An interesting issue of Diels-Alder selectivity discovered en route to 11-O-debenzoyltashironin

The hypervalent iodine-mediated oxidative dearomatization/Diels-Alder cascade was examined in the context of the natural product 11-O-debenzoyltashironin. Interestingly, the regioselectivity of the Diels-Alder reaction can be completely switched by changing the dienophile. Trapping of allyl alcohols during the oxidative dearomatization gives rise to the five-membered acetal, while trapping of allenyl alcohols results in the six-membered acetal. [reaction: see text]     

o-Quinone methide based approach to isoflavans: application to the total syntheses of equol, 3′-hydroxyequol and vestitol

A concise strategy is developed for the synthesis of isoflavans employing a Diels-Alder reaction between o-quinone methides and aryl-substituted enol ethers followed by reductive cleavage of the acetal group. The method is extended towards the total syntheses of equol, 3′-hydroxyequol and vestitol.     

Remarkable stereocontrol in the synthesis of 1,2,3,5-tetrasubstituted tetrahydropyrans via an asymmetric heterocycloaddition of a ketone-derived enol ether

The synthesis of chiral 1,2,3,5-substituted tetrahydropyrans has been realized via an asymmetric hetero Diels-Alder (HDA) reaction. The key step that involved a trisubstituted chiral enol ether derived from (R)-mandelic acid as the dienophile promoted the creation of three stereogenic centers with a remarkable and unprecedented endo and facial stereocontrol. The hydrogenation of the heteroadduct 2 was optimized by using Pd on charcoal and diisopropylethylamine, leading to a unique isomer. The chiral inductor was cleanly and stereoselectively removed via an acetal reduction, which demonstrated the potential of this methodology for the efficient construction of key intermediate of biologically active molecules.     

Synthetic studies on (-)-FR182877: construction of the ABCD ring system via the intramolecular cycloadditions (1)

Construction of the ABCD ring system of (-)-FR182877 via the highly diastereoselective intramolecular Diels-Alder (IMDA) reaction is described. The IMDA reaction of the α,β-unsaturated aldehyde generated in situ from the corresponding acetal successfully provided the desired product 14 possessing the AB ring system as the single diastereomer. The CD ring system was constructed by the subsequent IMHDA reaction and the additional experiment suggested that the diastereoselectivity of the IMHDA reaction could be related to the E/Z geometry of alkene 17, which was generated in situ from 16.     

Investigation of the asymmetric ionic Diels-Alder reaction for the synthesis of cis-decalins

The ionic Diels-Alder reaction, whereby an alpha,beta-unsaturated acetal in combination with a Lewis or Bronsted acid forms an equilibrium concentration of an activated dienophile, has been developed to provide an enantioselective synthesis of cis-decalins. Cyclohex-2-enone type chiral acetals of (2R,3R)-butane-2,3-diol have been screened against Lewis and Br?nsted acids with a variety of dienes and are efficient for the synthesis of a limited subset of cis-decalin structures. Diastereoselectivities of 73% and 82% have been found for the asymmetric ionic Diels-Alder reaction between the chiral acetal derivatives of cyclohex-2-enone (6) and 2-methylcyclohex-2-enone (18) with 2,3-dimethyl-1,3-butadiene (7). Terminal substituents on the diene partner in general render the system unreactive. However a synthetically useful cis-decalin 31, derived from the reaction of 2-methylcyclohex-2-enone and Z-3-t-butyldimethyl-silyloxypenta-1,3-diene has been prepared in enantiomerically pure form in 74% isolated yield using this asymmetric ionic Diels-Alder protocol.     

Synthesis of a key intermediate for the total synthesis of pseudopteroxazole

A facile synthesis of a key intermediate for the total synthesis of anti-mycobacterial compound pseudopteroxazole is described employing an intramolecular Diels-Alder cyclization and an iodine-mediated oxidative aromatization step.     

A general route to 11-deoxyanthracyclines

Diels-Alder type cycloaddition of unsaturated ketene acetal $\text{5}$ with various naphtoquinones affords a short and regiospecific access to tetracyclic ketones, key intermediates for the further synthesis of 11-deoxyanthracyclines.     

