Unsaturated, enantioselective Reaction

In 1993, we reported that various unsaturated heterocycles can be alkylated with Et-, wPr- and nBuMgCl in the presence of optically pure (EBTHI)ZrCl2 (3a) or (EBTHI)Zr-binol (3b) to afford the derived unsaturated products in >90% ee (cf. 5 6, Scheme 2) [4a]. Many of the simpler five- and six-membered starting materials are available commercially or can be prepared by established procedures. In contrast, catalytic enantioselective reactions involving unsaturated medium ring hetero cycles were not a trivial undertaking the synthesis of these olefinic substrates, by the extant methods, was prohibitively cumbersome. 

R)-product. Although there is still room for further improvement of the enantioselectivity, this first example of an enantioselective reaction with a,(S-unsaturated ketones reveals the potential of acylzirconocene chlorides as unmasked acyl anion donors. 

The cationic chiral Lewis acids 10, generated from the corresponding oxazaboroli-dines by protonation by trifluoromethanesulfonic acid, are excellent catalysts for the enantioselective reaction of 2-substituted acroleins, a-unsaturated a,p-enones, a-unsaturated acrylic acid esters, and a-unsaturated acrylic acids with a variety... 

In early studies of these reactions, the turnover efficiency was not always high, and stoichiometric amounts of the promoters were often necessary to obtain reasonable chemical yields (Scheme 105) (256). This problem was first solved by using chiral alkoxy Ti(IV) complexes and molecular sieves 4A for reaction between the structurally elaborated a,/3-unsaturated acid derivatives and 1,3-dienes (257). Use of alkylated benzenes as solvents might be helpiul. The A1 complex formed from tri-methylaluminum and a C2 chiral 1,2-bis-sulfonamide has proven to be an extremely efficient catalyst for this type of reaction (258). This cycloaddition is useful for preparing optically active prostaglandin intermediates. Cationic bis(oxazoline)-Fe(III) catalysts that form octahedral chelate complexes with dienophiles promote enantioselective reaction with cyclopentadiene (259). The Mg complexes are equally effective. 

This review continues from one entitled The Chemistry of a,P-Unsaturated Sulfoxides which was recently published in a monograph of organosulfur chemistry. 1 In addition, the coverage has been extended to include the analogous a,P-unsaturated sulfones. The focus of the present review are recent advances in the chemistry of a,P-unsaturated sulfoxides and sulfones, especially those which have been published since 1993. The synthesis of a,P-unsaturated sulfoxides and sulfones has already been reviewed extensively by Rayner2 and hence will not be covered here. Only the chemistry of vinyl (alkenyl) sulfoxides and sulfones will be considered. The chemistry of other a,P-unsaturated sulfoxides and sulfones such as dienyl, allenyl, and propargyl (alkynyl) sulfoxides and sulfones is beyond the scope of this review. Considerable emphasis has been placed on stereo- and enantioselective reactions, reflecting the current interest in this area. 

In the meantime, the effect of Lewis acid coordination on the inherent conformational preferences adjacent to the carbonyl group should be discussed. In particular, the answer to how is the s-cisis-trans equilibrium of a, -unsaturated carbonyls affected by Lewis acid complexation must enable the exposure of one or the other face of the unsaturated system to a given nucleophile, which will surely be of great importance when dealing with enantioselective reactions. 

In 2008, Zhang, Ying, and co-workers reported an organocatalytic p-amination reaction of a,p-unsaturated aldehydes with nitrosobenzene catalyzed by an NHC. Specifically, the addition of NHC to a,p-unsaturated aldehyde generates a homoenolate intermediate that reacts with nitrosobenzene to afford Af-phenylisoxazolidin-5-ones, followed by an acid-catalyzed esterification and Bamberger-type rearrangement to produce Af-PMP-protected p-amino esters. A preliminary study on the enantioselective reaction of... 

Recently, Chi and coworkers disclosed the formal LUMO activation of a,p-unsaturated esters by NHC catalysis for highly enantioselective reactions with enamides. NHCs D5 and H6 provided best results in terms of the yields and stereoselectivities for lactams 213 and 215 from p-disubstituted and a-substituted esters, respectively (Scheme 20.88). 

In the case of the hydrogenation of 26 the transition state for the oxidative addition of H2 in the unsaturated pathway was computed to be 7.2 kcal/mol less stable than the transition state of the double bond coordination. This value only slightly decreases at 173 K, hence the unsaturated pathway is not interfering with the dihydride route in this case at any temperature. Therefore, the optical yield of the catalytic hydrogenation of 2a catalyzed by 5 is determined solely by the value of AG, which was computed to be virtually the same at 298 K and at 173 K. Although the AG = P in this case is notably higher than computed AG, the computations reliably reproduce R-enantioselective reaction with the optical yield of about 96% ee which is not affected by the temperature changes (see also below). 

