Intermolecular asymmetrical

An interesting antibody-catalyzed intermolecular asymmetric 1,3-dipolar cycloaddition reaction between 4-acetamidobenzonitrile N-oxide and N,N-dimethylacrylamide generating the corresponding 5-acylisoxazoline was observed (216). Reversed regioselectivity of nitrile oxide cycloaddition to a terminal alkene was reported in the reaction of 4-A rt-butylbenzonitrile oxide with 6A-acrylamido-6A-deoxy-p-cyclodextrin in aqueous solution, leading to the formation of the 4-substituted isoxazoline, in contrast to the predominance of the 5-substituted regioisomer from reactions of monosubstituted alkenes (217). 

Intramolecular cyclopropanation has a noteworthy advantage. Unlike intermolecular asymmetric cyclopropanation, the intramolecular reaction produces only one diastereomer due to geometric constrains on the fused bicyclic products. Doyle has extensively studied the intramolecular enantioselective reactions of a variety of alkenyl diazoacetates catalyzed by chiral rhodium carboxamides 198 and 200 and has achieved excellent results. 

Palladium-catalyzed arylation of olefins and the analogous alkenylation (Heck reaction) are the useful synthetic methods for carbon-carbon bond formation.60 Although these reactions have been known for over 20 years, it was only in 1989 that the asymmetric Heck reaction was pioneered in independent work by Sato et al.60d and Carpenter et al.61 These scientists demonstrated that intramolecular cyclization of an alkenyl iodide or triflate yielded chiral cyclic compounds with approximately 45% ee. The first example of the intermolecular asymmetric Heck reaction was reported by Ozawa et al.60c Under appropriate conditions, the major product was obtained in over 96% ee for a variety of aryl triflates.62... 

Mur 207), has received renewed interest in recent years. A fine review covering the intermolecular asymmetric Diels-Alder reaction was compiled by Mori 208>. In this article the use of terpenes and carbohydrates as chiral auxiliaries is discussed no amino acid derivatives are mentioned in this context. A chiral a-hydroxycarboxylic acid derivative was also used to achieve an asymmetric Diels-Alder reaction 209). High asymmetric induction could be detected in the intramolecular Diels-Alder reaction of chiral molecules. 

This method is particularly effective with cyclic substrates, and the combined effects of intramolecular and intermolecular asymmetric induction give up to 76 1 (kf/ks) differentiation between enantiomers of a cyclic allylic alcohol. This kinetic resolution provides a practical method to resolve 4-hydroxy-2-cyclopentenone, a readily available but sensitive compound. Hydrogenation of the racemic compound at 4 atm H2 proceeds with kf/ks =11, and, at 68% conversion, gives the slow-reacting R enantiomer in 98% ee. The alcoholic product is readily convertible to its crystalline, enantiomerically pure fert-butyldimethylsilyl ether, an important building block in the three-component coupling synthesis of prostaglandins (67). 

AMI calculations have been used to explain the regioselectivities of the intermolecular asymmetric 1,3-dipolar cycloadditions of 2,2-dimethyl-3,4-dihydro-2//-pyrrolc N-oxides with chiral a, /J-unsatu rated esters.96 MO calculations have shown that only in-plane aromaticity is operating in transition structures+associated with the... 

In addition to the many intermolecular asymmetric (organo)catalytic aldol reactions, analogous intramolecular syntheses are also possible. In this connection it is worthy of note that the first example of an asymmetric catalytic aldol reaction was an intramolecular reaction using an organic molecule, L-proline, as chiral catalyst. This reaction - which will be discussed in more detail below - is the so-called Hajos-Parrish-Eder-Sauer-Wiechert reaction [97-101], which was discovered as early as the beginning of the 1970s. 

There seems to be one example only of a catalytic intermolecular asymmetric Stetter reaction. As shown in Scheme 6.107, Enders reported that the thiazolium cation 243 afforded a moderate enantiomeric excess in the coupling of w-butanal with F-chalcone to give the 1,4-diketone 244 [257]. 

Scheme 1. The direct intermolecular asymmetric aldol reaction using L-proline.

Scheme 2. Further L-proline-catalyzed intermolecular asymmetric aldol reactions.