Enantiospecific synthesis of 1-deoxy-castanospermine, (6S,7R,8R, 8aR)-trihydroxyindolizidine,from D-glucose.

An enantiospecific synthesis of 1-deoxy-castanospermine (2) is described from D-glucose, where the key step involves oxidative bromination of a benzylidene acetal to afford 8-azido-3-O-benzoyl-5-bromo-5,6,7,8-tetradeoxy-1,2-O-isopropylidene-β-L-ido-octose (6).     

Synthesis of a 2-hydroxymethyl-dihydropyridone-system as a flexible building block for the preparation of azasugars

mCPBA induced oxidative cyclization of the aminoalcohol 1a under complete stereocontrol, generating after acetal formation a new diastereomerically pure key intermediate 2b for the flexible synthesis of azasugars. 2b could be converted to protected rac-mannonojirimycin, 3 in only three steps.     

Enantiospecific synthesis of polyhydroxylated indolizidines related to castanospermine:1 1-deoxy-castanospermine.

Enantiospecific synthesis of (6S,7R,8R,8aR)-6,7,8- trihydroxyindolizidine ( 1-deoxy-castanospermine ) (3) is described from readily available D-glucose, where the key step involves oxidative bromination of a benzylidene acetal to afford 8-azido-3-o-benzoyl-5-bromo-5,6,7,8-tetradeoxy-1,2-o-isopropylidene-β-L-ido-octose (16). The synthetic indolizidine (3) was tested against a range of glycosidases.     

Synthesis of the B-ring of FR182877. Investigation of the reactions of 6-fumaryl 1,3,8-nonatrienes

Investigation of the intramolecular Diels-Alder reactions of 6-fumaryl 1,3,8-nonatrienes, substituted at the C5 by a vinyl group, to afford the B-ring of FR182877 are reported. The synthesis of the required 1,3,8-nonatriene was achieved quickly and in high yield. 6-Fumaryl 1,3,8-nonatrienes substituted at the C5 by a vinyl group were found to undergo competing tandem sigmatropic rearrangement/Diels-Alder cyclisation when heated under standard Diels-Alder cyclisation conditions. This rearrangement became the exclusive pathway when the reaction was performed in the presence of a Lewis acid. As expected from modeling studies, the major intramolecular Diels-Alder cyclisation product was the desired exo-trans adduct, which was required for the synthesis of FR182877. Intrigued by the rearrangements, a number of alterations were made to the 1,3,8-nonatriene. Replacement of the fumaryl group by an acetyl group resulted in the diminished reactivity of the 1,3,8-nonatriene with neither rearrangements nor cycloadditions observed. Variation of the C5 substituent was found to be very important in determining the π-diastereoselectivity of the Diels-Alder cyclisation.     

En route to the total synthesis of tashironin: on the exercise of stereochemical control by a methyl group in mediating remote cyclization reactions

The synthesis of the [2.2.2]-bicyclic core (23) of the neurotrophic factor 11-O-debenzoyltashironin (1) has been achieved by an oxidative dearomatization-transannular Diels-Alder cascade. We have shown that the reaction sequence is also valuable for the efficient construction of related, complex [2.2.2]-bicyclic compounds (vide infra).     

Synthesis and structure of 1-(buta-1,3-dien-2-yl)pyrazoles and their behavior in Diels-Alder reactions

A convenient procedure has been developed for the synthesis of cis-and trans-isomeric 1-(buta-1,3-dien-1-yl)-1H-pyrazoles by reaction of the corresponding pyrazoles with β-methylacrolein diethyl acetal and subsequent 1,4-cleavage of the nucleophilic substitution products. The behavior of the title compounds in Diels-Alder reactions with maleic anhydride has been studied. According to the ¹H NMR data, 1-(buta-1,3-dien-1-yl)-1H-pyrazole is a mixture of cis and trans isomers. Butadienylpyrazoles having methyl groups in the pyrazole ring do not react with maleic anhydride.     

