Showing papers on "Intramolecular reaction published in 2002"

A highly enantioselective catalytic intramolecular Stetter reaction

Abstract: A family of chiral triazolium salts has been developed for inducing the asymmetric intramolecular Stetter reaction. The use of an aminoindanol-derived catalyst affords optimal results, with the product keto esters formed in 82-97% ee and very good chemical yield. Aromatic and aliphatic aldehydes are equally competent substrates for this reaction. The reaction conditions are reasonably mild and allow the isolation of the newly formed stereocenter without epimerization, although the presumed carbenic intermediates are strong bases.

Catalytic asymmetric intramolecular aminopalladation: enantioselective synthesis of vinyl-substituted 2-oxazolidinones, 2-imidazolidinones, and 2-pyrrolidinones.

Abstract: A new catalytic asymmetric synthesis of five-membered nitrogen heterocycles is reported. This synthesis employs ferrocenyloxazoline palladacycles (FOP trifluoroacetate catalysts) 2 and 4 and proceeds by a catalytic cycle involving Pd(II) intermediates. For example, prochiral (Z)-4-acetoxy-2-buten-1-ols are condensed with an arylsulfonyl isocyanate and the derived allylic N-arylsulfonylcarbamates cyclize in situ upon addition of 0.5−5 mol % of 2 or 4 to form 4-vinyloxazolidin-2-ones 6, 13, and 15 in high yield and 89−99% ee. The related 2-pyrrolidinone 19 and 2-imidazolidinone 18 are prepared in similar fashion. Pyrrolidinone 19 can be converted in two steps to the unnatural enantiomer of the GABA inhibitor vigabatrin 20.

Organocatalytic Michael cycloisomerization of bis(enones): the intramolecular Rauhut-Currier reaction.

Abstract: The utilization of enones as latent enolates enables regioselective enolate formation from chemically robust presursors. In this communication, we report a catalytic Michael cycloisomerization of bis(enones) under Morita−Baylis−Hillman conditions. Upon exposure to 10 mol % tributylphosphine, bis(enone) substrates afford both five- and six-membered ring products. Notably, unsymmetrical bis(enones) possessing sufficient steric or electronic bias yield single isomeric products.

Ammonium Chloride-Promoted Four-Component Synthesis of Pyrrolo[3,4-b]pyridin-5-one

Abstract: A novel multicomponent synthesis of 5-aminooxazole starting from simple and readily available inputs is described Thus, simply heating a methanol solution of an aldehyde 3, an amine 4, and an α-isocyanoacetamide 5 provided the 5-aminooxazole (1) in good to excellent yield The reaction of 1 with α,β-unsaturated acyl chloride 13 lead to the formation of pyrrolo[3,4-b]pyridin-5-one (2) in a single operation A triple domino sequence, acylation/IMDA/retro-Michael cycloreversion, is involved in this new scaffold-generating reaction After the observation that ammonium chloride can significantly accelerate the oxazole formation in toluene, a one-pot four-component synthesis of 2 is developed

The Vinylogous Intramolecular Morita−Baylis−Hillman Reaction: Synthesis of Functionalized Cyclopentenes and Cyclohexenes with Trialkylphosphines as Nucleophilic Catalysts

Abstract: The development of the vinylogous intramolecular Morita−Baylis−Hillman reaction for the synthesis of functionalized cyclopentenes and cyclohexenes is described. The reaction involves the trialkyphosphine-catalyzed cyclization of 1,6- or 1,7-diactivated 1,5-hexadienes or 1,6-heptadienes, containing carboxyaldehyde, methyl ketone, or methoxycarbonyl as the olefin activating groups. A representative example of this reaction is the Me3P-catalyzed cyclization of 1a in tert-amyl alcohol, which provides the substituted cyclopentene 2a in 95% yield and with 97:3 regioselectivity.

Catalyzed Intramolecular Olefin Insertion into a Carbon−Carbon Single Bond

Abstract: Intramolecular insertion of a C−C double bond into a C−C single bond was achieved by treatment of cyclobutanone bearing an o-styryl group at the 3-position with a catalytic amount of a cationic rhodium(I)-dppp complex. Initially, rhodium is inserted between the carbonyl carbon and the α-carbon of the cyclobutanone. Intramolecular coordination of the vinyl group results in its migratory insertion into the C−Rh linkage. Reductive elimination affords benzobicyclo[3.2.1]octan-3-one. Notably, a ring-opened α,β-unsaturated ketone was obtained when dppe was used instead of dppp. In this reaction, rhodium cleaved the bond between the α sp3 carbon and the β sp3 carbon of the cyclobutanone. The coordinating vinyl group directs this new regioselectivity of cleavage observed with the dppe ligand.

