Markovnikov cyclization

Anti-Markovnikov cyclizations For anti-Markovnrkov cyclizations of 4-alkynols to dihydropyrans such as glycals, the catalysts or reagents introduced by McDonald [150] remain synthetically important [151,152]. Another catalyst based on ruthenium was presented by the Trost group. A rather finely tuned catalyst based on a CpRuCl (PAr3)2 complex (Ar = aryl) achieved similar reactions like the McDonald catalyst (Scheme 25c) [153]. 

It is not surprising that there seems to be no appropriate chemical precedent for the a n -Markovnikov cyclization to a seven-membered ring. On the contrary, the ring contraction of secondary carbonium ion (64) to the tertiary bisabolyl ion should be very rapid. However, the Prins-like conversion of the cycloheptenone (66) to the carotol ether (67) in the presence of stannic chloride mimics, to some degree, the second cyclization in the biogenesis of carotol 119). 

It is possible to effect an anti-Markovnikov cyclization to the per-hydroazulene skeleton of the guaianes by the action of acid catalysts upon the 5,6-epoxides of various germacrene sesquiterpenes (727, 124). Markovnikov opening of the epoxode with participation of the transannular double bond (cyclobutane-like strain in transition state) does not compete. For contrast, the cyclization of the isomeric epoxide to eudesmanediol is also shown. 

Cyclizations of cyclodecadienyl carbonium ions have been observed by Hirose and co-workers in the acid-catalyzed reactions of bicyclo-germacrene (70) and germacrene D (85) 141, 142). In the former case, protonation presumably occurs on the exocyclic cyclopropane bond adjacent to the double bond affording an allylic carbonium ion resembling (82). This W-shaped allylic ion then apparently isomerizes to the sickle ion (81) (see above) prior to Markovnikov cyclization to 5-cadinene (86). 

Step 3 of Figure 27.14 Third Cyclization The third cationic cyclization is somewhat unusual because it occurs with non-Markovnikov regiochemistry and gives a secondary cation at C13 rather than the alternative tertiary cation at C14. There is growing evidence, however, that the tertiary carbocation may in fact be formed initially and that the secondary cation arises by subsequent rearrangement. The secondary cation is probably stabilized in the enzyme pocket by the proximity of an electron-rich aromatic ring. 

The addition, therefore, follows Markovnikov s rule. Primary alcohols give better results than secondary, and tertiary alcohols are very inactive. This is a convenient method for the preparation of tertiary ethers by the use of a suitable alkene such as Me2C=CH2. Alcohols add intramolecularly to alkenes to generate cyclic ethers, often bearing a hydroxyl unit as well. This addition can be promoted by a palladium catalyst, with migration of the double bond in the final product. Rhenium compounds also facilitate this cyclization reaction to form functionalized tetrahydrofurans. 

Phenylprop-2-enyl sulfates are cyclized stereospecifically and with Markovnikov regiochemical control. These are endo-6 cyclizations. 

Electronic factors also influenced the outcomes of these cyclization reactions cyclization of pyrrole 84 to bicyclic amine 85 is catalyzed by the sterically open complex 79a. In this reaction, initial insertion into the Y - H bond occurred in a Markovnikov fashion at the more hindered olefin (Scheme 19) [48]. The authors proposed that the Lewis basic aromatic ring stabilizes the electrophilic catalyst during the hydrometallation step, overriding steric factors. In the case of pyrroles and indenes, the less Lewis basic nitrogen contained in the aromatic systems allowed for the cyclization of 1,1-disubstituted alkenes. 

Usually, 5- and 6-membered Markovni-kov-type products are formed in other cases the process results in various open-chain products. The formation of an anti-Markovnikov adduct from 2-cyclohex-1-enyl-ethanol was explained by the cyclization of an episulfonium intermediate... 

The hydrative cyclization involves the formation of a ruthenium vinylidene, an anti-Markovnikov addition of vater, and cyclization ofan acylmetal species onto the alkene. Although the cyclization may occur through a hydroacylation [32] (path A) or Michael addition [33] (path B), the requirement for an electron- vithdra ving substituent on the alkene and lack of aldehyde formation indicate the latter path vay to be the more likely mechanism. Notably, acylruthenium complex under vent no decarbonylation in this instance. 

The a-enynyl complex Ru(Tp)[PhC=C(Ph)C=CPh](PMe Pr2) 10 efEciently catalyzed the regioselective cyclization of a,(D-alkynoic acids involving an anti-Markovnikov intramolecular addition to give unsaturated lactones [29] (Equation 10.5). 

The photoaddition of alcohols and phenols to alkenes has been observed.404 The equivalent intramolecular process results in cyclization and the formation of oxygen heterocycles. Irradiation of 2-allyl-4-(-butylphenol (388) affords 2,3-dihydro-2-methyl-5-<-butyl-benzofuran (389), whereas o-3-methylbut-2-enylphenol (390) gives 2,2-dimethylchroman (391). In both cases, therefore, the addition can be said to occur in a Markovnikov direction. 

