Peter Thaddeus Gallagher

An approach to the synthesis of gelsemine: the intramolecular reaction of an allylsilane with an acyliminium ion for the synthesis of one of the quaternary centres

Abstract We describe an efficient synthesis (summarised in Schemes 8 and 10) of an advanced intermediate (34) suitable for the synthesis of gelsemine. The key steps in the synthesis are (i) the Diels-Alder reaction between 1-tetrahydropyranyloxycyclohexa-1,3-diene (10) and methyl β-nitroacrylate (11) giving an adduct (12), in which the chiral centre in the tetrahydropyranyl ring is produced substantially in only one sense, (ii) the rearrangement of a bicyclo [2.2.2] octane (23) into a bicyclo[ 3.2.1] octane (24), where control of which bridge migrates is achieved by a choice of the counterion in the Lewis acid, and (iii) the efficient formation of the quaternary centre by an intramolecular reaction between an allylsilane group and an acyliminium ion (33 → 34).

Synthesis of 2,4,6-trisubstituted pyridines via an olefin cross-metathesis/Heck-cyclisation-elimination sequence

Heck reactions were performed on α,β-unsaturated-δ-sulfonamido intermediates, derived from cross metathesis, to allow the instalment of substituents at the β position. Subsequent one-pot cyclisation/elimination provides an operationally simple, catalytic and convergent synthesis of 2,4,6-trisubstituted pyridines.

An enantiospecific total synthesis of (–)-α-kainic acid

An enantiospecific synthesis of (–)-α-kainic acid (1) from L-aspartic acid (7) has been achieved in which the C-3 to C-4 bond is formed by a stereocontrolled enolate Claisen rearrangement [(13)→(14)] which delivers the correct geometry at the C-3 and C-4 asymmetric centres.

Chiral oximes in asymmetric synthesis. Addition of organometallic reagents to o-(1-phenylethyl) aldoximes

Abstract Addition of Grignard and organolithium reagents to O -(1-phcnylethyl) aldoximes in the presence of boron trifluoride etherate gives secondary hydroxylamines in 21–84% yield with up to 95% diastercomeric excess.

tert-Butyl 3-Carboxyethyl-3-phosphonodiethylpropionate. A Novel Reagent for Stobbe-Like Condensations

Abstract tert-Butyl-3-carboxyethyl-3-phosphonodiethylpropionate was prepared and reacted with a range of aldehydes to give, after hydrolysis, itaconic half esters.

Synthesis of the 2,3,4-trisubstituted indole fragments of nosiheptide and glycothiohexide

Two routes to the protected 4-hydroxymethyl-3-methylindole-2-carboxylate fragment 17 of the thiopeptide antibiotic nosiheptide are described starting from methyl 4-methylindole-2-carboxylate 11, itself prepared in two steps, or from 3-amino-4-chlorobenzoic acid 26. The first route can be adapted to the synthesis of a fragment of the related antibiotic glycothiohexide-alpha, the 3,4-bis(hydroxymethyl)indole-2-carboxylate in which the two hydroxymethyl groups are differentiated as in indole 19 or the lactone 20.

Novel immunosuppressive butenamides

2-[4-(1,1-Dimethylethyl)phenyl]thiophene 12 was carboxylated using butyllithium and carbon dioxide to give 5-[4-(1,1-dimethylethyl)phenyl]thiophene-2-carboxylic acid 13. Conversion of the acid 13 using diphenyl phosphazidate and triethylamine gave 5-[4-(1,1-dimethylethyl)phenyl]thiophene-2-carbonyl azide 14, which was rearranged in toluene at 110 °C with loss of nitrogen to give the isocyanate 15; this in turn was treated with sodium 1-cyanoprop-1-ene 2-oxide 16 in tetrahydrofuran to give 2-cyano-N-{5-[4-(1,1-dimethylethyl)phenyl]thiophen-2-yl}-3-hydroxybut-2-enamide 17. Analogous chemistry has been utilised to synthesize both phenylheteroarylbutenamides and phenylbutenamides which display immunosuppressive activity towards proliferating concanavalin A-stimulated T-lymphocytes.

Expedient syntheses of (+)-cis-(2R,3S)-3-hydroxyproline and (–)-(1S,5S)-2-oxa-6-azabicyclo[3.3.0]octan-3-one (the Geissman–Waiss lactone): formal enantioselective syntheses of (–)-retronecine and related pyrrolizidine alkaloids

Yeast reduction of the keto-proline (5) affords the hydroxyproline derivative (6)(diastereoisomeric excess > 99%cis; enantiomeric excess, e.e., 80%); subsequent hydrolysis and crystallisation gives (+)-cis-(2R,3S)-3-hydroxyproline (7)(93% e.e.) which has been homologated to the bicyclic lactones (10) and (11), precursors of (–)-retronecine, (+)-platynecine, (–)-croalbinecine and related pyrrolizidines.

A new synthesis of Rhein

Abstract A novel synthesis of Rhein ( 2 ), the active metabolite of the anti-osteoarthritic drug Diacetyl Rhein ( 1 ) has been acehived. Key steps include stereospecific olefination of aldehyde 21 with novel phosphonate 28 and the cyclisation of acid 31 to produce anthracene 32 .

A Route to Optically Active Trisubstituted Pyrrolidines using Claisen Rearrangements of Azalactones.

Abstract Chiral trisubstituted pyrrolidines [(13a) and (13b)] are obtained exclusively by Ireland enolate Claisen rearrangement of the corresponding azalactones [(12a) and (12b)].