Acid Catalyzed Ring Closure

Under the influence of strong acids jS-benzyl aspartyl residues give rise to aminosuccinyl peptides 

In peptides with glutamine as the N-terminal residue spontaneous pyrrolidone formation takes place the reaction is catalyzed by weak acids  

---

Acetal handle 78 synthesized from Merrifield resin and 4-hydroxy-benzaldehyde was applied to the solid-phase synthesis of carbohydrates and 1-oxacephams (Scheme 41) [90]. For the latter, a 1,3-diol was initially anchored to the support to form a cyclic acetal. A ring opening reaction with DIBAL generated a resin-bound alcohol which was converted to the corresponding triflate for A-alkylation with 4-vinyl-oxyazetidin-2-one. A Lewis acid catalyzed ring closure released 1-oxa-cephams from the support. 

Arnino-6,7-dihydro-l //,5//-pyrazolo[ 1,2- pyrazol-l-onc 269 is easily obtained in 57% yield as its hydrochloride by acid-catalyzed ring closure of nitrile 268 using hydrochloric acid. A better yield is described for the synthesis starting from the N-protected compound 267. Treatment with hydrochloric acid provides crystalline hydrochloride of 268, which is then cyclized by heating in ethanol (Scheme 33) <2001JHC613>. 

In the course of their studies of pseudouridine,164 Asbun and S. B. Binkley183 reported the synthesis of 5-/3-D-arabinofuranosyl- and 5-/3-D-xylofuranosyl-uracil (258 and 259) by the acid-catalyzed ring-closure of the corresponding alditol derivatives. The configuration at the anomeric carbon atom was determined on the basis of optical rotatory dispersion studies. 

The key step in Hu s synthesis of 51 was cyclization of 50 by heating with copper(I) iodide and sodium hydride in DME, followed by a 10% aqueous ammonia work-up. Intermediate 50 was prepared via Michael addition of ethyl acetamidocyano acetate to the appropriate chalcone followed by acid-catalyzed ring closure [42,43]. 

VI) was hydrogenated to the corresponding sorbitol derivative (VII) in which the only groups unsubstituted were those situated at Cl and C4. Acid-catalyzed ring closure gave a product identical with the tetramethyl derivative of arlitan. 

The Delft synthesis makes use of an acid-catalyzed ring closure - in fact an intramolecular aromatic alkylation - of a l-(3,5-dihydroxy-4-methoxybenzyl) isoquinoline derivative that is prepared starting from (natural) gallic acid. One of the hydroxyl groups is removed via a Pd/ C hydrogenation of the benzyl ether. Other catalytic steps play an important role some steps were improved recently [27]. The crucial step in the Rice synthesis makes use of a l-(2-bromo-5-hydroxy-4-methoxybenzyl)isoquinoline derivative that is also cyclized in an acid-catalyzed ring closure to the morphinan skeleton, followed by catalytic removal of the bromo substituent (Scheme 5.8). 

Scheme 5.8 Acid-catalyzed ring closures in the routes to morphine, according to Beyerman and Rice.

It appears, therefore, that such a rearrangement may occur also during the polyphosphoric acid-catalyzed ring closure of 2-thienyl dimethoxyethyl sulfide (23). Thus, the method of Tilak et can-... 

Pattenden and Teague have prepared tricyclic diol 684 which is epimeric to the naturally occurring A < -capnellene-8p,10a-diol (68S) Their strategy, which is summarized in Scheme LXXI, encompasses two critical cyclization steps. The first is the Lewis acid-catalyzed ring closure of enol acetate 686 and the second involves reductive closure of acetylenic ketone 687. It is of interest that the oxidation of 688 proved to be stereospecific. 

The addition of acid to Az-piperideine results in an iminium ion that readily reacts with nucleophilic species. This reaction has been particularly useful for the formation of carbon-carbon bonds in alkaloid total synthesis. For example, key steps in the total synthesis of ( )-porantherine (equation 36) (74JA6517), coccinelidine (equation 37) (77H(7)685) and eburnamonine (equation 38) (65JA1580) were acid-catalyzed ring closures between A2-piperideine derivatives and ends. Even the weakly nucleophilic carbon-carbon double bond can participate in this type of reaction (80JA5955), as has been demonstrated by a recent total synthesis of a morphinan derivative (Scheme 13). 

Two furo-annelated benzo[c]furans, a benzo[2,l-Z) 3,4-c ]difuran (341) and a benzo[1.2-/ 3,4-c ]difuran (344) have been described. Acid-catalyzed ring closure of bisfuran 340, which is available from trans-trans-1,4-dibenzo-ylbutadiene (339) and /ranx-dibenzoylethylene. yields 341 in 83% yield. An independent synthesis which starts from 4-benzoyl-2-phenylfuran (343) is outlined in Scheme 21 the isomeric compound has been obtained similarly (Scheme 22). 

