Malcolm Chandler

Synthesis of the potent influenza neuraminidase inhibitor 4-guanidino Neu5Ac2en. X-Ray molecular structure of 5-acetamido-4-amino-2,6-anhydro-3,4,5-trideoxy-D-erythro-L-gluco-nononic acid

An efficient and high-yielding synthesis of 4-guanidino Neu5Ac2en, the potent anti-influenza A and B compound, is described. The route exploits a stereospecific introduction of the key nitrogen functionality at C-4 via an oxazoline intermediate. Three different methods for the final-step conversion of the 4-amino into 4-guanidino derivatives are described. To explore the structure–activity relationship in this region of the molecule, a series of substituted guanidino derivatives were synthesized and their activity is described.

Stereocontrolled approaches to substituted tetrahydrofuran and cis-hydrindene derivatives via cyclohexadiene-Fe(CO)3 complexes☆

Oxidative cyclisation of the diol complex (6) followed by removal of Fe(CO)3 gives a single tetrahydrofuran derivative (7). Intramolecular nucleophile reaction of the salt (13) leads to cis-hydrindene derivative (14).

New approach to the synthesis of 6-ketosteroids via organoiron complexes.☆

New Methodology is described for the synthesis 6-ketosteroids, of potential value for the synthesis of β-ecdysone, via tricarbonyl (4-methoxy-1-methylcyclohexadienyl) iron hexafluorophosphate 1.

Organoiron complexes in organic synthesis. A facile TMS mediated decarboxylation of organoiron complexes

The adducts of TMS-ethanol keto esters and cyclohexadienyl-Fe(CO)3 salts are readily decarboxylated on treatment with fluoride ion in good yield.

Approaches to carbocyclic analogues of the potent neuraminidase inhibitor 4-guanidino-Neu5Ac2en. X-Ray molecular structure of N-[(1S,2S,6R)-2-azido-6-benzyloxymethyl-4-formylcyclohex-3-enyl]acetamide

Various approaches using Diels–Alder chemistry have been established for the synthesis of truncated carbocyclic analogues 4 and 6 of 4-guanidino-Neu5Ac2en. In the case of compound 4, elaboration of an initial adduct from Danishefskys diene and the dienophile 7 allowed access to the key enone 26. Methylenation of the carbonyl group and azide-induced opening of an intermediate oxazoline established the required framework regio- and stereo-specifically. Compounds 4 and 6 were found to retain interesting levels of antiviral activity comparable to those shown by their oxygen-containing counterparts.

Organoiron complexes in organic synthesis. Part 6. Dienolonium equivalents: tricarbonyl-[1-alkoxy-2-(1–5-η-4-methoxycyclohexa-2,4dienylium)ethane]iron hexafluorophosphates and related complexes leading to masked 4,4-disubstituted cyclohexenones

The dienolonium equivalents tricarbonyl-[2-methoxy-1-(1–5-η-4-methoxycyclohexa-2,4-dienylium)ethane]iron hexafluorophosphate (2e) and tricarbonyl-[2-methoxy-1-(1–5-η-4-methoxycyclohexa-2,4-dienylium)propane]iron hexafluorophosphate (2i) react with sodiomalononitrile highly regioselectively to give functionalised gem-disubstituted cyclohexadiene complexes which are potential precursors of 4,4-disubstituted cyclohexenones. The reactions of these and related complexes with other carbanions are also reported.

Organoiron complexes in organic synthesis. Part 7. Regio- and stereo-chemistry of ring connection reactions relevant to steroid and terpene synthesis. X-Ray crystal structure determination of tricarbonyl(methyl 1-[2–5-η-4-methoxy-1-methylcyclohexa-2,4-dienyl]-3-hydroxymethyl-3-methyl-2-oxocyclohexanecarboxylate)iron

Reaction of tricarbonyl(1–5-η-4-methoxy-1-methylcyclohexadienylium)iron hexafluorophosphate (1) with enolate anions of derivatives of methyl 2-oxocyclohexanecarboxylate and methyl 1-oxotetralin-2-carboxylate occurs with very high regioselectivity for the methylated dienylium terminus. The structure and stereochemistry of one of the products (18) was determined by X-ray crystallography and found to be in agreement with that derived from spectroscopic data.

Studies related to anthracyclines. Part 1. Some Diels–Alder reactions of 4a,9a-epoxy-4a,9a-dihydroanthracene-1,4,9,10-tetrone

The title compound (5b), prepared by the oxidation of anthracene-1,4,9,10-tetrone (4) with m-chloroperbenzoic acid, undergoes Dieels–Aldr reactions with cyclohexa-1,3-diene, cyclopentadiene, and 2-methylbuta-1,3-diene to give 5a,11a-epoxy-1,4-ethano-1,4,4a,5a,11a,12a-hexahydronaphthacene-5,6,11,12-tetrone (7a), 5a,11 a epoxy-1,4,4a,5a,11 a,12a-hexahydro-1,4-methanonaphthacene-5,6,11,12-tetrone (7b), and 5a,11a-epoxy-1,4,4a,5a,11a,12a-hexahydro-2-methylnaphthacene-5,6,11,12-tetrone (12), respectively. The foregoing cycloadducts, which are isolated as single stereoisomers, are assigned their stereo-structures on the assumption that the cycloaddition reactions occur by way of the least hindered endo-transition states. Reduction of the cycloadducts (7a), (7b), and (12) to give 1,4-ethano-1,4,4a,12a-tetrahydro-6,11-dihydroxynaphthacene-5,16-dione (10a), 1,4,4a,12a-tetrahydro-6,11-dihydroxy-1,4-methanonaphthacene-5,12-dione (10b), and 1,4,4a,12a-tetrahydro-6,11-dihydroxy-2-methylnaphthacene-5,12-dione (13), respectively, is achieved by using zinc in acetic acid or sodium dithionite in aqueous methanol. Lead(IV) acetate in acetic acid converts the dienes (10a), (10b), and (13) into 1,4-ethano-1,4,4a,12a-tetrahydronaphthacene-5,6,11,12-tetrone (9a), 1,4,4a,12a-tetrahydro-1,4-methanonaphthacene-5,6,11,12-tetrone (9b), and 1,4,4a,12a-tetrahydro-2-methylnaphthacene-5,6,11,12-tetrones (14), respectively. Aromatisation of the tetrones (9a), (9b), and (14) occurs in the presence of triethylamine to give the corresponding quinizarin derivatives (8a), (8b), and (15).

New approaches to quassinoid synthesis. Structure of a new Michael adduct

The structure of a new Michael addition product is reported from intermediates in a projected quassinoid synthesis.

Organoiron complexes in organic synthesis. Part 24. Studies in the synthesis and reactivity of 6-exo-substituted cyclohexadienylium(tricarbonyl)iron salts

Tricarbonyliron derivatives of 5-substituted cyclohexa-1,3-dienes bearing a β-hydroxy-group in the substituent undergo thallium(III)-promoted oxidative cyclisation to give tetrahydrobenzofuran(tricarbonyl)iron complexes. The metal can be removed to give the corresponding tetrahydrobenzofuran derivatives, or the complexes may be treated with tetrafluoroboric acid in acetic anhydride to give 6-exo-substituted cyciohexadienylium(tricarbonyl)iron complexes. Reactions of these cationic derivatives with nucleophiles is reported.