Quaternary stereogenic center

The construction of quaternary stereogenic centers with high diastereoselectivity was used in the synthesis of ( + )-0-methyljoubertiamine189. 

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. 

Bicyclic silyloxypyrrole, via the selective formation of a quaternary stereogenic center and a ring-closing metathesis as the main steps, was converted into new polyhydroxyindolizidines <2006TA53>. 

Furthermore, Rueping and coworkers applied their reaction conditions to the cyanation of ketimines [54]. The use of A-benzylated imines derived from aryl-methyl ketones generally gave comparable yields, but lower enantioselectivities. However, this method furnished Strecker products bearing a quaternary stereogenic center, which are valuable intermediates for the preparation of optically active a,a-disubstituted a-amino acids. 

Evans and Kennedy later combined the regioselective rhodium-catalyzed allylic alkylation, using a-substituted malonates, with ring-closing metathesis for the construction of five-, six-, and seven-membered carbocycles (Scheme 10.2) [13]. The combination of these methodologies allowed for the rapid and flexible assembly of carbocycles possessing vicinal ternary-quaternary or quaternary-quaternary stereogenic centers. 

Takeo Kawabata of the Institute for Chemical Research associated with Kyoto University reports (J. Am. Chem. Soc. 125 13012,2003) that unnatural amino acids can also be used to assemble four-, five-, six-, and seven-membered cyclic amines having quaternary stereogenic centers. Given the conventional wisdom that ester enolates are sp -hybridized, this memory effect is remarkable. 

These approaches led to ternary stereogenic centers. Brian Stoltz has found J. Am. Chem. Soc. 2004,126, 15044) that the Pd-mediated conversion of 7 to 8 can be induced to proceed in high enantiomeric excess. This appears to be a general method for the preparation of quaternary stereogenic centers. Wacker oxidation followed by aldol condensation converted 8 into the bicyclic enone 9. 

One of the severest challenges of asymmetric synthesis is the direct enantioselective construction of quaternary stereogenic centers. Brian Pagenkopof of the University of Texas has reported (Chem. Communications 2003 2592) that alkynyl aluminum reagents will open a trisubstituted epoxide such as 10 at the more substituted center, with inversion of absolute configuration. As the epoxide 10 is available in high from 9 by the method of Yian Shi of Colorado State (J. Am. Chem. Soc. 119 11224, 1997), this opens a direct route to quaternary cyclic stereogenic centers. 

Trost, B.M. and Andersen, N.G., Utilization of molybdenum- and palladium-catalysed dynamic kinetic asymmetric transformations for the preparation of tertiary and quaternary stereogenic centers a concise synthesis of tipranavir, J. Am. Chem. Soc., 2002, 124, 14320-14321. 

In the course of a total synthesis of aphidicolin (107), the conjugate addition of the dienoiate (104) to the chiral butenolide derivative (105) serves as a key step. A 7.4 1 mixture of diasteieomeric products is obtained, from which the major isomer (106) can be isolated in pure form after recrystaliization (Scheme 41).121 The selectivity of this remarkable reaction, in which two quaternary stereogenic centers are simultaneously generated in a highly selective manner, can be explained by the assumption that the reactants approach each other in the chelate-mode indicated in (108). 

An intramolecular reaction was used to establish a quaternary stereogenic center in a d.s-dccalin system by differentiation of two enantiotopic double bonds (Eq. 8E. 17). Despite the quite good enantioselectivity (83% ee), the major product was unfortunately the achiral bicyclic [4.2.2] compound. 

In the mid-1980s Merck chemists developed a method for asymmetric alkylation of a cyclic ketone in the presence of a simple cinchona alkaloid (see also Section 3.1) [50-52], The resulting product 23, bearing a quaternary stereogenic center, is an intermediate in the synthesis of indacrinone 20 (Scheme 14.9). It should be noted that this impressive contribution from Merck chemists was not only the first exam-... 

The various allylic substitution reactions are illustrated in a synthesis of Tipranavir (11), an HIV protease inhibitor. A palladium-catalyzed opening of a vinyl epoxide set the quaternary stereogenic center (Scheme 22.23). A molybdenum-catalyzed allylic nuclophilic displacement was used to access the benzylioc stereogenic center (Scheme 22.24).153... 

A key feature of intramolecular C-H insertion is the inherent ability to transform an acyclic tertiary stereogenic center into a cyclic quaternary stereogenic center, with retention of absolute configuration [12]. This was first demonstrated by rhodium-mediated cyclization of 29 to 30, leading to (+)-a-cuparenone (31) [13]. 

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). ... 

Mizorokf and Heck reported independently in the early 1970s the first palladium-mediated coupling of an aryl or vinyl halide or triflate with an alkene. This reaction is generally referred to as the Heck reaction. From the first reports on asymmetric intramolecular Heck reactions by Overman and Shibasakf in 1989 the asymmetric Heck reaction has emerged as a reliable method for the stereoselective formation of tertiary and quaternary stereogenic centers by C-C bond formation in polyfunctionalized molecules. ... 

The aminofiinction is then introduced by a selective organocatalyzed a-addition of this aldehyde to an azodicarboxylate moiety. In this way, the quaternary stereogenic center of an a-aminoaldehyde is built up catalytically without the need of any chiral auxiliary. 

Shortly thereafter, Zhou and coworkers independently reported the enantioselec tive F C reaction of indoles with a aryl substituted enamides catalyzed by chiral phosphoric acid catalyst lq (Scheme 3.22) [52], in which the quaternary stereogenic center bearing the nitrogen atom vas constructed in a highly enantioselective manner. 

Scheme 3.22 Enantioselective formation of quaternary stereogenic center bearing a nitrogen atom in the F C reaction.

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. 

The overwhelming effect of the suprafacial nature of the Claisen rearrangement is best demonstrated by examples in which the new bond is attached to a vicinal quaternary stereogenic center, c.g., rearrangement to 642. ... 

Quaternary stereogenic centers / to C-6 do not exhibit a significant chiral induction. The simple Claisen rearrangement of cyclohexanone acetal 1 with butyl vinyl ether in the presence of mercury(II) acetate at 175 °C results in a 45 55 diastereomeric mixture of products 2. The ortho ester variation gives a similar result631. 

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