Probing the Lewis acid-catalyzed intramolecular Diels-Alder cyclizations of allylic alkoxy-substituted (Z)-1,3-dienes

[reaction: see text] The Lewis acid-promoted Diels-Alder reaction of (E,Z,E)-trienal 1 provides not only the expected cis-fused cycloadduct 16 but also the trans-fused products 17 and 18. Trans-fused cycloadducts 17 and 18 are also products of the Lewis acid-promoted cyclization of (E,Z,E)-trienyl acetal 2. These products presumably derive from a stepwise cyclization pathway.     

Thermal and palladium-catalyzed [3 + 2] synthesis of cyclopentadienone acetals from cyclopropenone acetals and acetylenes

[reaction: see text] Substituted cyclopentadienone acetals (CPDAs) were synthesized by a thermal or palladium-catalyzed [3 + 2] cycloaddition reaction of a substituted cyclopropenone acetal to an electron-deficient acetylene. The synthesis afforded di-, tri-, and tetra-substituted CPDAs of considerable structural varieties that undergo Diels-Alder reaction to produce bicyclo[2.2.1]heptenes.     

Generation and reactions of new ether and acetal functionalized tricyclo[3.3.0.0]oct-1(5)-ene derivatives. DSC and NMR studies on the [2+2] retrocycloaddition of several cyclobutane dimers

Two new highly pyramidalized tricyclo[3.3.0.0^3,7]oct-1(5)-ene derivatives containing ether and acetal functionalities have been generated, trapped as Diels-Alder adducts and dimerized. The initially obtained diene dimers were photochemically converted into cyclobutane derivatives. The thermal reversion of several cyclobutane derivatives to the corresponding dienes has been studied by ¹H NMR, ab initio calculations and DSC. For the first time, transannular additions of bromine and iodine to a diene dimer of this series have been observed.     

Tether-controlled cycloadditions for the asymmetric synthesis of decalins: increased selectivity in acetonitrile solvent

[reaction: see text] The beneficial influence of cis-isopropylidene acetal tether control groups, to facilitate the asymmetric synthesis of substituted decalins by intramolecular Diels-Alder reactions, is described. Compared to trans-acetonides, these cases proceed under milder conditions to afford the cis-fused adducts from an endo transition state. An unusual acetonitrile solvent effect exerts a dramatic influence on the diastereoselectivity. This strategy leads to the chiral nonracemic bicyclo[4.4.0]decane core of diverse natural products.     

Controlling chemoselectivity—application of DMF di-t-butyl acetal in the regioselective synthesis of 3-monosubstituted indolizines

Among a number of DMF dialkyl acetals investigated for the regioselective synthesis of 3-acylindolizines, the di-t-butyl acetal, via its iminium intermediate readily formed in situ, provides the highest chemoselectivity for the intermolecular cyclization of picolinium salts. DMF di-t-butyl acetal was applied to the syntheses of a variety of 3-acylated indolizines including alkyl, aryl, and heteroaryl substituents.     

Coupling-isomerization-N,S-ketene acetal-addition sequences--a three-component approach to highly fluorescent pyrrolo[2,3-b]pyridines, [1,8]naphthyridines, and pyrido[2,3-b]azepines

Annelated 2-amino pyridines such as pyrrolo[2,3-b]pyridines, [1,8]naphthyridines, and pyrido[2,3-b]azepines can be synthesized in moderate to good yields in a consecutive one-pot three-component process by a coupling-isomerization-enamine-addition-cyclocondensation sequence of an electron-poor (hetero)aryl halide, a terminal propargyl N-tosylamine, and an N,S-ketene acetal. After the coupling-isomerization sequence, a Diels-Alder reaction with inverse electron demand of the intermediate enimine and the N,S-ketene acetal and subsequent aromatization furnish annelated 2-amino pyridines 4 that were unambiguously characterized by numerous X-ray structure analyses. These heterocycles are highly fluorescent and partially pH sensitive, and their electronic structure was studied with spectroscopic and computational methods.     

Selective mono-fluorination of diols via a cyclic acetal of N,N-diethyl-4-methoxybenzamide

Selective mono-fluorination of 1,2- and 1,3-diols was achieved using N,N-diethyl-4-methoxybenzamide diethyl acetal and Et₃N-3HF. The reaction proceeds through a cyclic acetal of the benzamide, and only one hydroxy group was fluorinated and another one was acylated.