Acid-catalyzed cyclizations

Open-chain 1,5-polyenes (e.g. squalene) and some oxygenated derivatives are the biochemical precursors of cyclic terpenoids (e.g. steroids, carotenoids). The enzymic cyclization of squalene 2,3-oxide, which has one chiral carbon atom, to produce lanosterol introduces seven chiral centres in one totally stereoselective reaction. As a result, organic chemists have tried to ascertain, whether squalene or related olefinic systems could be induced to undergo similar stereoselective cyclizations in the absence of enzymes (W.S. Johnson, 1968, 1976). 

A simple acid-catalyzed cyclization transforms i//-ionone into n-ionone (W. Kimel, 1957, 1958). Further treatment with protic acids transforms the tr-ionone to the thermodynamically more stable -ionone. 

The achiral triene chain of (a//-rrans-)-3-demethyl-famesic ester as well as its (6-cis-)-isoiner cyclize in the presence of acids to give the decalol derivative with four chirai centres whose relative configuration is well defined (P.A. Stadler, 1957 A. Escherunoser, 1959 W.S. Johnson, 1968, 1976). A monocyclic diene is formed as an intermediate (G. Stork, 1955). With more complicated 1,5-polyenes, such as squalene, oily mixtures of various cycliz-ation products are obtained. The 18,19-glycol of squalene 2,3-oxide, however, cyclized in modest yield with picric acid catalysis to give a complex tetracyclic natural product with nine chiral centres. Picric acid acts as a protic acid of medium strength whose conjugated base is non-nucleophilic. Such acids activate oxygen functions selectively (K.B. Sharpless, 1970). 

The early Escherunoser-Stork results indicated, that stereoselective cyclizations may be achieved, if monocyclic olefins with 1,5-polyene side chains are used as substrates in acid treatment. This assumption has now been justified by many syntheses of polycyclic systems. A typical example synthesis is given with the last reaction. The cyclization of a trideca-3,7-dien-11-ynyl cyclopentenol leads in 70% yield to a 17-acetyl A-norsteroid with correct stereochemistry at all ring junctions. Ozonolysis of ring A and aldol condensation gave dl-progesterone (M.B. Gravestock, 1978 see p. 279f.). 

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The following acid-catalyzed cyclizations leading to steroid hormone precursors exemplify some important facts an acetylenic bond is less nucleophilic than an olelinic bond acetylenic bonds tend to form cyclopentane rather than cyclohexane derivatives, if there is a choice in proton-catalyzed olefin cyclizations the thermodynamically most stable Irons connection of cyclohexane rings is obtained selectively electroneutral nucleophilic agents such as ethylene carbonate can be used to terminate the cationic cyclization process forming stable enol derivatives which can be hydrolyzed to carbonyl compounds without this nucleophile and with trifluoroacetic acid the corresponding enol ester may be obtained (M.B. Gravestock, 1978, A,B P.E. Peterson, 1969). 

The Lewis acid-catalyzed cyclization of 3-anaino-2-alkerLirnines (21) leads to a wide variety of alkyl- and aryl-substituted quinolines (59). The high regiospecificity and the excellent yields obtained make this process promising. 

In perfumery bisabolol functions as a fixative. The racemic form is manufactured by the acid-catalyzed cyclization of nerohdol (193). 

Diaryl derivatives of the 1,3-oxathiolylium system (29) are prepared by acid-catalyzed cyclization of the /3-keto thioesters (28) which are readily prepared from thioacid salts (27)... 

Application of the above principles to the synthesis of 1,3-diselenolylium ions has been successful. iVjA -Dialkyldiselenocarbamates as their oxo esters (30) undergo acid-catalyzed cyclization and dehydration to give the cation (31) in nearly 90% yield (75JOC746, 77CC505, 80CC866, 80CC866). 

An example of preferred conrotatory cyclization of four-7c-electron pentadienyl cation systems can be found in the acid-catalyzed cyclization of the dienone 12, which proceeds through the 3-hydroxypentadienyl cation 13. The stereochemistry is that expected for a conrotatory process. 

A-Nor-B-homo steroids with different substitution patterns than those described above may be prepared by acid catalyzed cyclization of 3)3-hydroxy-5(10)-seco-cholest-tra/w-l(l0)-en-5-one acetate (134a) formed in 30-40% yield by mercuric oxide-iodine sensitized irradiation of cholestane-3j3,5a-diol... 

Ryder reported the preparation of an interesting alkyl diaryl furan that was subsequently polymerized and studied as a conducting polymer. The monomer furan 49 was available fron the acid catalyzed cyclization of dione 48. ... 

Further elaboration of 152 resulted in the synthesis of (derived from the reduction of pyridinium salt 150b with excess of LiAlFt4 in THE Acid-catalyzed cyclization of 154 led to indoloquino-lizidine 155 (25% yield from 150b), a precursor of deplancheine (80TL2341) (Scheme 5). 

Compound 68 can also be obtained by an acid-catalyzed cyclization of 42, which was prepared by the Michael addition reaction of 39 to mesityl oxide as shown in Section IV.A. As for the product 69, the presence of the tosyloxy group at the 5 position instead of the 6 position is determined, utilizing the anisotropy effect of the 1-acetyl group to the C-7 proton, by comparing its H NMR spectrum with that of 70, obtained in 69% yield by the treatment of 69 with NaH and AcCl. 

Recently reported289 is an analogous reaction involving the acid-catalyzed cyclization of (lZ,3 ,5Z)-l,6-diphenylhexa-l,3.5-triene-l,6-diamine (14) in refluxing toluene to 2,7-diphenyl-3//-azepine (15). The l,6-bis(4-tolyl) and 1,6-dibenzyl derivatives behave similarly, but give substantially lower yields (14-18%). 

