Quaternary carbon asymmetric

Successful applications of these stereocontrolled conjugate additions have led to asymmetric syntheses of several natural products such as (+ )-cuparenone (39) which involves formation of a quaternary carbon center81, (- )-/ -vetivone (40)8° and steroidal equilenin 4182 the wavy lines in these structures indicate that C—C bond formed stereoselectively under the influence of a temporarily-attached stereogenic sulfoxide auxiliary group. 

They have developed direct asymmetric synthesis of quaternary carbon centers via addition-elimination process. The reactions of chiral nitroenamines with zinc enolates of a-substituted-8-lactones afford a,a-disubstituted-6-lactones with a high ee through addition-elimination process, in which (5)-(+)-2-(methoxy methy l)pyrrolidine (SMP) is used as a chiral leaving group (Eq. 4.96).119 Application of this method to other substrates such as a-substituted ketones, esters, and amides has failed to yield high ee. 

For an adamantane-type compound, it is possible to substitute the four tertiary hydrogen atoms and make four quaternary carbon atoms. These carbon atoms can be asymmetric if the four substituents are chosen properly. It is possible to specify these chiral centers separately, but their chiralities can also be so interlinked that they collectively produce one pair of enantiomers with only one chiral center. Usually it is more convenient to collectively specify the chirality with reference to a center of chirality taken as the unoccupied centroid of the adamantane frame. 

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. 

The study of Fuji et al. shows that the addition of lithium enolate 75 to ni-troamine 74 is readily reversible quenching conditions are thus essential for getting a good yield of product 76. An equilibrium mixture of the adducts exists in the reaction mixture, and the elimination of either the prolinol or lactone moiety can take place depending on the workup condition (Scheme 2-34). A feature of this asymmetric synthesis is the direct one pot formation of the enantiomer with a high ee value. One application of this reaction is the asymmetric synthesis of a key intermediate for indole type Aspidosperma and Hun-teria alkaloids.68 Fuji69 has reviewed the asymmetric creation of quaternary carbon atoms. 

Pd-catalyzed Heck reactions are among the most effective methods for the formation of quaternary carbon centers. Considering the significance and the strategic difficulties associated with the synthesis of quaternaiy carbons, particularly in the optically enriched or pure form, it is not a surprise that the development of catalytic asymmetric Heck reactions has held center stage for the past few years. One of the leading labs in this area is that of Shibasaki, who in 1993 reported a concise total synthesis of eptazodne 23 (Scheme 4).141 Thus, treatment of silyl ether 18 with 10 mol% Pd(OAc>2 and 25 mol% (S)-19 leads to the formation of 20 in 90 % yield and 90% ee As illustrated in Scheme 4, once the quaternary carbon center is synthesized efficiently and selectively, the target molecule is accessed in a few steps. 

T. Takemoto, M. Sodeoka, H. Sasai, M. Shibasaki Catalytic Asymmetric Synthesis of Benzylic Quaternary Carbon Centers. An Efficient Synthesis of (-)-Eptazocine , J. Am. Chem. Soc 1993,115, 8477-8478. 

Since the conversion of 235 to 233 requires only heating, it is possible to synthesise the vinylketenimine complex directly from the vinylketene merely by extending the reaction time sufficiently.69,87,89 Note that 233.j and 233.k were obtained as 1 1 mixtures of diastereoisomers. The subsequent reactivity of the vinylketenimine complexes,87,89,135,143 particularly their utility in the asymmetric synthesis of quaternary carbon centers,143 has also been investigated, but is beyond the scope of this review. 

Table 2) [43], The hydroxymethylation proceeded smoothly using an aqueous formaldehyde solution to afford the desired adducts in high yields with high enantioselectivities. It is noteworthy that asymmetric quaternary carbons were constructed with high selectivities. 

