Insertion reactions enantioselective, carbenes

In an exciting new challenge the Bristol-Myers-Squibb group carried out an ACP on a 100-kg scale with a chiral Ru Pybox catalyst, especially in two-phase media of water and ferf-butyl methyl ether (Scheme 5) [35]. The operations produced good yields and enantioselectivity,but separation was difficult. Similarly, Wurz and Charette [36] demonstrated ACP in aqueous media by using Ru, Rh, and Co catalysts including an O-H insertion reaction of carbenes. 

Chapter 10 considers the role of reactive intermediates—carbocations, carbenes, and radicals—in synthesis. The carbocation reactions covered include the carbonyl-ene reaction, polyolefin cyclization, and carbocation rearrangements. In the carbene section, addition (cyclopropanation) and insertion reactions are emphasized. Recent development of catalysts that provide both selectivity and enantioselectivity are discussed, and both intermolecular and intramolecular (cyclization) addition reactions of radicals are dealt with. The use of atom transfer steps and tandem sequences in synthesis is also illustrated. 

As shown in the previous two sections, rhodium(n) dimers are superior catalysts for metal carbene C-H insertion reactions. For nitrene C-H insertion reactions, many catalysts found to be effective for carbene transfer are also effective for these reactions. Particularly, Rh2(OAc)4 has demonstrated great effectiveness in the inter- and intramolecular nitrene C-H insertions. The exploration of enantioselective C-H amination using chiral rhodium catalysts has been reported by several groups.225,244,253-255 Hashimoto s dirhodium tetrakis[A-tetrachlorophthaloyl-(A)-/ r/-leuci-nate], Rh2(derived rhodium complex, Rh2(i -BNP)4 48,244 afforded moderate enantiomeric excess for amidation of benzylic C-H bonds with NsN=IPh. 

Few examples of preparatively useful intermolecular C-H insertions of electrophilic carbene complexes have been reported. Because of the high reactivity of complexes capable of inserting into C-H bonds, the intermolecular reaction is limited to simple substrates (Table 4.9). From the results reported to date it seems that cycloalkanes and electron-rich heteroaromatics are suitable substrates for intermolecular alkylation by carbene complexes [1165]. The examples in Table 4.9 show that intermolecular C-H insertion enables highly convergent syntheses. Elaborate structures can be constructed in a single step from readily available starting materials. Enantioselective, intermolecular C-H insertions with simple cycloalkenes can be realized with up to 93% ee by use of enantiomerically pure rhodium(II) carboxylates [1093]. 

Recent editions of Organic Reaction Mechanisms have highlighted a number of carbene and nitrene CH-insertion reactions. This field has now been reviewed with a focus on enantioselective reactions catalysed typically by dirhodium species.5 The use of C2-symmetric box ligands in asymmetric cyclopropanation reactions has been discussed in the context of a wider review of these ligands as a source of asymmetry.6... 

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. 

Metal Carbene TVansformations. The effectiveness of Rh2(55 -MEPY)4 and its 5R-form, Rh2 5R-MEPY)4, is exceptional for highly enantioselective intramolecular cyclopropanation and carbon-hydrogen insertion reactions. Intermolecular cyclopropanation occurs with lower enantiomeric excesses than with alternative chiral copper salicylaldimine or C2-symmetric semicorrin or bis-oxazoline copper catalysts, but intermolecular cyclopropenation exhibits higher enantio-control with Rh2(MEPY)4 catalysts. The methyl carboxylate attachment of Rh2(55-MEPY)4 is far more effective than steri-cally similar benzyl or isopropyl attachments for enantioselective metal carbene transformations. The significant enhancement in enantiocontrol is believed to be due to carboxylate carbonyl stabilization of the intermediate metal carbene and/or to dipolar influences on substrate approach to the carbene center. 

One important advantage of the intermolecular carbene insertion reactions is that simple starting materials can be employed and accordingly there is no need for the construction of complex substrates in advance. However, the intermolecular process requires a delicate balance between electronic and steric effects for metal carbenoids. On the other hand, there are several obstacles to be overcome, including chemo-, regio-, and enantioselectivity. Fortunately, great efforts have been devoted in the past decade and a series of carbene precursors and chiral Rh catalysts have been developed, so satisfactory yields and ee can be obtained in some catalytic systems. Generally, suitable carbene precursors, such as donor/acceptor diazo compounds, could reduce the chance of side product formation due to carbene dimerization. 

Apart from the utilization of aryl- and vinyl-diazoacetates that can achieve the moderate to high chemo-, regio-, and enantioselectivity in intermolecular asymmetric C—H bond insertion reactions, Af-sulfonyl-l,2,3-triazole 11 was found to be able to function as an alternative carbene precursor for diverse transformations (Scheme 1.4). One advantage for using the N-sulfonyl-1,2,3-triazole is that it could be easily prepared by the Cu -catalyzed azide-alkyne cycloaddition (CuAAC) reaction, and in some cases, delicately designed reactions can be conducted in a one-pot procedure starting from alkynes and sulfonyl azides. Moreover, since there exists an inherent equilibrium... 

