“…Considering the significance of the functionalized 2-oxabicyclo[3.3.0]octane system, we described in a previous paper the development of an efficient method to obtain, diastereoselectively, the cis isomers of (±)-3-hydroxymethyl-5-carboethoxy-2-oxabicyclo[3.3.0]octane, endo ( 7a ) and exo ( 7b ), exploring the diastereoselective cationic oxidative cyclization of 2-allyl-2-carboethoxycyclopentanol ( 8 ). Next, studies describing the chiral biocatalytic , and chemical diastereoselective reduction , of the ketone carbonyl group of 2-allyl-2-carboethoxycyclopentanone ( 9 ) allowed us to develop strategies to optimize the preparation of the bicyclic synthons 7a,b , which are useful key intermediates in the synthesis of new bioactive compounds, e.g. the prostacyclin analogue 10 and bicyclic PAF antagonists 11a,b (Scheme ).…”
mentioning
confidence: 99%
“…However, a limitation for the application of 7a,b as building blocks for synthetic bioactive substances consists of its enantiopure preparation and analysis. As described above, studies for enantioselective preparation of intermediates 8 and 9 have been recently concluded with success. − 2 …”
Chiral GC separation of (+/-)-2-allyl-2-carboethoxycyclopentanone (9) and the alcohols (+/-)-3-(hydroxymethyl)-5-carboethoxy-2-oxabicyclo[3.3.0]octane (7), (+/-)-2-allyl-2-carboethoxycyclopentanol (8), and their acetylated and trifluoroacetylated derivatives were investigated on three derivatized beta-cyclodextrins (CDs) diluted in SE-54 or 1701-OH: 2,3,6-tri-O-methyl-beta-CD (PMCD); 2,3-di-O-methyl-6-O-(tert-butyldimethylsilyl)-beta-CD (DIMETBCD); 2,3-di-O-acetyl-6-O-(tert-butyldimethylsilyl)-beta-CD (DIACTBCD). The understanding of these chiral separations is extremely relevant, since cyclopentanic and bicyclic cyclopentanic rings are common structural features of many important natural products and new pharmaceutical drugs. In general DIMETBCD diluted in SE-54 showed the best chiral resolution to alcohols 7 and 8 and only DIACTBCD showed enantioselectivity to 9. Hydrogen bonds prediction and dipole moments data were obtained by molecular modeling calculations for 7ab and 8ab and Ac and TFA derivatives. Comparison of these data with the chromatographic parameters for the related compounds were used to explain the differences of their elution orders and diastereo- and enantiomeric separations on the above chiral stationary phases (CSPs). The results suggest that the CSPs enantioselectivities are not affected by the carboethoxy-functionalized cyclopentanic and bicyclic cyclopentanic rings themselves but mainly by the functional group on the other stereogenic center.