Alkyl A-(3-oxobuten-l-yl)-2-aminobenzyl ketones 9 (as their cyclic acetals), formed by condensation of alkyl 2-aminobenzyl ketones with 3-methoxybut-3-ene-2-one, undergo acid-catalyzed cyclization to give rare examples of A -unsubstituted 1H-1 -benzazepines 10 in high yields.81... 

Acid-catalyzed cyclization of thiosemicarbazide 1 leads to the 1,2,4,6-tetrazocine 2.5... 

In order to improve the selectivities in these reactions, styrylepoxides 39 and 40 were prepared and subjected to acid-catalyzed cyclizations (Scheme 9.23) [113]. Both compounds, however, afforded almost identical mixtures of diastereomeric oxepanes 41 and 42 (83%, dr 21 79 and 66%, dr 20 80, respectively), while no tetrahydropyran 43 was formed. Clearly, the additional stabilization provided by... 

An analogous Lewis acid catalyzed cyclization of the oi-acctoxy derivatives 3 gives rise to one pair of diastereomers of 4 in the case of the ( )-alkenc, while the (Z)-alkene affords a diastereomeric mixture of (2S, 3/J, 4/J )-4 (major product) and (2,S, 3,S, 4/ )-4 (minor product)90. 

Rather surprisingly, exclusive formation of a five-membered ring is observed on acid-catalyzed cyclization of certain biscarbamates91. Presumably the number of trigonal atoms renders the transition state leading to the six-membered ring unfavorable. 

Chlorophenyl)-5-(4-methoxyphenyl)isoxazole has also been prepared from the dilithio derivative of 4-ehloroacetophenone oxime by two other methods (a) reaction with anisonitrile (4-methoxybenzoni-trile) followed by acid-catalyzed cyclization8 and (b) condensation of anisolyl chloride (4-methoxybenzoyl chloride) followed by acid-catalyzed cyclization. ... 

Scheme 25). The introduction of greater diversity at C-2 and C-4 can be achieved by intercepting the tetrahydropyridinone intermediate in a multi-step sequence involving C-2 ammonolysis, microwave-assisted N-acylation, acid-catalyzed cyclization (to introduce diversity at C-2), treatment with POCI3, and either microwave-assisted nucleophiUc substitution or Suzuki couphng (to introduce diversity at C-4) [89]. 

Support for the involvement of Fe comes from the observation that the kinetic chain length of the dimethyl ester increases with increasing concentration of added Fe together with a fourfold increase in the yield of 262 (216). However, as a vinyl cation bearing carbonyl substituents may be energetically unfavorable, an alternative mechanism, involving a ligand transfer from hydrated Fe ions followed by an acid-catalyzed cyclization, may be a more likely pathway ... 

The acid-catalyzed cyclization of p-toluenesulfonamides of A/-benzylaminoacetaldehyde usually yields 1,2-dihydroisoquinolines. However, cyclization of intermediates bearing a substitutent a to the carbonyl group affords 3-substituted 2-p-toluenesulfonyl tetrahydroisquinolin-4-ol derivatives, capable of further transformation into the related 1,2,3,4-tetrahydroisoquinolines <95CJC(73)1348>. 

A key step in the approach to 3(2//)-furanone ring systems via the acid-catalyzed cyclization-dehydration of appropriately substituted a -hydroxy-l,3-diketones involves the acylation of a-hydroxy-ketone dianions 11141... 

Scheme 36. Acid-catalyzed cyclization of the Hofmann degradation products of dihydro-protoberberines. Reagents a, cone HC1 b, POCl3 c, H2S04 d, 10% HC1. 

At first, acid-catalyzed cyclization of Hofmann degradation products was undertaken however, the cyclization proceeded via the 5-exo-trigonal mode instead of the 6-endo-trigonal mode, resulting in no benzo[c]phenanthridine skeleton. Dyke and Brown (114-117) reinvestigated Perkin s results (118,119) and established the structure of the cyclized products 196 and 197 derived from the methine base 194 (Scheme 36). Onda et al. (120,121) obtained the five-membered spiro compounds 198 and 199 by treatment of 195 with dilute hydrochloric acid. 

Further attempts to effect a one-step synthesis of the hasubanan skeleton via acid-catalyzed cyclization of urethane 28 and unsaturated amides 31 and 32 were explored, using trifluoroacetic acid (TFA) (Scheme 1). Treatment of... 

An alternative new synthetic approach to chrysene 1,2-dihydro-diol based on Method IV has recently been developed (60). This method (Figure 12) entails synthesis of 2-chrysenol via alkylation of 1-1ithio-2,5-dimethoxy-1,4-cyclohexadiene with 2-(1-naphthyl) e-thyl bromide followed by mild acid treatment to ge nerate the diketone 12. Acid-catalyzed cyclization of 12 gave the unsaturated tetracyclic ketone 13 which was transformed to 2-chrysenol via dehydrogenation of its enol acetate with o-chloranil followed by hydrolysis. Oxidation of 2-chrysenol with Fremy s salt gave chrysene... 

The Skraup cyclization is another reaction principle that provides rapid access to the quinoline moiety. Theoclitou and Robinson have published the preparation of a 44-member library based on the 2,2,4-trisubstituted 1,2-dihydroquinoline scaffold by the Lewis acid-catalyzed cyclization of substituted anilines or aminoheterocyc-les with appropriate ketones (Scheme 6.237) [420], The best results were obtained using 10 mol% of scandium(III) triflate as a catalyst in acetonitrile as solvent at... 

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