Dihydropyranone synthesis

Fig. 6 Catalytic asymmetric dihydropyranone synthesis through copper(l)-catalyzed asymmetric aldol reaction and subsequent silver(I)-catalyzed oxy-Michael reaction...

The enantioselection depends greatly on the nature of the R2 group at the boron atom, and the ee values were as high as 97 %. High enantioselectivity was observed in the synthesis of 4-dihydropyranones, based on the Diels-Alder reactions of aldehydes 74 and Danishefsky s diene, catalyzed by a BINOL-Ti(0-i-Pr)4-derived catalyst [75] (Equation 3.23). 

These authors also described a three-step synthesis of 13Z-retinoic acid [56], The obtained hydroxydihydropyrane (66%) was oxidized either by Jones s reagent (CrC>3, water, H2SO4, 90%) or Corey s reagent (pyridinium chlorochromate (PCC), 65%). Finally, the dihydropyranone was transformed into retinoic acid (as a mixture of 9E, 13Z, and 9Z,13Z), by /BuOK, according to a known procedure [57], Fig. (26). 

Formation of the isochroman system is considered to trigger the synthesis of the dibenzopyran (17, X = H2) by the acid catalysed cyclisation of c/s-enediynes (16, X = H2). In a similar manner, the carboxyl function in (16, X = O) promotes cylisation to a dihydropyranone derivative which is followed by a Myers cycloaromatisation to the dibenzopyranone (17, X = O) (95TL9165). 

The synthesis of 1,5-diketones 521 from 3,4-dihydropyranones 519 has been reported and is shown in Scheme 95 <1999T9333>. Organolithium reagents were used to open the lactone reagents, and best results were achieved when the reactions were quenched with trimethylsilyl chloride prior to hydrolytic workup. 

The synthesis of dihydropyranones by the asymmetric HDA reaction <07SL2147> and advances in approaches to natural product-based analogues <07EJO225> have been reviewed. 

Cyclobutane.—Further reports of grandisol (90) synthesis include Magnus s full paper (Vol. 6, p. 22) and an almost identical Japanese report of an earlier synthesis (Vol. 3, p. 25) based upon a dihydropyranone-ethylene cycloaddition.A third synthesis utilizes cyclopropanation of 4-methoxy-3,6,6-trimethylcyclohexa-2,4-dienone to yield (91) followed by rearrangement of the a-oxycyclopropylcarbinyl cation of (91) to (92). After reduction of the cyclobutanone, second-order Beckmann cleavage of the cyclopentanone oxime gave (93) from which grandisol (90) was readily obtained. 

Acetylketene [4 + 2] cycloaddition with vinyl n-butyl ether gave the useful dihydropyranone intermediate (32), from which various 2,6-dideoxy monosaccharides were obtained. The key steps in synthesis of racemic butyl olivoside (34) consisted of stereoselective 1,2-reduction of conjugated ketone with diisobutylaluminum hydride, followed by standard hyrobora-tion/oxidation procedure (Scheme 3) [53]. 

SCHEME 19 Synthesis of the dihydropyranone 51 and completion of the synthesis of acortarin A 20. 

Subsequently, the same group reported a synthetically useful protocol to stereospecific synthesis of syn- and a/rti-dihydropyranones containing a stereogenic trifluoromethyl substituent through NHC-catalyzed redox het-ero-Diels-Alder reactions of either E- or Z-p-trifluoromethyl enones with a-aroyloxyaldehydes. Kinetic experiments revealed the formation of 0-acylated enolate species when an achiral precatalyst was used in these reactions, accounting for the difference in reactivity observed compared with a chiral precatalyst. The measurement of a positive KIE suggests that deprotonation of the NHC-aldehyde adduct to form the Breslow intermediate is kinetically significant (Scheme 7.84). 

The Xiao group developed NHC-catalyzed annulations of ynals and enals with 1,3-dicarbonyls, which provide direct and efficient methods for stereoselective synthesis of functionalized dihydropyranones from simple starting materials. The molecular sieves played a crucial role in obtaining excellent yields and selectivity. The mild conditions and high enantiose-lectivity make this approach extremely attractive (up to 90% yield, 98% ee) (Scheme 7.97). 

