Catalytic asymmetric C-N bond formation: phosphine-catalyzed intra- and intermolecular γ-addition of nitrogen nucleophiles to allenoates and alkynoates.

Pin the amine on the gamma: A new method has been developed for the γ-addition of nitrogen nucleophiles to γ-substituted alkynoates or allenoates through intra- and intermolecular processes that are catalyzed by spirophosphine 1. An asymmetric version of this reaction affords enantioenriched pyrrolidines, indolines, and γ-amino-α,ß-unsaturated carbonyl compounds.

Phosphine-catalyzed enantioselective synthesis of oxygen heterocycles.

Chiral phosphepine 1 catalyzes the transformation of an array of hydroxy-2-alkynoates into saturated oxygen heterocycles with good enantioselectivity. Phenols are also shown to participate in such phosphine-catalyzed cyclizations, including an asymmetric variant. This method provides a new approach to the enantioselective synthesis of tetrahydrofurans, tetrahydropyrans, and dihydrobenzopyrans.

Intramolecular cyclopropanation of unsaturated terminal epoxides and chlorohydrins.

Lithium 2,2,6,6-tetramethylpiperidide (LTMP)-induced intramolecular cyclopropanation of unsaturated terminal epoxides provides an efficient and completely stereoselective entry to bicyclo[3.1.0]hexan-2-ols and bicyclo[4.1.0]heptan-2-ols. Further elaboration of C-5 and C-6 stannyl-substituted bicyclo[3.1.0]hexan-2-ols via Sn-Li exchange/electrophile trapping or Stille coupling generates a range of substituted bicyclic cyclopropanes. An alternative straightforward cyclopropanation protocol using a catalytic amount of 2,2,6,6-tetramethylpiperidine (TMP) allows for a convenient (1 g-7.5 kg) synthesis of bicyclo[3.1.0]hexan-2-ol and other bicyclic adducts. The synthetic utility of this chemistry has been demonstrated in a concise asymmetric synthesis of (+)-beta-cuparenone. The related unsaturated chlorohydrins also undergo intramolecular cyclopropanation via in situ epoxide formation.

N-Tetrahydroquinolinyl, N-quinolinyl and N-isoquinolinyl biaryl carboxamides as antagonists of TRPV1.

Starting from the high throughput screening hit (3), novel N-tetrahydroquinolinyl, N-quinolinyl and N-isoquinolinyl carboxamides have been identified as potent antagonists of the ion channel TRPV1. The N-quinolinylnicotinamide (46) showed excellent potency at human, guinea pig and rat TRPV1, a favourable in vitro DMPK profile and activity in an in vivo model of inflammatory pain.

Intramolecular cyclopropanation of unsaturated terminal epoxides.

Efficient lithium amide-induced intramolecular cyclopropanation of bishomoallylic and trishomoallylic epoxides is described. The methodology is used in an asymmetric synthesis of sabina ketone.

An unsaturated peptidomimetic assembly derived from a carbohydrate.

A strategy has been established for the synthesis of peptidomimetics derived from unsaturated carbohydrates, and exemplified by the use of methyl 2,6-anhydro-7-azido-3,7-deoxy-4,5-O-isopropylidene-D-lyxo-hept-2-enonate 9 as a dipeptide 'monomer' which can be elaborated from either end. Selective reduction of 9 gives a protected pseudodipeptide ester suitable for use as an amino component, and saponification gives an azido acid suitable for use as a carboxyl component. The 'dimer' product of coupling these two components with TBTU can be similarly elaborated at either end to give a 'trimer' and a further cycle of selective reduction and coupling gave a 'tetramer', 17, a pseudo-octapeptide.