A novel diastereoselective route to alpha-hydroxyalkyl dihydropyrans using a hetero Diels-Alder/allylboration sequence

The development of a new strategy for the synthesis of alpha-hydroxyalkyl dihydropyrans is reported. This approach is based on a tandem hetero[4+2]/allylboration reaction.     

A novel diastereoselective route to alpha-hydroxyalkyl dihydropyrans using an hetero Diels-Alder/allylboration sequence

The development of a new strategy for the synthesis of alpha-hydroxyalkyl dihydropyrans is reported. This approach is based on a tandem hetero[4 + 2]/allylboration reaction.     

Multi-component regio- and diastereoselective cobalt-catalyzed hydrovinylation/allylboration reaction sequence

The combination of a regioselective cobalt-catalyzed 1,4-hydrovinylation and the diastereoselective allylboronation reaction leads to a wide scope of functionalized hydroxydienyl esters in a one-pot reaction in excellent yields. With catalytic amounts of base, these products are easily converted either into α,β,γ,δ-unsaturated hydroxyl esters or complex tetrasubstituted tetrahydropyrans in chemo- and diastereoselective fashions. In addition, a high-yielding four-component one-pot reaction involving an acrylate, two different and unsymmetrical 1,3-dienes, and an unsaturated aldehyde is presented.     

Mechanisms of the Knoevenagel hetero Diels-Alder sequence in multicomponent reactions to dihydropyrans: experimental and theoretical investigations into the role of water

The role of water in a multicomponent domino reaction (MCR) involving styrene, 2,4-pentanedione, and formaldehyde was studied. Whereas anhydrous conditions produced no reaction, the MCR successfully proceeded in the presence of water, affording the targeted dihydropyran derivatives with good yield. The mechanism of this MCR (Knoevenagel hetero Diels-Alder sequence) was studied with and without explicit water molecules using the SMD continuum solvation model in combination with the B3LYP density functional and the 6-311++G** basis set to compute the water and acetone (aprotic organic solvent) solution Gibbs free energies. In the Knoevenagel step, we found that water acted as a proton relay to favor the formation of more flexible six-membered ring transition state structures both in concerted (direct H(2)O elimination) and stepwise (keto-enol tautomerization and dehydration) pathways. The inclusion of a water molecule in our model resulted in a significant decrease (-8.5 kcal mol(-1)ΔG(water)(?)) of the direct water elimination activation barrier. Owing to the presence of water, all chemical steps involved in the MCR mechanism had activation free energies barriers lower than 39 kcal mol(-1) at 25 °C in aqueous solvent (<21 kcal mol(-1) ZPE corrected electronic energies barriers). Consequently, the MCR proceeded without the assistance of any catalyst.     

Enantioselective synthesis of 1,5-anti- and 1,5-syn-diols using a highly diastereoselective one-pot double allylboration reaction sequence

Highly diastereo- and enantioselective syntheses of 1,5-disubstituted (E)-1,5-anti-pent-2-endiols 1 and (Z)-1,5-syn-pent-2-endiols 2 have been achieved via the one-pot coupling of two different aldehydes with either (E)-gamma-(1,3,2-dioxaborinanyl)-allyl]diisopinocampheylborane (4) or (E)-gamma-(4,4,5,5-tetraphenyl-1,3,2-dioxaborolanyl)allyl]diisopinocampheylborane (11), respectively. The indicated diols 1 and 2 are obtained in 63-95% yield with 89-96% ee and >/=20:1 diastereoselectivity in all cases. The bifunctional gamma-boryl-substituted allylborane reagents 4 and 11 were generated in situ by the hydroboration of allenes 3 and 10 with diisopinocampheylborane. The keys to the success of this method are the excellent stereocontrol in the allylboration step leading to 5 and the corresponding substituted methallylboronate derived from 11, the stereospecificity of the subsequent allylboration reaction of the substituted methallylboronate intermediates, and the ability of the diol auxiliary to induce equatorial or axial placement of the substituent alpha to boron in transition states 7 and 8.     

A novel group transfer polymerization of 1-trimethylsiloxy-benzocyclobutene via hetero Diels-Alder reaction

A novel group transfer polymerization via hetero-Diels-Alder reaction is described. When 1-trimethylsiloxybenzocyclobutene ( 1 ) was treated with a catalytic amount of p-anisaldehyde (4-methoxybenzaldehyde) and TASF (tris(dimethylamino)sulfonium difluorotrimethylsilanide) at room temperature for 0.5 h, poly[1,2-phenylene-1-(trimethylsiloxy)ethylene] was obtained quantitatively. The number-average molecular weight of the polymer was M̄_n = 2000 and the molecular weight distribution was narrow (ratio of weight-to number-average molecular weights M̄_w/M̄_n = 1.18). Structural characteristics suggested a polymerization mechanism involving isomerization of 1 to o-quinodimethane and successive hetero-Diels-Alder reaction leading to poly[1,2-phenylene-1-trimethylsiloxy ethylene]. The living-like nature of the polymerization was supported by a monomer addition experiment in which the molecular weight increased according to the increase of the added monomer.     