Highly enantioselective intra- and intermolecular [2 + 2] photocycloaddition reactions of 2-quinolones mediated by a chiral lactam host: host-guest interactions, product configuration, and the origin of the stereoselectivity in solution.

Abstract: The [2 + 2] photocycloaddition of 4-alkoxy-2-quinolones was conducted in the presence of the chiral lactams 5 or ent-5. At −60 °C in toluene as the solvent the intramolecular reaction of quinolones 6 and 8 as well as the intermolecular photocycloaddition of various alkenes 13 to quinolone 12 proceeded with excellent enantioselectivity (81−98% ee) and in high yields (61−89%). Styrene (13d) reacted sluggishly in the intermolecular reaction (29% yield, 83% ee). The absolute configuration of the intramolecular photocycloaddition products 7 and 9 was elucidated by single-crystal X-ray crystallography of the corresponding diastereomeric N-menthyloxycarbonyl derivatives. The relative configuration of the intermolecular photocycloaddition products 14 and 15 was assigned on the basis of NOESY experiments and on crystallographic evidence. The differentiation of the enantiotopic faces in the prochiral quinolones 6, 8, and 12 can be explained by assuming a coordination of these substrates to the lactams 5 or ent-5 vi...

Reactions of iodinated vinylidene complexes generated from 1-iodo-1-alkynes and W(CO)5(thf).

Abstract: We have succeeded in generating iodinated tungsten vinylidene complexes from 1-iodo-1-alkynes and W(CO)5(thf), and have employed these complexes for two types of synthetically useful reactions, that is, 6π-electrocyclization for o-(iodoethynyl)styrenes and endo-selective cyclization for ω-iodoacetylenic silyl enol ethers.

A highly enantioselective intramolecular Heck reaction with a monodentate ligand.

Abstract: An efficient enantioselective intramolecular Heck reaction of cyclohexadienones, using readily available and modular TADDOL-based mono- and bidentate phosphoramidites as chiral ligands and not requiring any additives, has been developed. Excellent enantioselectivities up to 96% ee are reached for the first time in a Heck reaction with monodentate ligands.

Synthesis of (-)-morphine.

Abstract: The preparation of the diastereomerically pure beta-tetralone ketal 4 is reported. Intramolecular alkylidene C-H insertion followed by hydrolysis of 4 proceeded to give the enantiomerically pure cyclopentene 15. The key step in this synthesis was the bis-intramolecular cyclization of keto aldehyde 2 to give the tetracyclic intermediate 20. Enone 20 was converted over several steps to (-)-morphine 1.

Rhodium complex-catalyzed Pauson-Khand-type reaction with aldehydes as a CO source

Abstract: With aldehydes as a CO source under solvent-free conditions, rhodium complex efficiently catalyzed an intramolecular carbonylative alkene−alkyne coupling (Pauson−Khand-type reaction) and various bicyclic enones were obtained in high yield. Experiments under argon flow and a 13C-labeling experiment suggested that almost no free carbon monoxide was generated in this reaction. When noncationic rhodium complex with chiral phosphine was used as a chiral catalyst, the reaction proceeded enantioselectively to give various chiral cyclopentenones in up to 90% ee under solvent-free conditions.

Highly Enantioselective Syntheses of Functionalized α-Methylene-γ-butyrolactones via Rh(I)-catalyzed Intramolecular Alder Ene Reaction: Application to Formal Synthesis of (+)-Pilocarpine

Abstract: A highly enantioselective Rh(I)-catalyzed intramolecular Alder ene reaction has been developed. The desired products, 3-vinyl, vinyl acetate, and vinyl ether-substitued α-methylene-γ-butyrolactones were formed in high yields. Aldehydes were produced with the formation of γ-lactones when alcohols were substituted at allylic position in the substrates. All reactions with listed substrates proceeded in over 99% ee. A formal synthesis of (+)-pilocarpine is an excellent example to demonstrate the synthetic utility of this methodology.

