Cycloaddition of o-quinone methides

Drawing from their success with catalytic [4 + 2] cycloaddition, Lectka group developed another highly enantioselective cycloaddition of o-quinone methide (o-QM) with silyl ketene acetals, using a chiral cinchona alkaloid derived ammonium, N-(3-nitrobenzyl)quinidinium fluoride Is, as a precatalyst. The free hydroxyl group of the cinchona alkaloid moiety was crucial to high optical induction. A variety of silyl ketene acetals had been screened to afford the cycloadducts 22 with good ee (72-90%) and excellent yield (84—91%) (Scheme 10.26) [35]. 

Scheme 10.26 Cycloaddition of o-quinone methide with silyl ketene acetal.

Two recent reports have detailed the [4 + 2] cycloadditions of o-quinone methides with heterodienophiles, thiones [Eq. (43)]168... 

Full details of a careful study of the regio- and stereospecific intramolecular [4 + 2] cycloadditions of o-quinone methides generated by the thermal or acid-catalyzed (CF3CO2H) dehydration of o-hydroxybenzyl alcohols have been described 75 and have found application in the total synthesis of enantiomerically pure (3/ )-26 and (3/ )-27 possessing the ring system and correct absolute configuration of the cannabinol family [Eq. (47)]. 

The intramolecular cycloaddition of o-quinone methide N-alky1imines with alkenes to form six-membered nitrogen rings is well documented but the intermolecular reaction is less well characterised. Ito et al. have now shown that the o-quinone methide N-alkylimines (182), generated in situ by treatment of the corresponding N-trimethylsilyltrimethylammonium salts (181) with fluoride ion, react with the electron-deficient alkenes (183)... 

Lower reaction temperatures favor the reversible formation of the Diels-Alder products, and higher reaction temperatures promote the irreversible ene reactions. Related observations of the competing or predominating intramolecular Diels-Alder reactions of a-cyano or a-acetyl a,/3-unsaturated esters have been reported in studies of the thermal and Lewis acid-promoted ene reaction (Table 7-II, entry 16).143 The complementary use of o-quinone methide intermediates in intra- as well as inter-molecular [4 + 2] cycloaddition reactions is discussed in the following section. 

Scheme 7.56 Metal-catalyzed generation of o-quinone methides and subsequent cycloaddition reactions.

With the exception of the abundant o-quinone methide Uterature (62), there is only a single example of a diene exocycUc to a ring [59]. The use of the very reactive o-quinone methide diene, for intramolecular cycloaddition, was introduced by Oppolzer in 1971 (64). Initially, these were prepared by thermolysis of a preformed benzocyclobutene [60, 61]. Later, Vollhardt demonstrated that 1,5 diacetylenes could serve as precursors to benzocyclo-butenes and thus, to o-quinone methides [62]. Since that time, several other methods for the generation of o-quinone methides have been developed [63-68], some of which allow generation of the o-quinone methide under very mild reaction conditions. These methods also allow the incorporation of more complex functionality in the ring system. 

Atroposelective cycloaddition reactions of A-2-(r-butylphenyl)- and A-2,5-(di-r-butylphenyl)-maleimide show good to excellent stereoselectivities and the high rotation barriers prevent cycloadducts from interconverting. The stereospeciflc hetero-Diels-Alder reaction of o-quinone methides (80) with o-quinones (79) in MeOH at room temperature produce the 4a,8-di(hydroxymethyl)chromane derivatives (81) and (82) in high yields (Scheme 29). The intramolecular inverse-electron-demand Diels-Alder reaction of o-quinone methides (84) derived from 2-(l-hydroxy-5-alkenyl)phenol derivatives (83) produces l,2,3,3a,4,9b-hexahydrocyclopenta[c][l]benzopyrans (85) under mild acidic conditions (Scheme 30). The Diels-Alder reactions between dimethyl-cyclohexadiene derivatives and di-(-)-menthyl acetylenedicarboxylate exhibit modest diastereoselectivity. ... 

Amouri and coworkers also demonstrated that the nucleophilic reactivity of the exocyclic carbon of Cp Ir(T 4-QM) complex 24 could be utilized to form carbon -carbon bonds with electron-poor alkenes and alkynes serving as electrophiles or cycloaddition partners (Scheme 3.17).29 For example, when complex 24 was treated with the electron-poor methyl propynoate, a new o-quinone methide complex 28 was formed. The authors suggest that the reaction could be initiated by nucleophilic attack of the terminal carbon of the exocyclic methylene group on the terminal carbon of the alkyne, generating a zwitterionic oxo-dienyl intermediate, followed by proton transfer... 

