Showing papers by "Leo A. Paquette published in 1997"

Total Synthesis of (+)-Epoxydictymene. Application of Alkoxy-Directed Cyclization to Diterpenoid Construction

Abstract: An enantioselective synthesis of (+)-epoxydictymene (1) is reported. Condensation of the enantiopure aldehydo ester 5 with (S)-3-isopropylcyclopentenyllithium proceeds selectively to afford 13. Once this lactone was methylenated with the Tebbe reagent, the newly formed allyl vinyl ether was induced into Claisen rearrangement under catalysis with triisobutylaluminum. Sequential hydroboration−oxidation of the resulting dicyclopentacyclooctenone derivative was followed by angular methylation and deoxygenation of the carbonyl functionality. Following epimerization at C-11, an α-hydroxyl was introduced regio- and stereoselectively. Some functional group manipulation led to 57 and 58, both of which underwent efficient cyclization to deliver the complete framework of the target molecule when irradiated with visible light in cyclohexane solution containing iodosobenzene diacetate and iodine. The generality of this key reaction, which efficiently constructs the strained oxabicyclo[3.3.0]octane subunit of 1, is dem...

Experimental Test of Setting Three Contiguous Stereogenic Centers in Water. Diastereoselective Coupling of Geometrically Biased Allylic Bromides to α-Oxy Aldehydes with Indium

Abstract: Indium-promoted additions of (Z)-2-(bromomethyl)-2-butenoate to several α-(tert-butyldimethylsiloxy) and α-(benzyloxy) aldehydes in water have been examined in order to assess the direction and sense of asymmetric induction in these coupling reactions. High levels of the 3,4-syn;4,5-anti diastereomers were produced, reflecting the promising synthetic potential of this chemistry. This stereodifferentiation has been attributed to the strong geometric bias exercised by this allylindium reagent and adherence to a Felkin−Ahn transition-state alignment. Support for this interpretation was gained by comparing the fate of (E)-cinnamyl bromide under comparable circumstances. In this case, the 3,4-anti;4,5-anti diastereomer predominated as expected.

Single Stereodifferentiation Associated with Carbon Atom Insertion during the Oxonium Ion-Initiated Pinacol Rearrangement of Dihydrofuranyl and Dihydropyranyl Carbinols

Abstract: The stereoselectivity of the acid-promoted rearrangement of dihydrofuranyl and dihydropyranyl carbinols to spirocyclic ketones has been examined. These kinetically controlled isomerizations result in the ring expansion of the hydroxyl-substituted ring with generation of a newly stereogenic spirocyclic carbon atom. All of the adducts formed from several 4,5-dihydrofurans and cyclobutanone, cyclopentanone, and 2,2-dimethylcyclopentanone proved to be reactive. Of the 5,6-dihydropyrans examined, only the cyclobutanone adducts were sufficiently reactive to warrant study. The product distributions arising from the furanoid systems were characterized by modest discrimination in most cases. The more stereodifferentiating pyranoid systems show product distributions as high as 30:1. These results are explained in terms of transition state geometries (conformationally more flexible in the five-membered examples) while also taking into account the principle of stereoelectronic control.

The Squarate Ester−Polyquinane Connection. An Analysis of the Capacity of Achiral Divinyl Adducts To Rearrange Spontaneously to Polycyclic Networks Housing Multiple Stereogenic Centers

Abstract: The condensation of diisopropyl squarate and related cyclobutene-1,2-diones with 2 equiv of the same alkenyl anion or 1 equiv each of two different alkenyl anions can be a very effective method for...

Practical Synthesis of Spirocyclic Bis-C,C-glycosides. Mechanistic Models in Explanation of Rearrangement Stereoselectivity and the Bifurcation of Reaction Pathways

Abstract: The susceptibility of glycal-derived carbinols to acid-catalyzed ring expansion is described. In the systems prepared from cyclopentanone, Ferrier ionization precedes the pinacol-like Wagner−Meerwein shift, thermodynamic control operates, and high stereoselectivity is seen if a C(6) substituent is present. In contrast, the adducts to cyclobutanone exhibit release of ring strain under kinetically controlled conditions and intercept the oxonium species reversibly formed via direct proton transfer. The results show that the substituents positioned on the glycal ring have a pronounced influence on whether a chair-like or twist-boat transition state geometry is adopted primarily. The composite reaction profiles reveal for the first time the fundamental importance of exothermicity and of substitution in these spiro glycosidation reactions. Since optical activity is preserved in all instances, the utility of this chemistry for the synthesis of bis-C,C-glycosides and more complex oxacyclics appears promising.

