Diastereo- and Enantioselective Synthesis of Bi- and Tricyclic <i>N</i>‑Heterocycle-Fused β‑Lactones

The utility of the nucleophile-catalyzed (Lewis base) aldol lactonization (NCAL) process for the diastereo- and enantioselective synthesis of <i>N</i>-heterocycle-fused-β-lactones from <i>N</i>-linked ketoacids is described. A series of bi- and tricyclic, <i>N</i>-heterocycle-fused, β-lactones were first synthesized in racemic fashion via the NCAL process with excellent diastereoselectivity (>19:1) utilizing 4-pyrrolidinopyridine as an effective achiral Lewis base. A catalytic, enantioselective version of this NCAL process using isothiourea catalysts provided access to bicyclic β-lactone-fused, <i>N</i>-heterocycles in moderate to good yields (up to 80%) with high enantiocontrol (up to >99:1 er). An unusual diastereodivergent NCAL process was discovered that leads to two different products; a tricyclic <i>N</i>-heterocycle-fused β-lactone and a bicyclic enamine derived from in situ decarboxylation of the diastereomeric tricyclic β-lactone. The reactivity of these adducts was briefly explored

Multicomponent, Enantioselective Michael–Michael-Aldol-β-Lactonizations Delivering Complex β‑Lactones

Optically active, tertiary amine Lewis bases react with unsaturated acid chlorides to deliver chiral, α,β-unsaturated acylammonium salts. These intermediates participate in a catalytic, enantioselective, three-component process delivering bi- and tricyclic β-lactones through a Michael–Michael-aldol-β-lactonization. In a single operation, the described multicomponent, organocascade process forms complex bi- and tricyclic β-lactones by generating four new bonds, two rings, and up to four contiguous stereocenters. In the racemic series, yields of 22–75% were achieved using 4-pyrrolidinopyridine as Lewis base. In the enantioselective series employing isothiourea catalysts, a kinetic resolution of the initially formed racemic Michael adduct appears operative, providing yields of 46% to quantitative (based on 50% max) with up to 94:6 er. Some evidence for a dynamic kinetic asymmetric transformation for tricyclic-β-lactone <b>1d</b> was obtained following optimization (yields up to 61%, 94:6 er) through a presumed reversible Michael

Concise Synthesis of the Isothiourea Organocatalysts Homobenzotetramisole and Derivatives

A concise approach to the synthesis of homobenzotetramisole and derivatives is described. Our strategy features a one-pot acylation–cyclization of 2-aminobenzothiazole with α,β-unsaturated acid chlorides to afford annulated pyrimidones. Subsequent Grignard addition followed by acid-promoted dehydration and reduction provides good overall yields of the title compounds in three steps and in quantities up to 10 g. The synthesis employs low-cost and readily available starting materials and enables access to both optical antipodes of these increasingly useful nucleophilic catalysts following chiral separation

A Diastereoselective, Nucleophile-Promoted Aldol-Lactonization of Ketoacids Leading to Bicyclic-β-Lactones

An improved, tandem acid activation/aldol-lactonization process is described. This more practical protocol shortens reaction times for the construction of bicyclic β-lactones from ketoacids and implements the use of commercially available reagents <i>p</i>-toluenesulfonyl chloride (<i>p</i>-TsCl) as activator and 4-dimethylaminopyridine (4-DMAP) as nucleophilic promoter (Lewis base). Substrates with β-substituents, with respect to the carboxylic acid, consistently showed excellent levels of diastereoselectivity during the bis-cyclization event

Acylammonium Salts as Dienophiles in Diels–Alder/Lactonization Organocascades

α,β-Unsaturated acyl­ammonium salts, generated <i>in situ</i> from commodity acid chlorides and a chiral isothio­urea organo­catalyst, comprise a new and versatile family of chiral dieno­philes for the venerable Diels–Alder (DA) cycloaddition. Their reactivity is unveiled through a highly diastereo- and enantio­selective Diels–Alder/lactonization organo­cascade that generates <i>cis</i>- and <i>trans</i>-fused bicyclic γ- and δ-lactones bearing up to four contiguous stereo­centers. Moreover, the first examples of DA-initiated, stereo­divergent organo­cascades are described delivering complex scaffolds found in bioactive compounds. The origins of stereo­selectivity are rationalized through computational studies. In addition, the utility of this methodology is demonstrated through a concise approach to the core structure of glaciolide and formal syntheses of fraxinellone, tri­sporic acids, and tri­sporols

Cyclopropanations of Olefin-Containing Natural Products for Simultaneous Arming and Structure Activity Studies

Cyclopropanations of alkene-containing natural products that proceed under mild conditions are reported for simultaneous arming and structure–activity relationship studies. An alkynyl diazo ester under Rh(II) catalysis is employed for cyclopropanations of electron-rich olefins while an alkynyl sulfonium ylide is used for electron-poor olefins. This approach enables simultaneous natural product derivatization for SAR studies and arming (i.e., via alkyne attachment) for subsequent conjugation with reporter tags (e.g., biotin, fluorophores, photoaffinity labels) for mechanism of action studies including cellular target identification and proteome profiling experiments

