Enantioselectivity inter-molecular

In 2008, Willis and co-workers developed a highly enantioselective inter-molecular hydroacylation reaction employing ortfto-S-substituted benzal-dehydes 51 and 1,3-disubstituted allenes 52 (Scheme 8.25). When using a (7 ,/ )-Me-DuPhos-derived cationie rhodium catalyst, excellent yields and ee were obtained. Extension of the substrate scope to a trisubstituted allene led to the product with high ee, but in a disappointingly low yield. It was revealed that the reaction was not a simple kinetic resolution of the racemic allene but rather proceeded by dynamie kinetie asymmetric transformation. 

An enantioselective inter-molecular oxidative dehydrogenative a-alkylation of aldehydes, via benzylic C—H bond activation in MeN02 using molecular O2 as the oxidant and (135) as an organocatalyst, was exemplified by the reaction of 9//-xanthene with hexanal. The ammonium salt catalysts played dual roles not only as enamine catalysts but also as acid catalysts and the desired product was obtained in 81% yields with 73% i... 

Buchwald and coworkers also disclosed a protocol for an enantioselective inter-molecular arylation and vinylation of racemic oxindoles 152 under palladium catalysis. Various aryl bromides but also 1-bromoalkenes were shown to react under the usual basic conditions maintained by an excess of sodium f-butoxide. It turned out that only axially chiral monophosphine ligands like 144b led to significant enantioselectivity. However, arylated products 154 were obtained in very high enantiomeric excess with the axially chiral and / -stereogenic ligand 153 (Scheme 5.50) [73]. 

As the first example of asymmetric radical addition using chiral aluminum Lewis acid, in 1995, Urabe and Sato reported enantioselective inter molecular radical addition of butyl radical generated from iodobutane to exo-methylene lactone (Scheme 6.172) [202]. In this reaction, chiral Lewis acid (i )-(14) derived from (R)-BINOL and Et2AlCl gave only low enantioselectivity (up to 23% ee). Shortly after this report, Nishida and coworkers reported that in the presence... 

Homoamino acids have been tested as enantioselective catalysts of intra- and inter-molecular aldols.119... 

A modification of this system was also used in intramolecular MBH reactions (also called as aldol cycloisomerization) [71, 74]. In this reaction, optically active pipecolinic acid 61 was found to be a better co-catalyst than proline, and allowed ee-values of up to 80% to be obtained, without a peptide catalyst. The inter-molecular aldol dimerization, which is an important competing side-reaction of the basic amine-mediated intramolecular MBH reaction, was efficiently suppressed in a THF H20 (3 1) mixture at room temperature, allowing the formation of six-membered carbocycles (Scheme 5.14). The enantioselectivity of the reaction could be improved via a kinetic resolution quench by adding acetic anhydride as an acylating agent to the reaction mixture and a peptide-based asymmetric catalyst such as 64 that mediates a subsequent asymmetric acylation reaction. The non-acylated product 65 was recovered in 50% isolated yield with ee >98%. 

Selig, P. and Bach, T. (2006) Photochemistry of 4-(2 -aminoethyl) quinolones enantioselective synthesis of tetracyclic tetrahydro-laH-pyrido [4, 3 2,3]-cydobuta[l,2-c] quinoline-2,11 (3H, 8H)-diones by intra- and inter-molecular [2 + 2] photocydoaddition reactions in solution. Journal of Organic Chemistry, 71, 5662—5673. 

The inter- and intramolecular Diels-Alder reactions of furans, and their applications to the synthesis of natural products as well as synthetic materials, were reviewed <1997T14179>. HfCU promoted the endo-seXccuve. inter-molecular Diels-Alder cycloadditions of furans with a,/3-unsaturated esters <2002AGE4079>. The cycloaddition between furan and methacrylate was also achieved under these conditions, providing, however the o-isomer as the major cycloadduct. A catalytic enantioselective Diels-Alder reaction between furan and acryloyl oxazolidinone to provide the < 46i-adduct in 97% ee was achieved by using the cationic bis(4-fer7-butyloxazoline)copper(ll) complex 55, as shown in Equation (41) <1997TL57>. 

Asymmetric catalysis of ene reactions was initially investigated for the intramolecular examples, because intramolecular versions are much more facile than their inter-molecular counterparts. The first reported example of an enantioselective 6-(3,4) car-bonyl-ene cyclization employed a BINOL-derived zinc reagent [81]. This, however, was successful only when excess zinc reagent (at least 3 equiv.) was used. An enantioselective 6-(3,4) olefin-ene cyclization has also been developed which uses a stoichiometric amount of a TADDOL-derived chiral titanimn complex (Sch. 26) [82]. In this ene reaction, a hetero Diels-Alder product was also obtained, the periselectivity depending critically on the solvent system employed. In both cases, geminal disubstitution is required of high ee are to be obtained. Neither reaction, however, constitutes an example of a truly catalytic asymmetric ene cyclization. 