Factors Influencing 1,4-Asymmetric Induction during Indium-Promoted Coupling of Oxygen-Substituted Allylic Bromides to Aldehydes in Aqueous Solution.

Abstract: The preparation and indium-promoted aldehyde addition reactions of a series of 3-substituted 3-oxy-1-bromo-2-methylidenepropanes under aqueous conditions are described. The (tert-butyldimethylsilyl)oxy derivatives 4a-d are the most diastereoselective of this group of reagents, giving rise to levels of syn-1,4-asymmetric induction in the range of 87-99%. Interestingly, syn stereoselectivity is eroded and reactions proceed more rapidly when the steric bulk of the oxygen substituent is reduced as in the hydroxy and methoxy derivatives. This dropoff in pi-facial differentiation with kinetic acceleration is attributed to the operation of chelation effects during oxidative addition of the metal into the carbon-bromine bond, but not during the coupling stage. Once the aldehyde enters into the coordination sphere of the indium, internal chelation to the proximal oxygen is disrupted and conformational restrictions are released. These effects, in combination with the absence of a powerful steric control element in the latter examples, permit competitive passage via syn and anti transition states.

First synthesis of cytotoxic 8,9-secokaurene diterpenoids. an enantioselective route to (-)-o-methylshikoccin and (+)-o-methylepoxyshikoccin

Abstract: A practical route for the total synthesis of 8,9-secokaurene diterpenes is described. The central step is the [3.3]sigmatropic rearrangement of spirocyclic intermediates such as 35, 40, and 41. All three compounds must necessarily respond identically to properly install the absolute configuration of the bridgehead methine carbon. The total synthesis of (−)-O-methylshikoccin (2b) was realized in 8% overall yield from the Wieland−Miescher ketone 9. Its naturally occurring epoxide 47 was prepared with comparable efficiency. The preparative route developed herein should provide a general entry into this important class of diterpenoids.

Realization of Complete Regiochemical Control during the Conversion of Squarate Esters into Complex Linear and Angular Polyquinanes. The Consequences of Incorporating a Leaving Group into One of the Alkenyllithium Reactants

Abstract: A useful method is presented for controlling whether linear or angular triquinanes are formed during a reaction cascade initiated by the 2-fold addition of alkenyl anions to diisopropyl squarate. The key feature of the process involves the incorporation of a leaving group into one of the original nucleophilic reagents. Placement of the nucleofuge within a cyclic anion leads ultimately to formation of a linear product. Extracyclic and intracyclic options are possible, with preference given to the better leaving group when a competitive situation exists. When the leaving group is incorporated into an acyclic component, angular triquinanes result instead. Several other aspects of this impressive scaffolding scheme are detailed.

Utilization of the Phenylthio Substituent as a Multipurpose Synthetic Tool. Direct Application to the Enantioselective Construction of (-)-Salsolene Oxide.

Abstract: The architecturally unprecedented sesquiterpene (-)-salsolene oxide (1) has been synthesized in enantioselective fashion from (R)-(-)-carvone. Generation of the phenylthio-substituted vinyl ketene 4 is followed by intramolecular cyclization to the functionalized cyclobutanone 9. Vinyllithium addition to this intermediate proceeds in that stereocontrolled fashion which enables oxy-Cope rearrangement to operate readily under conditions of kinetic control. After hydride reduction, the desulfurization of 16 proceeds with inversion of bridgehead olefin geometry to deliver 17. This access route to the thermodynamically more stable geometric arrangement permits direct entry to 1. Attention is called specifically to the critical 3-fold function played by a phenylthio group introduced at the outset.