The Dy(OTf)3-PyBOX ligand-catalyzed Friedel-Crafts alkylation of indoles with a,/3-unsaturated trifluoromethyl ketones represents the only known example of a highly enantioselective reaction that employs Dy(OTf)3 (eq 14). ... 

In 2009, Hoveyda reported the first metal-free C-B bond formation using an NHC catalyst (Scheme 14.23). The postulated coordination of the carbene to boron in [B(pin)]2 to activate the B-B bond towards electrophiles was validated by Marder, with the isolation of such an intermediate. The initial work on enones was then expanded to the enantioselective reactions with a,p-unsaturated esters, Weinreb amides, aldehydes, and ketones, including p-substituted ones, leading to products with boron-substituted quaternary... 

Chiral imidazolidinones like 20 serve as chiral organocatalysts for the enantioselective reactions of 2-siloxyfuran with a y9-unsaturated aldehydes through oc,fi-unsaturated iminium species (Scheme 3-83)J The Mukaiyama-Michael reaction with nitroolefines provides an access to 1,3-dicarbonyl compounds... 

SCHEME 22.16. Molecular diversity in the enantioselective reactions of (3-keto sulfones with a,p-unsaturated aldehydes. 

The influence of various factors was addressed in the enantioselective reaction catalyzed by La/Na/BINOL (LSB) catalytic systems (Scheme 8.68) [179]. The nature of the aldehyde (aromatic or a,) -unsaturated), substituents in the benzene ring, type of solvent, reaction temperature and substituents in the BINOL ligand were found to effect strongly the outcome of the reaction. The presence of the phenyl groups in 6,6 positions increased e.e., compared to the unsubstituted BINOL, while the present of EtO-group in the 3,3 positions decreased e.e. The... 

The catalytic oxidative carbonylation of allene with PdCb and CuCh in MeOH affords methyl a-methoxymethacrylate (559)[499]. The intramolecular oxidative aminocarbonylation of the 6-aminoallene 560 affords the unsaturated J-amino ester 561. The reaction has been applied to the enantioselective synthesis of pumiliotoxin (562)[500]. A similar intramolecular oxycarbonyla-tion of 6-hydroxyallenes affords 2-(2-tetrahydrofuranyl)acrylates[501]. 

L = P(CH3)3 or CO, oxidatively add arene and alkane carbon—hydrogen bonds (181,182). Catalytic dehydrogenation of alkanes (183) and carbonylation of bensene (184) has also been observed. Iridium compounds have also been shown to catalyse hydrogenation (185) and isomerisation of unsaturated alkanes (186), hydrogen-transfer reactions, and enantioselective hydrogenation of ketones (187) and imines (188). 

One interesting phenomenon was the effect of the boron substituent on enantioselectivity. The stereochemistry of the reaction of a-substituted a,/ -unsatu-rated aldehydes was completely independent of the steric features of the boron substituents, probably because of a preference for the s-trans conformation in the transition state in all cases. On the other hand, the stereochemistry of the reaction of cyclopentadiene with a-unsubstituted a,/ -unsaturated aldehydes was dramatically reversed on altering the structure of the boron substituents, because the stable conformation changed from s-cis to s-trans, resulting in production of the opposite enantiomer. It should be noted that selective cycloadditions of a-unsubsti-tuted a,/ -unsaturated aldehydes are rarer than those of a-substituted a,/ -unsatu-... 

To overcome these problems with the first generation Brmsted acid-assisted chiral Lewis acid 7, Yamamoto and coworkers developed in 1996 a second-generation catalyst 8 containing the 3,5-bis-(trifluoromethyl)phenylboronic acid moiety [10b,d] (Scheme 1.15, 1.16, Table 1.4, 1.5). The catalyst was prepared from a chiral triol containing a chiral binaphthol moiety and 3,5-bis-(trifluoromethyl)phenylboronic acid, with removal of water. This is a practical Diels-Alder catalyst, effective in catalyzing the reaction not only of a-substituted a,/ -unsaturated aldehydes, but also of a-unsubstituted a,/ -unsaturated aldehydes. In each reaction, the adducts were formed in high yields and with excellent enantioselectivity. It also promotes the reaction with less reactive dienophiles such as crotonaldehyde. Less reactive dienes such as isoprene and cyclohexadiene can, moreover, also be successfully employed in reactions with bromoacrolein, methacrolein, and acrolein dienophiles. The chiral ligand was readily recovered (>90%). 

The q cloaddition reaction catalyzed by complex 9d proceeds well for several aromatic and a,/ -unsaturated aldehydes and has been used in an enantioselective route to the carbon-branched pyranose derivative cis-3c (Scheme 4.10) [17]. 

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