Asymmetric Intramolecular Arylations

Almost two decades ago, ShibasaM et al. and Overman et al. reported independently asymmetric intramolecular Mizoroki-Heck reactions by either indirect (desymmetrization, see Section 7.2.3.3) or direct (congested quaternary carbons) formation of stereogenic carbons [65, 66]. Since that time, the exceptional efficiency of this enantioselective C—C bond-forming process is reflected in the syntheses of numerous structurally intriguing natural products [17, 67]. 

This fundamental experiment has strong implications on related catalyst-controlled Mizoroki-Heck cyclizations of precursors of this type. As axial chirality in 113 sets the stereochemistry in 114, enantioinduction was rationalized to arise from a dynamic kinetic resolution of (at elevated temperature) rapidly interconverting enanhomers of 113 in the oxidative addition step, rather than in the alkene coordination-migratory insertion event. Such a dynamic kinetic resolution process has been previously proposed by Stephenson et al. within their mechanistic study regarding the conformations of helically chiral 2-iodoanilides in intramolecular asymmetric Mizoroki-Heck reactions [72], 

In the previous synthesis, meso-123 was used as building block for a more complex natural product. Overman et al. also presented an elegant Mizoroki-Heck-based strategy for the diastereoselective construction of the vicinal 

The combination of these two effects accounts for the high diastereoselection in the first Mizoroki-Heck ring closure diastereoselectivity of the second cycliza-tion is simply determined by steric interactions with the previously formed spiro-oxindole. 

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Hartwig has reported the asymmetric intramolecular arylation of amides using a chiral carbene ligand (5) with up to 76% ee [43]. 

Scheme 8.44 Asymmetric intramolecular arylation of amides, as described by Murakami and coworkers...

Chan has discovered a completely atropdiasteroselective synthesis of a biaryl diphosphine by asymmetric intramolecular Ullmann coupling or Fe(m)-promoted oxidative coupling. A chiral atropisomeric biaryl bisphosphine ligand 2 was synthesized through this central-to-axial chirality transfer.38 Recently, a xylyl-biaryl bisphosphine ligand, Xyl-TetraPHEMP, was introduced by Moran, and is found to be effective for the Ru-catalyzed hydrogenation of aryl ketone.39... 

In a series of studies, Shibasaki examined the formation of chiral benzylic quaternary centers by using asymmetric intramolecular Heck reactions. The effect of double-bond stereochemistry was examined in the cyclization of aryl Inflates 9.1 and 9.3 (Scheme 8G.9) [22], As is commonly... 

Intermolecular insertion to aryl C—H bonds is possible. The asymmetric intramolecular reaction of the a-diazo compound 354 catalysed by Rh2[(S)-PTTL]4, Rh2[(S)—PTTL]4 = dirhodium tetrakis[N-phthaloyl(S)—t—leucinate], afforded indane... 

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). 

Mizorokf and Heck reported independently in the early 1970s the first palladium-mediated coupling of an aryl or vinyl halide or triflate with an alkene. This reaction is generally referred to as the Heck reaction. From the first reports on asymmetric intramolecular Heck reactions by Overman and Shibasakf in 1989 the asymmetric Heck reaction has emerged as a reliable method for the stereoselective formation of tertiary and quaternary stereogenic centers by C-C bond formation in polyfunctionalized molecules. ... 

The thiazolium-catalyzed addition of an aldehyde-derived acyl anion with a Michael acceptor (Stetter reaction) is a well-known synthetic tool leading to the synthesis of highly funtionalized products. Recent developments in this area include the thiazolylalanine-derived catalyst 191 for asymmetric intramolecular Stetter reaction of a,P-unsaturated esters <05CC195>. However, these cyclizations proceed only in moderate enantioselectivities and yields even under optimized conditions. Thiazolium salt 191 has been used successfully for enantioselective intermolecular aldehyde-imine cross coupling reactions <05JA1654>. Treatment of tosylamides 194 with aryl aldehydes in the presence of 15 mol% of 191 and 2... 

Table 8.11 Asymmetric intramolecular Heck reaction of aryl triflate...

Scheme 2.19 Organocatalytic asymmetric intramolecular a-arylation reactions of aldehydes reported by (a) Nicolaou, and (b) MacMillan, respectively.

The first example of direct enantioselective addition of a C—H bond to a ketone was reported by Shibata and co-workers in 2009 using the cationic Ir/ (S)-Hg-BINAP as the catalyst in the synthesis of a chiral 4-acetyl-3-hydroxy-3-methyl-2-oxindole with 72% ee. Recently, Yamamoto and co-workers developed a cationic Ir/(R,R)-Me-BIPAM catalyzed asymmetric intramolecular direct hydroarylation of a-keto amides 178 affording the chiral 3-substi-tuted 3-hydroxy-2-oxindoles 179 in high yields with complete regioselectivity and high enantioselectivity (84-98% ee). In their proposed reaction mechanism, the aryl iridium complex formed via C—H bond activation is coordinated with the two carbonyl groups of the amide (Scheme 5.65). 

Six-membered rings, particularly those with highly substituted benzylic stereocentres, are readily assembled by the asymmetric intramolecular Mizoroki-Heck reaction. In a seminal example, Shibasaki and coworkers [45] showed that (i )-alkenyl aryl triflate 75 can be cyclized in high yield with modest enantioselectivity to bicycle 76 (Scheme 12.18). 

Dounay, A.B., Hatanaka, K., Kodanko, J. et al. (2003) Catatytic asymmetric synthesis of quaternary carbons bearing two aryl substituents. Enantioselective s3mthesis of 3-alkyl-3-aryl oxindoles by catalytic asymmetric intramolecular Heck reactions. J. Am. Chem. Soc., 125, 6261-71. 

