5-Hexenoic acid, 3- iodolactonization

In addition to the procedures listed in Table 3.38, further reactions have been used to generate halides upon cleavage. In Section 3.5.2, iodolactonization is presented as a method for the preparation of iodomethyl lactones from resin-bound pentenoic or hexenoic acid derivatives. Closely related to the iodolactonization is the iodine-mediated formation of 2-(iodomethyl)tetrahydrofurans from resin-bound isoxazoli-dines (Entry 9, Table 3.38 for the mechanism, see Figure 15.5). Nitriles can also be prepared by cleavage and simultaneous dehydration of amides RCONH2 from the Rink or Sieber linkers with TFA anhydride (Entry 10, Table 3.38). 

Examples of 1,3-asymmetric induction in cyclizations to 8-lactones have been observed. Iodolactonization of 3-methyl-5-hexenoic acid to a 8-lactone under equilibrating conditions showed reasonable stereoselectivity (6 1 cis trans).l20b Recent studies have examined the formation of 8-lactones from cyclization of 5-hexenoic acids with a homoallylic oxygen substituent at C-3.135 Selenolactonization of 3-hydroxy-5-hexenoic acid under conditions of kinetic control provided the trans lactone in modest yield (40%) and high stereoselectivity.13515 Equilibrating conditions led to a slight preponderance of the cis... 

Low asymmetric induction is observed when (R)-3-benzyloxycarbonylamino-5-hexenoic acid (1, R = H) is iodolactonized under kinetic conditions (iodine/potassium iodide/sodium hydrogen carbonate). A mixture of the cis- and trww-iodo-5-lactones (60 40) in 94% yield is obtained. Better stereoselectivity can be obtained when the. V-benzyl derivative 1 (R = Bn) is cyclized under the same conditions. In fact, an 86 14 cisjtram) ratio is observed, showing that halolactonization is kinetically favored over halocarbamation, with the bulky substituent at nitrogen inducing high selectivity7. n n... 

Low 1,4-asymmetric induction1 is reported for the iodolactonization of 2-methyl-5-hexenoic acid (1) which gives a 64 36 (trans/cis) mixture of the corresponding lactones in 78% yield under kinetic control, On the other hand, when the reaction is carried out under thermodynamic conditions, the diastereomeric ratio is 52 48. 

In 2010, Veitch and Jacobsen [73] reported the first highly selective organo-catalytic iodolactonization (Scheme 13.36). A bifunctional hydrogen bonding urea catalyst was employed, and an iV-iodoimide was utilized as the electrophilic source of iodine. A variety of hexenoic acid substrates were examined, and one pentenoic acid substrate underwent iodolactonization in 82% yield and in 90% ee. Earlier examples of iodolactonization employing catalytic [74] or stoichiometric [75, 76]... 

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