Allylic substitution is well known and other metal-based complexes have been reported to catalyze reactions with hydroxyl leaving groups/ Indeed, with homogeneous Au-catalysis, a variety of reactions that proceed via cationic pathways have been reported. " While discussion is beyond the scope of this chapter, it is worth noting that the mechanism for this reaction has been extensively studied and does not appear to proceed via an allylic cation/ Further developments in this area have been reported by a variety of groups and now involve the use of nitrogen nucleophiles, carbon nucleophiles, and inter-molecular reactions as well as enantioselective variants/ While many of those reports came from our laboratory, our interests took us in a different direction and we became keen on using modified substrates to develop spiro-ketalization methods for applications in synthetic schemes. 

When a prochiral ( )-enolate is selectively (Si)-facially protonated, the result is the (H)-enantiomer. (Jle)-Facial protonation leads to the (S)-enantiomer. From the (Z)-enolate, the direct opposite is obtained. If it is not possible to control the ( )/(Z)-configuration of the enolate, in order to obtain good selectivity, one needs then an enantiomericaUy pure acid, whose protonation preference is dependent on the enolate configuration, i.e. for example, it transfers a proton (Si)-facially to the ( )-enolate, but (Re)-fadally to the (Z)-enolate. In many successful cases the enantiomericaUy pure acid is bonded to the metal of the enolate therefore, at the same time it acts also as a Lewis base. In addition, at least from a theoretical point ofview, enantioselective inter- and intra-molecular protonations with achiral acids are conceivable, in which another ligand of the enolate complex is enantionmericaUypure. 

In contrast to the Rh-catalyzed asymmetric intramolecular direct C—H bond functionalization reactions described above, their asymmetric inter-molecular variants have been rarely explored. In 2000, Murai and co-workers reported a Rh-catalyzed intermolecular asymmetric C—H activation/olefin coupling reaction of achiral biaryl pyridine (132) or isoquinoline derivatives to deliver axially chiral biaryls (133) (Scheme 5.46a). Although both the efficiency (up to 37% yield) and the enantioselectivity (up to 49% ee) of the reaction were only moderate, this protocol provided an alternative method for the synthesis of optically active biaryl compounds. To some extent, this reaction was similar to a formal dynamic kinetic resolution. The two atropisomers of the biaryl starting materials could interconvert with each other freely due to a low inversion energy barrier. A properly chosen chiral catalyst could react preferentially with one atropisomer. The increased steric bulkiness of the final alkylated products can prevent the epimerization and the biaryl compounds possessing a stable axial chirality are established. However, due to the relatively low efficiency of the catalyst, the yields of the desired products are generally low and the starting materials can be recovered (Scheme 5.46b). 

The enantioselective a-enolation of aldehydes reported by MacMillan and co-workers [136] proceeded well with various ir-rich silyl enolethers containing aUtyl, vinyl, or aryl moieties without loss of reaction efficiency and enantiocontrol. The incorporation of bulkier silyl group (TBS) not only increased substrate stability versus hydrolysis, but also led to increased enantioselectivity. Furthermore, inter-molecular enolation rather than intramolecular enolation was observed as preferred. 

Methods for enantioselective inter- and intra-molecular addition of a compound containing an sp C—H group to a C=C bond catalysed by transition metal or organocatalysts have been reviewed. ... 

The enormous potential of the intramolecular Heck reactions has been demonstrated impressively in elegant syntheses of even the most complicated natural product skeletons. The intramolecular Heck reaction on the achiral iodoalkenes 354 and the corresponding alkenyl triflates 357 with their pairs of enantiotopic double bonds in the cyclohexa-1,4-diene moieties, applying catalysts with chiral ligands, gave tetrahydronaphthalenes 359 or hydrindanes from precursors such as 354, 357 or corresponding precursors with one less carbon in the tether [204f], with excellent enantioselectivities. Complementary to the asymmetrically induced inter-molecular arylation with triflates (Scheme 8.72), reasonable asymmetric inductions in intramolecular reactions were also achieved with iodides on the addition of silver salts to promote the formation of cationic intermediates such as 356 (Scheme 8.73)... 

Enantioselective Reactions Due to syn- - or P"-hydride hydride elimination, stereogenic centers may be created in the presence of chiral ligands [3n-s, 17, 18]. The asymmetric intramolecular version (Scheme 19.14c) (Shibasaki, Overman) [17] is more developed than the asymmetric inter-molecular version (Scheme 19.14d) (Hayashi) [18]. 

