Pyrrolidines modified

Cook reported the syntheses of phosphonamidite and H-phosphonates derivatives of 3 -C-methylene modified thymidines (77a-e), 3 -C-methylene 5-methyl-iV-pyrrolidine-modified cytosine (78) and 3 -C-methylene 5-methyl modified uridine (79) having methoxy, fluoro, hydrogen and methoxyethoxy substituents at the 2 -positions. The H-phosphonates were synthesised from the corresponding key intermediate 3 -C-iodomethyl nucleosides through an... 

Fig. 4. Peptide and chemical structure, respectively, of the incretin mimetics exenatide and liraglutide and the DPP inhibitors sitagliptin ((2R)A-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8//)-yl]-l-(2,4,5-trifluorophenyl)butan-2-amine) and vUdagliptin (l-[[(3-hydroxy-l-adamantyl)amino]acetyl]-2-cyano-(S)-pyrrolidine). (Modified from Drucker and Nanck 2006 [145]).

Interestingly the pyrrolidine enamine of 3-t-butylcyclohexanone (41) consists of a 3 2 mixture of A and A isomers (79 and 80). The preference for the A isomer in this case is due to the relief of two of the four skew butane interactions, which are present in the isomer. The A isomer, owever, contains two additional interactions, i.e., one modified skew utane interaction 0.4 kcal/mole (42) and one interaction between c C-2 vinylic hydrogen atom and the ethyl portion of the t-butyl group hich is pointed toward it. 

The first reports on enantioselective addition reactions of achiral organometallic reagents, modified by aprotic chiral additives, described the addition of Grignard reagents to prostereogenic carbonyl compounds in the presence of ( + )-(/ ,/J)-2,3-dimethoxybutane (l)4 5, (-)-tetrahydro-2-methylfuran (2)6, (-)-l-[(tetrahydro-2-furanyl)methyl]pyrrolidine (3)7 or (-)-sparteine (4)8. The enantioselectivity, however, was poor (0-22% ee). 

Recently, SB-269970 (l-[3-hydroxy-phenyl-sulphonyl]-2-[2-(4-methyl-l-piperidinyl)-ethyl] pyrrolidine) and SB-656104 (6-((R)-2- 2-[4-(4-chloro-phenoxy)-piperidin-l-yl]-ethyl pyrrolidine-l-sulphonyl)-lH-indole) have been reported to be potent 5-HT7 receptor antagonists (Hagan et al., 2000 Forbes et al., 2002). Selective 5-HT7 receptor agonists are not available at the present time. Systemic administration of SB-269970 or SB-656104 to rats at the beginning of the light period has been shown to reduce the total amount of REMS and to increase REMS latency. Values of W and SWS were not significantly modified (Hagan et al., 2000 Thomas et al., 2003). Hedlund et al. (2005) established that 5-HT7... 

A different approach to 1 is available32,33 for somewhat larger quantities in good yields. The procedure (Scheme 2) is based upon the condensation of ethyl /f-bromomethacrylate (9) or its precursor, diethyl /i,/7 -dibromoisobutyr-ate, with the pyrrolidine enamine (10) of Af-toluene-p-sulfonylpiperid-4-one to afford the bicyclic intermediate (11). If the carbonyl group is modified... 

The same reaction sequence may be used to convert cyclo-dodecanone to cyclotetradecanone. Preparation of the pyrrolidine enamine of cyclododecanone requires 2-3 days at reflux, and reaction of the enamine with methyl propiolate is best carried out in refluxing hexane. The enamine-propiolate reaction may also be used to convert cycloheptanone to cyclononanone. In this case the procedure must be modified to provide for partial hydrogenation of the intermediate amino ester without prior hydrolysis.8 The reduced intermediate is saponified as described in the present procedure. 

These alkaloids contain pyrrole or modified pyrrole, e.g. pyrrolidine, ring system. The simplest example of this class is nicotine. A pyrrolidine ring is the central structure of the amino acids proline and hydroxyproline. These alkaloids are also found in many drug preparations, e.g. procyclidine hydrochloride, which is an antichohnergic drug mainly used for the treatment of drug-induced Parkinsonism, akathisia and acute dystonia. 

Preparation of the thioacids and their esters via SPPS is mainly restricted to the Boc methodology. The popular Fmoc approach is limited by aminolysis of the thioester bond during removal of the Fmoc group by piperidine. However, a modified Fmoc-deprotecting mixture (1-methyl pyrrolidine/hexamethyleneimine/HOBt/DMSO/NMP 25 2 2 35.5 35.5) gave the final desired peptide ester with 24% yield J24 ... 

Other reports also demonstrate the efficiency of this reaction for the synthesis of pyrrolidine prostacyclin analogues [183], ( )-indolizidine 209B [184], pyridinones [185] and pyrrolidine-2-ylidene esters [186], though in one case the structure of the substrate had to be modified to avoid an undesired reaction [187]. 

An interesting study of conformationally mobile systems involves iodo-methylation of nicotine derivatives 47, where steric effects of substituents at position-2 and -6 modify the alkylation rate at the pyridine nitrogen and at the two nitrogens (N trans and N cis) of the pyrrolidine conformers (80JA7741 81JOC3040) (Scheme 26b). 

Benzophenones have been described as useful sensitisers for PET catalysed conjugate addition reactions of a-amino alkyl radicals to enones (Bertrand et al. 2000). We tried to modify this reaction and synthesised the pyrrolidinylethyl-substituted quinolone 35 from the known bromide (Bauer et al. 2005). Upon electron transfer from the pyrrolidine to a given acceptor, a radical cyclisation occurs (Scheme 15), which after electron and proton transfer generates a pyrrolizidine. We found 4,4/-dimethoxybenzophenone to be a suitable catalyst for this reaction. Remarkably, the reaction proceeded with excellent simple diastereos-electivity and a single diastereoisomeric product rac-36 was obtained. With 10 mol% of the catalyst, a chemical yield of 71% was achieved. 

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