.50, CHCl3)Source of chirality: (−)-Shikimic acidAbsolute configuration: (1R,2R,3S,4S,5R)(1S,3R,4R,5R)-Ethyl 5-acetoxy-4-benzoyloxy-1,3-dihydroxy-cyclohexane carboxylateC18H22O8[α]D25 = −93.6 (c 1.51, CHCl3)Source of chirality: (−)-Shikimic acidAbsolute configuration: (1S,3R,4R,5R)(1S,3R,4S,5R)-Methyl 1,3,4,5-tetrahydroxycyclohexane carboxylateC8H14O6[α]D25 = −31.2 (c 1.60, CH3OH)Source of chirality: (−)-Shikimic acidAbsolute configuration: (1S,3R,4S,5R)

An efficient and general method for the highly stereoselective transformation of (1S,3S)-cis-1,3-disubstituted 1,2,3,4-tetrahydro-β-carbolines (THBCs) into (1S,3R)-trans-1,3-disubstituted THBCs is described. The method contains the following three steps: the enantiomerically pure (1S,3S)-cis-1,3-disubstituted THBCs 1 were first converted into (1S,3S)-cis-1,2,3-trisubstituted THBCs 2 by N-1-naphthylmethylation/benzylation; (1S,3S)-cis-1,2,3-trisubstituted THBCs2 were then converted into (1S,3R)-trans-1,2,3-trisubstituted THBCs 3 in high yields and with high stereoselectivities via a base-catalyzed epimerization at C-3; (1S,3R)-trans-1,2,3-trisubstituted THBCs 3 were subsequently converted into (1S,3R)-trans-1,3-disubstituted THBCs 4 after reductive removal of the 1-naphthylmethyl/benzyl group. In addition, as an application of this method, an improved and highly stereoselective synthesis of the PDE5 inhibitor tadalafil (Cialis®) starting from natural and less expensive l-tryptophan was developed.(1S,3S)-Methyl 1-(benzo[d][1,3]dioxol-5-yl)-2-(naphthalen-1-yl-methyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylateC31H26N2O4[α]D20=-83.4 (c 1.00, CH3OH)Source of chirality: l-TryptophanAbsolute configuration: (1S,3S)(1S,3S)-Methyl 1-(benzo[d][1,3]dioxol-5-yl)-2-benzyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylateC27H24N2O4[α]D20=-87.0 (c 1.60, CHCl3)Source of chirality: l-TryptophanAbsolute configuration: (1S,3S)(1S,3S)-Ethyl 1-(benzo[d][1,3]dioxol-5-yl)-2-(naphthalen-1-yl-methyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylateC32H28N2O4[α]D20=-69.4 (c 1.00, CH3OH)Source of chirality: l-TryptophanAbsolute configuration: (1S,3S)C30H25FN2O2(1S,3S)-Methyl 1-(4-fluorophenyl)-2-(naphthalen-1-ylmethyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylate[α]D20=-98.7 (c 1.00, CH3OH)Source of chirality: l-TryptophanAbsolute configuration: (1S,3S)(1S,3S)-Ethyl 2-(naphthalen-1-ylmethyl)-1-(3,4,5-trimethoxyphenyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylateC34H34N2O5[α]D20=-67.0 (c 1.05, CH3OH)Source of chirality: l-TryptophanAbsolute configuration: (1S,3S)(1S,3S)-Methyl 1-(3-hydroxyphenyl)-2-(naphthalen-1-ylmethyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylateC30H26N2O3[α]D20=-77.3 (c 1.00, CH3OH)Source of chirality: l-TryptophanAbsolute configuration: (1S,3S)(1S,3S)-Methyl 1-phenyl-2-(naphthalen-1-ylmethyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylateC30H26N2O2[α]D20=-43.9 (c 1.00, CHCl3)Source of chirality: l-TryptophanAbsolute configuration: (1S,3S)(1S,3S)-Methyl 1-(3,4-dimethoxyphenyl)-2-(naphthalen-1-ylmethyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylateC32H30N2O4[α]D20=-77.2 (c 1.00, CHCl3)Source of chirality: l-TryptophanAbsolute configuration: (1S,3S)(1S,3S)-Methyl 1-(4-ethoxy-3-methoxy-phenyl)-2-(naphthalen-1-ylmethyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylateC33H32N2O4[α]D20=-68.1 (c 3.00, CHCl3)Source of chirality: l-TryptophanAbsolute configuration: (1S,3S)(1S,3S)-Methyl 1-methyl-2-(naphthalen-1-ylmethyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylateC25H24N2O2[α]D20=-22.5 (c 1.10, CH3OH)Source of chirality: l-TryptophanAbsolute configuration: (1S,3S)(1S,3S)-Methyl 2-benzyl-1-methyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylateC21H22N2O2[α]D20=-6.1 (c 2.6, CH3OH)Source of chirality: l-TryptophanAbsolute configuration: (1S,3S)(1S,3S)-Methyl 1-ethyl-2-(naphthalen-1-ylmethyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylateC26H26N2O2[α]D20=-42.2 (c 1.02, CH3OH)Source of chirality: l-TryptophanAbsolute configuration: (1S,3S)(1S,3S)-Methyl 2-(naphthalen-1-ylmethyl)-1-propyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylateC27H28N2O2[α]D20=-33.2 (c 1.00, CHCl3)Source of chirality: l-TryptophanAbsolute configuration: (1S,3S)(1S,3S)-Methyl 1-hexyl-2-(naphthalen-1-ylmethyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylateC30H34N2O2[α]D20=-60.4 (c 1.10, CH3OH)Source of chirality: l-TryptophanAbsolute configuration: (1S,3S)(1S,3R)-Methyl 1-(benzo[d][1,3]dioxol-5-yl)-2-(naphthalen-1-yl-methyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylateC31H26N2O4[α]D20=+67.3 (c 1.20, CH3OH)Source of chirality: l-TryptophanAbsolute configuration: (1S,3R)(1S,3R)-Methyl 1-(benzo[d][1,3]dioxol-5-yl)-2-benzyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylateC27H24N2O4[α]D20=+91.4 (c 1.00, CHCl3)Source of chirality: l-TryptophanAbsolute configuration: (1S,3R)(1S,3R)-Ethyl 1-(benzo[d][1,3]dioxol-5-yl)-2-(naphthalen-1-yl-methyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylateC32H28N2O4[α]D20=+71.7 (c 1.00, CH3OH)Source of chirality: l-TryptophanAbsolute configuration: (1S,3R)(1S,3R)-Methyl 1-(4-fluorophenyl)-2-(naphthalen-1-ylmethyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylateC30H25FN2O2[α]D20=+67.5 (c 1.07, CH3OH)Source of chirality: l-TryptophanAbsolute configuration: (1S,3R)(1S,3R)-Ethyl 2-(naphthalen-1-ylmethyl)-1-(3,4,5-trimethoxyphenyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylateC34H34N2O5[α]D20=+44.3 (c 1.00, CH3OH)Source of chirality: l-TryptophanAbsolute configuration: (1S,3R)(1S,3R)-Methyl 1-(3-hydroxyphenyl)-2-(naphthalen-1-ylmethyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylateC30H26N2O3[α]D20=+67.1 (c 1.06, CH3OH)Source of chirality: l-TryptophanAbsolute configuration: (1S,3R)(1S,3R)-Methyl 1-phenyl-2-(naphthalen-1-ylmethyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylateC30H26N2O2[α]D20=+127 (c 1.00, CHCl3)Source of chirality: l-TryptophanAbsolute configuration: (1S,3R)C32H30N2O4(1S,3R)-Methyl 1-(3,4-dimethoxyphenyl)-2-(naphthalen-1-ylmethyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylate[α]D20=+102 (c 1.00, CHCl3)Source of chirality: l-TryptophanAbsolute configuration: (1S,3R)(1S,3R)-Methyl 1-(4-ethoxy-3-methoxy-phenyl)-2-(naphthalen-1-ylmethyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylateC33H32N2O4[α]D20=+100 (c 1.50, CHCl3)Source of chirality: l-TryptophanAbsolute configuration: (1S,3R)(1S,3R)-Methyl 1-methyl-2-(naphthalen-1-ylmethyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylateC25H24N2O2[α]D20=-27.4 (c 1.00, CH3OH)Source of chirality: l-TryptophanAbsolute configuration: (1S,3R)(1S,3R)-Methyl 2-benzyl-1-methyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylateC21H22N2O2[α]D20=-18.4 (c 1.10, CHCl3)Source of chirality: l-TryptophanAbsolute configuration: (1S,3R)(1S,3R)-Methyl 1-ethyl-2-(naphthalen-1-ylmethyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylateC26H26N2O2[α]D20=-29.2 (c 1.60, CH3OH)Source of chirality: l-TryptophanAbsolute configuration: (1S,3R)(1S,3R)-Methyl 2-(naphthalen-1-ylmethyl)-1-propyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylateC27H28N2O2[α]D20=-42.9 (c 1.30, CHCl3)Source of chirality: l-TryptophanAbsolute configuration: (1S,3R)(1S,3R)-Methyl 1-hexyl-2-(naphthalen-1-ylmethyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylateC30H34N2O2[α]D20=-34.7 (c 1.00, CH3OH)Source of chirality: l-TryptophanAbsolute configuration: (1S,3R)(1S,3R)-Methyl 1-(benzo[d][1,3]dioxol-5-yl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylateC20H18N2O4[α]D20=+33.0 (c 1.00, CHCl3)Source of chirality: l-TryptophanAbsolute configuration: (1S,3R)(1S,3R)-Ethyl 1-(benzo[d][1,3]dioxol-5-yl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylateC21H20N2O4[α]D20=+33.2 (c 1.50, CH3OH)Source of chirality: l-TryptophanAbsolute configuration: (1S,3R)(1S,3R)-Methyl 1-(4-fluorophenyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylateC19H17FN2O2[α]D20=+30.8 (c 1.05, CH3OH)Source of chirality: l-TryptophanAbsolute configuration: (1S,3R)(1S,3R)-Ethyl 2-(naphthalen-1-ylmethyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylateC23H26N2O5[α]D20=+27.3 (c 1.60, CH3OH)Source of chirality: l-TryptophanAbsolute configuration: (1S,3R)(1S,3R)-Methyl 1-(3-hydroxyphenyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylateC19H18N2O3[α]D20=+35.5 (c 1.00, CH3OH)Source of chirality: l-TryptophanAbsolute configuration: (1S,3R)(1S,3R)-Methyl 1-phenyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylateC19H18N2O2[α]D20=+44.5 (c 1.00, CHCl3)Source of chirality: l-TryptophanAbsolute configuration: (1S,3R)(1S,3R)-Methyl 1-(3,4-dimethoxyphenyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylateC21H22N2O4[α]D20=+26.0 (c 1.90, CHCl3)Source of chirality: l-TryptophanAbsolute configuration: (1S,3R)(1S,3R)-Methyl 1-(4-ethoxy-3-methoxy-phenyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylateC22H24N2O4[α]D20=+17.9 (c 2.00, CHCl3)Source of chirality: l-TryptophanAbsolute configuration: (1S,3R)(1S,3R)-Methyl 1-methyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylateC14H16N2O2[α]D20=-16.4 (c 1.10, CH3OH)Source of chirality: l-TryptophanAbsolute configuration: (1S,3R)(1S,3R)-Methyl 1-ethyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylateC15H18N2O2[α]D20=-27.5 (c 1.00, CH3OH)Source of chirality: l-TryptophanAbsolute configuration: (1S,3R)(1S,3R)-Methyl 1-propyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylateC16H20N2O2[α]D20=-4.5 (c 3.0, CHCl3)Source of chirality: l-TryptophanAbsolute configuration: (1S,3R)C19H26N2O2(1S,3R)-Methyl 1-hexyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylate[α]D20=-21.6 (c 1.00, CH3OH)Source of chirality: l-TryptophanAbsolute configuration: (1S,3R)

