Enantioselectivity quaternary carbon center formation

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). 

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]. 

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. 

The enantioselective formation of quaternary carbon centers remains a significant challenge to the synthetic chemist [65]. To use the AHR in this role has the obvious attraction of removing the problem of competing pathways in step C (see Scheme lb), as no P-hydrogen is present to compete with the desired P -hydride elimination step - the need to use endocyclic alkene substrates is thus removed. 

In the enantioselective synthesis of a cardenolide precursor, the congested quaternary carbon center and the cw-AB ring fusion in the steroid skeleton 224 were constructed by cyclization of the alkenyl triflate 223 [102]. Similarly critical quaternary carbon-aryl bond formation took place by the cyclization of the bromopyridine 225 to afford the pyridinomorphinan 226 using 60 mol% Pd triflu-oroacetate and PPhs [103]. 

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. 

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). ... 

Zr-catalyzed enantioselective intramolecular diene cyclizations with allylic alcohol and ether substrates afford carbocycles bearing quaternary carbon stereogenic centers the unexpected formation of the aldehyde product 19 is noteworthy. 

Radical reactions are also valuable strategies for the formation of quaternary carbon-based centers. An enantioselective variant of this has recently come to light utilizing aluminum as a Lewis acid complexed to chiral BINOL ligand 26 in the allylation of a-iodolactones 24 (Eq. 9, Table 1) [13]. 

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 " ... 

The key step in the enantioselective synthesis of a polycyclic target is the establishment of the first cyclic stereogenic center. Further construction can then be chrected by that initial center. This principle is nicely illustrated by a synthesis of (+)-estrone methyl ether (145), reported by Taber (Scheme 8). The specifically designed naphthylbomyl ester (141) is used to direct C—insertion selectively toward one of the two diastereotopic C—H bonds. The new ternary center so created then directs the formation of the adjacent quaternary center in the course of the alkylation. Finally, the chiral skew in the product cy-clopentanone (144) directs the relative and absolute course of the intramolecular cycloaddition, to give the steroid carbon skeleton. 

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