Quaternary carbon centers acids

The previous section discussed chelation enforced intra-annular chirality transfer in the asymmetric synthesis of substituted carbonyl compounds. These compounds can be used as building blocks in the asymmetric synthesis of important chiral ligands or biologically active natural compounds. Asymmetric synthesis of chiral quaternary carbon centers has been of significant interest because several types of natural products with bioactivity possess a quaternary stereocenter, so the synthesis of such compounds raises the challenge of enantiomer construction. This applies especially to the asymmetric synthesis of amino group-substituted carboxylic acids with quaternary chiral centers. 

An intriguing feature is that the previously unknown bisindoles 154 display atropisomerism as a result of the rotation barrier about the bonds to the quaternary carbon center. With the use of A-triflyl phosphoramide (1 )-41 (5 mol%, R = 9-phenanthryl), bisindole 154a could be obtained in 62% ee. Based on their experimental results, the authors invoke a Brpnsted acid-catalyzed enantioselective, nucleophilic substitution following the 1,2-addition to rationalize the formation of the bisindoles 154 (Scheme 65). 

Non-proteinogenic, chiral a.a-dialkyl-a-amino acids possessing stereochemically stable quaternary carbon centers have been significant synthetic targets, not only because they are often effective enzyme inhibitors but also because they are indispensable for the elucidation of enzymatic mechanisms. Accordingly, numerous studies have been conducted to develop truly efficient methods for their preparation [26], and in this respect phase-transfer catalysis has made unique contributions. 

Since the stereochemistry of the newly created quaternary carbon center was apparently determined in the second alkylation process, the core of this method should be applicable to the asymmetric alkylation of aldimine Schiffbase 42 derived from the corresponding a-amino adds. Indeed, di-alanine-, phenylalanine- and leucine-derived imines 42 (R1 = Me, CH2Ph, i-Bu) can be alkylated smoothly under similar conditions, affording the desired non-coded amino acid esters 43 with excellent asymmetric induction, as exemplified in Table 5.7 [19]. 

Chiral quaternary carbon centers. Meyers et al. have reported an enantioselective synthesis of chiral ot,(t-disubstituted- y-keto acids (6) via the lactam 3 prepared from l-valinol (1) and the y-keto acid 2. Alkylation of 3 with primary alkyl halides gives mainly the endo-isomer (4). /dkylation of 4 also proceeds with endo-selectivity to give 5 with a... 

Besides stereoselective alkylations of glycine-derived enolates, enantioselective construction of chiral quaternary carbon centers from a-amino acids is one of the most challenging topics in current organic synthesis , since nonproteinogenic a,a-disubstituted amino acids often show a remarkable influence on the conformation of peptides. Moreover, they can act as enzyme inhibitors or as building blocks for the synthesis of a wide range of natural products . 

The formation of a quaternary carbon center by the radical-mediated allylation of an a-iodolactone was examined for substrate 341 by Murakata, Jono, and Hos-hino [71]. Lewis acids for this reaction were prepared from a bis-sulfonamide and tri-methylaluminum in dichloromethane. Other aluminum compounds were employed in the preparation of the catalyst but all resulted in similar or lower asymmetric induction. The Lewis acid was complexed with the lactone and then the allylation procedure in Sch. 44 was performed. It was found that superior asymmetric induction could be achieved if the Lewis acid was prepared from the ligand with two equivalents of trimethylaluminum. It was also interesting that some turnover could be achieved, as indicated by the data obtained from use of 50 mol % catalyst. 

As shown in Scheme 8, reaction of (2,3-dimethyl-2-butene-l,4-diyl)magnesium 18 with an imine afforded the 1,2-addition adduct 27, which after treatment with carbon dioxide, acidic hydrolysis, and subsequent heating afforded a y-lactam 30 accommodating a quaternary carbon center in 62% isolated yield. For other examples of this type of transformation, see Table 7. 

Formation of Chiral Quaternary Carbon. Birch reduction-alkylation of benzoic acids and esters establishes quaternary carbon centers. Neighboring stereocenters will influence the stereochemical outcome of the tandem reaction sequence. The following example illustrates how a chiral auxiliary (derived from prolinol) controls the stereoselection in the Birch reduction-alkylation step. ... 

Radical reactions are also valuable strategies for the formation of quaternary carbon centers. An enantioselective variant of this has recently come to light utilizing aluminum as a Lewis acid complexed to a chiral binol ligand (103) in the allylation of -iodolactones 101 (Eq. (13.31), Table 13-6) [43]. It was established that diethyl ether as an additive in these reactions dramatically increases product enantioselectivities (compare entries 1 and 2, Table 13-6). Catalytic reactions were also demonstrated (entry 3) with no appreciable loss of selectivity. A proposed model for how diethyl ether functions to enhance selectivity in the enantioselective formation of these quaternary chiral centers is shown in 104. 

Reductive couplings. A synthesis of tartaric acid derivatives containing quaternary carbon centers is by reductive coupling of a-ketoamides." ... 

The Pd diaquo complex of BINAP 19 efficiently catalyzed the diastereoselective and enantioselective Michael addition of the y3-keto ester 20 to 3-penten-2-one (21), and the Michael adduct 22 was obtained in 89 % yield (diastereomeric ratio = 8/1) and the ee of the major isomer was 99%. Thus, congested vicinal tertiary and quaternary carbon centers were constructed. It is interesting to know that the Pd aquo complex 19 allows the successive supply of a Bronsted base and a Bronsted acid. The former activates the carbonyl compound to give the chiral palladium enolate and the latter cooperatively activates e enone [4]. 

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