Stereocentres quaternary

Rovis and co-workers have applied the asymmetric intramolecular Stetter reaction to the desymmetrisation of cyclohexadienones 140, generating a quaternary stereocentre and forming hydrobenzofuranones 141 in excellent yields and enantiose-lectivities. Substitution at the two, four and six-positions is tolerated, and even substitution at the three-position is accommodated (Scheme 12.29) [65]. 

Using a chiral 4-dimethylaminopyridine-ferrocenyl catalyst, acyclic silyl ketene acetals react with anhydrides to furnish 1,3-dicarbonyl compounds containing allcarbon quaternary stereocentres in good yield and ee.144 Evidence for dual activation (anhydride -> acylpyridinium, and acetal -> enolate) is presented. 

Quaternary stereocentres in /3-keto esters have been deracemized in an enantio-convergent decarboxylative allylation process, catalysed by palladium(II).202 One catalyst is involved in both C-C bond-breaking and -making steps. 

An efficient and highly selective access to enantioenriched a-carbonyl all-carbon-substituted quaternary stereocentres has been provided by enantioselective alkylations of tributyltin enolates catalyzed by Cr(salen)Cl (13, M = Cr).33... 

Sml2-mediated carbonyl- alkene cyclisations are also effective when the alkene contains a (3-substituent. For example, Enholm reported the Sml2-mediated cyclisation of aldehyde 42 in the presence of MeOH to provide the highly functionalised cyclopentanol 43 containing a quaternary stereocentre, in good yield (Scheme 5.32).62... 

The asymmetric intramolecular crossed benzoin reaction catalysed by a chiral triazolium salt has been used to synthesise 3-hydroxychroman-4-ones 34 in good to high yields and ee. The absolute configuration at the quaternary stereocentre C-3 has been shown to be S by X-ray analysis of the camphanyl ester <06SL2431>. Both enantiomers of 2-(2-phenylethyl)chroman-4-one, flindersiachromanone, have been obtained from racemic l-phenylhex-5-en-3-ol after resolution via lipase-catalysed acetylation <06H(68)483>. 

Step k was carried out by adding the LDA to the substrate. It was found that if the substrate was added to the base, an almost complete inversion of the newly formed quaternary stereocentre a to the imine was obtained. Suggest an explanation for this observation. 

Anilide 2a catalysed asymmetric intramolecular Michael reaction of formyl enones to chiral cyclic keto-aldehydes in excellent yields with good stereoselectivity (eqn. (1) in Scheme 6.3). The intramolecular Michael addition of a ketosulfone to an unsaturated ketone (eqn. (2) in Scheme 6.3) catalysed by 15e has heen used as a key step in the synthesis of the carbon tricyclic framework of Lycopodine. The same sulfonylprolinamide served as catalyst in the construction of all-carhon substituted quaternary stereocentre via Robinson-type annulation process (eqn. (3) in Scheme 6.3). 

Another example of combination secondary- and primary-amine catalyst is described by Moreau, Greek and coworkers in Michael/a-amination sequence for construction of quaternary stereocentres. ° ... 

The Barbas group further identified catalyst Id for asymmetric Michael additions using brine as the reaction medium 10 mol% diamine Id/TFA at ambient temperature afforded q n-Michael adducts in high yields and good to excellent stereoselectivities for cyclic ketones. The stereoselectivities decreased when aliphatic aldehydes were used as donors (Scheme 9.13). Moreover, the same authors demonstrated the first example of sym-metrical/unsymmetrical a,a-diallgrlaldehydes as donors in asymmetric Michael reactions to produce adducts featuring an all-carbon quaternary stereocentre. The use of 30 mol% (S )-l-(2-pyrrolidinylmethyl)pyrrolidine la in combination with an equal amount of TFA yielded products with moderate to high levels of diastereo- and enantioselectivity (Scheme 9.14). ... 

Barbas et al. described the construction of a quaternary stereocentre via the direct asymmetric a-amination of 3-(4-bromophenyl)-2-methylpropanal with dibenzyl azodicarbo>ylate using tetrazole 5a as the organocatalyst. The amination product was used for the enantioselective total synthesis of the cell adhesion inhibitor BIRT-377 (Scheme 9.44). 

Scheme 12.7 Formation of a quaternary stereocentre by organocatalysed Mannich...

In 2012, Kudo and coworkers examined the construction of all-carbon quaternary stereocentres via an asymmetric Michael addition, catalysed by resin-supported polypeptide 23. Using a,p-unsaturated aldehydes, comprising a short-chained allq l group in the p-position, and nitromethane as the Michael donor, a series of quaternaiy-carbon containing Michael adducts were synthesised with moderate to good yield (Scheme 13.16) The substitution pattern of the substrates has a vanishingly low impact on the enantioselectivity which was, in all cases, excellent. A further application of... 

