Enantioselective C-H insertion reactions

To improve these selectivities, Hashimoto studied several catalysts that had been found highly effective for enantioselective C—H insertion reactions. The new catalysts incorporated an additional benzene in the naphthyl system to increase the steric bias of the catalyst. By using the second-generation catalysts in trifluorotoluene as solvent, at 0 °C, and short reaction times gave ee ratios of 68-92%. Lowered reaction temperature generally resulted in reduced chemical yields but did not erode the ee ratio. Tether lengths one smaller or one larger also tended to erode the ee ratio (Scheme 4.73). 

Enantioselective C-H insertion reactions have been successfully performed by various rhodium catalysts over a broad range of substrates in both an intramolecular and an intermolecular manner. Of the many examples reported, a few are highhghted here. McKervey and coworkers have obtained good diastereoselectivity and enantioselectivity in the C-H insertion reaction of compound (9.91) catalysed by rhodium complex (9.92). Intramolecular cyclopropanation is not competitive in this case, since the alkene moiety is too remote. 

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. 

Liu W-J, Chen Z-L, Chen Z-Y, Hu W-H. Dirhodium catalyzed intramolecular enantioselective C—H insertion reaction of A-cumyl-A-(2-/)-anisylethyl)diazoacetamide synthesis of (—)-rolipram. Tetrahedron Asymm. 2005 16 1693-1698. 

The development of catalytic, enantioselective C-H insertion reactions has been relatively slow in comparison with the diastereoselective variants described in Section 15.7. It was only in 1990 that McKervey reported the first such example in the context of an intramolecular ring closure (Equation 28) [51]. Exposure of 169 to chiral rhodium catalyst 170 thus afforded 171 in 12% ee. 

Davies demonstrated that functionalized substrates including N-Boc-pyrrolidine (181) participated in enantioselective C-H insertion reactions to give products such as 182 in 94% ee and 96 4 dr (Equation 32) [97]. 

In the same area, good levels of enantioselectivity have been achieved in intramolecular C H insertion reactions of a-diazocarbonyl compounds... 

Activation of a C-H bond requires a metallocarbenoid of suitable reactivity and electrophilicity.105-115 Most of the early literature on metal-catalyzed carbenoid reactions used copper complexes as the catalysts.46,116 Several chiral complexes with Ce-symmetric ligands have been explored for selective C-H insertion in the last decade.117-127 However, only a few isolated cases have been reported of impressive asymmetric induction in copper-catalyzed C-H insertion reactions.118,124 The scope of carbenoid-induced C-H insertion expanded greatly with the introduction of dirhodium complexes as catalysts. Building on initial findings from achiral catalysts, four types of chiral rhodium(n) complexes have been developed for enantioselective catalysis in C-H activation reactions. They are rhodium(n) carboxylates, rhodium(n) carboxamidates, rhodium(n) phosphates, and < // < -metallated arylphosphine rhodium(n) complexes. 

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. 

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. ... 

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... 

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. 

Interestingly, while the chiral Rh2(4S-MACIM)4 catalyst gave the desired isomer from the C-H insertion reaction, the achiral Rh2(OAc)4 catalyst afforded the opposite diastereoisomer in low yield. The enantioselective preparation of / -lactams by C-H insertion has also been examined, and some like 34 and 35 are formed with high enan-tiocontrol [68], but the generality of this process has not yet been established. 

Muller has explored enantioselective C-H insertion using optically active rhodium complexes, NsN=IPh as the oxidant, and indane 7 as a test substrate (Scheme 17.8) [35]. Chiral rhodium catalysts have been described by several groups and enjoy extensive application for asymmetric reactions with diazoalkanes ]46—48]. In C-H amination experiments, Pirrung s binaphthyl phosphate-derived rhodium system was found to afford the highest enantiomeric excess (31%) of the product sulfonamide 8 (20equiv indane 7, 71% yield). 

Until recently, intermolecular C—H insertion reactions were more a curiosity than a synthetically productive undertaking. Davies and Antoulinakis discovered in the late 1990s that aryl- and vinyldiazoacetates undergo intermolecular insertion with a wide variety of hydrocarbons in high yield. With Rh2(5-DOSP)4 (12, Ar = C12H25C6H4) moderate-to-high enantioselectivities have been achieved, but diastereoselection is often low to moderate (e.g., Eq. 32, 33 ). Note that a... 

A critical development in efforts to achieve high enantiocontrol in C-H insertion reactions was the synthesis and applications of Rh2(MPPIM)4 [89]. This catalyst provided enhanced enantiocontrol in virtually all cases examined, but especially with 3-substituted-l-propyl diazoacetates (Eq. 5.32). Results obtained with various substrates are given in Table 5.11 [126,127], which show the unique ability of Rh2(MPPIM)4 to increase enantioselectivity. Notice also that the S-configured catalyst produces the. S -configured product and that the /f-catalyst produces the R-product. 

Allylic C-H insertions have been used in key steps of the enantioselective synthesis of the pharmaceuticals (+)-ceitedil (26) [21] and (+)-indatraline (27) [22] (Scheme 11). The allylic C-H insertion reaction is an exciting alternative to the Claisen rearrangement as a rapid method for the synthesis of y,c>-unsaturated ester [23 ]. Similarly, the allylic C-H insertion with vinyl silyl ethers generates protected 1,5-dicarbonyl compounds, a complimentary reaction to the Michael addition [24]. Both types of C-H insertion can be achieved with high diastereoselectiv-ity and enantioselectivity [23, 24]. 