A novel azide-free asymmetric synthesis of oseltamivir phosphate 1 (Tamiflu®) starting from Roche’s epoxide is described. Roche epoxide 2 was converted into N-acetyl aminoalcohol 3 in 95% yield via a BF3·OEt2-catalyzed epoxide-opening with acetonitrile as a nucleophile. Compound 3 was then transformed into a methanesulfonate 4 in 98% yield. Compound 4 was converted into aziridine 5 in 91% yield. Aziridine 5 was subsequently converted into oseltamivir phosphate 1 via two paths (a and b). In the path a, compound 5 underwent aziridine-opening with diallylamine as a nucleophile to afford compound 7 in 93% yield; compound 7 could then be converted into oseltamivir phosphate 1 in 88% yield. In path b, compound 5 underwent aziridine-opening with isopropyl 2,2,2-trichloroacetimidate as a nucleophile to afford compound 8 in 94% yield, which was then converted into oseltamivir phosphate 1 in 82% yield.(3R,4S,5R)-Ethyl 5-acetylamido-4-hydroxy-3-(pentan-3-yloxy)cyclohex-1-ene carboxylateC16H27NO5[α]D20=-171 (c 2.00, CHCl3)Source of chirality: (−)-Shikimic acidAbsolute configuration: (3R,4S,5R)(3R,4S,5R)-Ethyl 5-acetylamido-4-methanesulfonyloxy-3-(pentan-3-yloxy)cyclohex-1-ene carboxylateC17H29NO7S[α]D20=-118 (c 1.30, CHCl3)Source of chirality: (−)-Shikimic acidAbsolute configuration: (3R,4S,5R)(3R,4R,5R)-Ethyl 4,5-acetylimino-3-(pentan-3-yloxy)cyclohex-1-ene carboxylateC16H25NO4[α]D20=-46 (c 0.60, CHCl3)Source of chirality: (−)-Shikimic acidAbsolute configuration: (3R,4R,5R)(5R)-Ethyl 5-acetylamido-3-(pentan-3-yloxy)cyclohexa-1,3-diene carboxylateC16H25NO4[α]D20=+118 (c 1.10, CHCl3)Source of chirality: (−)-Shikimic acidAbsolute configuration: (5R)(3R,4R,5S)-Ethyl 4-acetylamido-5-diallylamino-3-(pentan-3-yloxy)cyclohex-1-ene carboxylateC22H36N2O4[α]D20=-30 (c 1.0, CHCl3)Source of chirality: (−)-Shikimic acidAbsolute configuration: (3R,4R,5S)(3R,4R,5S)-Ethyl 4-acetylamido-3-(pentan-3-yloxy)-5-(2,2,2-trichloroacetimido)cyclohex-1-enecarboxylateC18H27Cl3N2O5[α]D20=-45 (c 1.0, CHCl3)Source of chirality: (−)-Shikimic acidAbsolute configuration: (3R,4R,5S)

