Gerald Pattenden

Synthetic studies towards cyclic peptides. Concise synthesis of thiazoline and thiazole containing amino acids

Abstract Concise and efficient syntheses of optically pure thiazoline and thiazole containing amino acids of the constitution (26) and (27), based on simple condensation reactions between cysteine esters and N-protected imino ethers (22) and (25) derived from chiral amino acids, are described. The synthetic procedures are compatible with a range of amino acid side chains and protecting groups, and allow the preparation of a variety of small optically pure peptides i.e. (32) and (34) suitable for elaboration to naturally occurring cyclic peptides e.g. the lissoclinamides (3) and (4).

Total synthesis of (+)-phorboxazole A, a potent cytostatic agent from the sponge Phorbas sp.

A convergent total synthesis of phorboxazole A (1a), from the C(3-19), C(20-27) and C(33-46) fragments 5, 4 and 91, respectively, concentrating on stereocontrolled formation of the bonds at C(2-3), C(19-20) and C(27-28), is described. Although a coupling reaction between a macrolide ketone and the side chain substituted sulfone, at C(27-28) was not successful, a Wadsworth-Emmons olefination involving the oxane methyl ketone 4 and an oxazole produced the oxane 90 which was next coupled to 91 leading to the C(20-46) unit 100. A further coupling of 100 to 71c at C(19-20) then led to 105, ultimately, and the synthesis was completed by a macrocyclisation reaction from 105, at the C(2-3) alkene bond, followed by deprotection of 106.

Total synthesis of thiangazole, a novel inhibitor of HIV-1 from polyangium sp

Abstract A concise total synthesis of the cinnamyl-oxazole substituted tris-thiazoline containing metabolite thiangazole 1 is described.

Enantioselective Synthesis of 2-alkyl substituted cysteines

Treatment of the N-formyl derivative of the thiazolidine adduct derived from (R-cysteine methyl ester hydrochloride and pivalaldehyde, with LDA-DMPU at −90°C, followed by reaction with iodomethane produces the corresponding methylated thiazolidine containing the methyl and t-butyl groups virtually exclusively anti- to one another. Hydrolysis in the presence of 5M HCl then affords (R-2-methylcysteine hydrochloride in excellent yield and enantiomeric purity. A range of other 2-alkyl substituted cysteines of excellent optical purity are prepared by this modification of Seebachs “self-reproduction of chirality” protocol.

Perspectives on the structural and biosynthetic interrelationships between oxygenated furanocembranoids and their polycyclic congeners found in corals

Macrocyclic and polycyclic ‘cembranoid’ diterpenes are one of the most widespread groups of natural products that are found in the marine milieu. The macrocyclic cembranoids are linked to each other by a network of oxygenation processes, which often climax with the formation of furano- and furanobutenolide-based macrocyclic cembranoids commonly found in gorgonian and soft corals. These macrocycles are then prone to oxidative rearrangements, photochemical ring contraction, and transannular cyclisations amongst others, leading to a plethora of novel and architecturally attractive marine metabolites. Although there is a dearth of knowledge about the enzymes that trigger some of the steps in their biosynthesis, speculations are rife. In this personal perspective we have examined many of the structural relationships within oxycembranoids and their relatives isolated from corals. This has allowed us to speculate on the likely biosynthetic interrelationships between structurally similar metabolites, and then propose some likely key carbon-to-carbon bond forming reactions that are followed in vivo in linking macrocyclic cembranoids to their polycyclic congeners. Biomimetic synthesis studies, which vindicate some of the biosynthetic speculations, are interweaved in the discussion.

Cobalt-mediated reactions. A new synthetic approach to β-, γ- and δ-lactams

Abstract Unsaturated carbamylcobalt salophens, e.g . (2), undergo homolytic cleavage (Δ, sunlamp) producing carbamyl radicals, viz (4) which then undergo cyclisation, accompanied by trapping (with CoII or TEMPO) or dehydrocobaltation, leading to functionalised β-, γ-, and δ-lactams e.g . (3), (6), (8), (11), (13) and (16).

Terpenoids and an apocarotenoid from seeds of Bixa orellana

Abstract all - E -Geranylgeraniol is present in the oleoresin from Bixa orellana to the extent of 57%, or approximately 1% of dry seeds which makes B. orellana the richest known source of this important C 20 -terpene alcohol. Other compounds isolated for the first time from seeds of Bixa were the terpenes farnesylacetone, geranylgeranyl octadecanoate and geranylgeranyl formate, δ-tocotrienol, and an apocarotenoid.

Sequential alkoxy radical fragmentation - transannular radical cyclisation - radical ring expansion reactions. A new approach to bicyclo[5.3.0]decanones and to bicyclo[6.3.0]undecanones

Treatment of the unsaturated decanols (7), (9) and (16) with iodosylbenzene diacetate-iodine leads to the formation of intermediate allyloxy radicals viz (1) which undergo fragmentation followed by transannular cyclisation of the resulting carbon centered radicals (2) leading to the bicyclo [5.3.0]decanones [(3), “hydroazulenones”] (Scheme 1). When the iodomethylhydroazulenones (3) (R′=I) are treated with Bu3SnH-AIBN under high dilution, they undergo ring expansion to the isomeric bicyclo[6.3.0]undecanones (4).

A tandem radical macrocyclisation - radical transannulation strategy to the taxane ring system

Abstract Treatment of the iodo-trienone (8 b) with tri-n-butyltin hydride in the presence of AIBN is shown to produce the taxane ring system (11) by way of a tandem radical macrocyclisation - radical transannulation sequence, i.e. (8 b) → (9) → (11) (cf. Scheme 1).

The intramolecular Stille reaction in some target natural product syntheses

A chronological summary of the contributions made by researchers in Nottingham, UK, to developing the scope for the intramolecular Stille reaction in target natural product syntheses, e.g. leinamycin, the virginiamycins, macrolactin A, rhizoxin, the amphidinolides, lophotoxin, and pateamine, is described.