The magnitude of the chemical shift differences for the different methyl carbons indicates that the presence of an asymmetric carbon in the 1,2- and i,3-units has little effect on the chemical shifts and that primarily sequence distribution affects the chemical shifts in both the 13C NMR and 11 NMR spectra. This is further emphasized by the presence of two resonances of singlet multiplicity at 32.93 and 33.115 which are attributed to the quaternary carbon of the 1,4-structure. This carbon should be unaffected by tacticity in the polymer, and so these two resonances are probably due to two different triads. 

Scheme 82 shows the intramolecular version of the reaction using an alkenyl iodide in the presence of the same Pd system containing silver phosphate (194,195). The reaction can also be used for the asymmetric synthesis of quaternary carbon centers. 

For a recent review on catalytic asymmetric synthesis of quaternary carbon centers, see Corey, E. J. Guzman-Perez, A. Angew. Chem., Int. Ed. 1998, 37, 388. 

The asymmetric cyclopropanation of a-bromocyclohexenone with cyanoacetate 31 has been achieved under phase-transfer conditions by the use of cinchona alkaloid-derived catalyst, which constructs chiral quaternary carbons on the cyclopropane... 

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]. 

The highly enantioselective alkylation of a-substituted a-cyanoacetates was achieved using chiral phase-transfer catalysts of type le and lh to afford a,a-disubstituted a-cyanoacetates possessing an asymmetric quaternary carbon center with high enantioselectivity, as shown in Table 5.9 [34]. 

Ohno, H. Hiramatsu, K. Tanaka, T. Asymmetric construction of quaternary carbon centers by Ti-mediated stereospecific allylation of 2,3-epoxy alcohol derivatives. Tetrahedron Lett. 2004, 45, 75-78. 

The first examples of catalytic asymmetric conjugate addition of alkylzinc reagents to trisubstituted nitroalkenes, such as PhC(Me)=CHN02, leading to the formation of nitroalkanes bearing a quaternary carbon stereogenic centre, have been reported. Reactions are promoted by the readily available amino acid-based phosphine (211)... 

In contrast with previous reports, Sodeoka s reaction conditions were applicable to a variety of /8-ketoesters (Scheme 2) [5]. With the Pd aqua complex 3, the Michael adducts were obtained in high yield with high enantioselectivity. For example, the reaction of the /8-ketoester 4 with less reactive /3-substituted enones such as 3-penten-2-one proceeded smoothly to give 5 in 99 % ee. In this reaction, catalytic asymmetric construction of the highly crowded vicinal tertiary and quaternary carbon centers was achieved in one step. Furthermore, the reaction of 1,3-diketones with enones was successfully performed, and the desired triketone 6 was obtained in good yield and with 90 % ee. In contrast, conventional basic conditions (tertiary amines, alkoxides, or ammonium hydroxides) gave complex mixtures, probably because of the instability, under the basic conditions, of the triketone produced. This result clearly indicates that the reaction using the Pd aqua complex 3 is quite mild. 

The palladium-catalyzed arylation and alkenylation of olefins, which were first discovered in the 1970 s by Heck (7,2) and Mizoroki (3) and have been often called the "Heck reaction", are versatile synthetic means for making a carbon-carbon bond. These reactions have been extensively used for organic synthesis during the past two decades (4-7). However, no reports on the "asymmetric Heck reaction" have been appeared until very recently. Shibasaki reported an asymmetric intramolecular cyclization of alkenyl iodides to give c/j-decalin derivatives of 80-91% ee (8-10). Overman reported an intramolecular cyclization of alkenyl triflate, giving a chiral quaternary carbon center of 45% ee (77). We report herein the first example of intermolecular asymmetric Heck-type arylation of cyclic olefins catalyzed by (7 )-BINAP-coordinated palladium complexes (Scheme 1) (12,13). 

Several structural features of (-)-rhazinilam 3 raise interesting synthetic challenges the axially chiral phenyl-pyrrole A-C biaryl bond, the fused pyrrole-piperidine C-D rings, the stereogenic quaternary carbon (C-20) ortho to the phenyl-pyrrole axis, the nine-membered lactam firing. Three racemic (Smith, Sames, Magnus) and one asymmetric (Sames) total syntheses have been published to date, which all proceed via construction of the pyrrole ring and diastereoselective control of the axial chirality by the central chirality at C-20. 

