Total synthesis of the antitumor antibiotic (±)-streptonigrin: first- and second-generation routes for de novo pyridine formation using ring-closing metathesis.

The total synthesis of (±)-streptonigrin, a potent tetracyclic aminoquinoline-5,8-dione antitumor antibiotic that reached phase II clinical trials in the 1970s, is described. Two routes to construct a key pentasubstituted pyridine fragment are depicted, both relying on ring-closing metathesis but differing in the substitution and complexity of the precursor to cyclization. Both routes are short and high yielding, with the second-generation approach ultimately furnishing (±)-streptonigrin in 14 linear steps and 11% overall yield from inexpensive ethyl glyoxalate.

Tethered aminohydroxylation: synthesis of the β-amino acid of microsclerodermins A and B.

The utility of the tethered aminohydroxylation (TA) has been demonstrated by synthesis of the complex β-amino acid residue of microsclerodermins A and B. The TA provided a regio- and stereoselective functionalization of a complex homoallylic alcohol. The route includes late-stage introduction of the aliphatic side chain via a cuprate addition and cross metathesis, a tactic designed to render the synthesis applicable to other microsclerodermins.

Direct preparation of thiazoles, imidazoles, imidazopyridines and thiazolidines from alkenes.

A range of heterocycles, namely thiazoles, imidazoles, imidazopyridines, thiazolidines and dimethoxyindoles, have been synthesised directly from alkenes via a two-step ketoidoination/cyclisation protocol. The alkene starting materials are themselves readily accessible using many different and well-established approaches, and allow access to a variety of heterocycles with excellent yields and regioselectivity.

The influence of exocyclic stereochemistry on the tethered aminohydroxylation reaction.

A new strategy that employs an exocyclic stereocenter to effect diastereocontrol in the tethered aminohydroxylation (TA) reaction is applied to the stereoselective synthesis of a range of amino alcohols in good to excellent yields, and with anti selectivities of up to 20:1. The influence of the reaction conditions and substrate parameters on the level of diastereocontrol is described. Furthermore, an "inside alkoxy" model is employed to rationalize the sense and degree of stereoselectivity observed in these systems.

Intramolecular hydride addition to pyridinium salts: new routes to enantiopure dihydropyridones.

The transformation of a simple disubstituted pyridine into a pyridinium ion bearing an exocyclic hydroxyl group, protected as a silane, enabled an intramolecular hydride transfer reaction to take place when fluoride was used as a nucleophile. The addition was both regio- and stereoselective and enabled the formation of enantiopure dihydropyridones when enantiopure pyridine derivatives were used in this sequence. The heterocyclic products contain ample functionality for further elaboration reactions and subsequent derivatization.

Recent developments in methodology for the direct oxyamination of olefins.

1,2-Amino alcohols are high-value, versatile functional groups that are found in scores of biologically active molecules and other interesting synthetic targets such as ligands and auxiliaries. Given their prominent position within organic compounds of import, it is no surprise to note that many routes have been developed to access this motif and there are many different starting points from which a synthetic chemist might embark on a synthesis. However, one particular approach stands out from the others, and this is the direct conversion of an alkene to a vicinal amino alcohol derivative (oxyamination).

Synthesis and phytotoxic activity of new pyridones derived from 4-hydroxy-6-methylpyridin-2(1H)-one.

Commercial dehydroacetic acid was converted into 4-hydroxy-6-methylpyridin-2(1H)-one (3), which was then condensed with several aliphatic aldehydes to produce seven new title compounds in variable yields (35-92%). Reaction of 3 with alpha,beta-unsaturated aldehydes resulted in the formation of condensed pyran derivatives 4g' and 4h'. A mechanism is proposed to explain the formation of such compounds.