Two syntheses of phosphindole derivatives via acid-catalyzed ring closure are shown in equations (47) and (48) (76JOC1403, 76JCS(P1)2556, 74AJC831). 

Furans have been prepared from 1,4-dialdehydes, usually in the more accessible acetal form by acid catalyzed ring closure. Using this approach, furan-3,4-dicarboxyIic acid has been obtained in 70% yield as the ester from 2-(dialkoxymethyl)-l-formyl succinic ester (54JOC1671). c/s-2-Butene-l,4-diol on oxidation to the monoaldehyde is cyclized to furan (61 ACSll77). The acetals (83) and (84) have been converted to the corresponding furan... 

The acid-catalyzed ring closure of the alkenols follows much the same pattern, although the intermediate carbocation from hex-5-en-l-ol undergoes rearrangement and gives a mixture of 2-methyltetrahydropyran and 2-ethyltetrahydrofuran (79MI22402). 

Diaryl-2-hydroxypropiophenones (607) are obtained from 4-hydroxychalcone and a reactive phenol on treatment with alkaline hydrogen peroxide in an epoxide-mediated coupling reaction. The ketones undergo a base-catalyzed a-ketol rearrangement to the isomeric l-hydroxypropan-2-ones (608) and acid-catalyzed ring closure provides a route to 4-arylflavan-3-ones (Scheme 231) (80JCS(Pl)1025). 

Hydroxy-5,10-seco-estrane-3,5,10-trione acetate (124a) produced by ozonolysis of 17/ -hydroxyestr-5(10)-en-3-one acetate (123a) readily undergoes acid-catalyzed ring closure to give 17j3-hydroxy-10(5 -> 4) Z>eo-estr-4( 10)-ene-... 

The secocorrin nickel complex (101) can also be induced to undergo an electrochemical cyclization to corrin (100) but only in low yield. The experimental conditions involve a one-electron oxidation, followed by a one-electron reduction.269 The same secocorrin complex (101) is the starting material for two cyclization sequences leading to a didehydrocorrin complex (107) with a chromophore of seven double bonds (Scheme 67).269,270 The most interesting feature of these sequences is the remarkably easy acid-catalyzed ring closure of the secocorrinoid complex (106) to corrin (107). 

In an equivalent pattern, 3-phenyl-5-ethynyl-pyrazole 349) is synthesized by transforming l,4-bis(TMS)-butadiyne 38) via benzoylchloride 242) into the corresponding l-benzoyl-4-TMS-l,3-butadiyne (J47)48. Subsequent acid-catalyzed ring closure with hydrazine hydrate and then hydrolysis under basic conditions yields 3-phenyl-5-ethynyl-pyrazole (349)208 (Scheme 49). 

Further acid-catalyzed reactions include the use of />-toluene sulfonic acid-DMF in a cyclization of the protected amino acid 17 (DMF = dimethylformamide Scheme 15) <20040L4941>. This was the key step in the stereoselective synthesis of 5-hydroxypipecolic acid. A similar acid-catalyzed ring closure of a hemiacetal yielded the fused piperidine 18 <2004JOC1872> (Equation 32). The indolizidine alkaloid can be accessed by a Barton-Ester method utilizing a polyphosphoric acid (PPA) cyclization (Scheme 16) <1994T19157>. 

A further efficient and general synthesis of l,3-dithiole-2-thiones (169) with a variety of functional groups is the acid-catalyzed ring closure of j8-keto f-butyl trithiocarbonates of type (261) which are readily available from a-halo ketones and sodium t-butyl trithiocarbon-ate. The intermediates (262) fragment into isobutene and l,3-dithiole-2-thiones (169) (80JOC175). 

For photochemical ring closure, see page 413, Section 2.2, and for Lewis acid-catalyzed ring closures, see page 410, Section 2.1. 

The last step of the synthesis of the natural product (—)-semburin 329 involved the cyclization of the primary alcohol 328 catalyzed by pyridinium />-toluenesulfonate (Equation 40). In analogous fashion, starting from the suitable primary alcohol, the (—)-isosemburine was also obtained <2002SL334>. Similar acid-catalyzed ring-closure was observed in the synthesis of the benzodioxocin 303 from the dialcohol 330 (Equation 41) <2003JOC1081>. 

Evans and Mitch( 101 elaborated this synthesis to afford a general approach to morphinans and to include a total synthesis of ( )-morphine (Scheme 3.7). The diastereomerically pure aziridinium salt, 43, was prepared as illustrated and converted to the aldehyde (44) in 95% yield simply by dissolving in anhydrous DMSO at ambient temperature (Kornblum oxidation). Lewis acid catalyzed ring closure occurred in high yield (80%) to the isomorphinan-10-ol... 

---