Spirocyclic pyran

Acetalization of oxo aldehydes is used to protect sensitive aldehyde products, especially in asymmetric hydroformylation preventing racemization of an a-chiral aldehyde product [18-22,27]. Acetal formation can also be applied to the synthesis of monocyclic or spirocyclic pyranes as potential precursors and building blocks for natural products such as pheromones or antibiotics. A representative example is the synthesis of the pyranone subunit of the Prelog-Djerassi lactone. For this purpose, various 1,2-disubstituted homoal-lylic alcohols were used (Scheme 3) [32],... 

Sames and coworkers have very recently introduced BF3 OEt2 catalysis to promote room temperature hydroalkylation of electron deflcient olefins as a formal sp C-H functionalization process. Coordination of the Lewis acid to the alkene moiety of the tetrahydropyran (121) facilitates a 1,5-hydride shift to afford a zwitterionic species, (122), which is followed by nucleophilic attack at the oxocarbonium center to furnish the requisite spirocyclic pyran (123) (Equation 74) [77]. 

The application of RCM to dihydropyran synthesis includes a route to 2,2-disubstituted derivatives from a-hydroxycarboxylic acids. In a one-pot reaction, the hydroxy esters undergo sequential O-allylation, a Wittig rearrangement and a second O-allylation to form allyl homoallyl ethers 8. A single RCM then yields the 3,6-dihydro-2//-pyran 9. The process is readily adapted not only to variably substituted dihydropyrans but also to 2-dihydrofuranyl and 2-tetrahydrooxepinyl derivatives and to spirocycles e.g. 10 through a double RCM (Scheme 4) <00JCS(P1)2916>. 

The 4/f-pyran ring C in spirocyclic derivative 18 is almost planar with maximum deviations about 4 pm and is somewhat distorted by nonbonded interactions due to the bulky 2,6-/er/-butyl groups52 (see Table I). 

The formation of the spirocyclic 4//-pyran 18 from 4,4 -bis-(2,2, 6,6 -tetra-terf-butyl)pyrylium diperchlorate (214) by heating with aqueous KOH or AcOH-AcONa is explained by the mechanism shown in Scheme 13.52... 

Dinitrobenzylidene derivatives 349 are converted quantitatively to spirocyclic 4//-pyrans 350 by UV irradiation.333... 

Bis-4,4 -pyrylium salts 214 (R = r-Bu, Ph) were obtained from trityl perchlorate with 163b,c221 or perchloric acid with spirocyclic 4//-pyran 18.52... 

Ketol 146, on the other hand, was formed after the reaction of spirocyclic 4//-pyran 147 with methanolic hydrogen chloride.191... 

Spirocyclic 4//-pyran derivative 18 undergoes opening of both rings with phenylhydrazine or with hydroxylamine hydrochloride to provide corresponding dihydrazone 509a or dioxime 509b, respectively.52... 

The photochemical transformation of the spirocyclic 4//-pyran derivative 622 shown in Eq. (47)333 resembles the reverse of the phototransformation 349->350. Upon reaction with Pb02 622 gave a stable nitroxide radical.454... 

Spirocyclic 4//-pyrans 69a (90ACS833) and 69b were prepared in the same way. In the case of 69b the starting a,)8-unsaturated component was generated in situ from enolacetate 70 (89CB1285). Analogous procedures with HC=COEt were used for the preparation of other spirocyclic products 71 and 72 (89CB1285). 

Two independent reports have appeared that detail methodology for the introduction of pyran or oxepene spirocychc moieties onto oxindole scaffolds by means of a Prins cyclization (Scheme 35). In one study by Zhang and Panek, treatment of isatin dimethylketal 134 with sUyl alcohol (S )-135 afforded predominately c -137 or trans-Vi9 depending on reaction time and solvent polarity [78]. A mechanism involving epimerization of the cis-product to the trans adduct was put forward to explain the observed frans-selectivity with increased reaction time in polar solvents. A cyclic transition state involving a (Z)-oxonium intermediate formed via condensation of silyl alcohol 135 with isatin 134 was invoked to rationalize the preferential formation of the cis-spirocycle under kinetic control. Further optimization led to the formation of spirooxindoles 138, e.g., R, = Me, as single... 

The tetrahydropyranol ring system was also formed in a domino Michael-ketabzation reaction. The reaction between cyclohexanone and nitro alkenols in the presence of prohne-based organocatalysts was used to successfully prepare fused cyclohexyl pyran derivatives [111]. Rodrigues and Coquerel reported an NHC-catalyzed Michael-based spirocyclization from 1,3-dicarbonyl compounds bearing... 

Walters, M.A. et al.. Templates for exploratory library preparation. Derivatization of a functionalized spirocyclic 3,6-dihydro-2H-pyran formed by ring-closing metathesis reaction, J. Comb. Chem., 4,125, 2002. 

A metal-firee oxidative spirocyclization of hydroxy methylacrylamide with 1,3-dicarbonyl compounds provides a range of spirooxindole 3,4-dihydro-2H-pyrans, in moderate to good yields. This strategy involves the formation of two C-C bonds and one C-O bond in one step (Scheme 7) (130L5254). 

C-1,2-addition pathway. The reaction of pyrone 15 led to the pyran product 16 in an improved yield, and gave previously unknown products 37b and 37c (Scheme 12.6). Our protocol allowed preparations of analogs such as 30,38, and 39, with 30 being comparable to the yields of Hua et al. In addition, we were able to constmct oxa-spirocycles such as 40-42, with 41 (the major isomer is shown) and 42 possessing moderate diastereoselectivities [25]. 

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