“…Considering the significance of the functionalized 2-oxabicyclo[3.3.0]octane system, we described in a previous paper the development of an efficient method to obtain, diastereoselectively, the cis isomers of (±)-3-hydroxymethyl-5-carboethoxy-2-oxabicyclo[3.3.0]octane, endo ( 7a ) and exo ( 7b ), exploring the diastereoselective cationic oxidative cyclization of 2-allyl-2-carboethoxycyclopentanol ( 8 ). Next, studies describing the chiral biocatalytic , and chemical diastereoselective reduction , of the ketone carbonyl group of 2-allyl-2-carboethoxycyclopentanone ( 9 ) allowed us to develop strategies to optimize the preparation of the bicyclic synthons 7a,b , which are useful key intermediates in the synthesis of new bioactive compounds, e.g. the prostacyclin analogue 10 and bicyclic PAF antagonists 11a,b (Scheme ).…”
mentioning
confidence: 99%
“…However, a limitation for the application of 7a,b as building blocks for synthetic bioactive substances consists of its enantiopure preparation and analysis. As described above, studies for enantioselective preparation of intermediates 8 and 9 have been recently concluded with success. − 2 …”
Chiral GC separation of (+/-)-2-allyl-2-carboethoxycyclopentanone (9) and the alcohols (+/-)-3-(hydroxymethyl)-5-carboethoxy-2-oxabicyclo[3.3.0]octane (7), (+/-)-2-allyl-2-carboethoxycyclopentanol (8), and their acetylated and trifluoroacetylated derivatives were investigated on three derivatized beta-cyclodextrins (CDs) diluted in SE-54 or 1701-OH: 2,3,6-tri-O-methyl-beta-CD (PMCD); 2,3-di-O-methyl-6-O-(tert-butyldimethylsilyl)-beta-CD (DIMETBCD); 2,3-di-O-acetyl-6-O-(tert-butyldimethylsilyl)-beta-CD (DIACTBCD). The understanding of these chiral separations is extremely relevant, since cyclopentanic and bicyclic cyclopentanic rings are common structural features of many important natural products and new pharmaceutical drugs. In general DIMETBCD diluted in SE-54 showed the best chiral resolution to alcohols 7 and 8 and only DIACTBCD showed enantioselectivity to 9. Hydrogen bonds prediction and dipole moments data were obtained by molecular modeling calculations for 7ab and 8ab and Ac and TFA derivatives. Comparison of these data with the chromatographic parameters for the related compounds were used to explain the differences of their elution orders and diastereo- and enantiomeric separations on the above chiral stationary phases (CSPs). The results suggest that the CSPs enantioselectivities are not affected by the carboethoxy-functionalized cyclopentanic and bicyclic cyclopentanic rings themselves but mainly by the functional group on the other stereogenic center.
A practical asymmetric synthesis of enantiopure spiroA C H T U N G T R E N N U N G [4,4]nonane-1,6-dione, a valuable precursor for chiral ligand development, is reported. This synthetic strategy includes a kinetic resolution of the readily synthesized ketone precursor with a chiral quaternary carbon center by bioreduction with bakers yeast as the key step, followed by a hydroformylation, oxidation, esterification and Dieckmann cyclization reaction sequence to generate the spiro five-membered ring. It was found that the masking of the b-ketone carbonyl group of enantiopure ethyl 1-allyl-2-oxocyclopentanecarboxylate via formation of a ketal with 1,3-diol derivative is necessary during the process of Dieckmann condensation in order to prevent its racemization under basic conditions. This method allows the gram-scale preparation of both enantiomers of spiroA C H T U N G T R E N N U N G [4,4]nonane-1,6-dione (1) with excellent enantiopurities (up to > 99% ee) in the overall yields of 54% [(R)-1] and 42% [(S)-1], respectively. The practicality of the present synthetic procedure has provided a fundamental platform for the development of spiroA C H T U N G T R E N N U N G [4,4]nonane-1,6-dione-based chiral chemistry.
Medicinal chemists are keen to explore tridimensional compounds, especially when it comes to small molecules. It has already been stressed that the majority of known drugs tend to be flat, whereas natural products tend to be more tridimensional and represent a good source of active compounds. 3D metrics have been implemented and computational descriptors are available to evaluate and prioritize compounds based on their 3D geometry. This is usually done by comparing the saturated carbon atoms in a molecule with the total number of its non‐hydrogen atoms (the Fsp3 value). While this aspect is clear, still there are not enough synthetic tools that support the realization of novel chemotypes that conform to these criteria. Herein we describe a diversity oriented synthesis (DOS) synthetic cascade technology that starts from two simple reagents, and generates highly enriched Fsp3 novel and diverse spiro‐scaffolds with pragmatic synthetic handles (points of diversity). The spiro nature of these scaffolds not only ensures high Fsp3 values but renders the compounds more rigid and therefore more effective in forming precise stereo‐interactions with their potential biological targets. These compounds were also profiled for their drug‐like properties and as potential modulators of the NNMT enzyme.
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