Spirocyclization enantioselective

Nair and co-workers have demonstrated NHC-catalysed formation of spirocyclic diketones 173 from a,P-unsaturated aldehydes 174 and snbstitnted dibenzylidine-cyclopentanones 175. Where chalcones and dibenzylidene cyclohexanones give only cyclopentene products (as a result of P-lactone formation then decarboxylation), cyclopentanones 175 give only the spirocychc diketone prodncts 173 [73]. Of particular note is the formation of an all-carbon quaternary centre and the excellent level of diastereoselectivity observed in the reaction. An asymmetric variant of this reaction has been demonstrated by Bode using chiral imidazolium salt 176, obtaining the desymmetrised product with good diastereo- and enantioselectivity, though in modest yield (Scheme 12.38) [74],... 

An enantioselective variant of the diene cydization reaction has been developed by application of chiral zirconocene derivatives, such as Brintzinger s catalyst (12) [10]. Mori and co-workers demonstrated that substituted dial-lylbenzylamine 25 could be cyclized to pyrrolidines 26 and 27 in a 2 1 ratio using chiral complex 12 in up to 79% yield with up to 95% ee (Eq. 4) [ 17,18]. This reaction was similarly applied to 2-substituted 1,6-dienes, which provided the analogous cyclopentane derivatives in up to 99% ee with similar diastereoselectivities [19]. When cyclic, internal olefins were used, spirocyclic compounds were isolated. The enantioselection in these reactions is thought to derive from either the ate or the transmetallation step. The stereoselectivity of this reaction has been extended to the selective reaction of enantiotopic olefin compounds to form bicyclic products such as 28, in 24% yield and 59% ee after deprotection (Eq. 5) [20]. 

Scheme 15. Enantioselective synthesis of carbocyclic tertiary ethers and spirocycles through Mo-catalyzed asymmetric olefin metathesis...

A process related to those shown in Scheme 14 involves the asymmetric Mo-catalyzed conversion of tertiary carbocyclic cyclopentenyl ethers to the corre-sponsing cyclohexenyl ethers with enantioselectivity (e.g., 67—>69, Scheme 15) [25]. A remarkable and unusual attribute of this class of transformations is that significantly higher levels of enantioselectivity are observed when ten substrate equivalents of THF are used as an additive. As an example, 69 (Scheme 15) is formed in only 58% ee in the absence of THF (<5% conversion is observed when THF is used as solvent). As also shown in Scheme 15 (70—471), enantioenriched spirocycles may be accessed easily by a similar approach in this case, no additive effect is observed. 

R,R-diphenyl ethylene carbonate CR,R-DPEC)) with a racemic zirconaaziridine. (C2-symmetric, cyclic carbonates are attractive as optically active synthons for C02 because optically active diols are readily available through Sharpless asymmetric dihydroxylations [67].) Reaction through diastereomeric transition states affords the two diastereomers of the spirocyclic insertion product protonolysis and Zr-mediated transesterification in methanol yield a-amino acid esters. As above, the stereochemistry of the new chiral center is determined by the competition between the rate of interconversion of the zirconaaziridine enantiomers and the rate of insertion of the carbonate. As the ratio of zirconaaziridine enantiomers (S)-2/(R)-2 is initially 1 1, a kinetic quench of their equilibrium will result in no selectivity (see Eq. 32). Maximum diastereoselec-tivity (and, therefore, maximum enantioselectivity for the preparation of the... 

The enantioselective alkylation of A-protected a-amino esters has been studied with many chiral catalysts, including spirocyclic ammonium salt 10A, while (lOB) containing two binaphthyl components is an effective mediator for alkylation of protected glycine under phase-transfer conditions.p-f-Boc-amino acid derivatized with (-l-)-pseu-doephedrine enables enantioselective alkylation of the ensuing amides. - Note the enolate derived from 11 remains chiral, alkylation products are produced in high ee. ... 

In summary, the enantioselective total synthesis of (-)-TAN1251A was accomplished by Wardrop in 17 steps and with 3% overall yield, the key step being the jV-methoxy-yV-acylnitrenium ion-induced spirocyclization. 

The imine (101) derived from a 2-aryltryptamine and ethyl glyoxylate undergoes a diastereo-selective spirocyclization to the indolenine (102) (Equation (27)). Replacement of the ethyl ester by chiral esters, such as the 8-phenylmenth-3-yl ester, leads to asymmetric induction at the spiro carbon atom <90HCA439>. Imines derived from tryptophan esters have also been studied as substrates for the Pictet-Spengler cyclization (e.g., <87tlii31 . Enantioselective cyclizations have made use of enantiomerically pure aldehydes and tryptophan esters <92H(34)517, 93JCS(pi)43i, 93T8589>. 

Scheme 32 Lewis-Acid promoted enantioselective spirocyclization...

Several other groups have reported effective dioxirane systems employing Oxone as the terminal oxidant. For example, Armstrong et al. have developed a spirocyclic iV-carbethoxy-azabicyclo[3.2.1]octanone precatalyst, which affords up to 91.5% ee in the epoxidation of stilbenes (eq 102). Shing et al. have developed an arabinose-derived ketone and employed this in the enantioselective synthesis of the Taxol side chain however, enantioselectivities for the epoxidation were only up to 68% (eq 103). Bortolini et al. have also described the epoxidation of alkenes with the stoichiometric keto bile acid-Oxone system, a range of ee values were observed over several substrate types but up to 98% was observed for the epoxidation of tran -stilbene, although the yield was only 50% (eq 104). ... 

Hypervalent iodine induced oxidative dearomatization of orf/io-substituted phenolic substrates in the intramolecular mode has been realized as an enantioselective reaction. In particular, Kita and coworkers have developed the enantioselective spirocyclization reaction of the orfho-substituted phenolic substrates 275 using chiral aryliodine(III) diacetate 276 having a rigid spirobiindane backbone (Scheme 3.115) [346]. Similar enantioselective oxidative spirocyclization reactions of the ort/io-substituted phenolic substrates under catalytic conditions in the presence of chiral iodoarenes or chiral quaternary ammonium iodide catalysts are discussed in Sections 4.1.6 and 4.4. 

In 2012, Ye, Jiao, and co-workers described the first application of iV-aryl isatin imines as the electrophiles in NHC-catalyzed homoenolate additions, providing a simple and efficient approach to spirocyclic y-lactam oxindoles. Utilizing the catalyst with free hydroxyl group first developed in the Ye group, an asymmetric variant of this reaction was demonstrated in a moderate enantioselective manner (80% yield, 6 1 dr, 74% ee) (Scheme 7.48). 

On the other hand, the Chi group reported NHC-catalyzed homoeno-late additions of a,p-unsaturated aldehydes to isatin-derived Boc-protected ketimines to afford spirocyclic oxindole-y-lactams with high diastereo- and enantioselectivity (up to 83% yield, 99% ee, and 20 1 dr) (Scheme 7.49). ... 

In 2012, the Chi group demonstrated a diastereoselective NHC-catalyzed access to p-lactam fused spirocyclic oxindoles with an all-carbon quaternary stereogenic center, employing oxindole-derived p,p-disubstituted a,p-unsaturated imines and enals as substrates. The p-lactam products, stable at room temperature, were easily converted to cyclopentenes at 50 °C. An asymmetric example of the annulation reaction was presented with moderate enantioselectivity (89% yield and 51% ee by using the amino indanol derived catalyst), which is probably due to the sterical hindrance of p,p-disubstituted a,p-unsaturated imines (Scheme 7.58). 

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