Palladium-Catalyzed Intramolecular α-Arylation of α-Amino Acid Esters

Abstract: The Pd-catalyzed intramolecular α-arylation of α-amino acid esters is described. Starting from readily available amino acids, the synthesis of a variety of isoindolines and tetrahydroisoquinoline carboxylic acid esters has been accomplished. Additionally, fused tricyclic systems can be efficiently prepared from cyclic amino acid esters. Reaction conditions have been found that allow the use of tert-butyl ester and N-(benzyloxycarbonyl) protecting groups.

Regiospecific Synthesis of Bicyclo- and Heterobicyclo-gem-difluorocyclobutenes Using Functionalized Fluoroallenes and a Novel Mo-Catalyzed Intramolecular [2 + 2] Cycloaddition Reaction

Abstract: The first synthesis of functionalized gem-difluoroallenes 4 served as platform for an unprecedented molybdenum-catalyzed intramolecular allene-alkyne [2 + 2]-cycloaddition that produced 6, a hitherto unknown class of bicyclo- and heterobicyclo-CF2-containing cyclobutenes.

Asymmetric intramolecular [3 + 2] cycloaddition reactions of acylhydrazones/olefins using a chiral zirconium catalyst

Abstract: Catalytic asymmetric intramolecular [3 + 2] cycloaddition of hydrazone/olefins has been attained. In the presence of a chiral zirconium catalyst prepared from zirconium alkoxide and a BINOL derivative, the desired pyrazolidine derivatives were obtained in high yields with high selectivities. The products were easily converted to 1,3-diamine or beta-aminonitrile derivatives by N-N bond cleavage.

Endo-Oxacyclizations of Polyepoxides: Biomimetic Synthesis of Fused Polycyclic Ethers

Abstract: Boron trifluoride-etherate promotes the endo-selective oxacyclization of polyepoxides derived from various acyclic terpenoid polyalkenes, including geraniol, farnesol, and geranylgeraniol, providing an efficient and stereoselective synthesis of substituted oxepanes and fused polyoxepanes. The mechanism of the oxacyclization reaction probably involves intramolecular nucleophilic addition of epoxide oxygen to open another epoxide that is activated as an electrophile by the Lewis acid. These oxacyclizations proceed stereospecifically with inversion of configuration upon opening of each epoxide to provide trans-fused polycyclic products. The oxacyclization cascade is terminated by a tethered nucleophile, which may be the carbonyl oxygen of a ketone, ester, or carbonate, or a trisubstituted alkene. The best oxacyclization yields are generally observed with tert-butyl carbonate as the terminating nucleophile, although in some cases the oxacyclization products include formation of tert-butyl ethers as a minor product. The oxacyclization transformations described herein may mimic ring-forming steps in the biosynthesis of trans-syn-trans-fused polycyclic ether marine natural products.

Synthesis of Aza Polycyclic Compounds Derived from Pyrrolidine, Indolizidine, and Indole via Intramolecular Diels−Alder Cycloadditions of Neutral 2-Azadienes

Abstract: A method for the preparation of novel oxaza and diaza polycyclic 9-oxa-4-azaphenanthrene, 5H-pyrido[2,3-a]pyrrolizine, 5H,6H-pyrido[3,2-g]indolizine, and 5H,6H-indeno[2,1-a]indole is described, based on tandem reactions: aza-Wittig reaction of N-vinylic phosphazenes with functionalized aldehydes and an intramolecular aza-Diels-Alder reaction.

Stereoselective total syntheses of the racemic form and the natural enantiomer of the marine alkaloid lepadiformine via a novel N-acyliminium ion/allylsilane spirocyclization strategy

Abstract: Stereoselective total syntheses of the racemic form and the natural enantiomer of the tricyclic marine alkaloid lepadiformine (6) have been accomplished using a novel intramolecular spirocyclization of an N-acyliminium ion with an allylsilane to form the A/C rings as the key step. Introduction of the hydroxymethyl group at C-13 of the racemic spirocycle 11 was achieved using our methodology for oxidative radical-based remote functionalization of o-aminobenzamides, followed by copper-catalyzed addition of Grignard reagent 16 to the N-acyliminium ion intermediate derived from 15. Subsequent Tamao oxidation of silane 17 then afforded the requisite hydroxymethyl compound 19, which was converted to the dimethyl acetal 25 via hydroformylation followed by aldehyde protection. Hydrolysis of the benzamide moiety of 25 and subsequent protection of the primary alcohol gave amino acetal 27. The synthesis was concluded from 27 by a four-step procedure: acid-catalyzed ring closure, amino nitrile formation, introductio...

