Intermolecular chiral catalysts

The rhodium-catalyzed tandem carbonyl ylide formation/l,3-dipolar cycloaddition is an exciting new area that has evolved during the past 3 years and high se-lectivities of >90% ee was obtained for both intra- and intermolecular reactions with low loadings of the chiral catalyst. 

As described hitherto, diastereoselectivity is controlled by the stereogenic center present in the starting material (intramolecular chiral induction). If these chiral substrates are hydrogenated with a chiral catalyst, which exerts chiral induction intermolecularly, then the hydrogenation stereoselectivity will be controlled both by the substrate (substrate-controlled) and by the chiral catalyst (catalyst-controlled). On occasion, this will amplify the stereoselectivity, or suppress the selectivity, and is termed double stereo-differentiation or double asymmetric induction [68]. If the directions of substrate-control and catalyst-control are the same this is a matched pair, but if the directions of the two types of control are opposite then it is a mismatched pair. 

The development of catalytic asymmetric reactions is one of the major areas of research in the field of organic chemistry. So far, a number of chiral catalysts have been reported, and some of them have exhibited a much higher catalytic efficiency than enzymes, which are natural catalysts.111 Most of the synthetic asymmetric catalysts, however, show limited activity in terms of either enantioselectivity or chemical yields. The major difference between synthetic asymmetric catalysts and enzymes is that the former activate only one side of the substrate in an intermolecular reaction, whereas the latter can not only activate both sides of the substrate but can also control the orientation of the substrate. If this kind of synergistic cooperation can be realized in synthetic asymmetric catalysis, the concept will open up a new field in asymmetric synthesis, and a wide range of applications may well ensure. In this review we would like to discuss two types of asymmetric two-center catalysis promoted by complexes showing Lewis acidity and Bronsted basicity and/or Lewis acidity and Lewis basicity.121... 

If chiral catalysts are used to generate the intermediate oxonium ylides, non-racemic C-O bond insertion products can be obtained [1265,1266]. Reactions of electrophilic carbene complexes with ethers can also lead to the formation of radical-derived products [1135,1259], an observation consistent with a homolysis-recombination mechanism for 1,2-alkyl shifts. Carbene C-H insertion and hydride abstraction can efficiently compete with oxonium ylide formation. Unlike free car-benes [1267,1268] acceptor-substituted carbene complexes react intermolecularly with aliphatic ethers, mainly yielding products resulting from C-H insertion into the oxygen-bound methylene groups [1071,1093]. 

A variety of chiral catalysts have been evaluated in intermolecular cyclopropanations of donor/acceptor carbenoid systems, but few come close to the levels of asymmetric induchon furnished by the prolinate catalysts [11, 37, 38, 40, 49]. The only system that... 

In summary, the chemistry of the donor/acceptor-substituted carbenoids represents a new avenue of research for metal-catalyzed decomposition of diazo compounds. The resulting carbenoids are more chemoselective than the conventional carbenoids, which allows reactions to be achieved that were previously inaccessible. The discovery of pan-tolactone as an effective chiral auxiliary, and rhodium prolinates as exceptional chiral catalysts for this class of rhodium-carbenoid intermediate, broadens the synthetic utility of this chemistry. The successful development of the asymmetric intermolecular C-H activation process underscores the potential of this class of carbenoids for organic synthesis. 

Oxidative amination of carbamates, sulfamates, and sulfonamides has broad utility for the preparation of value-added heterocyclic structures. Both dimeric rhodium complexes and ruthenium porphyrins are effective catalysts for saturated C-H bond functionalization, affording products in high yields and with excellent chemo-, regio-, and diastereocontrol. Initial efforts to develop these methods into practical asymmetric processes give promise that such achievements will someday be realized. Alkene aziridina-tion using sulfamates and sulfonamides has witnessed dramatic improvement with the advent of protocols that obviate use of capricious iminoiodinanes. Complexes of rhodium, ruthenium, and copper all enjoy application in this context and will continue to evolve as both achiral and chiral catalysts for aziridine synthesis. The invention of new methods for the selective and efficient intermolecular amination of saturated C-H bonds still stands, however, as one of the great challenges. 

The inclusion of a separate chapter on catalysed cyclopropanation in this latest volume of the series is indicative of the very high level of activity in the area of metal catalysed reactions of diazo compounds. Excellent, reproducible catalytic systems, based mainly on rhodium, copper or palladium, are now readily available for cyclopropanation of a wide variety of alkenes. Both intermolecular and intramolecular reactions have been explored extensively in the synthesis of novel cyclopropanes including natural products. Major advances have been made in both regiocontrol and stereocontrol, the latter leading to the growing use of chiral catalysts for producing enantiopure cyclopropane derivatives. 