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). 

Intermolecular asymmetric aminations are at an early stage of development, and consequently much lower turnover frequencies and catalytic yields have been observed at this stage. In the example shown, a key aspect is the activation of the iridium complex catalyst by fluoride ion [111] (Scheme 38). 

In contrast to the number of intramolecular asymmetric hydrogen abstraction reactions using supramolecular approaches (Sec. IV.D.), intermolecular asymmetric hydrogen abstraction reactions have been scarcely reported. Only two examples are presented these occur in inclusion crystals of deoxycholic acid with ketones and crystals of cyclodextrin with acetophenone. 

The BINAP-Ru-catalyzed hydrogenation of the allylic alcohol 94 results in the diastereoselective formation of 95, an intermediate for 1/9-methylcarbapenems (96) possessing an improved stability toward dehydropeptidase (Scheme 28). The combined effects of tbe intermolecular asymmetric induction caused by the (/ )-Tol-BINAP-Ru catalyst (Tol-BINAP = p-tolyl analog of BINAP) and the intramolecular asymmetric induction originating from the pre-existing chiral moiety in the substrate 94 cooperate in the generation of the extremely high diastereos-electivity, /5 a = 99.9 0.1, to form the y8-methylated isomer 96 [87]. 

For intermolecular asymmetric Heck reaction between aryl triflates and 2,3-dihydrofuran the hindered diphosphine 1 is superior to BINAP. Improved enantioselectivity is due to the bulky f-butyl substituents to create a more ideal chiral pocket in the metal complexes. 

One of the most studied processes is the direct intermolecular asymmetric aldol condensation catalysed by proline and primary amines, which generally uses DMSO as solvent. The same reaction has been demonstrated to also occur using mechanochemical techniques, under solvent-free ball-milling conditions. This chemistry is generally referred to as enamine catalysis , since the electrophilic substitution reactions in the a-position of carbonyl compounds occur via enamine intermediates, as outlined in the catalytic cycle shown in Scheme 1.1. A ketone or an a-branched aldehyde, the donor carbonyl compound, is the enamine precursor and an aromatic aldehyde, the acceptor carbonyl compound, acts as the electrophile. Scheme 1.1 shows the TS for the ratedetermining enamine addition step, which is critical for the achievement of enantiocontrol, as calculated by Houk. ... 

While no catalytic intermolecular asymmetric hydroamination of allenes has... 

The intermolecular asymmetric Heck reaction, a palladium-catalysed carbon-carbon bond forming process, is an efficient method for the preparation of optically active cyclic compounds.[1] Very recently, a new catalytic system has been developed based on palladium complexes having l-[4-(5)-tert-butyl-2-oxazolin-2-yl]-2-(5)-(diphenylphosphino)ferrocene (1) as the chiral ligand121 (Figure 5.2), which we have shown to be efficient catalysts for the enantioselective intermolecular Heck reaction of 2,3-dihydrofuran (2).[3] In contrast to complexes derived... 

Hennessy, A.J., Malone, Y.M. and Guiry, PJ. (1999) 2,2-Dimethyl-2,3-dihydrofuran, a new substrate for intermolecular asymmetric Heck reactions. Tetrahedron Letters, 40, 9163-9166 Hennessy, A.J., Malone, Y.M. and Guiry, P.J. (2000) The asymmetric cyclohexenylation of 2,2-dimethyl-2,3-dihydrofuran. Tetrahedron Letters, 41,2261-2264 Hennessy, A.J., Connolly, D.J., Malone, Y.M. and Guiry, PJ. (2000) Intermolecular asymmetric Heck reactions with 2,2-diethyl-2,3-dihydrofuran. Tetrahedron Letters, 41, 7757-7761. 

After the seminal reports on the intramolecular and intermolecular asymmetric aldol addition using trans-4-f-butyl-diphenyl-sililo y proline, (2S,4R)-4-hydro y-proline trans-4) has become one of the most used starting material for introducing different substituents on the proline scaffold, in such a way as to modify its properties and activity. The use of trans-4 and its derivatives in asymmetric organocatalysis is reviewed in Chapter 10 and will not be discussed here. 

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