A practical enantioselective total synthesis of (−)-(S)-stepholidine

A convergent enantioselective total synthesis of (−)-(S)-stepholidine, a drug candidate for the treatment of schizophrenia and/or drug abuse, was described, which represented the first example of successful auxiliary-assisted Bischler–Napieralski cyclization of amide bearing bromine atom at 2-position of the C ring, followed by an introduction of the aryl methyl ester via Br–Li exchange. (−)-(S)-Stepholidine was synthesized in 6 steps, with 52% overall yield and >99% ee. The reported synthesis is practically free from chromatographic separation.     

Biotransformation of (+)-(1R,2S)-fenchol by the larvae of common cutworm (Spodoptera litura)

Biotransformation of (+)-(1R,2S)-fenchol by the larvae of Spodoptera litura was carried out. Substrate was converted to three new terpenoids, (+)-(1R,2S)-10-hydroxyfenchol, (+)-(1R,2R,3S)-8-hydroxyfenchol and (−)-(1S,2S,6S)-6-exo-hydroxyfenchol, and one known terpenoid, (−)-(1R,2R,3R)-9-hydroxyfenchol. These structures were established by NMR, IR, specific rotation and mass spectral studies.     

Asymmetric synthesis of (−)-(S,S)-homaline

The asymmetric synthesis of (−)-(S,S)-homaline was achieved in 8 steps from commercially available starting materials using the diastereoselective conjugate addition of the novel lithium amide reagent lithium (R)-N-(3-chloropropyl)-N-(α-methyl-p-methoxybenzyl)amide to methyl cinnamate to install the correct stereochemistry. Subsequent functional group manipulation of the resultant β-amino ester and Sb(OEt)₃-mediated macrolactamisation was followed by homodimerisation to give (−)-(S,S)-homaline in 18% overall yield, representing the first asymmetric, and by far the most efficient synthesis of this natural product reported to date.     

Rearrangement of N-alkyl 1,2-amino alcohols. Synthesis of (S)-toliprolol and (S)-propanolol

N-alkyl 1,2-amino alcohols were rearranged stereospecifically by using TFAA/Et₃N. This rearrangement has been used to synthesize N-isopropyl-3-(aryloxy)-2-hydroxypropylamines, β-adrenergic blocking agents such as (S)-toliprolol and (S)-propanolol.     

Stereoselective synthesis of protected (2S,3S)-N-methyl-5-hydroxyisoleucine, a component of halipeptins

The stereocontrolled synthesis of the protected (2S,3S)-N-methyl-5-hydroxyisoleucine, a component of halipeptins A and B with potent anti-inflammatory activity, has been achieved. The key steps include (i) installation of a double bond to bicyclic lactam 4 using N-tert-butyl phenylsulfinimidoyl chloride, (ii) highly exo-selective Michael reaction with lithium dimethylcuprate in the presence of chlorotrimethylsilane, and (iii) Ru-catalyzed oxidative deprotection of N,O-benzylidene acetal to the acid anhydride.     

A convenient and efficient synthesis of (S)-lysine and (S)-arginine homologues via olefin cross-metathesis

A convenient five step synthesis of (S)-homolysine, incorporating a key olefin cross-metathesis step in the chain extension methodology, has been developed, together with a six step related synthesis of a new homologue of arginine, (S)-bishomoarginine.     

Chiral separation of (R,S)-2-phenyl-1-propanol through cellulose acetate butyrate membranes

As the cellulose acetate butyrate possessed multichiral carbon atoms in its molecular structure unit, enantioselective membrane was prepared using cellulose acetate butyrate as membrane material. The flux and permselective properties of membrane using aqueous solutions of (R,S)-2-phenyl-1-propanol as feed solution was studied. The top surface and cross-section morphology of the resulting membranes were examined by scanning electron microscopy. When the membrane was prepared with 15 wt.% cellulose acetate butyrate and 20 wt.% DMF in the casting solution, and the operating pressure and feed concentration of racemate were 2 kgf/cm² and 5 mmol/L, respectively, over 98% of enantiomeric excess (e.e.) was obtained. This is a report, for the first time, that the cellulose acetate butyrate is used as optical resolution membrane material for isolating the optical isomers of (R,S)-2-phenyl-1-propanol.     

Practical synthesis of (2S,3R)-3-hydroxy-3-methylproline, a constituent of papuamides, using a diastereoselective tandem Michael-aldol reaction

(2S,3R)-3-Hydroxy-3-methylproline, a constituent of cyclodepsipeptides polyoxypeptins A and B, was efficiently synthesized by lithium chloride-induced diastereoselective tandem Michael-aldol reaction using methyl vinyl ketone and N-1-naphthylsulfonylglycine (R)-binaphthyl ester and subsequent hydrolysis of the product in 39% overall yield and five steps.     

Racemic N-sulfonyloxaziridines as highly diastereoselective enolate hydroxylating agents: enantioselective synthesis of (2S,3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide

A new, highly enantioselective synthesis of (2S,3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide, a synthetic fragment of the experimental hepatitis C drug Telaprevir, has been described. Conjugate addition of the enantiomerically pure Davies lithium amide followed by hydroxylation of the in situ generated β-amino enolate was employed for the formation of the required stereogenic centres. Importantly, very high diastereoselectivities can still be achieved in the key-step when the relatively expensive and enantiopure (camphorsulfonyl)oxaziridine hydroxylating agent is replaced by racemic trans-N-sulfonyloxaziridines. Among the tested N-sulfonyloxaziridines the iso-propyl substituted analogue proved to be the ideal choice from an economic viewpoint.     

