Synthetic study of 1,3-butadiene-based IMDA approach to construct a [5-7-6] tricyclic core and its application to the total synthesis of C8-epi-guanacastepene O

An efficient intramolecular Diels-Alder (IMDA) strategy for the construction of the [5-7-6] tricyclic core (18) of guanacastepenes has been developed from cis- and trans-1,3-butadiene-tethered 4-oxopent-2-ynoic acid ethyl esters 10 and 11. This method facilitates the synthesis of C8-epi-guanacastepene O (36) in a very efficient manner.     

Enantioselective synthesis of bridged bicyclic ring systems

The type 2 intramolecular Diels-Alder (IMDA) reaction is a valuable method for synthesis of both carbocyclic and heterocyclic bridged bicyclo[5.3.1]undecane and bicyclo[4.3.1]decane ring systems. These structures are common to a number of biologically important natural products. Asymmetric variants of the type 2 IMDA reaction incorporating oxazolidinone chiral auxiliaries have been evaluated. This study has resulted in systems that deliver bridged bicyclic [5.3.1] and [4.3.1] ring systems in high diastereomeric (97-99% de) and enantiomeric purity.     

Synthetic studies toward the guanacastepenes

[reaction: see text]. An asymmetric approach toward the [6-7] ring system of the guanacastepenes is described.     

Catalyst-Controlled Regiodivergent Alkyne Insertion in the Context of C−H Activation and Diels–Alder Reactions: Synthesis of Fused and Bridged Cycles

Rhodium(III)- and cobalt(III)-catalyzed C−H activation of indoles and coupling with 1,6-enynes is discussed. Under rhodium(III) catalysis, the alkyne insertion follows 2,1-regioselectivity with a subsequent type-I intramolecular Diels–Alder reaction (IMDA) to afford [6,5]-fused cycles. When catalyzed by the cobalt(III) congener, 1,2-insertion of the alkyne is preferred, and followed by a rare type-II IMDA, thus leading to bridged [3,3,1]-cycles. This selectivity of the alkyne insertion was mainly tuned by the steric sensitivity of the catalyst.     

An electrochemical approach to the guanacastepenes

An asymmetric approach toward the [6-7-5] ring system of the guanacastepenes is described. [structure: see text]     

Synthetic approaches to guanacastepenes. Enantiospecific syntheses of BC and AB ring systems of guanacastepenes and rameswaralide

[reaction: see text] A simple and efficient approach for the BC and AB ring systems of the novel diterpenes guanacastepenes and rameswaralide starting from the readily and abundantly available monoterpene (R)-carvone employing RCM reaction as the key step is described.     

Intramolecular Diels-Alder cycloadditions of fulvenes. Application to the kigelinol, neoamphilectane, and kempane skeletons

A variety of polycyclic ring skeletons (e.g., kigelinol, neoamphilectane, and kempene systems) can be prepared rapidly via intramolecular Diels-Alder cycloadditions (IMDA) of fulvenes. The length of the tethers and the diversity of the substituents on the fulvene core dictate the nature of the IMDA pathway. [reaction: see text]     

Catalyst‐Controlled Regiodivergent Alkyne Insertion in the Context of C−H Activation and Diels–Alder Reactions: Synthesis of Fused and Bridged Cycles

Rhodium(III)‐ and cobalt(III)‐catalyzed C−H activation of indoles and coupling with 1,6‐enynes is discussed. Under rhodium(III) catalysis, the alkyne insertion follows 2,1‐regioselectivity with a subsequent type‐I intramolecular Diels–Alder reaction (IMDA) to afford [6,5]‐fused cycles. When catalyzed by the cobalt(III) congener, 1,2‐insertion of the alkyne is preferred, and followed by a rare type‐II IMDA, thus leading to bridged [3,3,1]‐cycles. This selectivity of the alkyne insertion was mainly tuned by the steric sensitivity of the catalyst.     