A novel and high-yielding asymmetric synthesis of oseltamivir phosphate 1 (Tamiflu®) is described. The target compound 1 was obtained in 55% overall yield via an 11-step asymmetric synthesis starting from the naturally abundant (−)-shikimic acid. The present synthesis is characterized by some advantages such as the easy separation of intermediate 6 from triphenylphosphine oxide by using its large water-solubility, the use of inexpensive reagents throughout the synthesis, the lack of toxic heavy metals, mild reaction conditions and high yields for all steps. The stereochemical structure of the key intermediate 6 was unequivocally confirmed by X-ray crystallographic analysis.C10H14O8S2Ethyl (3R,4S,5R)-3,4-O-thionyl-5-O-methanesulfonyl-shikimate[α]D20=+19 (c 1.5, EtOAc)Source of chirality: (−)-shikimic acidAbsolute configuration: (3R,4S,5R)C10H15N3O6SEthyl (3S,4R,5R)-3-azido-4-hydroxy-5-methanesulfonyloxy-cyclohex-1-ene-1-carboxylate[α]D20=+31 (c 2.3, CHCl3)Source of chirality: (−)-shikimic acidAbsolute configuration: (3S,4R,5R)C9H13NO3Ethyl (3S,4S,5S)-5-hydroxy-3,4-imino-cyclohex-1-ene-1-carboxylate[α]D20=-296 (c 2.0, CHCl3)Source of chirality: (−)-shikimic acidAbsolute configuration: (3S,4S,5S)C11H15NO4Ethyl (3S,4S,5S)-3,4-acetylimino-5-hydroxy-cyclohex-1-ene-1-carboxylate[α]D20=-105 (c 0.8, CHCl3)Source of chirality: (−)-shikimic acidAbsolute configuration: (3S,4S,5S)C16H27NO5Ethyl (3R,4R,5S)-4-acetamido-3-(1-ethyl-propoxy)-5-hydroxy-cyclohex-1-ene-1-carboxylate[α]D20=-60 (c 2.5, CHCl3)Source of chirality: (−)-shikimic acidAbsolute configuration: (3R,4R,5S)C17H29NO7SEthyl (3R,4S,5S)-4-acetamido-3-(1-ethyl-propoxy)-5-methanesulfonyloxy-cyclohex-1-ene-1-carboxylate[α]D20=-29 (c 1.0, CHCl3)Source of chirality: (−)-shikimic acidAbsolute configuration: (3R,4S,5S)C16H25NO4Ethyl (3R,4R,5R)-4,5-acetylimino-3-(1-ethyl-propoxy)-cyclohex-1-ene-1-carboxylate[α]D20=-46 (c 1.6, CHCl3)Source of chirality: (−)-shikimic acidAbsolute configuration: (3R,4R,5R)C16H26N4O4Ethyl (3R,4R,5S)-4-acetamido-5-azido-3-(1-ethylpropoxy)-cyclohex-1-ene-1-carboxylate[α]D20=-43 (c 1.0, CHCl3)Source of chirality: (−)-shikimic acidAbsolute configuration: (3R,4R,5S)

A novel and simple process for the preparation of enantiomerically pure (SS)-benzenesulfinamide (SS)-3a, (SS)-p-toluenesulfinamide (SS)-3b, (SS)-p-chloro-benzenesulfinamide (SS)-3c and (SS)-p-fluorobenzenesulfinamide (SS)-3d has been developed. The treatment of arylsulfinyl chlorides with (R)-N-benzyl-1-phenylethanamine in the presence of excess triethylamine gave diastereomeric mixtures of N-benzyl-N-(1-phenylethyl)-arylsulfinamides 1, which underwent spontaneous crystallization to furnish diastereomerically pure (R,SS)-N-benzyl-N-(1-phenylethyl)-arylsulfinamides (R,SS)-1a–1d in 28%, 29%, 27% and 31% yields, respectively. The diastereomerically pure compounds (R,SS)-1 were then converted into four enantiopure (RS)-methyl arylsulfinates (RS)-2, and finally into four enantiopure (SS)-arylsulfinamides (SS)-3 in good yields.(R,SS)-N-Benzyl-N-(1-phenylethyl)benzenesulfinamideC21H21NOS[α]D20=+42.2 (c 1.1, EtOAc)Source of chirality: (R)-1-phenylethanamineAbsolute configuration: (R,SS)(R,RS)-N-Benzyl-N-(1-phenylethyl)benzenesulfinamideC21H21NOS[α]D25=+111.1 (c 4.1, EtOAc)Source of chirality: (R)-1-phenylethanamineAbsolute configuration: (R,RS)(R,SS)-N-Benzyl-N-(1-phenylethyl)-p-toluenesulfinamideC22H23NOS[α]D25=+32.1 (c 1.2, EtOAc)Source of chirality: (R)-1-phenylethanamineAbsolute configuration: (R,SS)(R,RS)-N-Benzyl-N-(1-phenylethyl)-p-toluenesulfinamideC22H23NOS[α]D25=+128.7 (c 4.4, EtOAc)Source of chirality: (R)-1-phenylethanamineAbsolute configuration: (R,RS)(R,SS)-N-Benzyl-N-(1-phenylethyl)-p-chlorobenzenesulfinamideC21H20ClNOS[α]D25=+22.7 (c 1.2, EtOAc)Source of chirality: (R)-1-phenylethanamineAbsolute configuration: (R,SS)(R,RS)-N-Benzyl-N-(1-phenylethyl)-p-chlorobenzenesulfinamideC21H20ClNOS[α]D25=+137.4 (c 2.3, EtOAc)Source of chirality: (R)-1-phenylethanamineAbsolute configuration: (R,RS)(R,SS)-N-Benzyl-N-(1-phenylethyl)-p-fluorobenzenesulfinamideC21H20FNOS[α]D25=+39.7 (c 1.0, EtOAc)Source of chirality: (R)-1-phenylethanamineAbsolute configuration: (R,SS)(R,RS)-N-Benzyl-N-(1-phenylethyl)-p-fluorobenzenesulfinamideC21H20FNOS[α]D25=+105.8 (c 1.2, EtOAc)Source of chirality: (R)-1-phenylethanamineAbsolute configuration: (R,RS)(RS)-Methyl benzenesulfinateC7H8O2S[α]D20=-195.0 (c 1.2, EtOH)Source of chirality: (R)-1-phenylethanamineAbsolute configuration: (RS)(RS)-Methyl p-toluenesulfinateC8H10O2S[α]D20=-210.2 (c 1.4, EtOH)Source of chirality: (R)-1-phenylethanamineAbsolute configuration: (RS)(RS)-Methyl p-chlorobenzenesulfinateC7H7ClO2S[α]D20=-173.0 (c 1.3, EtOH)Source of chirality: (R)-1-phenylethanamineAbsolute configuration: (RS)(RS)-Methyl p-fluorobenzenesulfinateC7H7FO2S[α]D20=-171.9 (c 1.3, EtOH)Source of chirality: (R)-1-phenylethanamineAbsolute configuration: (RS)(SS)-BenzenesulfinamideC6H7NOS[α]D20=+83.1 (c 1.0, acetone)Source of chirality: (R)-1-phenylethanamineAbsolute configuration: (SS)(SS)-p-ToluenesulfinamideC7H9NOS[α]D20=+85.5 (c 1.0, CHCl3)Source of chirality: (R)-1-phenylethanamineAbsolute configuration: (SS)(SS)-p-ChlorobenzenesulfinamideC6H6ClNOS[α]D20=+72.3 (c 0.7, CHCl3)Source of chirality: (R)-1-phenylethanamineAbsolute configuration: (SS)(SS)-p-FluorobenzenesulfinamideC6H6FNOS[α]D20=+80.0 (c 0.7, CHCl3)Source of chirality: (R)-1-phenylethanamineAbsolute configuration: (SS)

