Ozonolysis of cyclic enol ethers: an efficient strategy to aldol and homoaldol compounds

Abstract

In our ongoing studies to develop asymmetric, catalytic methodology to functionalized acyclic compounds, we envisioned substituted cyclic enol ethers 1 as direct precursors to aldol and homoaldol products. Since a variety of catalytic,l as well as noncatalytic,2 methods to enantiomerically enriched dihydrofurans and dihydropyrans are known, we investigated the possibility of their oxidative ring opening by ozonolysis to develop a new access to aldol3 and homoaldo14 products.Although enol ethers play an important role in synthetic chemistry, their ozonolysis has not widely been ~t u d i e d .~ In particular, there are only a few accounts on the ozonolysis of cyclic enol ethers.6 Nevertheless, Danishef-sky7 et al. have noted that dihydro-y-pyrones can be unmasked as aldol compounds by ozonolysis. In this paper we wish to report that dihydropyrans 1 ( n = 1) are excellent equivalents for homoaldol as well as dihydrofurans 3 (n = 0 ) for aldol compounds.Our results are summarized in Table I. Since ozonolysis of 3,Cdihydro-W-pyran under reductive conditions leads to a mixture of products,6d it was desirable for the cleavage (1) (a) Hudlicky, T.; Reed,of 8-unsubstituted enol ethers to create a stable este9 rather than an aldehyde functionality. Therefore, the dihydropyrans Id-f, as well as the dihydrofurans 3 were ozonolyzed in a dichloromethane/methanol mixture under conditions developed by Schreiberg for carbocycles. According to this procedure the hydroperoxides, which are generated in situ, are dehydrated with triethylamine/acetic anhydride after azeotropic removal of methanol with benzene. These conditions could be successfully applied to cyclic enol ethers; however, it was discovered that the removal of methanol can be omitted with equally good results. This variation is especially useful for large-scale preparations,since the hydroperoxides which result from the ozonolysis of e g . 3a are very explosive and should only be handled at low temperatures. Thus, the 3-formyloxy ester 4a was conveniently prepared by this protocol (entry 10) as the sole product. Also, 3,4-dihydro-6-phenyl-2H-pyran (le) (entry 8) gave rise to the 4-formyloxy ester 2e in 91 % isolated yield accompanied by minor amounts (<3% as judged by IH NMR of the crude) of an unidentified byproduct. In an even better yield (94%) the 3-formyloxy ester 4b was obtained through ozonolysis of 5-phenyl-2,3-dihydrofuran 3b (entry 11). Cinnamylaldehyde was identified as the only byproduct (<3 % by lH NMR).Chiral dihydrofurans and dihydropyrans are opened under the applied conditions without loss of optical purity (entries 9 and 11). Multiple functionalized dihydropyran derivatives with usual protecting groups are also readily transformed into the corresponding acyclic compounds by ozonolysis (entries 4,5, and 9).l0 Moreover, the resulting products are stable to epimerization, since e.g. in 4b the formyl group prevents racemization via a retroaldol/aldol process.To test the limits of this fragmentation, a series of vinylsubstituted dihydropyrans were subjected...

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