A Synthesis of (+)-Oblongolide

The absolute configuration of natural oblongolide is reassigned as (3aS,5aR,7S,9aS,9bS)-3a,5a,6,7,8,9,9a,9b-octahydro-7,9b-dimethylnaphtho[1,2-c]furan-1(3H)-one 2 by a 7-stage synthesis of its enantiomer 1 from (+)-citronellol involving a regioselective reduction and an intramolecular Diels-Alder reaction (IMDA) as the key steps. (+)-Citronellol was converted into methyl (2E,4E,10E)-(S)-(+)-11-tert-butoxycarbonyl-7-methyl-undeca-2,4,10-trienoate 7 by sequential Lemieux-Johnson oxidation, Wittig reaction, pyridinium chlorochromate oxidation, and Wadsworth-Emmons-Homer alkenation. A regioselective reduction of the methoxycarbonyl group in 7 afforded tert-butyl (2.E,8E,10E)-(S)-(+)-2,6-dimethyl-12-hydroxy-dodeca-2,8,10-trienoate 8 from which (+)-oblongolide was readily obtained via an IMDA reaction.     

Stereocontrolled IMDA reaction of styrene derivatives. A way to enantiopure 3a,4,9,9a-tetrahydrobenz[f]isoindolines

IMDA reactions on chiral perhydro-1,3-benzoxazines, derived from (-)-8-amino menthol, bearing a styrene substituent at C-2 acting as diene and an acryl amide acting as dienophile occur with high stereoselection and excellent chemical yields. After elimination of the chiral appendage, enantiopure 3a,4,9,9a-tetrahydrobenz[f]isoindolines are prepared in this way. The effect of the substituents at both diene and dienophile are studied, showing that a methyl group at C-1 in the diene inhibited the reaction, while the ene adduct, instead of the IMDA product, was obtained when a methyl group was at C-2.     

Application of RCM reaction in the construction of ABC ring of micrandilactone A

[reaction: see text] The functionalized ABC ring system of micrandilactone A was successfully constructed in 14 steps. The key reactions in this synthesis are the intermolecular Diels-Alder reaction (IMDA) and the eneyne ring-closing metathesis (RCM) reaction.     

Cyclohexyne Cycloinsertion in the Divergent Synthesis of Guanacastepenes

The guanacastepenes are a family of 15 diterpenes that share a common 5‐6‐7 tricyclic core, which is decorated with quaternary centers, unsaturation, hydroxyl and carbonyl groups. Some of these natural products show interesting antimicrobial potency. Their collective structural and biological features have stirred up vibrant activity among organic chemists. Herein, we disclose an account of our studies toward the synthesis of a number of guanacastepenes. The synthetic strategy relies on the use of cyclohexyne in a cycloinsertion reaction to rapidly construct the guanacastepene core. Isolation of a cyclobutenol as intermediate in the cyclohexyne cycloinsertion provided us with the possibility to study further the reactivity of this metastable compound, and we uncovered novel rearrangements and ring‐opening reactions. Stereoselective, late‐stage oxidative diversification of the carbon scaffold allowed the synthesis of guanacastepenes N and O and paved the way for the synthesis of guanacastepenes H and D.     

Convergent, enantioselective syntheses of guanacastepenes A and E featuring a selective cyclobutane fragmentation

The evolution of a convergent strategy that led to efficient, enantioselective syntheses of both natural (+)- and unnatural (-)-guanacastepene E and formal total syntheses of (+)- and (-)-guanacastepene A is described. A union of five- and six-membered ring intermediates by an efficient pi-allyl Stille cross-coupling reaction was followed by an intramolecular enone-olefin [2 + 2] photocycloaddition and a stereoelectronically controlled, reductive fragmentation of the resulting cyclobutyl ketone. The latter two transformations enabled controlled formation of the C-11 quaternary stereocenter and the central seven-membered ring of the guanacastepenes. An enantiospecific synthesis of the functionalized five-membered ring vinyl stannane from the monoterpene R-(-)-carvone featuring a carbon-carbon bond forming ring contraction was also developed.     