Transformation of esters into allyl halides via substituted cyclopropanols. Application in the synthesis of (2S,3R,7R/S)-3,7-dimethyltridec-2-yl acetate and propionate, sex attractants of pine sawfly Diprion pini

A convenient new approach to the synthesis of the acetate and the propionate of (2S,3R,7R/S)-3,7-dimethyltridecan-2-ol, sex attractants of Diprion pini L., using the cyclopropanation of the ethoxycarbonyl group in O-THP protected ethyl (S)-lactate with ethylmagnesium bromide in the presence of titanium(IV) isopropoxide followed by C-2-C-3 cyclopropane ring opening as the key steps has been performed.     

Ru-catalyzed enantioselective preparation of methyl (R)-o-chloromandelate and its application in the synthesis of (S)-Clopidogrel

The preparation of methyl (R)-o-chloromandelate via Ru-catalyzed asymmetric hydrogenation and transfer hydrogenation was investigated. With Ru-(R,R)-2,4,6-triisopropyl C₆H₂SO₂-DPEN as the catalyst and HCOOH-Et₃N azeotrope as the hydrogen donor, up to 92% ee was obtained in an optional condition. The synthesis of (S)-Clopidogrel was also studied.     

A new synthetic approach for 4(S)-hydroxycyclopent-2-enone: a precursor to prostanoid synthesis

A new and efficient approach to 4(S)-hydroxycyclopent-2-enone is presented. This methodology allows the preparation of 4(S)-hydroxycyclopent-2-enone in large scale and with high optical purity.     

The fragmentation reaction of 16R-bromopregnane-3S,20S-diol

16R-Bromopregnane-3S,20S-diol reacted with potassium t-butoxide to afford androst-16-en-3S-ol in a moderate yield via fragmentation reaction. The latter is a key intermediate for the synthesis of 5α-androst-16-en-3-one, as boar sex pheromone, and other steroidal drugs. In addition, 16R,20S-epoxypregnane-3S-ol was also obtained as a major product by changing the reaction solvent.     

Pheromone synthesis. Part 244: Synthesis of the racemate and enantiomers of (11Z,19Z)-CH503 (3-acetoxy-11,19-octacosadien-1-ol), a new sex pheromone of male Drosophila melanogaster to show its (S)-isomer and racemate as bioactive

The enantiomers of (11Z,19Z)-3-acetoxy-11,19-octacosadien-1-ol were synthesized from the enantiomers of 3,4-epoxy-1-butanol PMB ether. Its racemate was also synthesized. Its (S)-isomer and racemate were shown to possess the same pheromone activity as CH503, a long-lived inhibitor of male courtship in Drosophila melanogaster, although the racemate was less active.     

Synthesis of (3′R,5′S)-3′-hydroxycotinine using 1,3-dipolar cycloaddition of a nitrone

To synthesize (3′R,5′S)-3′-hydroxycotinine [(+)-1], the main metabolite of nicotine (2), cycloaddition of C-(3-pyridyl)nitrones 3a, 3c, and 15 with (2R)- and (2S)-N-(acryloyl)bornane-10,2-sultam [(2R)- and (2S)-8] was examined. Among them, l-gulose-derived nitrone 15 underwent stereoselective cycloaddition with (2S)-8 to afford cycloadduct 16, which was elaborated to (+)-1.     

Biomimetically inspired total synthesis of (12S)-12-hydroxymonocerin and (12R)-12-hydroxymonocerin

A concise asymmetric total synthesis of (12S)-12-hydroxymonocerin (1) and (12R)-12-hydroxymonocerin (2) were efficiently achieved from the known 4-bromo-2,6-dimethoxyphenol. The synthetic approach was inspired by our biomimetic synthesis of (+)-monocerin (3) and 7-O-demethylmonocerin (4). The cis-fused furobenzopyranones of 1 and 2 was efficiently constructed via an intramolecular nucleophilic trapping of a quinonemethide intermediate, which was obtained by benzylic oxidation of compound 10 using 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ).     

Synthesis and regioselective substitution of C-6 alkoxy derivatives of (S)-nicotine

Enantiopure (S)-6-alkoxynicotine derivatives have been synthesized in two steps from (S)-nicotine via (S)-6-iodonicotine. Deprotonation and substitution at the C-5 position of the pyridine ring of (S)-6-methoxynicotine were achieved using mesityllithium as the base at 0 °C. Conditions for the C-4 lithiation/substitution of (S)-6-isopropoxynicotine and (S)-5-chloro-6-methoxynicotine were also developed.     

Iridium-catalyzed enantioselective allylation of sodium 2-aminobenzenethiolate: an access to chiral benzo-fused N,S-heterocycles

The use of sodium 2-aminobenzenethiolate in the enantioselective iridium catalyzed allylic substitution with a range of methyl allyl carbonates allows the concise synthesis of the branch-type products with both excellent regio- and enantioselectivities, which are functionalized N,S-containing allylic intermediates for the formation of chiral benzo-fused N,S-heterocycles.     

Formation of chiral 21-helical columnar host system with phenylacetylene unit by using (1R,2S)-2-amino-1,2-diphenylethanol

A tunable supramolecular phenylacetylene host system with a chiral channel-like cavity is developed by using (1R,2S)-2-amino-1,2-diphenylethanol. This host system possesses a chiral 2₁-helical columnar structure; chiral cavities are constructed by the self-assembly of the 2₁-helical column, and guest molecules are included by varying the packing of this column.     

2-Cyanopyridazin-3(2H)-ones: effective and chemoselective electrophilic cyanating agents

2-Cyanopyridazin-3(2H)-ones are novel, effective, selective and electrophilic cyanating agents. A variety of amino, thiol and carbon nucleophiles are chemoselectively N-, S- or C-cyanated in excellent yield using 2-cyanopyridanzin-3(2H)-ones in water or tetrahydrofuran.