Olefins aldehyde cyclization

TiCl4 is used extensively as a Lewis acid in numerous organic transformations, forming adducts that mediate reactivity. Such reactions include Diels Alder, 54,355 hetero Diels Alder,356 cyclization of olefinic aldehydes,357 Flosomi Sakurai allylic coupling reactions,358 cyclopropanations,359 chal-cogen-Baylis Flillman,360 Mukaiyama Aldol reactions,36 363 reductions of ketones to alcohols 364 and stereoselective nucleophilic additions to aldehydes.365... 

The initial step of olefin formation is a nucleophilic addition of the negatively polarized ylide carbon center (see the resonance structure 1 above) to the carbonyl carbon center of an aldehyde or ketone. A betain 8 is thus formed, which can cyclize to give the oxaphosphetane 9 as an intermediate. The latter decomposes to yield a trisubstituted phosphine oxide 4—e.g. triphenylphosphine oxide (with R = Ph) and an alkene 3. The driving force for that reaction is the formation of the strong double bond between phosphorus and oxygen ... 

Olefination Reactions Involving Phosphonium Ylides. The synthetic potential of phosphonium ylides was developed initially by G. Wittig and his associates at the University of Heidelberg. The reaction of a phosphonium ylide with an aldehyde or ketone introduces a carbon-carbon double bond in place of the carbonyl bond. The mechanism originally proposed involves an addition of the nucleophilic ylide carbon to the carbonyl group to form a dipolar intermediate (a betaine), followed by elimination of a phosphine oxide. The elimination is presumed to occur after formation of a four-membered oxaphosphetane intermediate. An alternative mechanism proposes direct formation of the oxaphosphetane by a cycloaddition reaction.236 There have been several computational studies that find the oxaphosphetane structure to be an intermediate.237 Oxaphosphetane intermediates have been observed by NMR studies at low temperature.238 Betaine intermediates have been observed only under special conditions that retard the cyclization and elimination steps.239... 

Cationic polymerization of alkenes and alkene derivatives has been carried out frequently in aqueous media.107 On the other hand, the reaction of simple olefins with aldehydes in the presence of an acid catalyst is referred to as the Prins reaction.108 The reaction can be carried out by using an aqueous solution of the aldehyde, often resulting in a mixture of carbon-carbon bond formation products.109 Recently, Li and co-workers reported a direct formation of tetrahydropyranol derivatives in water using a cerium-salt catalyzed cyclization in aqueous ionic liquids (Eq. 3.24).110... 

The unsubstituted quinazolidine system 5 was constructed from mesylate 173. The key feature in this synthesis is based on a cyclohydrocarbonylation of the protected 4-amino-l,6-heptadiene 169 catalyzed by Rh(acac)(CO)2-BIPHEPHOS. Formation of the hemiamidal-aldehyde 171 took place by hydroformylation of the two olefin moieties and cyclization. Elimination of water gave 172, which, after treatment with NaBFE, subsequent mesylation to 173, and catalytic hydrogenation, afforded 5 (Scheme 29) <1998TL4599>. 

In addition to this, asymmetric 1,3-dipolar cyclization reactions of nitrones with olefins,40 41 catalytic enantioselective cyanation of aldehydes,42 catalytic enantioselective animation,43 and aza-Michael reactions44 have been reported, and high enantioselectivities are observed. 

If the hydroformylation of olefins is conducted in the presence of aromatic hydrazines and Bronsted or Lewis acids indoles can be obtained directly in one pot [91-93,95]. Hydroformylation of the olefin gives an intermediate aldehyde, which is trapped immediately by the present aromatic hydrazine as an aromatic hydrazones similar to the formation of imines under hydroformylation conditions. Under acid mediation these aromatic hydrazones undergo a Fischer indolization, consisting of a [3,3]-sigmatropic rearrangement followed by a cyclization and elimination of ammonia (Scheme 38). 

