{{Short description|Chemical reaction}} {{Reactionbox | Name = Halolactonization | Type = Ring forming reaction }} '''Iodolactonization''' (or, more generally, '''halolactonization''') is an organic reaction that forms a ring (the [[lactone]]) by the addition of an oxygen and iodine across a carbon-carbon double bond. It is an [[intramolecular reaction|intramolecular]] variant of the [[halohydrin]] synthesis reaction. The reaction was first reported by M. J. Bougalt in 1904 and has since become one of the most effective ways to synthesize lactones.<ref name=DowleandDavies>{{Cite journal | last1 = Dowle | first1 = M. D. | last2 = Davies | first2 = D. I. | title = Synthesis and synthetic utility of halolactones | journal = Chemical Society Reviews | volume = 8 | issue = 2 | pages = 171 | year = 1979 | doi = 10.1039/CS9790800171}}</ref> Strengths of the reaction include the mild conditions and incorporation of the versatile iodine atom into the product.
:[[File:IodolactonizationIntroduction.svg|center|300px|IodolactonizationIntroduction]]
Iodolactonization has been used in the synthesis of many [[natural products]] including those with medicinal applications such as [[vernolepin]] and vernomenin,<ref name=DanIodolact>{{Cite journal | last1 = Danishefsky | first1 = S. | last2 = Schuda | first2 = P. F. | last3 = Kitahara | first3 = T. | last4 = Etheredge | first4 = S. J. | title = The total synthesis of ''dl''-vernolepin and ''dl''-vernomenin | journal = Journal of the American Chemical Society | volume = 99 | issue = 18 | pages = 6066 | year = 1977 | doi = 10.1021/ja00460a038}}</ref> two compounds used in tumor growth inhibition, and [[vibralactone]], a [[pancreatic lipase]] inhibitor.<ref name=VibraIodolact>{{Cite journal | last1 = Zhou | first1 = Q. | last2 = Snider | first2 = B. B. | title = Synthesis of (±)-Vibralactone | journal = Organic Letters | volume = 10 | issue = 7 | pages = 1401–1404 | year = 2008 | pmid = 18311992 | pmc = 2745174 | doi = 10.1021/ol800118c}}</ref> Iodolactonization has also been used by [[Elias James Corey]] to synthesize numerous [[prostaglandins]].<ref name=CoreyIodolact>{{Cite journal | last1 = Corey | first1 = E. J. | last2 = Weinshenker | first2 = N. M. | last3 = Schaaf | first3 = T. K. | last4 = Huber | first4 = W. | title = Stereo-controlled synthesis of ''dl''-prostaglandins F<sub>2α</sub> And E<sub>2</sub> | journal = Journal of the American Chemical Society | volume = 91 | issue = 20 | pages = 5675–5677 | year = 1969 | pmid = 5808505 | doi = 10.1021/ja01048a062}}</ref>
==History== Bougalt's report of iodolactonization represented the first example of a reliable lactonization that could be used in many different systems. Bromolactonization was actually developed in the twenty years prior to Bougalt’s publication of iodolactonization.<ref name=DowleandDavies/> However, bromolactonization is much less commonly used because the simple [[electrophilic addition]] of bromine to an [[alkene]], seen below, can compete with the bromolactonization reaction and reduce the yield of the desired lactone.<ref>{{Cite journal | last1 = Brown | first1 = R. S. | title = Investigation of the Early Steps in Electrophilic Bromination through the Study of the Reaction with Sterically Encumbered Olefins | journal = Accounts of Chemical Research | volume = 30 | issue = 3 | pages = 131–137 | year = 1997 | doi = 10.1021/ar960088e}}</ref>
[[File:Bromolactonization.svg|center|400px|Bromolactonization]]
Chlorolactonization methods first appeared in the 1950s<ref name=DowleandDavies/> but are even less commonly employed than bromolactonization. The use of elemental chlorine is procedurally difficult because it is a gas at room temperature, and the electrophilic addition product can be rapidly produced as in bromolactonization.<ref>{{Cite journal | last1 = Garratt | first1 = D. G. | last2 = Ryan | first2 = M. D. | last3 = Beaulieu | first3 = P. L. | doi = 10.1021/jo01293a016 | title = Additions of Group 6A and 7A electrophilic reagents to dimethyl ''endo'',''endo''-bicyclo[2.2.2]oct-5-ene-2,3-dicarboxylate: Competitive formation of γ- and δ-lactones | journal = The Journal of Organic Chemistry | volume = 45 | issue = 5 | pages = 839 | year = 1980}}</ref>
==Mechanism== The reaction mechanism involves the formation of a positively charged [[halonium ion]] in a molecule that also contains a [[carboxylic acid]] (or other [[functional group]] that is a precursor to it). The oxygen of the carboxyl acts as a [[nucleophile]], attacking to open the halonium ring and instead form a lactone ring. The reaction is usually performed under mildly basic conditions to increase the nucleophilicity of the carboxyl group.
