Dihydropyranone

Dihydropyrans [71] and 4-dihydropyranones [72] have been prepared by BF3 or Me2AlCl catalyzed Diels-Alder reactions of alkyl and aryl aldehydes with dienes 72 and 73 (Equations 3.20 and 3.21). Allylic bis-silanes are useful building blocks for synthesizing molecules of biological interest [73], 4-Pyra-nones have been obtained by cerium ammonium nitrate (CAN) oxidation of the cycloadducts. 

The Diels Alder reaction of aldehydes 74 with dienes 75 in the presence of chiral acyloxyborane (CAB) catalysts 76 provides enantioselectively chiral 4-dihydropyranones (Equation 3.22) after CF3CO2H treatment of the cycloadducts [74]. 

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). 

Further studies by Bode and co-workers have shown that enolate formation from a-chloroaldehydes and subsequent reaction with 4-oxo-enoates or unsaturated a-ketoesters 232 generates dihydropyranones 233 in excellent diastereo- and enantio-selectivities, and with impressively low catalyst loadings [90], This work has been extended to the generation of enolate equivalents from bisulfite adducts of a-haloaldehydes 234 under aqueous conditions (Scheme 12.50) [91]. 

A survey of Wacker-type etherification reactions reveals many reports on the formation of five- and six-membered oxacycles using various internal oxygen nucleophiles. For example, phenols401,402 and aliphatic alcohols401,403-406 have been shown to be competent nucleophiles in Pd-catalyzed 6- TZ /fl-cyclization reactions that afford chromenes (Equation (109)) and dihydropyranones (Equation (110)). Also effective is the carbonyl oxygen or enol of a 1,3-diketone (Equation (111)).407 In this case, the initially formed exo-alkene is isomerized to a furan product. A similar 5-m -cyclization has been reported using an Ru(n) catalyst derived in situ from the oxidative addition of Ru3(CO)i2... 

Levoglucosenone, a bicyclic dihydropyranone, is accessible even more directly by vacuum pyrolysis of waste paper." Although the yield attainable is relatively low—levoglucosan is also formed, the amount depending on the exact conditions... 

Scheme 12.23 Danishefsky transformation dihydropyranone product Pj obtained from Pi after acidic work-up with trifluoroacetic acid (TFA).

ZnCl2 was also used for a hetero-Diels-Alder reaction of 192 with Danishefsky diene. The dihydropyranone was obtained in 61% yield and good diastereoselectivity (Equation 59) <1998T14573>. 

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). 

Another general approach to sugars starts from (2-furyl)methanols (furfuryl alcohols, 22). Bromination at low temperature in methanol (Clauson-Kaas reaction) and subsequent mild acidic hydrolysis of 2,5-dimethoxy-2,5-dihydrofurans 23 obtained, leads to 6-hydroxy-2,3-dihydro-6//-pyran-3-ones 24 (Scheme 8) [40], The same dihydropyranones can be... 

There is little information on the mass spectra of monocyclic dihydropyranones. 

The sofa or 1,2-diplanar conformation in which five adjacent atoms lie in one plane is predicted for dihydropyranones (66MI22202). 

In an extension of this method, the cycloaddition of dichloroketene to the heterocyclic aminomethyleneketone (341) yields the dihydropyranone which is dehydrochlorinated with DBN to the fused pyran-2-one (Scheme 104) (78JHC181). Similar behaviour is shown by the benzologue of the enamine. 

The enaminones (342) also react with dichloroketene, forming 3,4-dihydropyranones (80JHC61). Dehydrochlorination with triethylamine gives the substituted pyrano[3,2-c]-[l]benzopyran-2-ones (343 Scheme 105). Yields are notably better when at least one of the substituents on the amine is aromatic. 

Ketene itself reacts with enamines and if in excess produces pyran-2-ones which are substituted in the 4-, 5- and 6-positions (65JOC2642). It seems likely that the acylated enamine undergoes a 1,4-addition with ketene to give an intermediate 4-amino-3,4-dihydropyranone, which eliminates the secondary amine on further reaction with ketene. 

The compounds covered in this section include dihydropyranones, tetrahydropyranones and their benzologues (dihydrocoumarins, chromanones and isochromanones). The area of greatest interest is undoubtedly the chromanones because of their relationship to a number of natural products and presumably also because of their ease of formation, stability and value as precursors of other heterocycles. Tetrahydropyran-2-ones comprise one of those nebulous areas of heterocyclic chemistry and usually feature in text books as 5-lactones under derivatives of hydroxy acids. 

Interest has been expressed in the use of dihydropyranones as synthons for natural products and this has led to the development of a valuable route to 5,6-dihydropyranones. Electron-rich dienes bearing a trimethylsilyloxy substituent undergo cycloadditions with carbonyl compounds at room temperature in the presence of a Lewis acid (Scheme 210) (82JA358). The intermediacy of a reduced pyran has been postulated. 

In practice, oxidations of this type have been observed and generally have been carried out with a substrate bearing a racemic secondary alcohol so that kinetic resolution is achieved. Although these oxidations are not strictly within the scope of this chapter, they are summarized briefly in Eqs. 6A.7-6A.9 to acquaint the reader with other potential uses for the Ti-tartrate catalytic complex. In the kinetic resolutions shown in Eqs. 6A.7 and 6A.8, the oxidations are controlled by limiting the amount of oxidant used to 0.6 equiv. Only modest resolution was attained for the acetylenic alcohol (Eq. 6A.7, 21% ee) [77] and the allenic alcohol (Eq. 6A.8, 40% ee) [77]. Resolutions of the furanols [142] or the thiophene alcohols [143] of Eq. 6A.9 generally are excellent (90-98% ee except when Rj is a I-butyl group). Only in the kinetic resolution of the furanols has the oxidation product been identified and, in that case, is a dihydropyranone. 

Manoalide, a marine anti-inflammatory sesterterpenoid, has been synthesized555 using a 1,2-metallate rearrangement of a higher order cuprate and a Pd(0)-catalysed carbonylation of an iodoalkene to generate the central dihydropyranone ring. 

A key step in a synthesis32 of 18-O-methyl mycalamide B involved the conjugate addition of TBDMSCN, with TBDMSOTf catalysis, to give a dihydropyranone this proceeded with very high 1,3-asymmetric induction (equation 7). 

A transformation of dihydropyranones to substituted oxepanes is described <2001H(55)855, 2001TL1095>. The key steps are ring-enlargement followed by the action of a silyl enolate (Scheme 48). 

Cyclocurcumin differs from curcumin in the p-diketone link. In this molecule, the a, p-unsaturated p-diketone moiety of curcumin is replaced by a, p-unsaturated dihydropyranone moiety. Up to now, not many biological studies are reported with cyclocurcumin except for one study on inhibition of MCF-7 tumor cell proliferation by Simon et al. [1998] where it has been found to be ineffective in inhibiting cell proliferation and arrest of cell-cycle progression. 

The polymer-bound Mn and Cr complexes were used as catalysts for epoxidations of six phenyl-substituted olefins with m-CPBA/NMO and for dihydropyranone formation from the Danishefsky diene and aldehydes. There are several remarkable features of the novel immobilized salens ... 

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. 

Elimination of the sulfone from the tetrahydropyran-2-one 661 occurs with a concomitant shift of the exocyclic methylene bond to afford the meta-bridged 277-pyran-2-one 662 (Equation 268) <1999JOC8281>. The addition of bromine to dihydropyranones and elimination of 2 equiv of HBr yields 277-pyran-2-ones < 1984CHEC, 1996CHEC-II>. 

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