With regard to 1,4-eyelohexadiene (Table 1.8), all these above groups realized the intermoleeular C—H bond insertion reaction with the Ir-carbenoids derived from a-diazo esters 88 to achieve the corresponding adducts 89 in excellent yields and enantioselectivity. It is worth noting that, in Katsuki s work, the methyl a-diazopropionate (88, R = Me) was recognized as a feasible metallo-carbene precursor in this reaction. Historically, intermolecular reactions with... 

Certain dinuclear Rh(II) carbene complexes react with alkanes to generate products from insertion of the carbene imit into the alkane C-H bond with high diastereo- and enantioselectivity (Equation 6.59). ° These reactions occur by mechanisms distinct from those of the reactions of C-H bonds witti the tungsten alkylidene and alkylid5me complexes just described. The reactions of the dinuclear Rh(II) carbene complexes appear to occur by a mechanism that involves direct reaction of the carbene at the C-H bond without coordination of the alkane and addition across the M=C bond of the carbene. Such rhodium carbene complexes have not been isolated, but the absence of an open coordination site cis to the carbene ligand in the accepted carbene intermediate is thought to preclude initial reaction of tire substrate at the metal center to form a new metal-carbon bond. The catalytic chemistry that occurs via these carbene complexes is presented in more detail in Chapter 18 (catalytic C-H bond functionalization). 

In the area of carbocyclic nucleoside antibiotics, hydrolysis of the racemic esters 40 (R= n-Bu or ii-CeHis) by the lipase from Candida rugosa proceeds with very high enantiomeric selectivity, and from the resolved materials both enantiomers of aristeromydn were made by an established route. The authors report that a previous similar method (Vol.21, p. 182) is not as enantioselective. In a new synthesis of neplanocin A (43), the alcohol 41, derived from D-ribose, was converted to the cyclopentene 42 using an intramolecular insertion reaction of an alkylidene carbene. The new stereocentre in 42 was mostly of the wrong P-configuration, but could be corrected by a process of desilylation, oxidation and borohydride reduction. The biosynthesis of neplanocin A (43) and aristero-mycin has been reinvestigated, and the cyclopentenone 44 has been proposed as an intermediate, which is converted to aristeromycin via neplanocin A without any bifurcation. The 3-deaza-analogue 45 of 5 - or-aristeromydn has been prepared, and the antiviral activity of it and of the 7-deaza-compound (Vol.27, p. 235) are reported. ... 

Many rhodium(II) complexes are excellent catalysts for metal-carbenoid-mediated enantioselective C-H insertion reactions [101]. In 2002, computational studies by Nakamura and co-workers suggested the dirhodium tetracarboxylate catalyzed diazo compounds insertion reaction to alkanes C-H bonds proceed through a three-centered hydride-transfer-like transition state (Fig. 25) [102]. Only one rhodium atom of the catalyst is involved in the formation of rhodium carbene intermediate, while the other rhodium atom served as a mobile ligand, which enhanced the electrophilicity of the first one and facilitate the cleavage of rhodium-carbon bond. In this case, the metal-metal bond constitutes a special example of Lewis acid activation of Lewis acidic transition-metal catalyst. 

An alternative organometallic approach for functionalizing C-H bonds is by means of metal carbene- or metal nitrene-induced C-H insertions (Equations (1) and (2)).35 36 A major advantage of this approach over other methods is that the reaction is routinely catalytic and by using chiral catalysts, high enantioselectivity can be achieved. One of the major challenges with the metal carbene- and metal nitrene-induced C-H insertion is controlling the... 

The most spectacular application of the donor/acceptor-substituted carbenoids has been intermolecular C-H activation by means of carbenoid-induced C-H insertion [17]. Prior to the development of the donor/acceptor carbenoids, the intermolecular C-H insertion was not considered synthetically useful [5]. Since these carbenoid intermediates were not sufficiently selective and they were very prone to carbene dimerization, intramolecular reactions were required in order to control the chemistry effectively [17]. The enhanced chemoselectivity of the donor/acceptor-substituted carbenoids has enabled intermolecular C-H insertion to become a very practical enantioselective method for C-H activation. Since the initial report in 1997 [121], the field of intermolecular enantioselective C-H insertion has undergone explosive growth [14, 15]. Excellent levels of asymmetric induction are obtained when these carbenoids are derived... 

So what is left to be accomplished During the current decade one can expect further asymmetric applications and catalyst designs for metathesis reactions, a maturing of chiral catalyst development for cyclopropanation and insertion with increasing synthetic applications, and decreased reliance on traditional Fischer carbenes in synthesis. Major changes remain for ylide applications, especially those that can be enantioselective, in catalytic carbene chemistry, and advances in nitrene chemistry that are comparable to those achieved over the years in carbene chemistry are in their infancy. 

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