A convergent strategy towards febrifugine and related compounds.

We report a modular five step synthetic route to the febrifugines that employs 2-(chloromethyl)allyl-trimethylsilane as a conjunctive reagent for the coupling of the piperidine and quinazolinone groups. We also demonstrate the application of a recent Rh-catalyzed quinazolinone synthesis for the facile generation of febrifugine analogs.

Solid-phase synthesis of isoxazoles using vinyl ethers as chameleon catches.

[reaction: see text] Regioselective 1,3-dipolar cycloadditions of supported vinyl ethers R(1)C(=CH(2))O-CH(2)-polymer, prepared by the Tebbe olefination of R(1)CO(2)-CH(2)-polymer, with ethyl cyanoformate N-oxide gave supported isoxazoline derivatives. Release from the support under mild acidic conditions gave the isoxazoles ethyl 5-R(1)-isoxazole-3-carboxylates. Alternatively, further on-resin functionalization of the R(1) substituent using Suzuki coupling reactions and release from the support under acidic conditions gave more structurally diverse isoxazoles.

Oxazole synthesis with minimal purification: synthesis and application of a ROMPgel Tosmic reagent.

[figure: see text] The synthesis of ring opening metathesis, polymer-supported Tosmic reagent 1 is described. This reagent was utilized in the conversion of aldehydes to oxazoles in good yields and purities.

Synthesis and characterization of coronanes: multicyclopropane-fused macrocyclic arrays.

Stepwise macrocyclization of the all syn-trans-1,15-quinquecyclopropanedimethanol (4) with iso- and terephthaloyl chlorides and 4,4'-methanediyl-dibenzoic acid (28) gave the corresponding coronanes 22, 23, and 32. The same protocol was used with all syn-trans-1,21-septecyclopropanedimethanol (5) and 2,3-naphthalenedicarboxylic acid to obtain the macrolide 27. Direct macrocyclization of diol 4 and 1,10-phenanthroline-2,9-dicarbonyl chloride (33) and 2,2'-bipyridine-4,4'-dicarbonyl chloride (35) gave the coronanes 34 and 36, respectively. Ring closing metathesis (RCM) of the diene 42 using Cl2(Cy3P)2Ru=CHPh (48) (Grubbs's catalyst) gave the macrocyclic lactone 45. The structures of coronanes 22, 23, 32, 34, 36, and 45 were confirmed by X-ray crystallographic studies which showed the cyclopropyl chain to adopt very differing conformations throughout the series. Several of the macrocycles have significant free pathways through their ring centers, and in the case of compound 34 there is a water molecule hydrogen bonded within the ring. This latter compound has the potential to act as a chiral ligand to metal centers.

Novel glucocorticoid antedrugs possessing a 17beta-(gamma-lactone) ring.

The chemical synthesis and structure-activity relationships of a novel series of 17beta-glucocorticoid butyrolactones possessing either a 16alpha,17alpha-isopropylidene or -butylidene group are described. The sulfur-linked gamma-lactone group was incorporated onto the 17beta-position of the androstane nucleus via Barton ester decarboxylation and trapping the generated 17-radical with butyrolactone disulfides. The glucocorticoid butyrolactones were hydrolyzed in human plasma by the enzyme paraoxonase to the respective hydroxy acids, which were very weak glucocorticoid agonists. The rate of hydrolysis in plasma was very rapid (t1/2 = 4-5 min) in the case of lactones possessing a sulfur atom in the alpha-position of the butyrolactone group, whereas carbon-linked lactones were stable in plasma. 16alpha,17alpha-Butylidenes were more potent glucocorticoid agonists than the corresponding isopropylidene derivatives. Similarly, 1,4-dien-3-ones were more potent than the corresponding 4-en-3-ones. The butyrolactones linked to the steroidal nucleus via the beta-position were more potent glucocorticoid agonists than those linked through the alpha-position of the lactone. The most potent compounds were also shown to be stable in human lung S9 fraction, showed much lower systemic effects than budesonide in the thymus involution test, and possessed topical antiinflammatory activity in the rat ear edema model.

