Atroposelection

Atroposelective cleavage of configurationally unstable lactone cycle in biaryl derivatives as effective route to chiral natural products and useful reagents 99S525. 

Removal of the amide function is much easier if the reaction is intramolecular, and —CONEt2 amides (sometimes even —CONPr-i2 amides) may be converted to lactones, lactams and other heterocycles in this way . Addition of an aldehyde or ketone as an electrophile generates a hydroxyl group (in some cases, atroposelectively, as it happens —though this is usually irrelevant to the stereochemistry of the product) which cyclizes to give a lactone via a benzylic cation in acid. This reaction has found wide use in the synthesis of polycyclic aromatics, particularly alkaloids. 

By carrying out a subsequent ortholithiation at low temperature, it was possible to show that tertiary benzamides also react atroposelectively in laterally lithiation-electrophilic quench sequences . Either atropisomer 575 or 578 could be made starting from 573 or 576 (Scheme 231). 

The broad applicability of the strategy has been proven in the atroposelective Synthesis of a broad series of structurally different bioactive natural biaryl products like the... 

The mechanism of the atroposelective ring opening of a lactone-bridged biaryl, dinaphtho[2,l-t l, 2 -< ]oxepin-3(5//)-one, with a chiral oxazaborolidine-BH3 complex (Scheme 2) was studied using semi-empirical AMI calculations <2000JOC2517>. 

Chelation-assisted C-H/olefin coupling can be applied to the atroposelective alkylation of biaryl compounds. The reaction of 2-(l-naphthyl)-3-methylpyri-dine with ethylene using [RhCl(coe)2]2 where coe is cyclooctene, and PCy3 results in the formation of an ethylation product in 92% yield (Eq. 21) [20]. In place of the PCy3 ligand, the use of (R) - (1 - [ (S) - 2- diphenylphosphino ] ferro-cenyl)ethyl methyl ether [(R),(S)-PPFOMe] leads to the atropselective alkyla-... 

Curran [12] showed in 1994 that maleimides bearing ortho-substituted aryl groups could react diastereoselectively, favouring a single atropi-somer of the product (Curran termed these reactions atroposelective ). Racemic maleimide 8 underwent radical reactions and cycloadditions from the face unshielded by the tert-butyl group, as shown in Scheme 4. 

In our own group, we [17] have shown that ro-tationally restricted aromatic amides (ArCONRj) can be functionalised atroposelectively, both by nucleophiles and electrophiles [18]. Atroposelective additions to carbonyl groups are possible ... 

The search for a general synthesis of enantio-merically pure non-biaryl atropisomers has been given added impetus by the discovery [26, 27] that the absolute configuration of some atropiso-meric amides affects their biological activity. The enantiomeric atropisomers 21 and 22 (Scheme 13) differed in activity at the tachykinin NK, receptor by a factor of 6-13, with 21 being the more active. Atroposelectivity must now be an important new consideration in drug synthesis. 

Both total syntheses of Evans et al. and Nicolaou et al. first perform synthesis of the AB/C-O-D-ring systems before condensation with the D-O-E ring system. The Evans et al. route was extended by several synthetic steps by the conversion of the 2-OH-group of Hpg and the conversion of nitro substituents after SnAt into hydrogen substituents. Problems developed with the transformation of the C-terminal amide into the carboxy function during deprotection steps. In contrast, Nicolaou et al. had to face the relatively moderate atroposelectivities and had to solve the somewhat obscure conversion of the triazene into a phenolic group. Both syntheses have been compared and discussed in the literature. ... 

Because both radical-nucleophile and radical-radical coupling (electropolymerization [316]) can occur under anodic conditions mechanistic differentiation is often difficult. Under chemical oxidation [279b] and PET conditions [279a], however, only radical-nucleophile coupling is encountered. Intermolecular [280] and intramolecular [281] C-C bond formation used for biomimetic atroposelective coupling [282] and for natural product synthesis [283] is nowadays a well-established synthetic tool. 

An efficient atropo-enantioselective total synthesis of the axially chiral bicoumarin (+)-isokotanin was accomplished by J. Bringmann and co-workers.The key steps in this synthetic approach were the formation of a configurationally stable seven-membered biaryl lactone by the Cannizzaro reaction of the corresponding biaryl dialdehyde followed by a kinetic resolution by atroposelective ring cleavage. 

Dynamic kinetic resolution atroposelective lactone ring opening and its use in the synthesis of natural products and chiral auxiliaries 03T8291. 

Bringmann G, Price Mortimer AJ, Keller PA, Gresser MJ, Gamer J, Breuning M (2005) Atroposelective synthesis of axially chiral biaryl compounds. Angew Chem Int Ed 44 5384-5427... 

The value of naphtho[2,l-()]coumarins in the atroposelective synthesis of axially chiral hiaryls, the so-called lactone method, has been discussed with emphasis on an approach to chiral phosphineamines <04T4349, 04T6335>. 

In specifying selectivity of ligogenic processes, the focus of attention is on either whole molecules, or, molecular sites. Selectivity for whole molecules is based cn their morphic relationships and is termed morphoselectivity. In contrast, if the emphasis is on selective transformations at molecular sites, then one is dealing with situselectivityP The latter term is synonymous with site selectivity, site specificity, positional selectivity, locoselectivity, atroposelectivity, regioselectivity (intramolecular), regiospecificity, chemoselectivity (intramolecular), intramolecular selectivity, fimctional selectivity, and sequence selectivity. This chapter deals with the concept of situselectivity, and establishes the commonality of all the previous terms. 

Kakiuchi et al. succeeded in the atroposelective alkylation of the 2-(l-naphthyl)-3-methylpyridine with ethylene catalyzed by [RhCl(coe)2]2 and a chiral ferrocenyl phosphine (R) or (S)-PPFOMe (Figure 15). This is a kind of dynamic kinetic resolution. The pelds were moderate with fair to good ees (00TA2647). 

A review by Bringmann, Breuning et al. (05AG(1E)5384) entitled Atroposelective synthesis of axially chiral biaryl compounds contains a few examples of heteroaromatic compounds but methodologically it is of... 

As with atropisomeric biaryls, axial chirality in atropisomeric amides maybe introduced by stereochemical control in the atroposelective reactions of planar chiral complexes [115]. Enantioselective lithiation was reported in this context by Uemura, who showed that the achiral complexes 195,198,201 and 204 are de-protonated enantioselectively by treatment with chiral lithium amide bases (Scheme 50) [116-118]. The stereogenic C-C and C-N axes in these compounds are orientated such that the larger NR2 and acyl groups, respectively, are directed away from the chromium. A range of chiral lithium amides was investigated, and by careful selection it was possible to obtain products 196,199,202 and 205... 

The atroposelective synthesis of axially chiral biaryls via configurationally unstable, lactone-bridged biaryls 02JOM(661)31. 

The methods for the preparation of enantioenriched axially chiral biaryl compounds include en miatic or chemical resolution of their racemic mixture, atroposelective coupling reactions, transition metal-catalyzed asymmetric... 

Organocatalysis has also found applications in the area of asymmetric oxidative biaryl coupling reactions. Very recently, the groups of Kurti" and List" independently devised atroposelective [3,3]-rearrangement reactions of N,N -diaryl hydrazines to synthesize enantioenriched BINAM derivatives (Scheme 3.16). 

Scheme 5.1 Atroposelective approaches to biaryl compounds through DKR.

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