Exo closure

In these reactions, a er-bond is formed at the expense of two re-bonds and, thus, the process leads to a net loss of one chemical bond that is intrinsically unfavorable thermodynamically. Formation of the new er-bond leads to ring closure, whereas the net loss of a bond leads to the formation of two radical centers, which can be either inside (the endo pattern in Scheme 1) or outside of the newly formed cycle (the exo pattern). Note that er-radicals are formed through the endo path, while exo-closures may produce either a er-radical when a triple bond is involved or a conjugated re-radical when the new bond is formed at the central carbon of an allene. The parent version of this process is the transformation of enediyne 1 into p-benzyne diradical2 (the Bergman cyclization), shown in Scheme 2. 

Substituent effects on cyclizations of simple nucleophilic hexenyl radicals have been well studied, and much quantitative rate data is available.12 The trends that emerge from this data can often be translated to qualitative predictions in more complex settings. Once the large preference for S-exo cyclization is understood, other substituent effects can often be interpreted in the same terms as for addition reactions. For example, electronegative substituents activate the alkene towards attack, and alkyl substituents retard attack at the carbon that bears them. The simple hexenyl radical provides a useful dividing point = 2 x 10s s-1. More rapid cyclizations are easily conducted by many methods, but slower cyclizations may cause difficulties. Like the hexenyl radical, most substituted analogs undergo irreversible S-exo closure as the predominate path. However, important examples of kinetic 6-endo closure and reversible cyclization will be presented. 

Shibasaki and co-workers have described a regioselective Heck cyclization of aryl triflate 12.1, which ultimately provides tricyclic enone 12.4, a key intermediate in a number of diterpene syntheses (Scheme 8G.12) [25], Treatment of 12.1 under typical cationic conditions resulted in preferential 6-exo closure to give 12.2 and 12.3 as a 3 1 mixture in 62% overall yield and with 95% ee for both products. The complete selectivity for 6-exo cyclization is noteworthy because 6-endo, 5-exo, and 7-endo cyclization modes were also possible. An analysis of the steric interactions involved in the various cyclization modes was presented and was used to rationalize the observed selectivity. Non-conjugated diene 12.2 could be isomerized to the fully conjugated diene 12.3 in quantitative yield by using catalytic naphthalene Cr(CO)3. Both Heck products could be converted to the enone 12.4,... 

Generally, most radical cyclizations proceed kinetically in an exo fashion to provide the smaller of the two possible rings. Nonetheless, as an important exception, 1-endo and 8-endo cyclizations do occur when the (conformationally restrained) intermediate radicals possess geometrical restrictions, i.e. less degrees of freedom relative to normal heptenyl radicals. It also should be noted that the rate constants for 1-exo and 8-endo cyclization of 7-octenyl radical are almost identical—the preference for exo-closure decreases as the rings get bigger [86]. 

The stereochemistry of exo closure in a case like the radical 7.56, giving the cis product 7.58 (cis-.trans 72 28), is controlled by the usual preference for the resident substituent to adopt an equatorial orientation 7.57 and for the chain of atoms to adopt a chair-like conformation. 

Lactones,6 Successive treatment of alkenes with QHjSeCl and silver crotonate affords p-phenylselenocrotonates. The products undergo ring closure to 7-lactones when treated with (C6H5)3SnH and a radical initiator. Application of this sequence to cyclohexene (equation I) or cyclopentene results in two bicyclo-y-lactones. Both are cw-fused, and the major product results from exo-closure. 

When the alkoxypalladation of alkenols is carried out in methanol under a carbon monoxide atmosphere, the alkylpalladium intermediate is cleaved to afford methyl 2-(tetrahydro-2//-pyran-2-yl)acetates. Starting from 5-alkenols, the reaction proceeds by a 6-exo closure with total regio-and stereoselectivity. In fact, only the tetrahydro-2//-pyrany derivative is formed, in 74% yield, and the cis-2,6-isomer is the major component of the reaction mixture. This result is due to the more stable 2,6-diequatorial configuration of the substituted tetrahydro-2/7-pyran ring82. 

The regiosclcction of 4-alkcnol cyclization (i.e., 6-endo vs. 5-exo closure) is affected by the geometry of the double bond. ( >2-Methyl-8-decen-5-ol [( )-5] affords the 2,3-trans-2,6-cis-te-trahydro-2//-pyran-3-carboxylate 6A as 70 % of the product, along with 30 % of an inseparable mixture of the 2,5-cis- and trani-tetrahydrofuran-2-acetates 7A82. 

Another 6-exo closure from our enantioselective total synthe.ses of (—)-morphine (40) and its enantiomer was published in 1993 (Scheme 6-7) [12]. The pivotal cyclization of 38 to 39 was accomplished in 60% yield. This is a demanding intramolecular Heck reaction, since the palladium-bond arylmethyl side chain of 38 must rotate over the octahydroisoquinoline ring to coordinate with the trisubstituted alkene. Reflecting this difficulty, Pd(OCOCF3)2(PPh3)7 [a precatalyst that generates the reactive Pd(0) catalyst Pd(PPh3)2] cyclization temperature of 120 °C were required. 

Finally, in Rawafs total synthesis of ( )-strychnine, Heck cyclization of vinyl iodide 68 was employed to access the hexacyclic Strychnos alkaloid skeleton and deliver ( -) isostrychnine (69) in 74% yield [25J. Rearrangement in this case would not have been expected since the intermediate formed upon 6-exo closure would contain a particularly unstable tertiary C—Pd bond. The success of the transformation of 68 to 69 in spite of this potential obstacle is noteworthy. 

The stereochemistry of exo closure in a case like the radical 7.92, giving the cis product 7.94 (cis. trans 72 28), is controlled by the usual preference for the resident substituent to adopt an equatorial orientation 7.93 and for the chain of atoms to adopt a chair-like conformation.1031 In the case of a radical like 7.95, however, there is a clearly contrathermodynamic preference for the formation of the cis product 7.97.1032 It has been suggested that the endo-like transition structure 7.96 might have an attractive secondary orbital interaction from the filled hyperconjugative orbitals with the n orbital, rather like that used to explain the endo rule for Diels-Alder reactions. The preference for cis products like 7.97 does not extend to all substituents on the radical centre, and Z-substituents often lead to trans products, possibly because they lack the same set of orbitals, but probably also because they are larger than a methyl group. 

---