Martin E. Fox

A novel synthesis of 5-hydroxy-2,2-dimethyl-10-propyl-2H-pyrano[2,3-f]chromen-8-one

A concise synthesis of 5-hydroxy-2,2-dimethyl-10-propyl-2H-pyrano[2,3-f]chromen-8-one utilising a novel selective desulfonylation protocol is described. This method provides facile access to a key intermediate for the asymmetric synthesis of calanolide A.

Hydroxylamine-alkyne cyclisations. A new method for the synthesis of cyclic nitrones

Abstract The intramolecular cyclisation of the alkynylhydroxylamines 2 , 5a , 8 , 11 , 16 and 19 provides the cyclic nitrones 3 , 9 , 12 , 17 and 20 in good yields.

N-alkenyl nitrone dipolar cycloaddition routes to piperidines and indolizidines. Part 7. Hydroxylamine–alkyne cyclisations. Formation of cyclic nitrones and application to the synthesis of the proposed structure for (±)-acacialactam

The cyclisation of the alkynylhydroxylamines 2, 13, 14, 19, 27, 34, 39, 46 and 47 to give five-, six- and seven-membered cyclic nitrones is described. A concerted intramolecular ene-like pathway is proposed for the addition of the N–O–H group across the triple bond. Using the nitrone 48 as the starting material, the seven-membered lactam structure 49 proposed for the natural product acacialactam was prepared and was found to be incorrect.

Hydroxylamine-alkyne cyclisations. Synthesis of the seven-membered lactam structure proposed for (±)-acacialactam

Abstract The cyclic nitrone 2 was converted via the key intermediates 7, 12 and 14 into the seven-membered lactam structure 3 proposed for acacialactam. The spectra of the synthetic material differed from that of the product for which an alternative structure 15 is tentatively proposed.

The total synthesis of (±)-indolizidines 235B and 235B′

The total synthesis of racemic indolizidines 235B 1 and 235B′2 is described, in which the key step is the intramolecular thermal cycloaddition of the (Z)-N-alkenylnitrones 10b and 10a, respectively. Cyclisation of the isoxazolidines 12, followed by reductive N–O bond cleavage, epimerisation of the resulting axial hydroxymethyl side chain to the equatorial configuration, and further reduction to a methyl group gave the target molecules. Intramolecular cyclisation of the related nitrone 18, a potential precursor to the solenopsins, was less regioselective, affording a 6:1 mixture of the adducts 19 and 20, which indicates a dependence on the nature of the substituent α to nitrogen.

An Enantioselective Formal Synthesis of Montelukast Sodium

A formal synthesis of the antiasthma drug montelukast sodium is described, wherein the key chiral diol intermediate was accessed with greater convergence of the C-C bond-forming steps as compared to previous routes. Improved synthetic efficiency was achieved by deploying homogeneous metal-based catalysis in two pivotal steps. In the first, a tandem Mizoroki-Heck reaction and double-bond isomerization between a previously known allyl alcohol intermediate and a hindered 2-(2-halophenyl)propan-2-ol secured direct access to the 3-(2-(2-hydroxypropan-2-yl)phenyl)-1-phenylpropan-1-one moiety in the product. In the second step, asymmetric hydrogenation of the ketone functionality in the Mizoroki-Heck reaction product provided a convenient method to introduce the benzylic alcohol chiral center and obtain the desired chiral diol precursor of montelukast sodium. A detailed catalyst screening led to the identification of ((R)-Xyl-BINAP)((R,R)-DPEN)RuCl2 as a catalyst that afforded an enantioselectivity of 99% ee in the hydrogenation step on a multigram lab scale at a molar substrate:catalyst loading of 5000:1.

Nitrone dipolar cycloaddition routes to piperidines and indolizidines. Part 9. Formal synthesis of (−)-pinidine and total synthesis of (−)-histrionicotoxin, (+)-histrionicotoxin and (−)-histrionicotoxin 235A

An intramolecular hydroxylamine-alkyne cyclisation is used for the enantioselective synthesis of the cyclic nitrones 36 and 44. We have demonstrated the use of a novel nitrone protection strategy by cycloaddition of styrene to the cyclic nitrone 44 in the synthesis of the spirocyclic core of the histrionicotoxin family of alkaloids. Deprotection by dipolar cycloreversion of the styrene adduct (the bicyclic isoxazolidine 39) and in situ intramolecular dipolar cycloaddition of a pendant (Z)-α,β-unsaturated nitrile to the intermediate nitrone 50 gave the isoxazolidine 51 in high yield with a surprising degree of regioselectivity compared with the corresponding (Z)-enyne 36. The method is amenable to the synthesis of both enantiomers 51 and 62 of the tricyclic core structure which can be converted by way of the common intermediates (e.g.53 and ent-53) respectively into the natural configuration of alkaloids (−)-histrionicotoxin 1 and (−)-histrionicotoxin 235A 65 as well as the unnatural (+)-histrionicotoxin 63.