The organometallic approach to the functionalization of five- and six-membered nitrogen heterocycles

The present thesis work concerns the preparation and optionally site selective functionalization of five- and six-membered nitrogen heterocycles and the investigation of atropisomerism of α,o-bis(methoxymethyl)-1-phenylindole. Mono- and disubstituted 2-bromo-3-fluoroquinolines can be converted into the 3-fluoroquinoline-2-carboxylic acids by consecutive halogen/metal permutation and into the 2-bromo-3-fluoroquinoline-4-carboxylic acids by consecutive deprotonation and carboxylation. These latter compounds can be reduced to afford the 3-fluoroquinoline-4-carboxylic acids. Rather than to introduce one functional group alternatively at the 2- and 4-position, one may also attach two different functional groups sequentially to both sites. An expedient route to all three monobrominated and all three dibrominated isomers of 4-(trifluoromethyl)pyrimidine, and several other halogenated pyrimidines, is described. Pyrimid-5-yllithium species are fairly stable when the metal is flanked by two electron-withdrawing substituents such as trifluoromethyl and chlorine or bromine. Thus, introduction of a carboxy group into the 5-position of 4(6)-(trifluoromethyl)pyrimidine can be achieved by carboxylation of the corresponding lithio species. This later compound can readily obtained by either butyllithium mediated permutational halogen/metal interconversion of 5-bromo-6-chloro-4(trifluoromethyl)pyrimidine or by reaction of 2,4-dibromo- or 2,4-dichloro-6-(trifluoromethyl)pyrimidine with an amide type base. In contrast, functionalization of 4(6)-(trifluoromethyl) pyrimidine at the 2- or 4-position is hampered by the low stability of the lithium species and by a permanently menacing side reaction which results bipyrimidine. Functionalization of 1-phenylindole selectively at the α- and ortho-position as well as simultaneously at both sites is accomplished by application of organometallic reagents. The analog bearing diastereotopic α,o-bis(methoxymethyl) group, prepared from the α,o-diformyl derivative, can serve as a "probe" for the evaluation of the activation barrier for free rotation by means dynamic 1H-NMR technique. When 1-(4-methoxybenzyl)pyrazole is treated with either butyllithium or lithium diisopropylamide, the substrate undergoes metalation at the exocyclic α-position but mutates to the 5-lithio species in the course of few minutes or hours. Trapping the intermediate with a rapidly reacting electrophile such as chlorotrimethylsilane or carbon dioxide offers a selective access to either of the two possible regioisomers. On the other hand, the relatively inert 1-iodobutane and butyl trifluoromethanesulfonate ("triflate") inevitably give rise to product mixture as the 5-lithio species is more slowly intercepted than it can revert to the α-metallomer by rapid dynamic equilibration process

Metalated 1-(p-methoxybenzyl)pyrazole: a structural chameleon

When treated with either butyllithium or lithium diisopropylamide, 1-(p-methoxybenzyl)pyrazole undergoes metalation at the exocyclic alpha-position but mutates to the 5-lithio species in the course of a few minutes or hours. Trapping the intermediates with a rapidly reacting electrophile such as chlorotrimethysilane or carbon dioxide offers selective access to either of the two possible regioisomers. On the other hand, the relatively inert 1-iodobutane and Bu triflate inevitably give rise to product mixts., as the 5-lithio species is more slowly intercepted than it can revert to the alpha-metalomer by a rapid, though intermol., dynamic equilibration process. [on SciFinder (R)

Brominated 4-(trifluoromethyl)pyrimidines: A convenient access to versatile intermediates. [Erratum to document cited in CA141:395506]

Throughout the paper, the incorrect reagent names "phosphorus tribromide\" and "phosphorus trichloride" should be replaced by the correct names "phosphoric tribromide" (POBr3) and "phosphoric trichloride" (POCL3). [on SciFinder (R)

Metal-bearing and trifluoromethyl-substituted pyrimidines: generation and functionalization

5-Pyrimidyllithium species are fairly stable when the metal is flanked by two electron-withdrawing substituents such as trifluoromethyl and chlorine or bromine. Thus, the corresponding 5-carboxylic acids are produced in high yields from 4,5-dibromo-6-(trifluoromethyl)pyrimidine and 5-bromo-4-chloro-6-(trifluoromethyl)pyrimidine upon halogen/metal permutation accomplished with isopropylmagnesium chloride or butyllithium followed by carboxylation. Satisfactory or excellent yields of 5-carboxylic acids are equally obtained when 4-chloro-, 2,4-dichloro- and 2,4-dibromo-6-(trifluoromethyl)pyrimidine are deprotonated with lithium diisopropylamide before being allowed to react with dry ice. In contrast, consecutive treatment of 2-bromo-4-(trifluoromethyl)pyrimidine and 2-chloro-5-iodo-4-(trifluoromethyl)pyrimidine with butyllithium affords the expected carboxylic acids in only poor yields and not even trace amts. of acid were detected when 4-bromo-6-(trifluoromethyl)pyrimidine served as the substrate. The formation of bipyrimidines, emerging from either one of two competing mechanistic pathways, is a permanently menacing side reaction. [on SciFinder (R)

Metalation/functionalization sequences applied to 2-bromo-3-fluoroquinolines

Mono- and disubstituted 2-bromo-3-fluoroquinolines are readily accessible. They can be converted into the 3-fluoroquinoline-2-carboxylic acids by consecutive halogen/metal permutation and into the 2-bromo-3-fluoroquinoline-4-carboxylic acids by consecutive deprotonation and carboxylation. The latter compds. can be reduced to afford the 3-fluoroquinoline-4-carboxylic acids. The yields are excellent throughout. Rather than introduction of one functional group alternatively at the 2- or 4-position, one may also attach two different functional groups sequentially to both sites. [on SciFinder (R)

Structure–Activity Relationship of Azaindole-Based Glucokinase Activators

7-Azaindole has been identified as a novel bidentate anchor point for allosteric glucokinase activators. A systematic investigation around three principal parts of the new small molecule glucokinase activators led to a robust SAR in agreement with structural data that also helped to assess the conformational flexibility of the allosteric activation site. The increase in glucose uptake resulting from glucokinase activation in hepatocytes in vitro translated into the efficient lowering of glucose levels in vivo with the best compounds

The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models

Avoidance of apoptosis is critical for the development and sustained growth of tumours. The pro-survival protein myeloid cell leukemia 1 (MCL1) is overexpressed in many cancers, but the development of small molecules targeting this protein that are amenable for clinical testing has been challenging. Here we describe S63845, a small molecule that specifically binds with high affinity to the BH3-binding groove of MCL1. Our mechanistic studies demonstrate that S63845 potently kills MCL1-dependent cancer cells, including multiple myeloma, leukaemia and lymphoma cells, by activating the BAX/BAK-dependent mitochondrial apoptotic pathway. In vivo, S63845 shows potent anti-tumour activity with an acceptable safety margin as a single agent in several cancers. Moreover, MCL1 inhibition, either alone or in combination with other anti-cancer drugs, proved effective against several solid cancer-derived cell lines. These results point towards MCL1 as a target for the treatment of a wide range of tumours