Recently, the transition-metal-catalyzed addition of active methylene C-H bonds to electron-deficient olefins having a carbonyl, a nitrile, or a sulfonyl group has been extensively studied by several research groups. In particular, the asymmetric version of this type of catalytic reaction provides a new route to the enantioselective construction of quaternary carbon centers [88]. Another topic of recent interest is the catalytic addition of active methylene C-H bonds to acetylenes, allenes, conjugate ene-ynes, and nitrile C-N triple bonds. In this section, the ruthenium-catalyzed addition of C-H bonds in active methylene compounds to carbonyl groups and C-C multiple bonds is described. 

Novel methods for functionalizing piperidines at the 3- and 4-positions were also introduced. Mete and co-worker synthesized 3-diazo-piperidin-2-one and characterized its reactivity in transition-metal catalyzed reactions, particularly H-X insertion reactions and cyclopropanation reactions <02T3137>. Christoffers and co-workers developed an asymmetric Michael addition reaction with a chirally modified 4-piperidone-enamine. They were able to create a quaternary carbon center in >95% de and elaborate the compound on through classical means to the functionalized piperidine 107 (Scheme 21) <02EJ01505>. 

In a major development of RCM methodology, it has been found that chiral Mo complexes e.g. 4, offer vastly superior ee than conventional Ru catalysts in the conversion of achiral vinyl alkadienyl ethers into dihydropyrans. The enantioselective synthesis of tertiary carbon stereogenic centres proceeds with typical ee of 80 - 90% while such asymmetric RCMs generate quaternary carbon stereogenic centres with even higher ee (Scheme 4) <06JA5153>. 

A Pd(ll) catalyst system with an oxazoline ligand 44 has been described that allows the desymmetrization of meso-Z-alkyl-2-propargylcyclohexane-l,3-diols in an asymmetric cyclization-carbonylation reaction. The products which contain a chiral quaternary carbon were obtained in excellent yields with high ee s (Scheme 56) <2006T9988>. 7-Hydroxy terminal <2005JOC3099> and internal <2006TL2793> alkenes can be converted to tetrahydrofurans by Pd(0)-catalyzed carboetherification reactions combined with a coupling of aryl or vinyl halides. 

Intramolecular Heck reactions for building up complex oxacyclic skeletons are a common theme in the synthesis of natural products. These reactions are exceptionally valuable for the installation of quaternary carbon stereocenters. In the morphine total syntheses by Overman <1994PAC1423> and Trost et al., intramolecular Heck reactions to form dihydrobenzofurans served as strategic key steps (Equation 138) <2005JA14785>. Asymmetric variants of intramolecular Heck reactions based on BINAP ligands to yield dihydrobenzofurans have also been investigated <1998T4579>. 

Mase, N. Tanaka, E Barbas, C. F., HI Synthesis of hydroxyaldehydes with stee-ogenic quaternary carbon centers by direct organocatalytic asymmetric aldol reactions, Angew. Chem. Int. Ed. 2004,43, 2420-2423. 

An efficient asymmetric synthesis of six-membered quinoline derivatives bearing a quaternary carbon center or a spiro-ring by an ene-type cyclization of 1,7-enynes catalyzed by the cationic BINAP-Pd(ll) complex was reported <03JA4704>. 

The method for producing chiral 1,2-diol units is also applicable to the construction of asymmetric quaternary carbons contained in aldol units. In the presence of a chiral promoter consisting of the chiral diamine 1, tin(II) trifluoromethanesulfonate, and di-n-butyltin diacetate, various optically active a-alkoxy-a-methyl- -hydroxy thioesters and esters are synthesized in good yields with high stereoselectivities (eqs 28 and 29). ... 

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