Showing papers by "Leo A. Paquette published in 2001"

Total asymmetric synthesis of the putative structure of the cytotoxic diterpenoid (-)-sclerophytin a and of the authentic natural sclerophytins A and B.

Abstract: An enantioselective synthetic route to the thermodynamically most stable diastereomer of the structure assigned to sclerophytin A (5) has been realized. The required tricyclic ketone 33 was prepared by sequential Tebbe−Claisen rearrangement of lactones 29 and 30, which originated from the Diels−Alder cycloaddition of Danishefsky's diene to (5S)-5-(d-menthyloxy)-2(5H)-furanone (14). An allyl and a cyano group were introduced into the resulting adduct by means of stereocontrolled allylindation under aqueous Barbier-like conditions and by way of cyanotrimethylsilane, respectively. Following stereocontrolled nucleophilic addition of a methyl group to 33, ring A was elaborated by formation of the silyl enol ether, ytterbium triflate-catalyzed condensation with formaldehyde, O-silylation, and Cu(I)-promoted 1,4-addition of isopropylmagnesium chloride. The superfluous ketone carbonyl was subsequently removed and the second ether bridge introduced by means of oxymercuration chemistry. Only then was the exocyclic ...

1-Oxaspiro[4.4]nonan-6-ones. Synthetic Access via Oxonium Ion Technology, Optical Resolution, and Conversion into Enantiopure Spirocyclic α,β-Butenolides

Abstract: A general approach to the synthesis of enantiomerically pure spirocyclic α,β-butenolides is presented where the fundamental framework is rapidly elaborated by acid- or bromonium ion-induced rearrangement of the carbinol derived by addition of 2-lithio-4,5-dihydrofuran to cyclobutanone. Subsequent resolution of the resulting ketones by either sulfoximine or mandelate acetal technology has been applied effectively. The availability of these building blocks makes possible in turn the acquisition of the enantiomers of dihydrofurans typified by 17, 35, and 38 and lactones such as 25 and 31, as well as the targeted title compounds. Complementary reductions of the early intermediates provide the added advantage that the α- and β-stereoisomeric carbinol series can be obtained on demand. These capabilities have been coordinated to allow the crafting of any member of the series in relatively few steps.

Intercalation of Multiple Carbon Atoms between the Carbonyls of α-Diketones

Abstract: The reaction of open-chain or cyclic α-diketones with specific ω-alkenyl organometallics leads readily under the proper conditions to 1,2-diols bonded to terminal olefinic chains. With 1-phenyl-1,2-propanedione, biacetyl, and cyclohexane-1,2-dione, allylindation in aqueous THF proceeds readily at both adjacent carbonyls. For cyclododecane-1,2-dione, recourse must be made to allylmagnesium bromide for completing the second-stage condensation. Grignard reagents have also served well as reactants for biacetyl monoadducts. In contrast, monoallylated camphorquinone is reluctant to couple to Grignard reagents and reacts only when Barbier-type alkyllithium reactions are applied. The ring closing metatheses of these products have been examined. Where six-membered ring formation operates, cyclization can be performed directly on diols. When larger rings are involved, the diols will react only if structural preorganization capable of facilitating mutual approach of the two double bonds is at play. For this purpose,...

Selective lithium ion binding involving inositol-based tris(spirotetrahydrofuranyl) ionophores: formation of a rodlike supramolecular ionic polymer from a homoditopic dimer.

Abstract: The stereoselective replacement of all three hydroxyl groups in myo-inositol orthoformate by spirotetrahydrofuran rings in that manner which projects the C−O bonds in the molecular interior has been examined. The heterocyclic components were introduced sequentially, a protocol that demonstrated the utility of precomplexation to LiClO4 as a stereocontrol tactic. The capability of 3 to coordinate to alkali metal ions was quantified. The conformationally restricted nature of this ligand conveys high selectivity for binding to lithium ion. Beyond that, the ionophore prefers to form 2:1 complexes with Li+ and exhibits little tendency for 1:1 stoichiometry. These properties are shared by the “dimer” 36, in which two building blocks of type 3 have been conjoined by a 1,3-butadiyne tether positioned at the ortho ester terminus. This bifacial ligand reacts with one equivalent of LiClO4 or LiBF4 to form rodlike ionic polymers. Alternative recourse to lithium picrate results in production of the doubly capped homodi...

Direct Synthesis of Previously Inaccessible Bridgehead Azabicyclics by Intramolecular Cyclization of α-Sulfonamido and α-Sulfonimido Radicals

Abstract: Syntheses of the first bridgehead sultams and the only known bridgehead disulfonimide are described. Both approaches capitalize on the electrophilicity of α-sulfonyl radicals and their propensity to undergo intramolecular ring closure. Where double bonds are concerned, 5-exo and 6-exo pathways operate preferentially as long as structural strain is not excessive. When the reaction center is a carbon−carbon triple bond, the first cyclization gives rise to vinyl radicals that hold sufficient reactivity to capture solvent benzene. In the case of 45, this sequential reaction leads importantly to the introduction of a styrene functionality sufficiently activated to allow a second ring closure to be kinetically feasible. The solid-state structural features of 12 and 17 have been elucidated by X-ray crystallographic methods. Despite key differences from the norm in the alignment of the nitrogen lone pair relative to the adjacent sulfonyl groups, these compounds exhibit good hydrolytic stability. For 13, generatio...

