Synthetic and computational studies on the tricarboxylate core of 6,7-dideoxysqualestatin H5 involving a carbonyl ylide cycloaddition–rearrangement

Reaction of diazodiketoesters 17 and 28 with methyl glyoxylate in the presence of catalytic rhodium(II) acetate generates predominantly the 6,8-dioxabicyclo[3.2.1]octanes 29 and 30, respectively. Acid-catalysed rearrangement of the corresponding alcohol 31 favours, at equilibrium, the 2,8-dioxabicyclo[3.2.1]octane skeleton 33 of the squalestatins–zaragozic acids. Force field calculations on the position of the equilibrium gave misleading results. DFT calculations were correct in suggesting that the energy difference between 31 and 33 should be small, but did not always suggest the right major product. Calculation of the NMR spectra of the similar structures could be used to assign the isomers with a high level of confidence

Preparation of tyrosine amide derivatives as Rho-​kinase inhibitors

The invention relates to compds. of formula I and pharmaceutically acceptable salts and solvates thereof (wherein X1 and X2 are independently CH and N; p = 1 - 3; each R when present is halo; R0 and R1 are independently H, halo, CN, etc.; R2 and R3 are independently H, C1-​6 alkyl, C3-​10 cycloalkyl, etc.; R4 and R5 are independently H, C1-​6 alkyl, C1-​6 aminoalkyl, etc.; R6 is H, C1-​6 (halo)​alkyl, etc.;) as Rho kinase inhibitors, methods of prepg. such compds., pharmaceutical compns. contg. them and therapeutic use thereof. Particularly the compds. of the invention may be useful in the treatment of many disorders assocd. with ROCK enzymes mechanisms, such as pulmonary diseases including asthma, chronic obstructive pulmonary disease (COPD)​, idiopathic pulmonary fibrosis (IPF) and pulmonary arterial hypertension (PAH)​. Example compd. II was prepd. by a multistep procedure (procedure given)​. The invention compds. were evaluated for their ROCK1 and ROCK2 inhibitory activities. From the assay, it was detd. that compd. II exhibited Ki value of < 3 nM

A formal synthesis of (-)-pumiliotoxin C

An asymmetric synthesis of an advanced intermediate in the synthesis of natural (-)-pumiliotoxin C has been achieved in six steps and in 61% overall yield employing as the key step a highly diastereoselective lithium amide 1,4-conjugate addition to a dienoic ester derived from (R)-(+)-pulegone

Dyad beads and the combinatorial discovery of catalysts

Dyad beads, bearing both a substrate and a catalyst, were prepared to enable direct split and mix bead based screening for catalysis

Hexadienyloxycarbonyl (Hdoc) - a mild acid labile protecting group for amines

Hexadienyloxycarbonyl is an amine protecting group which can be cleaved with 1% TFA in CH2Cl2. It is stable to Pd(0) and basic conditions and is proposed as a useful alternative to the trityl and Bpoc protecting groups