A novel asymmetric synthesis of oseltamivir phosphate 1 from the naturally abundant (−)-shikimic acid via 3,4-cyclic sulfite intermediate 3 (Scheme 1) is described. Target compound 1 was obtained in 39% overall yield from this nine-step synthesis, and the characteristic step of the synthesis is the regio- and stereospecific nucleophilic substitution with sodium azide at the allylic (C-3) position of 3,4-cyclic sulfite 3. Since the yield of the direct-aziridine-formation from the unprotected dihydroxyl azide 4 was not satisfactory, two improved preparations of the established compound 7 via protected 3,4-cyclic sulfites 10 and 13 (Scheme 2) have been developed. In these two improved preparations, compound 7 was obtained from 3,4-cyclic sulfite 3 in 7-steps in 64% or 62% overall yield, respectively.Ethyl (3R,4S,5R)-3,4-cyclic sulfite-shikimateC9H12O6S[α]D20=+52.0 (c 1.5, CHCl3)Source of chirality: (−)-shikimic acidAbsolute configuration: (3R,4S,5R)Ethyl (3S,4R,5R)-3-azido-4,5-dihydroxycyclohex-1-ene-1-carboxylateC9H13N3O4[α]D20=+67.7 (c 4.3, CHCl3)Source of chirality: (−)-shikimic acidAbsolute configuration: (3S,4R,5R)Ethyl (1S,5R,6S)-5-hydroxy-7-azabicyclo[4.1.0]hept-2-ene-3-carboxylateC9H13NO3[α]D20=-219.8 (c 1.1, CHCl3)Source of chirality: (−)-shikimic acidAbsolute configuration: (1S,5R,6S)Ethyl (1S,5R,6S)-7-acetyl-5-hydroxy-7-azabicyclo[4.1.0]hept-2-ene-3-carboxylateC11H15NO4[α]D20=-90.7 (c 1.0, CHCl3)Source of chirality: (−)-shikimic acidAbsolute configuration: (1S,5R,6S)Ethyl (3R,4S,5R)-5-O-benzoyl-3,4-cyclic sulfite-shikimateC16H16O7S[α]D20=+17.2 (c 9.7, CHCl3)Source of chirality: (−)-shikimic acidAbsolute configuration: (3R,4S,5R)Ethyl (3S,4R,5R)-3-azido-5-benzoyloxy-4-hydroxy-cyclohex-1-ene-1-carboxylateC16H17N3O5[α]D20=-4.7 (c 3.0, CHCl3)Source of chirality: (−)-shikimic acidAbsolute configuration: (3S,4R,5R)Ethyl (3R,4S,5R)-5-O-acetyl-3, 4-cyclic sulfite-shikimateC11H14O7S[α]D20=+62.9 (c 2.6, CHCl3)Source of chirality: (−)-shikimic acidAbsolute configuration: (3S,4R,5R)Ethyl (3S,4R,5R)-3-azido-5-acetoxy-cyclohex-1-ene-1-carboxylateC11H15N3O5[α]D20=+24.2 (c 1.2, EtOAc)Source of chirality: (−)-shikimic acidAbsolute configuration: (3S,4R,5R)Ethyl (3S,4R,5R)-3-azido-5-acetoxy-4-methanesulfonyloxy-cyclohex-1-ene-1-carboxylateC12H17N3O7S[α]D20=+51.5 (c 4.3, EtOAc)Source of chirality: (−)-shikimic acidAbsolute configuration: (3S,4R,5R)Ethyl (1S,5R,6S)-5-acetoxy-7-azabicyclo[4,1,0]hept-2-ene-3-carboxylateC11H15NO4[α]D20=-139.7 (c 1.4, EtOAc)Source of chirality: (−)-shikimic acidAbsolute configuration: (1S,5R,6S)Ethyl (1S,5R,6S)-5-acetoxy-7-acetyl-7-azabicyclo[4,1,0]hept-2-ene-3- carboxylateC13H17NO5[α]D20=-36.5 (c 1.9, EtOAc)Source of chirality: (−)-shikimic acidAbsolute configuration: (1S,5R,6S)Ethyl (3R,4R,5R)-4-acetamido-5-acetoxy-3-(1-ethylpropoxy)-cyclohex-1-ene-1-carboxylateC18H29NO6[α]D20=-76.4 (c 2.0, EtOAc)Source of chirality: (−)-shikimic acidAbsolute configuration: (3R,4R,5R)

A general method for the synthesis of the mitotic kinesin Eg5 inhibitor HR22C16 1 and its analogues based on protecting group (PG)-modulated highly diastereoselective Pictet–Spengler reaction of l-tryptophan methyl ester hydrochloride with meta-(RO)-benzaldehyde is described. By using the enantiomerically pure (1R,3S)-1,3-disubstituted tetrahydro-β-carboline trans-4c as a common chiral synthon, HR22C16 1 and its analogues 2 and 3 were synthesized in 90.1%, 90.2%, and 86.5% overall yields, respectively.(5R,11aS)-2-(5-Azido-pentyl)-5-(3-benzoyloxyphenyl)-6H-1,2,3,5,11,11a-hexahydro-imidazo[1,5-b]-β-carboline-1,3-dioneC31H28N6O4[α]D20=-168.4 (c 0.9, CHCl3)Source of chirality: l-tryptophanAbsolute configuration: (5R,11aS)(5R,11aS)-2-(5-Azido-pentyl)-5-(3-hydroxyphenyl)-6H-1,2,3,5,11,11a-hexahydro-imidazo[1,5-b]-β-carboline-1,3-dioneC24H24N6O3[α]D20=-204.8 (c 0.2, CHCl3)Source of chirality: l-tryptophanAbsolute configuration: (5R,11aS)(5R,11aS)-2-Butyl-5-(3-hydroxyphenyl)-6H-1,2,3,5,11,11a-hexahydro-imidazo[1,5-b]-β-carboline-1,3-dioneC23H23N3O3[α]D20=-162.2 (c 0.2, CHCl3)Source of chirality: l-tryptophanAbsolute configuration: (5R,11aS)(5R,11aS)-2-Benzyl-5-(3-hydroxyphenyl)-6H-1,2,3,5,11,11a-hexahydro-imidazo[1,5-b]-β-carboline-1,3-dioneC26H21N3O3[α]D20=-162.6 (c 0.9, CHCl3)Source of chirality: l-tryptophanAbsolute configuration: (5R,11aS)(5R,11aS)-2-(5-Amino-pentyl)-5-(3-hydroxyphenyl)-6H-1,2,3,5,11,11a-hexahydro-imidazo[1,5-b]-β-carboline-1,3-dioneC24H26N4O3[α]D20=-151.5 (c 0.4, CHCl3)Source of chirality: l-tryptophanAbsolute configuration: (5R,11aS)(1S,3S)-Methyl 1-(3-hydroxyphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylateC19H18N2O3[α]D20=-45.1 (c 1.5, DMF)Source of chirality: l-tryptophanAbsolute configuration: (1S,3S)(1R,3S)-Methyl 1-(3-benzoyloxyphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylateC26H22N2O4[α]D20=-33.5 (c 0.9, CHCl3)Source of chirality: l-tryptophanAbsolute configuration: (1R,3S)(1S,3S)-Methyl 1-(3-acetoxyphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylateC21H20N2O4[α]D20=-7.2 (c 3.3, CHCl3)Source of chirality: l-tryptophanAbsolute configuration: (1S,3S)(1R,3S)-Methyl 1-(3-allyloxyphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylateC22H22N2O3[α]D20=-34.5 (c 1.2, CHCl3)Source of chirality: l-tryptophanAbsolute configuration: (1R,3S)(5R,11aS)-2-Benzyl-5-(3-benzoyloxyphenyl)-6H-1,2,3,5,11,11a-hexahydro-imidazo[1,5-b]-β-carboline-1,3-dioneC33H25N3O4[α]D20=-146.8 (c 1.7, CHCl3)Source of chirality: l-tryptophanAbsolute configuration: (5R,11aS)