Intramolecular hydrogen abstraction reaction promoted by alkoxy radicals in carbohydrates. Synthesis of chiral 2,7-dioxabicyclo[2.2.1]heptane and 6,8-dioxabicyclo[3.2.1]octane ring systems.

Abstract: The reaction of specifically protected anhydroalditols with (diacetoxyiodo)benzene or iodosylbenzene and iodine is a mild and selective procedure for the synthesis of chiral 6,8-dioxabicyclo[3.2.1]octane and 2,7-dioxabicyclo[2.2.1]heptane ring systems under neutral conditions. This reaction can be considered to be an intramolecular glycosidation that goes through an intramolecular hydrogen abstraction promoted by an alkoxy radical followed by oxidation of the transient C-radical intermediate to an oxycarbenium ion. This methodology is useful not only for the preparation of chiral synthons but also for the selective oxidation of specific carbons of the carbohydrate skeleton, constituting a good procedure for the synthesis of protected uloses.

Intramolecular Silicon-Assisted Cross-Coupling: Total Synthesis of (+)-Brasilenyne

Abstract: The first, total synthesis of (+)-brasilenyne (1) has been achieved in 19 steps from l-(S)-malic acid. The key elements of this approach are a highly diastereoselective ring-opening of a 1,3-dioxolanone with bis(trimethylsilyl)acetylene) promoted by TiCl4 to set a propargylic stereocenter and the successful application of the sequential ring closing metathesis/silicon-assisted intramolecular cross-coupling reaction for construction of the oxonin core structure of 1.

Cobalt−Phosphite-Catalyzed Asymmetric Pauson−Khand Reaction

Abstract: A complex formed from dicobalt octacarbonyl and a chiral aryl bisphosphite served as a catalyst for the intramolecular asymmetric Pauson-Khand reaction. Bicyclic cyclopentenones were obtained in up to 75% enantiomeric excess. For a terminal 1,6-enyne, the incremental enantiomeric excess was found to increase from 4 to 26% over the course of the reaction. The scope of this process was examined for a variety of 1,6- and 1,7-enynes, and a moderate degree of enantioselectivity was maintained only in the case of aryl-substituted 1,6-enynes.

