Roger John Taylor

Phospho-transfer catalysis: On the asymmetric hydrophosphonylation of aldehydes

Abstract We report here a precise, in situ 31 P{ 1 H}-NMR method of assaying enantiopurity of α-hydroxyphosphonate esters, the products of the carbonyl hydrophosphonylation (Pudovik) reaction. This method is based upon a diazaphospholidine chiral derivatising agent (CDA) which satisfies all of the criteria for a precise assay; (i) derivatisation of α-hydroxyphosphonate esters is both rapid and clean, (ii) kinetic resolution is absent and (iii) 31 P{ 1 H} chemical shift dispersions are excellent (>5ppm). Calibration of this assay has been achieved by cross-referencing the 31 P{ 1 H}-NMR signals obtained for the CDA-derivatised ester of (MeO) 2 P(O)CHPh(OH) to optical rotation measurements from scalemic material obtained upon lipase catalysed hydrolysis (F–AP 15, Rhizopus oryzae ) of (MeO) 2 P(O)CHPh(OAc). Analysis of NMR chemical shift and coupling parameters for a closely related series of derivatised α-hydroxyphosphonate esters support further configuration assignments on the basis of inference. We report also on the configurational stability of α-hydroxyphosphonate esters in the presence of acids, organonitrogen bases and metal salts. 2 H-labelling and carbonyl crossover experiments reveal that low levels of epimerisation ( α ) of α-hydroxyphosphonate esters is possible under certain conditions of catalysis and within certain limits. A design strategy for the construction of catalyst systems in the Pudovik reaction is outlined based upon a combination of Lewis acidic ( E ) and Lewis basic ( N ) sites. Four types of catalyst are outlined, members of two distinct Classes I and II according to the nature of the acid and base sites, along with our investigations of representative examples of each Class. A variety of Class I.1 systems based on β-amino alcohols (one hydrogen bonding E site and one organonitrogen N site), have been assayed in the model reaction between (MeO) 2 P(O)H and PhCHO. Results suggest that catalysis of the Pudovik reaction is clean and efficient in certain cases but that catalytic activity is strongly dependent upon the nature of the basic ( N ) nitrogen centre. Moreover, only low levels ( E and/or N sites) have been examined to model carbonyl and H-phosphonate binding; an amphoteric receptor based on a pyridine dicarboxamide scaffold has been synthesised and shown to bind benzaldehyde >50% more strongly ( K 11 0.53 mol −1 dm 3 ) than dimethyl-H-phosphonate ( K 11 0.34 mol −1 dm 3 , 298 K) and to catalyse the hydrophosphonylation reaction between these two substrates with a second order rate constant comparable to that of triethylamine (both k 2 5.9×10 −2 mol −1 dm 3 h −1 , 293 K). However, one of the major limitations of this model is that competitive product inhibition dominates after some 15 turnovers (75% completion). Model studies reveal that hydrophosphonylation catalysis via a nitrogen Lewis base is accelerated up to 10-fold upon the introduction of [Zn(OSO 2 CF 3 ) 2 ] as co-catalyst. Consequently, Class II.1 systems employ metal salts [Zn(OSO 2 CF 3 ) 2 ] as Lewis acidic E sites and chiral co-catalysts capable of binding to the metal and also acting as Lewis basic N sites. Such systems catalyse the addition of (MeO) 2 P(O)H to PhCHO cleanly with modest turnover numbers ( E and N sites with more basic N functions and consequently are far more active as catalysts than the other classes. This increased catalytic activity is exemplified by one of the simplest achiral members, diethylzinc which catalyses the 100% chemo- and regioselective addition of (MeO) 2 P(O)H to PhCHO to afford (MeO) 2 P(O)CHPh(OH) with an average turnover rate (over a 1 h reaction time at 298 K) of 115 h −1 compared to ca. 1 h −1 for NEt 3 under analogous conditions. Chiral variants are proposed.

A convergent synthesis of the renin inhibitor CGP60536B

Abstract Pseudoephedrine serves as a dual purpose chiral auxiliary and protecting group in the synthesis of the novel orally active renin inhibitor CGP60536B.