Tandem ireland-claisen rearrangement ring-closing alkene metathesis in the construction of bicyclic beta-lactam carboxylic esters.

4-Alkenyl-2-azetidinone systems were converted to the corresponding ethyl 2-¿4-alkenyl-2-oxo-1-azetidinyl-4-pentenoates. In addition, 4-(2-propenyl-1-oxy)-, 4-(2-propenyl-1-thio)-, 4-¿N-(2-propenyl)-(4-toluenesulfonyl)- and (3S, 4R)-4-(2-propenyl)-3-¿(1R)-1-(tert-butyldimethylsilyloxy)ethyl-++ +azeti din-2-one were converted into beta-lactam dienes via sequential N-alkylation, Ireland-Claisen ester enolate rearrangement and esterification. Ring-closing metathesis using the Schrock ¿(CF(3))(2)MeCO(2)Mo(=CHCMe(2)Ph)(=NC(6)H(3)-2,6-iso-Pr(2)) (1) or Grubbs Cl(2)(Cy(3)P)(2)Ru=CHPh (2) carbenes gave a series of ¿5.2.0 and ¿6.2.0 bicycles. Subsequent elaboration of the analogous (2R,7R, 8S)-tert-butyl 8-¿(1R)-(tert-butyldimethylsilyloxy)ethyl-1-aza-9-oxobicyclo++ +¿5.2. 0non-4-ene-2-carboxylate (15), via selenation and desilylation, gave (+)-(2S,7R,8S)-tert-butyl 8-¿(1R)-hydroxyethyl-1-aza-9-oxobicyclo¿5.2.0nona-2, 4-diene-2-carboxylate (18), a novel type of bicyclic beta-lactam. Diels-Alder cycloaddition further afforded tetracyclic systems exemplified by tert-butyl (1R,4S,5R,7S)-4-¿(1R)-1-hydroxyethyl-3,9, 11-trioxo-10-phenyl-2,8,10,12-tetraazatetracyclo¿5.5.2.0.(2, 5)0(8, 12)tetradec-13-ene-1-carboxylate (19).

Thrombin inhibitors based on [5,5] trans-fused indane lactams.

A series of trans-fused lactams containing the indane nucleus has been prepared. Compound 19 has much enhanced plasma stability compared with its lactone counterpart and shows appreciable in vitro anticoagulant activity.

The squalestatins: inhibitors of squalene synthase. Enzyme inhibitory activities and in vivo evaluation of C3-modified analogues.

Squalestatin analogues modified at C3 were prepared and evaluated for their ability to inhibit rat liver microsomal squalene synthase in vitro. While the 4,6-dimethyloctenoate ester group at C6 was maintained, a number of modifications to the C3 carboxylic acid were well tolerated. However, in the absence of the C6 ester group, similar modifications to the C3 carboxyl group caused loss of activity. Selected compounds were evaluated for their ability to inhibit cholesterol biosynthesis in vivo in rats 1 and 6 h postadministration. Analogues of squalestatin 1 (S1) modified at C3 were found to possess a shorter duration of effect in vivo which is reflected in their substantially reduced ability to lower serum cholesterol levels in marmosets. Significant cholesterol lowering (up to 62%) for the C3 hydroxymethyl analogue 1b was observed only when this compound was dosed three times a day for 3 days.

The squalestatins: decarboxy and 4-deoxy analogues as potent squalene synthase inhibitors.

Squalestatins without either the hydroxy group at C-4 or the carboxylic acid at C-3 or C-4 were prepared and evaluated for their ability to inhibit rat liver microsomal squalene synthase (SQS) in vitro. These modifications were well tolerated for compounds with the 4,6-dimethyloctenoate ester at C-6 (S1 series). However in analogues without the C-6 ester (H1 series), removal of the C-4 hydroxy group gave compounds with reduced potency, whereas decarboxylation at C-3 resulted in a dramatic loss of SQS inhibitory activity. In comparison with S1 1, C-4 deoxyS1 3 and C-3 decarboxyS1 10 have shorter in vivo durations of action on the inhibition of hepatic cholesterol biosynthesis in rats. C-4 deoxyS1 3 retains good serum cholesterol-lowering ability in marmosets, while C-3 decarboxyS1 10 showed only a marginal effect even at high dose.