Metathesis Polymer Cyclization with Telechelic Poly(THF) Having Allyl Groups

Abstract: Introduction. Topologically unique macromolecules comprising a single cyclic and multicyclic polymer units have gained growing interest due to their distinctive behaviors from linear and branched counterparts.1-5 Polymer cyclization was performed first through the coupling reaction of a bifunctional linear polymer precursor, such as a bifunctionally living polymer like polystyrene, with a complementarily reactive bifunctional reagent, typically dihaloalkanes or dihalosilanes (Scheme 1).6-9 This bimolecular reaction should be conducted under high dilution to suppress the intermolecular chain extension reaction and at the same time under rigorous stoichiometric balance between large and small molecules. Hence, the process is often kinetically circumvented to limit this straightforward polymer cyclization process from wide applications. A psuedo-unimolecular reaction by an “electrostatic self-assembly and covalent fixation” technique was recently developed as an alternative polymer cyclization process (Scheme 1).5,10-14 Thus, a linear polymer precursor having moderately strained onium salt groups, typically five-membered cyclic ammonium or six-membered bicyclic ammonium salt groups, carrying appropriately reactive counteranion like dicarboxylate, was employed. The cations and anions always balance the charges, and the selective nucleophilic ring-opening reaction occurred at an appropriately elevated temperature under dilution, to convert the ionic interaction into the permanent covalent linkage. A strictly unimolecular polymer cyclization process using an R,ω-heterobifunctional linear polymer precursor was developed by Deffieux et al. and applied further by several groups (Scheme 1).15-19 In this process, the two end groups of the polymer precursor become complementarily reactive with each other after the deprotection or the activation, and the reaction under dilution gives a cyclic polymer product. The cyclization efficiency was notably improved since the inherent stoichiometric balance is maintained between complementarily reactive groups located within the same polymer molecule, and the reaction follows the unimolecular kinetics depending solely on the concentration of the polymer precursor. Nevertheless, the synthesis of the heterobifunctional polymer precursor often requires multistep processes involving protection/deprotection of reactive end groups, limiting its synthetic usefulness. We show here a novel strictly unimolecular polymer cyclization process involving bifunctional polymer precursor having identical reactive end groups (Scheme 1). Thus, a linear polymer precursor having allyl groups was prepared and subjected to a metathesis condensation, also known as a ring-closing metathesis (RCM), under dilution in the presence of a Grubbs catalyst, ruthenium(II) dichloride phenylmethylene bis(tricyclohexylphosphine) [RuCl2(PCy3)2(dCHPh)]. The metathesis condensation process has so far been successfully applied for the cyclization of smallto medium-sized substrates having terminal allyl groups20,21 and for the synthesis of a variety of topologically unique molecules like catenanes and knots22-24 as well as for the polycondensation of acyclic dienes (ADMET) to produce a variety of functional polymer materials.25-29 Furthermore, the equilibrium between cyclic and linear chains during a ring-opening metathesis polymerization (ROMP) has been a subject of continued studies.30 In the present communication, we demonstrate a versatile means to produce large-sized cyclic polymers using a readily accessible precursor, i.e., telechelics having allyl groups, in the presence of a commercially available metathesis catalyst. Results and Discussion. Telechelic poly(THF) having allyl end groups, 1, was prepared by the end-capping reaction of a bifunctionally living poly(THF)12 with sodium allyloxide (for details, see Supporting Information). 1H NMR analysis of 1, having the MW of 5060 and the PDI of 1.27, showed characteristic signals due to allyl protons at 5.17 and 5.90 ppm (Figure 1, top). The metathesis condensation was subsequently performed under reflux in methylene chloride at polymer concentration of 0.2-2.0 g/L in the presence of a Grubbs catalyst. The catalyst was charged in the comparable molar quantity to allyl groups at the polymer chain ends * Corresponding author: Tel +81 3/5734-2498, Fax +81 3/57342876, e-mail ytezuka@o.cc.titech.ac.jp. Scheme 1 8667 Macromolecules 2002, 35, 8667-8669

Intramolecular silicon-assisted cross-coupling reactions: General synthesis of medium-sized rings containing a 1,3-cis-cis diene unit

Abstract: The combination of ring-closing metathesis and Pd-catalyzed, silicon-assisted intramolecular cross-coupling has been developed to provide an effective and powerful method for construction of medium-sized rings with an internal 1,3-cis-cis diene unit. Allylic alcohols bearing a Z-iodoalkenyl tether can be silylated with chlorodimethylvinylsilane and subjected to Mo-catalyzed ring-closing metathesis to form unsaturated siloxanes. Activation of the siloxane with tetrabutylammonium fluoride in the presence of [allylPdCl](2) leads to high yielding ring-closing reactions to form 9-, 10-, 11- and 12-membered rings. Extension to the synthesis of 9-membered ring unsaturated ethers has also been accomplished. Noteworthy features of this process include: (1) a highly stereospecific intramolecular coupling process, (2) flexible positioning of the hydroxy group, and (3) potential extension to other medium-sized carbocycles and heterocycles.

Ruthenium-catalyzed intramolecular oxidative amination of aminoalkenes enables rapid synthesis of cyclic imines.

Abstract: [RuCl2(CO)3]2/dppp is shown to be a highly effective catalyst system for the first intramolecular oxidative amination of a variety of aminoalkenes when it is used concomitantly with K2CO3 and allyl acetate in N-methylpiperidine, to give the corresponding cyclic imines and indoles in excellent yields. For example, the reaction of 2,2-diphenyl-4-pentenyl-1-amine performed in the presence of 2 mol % of [RuCl2(CO)3]2, 4 mol % of dppp, K2CO3, and allyl acetate in N-methylpiperidine at 140 °C for 8 h gives 4,4-diphenyl-2-methyl-1-pyrroline in quantitative (>99%) yield.

