A Convergent Synthesis of Enantiopure Open-Chain, Cyclic, and Fluorinated α-Amino Acids.

A radical based synthesis of a broad variety of protected enantiopure α-amino acids, including fluorinated derivatives, is described. The radical addition furnishes naturally latent mercapto-α-amino acids ideally equipped for native chemical ligation.

5-Exo-cyclizations of pentenyliminyl radicals: inversion of the gem-dimethyl effect.

This paper describes how the rates of 5-exo-ring closures of unsaturated iminyl radicals to pyrrolomethyl radicals respond to substituents in the pentenyl chain and at the C=N bond. Benzyl- and acyl oxime esters, as well as dioxime oxalates, were identified as suitable iminyl radical sources for electron paramagnetic resonance (EPR) spectroscopy. Pentenyliminyl radicals with aryl substituents at their C=N bonds, and one with an alkyl substituent at its C=N bond, were studied in solution by steady-state continuous wave EPR spectroscopy. All the pentenyliminyls selectively ring closed in the 5-exo-mode rather than the 6-endo-mode. EPR monitoring of the decay of the 2,2-dimethyl-1-phenylpent-4-enyliminyl radical showed that it underwent bimolecular combination at about the diffusion controlled limit (2kt approximately 3 x 10(8) M(-1) s(-1) at 245 K). The rate constant for 5-exo-ring closure of phenylpentenyliminyl (8.8 x 10(3) s(-1) at 300 K) was a factor of 25 smaller than the rate constant for hex-5-enyl radical cyclization. The rate of cyclization was slower for an iminyl having a Me group at the site of 5-exo-cyclization but faster for an iminyl with an Et substituent at the terminus of the C=C double bond. Surprisingly, the 2,2-dimethyl-1-phenylpent-4-enyliminyl radical, with a bismethyl group in its pentenyl chain, ring closed more slowly than the unsubstituted analogue. DFT computations were in accord with this inverse gem-dimethyl effect and suggested it resulted from steric interaction of the Ph and bis-Me groups which forced the aromatic ring out of the plane of the imine moiety. To check on the role of the Ph substituent, pentenyliminyls lacking this group were sought. A pentenyliminyl radical with an alkyl group in place of the Ph group, and a single Me group in its pentenyl chain, was generated by means of an unsymmetrical dioxime oxalate precursor. The k(c) for this species was a factor of 2.5 larger than k(c) for the original pentenyliminyl, suggesting that the normal positive gem-dimethyl effect does operate for pentenyliminyls lacking the aromatic substituent at the C=N bond. DFT computations also successfully reproduced this trend for model iminyls. It appears that for alkenyliminyl radicals positive or negative gem-dimethyl effects on the cyclization can be induced by appropriate choice of the second substituent on the C=N bond.

Microwave-promoted syntheses of quinazolines and dihydroquinazolines from 2-aminoarylalkanone O-phenyl oximes.

A wide range of biologically active compounds contain the quinazoline ring system. A new free-radical-based method of making functionalized quinazolines is described, which relies on microwave-promoted reactions of O-phenyl oximes with aldehydes. A small set of 2-aminoaryl alkanone O-phenyl oximes was prepared and shown to produce dihydroquinazolines when mixed with an aldehyde in toluene and subjected to microwave heating. When ZnCl(2) was included in the reaction mixture, fully aromatic quinazolines were produced in high yields by a rapid and convenient process. The method worked well with alkyl, aryl, and heterocyclic aldehydes and for a variety of substituents in the benzenic part of the molecule. Similar reactions employing ketones instead of aldehydes were less efficient. Although some dihydroquinazolines did form, they were accompanied by several byproducts. Surprisingly, in each case, one of the byproducts was a quinoline derivative, and a plausible mechanism to account for this rearrangement is proposed.

Thermal rearrangement of indolyl oxime esters to pyridoindoles.

Acyl oximes derived from a variety of indolylalkanones underwent a ring closure sequence during FVP to afford 9H-pyrido[2,3-b]indoles. Unlike UV light promoted reactions of oxime esters, the mechanism is almost certainly not mediated by iminyl radicals but probably involves tautomerism, elimination of acetic acid, and a final electrocyclic ring closure.

From dioxime oxalates to dihydropyrroles and phenanthridines via iminyl radicals.

Dioxime oxalates are useful precursors for the clean generation of iminyl radicals by sensitised UV photolysis and can be adapted for serviceable preparations of 3,4-dihydro-2H-pyrroles and phenanthridines.

Microwave-assisted syntheses of N-heterocycles using alkenone-, alkynone- and aryl-carbonyl O-phenyl oximes: formal synthesis of neocryptolepine.

This research aimed to provide a new and "clean" synthetic method that would enable both known and novel N-heterocycles to be prepared efficiently. O-Phenyl oximes were found to be excellent precursors for iminyl radicals with a variety of acceptor side chains. Dihyropyrroles were made in good yields from O-phenyl oximes containing pent-4-ene acceptors. The analogous process with a hex-5-enyl acceptor did not yield a dihydropyridine, probably because the 6-exo-trig ring closure of the iminyl radical was too slow to compete with H-atom abstraction. The iminyl radical from a precursor with a pent-4-yne type side chain underwent ring closure followed by rearrangement to afford a pyrrole derivative. Suitably substituted iminyl radicals ring closed readily onto aromatic acceptors, thus enabling several polycyclic systems to be accessed. Quinolines were made from 3-phenylpropanones via their O-phenyl oximes. Syntheses of phenanthridines starting from 2-formylbiphenyls were particularly efficient, and this approach enabled the natural product trisphaeridine to be made. Starting from 2-phenylnicotinaldehyde derivatives, ring closures of the derived iminyl radicals onto the phenyl rings yielded benzo[h][1,6]naphthyridines. Similarly, ring closure onto a phenyl ring from a benzothiophene-based iminyl yielded a benzo[b]thieno[2,3-c]quinoline. By way of contrast, iminyl radical ring closure onto pyridine rings was not observed. However, iminyl radicals did cyclize onto indoles, enabling indolopyridines to be prepared. The latter route was exploited in a short formal synthesis of neocryptolepine starting from 2-((1H-indol-3-yl)methyl)cyclohexanone.

2-(Aminoaryl)alkanone O-phenyl oximes: versatile reagents for syntheses of quinazolines.

Microwave irradiations of 2-(aminoaryl)alkanone O-phenyl oximes and carbonyl compounds generate iminyl radicals in company with imines; iminyl on imine ring closure yields dihydroquinazolines or quinazolines when ZnCl2 is included in the mixture.

Microwave-assisted preparations of dihydropyrroles from alkenone O-phenyl oximes.

Microwave irradiation of alkenone O-phenyl oximes produces iminyl radicals that ring close to yield dihydropyrrole derivatives; pyrroles and pyridines can be obtained from related precursors.