(1RS,2SR,5SR)-9-Benzyl-2-[(1RS)-1-hy­droxy­benz­yl]-9-aza­bicyclo­[3.3.1]nonan-3-one from synchrotron data

In the crystal structure of the racemic title compound, C22H25NO2, solved and refined against sychrotron diffraction data, the hy­droxy group and the carbonyl O atom participate in the formation of O—H⋯O hydrogen bonds between pairs of enanti­omers related by a crystallographic centre of symmetry

An Investigation of the Enolization and Isomeric Products Distribution in the Water Promoted Aldol Reaction of Tropinone and Granatanone

The exo,anti/exo,syn-diastereoselectivity of water promoted direct aldol reactions of tropinone and granatanone (pseudopelletierine) is strongly dependent on the amount of water added and aromatic aldehyde used. DFT methods were applied to calculate the free energies of tropinone and granatanone enols, transition states, and isomeric aldol products. A theoretical model was verified by comparison of results from several DFT methods and functionals with experiments. The 6-31g(d)/CPCM method proved most suited to the problem, although all methods tested predicted similar trends. Explicit inclusion of a water molecule bonded to the amino ketones resulted in increased stability of the enol forms. The dependence of the anti/syn-diastereoselectivity on the amount of water used may be rationalized on the basis of change in the polarity of the reaction medium. The predicted stabilities of competing products agreed with experimental results supporting the notion of thermodynamic control. The isomeric products distributions for the aldol reaction of several aromatic aldehydes in solventless (neat) conditions were accurately calculated from free energies of the aldol addition step in the gas phase using B3LYP/6-31g(d) method and in aqueous conditions using the CPCM-B3LYP/6-31g(d) model. Our methodology can be useful for predicting the outcome of this type of aldol reactions

Facile access to a heterocyclic, sp3-rich chemical scaffold via a tandem condensation/intramolecular nitrone–alkene [3+2] cycloaddition strategy

A heterocyclic, sp3-rich chemical scaffold was synthesised in just 6 steps via a highly regio- and diastereo-selective tandem nitrone formation/intramolecular nitrone–alkene [3+2] cycloaddition reaction. A library of 543 lead-like compounds based on the scaffold core has been produced

Naturally Inspired Peptide Leads: Alanine Scanning Reveals an Actin-Targeting Thiazole Analogue of Bisebromoamide

Systematic alanine scanning of the linear peptide bisebromoamide (BBA), isolated from a marine cyanobacterium, was enabled by solid‐phase peptide synthesis of thiazole analogues. The analogues have comparable cytotoxicity (nanomolar) to that of BBA, and cellular morphology assays indicated that they target the actin cytoskeleton. Pathway inhibition in human colon tumour (HCT116) cells was explored by reverse phase protein array (RPPA) analysis, which showed a dose‐dependent response in IRS‐1 expression. Alanine scanning reveals a structural dependence to the cytotoxicity, actin targeting and pathway inhibition, and allows a new readily synthesised lead to be proposed

EPC synthesis of tropane alkaloids via enantioselective deprotonation

This dissertation deals with the application of enantiotopic group selective reactions to the synthesis of enantiomerically pure compounds (EPC). Deprotonation of tropinone with optically pure, chiral lithium amides was studied. The effects of additives such as lithium chlorids and other lithium salts (LiBr, Lil, LiClO4) on enantioselectivity of deprotonation of tropinone with chiral lithium amides were investigated. Increased selectivity was observed upon addition of lithium chloride in all tested deprotonation reactions. During these studies enantioselectivity as high as 97% ee was achieved in reactions of tropinone with chiral lithium amides prepared from $(S,S)$-$(-)$-$N,N$-bis(1-phenylethyl)amine hydrochloride and $(R)$-1-((2,2-dimethylpropyl)amino-2-phenylethyl) piperidine. Two different protocols for the highly enantioselective deprotonation of tropinone were employed in EPC syntheses of tropane alkaloids: chalcostrobamine, darlingine, isobellendine, knightinol, alkaloid KD-B, physoperuvine, 7β-acetoxy-3α-tigloyloxytropane, and 3$\alpha,7\beta$-diacetoxytropane. The products were obtained in good overall yields and in high optical purity (91-97%). The presented work shows that the enantioselective deprotonation of cyclic Cs symmetrical ketones is an attractive approach to the synthesis of enantiomerically pure natural products