The pyrano[3,2-c][l]benzopyran system is available from the reaction between salicylaldehyde and 5-phenylthio-4-penten-l-ols which proceeds by an intramolecular cycloaddition of an o-quinone methide desulfurisation is facile (Scheme 29) <00TL2643>. Mild conditions have been established for the synthesis of (-)-hexahydrocannabinol 50 from the olivetol derivative 49 which also involves a quinone methide (Scheme 30) <00SC1431>. 

Cycloaddition Anodically generated phe-noxy cations, o-quinones, and o-quinone methides react with olefins to bicyclic and tricyclic annelated compounds in stereoselective cycloadditions [250-252]. In the synthesis of a Euglobal skeleton, a quinone methide has been generated in situ by anodic oxidation mediated by DDQ. The cycloaddition was promoted by the use of lithium perchlorate... 

There are a number of examples of the synthesis of chromans using o-quinone methides as the heterodiene in a hDA reaction. Both pyrano[3 -c]-benzopyrans and cyclopenta[c][l]benzopyrans result from an intramolecular cycloaddition of a substituted o-quinonemethide generated under mild conditions. In the former case, salicylaldehyde and an unsaturated alcohol yield the rra/is-fused tetrahydropyranobenzopyran (Scheme 10) <99JOC9507>. However, the latter synthesis (Scheme 11) is less selective <99BCJ73>. 

The JACS paper describes the total synthesis of the more highly oxygenated (-)-tetracycline 16. To this end, the alcohol S was carried on to the enone 10. Opening of the cyclobutane 11 to the o-quinone methide followed by Diels-Alder cycloaddition to 10 delivered the endo adduct 12. 

The one-pot reaction of 0-BOC protected salicylaldehydes and salicyl alcohols with electron-rich alkenes and a Grignard reagent involves a diastereoselective cycloaddition to an o-quinone methide and offers access to a wide range of 4-substituted chromans <02JOC6911>. 

Saegusa s group (81JA5250) found that [o-[(trimethylsilyl)alkylamino]-benzyljtrimethylammonium halide underwent the fluoride-anion induced 1,4-elimination under mild conditions to generate an o-quinone methide N-alkylamine intermediate. They performed the formal synthesis of gephyro-toxin 434 on the basis of an intramolecular cycloaddition of the o-quinone methide A-alkylamine 426 (83TL2881). Treatment of azadiene precursor 425... 

Fluoride-induced fragmentation reactions were used in two stages of a synthesis of hexahydrocannabi-nol methyl ether (144 Scheme 52). One of the phenolic hydroxy functions in the resorcinol derivative (140) was selectively liberated from the SEM ether to give the diol (141), which was converted to the bis (trimethylsilyl) ether (142). Subsequent treatment with CsF resulted in a 1,4-elimination to the o-quinone methide (143) intermediate, which underwent an intramolecular [4 -i- 2] cycloaddition to give the product in good yield. 

Methylenedioxy-6-propenylphenol (42) underwent le oxidation followed by radical coupling resulting in the formation of dimeric o-quinone methide 43, which was further converted to carpanone (44) and seven-membered ether 45 in 11 and 44% yields, respectively, as shown in Scheme 8. The former is produced by an intramolecular [4 + 2] cycloaddition . Carpanone has also been synthesized using oxidants such as palladium chloride and molecular oxygen in the presence of Co(II)salen. ... 

The various methods of generating o-quinone methides,4-5 including the thermal or (Lewis) acid-catalyzed elimination of a phenol Mannich base,149 150-160-161163 the thermal or (Lewis) acid-catalyzed dehydration of an o-hydroxybenzyl alcohol (ether),147-149-151-153-156-157-162-163-165-168 171-175-178-183 the thermal 1,5-hydride shift of an o-hydroxy styrene,171-173 175 178-183 the thermal dissociation of the corresponding spirochromane dimer,158 163-164,166 oxidation of substituted o-alkylphenols,152-170 and the thermal or photochemical-promoted cheletropic extrusion154-155 159 of carbon monoxide, carbon dioxide, or sulfur dioxide (Scheme 7-III), as well as their subsequent in situ participation in regiospecific, intermolecular [4 + 2] cycloadditions with simple olefins and acetylenes,147 149-151 152 153159 162-164... 

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