Synthesis of benzodioxinopyrroles as selective alpha 2-adrenoceptor antagonists.

A novel series of tetrahydrobenzodioxinopyrroles has been identified as potent and selective alpha 2-adrenoceptor antagonists. Convergent syntheses have been developed that allowed the preparation of analogues and their enantiomers. A compound of particular interest is the 5-fluoro substituted analogue (fluparoxan).

The squalestatins: synthesis and biological activity of some C3-modified analogues; replacement of a carboxylic acid or methyl ester with an isoelectronic heterocyclic functionality.

A series of squalestatins modified at the C3-position with a heterocyclic functionality was prepared and evaluated in vitro as inhibitors of squalene synthase (SQS). Structure-activity relationships for compounds with the 4,6-dimethyloctenoate at C6(S1 analogues) were different from those for analogues lacking the C6 ester (H1 analogues), with a greater dependence on the nature of the C3-substituent for the H1 series. Potent SQS inhibitory activity equivalent to that of H1 is retained by a C3-(tetrazol-5-yl) analogue, i.e., a carboxylic acid mimetic. The C3-methyl ester derivative is 10-fold less active than H1, and SQS inhibitory activity similar to that of the methyl ester was retained only in those C3-heterocycle-substituted H1 analogues for which electrostatic potential maps of the C3-substituent were closely similar to that of a methyl ester.

The squalestatins: novel inhibitors of squalene synthase. Enzyme inhibitory activities and in vivo evaluation of C1-modified analogues.

Squalestatin analogues modified in the C1 side chain were prepared and evaluated for their ability to inhibit rat liver microsomal and Candida squalene synthase (SQS) in vitro. While maintaining the 4,6-dimethyloctenoate or 4,6-dimethyloctanoate ester groups at C6, a number of modifications to the C1 side chain were well tolerated. However, in the absence of the C6 ester group, similar modifications to the C1 side chain caused substantial loss of activity. Compounds were also evaluated for their ability to inhibit cholesterol biosynthesis in vivo in rats and to reduce serum cholesterol levels in marmosets. These studies revealed that compounds with similar SQS inhibitory activities can possess different in vivo durations of action and lipid-lowering abilities.

Inhibitors of cholesterol biosynthesis. 2. 3,5-Dihydroxy-7-(N-pyrrolyl)-6-heptenoates, a novel series of HMG-CoA reductase inhibitors.

A series of 7-[2,3-diaryl-5-(1-methylethyl)-1H-pyrrol-1-yl]-3,5- dihydroxy-6-heptenoates was prepared and evaluated for its ability to inhibit the enzyme HMG-CoA reductase in vitro. Maintaining a 5-(1-methylethyl) substituent found to be optimal in related studies, structure-activity relationships were established for compounds modified at positions 2, 3, and 4 of the pyrrole ring. The 4-fluorophenyl group was preferred at the pyrrole 2-position, while incorporation of a range of substituted phenyl groups and pyridyl substituents at the 3-position provided compounds with equivalent enzyme inhibitory activities and widely different lipophilicities. Pentasubstituted pyrrole 3h was found to have a 10-fold greater potency than lovastatin.

The squalestatins, novel inhibitors of squalene synthase produced by a species of Phoma. II. Structure elucidation.

Three novel fungal metabolites 1-3 isolated from cultures of a Phoma sp. C2932, are potent and selective inhibitors of squalene synthase. Their structures have been determined by a combination of spectroscopic, X-ray crystallographic and chemical methods; these natural products incorporate the highly functionalised bicyclic core, [1S-(1 alpha, 3 alpha, 4 beta, 5 alpha, 6 alpha, 7 beta]-4,6,7-trihydroxy- 2,8-dioxabicyclo-[3.2.1]octane-3,4,5-tricarboxylic acid.