The SN2 reaction of enantiomerically pure sulfonates with the tunable complex of R3N–R′COOH in toluene has been extensively studied. It was revealed that the molar ratio of the tertiary amines and carboxylic acids in the complex of R3NR′COOH is crucial for the SN2 reaction, and should be tuned for each sulfonate to give the best yield. Fifteen sulfonates 1 and 3–13 (Scheme 2) were prepared and transformed into 22 corresponding inverted esters 2 and 14–24 (Scheme 2) in good to high yields.(R)-1-(2,3-Difluoro-6-nitrophenoxy)propan-2-yl formateC10H9F2NO5[α]D20=+22.0 (c 4.5, CHCl3)Source of chirality: alcohol inversionAbsolute configuration: (R)(R)-1-(2,3-Difluoro-6-nitrophenoxy)propan-2-yl acetateC11H11F2NO5[α]D20=+35.0 (c 6.7, CHCl3)Source of chirality: alcohol inversionAbsolute configuration: (R)(R)-1-(2,3-Difluoro-6-nitrophenoxy)propan-2-yl benzoateC16H13F2NO5[α]D20=-21.0 (c 4.1, CHCl3)Source of chirality: alcohol inversionAbsolute configuration: (R)(3S,4S,5R)-Ethyl 3-acetoxy-5-benzoyloxy-4-(methylsulfonyloxy)cyclohex-1-ene carboxylateC19H22O9S[α]D20=-36.8 (c 2.1, EtOAc)Source of chirality: alcohol inversionAbsolute configuration: (3S,4S,5R)(3S,4S,5R)-Ethyl 3,5-dibenzoyloxy-4-(methylsulfonyloxy)cyclohex-1-ene carboxylateC24H24O9S[α]D20=+15.1 (c 1.5, EtOAc)Source of chirality: alcohol inversionAbsolute configuration: (3S,4S,5R)Cholest-5-en-3α-yl acetateC29H48O2[α]D20=-12.0 (c 1.5, CHCl3)Source of chirality: alcohol inversionAbsolute configuration: (3R)Cholest-5-en-3α-yl benzoateC34H50O2[α]D20=-18.9 (c 1.5, CHCl3)Source of chirality: alcohol inversionAbsolute configuration: (3R)5α-Cholestan-3α-yl acetateC29H50O2[α]D20=+24.8 (c 1.6, CHCl3)Source of chirality: alcohol inversionAbsolute configuration: (3R)5α-Cholestan-3α-yl benzoateC34H52O2[α]D20=+25.6 (c 1.5, CHCl3)Source of chirality: alcohol inversionAbsolute configuration: (3R)17α-Estra-3-methanesulfonyloxy-17-yl benzoateC26H30O5S[α]D20=-9.2 (c 2.1, acetone)Source of chirality: alcohol inversionAbsolute configuration: (17R)(R)-1-Phenylpropan-2-yl acetateC11H14O2[α]D20=+28.5 (c 4.0, benzene)Source of chirality: alcohol inversionAbsolute configuration: (R)((2S,3S,4R,5R)-3,4-Diacetoxy-2-((2R,3R,4S,5S,6R)-3,4,5-triacetoxy-6-acetoxymethyl-tetrahydro-2H-pyran-2-yloxy)-tetrahydrofuran-2,5-diyl) bis(methylene) dibenzoateC38H42O19[α]D20=+52.5 (c 0.5, acetone)Source of chirality: alcohol inversionAbsolute configuration: (2S,3S,4R,5R)(2R,3R,5R)-2-(Acetoxymethyl)-5-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-tetrahydrofuran-3-yl benzoateC19H20N2O7[α]D20=+74.5 (c 1.5, acetone)Source of chirality: alcohol inversionAbsolute configuration: (2R,3R,5R)(2R,3R,5R)-2-(Benzoyloxymethyl)-5-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-tetrahydrofuran-3-yl benzoateC24H22N2O7[α]D20=+66.0 (c 1.3, acetone)Source of chirality: alcohol inversionAbsolute configuration: (2R,3R,5R)(R)-Ethyl 3-acetoxy-butanoateC8H14O2[α]D20=+2.9 (c 1.0, CHCl3)Source of chirality: alcohol inversionAbsolute configuration: (R)(R)-Ethyl 3-benzoyloxy-butanoateC13H16O4[α]D20=-16.0 (c 1.4, CHCl3)Source of chirality: alcohol inversionAbsolute configuration: (R)(R)-4-(4-Tosyloxyphenyl)butan-2-yl acetateC19H22O5S[α]D20=+3.3 (c 4.2, acetone)Source of chirality: alcohol inversionAbsolute configuration: (R)(1S,2S,5R)-2-Isopropyl-5-methylcyclohexyl formateC11H20O2[α]D20=+24.0 (c 2.4, EtOH)Source of chirality: alcohol inversionAbsolute configuration: (1S)(1S,2S,5R)-2-Isopropyl-5-methylcyclohexyl acetateC12H22O2[α]D20=+35.6 (c 2.4, EtOH)Source of chirality: alcohol inversionAbsolute configuration: (1S,2S,5R)(1S,2S,5R)-2-Isopropyl-5-methylcyclohexyl benzoateC17H24O2[α]D20=+13.0 (c 2.4, EtOH)Source of chirality: alcohol inversionAbsolute configuration: (1S,2S,5R)(1R,2S,5R)-2-Isopropyl-5-methylcyclohexyl acetateC12H22O2[α]D20=-80.4 (c 2.1, CHCl3)Source of chirality: alcohol inversionAbsolute configuration: (1R,2S,5R)(1R,2S,5R)-2-Isopropyl-5-methylcyclohexyl benzoateC17H24O2[α]D20=-91.2 (c 1.3, CHCl3)Source of chirality: alcohol inversionAbsolute configuration: (1R,2S,5R)

The first synthesis of tadalafil 1 (Cialis) from l-tryptophan is described. The title compound 1 was synthesized via seven steps from l-tryptophan methyl ester hydrochloride in 42.3% overall yield. Two characteristic steps involved in this synthesis are the base-catalyzed epimerization of the C-3 position of (1S,3S)-1,2,3-trisubstituted-tetrahydro-β-carboline 3a and the acid-catalyzed epimerization of the C-1 position of (1S,3R)-1,3-disubstituted-tetrahydro-β-carboline 5. The (S)-configurations at C-1 and C-3 were inverted to (R)-configurations during the epimerization reactions. The base-catalyzed epimerization of C-3 of (1S,3S)-1,2,3-trisubstituted-tetrahydro-β-carbolines 3a–3e was also studied in detail.(1S,3S)-Methyl1-(benzo[d][1,3]dioxol-5-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylateC20H18N2O4[α]D20=-25 (c 1.2, CHCl3)Source of chirality: l-tryptophanAbsolute configuration: (1S,3S)(1S,3S)-2-Benzyl 3-methyl 1-(benzo[d][1,3]dioxol-5-yl)-3,4-dihydro-1H-pyrido[3,4-b]indole-2,3-dicarboxylateC28H24N2O6[α]D20=+115 (c 1.5, CHCl3)Source of chirality: l-tryptophanAbsolute configuration: (1S,3S)(1S,3S)-2-Ethyl 3-methyl 1-(benzo[d][1,3]dioxol-5-yl)-3,4-dihydro-1H-pyrido[3,4-b]indole-2,3-dicarboxylateC23H22N2O6[α]D20=+132 (c 0.3, CHCl3)Source of chirality: l-tryptophanAbsolute configuration: (1S,3S)(1S,3S)-2-Isobutyl 3-methyl 1-(benzo[d][1,3]dioxol-5-yl)-3,4-dihydro-1H-pyrido[3,4-b]indole-2,3-dicarboxylateC25H26N2O6[α]D20=+131 (c 0.2, CHCl3)Source of chirality: l-tryptophanAbsolute configuration: (1S,3S)(1S,3S)-3-Methyl 2-phenyl 1-(benzo[d][1,3]dioxol-5-yl)-3,4-dihydro-1H-pyrido[3,4-b]indole-2,3-dicarboxylateC27H22N2O6[α]D20=+116 (c 0.3, CHCl3)Source of chirality: l-tryptophanAbsolute configuration: (1S,3S)(1S,3S)-2-t-Butyl 3-methyl 1-(benzo[d][1,3]dioxol-5-yl)-3,4-dihydro-1H-pyrido[3,4-b]indole-2,3-dicarboxylateC25H26N2O6[α]D20=+122 (c 1.2, CHCl3)Source of chirality: l-tryptophanAbsolute configuration: (1S,3S)(1S,3R)-2-Benzyl 3-methyl 1-(benzo[d][1,3]dioxol-5-yl)-3,4-dihydro-1H-pyrido[3,4-b]indole-2,3-dicarboxylateC28H24N2O6[α]D20=+41 (c 0.4, CHCl3)Source of chirality: l-tryptophanAbsolute configuration: (1S,3R)(1S,3R)-2-Ethyl 3-methyl 1-(benzo[d][1,3]dioxol-5-yl)-3,4-dihydro-1H-pyrido[3,4-b]indole-2,3-dicarboxylateC23H22N2O6[α]D20=+49 (c 0.4, CHCl3)Source of chirality: l-tryptophanAbsolute configuration: (1S,3R)(1S,3R)-2-Isobutyl 3-methyl 1-(benzo[d][1,3]dioxol-5-yl)-3,4-dihydro-1H-pyrido[3,4-b]indole-2,3-dicarboxylateC25H26N2O6[α]D20=+55 (c 0.2, CHCl3)Source of chirality: l-tryptophanAbsolute configuration: (1S,3R)(1S,3R)-3-Methyl 2-phenyl 1-(benzo[d][1,3]dioxol-5-yl)-3,4-dihydro-1H-pyrido[3,4-b]indole-2,3-dicarboxylateC27H22N2O6[α]D20=+89 (c 0.7, CHCl3)Source of chirality: l-tryptophanAbsolute configuration: (1S,3R)(1S,3R)-2-t-Butyl 3-methyl 1-(benzo[d][1,3]dioxol-5-yl)-3,4-dihydro-1H-pyrido[3,4-b]indole-2,3-dicarboxylateC25H26N2O6[α]D20=+42 (c 0.6, CHCl3)Source of chirality: l-tryptophanAbsolute configuration: (1S,3R)(1S,3R)-Methyl 1-(benzo[d][1,3]dioxol-5-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylateC20H18N2O4[α]D20=+33 (c 1.0, CHCl3)Source of chirality: l-tryptophanAbsolute configuration: (1S,3R)(1R,3R)-Methyl 1-(benzo[d][1,3]dioxol-5-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylateC20H18N2O4[α]D20=+25 (c 0.9, CHCl3)Source of chirality: l-tryptophanAbsolute configuration: (1R,3R)(1R,3R)-Methyl 1-(benzo[d][1,3]dioxol-5-yl)-2-(2-chloroacetyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylateC22H19ClN2O5[α]D20=-126 (c 1.2, CHCl3)Source of chirality: l-tryptophanAbsolute configuration: (1R,3R)(6R,12aR)-6-(Benzo[d][1,3]dioxol-5-yl)-2,3,6,7,12,12a-hexahydro-2-methylpyrazino[1′,2′:1,6]pyrido[3,4-b]indole-1,4-dioneC22H19N3O4[α]D20=+71 (c 1.2, CHCl3)Source of chirality: l-tryptophanAbsolute configuration: (1R,3R)