An atom-economical approach to conformationally constrained tricyclic nitrogen heterocycles via sequential and tandem Ugi/intramolecular Diels-Alder reaction of pyrrole

An efficient approach to rigid tricyclic nitrogen heterocycles via sequential and tandem Ugi/intramolecular Diels-Alder (IMDA) cycloaddition of pyrrole is described. The one-pot Ugi four-component condensation (4CC) reaction was used as the key transformation to prepare trienes with a carboxamide substituent on the tether. The use of acrylic acid (21) and N-propyl- and N-benzylmaleamic acids (24b and 24C) as the acid components provided trienes 22, 25b, and 25c, respectively, which upon heating at 120 degrees C for 12 h yielded the corresponding [4 + 2] cycloaddition products. In the case of maleic acid derivative 24a, heating the reaction mixture at 60 degrees C for 6 h promoted the cycloaddition reaction and provided the desired product 26a in 78% yield. In contrast, fumaric acid monoethyl ester (27a) and 3-acetyl- and 3-(4-methylbenzoyl) acrylic acids (27b-c) directly yielded the corresponding Ugi/IMDA cycloaddition products 29a-c in high yields at room temperature without any trace of initially formed trienes 28a-c. The IMDA cycloaddition reactions proceed with excellent stereoselectivity with the formation of five stereogenic centers and three rings.     

Formal synthesis of cortistatins

A unified strategy toward the asymmetric facile construction of the [6.7.6.5]oxapentacyclic skeleton of cortistatins is reported, featuring intramolecular Diels-Alder (IMDA), oxidative dearomatization, and an oxy-Michael addition reaction.     

Intramolecular Diels-Alder reaction in ionic liquids: effect of ion-specific solvent friction

The present work aims at understanding the role of viscosity or solvent friction in ionic liquids for an intramolecular Diels-Alder (IMDA) reaction of (E)-1-phenyl-4-[2-(3-methyl-2-butenyloxy)benzylidene]-5-pyrazolone (1). The results have been analyzed on the basis of the current theoretical models, and their failure to account for the observed trends is discussed in terms of "effective" viscosity or microviscosity. The rates of the reaction decrease with the increasing viscosity of the ionic liquids. As evident from the anionic effect, the solute-solvent specific interactions play a role in governing the kinetics of the reaction. The lower viscosities of the bistrifluoromethanesulfonimide [NTf2](-) based ionic liquids as compared to those based on tetrafluoroborate [BF4](-) anion fail to result in a corresponding acceleration in the rates of the reaction. These contradictory results indicate that solvent microviscosity, rather than the bulk macroscopic viscosity, should be the criteria for selecting the ionic liquids as reaction media.     

Intramolecular Diels-Alder reactions of ester-linked 1,3,8-nonatrienes

[structures: see text] Penta-1,3-dienyl acrylates undergo kinetically controlled intramolecular Diels-Alder (IMDA) reactions and DFT calculations (B3LYP/6-31+G(d)) predict stereoselectivities that are in very good agreement with the experimental values. The nature of the diene C1 substituent has virtually no influence upon reactivity or trans/cis-stereoselectivity whereas terminal C9 dienophile substituents have a substantial effect on both the reactivity and stereoselectivity of these IMDA reactions. The TSs highlight contributions from strain in the developing tether-containing ring, and steric and electronic effects between tether and dienophile substituents, thus providing insight into the origins of IMDA reactivity and stereoselectivity.     

Nature-inspired total synthesis of (-)-fusarisetin A

A concise, protecting group-free total synthesis of (-)-fusarisetin A (1) was efficiently achieved in nine steps from commercially available (S)-(-)-citronellal. The synthetic approach was inspired by our proposed biosynthesis of 1. Key transformations of our strategy include a facile construction of the decalin moiety that is produced via a stereoselective IMDA reaction and a one-pot TEMPO-induced radical cyclization/aminolysis that forms the C ring of 1. Our route is amenable to analogue synthesis for biological evaluation.     

IMDA/retro-Mannich approach to cis-perhydroquinoline Lycopodium alkaloids: asymmetric synthesis of (+)-luciduline

[formula: see text] The first chiral auxiliary mediated asymmetric synthesis of the naturally occurring Lycopodium alkaloid (+)-luciduline has been accomplished. Key steps include an IMDA reaction of a chiral dihydropyridine, a subsequent retro-Mannich ring opening, and a novel cationic reductive cyclization reaction.     

Rapid construction of the unique BCD ring system of tricyclo[6.2.1.0] undecane in the C19-diterpenoid alkaloid aconitine

A model study leading to the preparation of the unique tricyclo [6.2.1.0] undecane BCD ring systems of aconitine is described. The synthesis features an unprecedented diastereoselective oxidative dearomatization/dimerization/retro-DA/IMDA cascade reaction and a highly efficient Wagner-Meerwein rearrangement.