Mechanistic Investigation of a Novel Vitamin B12-Catalyzed Carbon−Carbon Bond Forming Reaction, the Reductive Dimerization of Arylalkenes

Abstract: In the presence of catalytic vitamin B(12) and a reducing agent such as Ti(III)citrate or Zn, arylalkenes are dimerized with unusual regioselectivity forming a carbon [bond] carbon bond between the benzylic carbons of each coupling partner. Dimerization products were obtained in good to excellent yields for mono- and 1,1-disubstituted alkenes. Dienes containing one aryl alkene underwent intramolecular cyclization in good yields. However, 1,2-disubstituted and trisubstituted alkenes were unreactive. Mechanistic investigations using radical traps suggest the involvement of benzylic radicals, and the lack of diastereoselectivity in the product distribution is consistent with dimerization of two such reactive intermediates. A strong reducing agent is required for the reaction and fulfills two roles. It returns the Co(II) form of the catalyst generated after the reaction to the active Co(I) state, and by removing Co(II) it also prevents the nonproductive recombination of alkyl radicals with cob(II)alamin. The mechanism of the formation of benzylic radicals from arylalkenes and cob(I)alamin poses an interesting problem. The results with a one-electron transfer probe indicate that radical generation is not likely to involve an electron transfer. Several alternative mechanisms are discussed.

Total Synthesis of Anhydrolycorinone Utilizing Sequential Intramolecular Diels−Alder Reactions of a 1,3,4-Oxadiazole

Abstract: A convergent total synthesis of anhydrolycorinone is detailed, enlisting sequential intramolecular Diels−Alder reactions of a suitably substituted 2-amino-1,3,4-oxadiazole defining a novel oxadiazole → furan → benzene Diels−Alder strategy.

Reversible Intramolecular Hydride Transfer between Tantalum and an Aromatic Ring: An η5-Cyclohexadienyl Complex as a Masked Hydride

Abstract: The methyl triflate complex (2,6-Mes2C6H3N)(2,6-Mes2C6H3NH)TaMe(OSO2CF3) reacts cleanly with H2 to give the η5-cyclohexadienyl complex 3. Complex 3 therefore results from the insertion of an arene ring into an M−H bond, which has been proposed as the first step in catalytic arene hydrogenations. This insertion is reversible, such that 3 behaves as a “masked hydride” in its reaction chemistry.

Chiral Nonracemic α-Alkylidene and α-Silylidene Cyclopentenones from Chiral Allenes Using an Intramolecular Allenic Pauson−Khand-Type Cycloaddition

Abstract: We have successfully effected a transfer of chirality from a chiral nonracemic allene to an α-alkylidene and an α-silylidene cyclopentenone. The molybdenum-mediated examples possessing a silyl group on the terminus of the allene show good facial selectivities, but isomerization of the (E)-silylidene cyclopentenone to the (Z)-silylidene cyclopentenone occurs upon purification of these products. Alternatively, an alkyl group on the terminus of the allene undergoes cycloaddition with moderate selectivities but gives products that undergo an isomerization of the (Z)-alkylidene cyclopentenone to the (E)-alkylidene cyclopentenone when exposed to acidic conditions. Thus, erosion of the enantiomeric excesses is observed for one of the two products as a result of this isomerization. The allenic Pauson−Khand-type cycloaddition has also been effected by first isolation the (η6-arene)molybdenum tricarbonyl complex, demonstrating for the first time that this is most likely the active complex in the molybdenum-mediated...

Dramatic decrease of the cis content and molecular weight of cis‐transoidal polyphenylacetylene at 23 °C in solutions prepared in air

Abstract: The thermal cis-trans isomerization of cis-transoidal polyphenylacetylene (PPA) synthesized with Noyori's catalyst [Rh(C≡CPh)(norbornadiene)(PPh 3 ) 2 ] has been investigated under both ambient and inert atmospheres in solution and in bulk. In all cases, an intramolecular cyclization results in cis-trans isomerization, and subsequent chain cleavage produces 1,3,5-triphenylbenzene. This reaction is accelerated by the presence of air, particularly when the reaction takes place in solution. Decreases in the cis content and molecular weight show that the intramolecular cyclization process takes place at 23 °C in solution. The mechanism of this reaction is identical to that reported previously for cis-cisoidal and cis-transoidal PPA synthesized with Ziegler-Natta catalysts.

Asymmetric total synthesis of (+)-brefeldin A from (S)-lactate by triple chirality transfer process and nitrile oxide cycloaddition.

Abstract: A novel synthesis of (+)-brefeldin A (1) has been accomplished on the basis of triple chirality transfer methodology, intramolecular ester enolate alkylation, and both intra- and intermolecular nitrile oxide cycloaddition strategies.