Oseltamivir phosphate 1 was synthesized starting from a readily available acetonide, that is, ethyl (3R,4S,5R)-3,4-O-isopropylidene shikimate 2, through a new route via 11 steps and in 44% overall yield. The synthesis described in this article is characterized by two particular steps: the highly regioselective and stereoselective facile nucleophilic replacement of an OMs by an N3 group at the C-3 position of ethyl (3R,4S,5R)-3,4-O-bismethanesulfonyl-5-O-benzoyl shikimate 5, and the mild ring-opening of an aziridine with 3-pentanol at the C-1 position of ethyl (1S,5R,6S)-7-acetyl-5-benzoyloxy-7-azabicyclo[4,1,0]hept-2-ene-3-carboxylate 8.Ethyl (3R,4R,5R)-4-N-acetylamino-3-(1-ethyl-propoxy)-5-hydroxy-cyclohex-1-ene-1-carboxylateC16H27NO5[α]D25=-104 (c 3.0, EtOAc)Source of chirality: (−)-Shikimic acidAbsolute configuration: (3R,4R,5R)Ethyl (3R,4S,5R)-4-N-acetylamino-3-(1-ethyl-propoxy)-5-methansulfulonyloxy-cyclohex-1-ene-1-carboxylateC17H29NO7S[α]D25=-85 (c 0.7, EtOAc)Source of chirality: (−)-Shikimic acidAbsolute configuration: (3R,4S,5R)Ethyl (3R,4R,5S)-4-N-acetylamino-5-azido-3-(1-ethyl-propoxy)-cyclohex-1-ene-1-carboxylateC16H26N4O4[α]D20=-44 (c 1.5, CHCl3)Source of chirality: (−)-Shikimic acidAbsolute configuration: (3R,4R,5S)Osetamivir phosphate (Tamiflu)C16H31N2O8P[α]D20=-39 (c 1, H2O)Source of chirality: (−)-Shikimic acidAbsolute configuration: (3R,4R,5S)Ethyl (3R,4S,5R)-3,4-O-isopropylidene-shikimateC12H18O5[α]D20=-31 (c 3.0, EtOAc)Source of chirality: (−)-Shikimic acidAbsolute configuration: (3R,4S,5R)Ethyl (3R,4S,5R)-5-O-benzoyl-3,4-O-isopropylidene-shikimateC19H22O6[α]D25=-55 (c 3.4, EtOAc)Source of chirality: (−)-Shikimic acidAbsolute configuration: (3R,4S,5R)Ethyl (3R,4R,5R)-5-O-benzoyl-shikimateC16H18O6[α]D25=-122 (c 2.7, EtOAc)Source of chirality: (−)-Shikimic acidAbsolute configuration: (3R,4R,5R)Ethyl (3R,4S,5R)-5-O-benzoyl-3,4-O-bismethansulfonyl-shikimateC18H22O10S2[α]D25=-135 (c 1.9, EtOAc)Source of chirality: (−)-Shikimic acidAbsolute configuration: (3R,4S,5R)Ethyl (3S,4R,5R)-3-azido-5-benzoyloxy-4-methanesulfonyloxy-cyclohex-1-ene-1-carboxylateC17H19N3O7S[α]D25=-27 (c 2.8, EtOAc)Source of chirality: (−)-Shikimic acidAbsolute configuration: (3S,4R,5R)Ethyl (1S,5R,6S)-5-benzoyloxy-7-aza-bicyclo[4,1,0]hept-2-ene-3 -carboxylateC16H17NO4[α]D25=-63 (c 0.8, EtOAc)Source of chirality: (−)-Shikimic acidAbsolute configuration: (1S,5R,6S)Ethyl (1S,5R,6S)-7-acetyl-5-benzoyloxy-7-aza-bicyclo[4,1,0]hept-2-ene-3 -carboxylateC18H19NO5[α]D25=-41 (c 1.6, EtOAc)Source of chirality: (−)-Shikimic acidAbsolute configuration: (1S,5R,6S)Ethyl (3R,4R,5R)-4-N-acetylamino-5-benzoyloxy-3-(1-ethyl-propoxy)-cyclohex-1-ene-1-carboxylateC23H31NO6[α]D25=-113 (c 1.6, EtOAc)Source of chirality: (−)-Shikimic acidAbsolute configuration: (3R,4R,5R)

