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

Two variations of a parallel solution-phase synthesis of N-substituted dimethyl 4-oxo-1,4-dihydropyridine-3,5-dicarboxylates 4 and methyl 3-oxo-3,5-dihydro-2H-pyrazolo[4,3-c]pyridine-7-carboxylates 9 from dimethyl acetone-1,3-dicarboxylate (1) were developed. The first synthetic method comprises preparation of the bis-enaminone reagents 2 and 8 and their cyclization with primary amines 3 via double substitution of both dimethylamino groups to give dihydropyridines (DHPs) 4 and 9, respectively. Another variation consists of preparation of the monoenaminone reagents 5 and 10, followed by substitution of the dimethylamino group with primary amines 3, and cyclization of the so formed intermediates 6 with N,N-dimethylformamide dimethylacetal (DMFDMA). In this manner, a library of 46 analytically pure compounds, 24 intermediates 6, 11, and 13, and 22 final dihydropyridines 4 and 9 was obtained employing just a simple filtration workup.

Bis-enaminone Based Parallel Solution-Phase Synthesis of 1,4-Dihydropyridine Derivatives.

Diethyl 2-[(dimethylamino)methylene]-3-oxopentanedioate (2), prepared from acetone- 1,3-dicarboxylates (1) and N,N-dimethylformamide dimethyl acetal (DMFDMA) was, without isolation, transformed by treatment with guanidine hydrochloride into ethyl 2-amino-4-(2-ethoxycarbonylmethyl)-pyrimidine-5-carboxylate (3). Compound 3 was transformed with DMFDMA first into intermediate 4 and with an excess of DMFDMA into ethyl 4-[l-(dimethylamino)-3-ethoxy-3-oxoprop-1-en-2-yl]-2-[(dimethylamino)methyle neamino]pyrimidine-5-carboxylate (5). By treatment of compound 5 with ammonia, primary amines, hydrazine or hydroxylamine intermediates 6a-j were formed, which cyclized into 6-substituted 2-amino-5-oxo-5,6-dihydropyrido[4,3-d]pyridine-8- carboxylates (7a-j).

Transformations of Diethyl 2‐[(Dimethylamino)methylene]‐3‐oxopentanedioate. A Simple Synthesis of Substituted 2‐Amino‐5‐oxo‐5,6‐dihydropyrido[4,3‐d]pyrimidine‐8‐carboxylates.

A New Approach to 5H‐Pyrrolo[3,2‐d]pyrimidines (9‐Deazapurines) from 3‐Aminopyrrole‐2‐carboxylates.

New, highly functionalised (1 E ,3 E )-1-(benzoylamino)-4-(dimethylamino)buta-1,3-diene-1,2,3-tricarboxylates proved to be useful and versatile reagents in the formation of highly substituted pyridine, N -aminopyridine, pyrrole and pyrido[3,4- c ]pyridazine derivatives. The formation of the particular type heterocyclic system is dependent on the starting (1 E ,3 E )-1-(benzoylamino)-4-(dimethylamino)buta-1,3-diene-1,2,3-tricarboxylate. By an appropriate choice of different ester groups it is possible to drive the reactions towards the formation of either pyridine or pyrrole derivatives.

Transformations of (1E,3E)-1-(Benzoylamino)-4- (dimethylamino)buta-1,3-diene-1,2,3-tricarboxylates into Pyridine and Pyrrole Derivatives.

Dedicated to Professor Emeritus Miha Tisler on the occasion of his 75th birthday



Treatment of methyl (S)-5-[(E)-(dimethylamino)methylidene]-2-oxotetrahydrofuran-5-carboxylate (2) with potassium cyanide in acetic acid gave (S)-5-[(E)-cyanomethylidene]-2-oxotetrahydrofuran-5-car-boxylate (3), which was used as chiral dipolarophile in 1,3-dipolar cycloadditions. Reactions of 3 with diazomethane (4) and nitrile oxides 5a-c afforded spirolactones 6–8 in 24-34% diastereomeric excess, while with diazomethane (4) in the presence of triethylamine, methyl 3-cyanomethyl-2-methoxyfuran-5-carboxylate (12) was obtained.

Branko Stanovnik

Papers

Bis-enaminone Based Parallel Solution-Phase Synthesis of 1,4-Dihydropyridine Derivatives.

Transformations of Diethyl 2‐[(Dimethylamino)methylene]‐3‐oxopentanedioate. A Simple Synthesis of Substituted 2‐Amino‐5‐oxo‐5,6‐dihydropyrido[4,3‐d]pyrimidine‐8‐carboxylates.

A New Approach to 5H‐Pyrrolo[3,2‐d]pyrimidines (9‐Deazapurines) from 3‐Aminopyrrole‐2‐carboxylates.

Transformations of (1E,3E)-1-(Benzoylamino)-4- (dimethylamino)buta-1,3-diene-1,2,3-tricarboxylates into Pyridine and Pyrrole Derivatives.

Synthesis of Spirolactones by 1,3-Dipolar Cycloadditions to Methyl (S)-3-[(E)-Cyanomethylidene]-2-oxotetrahydrofuran-5-carboxylate.