Michael G. Lester

Structurally simplified squalestatins: A convenient route to a 67-unsubstituted derivative

Abstract The squalestatin 1 , has been converted into the 6,7-unsubstituted analogue, 3 , via inversion of the alcohol at C7, selective removal of the α,β-unsaturated ester at C6 followed by a Corey-Hopkins deoxygenation of the generated 6 R ,7 S -diol.

Structurally simplified squalestatins : monocyclic 1,3-dioxane analogues

Abstract Monocyclic analogues of squalestatin 1 based on a 1,3-dioxane ring were prepared and evaluated for their ability to inhibit squalene synthase in vitro. The compound 16a possessing a 4,6-dimethyloctenoyloxymethyl group at C4 and a carboxamide at C2 showed similar inhibitory activity to 1.

The squalestatins: cleavage of the bicyclic core via the novel 6,8-dioxabicyclo[3.2.1]octane ring system

Squalestatin S1 1 has been converted into its 4,7-bis(2-methoxyethoxymethyl)ether 4,5-dimethyl ester 11 and thence to its 3-(tert-butoxycarbonyl)amino derivative 12via a Schmidt degradation. Acid-catalysed hydrolysis of 12 brought about a molecular rearrangement of the 2,8-dioxa- to the novel 6,8-dioxa-bicyclo[3.2.1]octane ring system 3. Oxidation of 3 followed by methanolysis gave the novel spiroketal 17. Treatment of 3 with trimethyl phosphonoacetate gave the acyclic derivative 18.

The squalestatins: effects of changes at the allylic centre in the C1 sidechain

Abstract The C4′ acetoxy group in squalestatin 2a has been replaced by alkoxy, acyloxy and acetamido groups. The ethers 5b, 5c, 5e and 5g retain SQS inhibitory activity equivalent to that of 2a and are metabolically more stable. All other compounds tested are significantly less active.

Synthesis of some aromatic prostaglandin analogues. Part 1

7-[2-(3-Hydroxyoct-1-enyl)-3,5-dimethoxyphenyl)heptanoic acid (4) has been prepared in six steps from 3,5-dimethoxybenzaldehyde.

NOVEL SQUALESTATIN DERIVATIVES ARISING FROM REACTIONS AT THE ALLYLIC CENTRE OF THE C1-SIDE CHAIN

Reaction of 2 with Ac2O–TMSOTf gives the triacetate 5, which on further reaction gives isomer 6, arising from an allylic rearrangement, whereas reaction of 2 with Et3SiH–TMSOTf gives tricycle 7 arising from addition of the C7-OH to the allylic centre. Attempted ionic reduction of triacetate 5 gives benzocycloheptene 8, arising from Friedel-Crafts alkylation of the phenyl ring by the allylic centre. Similar alkylation has been obtained with analogue 9, and with the trifluoromethanesulfonate ester of the allylic alcohol 13. Attempted ionic reduction of 17, lacking the allylic centre, gives 20 arising from ester hydrolysis at C4.