New asymmetric syntheses of (−)-methyl shikimate 1 and (−)-5a-carba-β-d-gulopyranose 11 from d-arabinose through a common route which employed Mukaiyama-type intramolecular aldolization as a key step were described.(−)-Methyl shikimateC8H12O5[α]D25=-131.5 (c 0.75, EtOH)Source of chirality: d-arabinoseAbsolute configuration: (3R,4S,5R)(E)-(4R,5S,6R)-Ethyl 4,5,6,7-tetrahydroxy-hept-2-enoateC9H16O6[α]D25=+15.1 (c 0.4, MeOH)Source of chirality: d-arabinoseAbsolute configuration: (4R,5S,6R)(4R,5S,6R)-Ethyl 4,5,6,7-tetrahydroxy-heptanoateC9H18O6[α]D25=+9.2 (c 0.5, H2O)Source of chirality: d-arabinoseAbsolute configuration: (4R,5S,6R)(4R,5S,6R)-Ethyl 4,5,6-trihydroxy-7-triphenylmethoxy-heptanoateC28H32O6[α]D25=+6.8 (c 2.6, EtOAc)Source of chirality: d-arabinoseAbsolute configuration: (4R,5S,6R)(−)-Methyl 3,4,5-O-triacetyl shikimateC14H18O8[α]D25=-172.4 (c 0.47, CHCl3)Source of chirality: d-arabinoseAbsolute configuration: (3R,4S,5R)(4R,5S,6R)-5,6-Diallyloxy-7-triphenylmethoxy-heptano-1,4-lactoneC32H34O5[α]D25=-5.7 (c 3, EtOAc)Source of chirality: d-arabinoseAbsolute configuration: (4R,5S,6R)(4R,5S,6R)-5,6-Diallyloxy-7-hydroxy-heptano-1,4-lactoneC13H20O5[α]D25=-37.5 (c 1.4, EtOAc)Source of chirality: d-arabinoseAbsolute configuration: (4R,5S,6R)(1S,2S,3S,4S,5R)-2-(tert-Butyldimethylsilyloxy)-3,4-diallyloxy-6-oxa-bicyclo[3,2,1]octan-7-oneC19H32O5Si[α]D25=+56.0 (c 1.05, EtOH)Source of chirality: d-arabinoseAbsolute configuration: (1S,2S,3S,4S,5R)(1S,2S,3R,4S,5R)-Methyl 2,3,4,5-tetraacetoxy-cyclohexanecarboxylateC16H22O10[α]D25=-3.3 (c 1.5, CHCl3)Source of chirality: d-arabinoseAbsolute configuration: (1S,2S,3R,4S,5R)(1R,2S,3R,4S,5R)-5-Hydroxymethyl-cyclohexane-1,2,3,4-tetrolC7H14O5[α]D25=-58.3 (c 0.4, MeOH)Source of chirality: d-arabinoseAbsolute configuration: (1R,2S,3R,4S,5R)(1R,2S,3S,4S,5R)-4-(tert-Butyldimethylsilyloxy)-2,3-diallyloxy-5-hydroxymethyl cyclohexanolC19H36O5Si[α]D25=-38.3 (c 1.2, EtOH)Source of chirality: d-arabinoseAbsolute configuration: (1R,2S,3S,4S,5R)(1R,2S,3R,4S,5R)-5-Acetoxymethyl-1,4-diacetoxy-2,3-diallyloxy-cyclohexaneC19H28O8[α]D25=-43.7 (c 1.1, MeOH)Source of chirality: d-arabinoseAbsolute configuration: (1R,2S,3R,4S,5R)(1R,2S,3R,4S,5R)-1,2,3,4-O-Tetraacetyl-5-acetoxymethyl-cyclohexane-1,2,3,4-tetrolC17H24O10[α]D25=-22.3 (c 1, CHCl3)Source of chirality: d-arabinoseAbsolute configuration: (1R,2S,3R,4S,5R)

A highly stereoselective Pictet–Spengler reaction of d-tryptophan methyl ester hydrochloride 1-HCl with various aldehydes via a CIAT (crystallization-induced asymmetric transformation) process is described. It was revealed that the CIAT process should be performed in a mixed solvent of nitromethane and toluene, and a fine tuning of the ratio of nitromethane and toluene for each epimer mixture of 2-HCl was necessary in order to get as high yields and stereoselectivities as possible. Enantiomerically pure cis (or trans) 1,3-disubstituted tetrahydro-β-carbolines 2a–2v were obtained by recrystallization or flash chromatography after neutralization of the corresponding hydrochloride salts cis-2-HCl or trans-2-HCl.(1R,3R)-Methyl 1-hexyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylateC19H26N2O2[α]D20=+57.8 (c 1.6,CHCl3)Source of chirality: d-tryptophanAbsolute configuration: (1R,3R)(1R,3R)-Methyl 1-(2-methoxyphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylateC20H20N2O3[α]D20=-14.1 (c 1.5, CHCl3)Source of chirality: d-tryptophanAbsolute configuration: (1R,3R)(1R,3R)-Methyl 1-(2-ethoxyphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylateC21H22N2O3[α]D20=+1.6 (c 4.1, CHCl3)Source of chirality: d-tryptophanAbsolute configuration: (1R,3R)(1R,3R)-Methyl 1-(2-chlorophenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylateC19H17N2O2Cl[α]D20=-20.6 (c 0.9, CHCl3)Source of chirality: d-tryptophanAbsolute configuration: (1R,3R)(1R,3R)-Methyl 1-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylateC14H16N2O2[α]D20=+93.6 (c 2.5, CHCl3)Source of chirality: d-tryptophanAbsolute configuration: (1R,3R)(1R, 3R)-Methyl 1-ethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylateC15H18N2O2[α]D20=+9.8 (c 1.6, CHCl3)Source of chirality: d-tryptophanAbsolute configuration: (1R,3R)(1S,3R)-Methyl 1-(4-acetoxy-3-methoxyphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylateC22H22N2O5[α]D20=+30.4 (c 1.2, CHCl3)Source of chirality: d-tryptophanAbsolute configuration: (1S,3R)(1R,3R)-Methyl 1-(4-benzoyloxy-3-methoxyphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylateC27H24N2O5[α]D20=+8.1 (c 1.4, CHCl3)Source of chirality: d-tryptophanAbsolute configuration: (1R,3R)(1R,3R)-Ethyl 1-(3,4,5-trimethoxyphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylateC23H26N2O5[α]D20=+20.5 (c 0.4, CHCl3)Source of chirality: d-tryptophanAbsolute configuration: (1R,3R)(1S,3R)-Ethyl 1-(3,4-dimethoxyphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylateC22H24N2O4[α]D20=+26.0 (c 1.9, CHCl3)Source of chirality: d-tryptophanAbsolute configuration: (1S,3R)(1S,3R)-Methyl 1-(3,4,5-trimethoxyphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylateC22H24N2O5[α]D20=+11.3 (c 1.3, CHCl3)Source of chirality: d-tryptophanAbsolute configuration: (1S,3R)(1S,3R)-Ethyl 1-(4-methoxyphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylateC21H22N2O3[α]D20=+49.7 (c 0.3, CHCl3)Source of chirality: d-tryptophanAbsolute configuration: (1S,3R)(1R,3R)-Ethyl 1-(benzo[d][1,3]dioxol-5-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylateC21H20N2O4[α]D20=+32.2 (c 1.0, EtOAc)Source of chirality: d-tryptophanAbsolute configuration: (1R,3R)C22H22N2O4(1R,3R)-Propyl 1-(benzo[d][1,3]dioxol-5-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate[α]D20=+36.2 (c 1.0, EtOAc)Source of chirality: d-tryptophanAbsolute configuration: (1R,3R)(1R,3R)-Methyl 1-(3,4-dimethoxyphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylateC21H22N2O4[α]D20=+21.9 (c 1.6, CHCl3)Source of chirality: d-tryptophanAbsolute configuration: (1R,3R)(1S,3R)-Methyl 1-phenyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylateC19H18N2O2[α]D20=+44.5 (c 1.0, CHCl3)Source of chirality: d-tryptophanAbsolute configuration: (1S,3R)(1S,3R)-Methyl 1-deutero-1-(3,4-dimethoxyphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylateC21H21DN2O4[α]D20=+24.5 (c 1.0, CHCl3)Source of chirality: d-tryptophanAbsolute configuration: (1S,3R)(R)-Methyl 2-amino-3-(2-(3,4-dimethoxybenzyl)-1H-indol-3-yl)propanoateC21H24N2O4[α]D20=+17.3 (c 1.2, CHCl3)Source of chirality: d-tryptophanAbsolute configuration: (R)(1S,3R)-Methyl 1-(3,4-dimethoxyphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylateC21H22N2O4[α]D20=+25.4 (c 1.7, CHCl3)Source of chirality: d-tryptophanAbsolute configuration: (1S,3R)(1S,3R)-Methyl 1-(4-methoxyphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylateC20H20N2O3[α]D20=+44.0 (c 2.0, CHCl3)Source of chirality: d-tryptophanAbsolute configuration: (1S,3R)(1R,3R)-Methyl 1-phenyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylateC19H18N2O2[α]D20=+14.2 (c 1.5, CHCl3)Source of chirality: d-tryptophanAbsolute configuration: (1R,3R)(1R,3R)-Methyl 1-(4-hydroxy-3-methoxyphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylateC20H20N2O4[α]D20=+39.8 (c 1.1, CHCl3)Source of chirality: d-tryptophanAbsolute configuration: (1R,3R)(1R,3R)-Methyl 1-(4-hydroxyphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylateC19H18N2O3[α]D20=+34.2 (c 1.0, acetone)Source of chirality: d-tryptophanAbsolute configuration: (1R,3R)(1R,3R)-Methyl 1-(4-nitrophenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylateC19H17N3O4[α]D20=+5.4 (c 1.0,CHCl3)Source of chirality: d-tryptophanAbsolute configuration: (1R,3R)(1S,3R)-Methyl 1-isopropyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylateC16H20N2O2[α]D20=-53.4 (c 1.6, CHCl3)Source of chirality: d-tryptophanAbsolute configuration: (1S,3R)(1R,3R)-Methyl 1-(2-nitrophenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylateC19H17N3O4[α]D20=+22.6 (c 6.6,CHCl3)Source of chirality: d-tryptophanAbsolute configuration: (1R,3R)