Perlmutter used an oxymercuration/demercuration of a y-hydroxy alkene as the key transformation in an enantioselective synthesis of the C(8 ) epimeric smaller fragment of lb (and many more pamamycin homologs cf. Fig. 1) [36]. Preparation of substrate 164 for the crucial cyclization event commenced with silylation and reduction of hydroxy ester 158 (85-89% ee) [37] to give aldehyde 159, which was converted to alkenal 162 by (Z)-selective olefination with ylide 160 (dr=89 l 1) and another diisobutylaluminum hydride reduction (Scheme 22). An Oppolzer aldol reaction with boron enolate 163 then provided 164 as the major product. Upon successive treatment of 164 with mercury(II) acetate and sodium chloride, organomercurial compound 165 and a second minor diastereomer (dr=6 l) were formed, which could be easily separated. Reductive demercuration, hydrolytic cleavage of the chiral auxiliary, methyl ester formation, and desilylation eventually led to 166, the C(8 ) epimer of the... 

In a related study, the oxidation-reduction sequence was carried out in the presence of an olefin (Scheme 21). Two products were formed. The major product resulted from the net reduction of the carboxylic acid to an aldehyde. The minor product resulted from trapping of the radical anion intermediate generated from the reduction reaction by the olefin. It should be noted that, in the absence of a trapping group, the acid can be selectively reduced to the aldehyde without any over-reduction. Although not in the scope of this review, this is a very useful transformation in its own right [35]. At this time, the yields of the cyclized products from the cyclization reaction of the radical anion with the olefin remain low. 

After epoxidation of the terminal olefin in syn-89 the pyrrolidine 91 was formed by reductive cleavage of the Cbz-protection and concomitant Sn2 cyclization of the free amine to epoxide 90. In five additional steps (+)-preus-sin (2) was synthesized with an overall yield of 19%. After AT-methoxycar-bonylation and oxidation of the alcohol to an aldehyde the alkyl side chain was introduced by a Wittig reaction. 

In 1992, Sakai provided the first examples of highly enantioselective (>80% ee) hydro-acylations of olefins with aldehydes, the Rh(l)/BlNAP-catalyzed cyclization of 4-aUce-nals (Eq. 12) [14]. Additional work from the same laboratory established that certain 4-aryl-substituted substrates also undergo ring formation with good enantioselectivity... 

Another stereoselective synthesis (Scheme 11) is based on sugar aldehyde 35 and intermediate 36 subsequent 1,2-O-isopropylidine deprotection, N,0-debenzylation/olefin reduction/reductive cyclization in a single pot, and O-acetylation result in the formation of bicyclic aza sugar 37 (09TA1217). 

The medicinal chemistry of Alzheimers is complicated by the fact that the etiology of this disease is still far from clear. Evidence points to an association with decreased levels of acetyl choline in the brain. Many of the drugs that have been introduced to date for treating this disease thus comprise agents intended to raise the deficient levels of that neurotransmitter by inhibiting the loss of existing acetylcholine due to the action of cholinesterase. A compound based on an indene that, perhaps surprisingly, inhibits that enzyme has been proposed for the treatment of Alzheimer s. Aldol condensation of piperidine aldehyde (4-2) with the indanone (4-1) from cyclization of 3,4-dimethoxycinnamic acid leads to the olefin (4-3). Catalytic reduction removes the double bond to afford donepezil (4-4) [3]. 

Certain unsaturated aldehydes may be converted to cyclic ketones by a related mechanism. The formyl group reacts with Rh(I) complexes to form an acyl-Rh hydride species, which undergoes intramolecular reaction with the olefinic linkage present in the same molecule (117a). Asymmetric induction is observed with a chiral diphosphine ligand (Scheme 53) (117b-d). Enantioselective cyclization of 4-substituted 4-pentanals into 3-substituted cyclopentanones in greater than 99% ee is achieved with a cationic BINAP-Rh complex. 

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