Mechanistic Investigations of the ZnCl₂-Mediated Tandem Mukaiyama Aldol Lactonization: Evidence for Asynchronous, Concerted Transition States and Discovery of 2-Oxopyridyl Ketene Acetal Variants

The ZnCl₂-mediated tandem Mukaiyama aldol lactonization (TMAL) reaction of aldehydes and thiopyridyl ketene acetals provides a versatile, highly diastereoselective approach to <i>trans</i>-1,2-disubstituted β-lactones. Mechanistic and theoretical studies described herein demonstrate that both the efficiency of this process and the high diastereoselectivity are highly dependent upon the type of ketene acetal employed but independent of ketene acetal geometry. Significantly, we propose a novel and distinct mechanistic pathway for the ZnCl₂-mediated TMAL process versus other Mukaiyama aldol reactions based on our experimental evidence to date and further supported by calculations (B3LYP/BSI). Contrary to the commonly invoked mechanistic extremes of [2+2] cycloaddition and aldol lactonization mechanisms, investigations of the TMAL process suggest a concerted but asynchronous transition state between aldehydes and thiopyridyl ketene acetals. These calculations support a boat-like transition state that differs from commonly invoked Mukaiyama “open” or Zimmerman–Traxler “chair-like” transition-state models. Furthermore, experimental studies support the beneficial effect of pre-coordination between ZnCl₂ and thiopyridyl ketene acetals prior to aldehyde addition for optimal reaction rates. Our previously proposed, silylated β-lactone intermediate that led to successful TMAL-based cascade sequences is also supported by the described calculations and ancillary experiments. These findings suggested that a similar TMAL process leading to β-lactones would be possible with an oxopyridyl ketene acetal, and this was confirmed experimentally, leading to a novel TMAL process that proceeds with efficiency comparable to that of the thiopyridyl system

Dyotropic Rearrangements of Fused Tricyclic β‑Lactones: Application to the Synthesis of (−)-Curcumanolide A and (−)-Curcumalactone

Dyotropic rearrangements of fused, tricyclic β-lactones are described that proceed via unprecedented stereospecific, 1,2-acyl migrations delivering bridged, spiro-γ-butyrolactones. A unique example of this dyotropic process involves a fused bis-lactone possessing both β- and δ-lactone moieties which enabled rapid access to the core structures of curcumanolide A and curcumalactone. Our current mechanistic understanding of the latter dyotropic process, based on computational studies, is also described. Other key transformations in the described divergent syntheses of (−)-curcumanolide A and (−)-curcumalactone from a common intermediate (11 and 12 steps from 2-methyl-1,3-cyclopentanedione, respectively), include a catalytic, asymmetric nucleophile (Lewis base)-catalyzed aldol-lactonization (NCAL) leading to a tricyclic β-lactone, a Baeyer–Villiger oxidation in the presence of a β-lactone, and highly facial-selective and stereocomplementary reductions of an intermediate spirocyclic enoate. The described dyotropic rearrangements significantly alter the topology of the starting tricyclic β-lactone, providing access to complex spirocyclic cyclopentyl-γ-lactones and bis-γ-lactones in a single synthetic operation

Dyotropic Rearrangements of Fused Tricyclic β‑Lactones: Application to the Synthesis of (−)-Curcumanolide A and (−)-Curcumalactone

Dyotropic rearrangements of fused, tricyclic β-lactones are described that proceed via unprecedented stereospecific, 1,2-acyl migrations delivering bridged, spiro-γ-butyrolactones. A unique example of this dyotropic process involves a fused bis-lactone possessing both β- and δ-lactone moieties which enabled rapid access to the core structures of curcumanolide A and curcumalactone. Our current mechanistic understanding of the latter dyotropic process, based on computational studies, is also described. Other key transformations in the described divergent syntheses of (−)-curcumanolide A and (−)-curcumalactone from a common intermediate (11 and 12 steps from 2-methyl-1,3-cyclopentanedione, respectively), include a catalytic, asymmetric nucleophile (Lewis base)-catalyzed aldol-lactonization (NCAL) leading to a tricyclic β-lactone, a Baeyer–Villiger oxidation in the presence of a β-lactone, and highly facial-selective and stereocomplementary reductions of an intermediate spirocyclic enoate. The described dyotropic rearrangements significantly alter the topology of the starting tricyclic β-lactone, providing access to complex spirocyclic cyclopentyl-γ-lactones and bis-γ-lactones in a single synthetic operation

Chemical Mechanism of the Phosphotriesterase from <i>Sphingobium</i> sp. Strain TCM1, an Enzyme Capable of Hydrolyzing Organophosphate Flame Retardants

The mechanism of action of the manganese-dependent phosphotriesterase from <i>Sphingobium</i> sp. strain TCM1 that is capable of hydrolyzing organophosphate flame retardants was determined. The enzyme was shown to hydrolyze the <i>R</i>_P-enantiomer of <i>O</i>-methyl <i>O</i>-cyclohexyl <i>p</i>-nitrophenyl thiophosphate with net inversion of configuration and without the formation of a covalent reaction intermediate. These results demonstrate that the enzyme catalyzes the hydrolysis of substrates by activation of a nucleophilic water molecule for direct attack at the phosphorus center