Accurate in situ 31P{1H} assay of enantiopurity in α-hydroxyphosphonate esters using a diazaphospholidine derivatizing agent

Abstract A rapid, convenient and efficient in situ assay of enantiomeric excess in α-hydroxyphosphonate esters is reported exploiting 31 P{ 1 H} NMR analysis of the diastereoisomers formed upon condensation with a phosphorochloridite reagent containing a chiral diazaphospholidine ring. Use of this chiral framework affords chemical shift dispersions > 5 ppm between diastereoisomers. Accurate integrations are thus possible once account is taken of differential n.O.e. effects and spin lattice T 1 relaxation times of the phosphorus nuclei.

A physical properties based approach for the exploration of a 4-hydroxybenzothiazolone series of β2-adrenoceptor agonists as inhaled long-acting bronchodilators

The chiral synthesis of a 4-hydroxybenzothiazolone based series of beta(2)-adrenoceptor agonists is described. Using this methodology a library of N-substituted analogues were prepared for the rapid identification of leads with the potential to be fast onset and long-acting inhaled bronchodilators with improved therapeutic margins. The design of the library to achieve the targeted profile was based upon lipophilicity and metabolism based hypotheses. This approach identified beta-phenethyl, alpha-substituted cyclopentyl and monoterpene N-substituents to be of particular interest for further evaluation, as exemplified by structures 19, 29 and 33, respectively.

Solubility-Driven Optimization of Phosphodiesterase-4 Inhibitors Leading to a Clinical Candidate

The solubility-driven optimization of a series of 1,7-napthyridine phosphodiesterase-4 inhibitors is described. Directed structural changes resulted in increased aqueous solubility, enabling superior pharmacokinetic properties with retention of PDE4 inhibition. A range of potent and orally bioavailable compounds with good in vivo efficacy in animal models of inflammation and reduced emetic potential compared to previously described drugs were synthesized. Compound 2d was taken forward as a clinical candidate for the treatment of COPD.

On the hydrolysis of dimethyl-H-phosphonate. An 18O-labelling and 31P-NMR study

Abstract Quantitative 31P-NMR examination of the hydrolysis of dimethyl-H-phosphonate using 18O-enriched water under base-catalysed conditions supports a mechanism involving exclusive [PO] bond cleavage as opposed to the alternative [CO] bond cleavage.

Discovery and Optimization of 4-(8-(3-Fluorophenyl)-1,7-naphthyridin-6-yl)transcyclohexanecarboxylic Acid, an Improved PDE4 Inhibitor for the Treatment of Chronic Obstructive Pulmonary Disease (COPD).

Herein we describe the optimization of a series of PDE4 inhibitors, with special focus on solubility and pharamcokinetics, to clinical compound 2, 4-(8-(3-fluorophenyl)-1,7-naphthyridin-6-yl)transcyclohexanecarboxylic acid. Although compound 2 produces emesis in humans when given as a single dose, its exemplary pharmacokinetic properties enabled a novel dosing regime comprising multiple escalating doses and the resultant achievement of high plasma drug levels without associated nausea or emesis.

The identification of 7-[(R)-2-((1S,2S)-2-benzyloxycyclopentylamino)-1-hydroxyethyl]-4-hydroxybenzothiazolone as an inhaled long-acting β2-adrenoceptor agonist

The optimisation of two series of 4-hydroxybenzothiazolone derived β2-adrenoceptor agonists, bearing α-substituted cyclopentyl and β-phenethyl amino-substituents, as inhaled long-acting bronchodilators is described. Analogues were selected for synthesis using a lipophilicity based hypothesis to achieve the targeted rapid onset of action in combination with a long duration of action. The profiling of the two series led to identification of the α-substituted cyclopentyl analogue 2 as the optimal compound with a comparable profile to the inhaled once-daily long-acting β2-adrenoceptor agonist indacaterol. On the basis of these data 2 was promoted as the backup development candidate to indacaterol from the Novartis LABA project.