Intramolecular chiral catalysts

The chiral catalyst 142 achieves selectivities through a double effect of intramolecular hydrogen binding interaction and attractive tt-tt donor-acceptor interactions in the transition state by a hydroxy aromatic group [88]. The exceptional results of some Diels-Alder reactions of cyclopentadiene with substituted acroleins catalyzed by (R)-142 are reported in Table 4.21. High enantio- and exo selectivity were always obtained. The coordination of a proton to the 2-hydroxyphenyl group with an oxygen of the adjacent B-0 bond in the nonhelical transition state should play an important role both in the exo-endo approach and in the si-re face differentiation of dienophile. 

Keywords carbonyl compounds, chiral dienophiles, chiral dienes, chiral catalysts, intramolecular cycloadditions, chiral Lewis acids... 

Aldol addition and related reactions of enolates and enolate equivalents are the subject of the first part of Chapter 2. These reactions provide powerful methods for controlling the stereochemistry in reactions that form hydroxyl- and methyl-substituted structures, such as those found in many antibiotics. We will see how the choice of the nucleophile, the other reagents (such as Lewis acids), and adjustment of reaction conditions can be used to control stereochemistry. We discuss the role of open, cyclic, and chelated transition structures in determining stereochemistry, and will also see how chiral auxiliaries and chiral catalysts can control the enantiose-lectivity of these reactions. Intramolecular aldol reactions, including the Robinson annulation are discussed. Other reactions included in Chapter 2 include Mannich, carbon acylation, and olefination reactions. The reactivity of other carbon nucleophiles including phosphonium ylides, phosphonate carbanions, sulfone anions, sulfonium ylides, and sulfoxonium ylides are also considered. 

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. 

LA represents Lewis acid in the catalyst, and M represents Bren sled base. In Scheme 8-49, Bronsted base functionality in the hetero-bimetalic chiral catalyst I can deprotonate a ketone to produce the corresponding enolate II, while at the same time the Lewis acid functionality activates an aldehyde to give intermediate III. Intramolecular aldol reaction then proceeds in a chelation-controlled manner to give //-keto metal alkoxide IV. Proton exchange between the metal alkoxide moiety and an aromatic hydroxy proton or an a-proton of a ketone leads to the production of an optically active aldol product and the regeneration of the catalyst I, thus finishing the catalytic cycle. 

Our initial objective, in this investigation, had been to design a useful chiral auxihary. We were pleased to find that naphthylborneol 31, upon optimization of the catalyst and the reaction temperature, served effectively. Until useful chiral catalysts are developed, naphthylborneol 31 will be of significant practical value for directing the absolute course of cyclopentane construction by rhodium-mediated intramolecular C-H insertion. 

Intramolecular rhodium-catalyzed carbamate C-H insertion has broad utility for substrates fashioned from most 1° and 3° alcohols. As is typically observed, 3° and benzylic C-H bonds are favored over other C-H centers for amination of this type. Stereospecific oxidation of optically pure 3° units greatly facilitates the preparation of enantiomeric tetrasubstituted carbinolamines, and should find future applications in synthesis vide infra). Importantly, use of PhI(OAc)2 as a terminal oxidant for this process has enabled reactions with a class of starting materials (that is, 1° carbamates) for which iminoiodi-nane synthesis has not proven possible. Thus, by obviating the need for such reagents, substrate scope for this process and related aziridination reactions is significantly expanded vide infra). Looking forward, the versatility of this method for C-N bond formation will be advanced further with the advent of chiral catalysts for diastero- and enantio-controlled C-H insertion. In addition, new catalysts may increase the range of 2° alkanol-based carbamates that perform as viable substrates for this process. 

Chiral catalysts (see Section 6.1.4) can also achieve enantioselectivity in intramolecular Diels-Alder reactions. 

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. 

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. 

Intramolecular C-H insertions of aryldiazoacetates have been effectively achieved with high asymmetric induction by using either Rh2(S-DOSP)4[13] or Rh2(S-PTLL)4[14] as catalyst. An impressive recent example is a key step (18 to 19) in the synthesis of (-)-ephedradine A (20) (Scheme 8) [15]. In this particular case, a double stereodifferentiation with a chiral catalyst and auxiliary gave the best asymmetric induction. 

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. 

A Lewis-acid-mediated intramolecular cyclization of allenyl stannane 344 furnishes 2,6- //-tetrahydropyran as the major product, the stereochemistry of which can be switched to syn with moderate effect if a propargylstannane 345 is used as a substrate (Equation 147, Table 16) <1996TL3059>. The stereoselectivity observed in an analogous system, the intramolecular cyclization of y-alkoxyallyl stannanes 346 with a tethered aldehyde, can be controlled by changing the geometry of the alkene (Scheme 83) <1997JOC7439>. y-Alkoxyallyl stannanes are also known to cyclize both diastereoselectively and enantioselectivity, by incorporation of both a chiral auxiliary and a chiral catalyst respectively into the reaction <1999JOC4901>. 

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). 

Several iodonium ylides, thermally or photochemically, transferred their carbene moiety to alkenes which were converted into cyclopropane derivatives. The thermal decomposition of ylides was usually catalysed by copper or rhodium salts and was most efficient in intramolecular cyclopropanation. Reactions of PhI=C(C02Me)2 with styrenes, allylbenzene and phenylacetylene have established the intermediacy of carbenes in the presence of a chiral catalyst, intramolecular cyclopropanation resulted in the preparation of a product in 67% enantiomeric excess [12]. 

Aillaud, I., Lyubov, D., Collin, J. et al. (2008) Chiral amido alkyl rare earth complexes a new family of asymmetric intramolecular hydroamination catalysts. Organometallics, 27, 5929. 

An example of intramolecular [2 + 2] cycloaddition of a 1,6-diene 172 catalyzed by Cu(I) in the synthesis of grandisol is shown in Sch. 40 [78]. The bicycloheptanes can be prepared selectively by starting with chiral starting material, chiral catalysts or chiral auxiliaries. The reactions with chiral copper Lewis acids gave very poor selectivity (< 5 %ee). 

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