Asymmetric 1,3-Dipolar Cycloaddition Reactions

Chem. Pharm. Bull.(オピニオン)

Recent developments in the chemistry of enaminones

Synthesis of heterocycles from alkyl 3-(dimethylamino)propenoates and related enaminones.

Compounds, pharmaceuticals, kits and methods are provided for use with DPP-IV and other S9 proteases that comprise a compound comprising: 
wherein M is N or CR 4 ; Q 1 and Q 2 are each independently selected from the group consisting of CO, SO, SO 2 , and C═NR 9 ; and each L, X, R 1 , R 2 , and R 3 are as defined herein.

Dipeptidyl peptidase inhibitors

Pyrrole is an important heterocycle because its structure is incorporated in a variety of biologically important compounds, such as heme, chlorophyll, vitamin B12, and bile pigments. Besides, pyrrole and pyrrolidine partial structures occur in numerous natural products and synthetically important compounds [1]. Among numerous syntheses of pyrroles reported so far in the literature, three general methods have to be outlined: a) the Paal-Knorr synthesis of pyrroles from 1,4-dicarbonyl compounds and primary amines (5+1 cyclocondensation approach), b) the Knorr pyrrole synthesis from α-amino ketones and 1,3-dicarbonyl compounds (3+2 cyclocondensation approach), and c) the van Leusen synthesis of pyrroles from tosylmethyl isocyanide (Tosmic) and α ,β -unsaturated carbonyl compounds (3+2 cycloaddition approach) [1]. 2-Substituted alkyl 3-(dimethylamino)prop-2enoates and related enaminones are a group of enamino-masked alkyl α-formylacetates, which are easily available and are versatile reagents in heterocyclic synthesis [2]. In addition to their extensive use in the synthesis of various heterocyclic systems, recent applications of enaminones are mostly oriented towards the preparation of functionalised heterocyclic compounds including natural product analogues [2 – 4] and in combinatorial synthesis of functionalized heterocycles [5]. In this context, pyrrole derivatives have been prepared by intramolecular cyclisation of 2-(2-cyano-vinyl)amino-3-(dimethylamino)

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A Simple Synthesis of 1-Substituted Diethyl Pyrrole-3,4-dicarboxylates

Eleven (S)-1,6-dialkylpiperazine-2,5-diones and five (3S,6S)-1,3,6-trialkylpiperazine-2,5-diones were prepared in three steps from the corresponding (S)-α-amino acid esters comprising of reductive N-alkylation, N-acylation and cyclisation. The synthesis of (S)-1,6-dialkylpiperazine-2,5-diones has a broad scope allowing preparation of diketopiperazines with primary and secondary alkyl groups at N(1), while the synthesis of (3S,6S)-1,3,6-trialkylpiperazine-2,5-diones is limited to compounds with primary alkyl groups at N(1). Reductive alkylation of amino acid ester hydrochlorides by catalytic hydrogenation in the presence of a carbonyl compound proved to be a simple, efficient and general method for the preparation of stable (storable) α-alkylamino acid ester hydrochlorides. The structures of the novel compounds were determined by NMR and X-ray diffraction.

Synthesis and Structure of Novel (S)‐1,6‐Dialkylpiperazine‐2,5‐diones and (3S,6S)‐1,3,6‐Trialkylpiperazine‐2,5‐diones.

Open-chain C-nucleosides, 1-(s-triazolo[4,3-x]azinyl-3)polyols 13–18 were prepared by one-pot synthesis from hydrazinoazines 20a,c and various D-aldoses 1–6. No protective groups were required for these transformations. 1-(s-Triazolo[4,3-b]pyridazinyl-3)-D-xylo-tetritol (15a) was isolated and characterised in the form of its 4-O-triphenylmethyl derivative 19. Reaction of hydrazinopyridazines 20a,b with methyl 2,3-di-O-acetyl-L-threuronate (22), followed by treatment with bromine, gave the corresponding (2R,3S)-2,3-diacetoxy-3-(s-triazolo[4,3-b]pyridazinyl-3)propanoic acid methyl esters 24a,b. Acetonisation of 1-(6-chloro-s-triazolo[4,3-b]pyridazinyl-3)-D-gluco-pentitol (17a) gave a mixture of isomeric bis-acetonides 25 and 26, while acetonisation of 1-(6-chloro-s-triazolo[4,3-b]pyridazinyl-3)-D-manno-pentitol (18a) gave acetonide 27 as a single isomer.

A Simple One-Pot Synthesis of 1-(s-Triazolo[4,3-x]azinyl-3)substituted Polyols.

Various (1R,5S)-4-[(E)-alkylidene]-1,8,8-trimethyl-2-oxabicyclo[3.2. 1]octan-3-ones were prepared, stereoselectively, via coupling of (1R,5S)-4-[(E)-(dimethylamino)methylidene]-1,8,8-tri-methyl-2-oxabicyclo[3.2.1]octan-3-one with Grignard reagents, potassium cyanide, and 2-methyl-lH-indole.

Stereoselective Synthesis of (1R,5S)-4-[(E)-Alkylidene]-1,8,8-trimethyl-2-oxabicyclo[3.2.1]octan-3-ones

Methyl 2-benzoylamino-3-oxobutanoate (3) was prepared from hippuric acid (1) which was converted with N,N-dimethylacetamide and phosphorus oxychloride into 4-(1-dimethylaminoethylidene)-2-phenyl-5(4H)-oxazolone (2) followed by hydrolysis with hydrochloric acid in methanol. Compound 3 was treated with hydrazines 4 to give 4-benzoylamino-3-methyl-1H-pyrazol-5(2H)-one (6a) and its 1-substituted derivatives 6b-j. The corresponding hydrazones 5f, i, j were isolated as intermediates.

Transformation of 4-(1-Dimethylaminoethylidene)-2-phenyl-5(4H)-oxazolone into Methyl 2-Benzoylamino-3-oxobutanoate. The Synthesis of 1-Substituted 4-Benzoylamino-3-methyl-5(2H)-pyrazolones.

Branko Stanovnik

Papers

A Simple Synthesis of 1-Substituted Diethyl Pyrrole-3,4-dicarboxylates

Synthesis and Structure of Novel (S)‐1,6‐Dialkylpiperazine‐2,5‐diones and (3S,6S)‐1,3,6‐Trialkylpiperazine‐2,5‐diones.

A Simple One-Pot Synthesis of 1-(s-Triazolo[4,3-x]azinyl-3)substituted Polyols.

Stereoselective Synthesis of (1R,5S)-4-[(E)-Alkylidene]-1,8,8-trimethyl-2-oxabicyclo[3.2.1]octan-3-ones

Transformation of 4-(1-Dimethylaminoethylidene)-2-phenyl-5(4H)-oxazolone into Methyl 2-Benzoylamino-3-oxobutanoate. The Synthesis of 1-Substituted 4-Benzoylamino-3-methyl-5(2H)-pyrazolones.