Highly diastereoselective Diels-Alder reaction using a chiral auxiliary derived from levoglucosenone

[reaction: see text] A new chiral auxiliary derived from levoglucosenone is reported. The compound is obtained by a cycloaddition reaction with 9-methoxy methylanthracene followed by a diastereoselective reduction of the C-2 keto function. The auxiliary has been used as a chiral template in an asymmetric Diels-Alder reaction of the corresponding acrylic ester derivative with cyclopentadiene. The results showed excellent diastereomeric excess even at room temperature when the reaction was promoted by Et(2)AlCl as the Lewis acid.     

Catalytic, asymmetric trans-selective hetero Diels-Alder reactions using a chiral zirconium complex

[reaction: see text] The first catalytic, asymmetric 2,3-trans-selective hetero Diels-Alder reaction has been developed. The reactions of aldehydes with Danishefsky's dienes proceeded smoothly to afford the pyranone derivatives in high yields with high trans-selectivities and enantioselectivities in the presence of a chiral zirconium complex, which was prepared from zirconium tert-butoxide and (R)-3,3'-diiodobinaphthol or its derivatives, primary alcohol, and a small amount of water. This reaction was applied to the concise synthesis of (+)-prelactone C.     

A diastereoselective route to (±)-isoretronecanol

N-Unsubstituted imides react with 1-carboethoxycyclopropyltriphenylphosphonium tetrafluoroborate to yield N-acyl-Δ²-pyrroline, pyrrolizidine, and indolizidine derivatives.     

Conversion of a nitrosocarbonyl hetero Diels-Alder cycloadduct to useful isoxazoline-carbocyclic aminols

A new approach to useful precursors for the synthesis of isoxazoline-carbocyclic nucleosides is detailed, starting from the readily available N-benzoyl-2,3-oxazanorborn-5-ene and introducing more polar and hydrophilic functionalities through 1,3-dipolar cycloaddition of carbethoxyformonitrile oxide, generated either from the corresponding hydroximoyl chloride or, more conveniently, by catalyzed condensation with ethyl nitroacetate.     

Dienamines as Diels-Alder dienes. A novel benzannulation sequence

Diels-Alder reaction between (E)-dienamines 1, – 7 and methyl propiolate followed by elimination of Me₂NH from the intermediate cycloadducts III affords the aromatic methyl esters 8, – 14 in good yield.     

Enantioselective catalysis of hetero Diels-Alder reaction and diethylzinc addition using a single catalyst

[reaction: see text] Integration of two asymmetric reactions in one pot with the promotion of a single catalyst has been achieved in high efficiency and excellent stereoselectivity for hetero Diels-Alder reaction of Danishefsky's diene and diethylzinc addition to aldehydes. The strategy described in the present work demonstrated the ability of a single catalyst to promote two distinct enantioselective reactions in one pot.     

A Diels-Alder route to angularly functionalized bicyclic structures

A Diels-Alder-based route to trans-fused angularly functionalized bicyclic structures has been developed. This transformation features the use of a tetrasubstituted dienophile in the cycloaddition step.     

A direct route to fluostatin C by a fascinating Diels-Alder reaction

The Diels-Alder reactions between vinylindenes (5 or 6) as the dienes with quinoneketals (7 or 8) or with methacrolein as the dienophiles were investigated. The remarkable regioselectivities of these Diels-Alder adducts suggested that the regiopreferences of these dienes and dienophiles in these cases are not a fixed property of each component of the cycloaddition but are mutually contigent. This paper shows how the Diels-Alder reaction between 6 and 8 was applied to the inaugural total syntheses of fluostatin C and E.     

An atom-efficient conjugation approach to well-defined block copolymers using RAFT chemistry and hetero Diels-Alder cycloaddition

The tendency of electron-deficient dithioesters to undergo hetero Diels-Alder cycloadditions is successfully used to generate polymer conjugates between a RAFT-polymerized poly(styrene) and a diene-terminated poly(epsilon-caprolactone).     

A novel Diels-Alder approach to carbapenems

An inverse electron demand hetero-Diels-Alder reaction between 2-acylaminomethylene-3-oxobutanoic acid derivatives (5) and ketene acetals (6) yields crystalline dihydropyrans, which are versatile intermediates in the synthesis of carbapenems.     