Selectivity between a- and p-vinylation of enol ethers has been investigated again diphosphines and nitrogen-based ligands promote a-products. Cyclic enol ethers also remain popular substrates for asymmetric Heck reactions (40-96% ee). Use of hindered bases and BINAP facilitates these reactions. Similar strategies may be employed using 2-pyrrolines (up to 83% ee) or intramolecular arylations.446 Two examples of stereodirected Heck reactions and a kinetic resolution have also appeared... 

Chardonnens and Salamin also synthesized a number of substituted [l,2-h]IF diones, which were typically made in the same fashion as the [l,2-a]IF diones described earlier (Scheme 3) [43]. For example, treatment of 2,5-dibromoterephthalic acid (32) with thionyl chloride and subsequent Friedel-Crafts acylation with 33a-d provided 34a-d (Scheme 8). Intramolecular arylation at elevated temperatures furnished IF-diones 35a-d in 20-28% yield. This technique has also been successfully applied to asymmetric 1,3,4-trisubstituted diones as well as 2,3,8,9-tetrasubstituted diones [42]. 

Xestoquinone 420 (Asymmetric) intramolecular HR of an aryl triflate (bromide) [554]... 

A wide range of chromans result from the phosphine-promoted intramolecular conjugation of alkyl hahdes with electron-deficient olefins (13CC4570) and palladium(II)-catalyzed intramolecular asymmetric O-arylation of 2-(2-haloaryl)propane-l,3-diols (Scheme 30) (13OL6022). 

Recently, Trapp and coworkers presented a series of six-membered NHC-Pd complexes 69 [63]. Steric demand increases from 69a to 69c while retaining natural rf-(+)-camphor as the chiral motif. The complexes showed different catalytic profiles in the intramolecular asymmetric a-arylation of amides (Scheme 3.38). Whereas catalyst 69a showed no enantiodiscrimination and 69c gave dehaloge-nation products in attempted oxindole synthesis, 69b proved to be more effective producing the 3,3-disubstituted oxindoles in high yields (up to 98%) and moderate enantioselectivities (68% ee). 

Several other mechanistically distinct metal-catalyzed dearomatization procedures have been reported, and almost all involve phenol or naphthol derivatives undergoing dearomatization via intramolecular transformations. Intramolecular Pd- and Rh-catalyzed C4-arylation and alkylation of /)ara-substituted phenols has been used to construct compounds of general structure 82 (Fig. 15.1) [86]. These reactions rely on generation of electrophilic aryl or alkyl o-metal complex intermediates that participate in tandem C4 metalation-reductive elimination with an attached phenol. Ruthenium- and Pt-catalyzed reactions of naphthalenes and alkynes deliver spirocyclic products such as 83 [87, 88]. An asymmetric intramolecular naphthalene dearomatization catalyzed by Pd(0)-phosphine complexes has been used to prepare carbazole derivatives 84 in good enantiomeric excess from l-(AI-2-bromophenyl)aminonaphthalene precursors [89]. 

There has been a summary of computational and experimental studies of the use of palladium complexes with A -heterocyclic carbenes (NHCs) in the asymmetric coupling of -hybridized carbon-hydrogen bonds with aryl halides. It has been shown that the electronic and catalytic properties of NHCs fused to porphyrins may be modified by varying the inner metal in the porphyrin. A DPT study of the use of palladium-NHC complexes in the asymmetric intramolecular a-arylation of 2-bromoaryl amides to give 3,3-disubstituted oxindoles (101) has been reported. The likely pathway involves insertion of the palladium into the arene-bromine bond to form a palladacycle which deprotonates to give an (9-enolate. Conversion into the C-enolate followed by reductive elimination gives the product. The intramolecular reaction of 0 a cyclopropane carbon-hydrogen bond in a 2-bromoanilide derivative has been used to form cyclopropyloxindoles, (102), in a palladium-catalysed, silver-mediated reaction. 

Zeng and Chemler developed a copper-catalyzed preparation of six-membered N,S-heterocycle sultam derivatives using 3 equiv. of Mn02 as the oxidant (Scheme 8.122). The enantiomerically enriched N,S-heterocycle sultams were prepared by an asymmetric intramolecular carboamination of alkenes with moderate to good yield and high enantioselectivity. An intramolecular Cu-catalyzed aryl C(sp )-H functionalization process is included for this reaction [54]. 

SOMO catalysis, which has been the subject of considerable attention in recent years, is a unique and versatile activation mode that can participate in bond construction with various n-rich nucleophiles. The first asymmetric intramolecular a-arylation of aldehydes was reported by Nicolaou in 2009 using organo-SOMO catalysis [17a]. The authors applied imidazolidinone 23 as catalyst and cerium ammonium nitrate (CAN) as the oxidant Various 5-oxopentylbenzenes 36, or indole derivatives 38, could furnish the cyclic products 37 or 39, respectively, in good yields and with excellent ees (Scheme 36.11). Later, MacMillan disclosed similar research [17b], and a theoretical study of the intramolecular a-arylation of aldehydes was also reported by the same group via density functional theory [17c],... 

Organocatalysis in combination with oxidants enables intramolecular asymmetric a-arylation of carbonyl compounds. In 2009, Nicolaou and MacMillan independently reported asymmetric a-arylation of aldehydes (Scheme 7.15). Using MacMillan s imidazoline catalyst and an appropriate... 

Atropoisomeric a,a -binaphthyl (P,N) ligands have been used to effect Pd-catalysed asymmetric intramolecular a-arylation of a-branched aldehydes (Scheme 28). i... 

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