Few applications of cyclizations to form fused ring 8-lactones or tetrahydropyrans are found. Two consecutive bromolactonizations were used to effect stereoselective dihydroxylation of a cyclohexadi-enone system in a total synthesis of erythronolide B (Scheme S).64 Iodolactonization of an NJV-di-ethylbenzamide derivative to form a ds-fused benzolactone was a key step in a recent synthesis of pancratistatin.641 A di-fused tetrahydropyran was produced in good yield by intramolecular oxymercura-tion as shown in equation (17),59 although attempts to cyclize a more highly functionalized system have been reported to fail.65 Formation of a fused ring tetrahydropyran via an anti-Markovnikov 6-endo sel-enoetherification has been reported in cases where steric and stereoelectronic factors disfavor a 5-exo cyclization to a spirocyclic structure.38... 

The effect of conformational control on the regiochemistry of cyclizations in steroid systems has been studied extensively by KoCovsky. A cyclization which proceeds both in an anti-Markovnikov and 6-endo mode is shown in equation (25).91... 

Stereoisomeric alcohols (93) and (94) yielded identical ring-expansion products [e.g. (97)] on formation of carbocations.168 This is evidence of a stepwise reaction in sterol biosynthesis, whereby a tertiary cation [e.g. the model (95)] rearranges to a secondary cation (96)-an anti-Markovnikov rearrangement . The synthetic aspects of biomimetic cyclizations of isoprenoid polyenes were reviewed.169 Included was a detailed discussion of carbenium ion-initiated cyclizations, with a discussion of the different mechanisms that have been proposed. A novel biomimetic carbocation polyene cyclization of a daurichromenic ester was reported an unusual 2 + 2-carbocation cyclization occurred as a side reaction.170... 

The mechanism of selenocyclization of yS,y-unsaturated acids and their derivatives has been studied. The reactions of ( )-4-phenylbut-3-enoic acid and its silyl and alkyl esters (15 R = H, SiMe3, alkyl) with benzeneselenenyl halide PhSeX (X = Cl, Br) have been examined by VT-NMR and in situ IR spectroscopic methods. Whereas the reactions of the acid in the presence of a base were irreproducible and complicated, reactions of the silyl esters were clean and spontaneously and quantitatively afforded the corresponding chloroselenylation adduct at -70 °C as a single (Markovnikov) isomer. This adduct underwent three processes as the temperature was raised (1) reversal to the starting materials, (2) isomerization to the anti-Markovnikov product, and (3) cyclization to the selenolactone (16). All of these processes are believed to proceed via a seleniranium ion, the intermediacy of which was established by independent synthesis and spectroscopic identification. The reversible formation of chloroselenide adducts was unambiguously established by crossover experiments. The reaction of (15) with PhSeBr was found to be rapid but thermodynamically unfavourable at room temperature.29... 

The acid-induced cyclization of unsaturated thioacetals (19) gives anti-Markovnikov products (20), apparently involving sulfur elimination and readdition.37... 

Diphenyl diselenide is an especially useful co-reagent with [bis(acetoxy)-iodo]benzene. For example, the BAIB/PhSeSePh (2 1) combination has been employed for trans, Markovnikov additions of PhSeOAc and PhSeOH to alkenes [35]. Such formal additions appear to be regulated by seleniranium intermediates, and were extended to intramolecular cyclizations of olefinic alcohols, carboxylic acids, and / -dicarbonyl compounds (Scheme 12). 

PhsPAuOTf has been shown to catalyse the intermolecular addition of phenols and carboxylic acids to terminal alkenes, RCH2CH=CH2, at 85 °C in toluene with Markovnikov selectivity to produce RCH2CH(OR)Me.131 AUCI3 triggers the electrophilic 6(0)ir n-endo-dig cyclization of 2-(alk-l-ynyl)alk-2-en-l-ones to produce highly substituted furans in analogy with other electrophiles (see above Scheme 3).40... 

Ionene, a commercial fragrance, has been prepared traditionally by treatment of a- and /3-iononcs with hydriodic acid containing phosphorus or by distillative heating in the presence of 0.5% iodine. In an unoptimized demonstration, cyclization occurred more cleanly and simply by MBR with /3-ionone in water at 250 °C (Scheme 19) [83]. Work-up also was facilitated, as the need for removal of catalyst or the formation and separation of bi-products was avoided. At elevated temperature, the addition of water to olefins can occur readily, without adding catalyst. (S)-(+)-carvone in water for 10 min at 180 °C afforded optically pure 8-hydroxy-p-6-mcnlhcn-2-one as an intermediate toward carvacrol [84], Addition of water across the 8,9-double bond of carvone occurred regioselectively, by Markovnikov addition. Carvacrol itself was obtained almost quantitatively from carvone at 250 °C after 10 min (Scheme 19) [84]. 

A regioselective cyclization of pent-4-ynoic acid is catalyzed by a TpRu complex 825. The anti-Markovnikov 3,4-dihydropyran-2-one product is exclusively formed in excellent yield (Equation 339) <2001CC2324>. Similarly, alkynoic esters 826 undergo ICl-promoted iodolactonizations to afford 5-iodo-3,4-dihydropyran-2-ones in moderate yield (Equation 340) <2003JOC10175>. 

---