Anti-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 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. 

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). 

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... 

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>. 

The regioselective anti-Markovnikov addition of benzoic acid to phenyl-acetylene has also been carried out with success at 111 °C in the presence of ruthenium complexes containing a tris(pyrazolyl)borate (Tp) ligand [RuCl(Tp)(cod), RuCl(Tp)(pyridine), RuCl(Tp)(N,N,Ar,AT-tetramethylethyl-enediamine )] with a stereoselectivity in favour of the (E)-enol ester isomer [22]. The o-enynyl complex Ru(Tp)[PhC=C(Ph)C=CPh](PMe/-Pr2) (C) efficiently catalyses the regioselective cyclization of a,cu-alkynoic acids to give en-docyclic enol lactones [23] (Eq. 2). 

A Ni-catalyzed cyclization cross-coupling reaction of iodoalkenes with alkyl zinc halides has been employed for the synthesis of various tetrahydrofuran derivatives <2007AGE-ASAP>. The TiCU-catalyzed anti-Markovnikov hydration of alkynes has been applied to the synthesis of various benzo[3]furans <2007JOC6149>. 

S Synthesis from n-ribonolactone D-Ribonolactone has been converted to tre-hazolamine derivatives via the allylic alcohol 99, whose condensation with p-methoxybenzylisothiocyanate followed by anti-Markovnikov iodo cyclization with iodine afforded the iodo oxazolidinone 100 (82%) (Scheme 14). The latter was treated with a mixture of acetic anhydride and snlfnric acid followed by activated zinc to furnish the allylic acetate 101 (90%), which nnderwent inversion at C-2 nnder Mitsnnobu conditions and the resnlting alcohol was epoxidized to produce 102. Hydrolysis of the epoxide 102 followed by acetylation of the resulting triol 103 afforded 104, which was treated with CAN to furnish the triacetate 105. Finally, 105 was converted into hexaacetate 86 in three steps. 

S)-hydroxylunacrine (cf. 333) found in L. amara. The biosynthesis of (-)-(R)-lunasine is more likely to occur by anti-Markovnikov hydration of a prenylquinolone to an (S)-hydroxy derivative followed by cyclization to lunasine with inversion at the chiral center and thence conversion into lunacrine (335) (Scheme 29) direct cyclization of a prenylquinolone is less probable because at least in vitro acid-catalyzed reactions lead exclusively to pyranoquinolines. The (R)-hydroxy derivative lunacridine (cf. 337) has been obtained from L. amara but is probably an artifact arising from hydrolysis of (-)-(R)-lunasine during isolation, rather than a biosynthetic intermediate. 

L=AZARYPHOS, see Scheme 7) [86], to synthesize indoles from homo-propargylic amines/amides in good yields [105]. The use of doubly ethynylated substrates in the presence of water gave rise to the product derived from cyclization to the indole plus anti-Markovnikov hydration of the second terminal alkyne (Scheme 21). 

Cyclizations can be initiated by a nucleophilic attack, e.g. by H2O or a carboxylic acid, to a catalytic ruthenium vinylidene followed by trapping with an electrophile. Lee and coworkers described the Ru-catalyzed hydrative cyclization of 1,5-enynes (Scheme 33) to give functionalized cyclopentanones [147]. Treatment of 1,5-enynes bearing an internal Michael acceptor with a catalytic amount of [Ru3Cl5(dppm)3]PF6 in the presence of water initially afforded the corresponding ruthenium vinylidene species. Nucleophilic anti-Markovnikov addition of water... 

Cyclization of IV-allyl anilines (64) in superacidic medium has been reported to afford anti-Markovnikov products (65). Investigation by the in situ NMR spectroscopy, DFT calculations, and reactions with labelled substrates suggest that new ammonium-carbenium super-electrophiles are involved as intermediates. ... 

Titanium hydrides are good catalysts for cyclization of a,Cc>-dienes into the cyclic compounds. Generally, the cyclization starts with hydrotitanation of one of the double bonds, and because it can proceed in both Markovnikov and anti-Markovnikov mode it may result in the formation of two kinds of products the l-methylene-2-methylcycloalkanes 92 and methylenecycloalkanes 93 (Scheme 38). 

Recently, the cyclization of pent-4-yn-l-ols and but-3-yn-l-ols via anti-Markovnikov addition of the hydroxy group to the terminal carbon of the triple bond with a ruthenium catalyst in THF at 80°C and no other additive has been reported. All types of acetylenic alcohols, purely aliphatic and including a phenylacetylene fragment have been cycloisomerized in excellent yields. The catalyst is a cationic ruthenium(II) complex has depicted in Scheme 29 [114]. 

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