Oxy-Cope reactions

Participation of aromatic groups in oxy-Cope reaction sequences enables the synthesis of highly substituted polyquinane ring systems (Scheme 10, <96JOC7976>). 

An important improvement in the oxy-Cope reaction was made when it was found that the reaction is strongly catalyzed by base.212 When the C(3) hydroxy group is converted to its alkoxide, the reaction is accelerated by a factor of 1010-1017. These base-catalyzed reactions are called anionic oxy-Cope rearrangements, and their rates depend on the degree of cation coordination at the oxy anion. The reactivity trend is K+ > Na+ > Li+. Catalytic amounts of tetra-rc-butylammonium salts lead to accelerated rates in some cases. This presumably results from the dissociation of less reactive ion pair species promoted by the tetra-rc-butylammonium ion.213... 

The reaction in Entry 5 is a case in which the thermal conditions were preferable to the basic conditions because of the base sensitivity of the product. Entries 6 to 10 show anionic oxy-Cope reactions. Entries 6 and 7 are early examples of the application of the reaction in synthesis. Entries 8 and 9 involve rearrangements of bicyclo[2.2.1]hept-2-en-2-ol derivatives to give cw-fused bicyclo[4.3.0]non-7-en-3-ones. 

Figure 12 Oxy-Cope reaction catalyzed by antibody AZ28 raised against the hapten y and X-ray structure of the antibody AZ28-hapten y complex.

MacDougall, J. M. Santora, V. J. Verma, S. K. Turnbull, P. Hernandez, C. R. Moore, H. W. Cydobutenone-based syntheses of polyqui-nanes and bicydo[6.3.0]undecanes by tandem anionic oxy-Cope reactions. Total synthesis of ( )-precapnelladiene. J. Org. Chem. 1998, 63, 6905-6913. 

The effect is naturally more pronounced if the substituent is charged. The best known example is the so-called anionic oxy-Cope reaction,54 where an O- at position 3 induces a rate acceleration of 1010-1017-fold, a result generally attributed to the 3-4 bond weakening.47 55 The lone pairs of HN" lie at even higher energies than those of O-. The 3-4 bond breaking then becomes so easy that the anionic amino-Cope reaction occurs by a stepwise mechanism.56... 

The anionic oxy-Cope reaction is accelerated when a thiomethoxy group is put at positions 4 or 6. A methoxy group at the same positions slows down the reaction. Explain. 

Chiang OC, Kaeobamrung J, Bode JW (2007) Enantioselective, cyclopentene-forming annulations via NHC-catalyzed benzoin-oxy-cope reactions. J Am Chem Soc 129 3520-3521... 

Chuard et al. introduced a two-step radical alternative to the oxy-Cope reaction [95]. It relied on the opening of a strained cz-oxetanyl radical to the allyloxy radical. Because of the favorable geometry, further fragmentation delivered enone radicals that could undergo a 6-endo-trig cyclization, which led to bicyclic ketones in 69% yield. 

The [2,3] Wittig oxy-Cope reaction sequence proceeds with a high level of diastereoselectivity. Thus, aldehyde 14 a is obtained from 13 a (96% stereopurity) with 94% de and 99 % E. and 13 b (92% stereopurity) gives aldehyde 14b with 88% de and 97% E by the reaction sequence shown966. 

The Bode group documented a remarkable annulation reaction of 3-alkyl or 3-aryl enals with chalcone-derived imines which allows direct access to cyclopentyl-fused p-lactams with four contiguous stereocenters in an operationally simple process/ A pronounced effect of the catalytic base on the diastereoselectivity was discovered. Using 3-alkyl enals as the substrates, DBU performed as the most optimized base to afford products in up to 94% yield, >10 1 dr, and 99% ee. When cinnamaldehyde derivatives were used, it was necessary to choose DMAP as the catalytic base in order to ensure the formation of desired products in a diastereoselective manner (up to 80% yield, >20 1 dr, >99% ee). Supported by the stereochemical outcome, a tandem, or possibly concerted, crossed-benzoin/oxy-Cope reaction as the key bond-forming step was rationalized (Scheme 7.57). 

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