Stereoselectivity C -H insertion

The seemingly limited number of available methods to access cyclopropanes by standard transformations in the laboratory are a result of the inherent ring strain of these systems. The fact that carbenes are intrinsically high-energy species renders them unique in the construction of numerous natural and nonnatural products that include cyclopropanes (Sections 15.2-15.5). However, there have been recent developments in methods that provide access to cyclopropanes via alternative intermediates and mechanistic pathways that are strikingly efficient (Section 15.6). Additionally, carbene and carbenoid intermediates have been reported to partake in a variety of stereoselective C-H insertions (Sections 15.7-15.8). 

A key observation by Wenkert proved vital in the subsequent popularity of rhodium as a highly effective catalyst for the generation of carbenes from diazoketones and their engagement in C-H insertion reactions (Equation 27) [15, 16, 88], In this experiment, treatment of diazoketone 153 with Rh2(OAc)4 led to a stereoselective C-H insertion reaction to generate ketone 154 in 59% yield [88], Importantly, no cyclization was observed in the presence of CuSO,. 

Mioskowski et al. have demonstrated a route to spirocyclopropanes. As an example, treatment of epoxide 100 with n-BuLi in pentane stereoselectively gave tricyclic alcohol 101, albeit in only 47% yield (Scheme 5.21) [29]. With a related substrate, epoxide 102 stereoselectively gave dicydopropane 103 on treatment with PhLi uniquely, the product was isolable after column chromatography in 74% yield [35]. As was also seen with attempts to perform C-H insertion reactions in a non-transannular sense, one should note that steps were taken to minimize the formation of olefin products, either by the use of a base with low nudeophilicity (LTM P) and/or by slow addition of the base to a dilute solution (10-3 m in the case of 102) of the epoxide. 

C—H bond 174-280,28i por comparison, only trace amounts of cyclopentane resulted from the CuS04-catalyzed decomposition of 1 -diazo-2-octanone or l-diazo-4,4-dimethyl-2-pentanone 277). It is obvious that the use of Rh2(OAc)4 considerably extends the scope of transition-metal catalyzed intramolecular C/H insertion, as it allows for the first time, efficient cyelization of ketocarbenoids derived from freely rotating, acyclic diazoketones. This cyelization reaction can also be highly diastereo-selective, as the exclusive formation of a m is-2,3-disubstituted cyclopentane carboxylate from 307 shows281 a). The stereoselection has been rationalized by... 

Using the results of an earlier study concerning enantioselective copper-catalyzed intramolecular C—H insertion of metal carbenoids,109 an interesting system for optimizing the proper combination of ligand, transition metal, and solvent for the reaction of the diazo compound (75) was devised (see Scheme 19).110 The reaction parameters were varied systematically on a standard 96-well microtiter/filtration plate. A total of five different ligands, seven metal precursors, and four solvents were tested in an iterative optimization mode. Standard HPLC was used to monitor stereoselectivity following DDQ-induced oxidation. This type of catalyst search led to the... 

As a tool to improve the regio- and stereoselectivity of C-H insertion, activation of a specific C-H bond of substrates to be inserted seems to be appropriate in conjunction with the manipulation of carbene character. These two tools for the improvement of insertion selectivity will provide us with useful tools of the C-C bond formation by carbenes and carbenoids. 

The combined C-H activation/Cope rearrangement generates a new C-H bond in a highly stereoselective manner and, therefore, has the potential to be a strategic reaction in synthesis. An example of this is the enantiose-lective synthesis of (+)-sertraline as shown in Scheme l.91 The C-H insertion step proceeded smoothly to form 17 with 99% ee. The conversion of 17 to (+)-sertraline could be readily achieved using conventional steps. 

Dihydronaphthalenes are remarkable substrates for the combined C-H activation/Cope rearrangement, but under certain circumstances, further cascade reactions can occur. This was seen in the Rh -DOSP -catalyzed reaction of vinyldiazoacetate 26 with dihydronaphthalene 25 (Equation (35)).96 In this case, the isolated product was the formal C-H insertion product. The reaction proceeded through a combined C-H activation/Cope rearrangement to form 27, followed by the reverse Cope rearrangement. As both steps were highly stereoselective, the formal C-H insertion product 28 was produced with very high stereoselectivity (>98% de, 99.6% ee).96... 

Intramolecular C-H insertion reactions of metal carbenoids have been widely used for the stereoselective construction of substituted lactams, lactones, cyclopentanones, benzofurans, and benzopyrans. Several excellent reviews have been published covering the general aspects of intramolecular C-H insertion by metal carbenoids.46,47 62 71 99-104 The following section highlights the major advances made since 1994, especially in asymmetric intramolecular C-H insertion. 