Total Synthesis of (+)-Epoxydictymene. Application of Alkoxy-Directed Cyclization to Diterpenoid Construction.

Abstract: An enantioselective synthesis of (+)-epoxydictymene (1) is reported. Condensation of the enantiopure aldehydo ester 5 with (S)-3-isopropylcyclopentenyllithium proceeds selectively to afford 13. Once this lactone was methylenated with the Tebbe reagent, the newly formed allyl vinyl ether was induced into Claisen rearrangement under catalysis with triisobutylaluminum. Sequential hydroboration−oxidation of the resulting dicyclopentacyclooctenone derivative was followed by angular methylation and deoxygenation of the carbonyl functionality. Following epimerization at C-11, an α-hydroxyl was introduced regio- and stereoselectively. Some functional group manipulation led to 57 and 58, both of which underwent efficient cyclization to deliver the complete framework of the target molecule when irradiated with visible light in cyclohexane solution containing iodosobenzene diacetate and iodine. The generality of this key reaction, which efficiently constructs the strained oxabicyclo[3.3.0]octane subunit of 1, is dem...

The Squarate Ester-Polyquinane Connection. An Analysis of the Capacity of Achiral Divinyl Adducts to Rearrange Spontaneously to Polycyclic Networks Housing Multiple Stereogenic Centers.

Abstract: The condensation of diisopropyl squarate and related cyclobutene-1,2-diones with 2 equiv of the same alkenyl anion or 1 equiv each of two different alkenyl anions can be a very effective method for...

Single Stereodifferentiation Associated with Carbon Atom Insertion During the Oxonium Ion-Initiated Pinacol Rearrangement of Dihydrofuranyl and Dihydropyranyl Carbinols.

Abstract: The stereoselectivity of the acid-promoted rearrangement of dihydrofuranyl and dihydropyranyl carbinols to spirocyclic ketones has been examined. These kinetically controlled isomerizations result in the ring expansion of the hydroxyl-substituted ring with generation of a newly stereogenic spirocyclic carbon atom. All of the adducts formed from several 4,5-dihydrofurans and cyclobutanone, cyclopentanone, and 2,2-dimethylcyclopentanone proved to be reactive. Of the 5,6-dihydropyrans examined, only the cyclobutanone adducts were sufficiently reactive to warrant study. The product distributions arising from the furanoid systems were characterized by modest discrimination in most cases. The more stereodifferentiating pyranoid systems show product distributions as high as 30:1. These results are explained in terms of transition state geometries (conformationally more flexible in the five-membered examples) while also taking into account the principle of stereoelectronic control.

Realization of Complete Regiochemical Control During the Conversion of Squarate Esters into Complex Linear and Angular Polyquinanes. The Consequences of Incorporating a Leaving Group into One of the Alkenyllithium Reactants.

Abstract: A useful method is presented for controlling whether linear or angular triquinanes are formed during a reaction cascade initiated by the 2-fold addition of alkenyl anions to diisopropyl squarate. The key feature of the process involves the incorporation of a leaving group into one of the original nucleophilic reagents. Placement of the nucleofuge within a cyclic anion leads ultimately to formation of a linear product. Extracyclic and intracyclic options are possible, with preference given to the better leaving group when a competitive situation exists. When the leaving group is incorporated into an acyclic component, angular triquinanes result instead. Several other aspects of this impressive scaffolding scheme are detailed.

Stereocontrolled Synthesis of ent-Grindelic Acid. A Useful Example of Diastereofacial Guidance in an Oxonium Ion-Initiated Pinacolic Ring Expansion.

Abstract: An enantioselective synthesis of (+)-grindelic acid is described, confirming that the dextrorotatory enantiomer is antipodal to the natural diterpenoid. The optically pure bicyclic ketone 5 representing the AB ring system is constructed from the levorotatory Wieland−Miescher ketone and must therefore possess the absolute configuration shown. Coupling of 5 with the 5-lithio derivative of optically active 2,3-dihydrofuran 3 derived from (R)-(−)-linalool was effected for the purpose of realizing acid-catalyzed rearrangement with generation of the appropriate spirocyclic framework. This key step is highly stereocontrolled, leading predominantly to 7. Once the advanced intermediate 15 is available in this fashion, its subsequent exposure to oxidation and dehydration steps led to the target molecule. The synthesis demonstrates unequivocally that natural (−)-grindelic acid is a true labdane diterpenoid.

