Intramolecular enantioselective arylation

Intramolecular enantioselective arylation reactions of ketones 29 were described by Lu (Scheme 8.10) [27]. The cationic (BINAP)-palladiumhydroxo complex 30 works in combination with a basic anion-exchange resin as an additive to afford optically active cycloalkanols 31 in high yields and enantioselectivities. 

Scheme 14.3 Intramolecular enantioselective arylation of carbonyl compounds.

In 1990, Cabri el al. [40a] reported that the precursor Pd(OAc>2 associated with a biden-tate P P ligand as dppp (1,3-bis-diphenylphosphinopropane) appeared to be more efficient than PPhs in Mizoroki-Heck reactions performed from aryl Inflates and enol ethers (electron-rich alkenes) moreover, the regioselectivity in favour of the a-arylated alkenes was improved to 100%. Since that time, dppp associated with Pd(OAc)2 has been used extensively to catalyse Mizoroki-Heck reactions and to investigate the factors that control the regioselectivity [Ig, 40]. The chiral bidentate (7 )-Binap (2,2 -bis(diphenylphosphino)-1,1-binaphthyl) associated with Pd(OAc)2 has also been used by Shibasaki and coworkers [2b,d,41a] and Overman andPoon [41b] in intramolecular enantioselective Mizoroki-Heck reactions (also, see Link [2f] for an authorative review on the Overman-Shibasaki chemistry), as well as by Hayashi and coworkers [2a, 41c,d] to control the regioselectivity and enantioselectivity of intermolecular Mizoroki-Heck reactions performed from cyclic alkenes (see Schemes 1.3 and 1.2 (Z = O) respectively). 

Ripa, L. and Hallberg, A. (1997) Intramolecular enantioselective palladium-catalyzed Heck arylation of cyclic enamides. J. Org. Chem., 62, 595-602. 

Soon afterward, MacMillan and co-workers [142, 143] also reported enantio-selective intramolecular a-arylation of aldehydes via organo-SOMO catalysis. [Fe(Phen)3l [PFsl 3, instead of CAN, as a single-electron oxidant together with designed imidazolidinone catalysts LXVIII and LXIX were found to be optimal for reaction efficiency and enantioselectivity (Scheme 8.35). Moreover, ortho selectivity, when 1,3-disubstituted aromatic systems were used, was observed. Methodologies presented by Nicolaou and MacMillan represent a useful tool for the total synthesis of various naturally occurring compounds, such as dimethyl calamenene, tashiromine, and so on. 

A new mode of oxidative organocatalytic activation has been reported, termed organo-SOMO catalysis, which has been successfully applied using an enantioselective intramolecular a-arylation of aldehydes via catalytic oxidative radical cyclization (Eq. 9.25) [101]. In this approach, the exposure of an aryl-tethered aldehyde (124) to a chiral secondary amine catalyst 125 and a suitable oxidant leads to enantio-enriched 126 ... 

In 2011, Murakami and coworkers [82] reported that chiral NHC ligands having a 2,2 -bisquinoline-based Cj symmetric skeleton were efficient ligands in the palladium-catalyzed intramolecular a-arylation of amides to afford 3,3-disubstituted oxindoles with good yield and enantioselectivity (Scheme 8.44). The two fused rings attached to the NHC core played an important role in the reaction mechanism. 

In 2010, Dorta and coworkers [83] reported a new synthetic strategy to access functionalizable 3-allyl oxindoles bearing a chiral quaternary carbon stereocenter via a direct palladium-catalyzed a-arylation protocol. This elegant methodology, previously accessible only via a two-step procedure involving a Pd-catalyzed intramolecular a-arylation followed by an asymmetric Pd-catalyzed allylic alkylation [84], afforded impressive reactivities, and high chemoselectivities and enantioselectivities were also achieved in the synthesis of oxindoles using a new chiral Pd-NHC catalyst (Scheme 8.45). 

The concept of enantioselective intramolecular enolate arylation was also applied to obtain indanyl aldehydes 168, according to a protocol of Buchwald and Garda-Fortanet, from aryl bromides 167. A screening of ligands revealed the... 

Scheme 5.53 Enantioselective intramolecular enolate arylation of racemic ortho-bromoanilides 161, 163, and 165.

Nicolaou and coworkers reported efficient enantioselective syntheses of ( )-kinamycin C (3), ( )-kinamycin F (6), and ( )-kinamycin J (10) [39], Nicolaou s retrosyntheses of these targets are shown in Scheme 3.13. The authors envisioned that all three metabolites could be accessed from the common precursor 82. The a-hydroxyketone function of 82 was envisioned to arise from an intramolecular benzoin reaction of the ketoaldehyde 83. This key bond disconnection would serve to forge the cyclopentyl ring of the kinamycin skeleton. The ketoaldehyde 83 was deconstructed by an Ullmann coupling of the aryl bromide 84 and the a-iodoenone 85. The latter were anticipated to arise from the bromojuglone derivative 86 and the enantiomerically enriched enone 87, respectively. 

Chan has discovered a completely atropdiasteroselective synthesis of a biaryl diphosphine based on an enantioselective intramolecular Ullmann coupling or a Fe(III)-promoted oxidative coupling. A chiral atropisomeric biaryl bisphosphine ligand 2 was synthesized through this central-to-axial chirality transfer [30]. Recently, a xylyl-biaryl bisphosphine ligand, Xyl-TetraPHEMP was introduced by Moran, and found to be effective for the Ru-catalyzed hydrogenation of aryl ketones [31]. 

In 2007, Scheldt and co-workers reported the intramolecular desynunetrization of 1,3-diketones utilizing triazolinm pre-catalyst 249 (Scheme 39) [129], Generation of a homoenolate is followed by P-protonation and aldol reaction. In accordance with the proposed mechanism by Nair (Scheme 37), acylation occurs followed by loss of carbon dioxide. Cyclopentenes are formed in enantioselectivities up to 94% ee. The scope of this reaction is limited to aryl substitution of the diketone and alkyl substitution of R. 

Chiral dirhodium(II) carboxamidates are preferred for intramolecular cyclopropanation of allylic and homoallylic diazoacetates (Eq. 2). The catalyst of choice is Rh2(MEPY)4 when R " and R are H, but Rh2(MPPIM)4 gives the highest selectivities when these substituents are alkyl or aryl. Representative examples of the applications of these catalysts are listed in Scheme 15.1 according to the cyclopropane synthesized. Use of the catalyst with mirror image chirality produces the enantiomeric cyclopropane with the same enantiomeric excess [33]. Enantioselectivities fall off to a level of 40-70% ee when n is increased beyond 2 and up to 8 (Eq. 2) [32], and in these cases the use of the chiral bisoxazoline-copper complexes is advantageous. 

As mentioned previously, the partially reduced forms of five membered heteroaromatic systems might act as olefins in insertion reactions. This behaviour is characteristic particularly of dihydrofuranes. The olefin insertion and the following / hydride elimination should in principle lead to a trisubstituted olefin, which is rarely observed, however. Typical products of this reaction are 2-aryl-2,3-dihydrofuranes. A characteristic example of such a reaction is presented in 6.54. The coupling of 4-iodoanisole and dihydrofurane led to the formation of the chiral 2-anisyl-2,3-dihydrofurane in excellent yield.83 The shift of the double bond, which leads to the creation of a new centre of chirality in the molecule, opens up the way for enantioselective transformations. Both intermolecular and intramolecular variants of the asymmetric Heck reaction have been studied extensively.84... 

---