Recently, Yu and co-workers developed an operationally simple catalytic system based on [RuCl2(/>-cymene)]2 for stereoselective cyclization of a-diazoacetamides by intramolecular carbenoid C-H insertion.192 /3-Lactams were produced in excellent yields and >99% m-stereoselectivity (Equation (53)). The Ru-catalyzed reactions can be performed without the need for slow addition of diazo compounds and inert atmosphere. With a-diazoanilide as a substrate, the carbenoid insertion was directed selectively to an aromatic C-H bond leading to y-lactam formation (Equation (54)). 

Dioxo-derivatives 150 can be efficiently synthesized via Rh(ll)-catalyzed intramolecular C-H insertion from various a-diazoamides. For example, intramolecular C-H insertion occurred readily in 149 under refluxing benzene conditions and produced the corresponding 7-lactams 150 with improved yields and excellent stereoselectivity (Equation 21) <2004JOC9313>. 

Carbenes and transition metal carbene complexes are among the few reagents available for the direct derivatization of simple, unactivated alkanes. Free carbenes, generated, e.g., by photolysis of diazoalkanes, are poorly selective in inter- or intramolecular C-H insertion reactions. Unlike free carbenes, acceptor-substituted carbene complexes often undergo highly regio- and stereoselective intramolecular C-H insertions into aliphatic and aromatic C-H bonds [995,1072-1074,1076,1085,1086],... 

In acceptor-substituted carbene complexes with hydrogen at Cp fast hydride migration to the carbene will usually occur [1094,1095]. The resulting olefins are often formed with high stereoselectivity. 1,2-Hydride migration will also occur in P-hydroxy carbene complexes, ketones being formed in high yields (Table 4.2). Intramolecular 1,5-C-H insertion can sometimes compete efficiently with 1,2-insertion [1096]. 

C—H insertion reaction occurs in a stereoselective manner. Various attempts based on chiral lithium amide bases gave only moderate enantioselectivities. More efficiently, the reaction is carried out by means of s-butyl- or wo-propy 1-lithium in the presence of (—)-sparteine under these conditions, the bicyclic alcohol 92 was obtained in 74% yield and 83% ee. This concept has been extended to various meio-epoxides, an example of which is shown in equation 52. ... 

C-H Activation by Carbenoid-lnduced C-H Insertion 331 Tab. 14.13 Effect of catalyst and solvent on stereoselectivity of C-H activation. 

The Claisen rearrangement of allyl vinyl ethers is a classic method for the stereoselective synthesis of y,J-unsaturated esters. The allylic C-H activation is an alternative way of generating the same products [135]. Reactions with silyl-substituted cyclohexenes 197 demonstrate how the diastereoselectivity in the formation of 198 improves (40% to 88% de) for the C-H insertion reactions as the size of the silyl group increases (TMS to TBDPS) (Tab. 14.14). Indeed, in cases where there is good size differentiation between the two substituents at a methylene site, high diastereo- and enantioselectivity is possible in the C-H activation. 

Extending the reaction to acyclic trans-allyl silyl ethers 220 results in the highly diaster-eoselective formation of syn-aldol products 221 (Eq. 30) [143]. Even higher stereoselectivity can be achieved with the tetraalkoxysilanes 222, where both the diastereo- and en-antioselectivity for the formation of 223 are exceptional (Eq. 31) [144]. C-H insertion into tetraethoxysilane 222 generates the syn-aldol product 223 in 70% yield (>94% de) with 95% enantiomeric excess. 

In 2005, the group of Choi has reported a catalytic system based on [RuC12 (p-cymene)2] that produced the stereoselective cyclization of a-diazoacetamides by intramolecular carbenoid C-H insertion and afforded [I-lactams in excellent yield (>97%) with m-stereoselectivity (>99%), (Scheme 110), [239]. 

Ruthenium porphyrins are effective catalysts for the cyclization of A-tosylhydrazones via intramolecular carbenoid C-H insertion to afford azetidin-2-ones <2003OL2535, 2003TL1445>. A non-porphyrin-based ruthenium catalyst, [RuCl2(/>-cymene)]2, has been developed recently for catalytic carbenoid transformation <20050L1081>. A [RuCl2(/>-cymene)]2-catalyzed stereoselective cyclization of a-diazoacetamides 418 by intramolecular C-H insertion produced azetidin-2-ones 419 in excellent yields and excellent (>99%) air-stereoselectivity (Equation 168). 

It is also possible to achieve remarkable intramolecular remote C-H activation of sterically hindered tetrasubstituted olefins such as 50 (Scheme 9) [8, 9] The initial hydroboration of 50 leads to 51, which gives regio- and stereoselectively the six-membered intermediate organoborane 52, via a C-H insertion reaction (40 °C, 72 h). After oxidation, the diol 53 is obtained in 90% yield as only one diastereo-... 

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. 

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