The Biju group discovered an NHC-catalyzed generation of chiral a,p-unsaturated acylazoliums from 2-bromoenals followed by their interception with 1,3-dicarbonyl compounds or enamines, via a formal [3 + 3] annulation reaction. The reaction results in the enantioselective synthesis of synthetically and medicinally important dihydropyranones and dihydropyridinones, and tolerates a wide range of functional groups. It is noteworthy that the... 

The Biju group developed a highly enantioselective NHC-catalyzed lac-tonization of 2-bromoenals with enolizable aldehydes proceeding via the chiral a,p-unsaturated acyl azolium intermediates. The reaction offers a new approach for the asymmetric synthesis of synthetically important 4,5-disubstituted dihydropyranones. Mild reaction conditions, relatively low... 

The Yao group disclosed an NHC-catalyzed oxidative y-addition of a,p-unsaturated aldehydes to isatins, providing a facile access to a highly efficient synthesis of spiro oxindole-dihydropyranones. " An efficient construction of the spiro oxindole-dihydropyranone scaffold via the NHC-catalyzed oxidative y-functionalization of a,p-unsaturated aldehydes bearing y-H with isatin derivatives was achieved. Preliminary study on the asymmetric version of this methodology was also carried out. However, only moderate enantiose-lectivity was realized (up to 33% ee) (Scheme 7.117). 

A concise sequence was developed for the total synthesis of )-6-q>i-cleistenolide (14EJO8049). It required only five steps in an overall yield of 60% from the commercially available furylallyl alcohol.The aforementioned Achmatowicz reaction took place with the furan diol intermediate to give the dihydropyranone product.The final product was obtained via a sequence of oxidation, reduction, and acetylation. 

SuGiYAMA, T., T. Murayama, K. Yamashita, and T. Orttani Synthesis of Chiral Aspyrone, a Multi-functional Dihydropyranone Antibiotic. Biosci. Biotechnol. Biochem., 59, 1921 (1995). 

The same aza-HDA strategy has also been applied for the asymmetric catalytic synthesis of chiral dihydropyranones. Akiyama and his group used the chiral Br0nsted acid/pyridinium salt 81 to catalyze the cycloaddition of imines 79 with Brassard s diene 80 and the products 82 were isolated in moderate to good yield and between 92-99% ee (Scheme 6.18) [46]. 

Ye and co-workers [30] ingeniously replaced the enals by bromoenals and used a M-heterocyclic carbene (NHC) as chiral organocatalyst for the formation of the corresponding dihydropyranones in a formal enantioselective [3-1-3] annulation reaction (Scheme 16.14). Similarly, Scheldt s group [31] reported the synthesis of optically active bi- or tricyclic dihydropyranones by an NHC-catalyzed domino intramolecular Michael/acylation sequence. 

Indole-fused dihydropyranone 125 was synthesized in enantioselective [4 - - 2] cycloadditions of aryl(alkyl)ketenes with readily prepared 3-alkylenyloxindoles 124 under chiral NHC 46 catalysis conditions. This highly regio- and enantio-selective synthesis affords compound 125 in trans/cis, 10 1 ratio and 90 ee (Scheme 43) (2010JOC6973). 

Lupton et al. reported the total synthesis of (-) 7-deoxyloganin (82) in 18 steps from 2,5-dimethoxytetrahydrofuran in overall 0.8% yield. The key step of their synthetic strategy was the N-heterocyclic nucleophilic carbene-catalyzed rearrangement of ot,p-unsaturated enol ester (83) to dihydropyranone (84) (Scheme 97.7) [114]. 

Dihydropyranones The use of Meldrum s acid as a CHj-C(0) equivalent was successfully applied in the synthesis of 3,4-dihydropyranones. The reaction of Meldrum s acid 112 with several aldehydes 453 and dim-edone 15 under grinding conditions to form 3,4-dihydropyranones 454 was reported by Rong in 2007 (Scheme 13.95) [186]. 

SCHEME 13.95 Synthesis of 3,4-dihydropyranones 454/458 starting from 1,3-dicarbonyl compounds 15/47/455/456. 

SCHEME 13.96 Synthesis of 3,4-dihydropyranones 460/463 starting from stable enols 37/461. 

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