The sclerophytin A adventure.

Abstract: The structural designation A originally made by Sharma and Alam to sclerophytin A was considered to be ambiguous and so notably strained relative to B that the latter was targeted for de novo synthesis (Scheme 1). Our two successful routes began with (5S)-(d-menthyloxy)-2(5H)-furanone and involved the application of cycloaddition, Claisen ring expansion, transannular oxymercuration, and 1,2-carbonyl transposition tactics to arrive at B. It was immediately apparent from polarity considerations and spectroscopic data that the antileukemic marine metabolite in question was in need of more deep-seated structural revision. Following close re-examination of an acquired authentic sample by advanced NMR techniques, the strong inference was made that sclerophytin A actually lacked a second oxygen bridge and was in reality the triol C. This conclusion was unequivocally confirmed by diverting an advanced intermediate generated earlier into a short sequence beginning with regiocontrolled dihydroxylation and terminating with configurational inversion at the secondary carbinol center. The status of other members of this series is also presented. © 2001 John Wiley & Sons, Inc. and The Japan Chemical Journal Forum Chem Rec 1:311–320, 2001. 1

1-Oxaspiro[4.4]nonan-6-ones. Synthetic Access via Oxonium Ion Technology, Optical Resolution, and Conversion into Enantiopure Spirocyclic α,β-Butenolides.

Abstract: A general approach to the synthesis of enantiomerically pure spirocyclic α,β-butenolides is presented where the fundamental framework is rapidly elaborated by acid- or bromonium ion-induced rearrangement of the carbinol derived by addition of 2-lithio-4,5-dihydrofuran to cyclobutanone. Subsequent resolution of the resulting ketones by either sulfoximine or mandelate acetal technology has been applied effectively. The availability of these building blocks makes possible in turn the acquisition of the enantiomers of dihydrofurans typified by 17, 35, and 38 and lactones such as 25 and 31, as well as the targeted title compounds. Complementary reductions of the early intermediates provide the added advantage that the α- and β-stereoisomeric carbinol series can be obtained on demand. These capabilities have been coordinated to allow the crafting of any member of the series in relatively few steps.

Selective Lithium Ion Binding Involving Inositol‐Based Tris(spirotetrahydrofuranyl) Ionophores: Formation of a Rodlike Supramolecular Ionic Polymer from a Homoditopic Dimer.

Abstract: The stereoselective replacement of all three hydroxyl groups in myo-inositol orthoformate by spirotetrahydrofuran rings in that manner which projects the C−O bonds in the molecular interior has been examined. The heterocyclic components were introduced sequentially, a protocol that demonstrated the utility of precomplexation to LiClO4 as a stereocontrol tactic. The capability of 3 to coordinate to alkali metal ions was quantified. The conformationally restricted nature of this ligand conveys high selectivity for binding to lithium ion. Beyond that, the ionophore prefers to form 2:1 complexes with Li+ and exhibits little tendency for 1:1 stoichiometry. These properties are shared by the “dimer” 36, in which two building blocks of type 3 have been conjoined by a 1,3-butadiyne tether positioned at the ortho ester terminus. This bifacial ligand reacts with one equivalent of LiClO4 or LiBF4 to form rodlike ionic polymers. Alternative recourse to lithium picrate results in production of the doubly capped homodi...

Convergent Regiodirected Assembly of 2,3-Disubstituted Furans.

Abstract: The conjugate addition of organocopper reagents to alpha, beta-unsaturated enones results in the regiospecific generation of enolate anions, which can be made to undergo the aldol reaction with (tetrahydropyranyloxy)acetaldehyde under zinc chloride catalysis. Treatment of the resulting product with p-toluenesulfonic acid in THF affords the targeted 2,3-disubstituted furan.

Direct Synthesis of Previously Inaccessible Bridgehead Azabicyclics by Intramolecular Cyclization of α‐Sulfonamido and α‐Sulfonimido Radicals.

Abstract: Syntheses of the first bridgehead sultams and the only known bridgehead disulfonimide are described. Both approaches capitalize on the electrophilicity of α-sulfonyl radicals and their propensity to undergo intramolecular ring closure. Where double bonds are concerned, 5-exo and 6-exo pathways operate preferentially as long as structural strain is not excessive. When the reaction center is a carbon−carbon triple bond, the first cyclization gives rise to vinyl radicals that hold sufficient reactivity to capture solvent benzene. In the case of 45, this sequential reaction leads importantly to the introduction of a styrene functionality sufficiently activated to allow a second ring closure to be kinetically feasible. The solid-state structural features of 12 and 17 have been elucidated by X-ray crystallographic methods. Despite key differences from the norm in the alignment of the nitrogen lone pair relative to the adjacent sulfonyl groups, these compounds exhibit good hydrolytic stability. For 13, generatio...