Practical Synthesis of Spirocyclic Bis-C,C-glycosides. Mechanistic Models in Explanation of Rearrangement Stereoselectivity and the Bifurcation of Reaction Pathways.

Abstract: The susceptibility of glycal-derived carbinols to acid-catalyzed ring expansion is described. In the systems prepared from cyclopentanone, Ferrier ionization precedes the pinacol-like Wagner−Meerwein shift, thermodynamic control operates, and high stereoselectivity is seen if a C(6) substituent is present. In contrast, the adducts to cyclobutanone exhibit release of ring strain under kinetically controlled conditions and intercept the oxonium species reversibly formed via direct proton transfer. The results show that the substituents positioned on the glycal ring have a pronounced influence on whether a chair-like or twist-boat transition state geometry is adopted primarily. The composite reaction profiles reveal for the first time the fundamental importance of exothermicity and of substitution in these spiro glycosidation reactions. Since optical activity is preserved in all instances, the utility of this chemistry for the synthesis of bis-C,C-glycosides and more complex oxacyclics appears promising.

Use of Metalated Enecarbamates in the Squarate Cascade. Direct Access to Highly Functionalized 2,4‐Cyclooctadienones by Intramolecular Interception of the Mesocyclic Dienolates.

Abstract: A new method for constructing highly functionalized eight-membered ring ketones, fused to one or two additional rings as desired, is reported.

Factors Influencing 1,4-Asymmetric Induction During Indium-Promoted Coupling of Oxygen-Substituted Allylic Bromides to Aldehydes in Aqueous Solution.

Abstract: The preparation and indium-promoted aldehyde addition reactions of a series of 3-substituted 3-oxy-1-bromo-2-methylidenepropanes under aqueous conditions are described. The (tert-butyldimethylsilyl)oxy derivatives 4a-d are the most diastereoselective of this group of reagents, giving rise to levels of syn-1,4-asymmetric induction in the range of 87-99%. Interestingly, syn stereoselectivity is eroded and reactions proceed more rapidly when the steric bulk of the oxygen substituent is reduced as in the hydroxy and methoxy derivatives. This dropoff in pi-facial differentiation with kinetic acceleration is attributed to the operation of chelation effects during oxidative addition of the metal into the carbon-bromine bond, but not during the coupling stage. Once the aldehyde enters into the coordination sphere of the indium, internal chelation to the proximal oxygen is disrupted and conformational restrictions are released. These effects, in combination with the absence of a powerful steric control element in the latter examples, permit competitive passage via syn and anti transition states.

Synthetic Entry into the ent-Kaurene Framework. Application of an Unprecedented Transannular Cyclization for Forming the Central Bond Common to the B and C Rings.

Abstract: A stereocontrolled means for constructing the ent -kaurene framework is described. The key transformation involves transannular ring closure of an 8,9-seco precursor with migration of an interstitial methoxyl group.

Antimicrobial Algal Metabolites of Unusual Structure. Concise Synthesis of the Highly Oxygenated (4.4)Spirononene Dimethyl Gloiosiphone A by Ring Expansion of Dimethyl Squarate.

Abstract: A synthesis of dimethyl gloiosiphone A (2) has been realized. The key step involves the boron trifluoride-catalyzed eliminative ring expansion of a 2′-(dimethoxymethyl)-1′-(cyclopenten-1′-yl)-4-hydroxy-2-cyclobuten-1-one, which was directly assembled by condensation of the appropriate cycloalkenyllithium with dimethyl squarate. Following arrival at spirocyclic diketone 17 in only two steps, the cyclopentenedione A-ring was subjected to controlled reductive removal of one carbonyl group. Subsequent oxidation of the enol ether to unsaturated aldehyde 21 set the stage for proper elaboration of the α-hydroxy ketone part structure in ring B. The spectral properties of the synthetic material were identical to those of natural 2, which was originally isolated as a racemate.