:[[Image:IodolactonizationMechanism.svg|center|600px|Iodolactonization]]
==Scope== The iodolactonization reaction includes a number of nuances that affect product formation including [[regioselectivity]], ring size preference, and [[thermodynamic]] and [[kinetic control]]. In terms of regioselectivity, iodolactonization preferentially occurs at the most hindered carbon atom adjacent to the iodonium [[cation]]. This is due to the fact that the more substituted carbon is better able to maintain a partial positive charge and is thus more [[electrophilic]] and susceptible to nucleophilic attack. When multiple double bonds in a molecule are equally reactive, conformational preferences dominate. However, when one double bond is more reactive, that reactivity always dominates regardless of conformational preference.<ref name="Stereoselectivity2">{{Cite journal | last1 = Kurth | first1 = M. J. | last2 = Brown | first2 = E. G. | last3 = Lewis | first3 = E. J. | last4 = McKew | first4 = J. C. | title = Regioselectivity in the iodolactonization of 1,6-heptadien-4-carboxylic acid derivatives | journal = Tetrahedron Letters | volume = 29 | issue = 13 | pages = 1517 | year = 1988 | doi = 10.1016/S0040-4039(00)80340-8}}</ref> [[File:IodolactonizationRegioselectivity11.svg|center|400px|IodolactonizationRegioselectivity]]
Both five- and six-membered rings could be formed in the iodolactonization shown below, but the five-membered ring is formed preferentially as predicted by [[Baldwin's rules]] for ring closure.<ref>{{cite journal|last1=Baldwin|first1=Jack E.|title=Rules for ring closure|journal=Journal of the Chemical Society, Chemical Communications|issue=18|year=1976|pages=734|issn=0022-4936|doi=10.1039/c39760000734}}</ref> According to the rules, 5-exo-tet ring closures are favored while 6-endo-tet ring closures are disfavored.<ref>{{cite journal|last1=Hirschmann|first1=H.|last2=Hanson|first2=K.R.|title=Reflection-concordant stereospecific numbering|journal=Tetrahedron|volume=33|issue=8|year=1977|pages=891–897|issn=0040-4020|doi=10.1016/0040-4020(77)80042-2}}</ref> The regioselectivity of each iodolactonization can be predicted and explained using Baldwin's rules.
[[File:IodolactonizationRingSize5.svg|center|500px|Iodolactonization]]
Stereoselective iodolactonizations have been seen in literature and can be very useful in synthesizing large molecules such as the aforementioned vernopelin and vernomenin because the lactone can be formed while maintaining other stereocenters. The ring closure can even be driven by stereocenters adjacent to the carbon-carbon multiple bond as shown below.<ref name="Stereoselectivity2"/>
:[[File:IodolactonizationStereoselectivity4.svg|center|700px|Iodolactonization]]
Even in systems without existing stereocenters, Bartlett and coworkers found that stereoselectivity was achievable. They were able to synthesize the ''cis'' and ''trans'' five membered lactones by adjusting reactions conditions such as temperature and reaction time. The ''trans'' product was formed under thermodynamic conditions (e.g. a long reaction time) while the ''cis'' product was formed under kinetic conditions (e.g. a relatively shorter reaction time).<ref>{{Cite journal | last1 = Bartlett | first1 = P. A. | last2 = Myerson | first2 = J. | title = Stereoselective epoxidation of acyclic olefinic carboxylic acids via iodolactonization | journal = Journal of the American Chemical Society | volume = 100 | issue = 12 | pages = 3950 | year = 1978 | doi = 10.1021/ja00480a061}}</ref>
:[[File:BartlettIodolactonization.svg|center|500px|Iodolactonization]]
==Applications== Iodolactonization has been used in the synthesis of many biologically important products such as the tumor growth inhibitors vernolepin and vernomenin, the pancreatic lipase inhibitor vibralactone, and prostaglandins, a [[lipid]] found in animals. The following [[total syntheses]] all use iodolactonization as a key step in obtaining the desired product.
In 1977, [[Samuel Danishefsky]] and coworkers were able to synthesize the tumor growth inhibitors ''dl''-vernolepin and ''dl''-vernomenin via a multistep process in which a lactonization was employed.<ref name=DanIodolact/> This synthesis demonstrates the use of iodolactonization to preferentially form a five-membered ring over a four- or six-membered ring, as expected from Baldwin's rules.
:[[File:Danishefsky Iodolactonization.svg|center|Danishefsky iodolactonization]]
In 2006, Zhou and coworkers synthesized another natural product, vibralactone, in which the key step was the formation of a lactone.<ref name=VibraIodolact/> The stereoselectivity of the iodolactonization sets a critical stereochemical configuration for the target compound.
:[[File:VibralactoneIodolactonization4.svg|center|600px|Iodolactonization]]
In 1969, Corey and coworkers synthesized [[prostaglandin E2|prostaglandin E<sub>2</sub>]] using an iodolactone intermediate.<ref name="CoreyIodolact"/> Again, the stereoselectivity of the iodolactonization plays an integral role in product formation.
:[[File:Corey Iodolactonization4.svg|center|600px|Iodolactonization]]
==See also== * [[Iodolactamization]] — the [[lactam]] analogue * [[Halogen addition reaction]]
==References== {{Reflist}}
[[Category:Oxygen heterocycle forming reactions]] [[Category:Lactones]]