Oseltamivir phosphate (1) was synthesized from (−)-shikimic acid through a short and practical synthetic route via eight steps in 47% overall yield. In addition, the highly regioselective and stereoselective nucleophilic replacement of OMs by the N3 group in the third and seventh steps has been studied in detail, and the reaction conditions were optimized.

The acid-catalyzed Pictet–Spengler reaction of d-tryptophan methyl ester with piperonal in acetic acid has been reported, the best stereoselectivity (cis/trans = 92:8) was obtained with benzoic acid as the catalyst. The Pictet–Spengler reaction of d-tryptophan methyl ester hydrochloride with piperonal in various solvents has been extensively studied, the solvent-dependence of stereoselectivities could be principally attributed to the solubility-difference between cis and trans products 5-HCl in the used solvent, the best stereoselectivity (cis/trans = 99:1) was obtained using nitromethane or acetonitrile as the solvent. A base-catalyzed epimerization at 12a-position of Cialis 1 (tadalafil) in a DMSO-containing solvent was also exploited. Cialis, 12a-epi-Cialis 2, deuterium-labeled 3,3,12a-d3-Cialis 3, and 3,3,12a-d3-12a-epi-Cialis 4 were efficiently synthesized from d-tryptophan methyl ester hydrochloride.(1R,3R)-1-(3,4-Methylenedioxyphenyl)-2,3,4,9-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylic methyl esterC20H18N2O4[α]D20=+25.2 (c 1.0, CHCl3)Source of chirality: d-tryptophanAbsolute configuration: (1R,3R)(1S,3R)-1-(3,4-Methylenedioxyphenyl)-2,3,4,9-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylic methyl esterC20H18N2O4[α]D20=+33.1 (c 1.0, CHCl3)Source of chirality: d-tryptophanAbsolute configuration: (1S,3R)(1R,3R)-1-(3,4-Methylenedioxyphenyl)-2,3,4,9-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylic methyl ester hydrochlorideC20H19N2O4Cl[α]D20=+92.9 (c 1.1, MeOH)Source of chirality: d-tryptophanAbsolute configuration: (1R,3R)(1R,3R)-1-(3,4-Methylenedioxyphenyl)-2-chloroacetyl-2,3,4,9-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylic methyl esterC22H19N2O5Cl[α]D20=-126.0 (c 1.1, CHCl3)Source of chirality: d-tryptophanAbsolute configuration: (1R,3R)(6R,12aR)-2,3,6,7,12,12a-Hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino-[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dioneC22H19N3O4[α]D20=+71.5 (c 1.0, CHCl3)Source of chirality: d-tryptophanAbsolute configuration: (6R,12aR)(6R,12aS)-2,3,6,7,12,12a-Hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino-[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dioneC22H19N3O4[α]D20=-303.1 (c 1.2, CHCl3)Source of chirality: d-tryptophanAbsolute configuration: (6R,12aS)(6R,12aR)-2,3,6,7,12,12a-Hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-3,3,12a-trideutero-pyrazino-[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dioneC22H16D3N3O4[α]D20=+87.1 (c 1.0, CHCl3)Source of chirality: d-tryptophanAbsolute configuration: (6R,12aR)(6R,12aS)-2,3,6,7,12,12a-Hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-3,3,12a-trideutero-pyrazino-[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dioneC22H16D3N3O4[α]D20=-268.0 (c 1.2, CHCl3)Source of chirality: d-tryptophanAbsolute configuration: (6R,12aS)

Efficient preparations of (R)-(−)-apomorphine (R)-1 and (R)-(−)-aporphine (R)-2 based on a recycle process of resolution are described. In this recycle process of resolution, (RS)-(±)-10,11-dimethoxyaporphine 3 as the precursor of 1, and (RS)-(±)-aporphine 2 were successfully resolved into both enantiomers with (+)-dibenzoyltartaric acid (DBTA). The desired (R)-3 and (R)-2 were obtained and then, respectively, transformed to compound (R)-1, the hydrochloride salt of (R)-1, diacetate compound 4 and the hydrochloride salt of (R)-2; while the undesired (S)-3 and (S)-2 were racemized to obtain a racemate, which was suitable for further resolution. A method for the racemization of the undesired (S)-3 and (S)-2 was extensively studied, in order to obtain high-yielding racemization conditions. A plausible mechanism for the racemization of (S)-3 and (S)-2 was also proposed.(R)-(−)-Apomorphine hydrochlorideC17H18ClNO2[α]D20=-48.1 (c 1.0, water)Source of chirality: (−)-tartaric acidAbsolute configuration: (R)(R)-(−)-10,11-DiaetoxyaporphineC21H21NO4[α]D20=-137.1 (c 0.3, methanol)Source of chirality: (−)-tartaric acidAbsolute configuration: (R)(R)-(−)-AporphineC17H17N[α]D20=-151.6 (c 0.6, methanol)Source of chirality: (−)-tartaric acidAbsolute configuration: (R)(R)-(−)-Aporphine hydrochlorideC17H18NCl[α]D20=-106.6 (c 0.3, methanol)Source of chirality: (−)-tartaric acidAbsolute configuration: (R)(R)-(−)-10,11-DimethoxyaporphineC19H21NO2[α]D20=-172.3 (c 1.4, methanol)Source of chirality: (−)-tartaric acidAbsolute configuration: (R)

We describe here a synthesis of (4S)-2-(acetoxymethyl)-4-(tert-butyldiphenylsilyloxy)-2-cyclopenten-1-one 1 from l-malic acid in seven steps via an intramolecular aldolization–dehydration cyclization reaction of the acyclic 1,6-dialdehyde 10. The conditions of the intramolecular aldolization–dehydration cyclization reaction were also optimized.Graphic(2S)-Dimethyl-2-acetoxy-4,4-(propylenedithio)adipate[α]D=−158 (c 0.5, CH2Cl2)Source of chirality: l-malic acidAbsolute configuration: 2S(2S)-Dimethyl-2-(tert-butyldiphenylsilyloxy)-4,4-(propylenedithio)adipate[α]D=−226 (c 0.6, CH2Cl2)Source of chirality: l-malic acidAbsolute configuration: 2S(9S)-9-(tert-Butyldiphenylsilyloxy)-7-formyl-1,5-dithiaspiro[5,4]dec-7-ene[α]D=−112 (c 1.0, CH2Cl2)Source of chirality: l-malic acidAbsolute configuration: 9S(9S)-7-(Acetoxymethyl)-9-(tert-butyldiphenylsilyloxy)-1,5-dithiaspiro[5,4]dec-7-ene[α]D=−92 (c 1.1, CH2Cl2)Source of chirality: l-malic acidAbsolute configuration: 9S(4S)-2-(Acetoxymethyl)-4-(tert-butyldiphenylsilyloxy)-2-cyclopenten-1-one[α]D=−67 (c 0.8, CH2Cl2)Source of chirality: l-malic acidAbsolute configuration: 4S