Regioselective ene reaction

Highly regioselective ene reactions of singlet oxygen with alkyl-substituted alkenes can also be used for synthetic purposes. For example, in the photooxygenation ofl-t-butylcycloheptene only one allylic hydroperoxide, by the exclusive geminal hydrogen... 

A C(ip )-H amination of trimethylsilyl-substituted cyclopropenes proceeds via a tandem regioselective ene reaction between cyclopropenes and azodicarboxylate to generate a hydrazodicarboxylate intermediate followed its site-selective allylic transposition (Scheme 85). ... 

Adam, W. and Griesbeck, A., Synthesis of the first a-methylene-P-peroxylactone regioselective ene reaction of singlet oxygen with a,p-unsaturated carboxylic acids, Angew. Chem. Int. Ed. Engl, 24, 1070, 1985. 

Singlet oxygen reacts with olefins presumably by the "ene" reaction to form allyflc hydroperoxides (45,57), eg, l-methyl-2-propenyl hydroperoxide [20733-08-8] is produced from 2-butene (eq. 19). The regioselectivity of this reaction has been investigated (58). 

This excellent regiocontrol was exploited by subjecting terminal alkenes and hydroxyalkynoates to ruthenium catalysis conditions to afford butenolides and pentenolides (Equation (23)).36 The Alder-ene reaction occurs preferentially to form the G-G bond at the alpha-carbon of the alkynoate. The unusually high regioselectivity is attributed to a synergistic effect derived from an enhanced coordination of the hydroxyl group to the ruthenium. 

A mechanistic pathway is proposed based upon the observed regioselectivities and other results that were obtained during the exploration of the scope and limitations of the Alder-ene reaction.38 Initially, coordination of the alkene and alkyne to the ruthenium catalyst takes place (Scheme 5). Next, oxidative addition affords the metallocycles 42 and 43. It is postulated that /3-hydride elimination is slow and that the oxidative addition step is reversible. Thus, the product ratio is determined by the rate at which 42 and 43 undergo /3-hydride elimination. 

A key reaction in the formal total synthesis of (-)-mycalamide A involved the intermolecular ruthenium-catalyzed Alder-ene reaction between 157 and 158 to give the dienoate 159 (Scheme 35).94 This regioselective reaction provided a 63% yield of 159, which was subsequently transformed to a key building block 160 which was taken on to (-)-mycalamide A. 

A formal synthesis of the antifungal agent alternaric acid was realized in the Trost group.95 The skipped diene portion of the natural product was obtained via a ruthenium-catalyzed intermolecular Alder-ene reaction (Scheme 36). Several attempts to produce 162 from the protected fragment 161 gave low yields and unremarkable regioselectivity. The diol (R = H), however, performed satisfactorily, allowing the reaction to be carried out at room temperature. The product 162 was obtained in 51% isolated yield as an 8.9 1 mixture of branched to linear isomers. 

Clennan, E.L. and Sram, J.P. (2000). Photochemical reactions in the interior of a zeolite. Part 5. The origin of the zeolite induced regioselectivity in the singlet oxygen ene reaction. Tetrahedron 56, 6945-6950... 

Houk, K.N., Williams Jr., J.C., Mitchell, P.A. and Yamaguchi, K. (1981). Conformational control of reactivity and regioselectivity in singlet oxygen ene reactions Relationship to the rotational barriers of acyclic alkylethylenes. J. Am. Chem. Soc. 103, 949-951... 

The second product must incorporate two equivalents of the enol ether. We form C3-C5, C5-C4, and C5-S1 bonds, and we transfer a H from SI to C4. A hetero-ene reaction forms the C3-C5 bond and transfers the H. As for the other two bonds, since SI and C5 are at the ends of a four-atom unit, we might expect a Diels-Alder reaction. We can get to the requisite diene by eliminating the elements of BuOH by an Elcb mechanism. The hetero-Diels-Alder reaction gives the product with ertdo stereoselectivity and the expected regioselectivity. 

The Ti(0 Pr)2Cl2/D-DIPT poison has also been used for the Ti(0 Pr)2Cl2/ BINOL-catalyzed asymmetric carbonyl-ene reaction with chloral (Scheme 8.8). With the Ti(0 Pr)4/D-DIPT poison in a 1 3 ratio, both the regioselectivity and the enantioselectivity of the ene product are improved. 

Intermolecular reactions of propargylic alcohols with a-methylstyrene gave the corresponding 1-hexene-5-ynes in moderate yields with complete regioselectivity (Scheme 7.30). The incorporation of a deuterium atom at the C-6 position (acetylenic terminal carbon) of the product and a substantial isotope effect (kH/fco = 4) were observed when a-methylstyrene-methyl-dj was used in place of a-methylstyrene. It is considered that the Cp-Cy double bond of an allenylidene complex reacts with a-methylstyrene, where the allenylidene complex works as an enophile, to afford the corresponding vinylidene complex via an allenylidene-ene reaction, as shown in Scheme 7.30. 

Selective fomation of allylic hydroperoxides via singlet oxygen ene reaction 837 TABLE 2. Syn/anti regioselectivity in the photooxygenation of aUyUc alcohols 10- and 10-Z... 

TABLE 3. Syn/anti regioselectivity in the ene reaction of O2 with f, P-dimethylstyrene... 

However, the barrier to rotation does not always predict the regioselectivity of the ene reaction of O2 with alkenes. As shown latef, it is the non-bonded interactions in the isomeric transition states that control product formation and barriers to rotation are rather irrelevant. The calculated rotational barrier values, with the HF-STO-3G method, for the allylic methyls in a series of trisubstituted alkenes, as well as the experimentally observed ene regioselectivity of a series of selective substrates, are shown in Table 9. ... 

Synthetic applications involving regioselective or diastereoselective photooxygenation ene reactions, as key steps, are very common in the literature and some examples have already been reported in the previous sections. Additionally, the number of natural products... 

SCHEME 63. Regioselectively synthesized natural products via O2 ene reactions... 

Regioselective singlet oxygen ene reactions have been also used, as key steps, towards the synthesis of (+)-asteriscanolide (167) , a-D-sorbofuranose (2S,3R,5R) (168) and a-D-fmctofuranose (2S,3S,5R) (169) ° (Scheme 62). 

Additionally, some Pd-catalyzed type II zinc-ene cyclizations have been described. When the allylic acetate 181 was treated with EtiZn in the presence of a catalytic amount of Pd(PPh3)4, its slow conversion to a cyclic organozinc species by a type zinc-ene reaction was observed and iodinolysis afforded the six-membered ring 182 in relatively low yield. The regioselectivity was noteworthy as C-C bond formation occurred at the most substituted terminus of the allylmetal. By contrast, the type II palladium-ene cyclization of the allylic acetate 181, in conjunction with a /1-elimination process, proceeded with opposite regioselectivity and led to the six-membered ring 183 (equation 88)114. 

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