A vast array of chiral catalysts have been developed for the enantioselective reactions of diazo compounds but the majority has been applied to asymmetric cyclopropanations of alkyl diazoacetates [2]. Prominent catalysts for asymmetric intermolecular C-H insertions are the dirhodium tetraprolinate catalysts, Rh2(S-TBSP)4 (la) and Rh2(S-DOSP)4 (lb), and the bridged analogue Rh2(S-biDOSP)2 (2) [7] (Fig. 1). A related prolinate catalyst is the amide 3 [8]. Another catalyst that has been occasionally used in intermolecular C-H activations is Rh2(S-MEPY)4 (4) [9], The most notable catalysts that have been used in enantioselective ylide transformations are the valine derivative, Rh2(S-BPTV)4 (5) [10], and the binaphthylphosphate catalysts, Rh2(R-BNP)4 (6a) and Rh2(R-DDNP)4 (6b) [11]. All of the catalysts tend to be very active in the decomposition of diazo compounds and generally, carbenoid reactions are conducted with 1 mol % or less of catalyst loading [1-3]. 

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. 

The intermolecular C-H insertion on N-Boc-piperidine leads to the rapid access of the pharmaceutical agent threo-methylphenidate (30) [26], As this reaction is of commercial interest, a range of chiral catalysts have been examined [26], The best enantioselectivity was obtained with Rh2(S-biDOSP)2, which is a bridged second generation analog of Rh2(S-DOSP)4 [26a, b]. 

In summary, the C-H insertion chemistry of rhodium carbenoids is a very powerful method for transformation of C-H bonds. Highly regioselective and stereoselective reactions are possible and several classes of chiral catalyst are capable of very high asymmetric induction. The chemoselectivity in this chemistry is exceptional, as illustrated by the numerous intermolecular and intramolecular reactions described in this overview. Most notably, this chemistry offers new and practical strategies for enantioselective synthesis of a variety of natural products and pharmaceutical agents. 

Dirhodium(II) tetrakis(carboxamides), constructed with chiral 2-pyrroli-done-5-carboxylate esters so that the two nitrogen donor atoms on each rhodium are in a cis arrangement, represent a new class of chiral catalysts with broad applicability to enantioselective metal carbene transformations. Enantiomeric excesses greater than 90% have been achieved in intramolecular cyclopropanation reactions of allyl diazoacetates. In intermolecular cyclopropanation reactions with monosubsti-tuted olefins, the cis-disubstituted cyclopropane is formed with a higher enantiomeric excess than the trans isomer, and for cyclopropenation of 1-alkynes extraordinary selectivity has been achieved. Carbon-hydro-gen insertion reactions of diazoacetate esters that result in substituted y-butyrolactones occur in high yield and with enantiomeric excess as high as 90% with the use of these catalysts. Their design affords stabilization of the intermediate metal carbene and orientation of the carbene substituents for selectivity enhancement. 

A-Cu,N-Co, and P-Cu to carbenoid transformations have been limited to intermolecular reactions, for which they remain superior to chiral dirhodium(II) catalysts for intermolecular cyclopropanation reactions. Few examples other than those recently reported by Dauben and coworkers (eq 1) (35) portray the effectiveness of these chiral catalysts for enantioseleetive intramolecular cyclopropanation reactions, and these examples demonstrate their limitations. However, with Rh2(5S-MEPY)4 intramolecular cyclopropanation of 3-methyl-2-buten-1 -yl diazoacetate (eq 2) occurs in high yield and with 92% enantiomeric excess (36). 

Only very few reactions of this type have been reported in the literature. All of them are intermolecular in nature, and only carbonyl groups have thus far successfully served as EWGs attached to the C—C double bond. Of course, a chiral medium, preferably a chiral catalyst, is required to render the addition reaction stereoselective. Enzymes have been used for this purpose. 

In rhodium(II)-catalyzed intermolecular cyclopropanation reactions, chiral dirhodium(II) carb-oximidates provide only limited enantiocontrol. " Tetrakis(5-methoxycarbonyl-2-pyrrolidonato)dirhodium [18, Rh2(MEPY)J, in both enantiomeric forms of the carboxamide ligands, produces the highest enantioselectivities. As can be seen for the cyclopropanation of styrene with diazoacetates, a high level of double diastereoselectivity results from the combination of this chiral catalyst with /- or d-menthyl diazoacetate, but not with diazoacetates bearing other chiral residues.In terms of trans/cis selectivity and enantioselectivity for styrene giving 19 this catalyst is comparable to the Aratani catalysts, but they cannot match the high enantiocontrol of the chiral copper catalysts developed by Pfaltz, Masamune, and Evans vide supra). 

As already mentioned, there has been significant progress in the development of chiral catalysts for asymmetric hydroamination reactions over the last decade. However, significant challenges remain, such as asymmetric intermolecular hydro aminations of simple nonactivated alkenes and the development of a chiral catalyst, which is applicable to a wide variety of substrates with consistent high stereochemical induction and tolerance of a multitude of functional groups as well as air and moisture. Certainly, late transition metal based catalysts show promising leads that could fill this void, but to date, early transition metal based catalysts (in particular, rare earth metals) remain the most active and most versatile catalyst systems. 

In conclusion, the ruthenium complexes are the best chiral catalysts developed so far with metals other than Cu and Rh. Excellent diastereo- and enanti-oselectivities were observed with some specific systems, but the scope of the intermolecular reaction is somewhat limited. 