A novel and facile stereocontrolled synthetic method for polyhydro-quinolines and pyridopyridazines via a diene-transmissive Diels-Alder reaction involving inverse electron-demand hetero Diels-Alder cycloaddition of cross-conjugated azatrienes

Cross-conjugated azatrienes bearing an electron-withdrawing sulfonyl or benzoyl group on the nitrogen atom underwent, on heating or in the presence of a Lewis acid (TMSOTf), an initial inverse electron-demand hetero Diels-Alder reaction with electron-rich dienophiles (vinyl ether, vinyl thioether, and allenyl ether) to produce 1:1 cycloadducts with high endo selectivity. The initial cycloadducts thus obtained underwent a second Diels-Alder reaction stereoselectively on the newly formed diene unit with electron-deficient dienophiles to give the crossed bis-cycloadducts, octahydroquinolines, with high diastereo-π-facial selectivity. The N-sulfonylazatrienes tethering an ortho-cinnamyloxyphenyl dienophile at the triene terminal underwent an initial intramolecular hetero Diels-Alder reaction of the inverse electron-demand type. The subsequent second Diels-Alder reaction of the formed mono-cycloadducts completed the diene-transmissive hetero Diels-Alder protocol to give benzopyrano[3,4-c]quinolines in a highly stereoselective manner.     

A short diastereoselective synthesis of the putative alkaloid jamtine,using a tandem pummerer/mannich cyclization sequence

Treatment of 2-phenylhex-5-enal with benzylamine followed by sequential reaction with ethylthioacetyl chloride and sodium periodate oxidation afforded a E/Z mixture of alpha-sulfinylamides. As anticipated from a 4pi-conrotatory mechanism, cyclization of each olefin afforded fused isoquinoline lactams as single diastereomers epimeric at the ethylthio position without any cross contamination. Some preliminary studies were directed toward the synthesis of mesembrine using a 3,4-dimethoxy aryl group. In this case, the Z-enamide prefers to undergo electrophilic aromatic substitution to give a substituted azepinone as the preferred product in 87% yield. In contrast, the E-enamide isomer provided the desired hydroindolone. The convergency and stereochemical control associated with the tandem Pummerer /Mannich cyclization make it particularly suited for the assembly of jamtine, a tetrahydroisoquinoline alkaloid reputed for its therapeutic properties. The key step in the synthesis involves a domino thionium/N-acyliminium ion cyclization to provide the tricyclic ring skeleton 27a as the major diastereomer. Deprotonation of 27a with NaH gave 28a, which contains the fully assembled skeleton of jamtine. Completion of the synthesis entailed installation of the double bond and reduction of the lactam. Oxidation of a synthetic sample of jamtine with MCPBA afforded the corresponding N-oxide, which does not match the spectral data reported in the literature for this alkaloid. Our synthetic efforts raise the possibility of a revision of the earlier assignment.     

Organocatalytic multicomponent alpha-methylenation/Diels-Alder reactions: a versatile route to substituted cyclohexenecarbaldehyde derivatives

This article describes the design and optimization of an effective organocatalytic three-component domino alpha-methylenation/Diels-Alder reaction to produce vinyl-substituted cyclohexenecarboxaldehydes in a highly regioselective fashion. In these one-pot transformations, 2-formyl-1,3-butadienes (4) were prepared in situ from alpha,beta-unsaturated aldehydes and formalin and were subsequently trapped with a variety of buta-1,3-dienes. The outcomes of the reactions were dependent on the electronic properties of the dienes. 1-Vinylcyclohexenecarbaldehydes 6 were formed by use of acyclic electron-rich dienes, while the initially formed cycloadducts of 4 with cyclopentadiene underwent Cope rearrangements, leading to the formation of tetrahydro-3H-indene-5-carbaldehyde compounds 7. The mechanisms involved in these reactions were deduced from experimental findings. Furthermore, the method was also extended to one-pot domino methylenation/Diels-Alder reactions of dihydrofurans and dihydropyrans to yield spirocyclic lactols 22. In these reactions, the unstable intermediate hydroxyethyl and hydroxypropyl acroleins behaved as dienophiles, undergoing cycloaddition reactions with dienes with good yields and selectivities. The wide variety of functionalized 1-vinylcyclohex-3-enecarbaldehydes 6, 4-vinylcyclohex-1-enecarbaldehydes 7, and spiro lactols 22 generated through the use of these organocatalytic domino processes as a diversity-oriented synthesis provided useful intermediates for the construction of novel odorants.