2.4.4.6- Tetrasubstituted 477-pyrans

A nitrile oxide generated from a sugar derived aldoxime 30 underwent INOC reaction to the chiral pyranoisoxazoline 31 (Eq. 4) [20]. Reductive cleavage of isoxazoline 31 followed by acetylation provided the tetrasubstituted pyran 32. 

Tetrasubstituted pyran-2-ones result from the Ru-catalysed [3+2+1] cycloaddition involving vinyl ketones, silylalkynes and CO (Scheme 25) <07OL587>. 

Scheme 5.26 Stereoselective synthesis of a tetrasubstituted pyran starting with 05-carbamoyloxymethyl)allylsilane.

Ring closure to 2//-pyrans is more usual with unsaturated ketones. If suitable cis dienones are generated, their isomerization may proceed so rapidly that only the appropriate 2//-pyrans are identified and/or isolated from the 2,2,4,6-tetrasubstituted species 123 and 124.I63 165 Other cases were not recognized.166... 

The amount of a given isomer in reaction mixtures is affected by substitution patterns of the starting pyrylium ions and by the structure of a reagent, in accordance with quantum chemical interpretations using various LCAO-MO methods.201-2028 Almost all additions to 2,6-disubstituted pyrylium ions occur at position 4 to give 4//-pyrans. Unsubstituted or 2,4,6-trisubstituted substrates may be attacked, on the other hand, at a or y positions providing 2H- and/or 4//-pyrans. Limited information on tetrasubstituted and penta-substituted pyrylium ions leads to the conclusion that the former afford AH-pyrans, whereas the latter tend to be attacked by nucleophiles only at positions 2 or 6. 

The regioselectivity in the Grignard reactions of tetrasubstituted pyrylium salts is the consequence of simultaneous effects of substitution patterns in both the substrate and the reagent. Thus the reaction of MeMgl with 2,3,4,6-or 2,3,5,6-tetramethylpyrylium ions provide mixtures of isomeric 2//-pyrans 187 and 188 in the ratio 91 9 or of 2//-pyran 189 and 4i/-pyran 190 in the ratio 48 52, respectively.237... 

However, if a tetrasubstituted pyrylium ion possessed one or two condensed six-membered carbocyclic rings, then only 4//-pyrans 191, 192, 27, and 193 are isolable (35 to 92%) after reaction with PhCH2MgCl236 or with other Grignard reagents RMgX.210... 

Tetrasubstituted 4//-pyrans 153 and 431 were found to disproportionate with trifluoroacetic acid359 and with boron trifluoride-hydrogen bromide reagent360 to mixtures of pyrylium salts 395a,b and tetrahydro-pyrans 432359 or 433,360 respectively. 

Pyran decomposes in contact with moist air or adds but its tetrasubstituted derivatives, e.g. (155), are stable and are usefully converted into naphthalenes (156) by treatment with perchloric acid. A 4-benzyl or 4-naphthylmethyl substituent is essential. Pyran ring opening occurs and is followed by cyclization and elimination of a simple ketone which is formed from the 2- or 6-substituent. Alkyl groups at C-2 or C-6 are converted into the ketone more easily than a phenyl group (64LA(678)202). 

Finally, Szabo et al. examined the reactions of disubstituted allylsilanes 166 with aldehydes. In the presence of TMSOTf, the 2,3,5,6-tetrasubstituted tetrahydro-pyrans 167 are formed in good yields (Scheme 13.57). In complete analogy with the results of Ito [78] and Mohr [69], a remarkably high stereoselectivity was also observed. 

Some research groups have exploited the intrinsic reactivity of the bicycloadducts formed in the pyran-2-one Diels-Alder reactions. An example of this strategy is shown in Scheme 33, where the pyran-2-one decorated with indole functionality 255 was reacted with an assortment of electron-rich and electron-poor dienes <2000T5205>. The richly functionalized bicyclo[2.2.2]adduct 256 was then subjected to mild aminolysis to produce tetrasubstituted hexene 257 as single diastereoisomers. 

In most reactions of 2-pyrones, alkyl or aryl Grignard halides have been used. The best results have been achieved for 4,6-disubstituted 2-pyrones because of the general stability of 2,2,4,6-tetrasubstituted 2//-pyrans. Thus,... 

C) starting from more complex oligocyclic epoxides (81TL-4553 81TL4557). A preparatively more interesting synthesis from 2,5-disubstituted 1,3,4-oxadiazoles and cyclopropenes led to 2,4,4,6-tetrasubstituted 4//-pyrans 155 (88TL3231). 

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