Quaternary chiral centers, formation

A well-developed concept to achieve high stereocontrol in the formation of a quaternary chiral center has been introduced by Fraser-Reid, using the Claisen rearrangement along two lines. In the first approach a type III branched-chain sugar is prepared by Wittig... 

Allylic substitution reaction is an important tool of enantioselective synthesis. Starting from readily available chiral allylic alcohols, products with tertiary and quaternary chiral centers can be obtained highly diastereos-electively,180,180a 181 181a 181b thus allowing an enantioselective new C-C bond formation (Scheme 60). 

This sequence destroyed the two chiral centers of 12 that had assisted the formation of the quaternary chiral center required in 26. 

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. 

Another scenario for AHRs is the formation of quaternary chirality centers. Here, (3-elimination via path b is impossible (when Hb is replaced by a hydrocar-byl group). The downside, however, is that construction of such centers is difficult because it requires the insertion of trisubstituted C=C bonds, which normally react sluggishly in Heck reactions. Some of this lack of reactivity, however, can... 

The synthesis of gm-diallyl derivatives can be achieved by double alkylation of active methylene groups. We realized that installation of gem-diallyl functionality on a carbon atom, not activated by any electron-withdrawing group, is a difficult proposition. The problem becomes insurmountable on carbohydrate precursors because base-catalyzed reactions lead to tandem elimination of water molecules, resulting in the formation of complex mixtures, We observed interesting reactions with carbohydrate cyclopropyl precursors. For example, the radical-mediated cyclopropyl scission of the spirocyclopropyl bromide (86) with n-BusSnH gave the C-aUyl derivative (87) in a stereo-controlled fashion. On the other hand, hydrogenation of the cyclopropylaldehyde derivative (88) over Pd/C provided 89 with a quaternary chiral center (Scheme 30.14). 

This reaction has limited applications for the formation of quaternary chiral centers in benzofuran series. 

Michael Additions. Cu(OAc)2 in combination with chiral ligands has been extensively utilized as a catalyst for enantioselective conjugated-additions of organometallics and active methylene substrates to o , -unsaturated systems. The latter process, in particular, has been very useful synthetically, leading to the formation of quaternary chiral centers under mild, neutral conditions. Easily accessible natural a-amino acids or their derivatives were employed as efficient chiral auxiliaries and these could be recovered at the end of the reaction (eq 33). ... 

The inclusion of the allyl moiety in an appropriate ring system led to the formation of a new, chiral quaternary carbon center (3.13.), By the use of optically active starting material, Mori and co-workers were able to control the stereochemistry of the new chiral centre (N.B. the chirality of the first centre was also set by a palladium catalysed reaction, the Tsuji-Trost allylation).17... 

Koga has continued his research program in the enantioselective alkylations of achiral lithium enolates using chiral ligands. Previous examples had provided excellent ee and yields for tertiary carbon centers ligand 6 has now been designed that allows formation of quaternary carbon centers with high ee [44]. 

By converting the enol triflate 41 to the spiro-tricyclic dienone 42, Overman and co-workers had already shown in 1989 that the direct enantio-selective formation of quaternary chiral carbon centers ean be carried out through an intramolecular Heck reaction. While the enantioselectiv-ities were only moderate at the beginning [ 16], the same authors later succeeded in achieving the Pd(0)-BINAP-catalyzed cyclizalion of substrates of type 43 to spiro-oxindoles 44 with up to 95 % ee (Scheme 12) [17]. 

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). ... 

The asymmetric induction in the formation of 214 stems from an eiiantiodifferentiation of two double bonds. The intramolecular jr-enantiofacial discrimination (cf. Scheme 3-49 for the intermolecular version) has also been successful, as shown by the asymmetric construction of quaternary carbon centers in the preparation of spirooxindoles 217 from 216 (Scheme 3-51). It is amazing that each product enantiomer was obtained selectively by careful choice of reaction conditions and, remarkably, by applying exactly the same enantiomer of the chiral phosphane ligand [122]. 

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. ... 

Related substrates were repeatedly cyclized in an enantioselective fashion. t i For these examples the formation of a quaternary carbon as the chiral center is crucial. Very often BINAP has been applied as the chiral ligand the synthesis of the chiral aldehyde in Scheme 6 represents an important step in the synthesis of physostigmine.f " ... 

Ashimori, A. and Overman, L.E. (1992) Catalytic asymmetric synthesis of quaternary carbon centers. Palladium-catalyzed formation of either enantiomer of spirooxindoles and related spiro-cycles using a single enantiomer of a chiral diphosphine ligand. J. Org. Chem., 57, 4571-2. 

This work presents the first catalytic enantioselective cyclization strategy for accessing steroidal and terpenoidal frameworks using organocatalysis. It should be pointed out that the present domino cycHzation could be conducted at room temperature. The asymmetric construction of multiple C-C bonds and contiguous stereocenters using substrate 263 in the presence of the chiral imidazolidinone 259 resulted in the formation of 264 with four new C-C bonds, seven stereogenic centers, and three quaternary carbon centers with about 90% yield for each chemical bond formation and over 90% ee. 

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