Quaternary stereogenic carbon

Enantioselective deprotonation can also be successfully extended to 4,4-disubstituted cyclohexanones. 4-Methyl-4-phenylcyclohexanone (3) gives, upon reaction with various chiral lithium amides in THF under internal quenching with chlorotrimethylsilane, the silyl enol ether 4 having a quaternary stereogenic carbon atom. Not surprisingly, enantioselectivities are lower than in the case of 4-tm-butylcyclohexanone. Oxidation of 4 with palladium acetate furnishes the a./i-unsaturated ketone 5 whose ee value can be determined by HPLC using the chiral column Chiralcel OJ (Diacel Chemical Industries, Ltd.)59c... 

A quaternary stereogenic carbon center was effectively cOTistructed by the y-selective conjugate addition of this class of nucleophile to highly electrophilic, P-trifluoromethyl nitroolefins using cinchona alkaloid-derived thiourea 19c as a... 

The stereoselective formation of quaternary stereogenic carbons remains both a challenging and important area of investigation. There have been numerous pathways to synthesize the carbon centers among these attempts, enolate alkylation represents one synthetic strategy. The alkylation of the alpha carbon of a carbonyl remains one of the most fundamental reactions in organic chemistry. However, with this important reaction and the vast number of studies conducted on the generation of and substitution of the enolate, it stiU has a number of inherent limitations. ... 

Hojoh K, Shido Y, Ohmiya H, Sawamura M (2014) Construction of quaternary stereogenic carbon centers through copper-catalyzed enantioselective allylic cross-coupling with alkylboranes. Angew Chem Int Ed 53 4954-4958... 

The efficient constmetion of spiro quaternary stereogenic carbon centers is challenging and intriguing [35], and the spirocycUc pyrrolidine skeleton owns potential application for dmg discovery. In this context, recent advances in catalytic asymmetric [3+2] cycloadditions to constmet optically active spiropyrrolidines will be discussed. 

As shown earlier in many examples, the Claisen rearrangement of allyl vinyl ethers also provides a very powerful method for carbon-carbon bond formation in domino processes. Usually, the necessary ethers are formed in a separate step. However, both steps can be combined in a novel domino reaction developed by Buchwald and Nordmann [306]. This starts from an allylic alcohol 6/4-102 and a vinyl iodide 6/4-103, using copper iodide in the presence of the ligand 6/4-104 at 120 °C to give 6/4-105 (Scheme 6/4.25). The reaction even allows the stereoselective formation of two adjacent quaternary stereogenic centers in high yield. 

The 2 + 2-cycloaddition reaction of a-alkoxyketene-derived imines yields /l-lactams with quaternary stereogenic centres at C(4).33 The 2 + 2-cycloaddition of chiral aminoketenes with chiral imines yields cis-fi-lactams with the absolute stereochemistry of file C(3) and C(4) positions being controlled by the ketene partner only.34 The 2 + 2-cycloaddition of ketenes with (W)-2-/-butyldihydrooxazole (19) yields predominately the regioisomer (20) from steric control rather than the expected electronic control (Scheme 7).35 The double 2 + 2-cycloaddition reaction between ketenylidenetriphe-nylphosphorane (21) and carbon suboxide (22) produces the bis(ylidic) spirocyclobut-anedione (23) (Scheme 8).36 Semiempirical and ab initio calculations have been used to investigate the Lewis acid-promoted 2 + 2-cycloaddition leading to the formation of jS-lactones.37... 

The latter reaction afforded the products bearing all-carbon quaternary stereogenic centres in 67-98% yield and in 74-97% ee. Mechanistic models accounting for the observed levels and trends in enantioselectivity were provided.232... 

Chiraphos (210) has been found to induce high enantioselectivity in the construction of all-carbon quaternary stereogenic centres via the Rh-catalysed conjugate addi- tion of alkenylboronic acids to /T/i-disubstituted o /3-unsaluralcd 2-pyridylsulfones... 

In a similar manner, aldehydes can also be enantioselectively alkylated by this procedure. However, the enantiomeric excess obtained is much lower (47%). A special application of this method is the enantioselective alkylation of aldehydes for the construction of quaternary stereogenic centers. An example is the formation of the chiral quaternary carbon in 4-methyl-4-phenylcyclohex-2-en-1-one in high enantiomeric excess using this methodology (eq 4). ... 

They applied the intermediary oxocarbenium to a direct aldol type reaction of azlactones [78] via their oxazole tautomer and obtained the corresponding products with excellent enantio and diastereoselectivities (Scheme 3.35) [79]. The method enables efficient access to biologically and pharmaceutically intriguing p hydroxy a amino acid derivatives having a quaternary stereogenic center at the a carbon atom. 

Efficient access to biologically and pharmaceutically interesting hydroxy-oc-amino acids derivatives (145) having a quaternary stereogenic center at the a-carbon atom, through the direct aldol-type reaction of azalactone (144) with an oxocarbenium ion obtained via protonation of vinyl ethers (143), by a chiral phosphoric acid catalyst (127) in a highly enantio- and diastereoselective manner, have been developed by Terada and co-workers (Scheme 38). ... 

Recently, the Jia group reported AFC alkylation reactions of p,p-disub-stituted nitroalkenes with indoles. The AFC alkylation of indoles with p-CFa-p-disubstituted nitroalkenes 148 and acyclic a-substituted-p-nitroacry-lates 149 was achieved by using Ni(Cl04)2/bisoxazoline 147 complex as a catalyst, affording indoles bearing an all-carbon quaternary stereogenic center in good yields with excellent enantioselectivity (up to 97% ee) (Scheme 6.67). ... 

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). 

In 2012, Alexakis and co orkers disclosed the first stereoselective annulation reaction between ynals and a-cyano-l,4-diketones which is mediated by a catalytic amount of a triazolium salt precatalyst and a weak carboxylate base. This transformation proceeds smoothly under mild reaction conditions and generates three contiguous stereogenic centers, one of which is a quaternary acetal carbon, and affords privileged bicyclic scaffolds in 61-90% yields with up to 20 1 diastereomeric preference. A mechanistic rationalization for the NHC-catalyzed annulation of a-cyano-l,4-diketones with ynals is proposed as the following. Initially, the free carbene condenses with a molecule of ynal to form the key d,p-unsaturated acylazolium intermediate followed by a direct nucleophilic conjugate addition of 1,4-diketone. Subsequent intramolecular H-migration and an irreversible lactonization furnish the observed bicyclic product and liberate free carbene for the next catalytic cycle (Scheme 7.98). 

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