In 2002, Huang and Rawal found that the hetero Diels-Alder reaction of aminosiloxydienes with aldehydes was accelerated in alcoholic solvents [65], They subsequently elucidated that TADDOL (19) is an efficient chiral catalyst for the hetero-Diels-Alder reaction (Figure 10.17, Equation 10.33) [66]. The internal hydrogen bond in TADDOL observed in its crystal structure is expected to render the hydroxy proton more acidic, hence enabling it to participate better in intermolecular hydrogen bonding with the carbonyl group of the dienophile [67]. The Mukaiyama aldol reaction was also reported [68]. 

It is the primary aim of the present work to provide a concise analysis of the stereochemical features of transition states in a variety of reaction types. These control elements are only partly understood at present, but as the intra- and intermolecular forces that govern transition state assemblies come further into focus, the principles outlined in this book will be refined and improved. The ultimate (attainable ) goal is clear the production of any relative and absolute configuration of one or more stereogenic units through the use of chiral catalysts that do not require consideration of chirality elements extant in the substrate. 

However, these results could not be generalized for intermolecular [4 - - 2] cycloadditions (Scheme 7.6) [9]. 25 was formed in 38 % ee at normal pressure from isoprene (23) and the oxazolidone 24, while the enantioselectivity decreased at 5 kbar to only 21 % ee. Nevertheless, this study revealed another important factor that has to be taken into account for metal-catalyzed reactions under pressure. It was argued that the decreased selectivity may in part be due to a shift of the chiral catalyst 28 to the achiral catalyst precursor 26 induced by pressure, since this... 

Since its discovery over sixty years ago [1] the Diels-Alder reaction has lost none of its attraction. [2, 3] It enables, in a one-step inter- or intramolecular reaction, the rapid preparation of cyclic compounds having a six-membered ring. During the course of the [4 -I- 2] cycloaddition four new stereocenters can be introduced directly, and their stereo-control is a topic of major interest in modem synthetic chemistry. [4-6] In addition, in intermolecular reactions, the relative positions of the reaction partners (regiochemistry) must be taken into account. If a concerted reaction is assumed, both a cis addition (suprafacial mode) and a preferred endo orientation (Alder rules) can be expected. But how can the absolute configuration of the desired product be controlled There are three basic possibilities the use of a chirally modified diene, a chirally modified dienophile, or a chiral catalyst. Although the first successes resulted from the attractive, hut difficult, catalytic route, [4b, 7] the majority of the investigators are concerned with the stoichiometric... 

The fundamental principles of asymmetric synthesis employed throughout also apply to ene reactions. Chiral additives, chiral auxiliaries, and the preparation of chirons all lead to good enantioselectivity when applied to the ene reactions. Most chiral ene reactions seem to involve addition of a chiral catalyst or the use of a chiral auxiliary. Oppolzer et al. utilized a chiral auxiliary in 713 to prepare 714 (90 % de) in a synthesis of (+)-a-allokainic acid.515 Yamamoto used the chiral aluminum catalyst 715 for the intermolecular ene reaction of 1,6-dichlorobenzaldehyde and 2-phenylthio-l-propene to give 716 in 96% yield (65 % ee).5i6 These catalysts are similar to those used in Section 11.9.B. A similar titanium catalyst (717) was used to couple methylenecyclohexane and methyl glyoxalate, giving 89% of 718 (98 % ee). The titanium catalyst... 

As a different type of amination, the intermolecular hydroamination of nor-bornene with aniline was carried out with preformed Ir complexes 29 and 30 bearing bidentate ACTC ligands [15]. As it is commonly the case for the generation of such complexes, the catalyst precursors were isolated as an inseparable mixture of the respective cis- and trans-isomers. At 60 °C, only traces of the desired hydroamination product could be detected, and moderate enantioselectiv-ities of 51 and 70% ee were determined for catalysts derived from the cyclohexyl derivative 29 and the ferf-butyl derivative 30, respectively. Still, a significant improvement in rate is required to transform the present chiral catalyst system into a truly useful synthesis. 

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). 

Mechanistically related to the Mukaiyama aldol reaction, the carbonyl ene reaction is the reaction between an alkene bearing an allylic hydrogen and a carbonyl compound, to afford homoallylic alcohols. This reaction is potentially 100% atom efficient, and should be a valuable alternative to the addition of organometallic species to carbonyl substrates. However, the carbonyl ene reaction is of limited substrate scope and works generally well in an intermolecular manner only with activated substrates, typically 1,1-disubstituted alkenes and electron-deficient aldehydes (glyoxylate esters, fluoral, a,p-unsaturated aldehydes, etc.), in the presence of Lewis acids. The first use of chiral catalyst for asymmetric carbonyl ene was presented by Mikami et al. in 1989. ° By using a catalytic amount of titanium complexes prepared in situ from a 1 1 ratio of (rPrO)2titaniumX2 (X = Cl or Br) and optically pure BINOL, the homoallylic alcohols 70a,b were obtained in... 

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