Boronic acid-derived fluorescent chemosensors are unique in that the inter-molecular interaction is a covalent bond, and not hydrogen bonding as is the case for most conventional fluorescent molecular sensors used for the selective reeognition of hydroxyl carboxylic acids. This chapter summarizes the development of the boronic acid-based chiral fluorescent chemosensors over recent years and the enantioselective fluorescent reeognition of chiral a-hydroxyl carboxylic acids analytes in aqueous solutions. The fundamental scaffolds of these chiral sensors include a fluorophore, an arylboronie aeid binding site, and linker between the two units. The systems usually consist of a bis-boronic acid unit, which is required for enantioselective recognition of the chiral a-hydroxyl carboxylic acid analytes. However, mono-boronic acid fluorescent chemosensors have also been developed. All three components of the chiral boronic acid sensors play an important role in determining the... 

Pyrrolo[2,l-a]isoquinoline derivatives (27) were synthesized using Cgo-Bodipy dyads (28) as excellent photosensitizers (Scheme 13)/ Direct irradiation of glycine methyl ester to Ceo afforded [3 - - 2] cycloadduct/ Akasaka and his coworkers found the photocycloaddition of 2-ada-mantane-2,3-[3ff]diazirine and disilyliranes to Cso-metallofullerenes/ Intra- and inter-molecular photocycloaddition of alkenes to coumarin, quinolone, and isoquinolone derivatives have been reported by several groups. Griesbeck et al. found that the intramolecular photocycloaddition of cyclohexene moiety to coumarin (29) was catalysed by molecular ojygen. [2 + 2] Photocross dimer (33) of coumarin derivative (31) and 5-fluorouracil derivative (32) was obtained by laser irradiation/ Bach reported enantioselective intramolecular photocycloaddition of coumarins (34) to alkenes catalysed by a chiral Lewis acid (36) (Scheme 14)/ ... 

Recently, Fustero et al. [44] reported an efficient microwave-assisted inter-molecular aza-Michael reaction catalyzed by 9-amino-9-deoxy-epi-hydroquinine (20mol%) with pentafluoropropionic acid co-catalyst (Scheme 21.19). Chiral five-and six-membered aza-heterocycles, for example, piperidines and pyrrolidines, were synthesized with high enantioselectivities. CycUzation using microwave irradiation at 60 °C allowed a reduction of reaction time (e.g., from 20 to 1 h) and led to comparable results in terms of yield and enantioselectivity to the conventional method at room temperature. Unfortunately, no comparison of microwave heating with conventional oil bath heating at 60 °C was presented. 

They also reported high levels of enantioselection for the inter-molecular cycloadditions of ester-derived carbonyl ylides with DMAD (up to 93% ee, Rh2(S-PTTL)4) (Scheme 7.22) [58] and a-diazo ketone-derived carbonyl ylides with aromatic aldehydes (up to 92% ee, Rh2(S-BTPV)4) (Scheme 7.21) [59]. Dirhodium (II) tetrakis[A -tetrachIorophthaIoyI-(S)-ferf-Ieucinate], Rh2( 5-TCPTTL)4, was found to be an exceptionally effective catalyst for tandem carbonyl ylide formation/cycloaddition reactions of... 

The scope of this approach was widened by the observation of excellent enantioselectivities in inter-molecular [2-i2]-photocycloaddition reactions with various alkenes. 4-Methoxy-2-quinolone 27 was converted with high chemo- and regioselectivity to cyclobutanes 29 and 30 in the presence of an excess of alkene. With 4-penten-l-ol 28a, allyl acetate 28b, methyl acrylate 28c, and vinyl acetate 28d, the exo-diastereomers 29a-d were formed with high simple diastereoselectivity and high yields (80 to 89%). Under optimized irradiation conditions (2.4 eq. of host 21 or enr-21,-60"C), high enantiomeric excesses were achieved in all instances, as depicted in Scheme 11 these enantiomeric excesses are unprecedented for an intermolecular photochemical reaction. As in the intermolecular case, host 21 induced Re-attack at carbon C3, and host e r-21 induced a St-attack. 

Lithium thiolates add well to activated olefins, generating /i-sulfuri/cd lithium eno-lates175. Those can be used in tandem inter-176 or intra-177 molecular addition-aldolisation processes. In the presence of a catalytic amount of bi- or tridentate chiral ligands178, this addition becomes enantioselective and the newly created asymmetric center(s) can be almost totally controlled, provided the thiolate and the enone structures are well chosen (Scheme 40)179 l82. 

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