Natural Product Total Synthesis Formation of Quaternary Stereocentres... 

The identification of novel ways to incorporate an asymmetric intramolecular Mizoroki-Heck reaction as part of a cascade cyclization sequence has led to attractive approaches for assembling complex polycyclic molecules. Keay and coworkers [54] reported the use of a double Mizoroki-Heck cyclization as the pivotal step in the asymmetric total synthesis of xestoquinone (93), a reduced congener of halenaquinone (Scheme 16.20). In this step, naphthyl triflate 90 was cyclized with Pd2(dba)3 (dba = dibenzylideneace-tone), (5 )-BINAP and 1,2,2,6,6-pentamethylpiperidine (PMP) in toluene at 110°C to give pentacyclic product 92 with impressive efficiency and moderate enantioselectivity. This conversion proceeds by initial asymmetric 6-exo Mizoroki-Heck cyclization to form the central six-membered carbocycle and install the benzylic quaternary stereocentre. The first cyclization event is followed by a second Mizoroki-Heck reaction in which neopentyl... 

Overman and Rosen [76] reported a total synthesis of spirotryprostatin B (137), a structurally novel diketopiperazine alkaloid, that featured a cascade Mizoroki-Heck cyclization/jj -allylpalladium capture process and the exploration of a related catalytic asymmetric sequence (Scheme 16.36). The plan was to relay the relative configurations of the quaternary stereocentre and the adjacent tertiary stereocentre in the natural product from the geometry of the trisubstimted alkene in the Mizoroki-Heck cyclization substrate. It was anticipated that the favoured 5-exo intramolecular Mizoroki-Heck cyclization of enantiopure triene precursor 135 would generate an -allylpalladium intermediate, with a chiral palladium catalyst controlling the absolute configuration of the initially formed quaternary carbon stereocentre. 

In 2007, Jorgensen presented the first example of an asymmetric Mannich reaction involving imidoyl halides as an electrophilic equivalent to the imidoyl carbocation. This report demonstrated an effective and practical method for preparing optically active ketimines (89), a-functionalised with a quaternary stereocentre, and included several synthetic derivatisations with high yields and good diastereoselectivities (Scheme 16.29). ... 

Highly enantioselective construction of a quaternary stereocentre on p-keto esters under phase-transfer conditions has also been achieved using binaphthyl-based PTC (5 )-18 (Scheme 17.24). This system has a broader generality in terms of the structure of cyclic p-keto esters and allq l halides. Park and coworkers also reported the asymmetric alleviation of a-substituted malonic esters and a nonsubstituted malonamic ester as acyclic p-keto esters based on the discrimination of two different carbonyl moieties, in which the binaphthyl-based PTC (S,5 )-15 was found to be an efficient catalyst. ... 

In 2011, the enantioseleetive intramolecular Stetter reaction of unactivated olefins was reported by the Glorius group. Under the catalysis of NHC H3 derived from r-phenylalaninol, chromanone derivatives 31 containing a newly formed quaternary stereocentre were obtained in good yield with up to 99% enantiomeric excess. Both electron-donating substituents and electron-withdrawing substituents worked well (Scheme 20.15). 

Allylic alkylations have also been used to create optically pure all-carbon quaternary stereocentres, which is a daunting task in organic synthesis. Although some encouraging results have been obtained with SiocPhox ligands with acyclic nucleophiles, most of the work involves cyclic nucleophiles. For instance, a few examples of alkylations of (3-keto esters leading to quaternary centres are depicted in Scheme 8.10. 

Scheme 8.10 Examples of Pd-catalysed construction of quaternary stereocentres.

Jacobsen and Watson reported a nickel-catalysed intramolecular addition of arylnitriles across an alkeneic double bond (arylcyanation), giving access to chiral indanes bearing a quaternary stereocentre (78, Scheme 8.30). 

The best results were obtained by coupling the enolate of oxindole 79 with aryl and vinyl bromides. Arylated products 81, bearing an all-carbon quaternary stereocentre, were formed in good yield and excellent enantiomeric purity for several aryl and vinyl bromides. Interestingly, other binaphthyl-based phosphorus ligands without P-stereogenic centres led to inferior results. 

Aryl glyoxals, ArCOCHO, or their hydrates, ARCOCH(OH)2, as well as their aliphatic analogues, typically react with nucleophiles at the aldehyde carbon, but a chiral copper(II)-iminopyridine catalyst switches the reactivity, allowing Henry reaction at the ketone, and with high ee, giving a quaternary stereocentre in the product, without any specific protection of the aldehyde. ... 

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