Enantioselective Intramolecular Carbon-Hydrogen Insertion Reactions. The suitability of Rh2(55-MEPY)4 and Rh2(5R-MEPY)4 for enantioselective intramolecular C-H insertion reactions is evident in results with 2-alkoxyethyl diazoacetates (eq 4). Both lactone enantiomers are available from a single diazo ester. Other examples have also been reported, especially those with highly branched diazo substrate structures. ... 

The synthesis of substituted chromanones 369 via a C—H insertion reaction of a-diazo ketones 370 has demonstrated that high levels of enantiose-lectivity are attainable through the use of chiral rhodium carboxylates (92CC823). Treating diazo ketone 370 (R = CH=CH2, R = H) with Rh2[(S)(-l-)BINAP]4 leads enantioselectively to the cis isomer of chroma-none 369 (92TL5983). 

Enantioselective C-H insertion is clearly the domain of chiral dinuclear rhodium catalysts (see Chap. 16.2). Only very few examples of enantioselective copper-catalyzed reactions of this type have been reported. As a possible approach to the mitomycine ring system, Sulikowski has studied the cyclization of diazo esters 28 quite extensively using various chiral transition metal catalysts... 

In a useful extension of this methodology for enantioselection in intramolecular cyclopropanation, Doyle s group have used chiral rhodium (II) carbox-amidates to effect enantiomer differentiation in reactions of racemic secondary allylic diazoacetates [47]. The catalyst-enantiomer matching approach has also been applied very successfully to intramolecular C-H insertion reactions vide infra). The (R)- and (S)-enantiomers, (10) and (11), respectively, of cyclohex-2-en-1 -yl diazoacetate are displayed in Scheme 7. On exposure to Rh2(4i -MEOX)4 the (R)-enantiomer (10) undergoes cyclopropanation to form tricyclic ketone... 

The hT-benzenesulfonylprolinate catalyst, (3) of Fig. 1, provided the highest levels of stereocontrol. The binaphthyl hydrogen phosphate rhodium (II) catalyst also promoted chromanone formation and while the cis-diastereoselectivity was excellent (94%), the enantiocontrol was modest (33% ee) application of this catalyst to the P-lactam-forming C-H insertion reaction in Eq. (39) revealed high chemoselectivity (93% yield of trans),hut low enantioselectivity (26% ee) [28]. 

Doyle s chiral rhodium (II) carboxamidates have proved to be exceptionally successful for asymmetric C-H insertion reactions of diazoacetates and some diazoacetamides leading to lactones and lactams, respectively. With 2-alkoxyethyl diazoacetates and the Rh2(5S- and 5R-MEPY)4 catalysts, for example, highly enantioselective intramolecular C-H insertion reactions occur, the 5S-catalyst, Eq. (40), and 5R-catalyst furnishing the S- and R-lactone, respectively [58]. A polymer-bound version of Rh2(5S-MEPY)4 has also been applied to the cycliza-tion in Eq. (40) to yield the lactone with 69% ee (R=Me) the catalyst could be recovered by filtration and reused several times, but with decreasing enantiose-lection [59]. 

Examples of enantioselective intramolecular C-H insertion reactions of diazoacetamides are known and though less extensive than those with diazoester substrates, there already are indications that excellent levels of stereocontrol are attainable. It is very likely that catalyst development will extend further the scope of this approach to the enantioselective synthesis of iY-heterocycles. 

Fraile, Mayoral, and coworkers utilized copper BOX catalysts (115), both homogeneous and immobilized on a laponite support, for their C-H insertion reactions [96], They obtained similar yields and diastereoselectivities to the Rh2(5 -DOSP)4 catalyst (up to about 3 1), but the highest enantioselectivity was 88% ee. Woo [10] and Che [83] chose to use achiral iron porphyrin catalysts. Woo obtained the products in 62-82% yield in about 3.5 1 dr, and Che in 88% yield, but only 2 1 dr. By way of comparison, Perez obtained excellent yields for this insertion reaction with EDA (95-99%) utilizing copper homoscorpionate catalysts 67a and 67b, [36, 39] but the transformations were not asymmetric. 

Examples of more basic, but enantioselective intramolecular carbenoid C-H insertion reactions were displayed in two very similar total syntheses of the phosphodiesterase type IV inhibitor i -(-)-rolipram (179, Scheme 44) [125, 126], In 1999, Hashimoto and coworkers utilized acceptor/acceptor diazo compound 180, with the nitrogen atom protected with a p-nitrophenyl moiety, as the carbenoid precursor. After screening a number of phthalimide-based dirhodium catalysts, Rh2(5 -BPTTL)4 (30) was found to give the optimal results, providing the cyclized product in 74% yield and 88% ee. 

A-Phthaloyl-protected (S)-phenylalanine has been used as a ligand for rhodium in the formation of metallocarbenes from diazo compounds for C-H insertion reactions (Section D.1.2.2.3.2.). Ar-Sulfonyl-protected (S)-alanine and (S)-valine are efficient ligands for chiral Lewis acids used in the Diels-Alder reaction (Section D.1.6.1.1.1.3.). A -Sulfonyl-pro-tected (S)-phenylalanine methyl ester has been used for the enantioselective protonation of lactone enolates (Section D.2.I.). The terf-butyl ester of (S)-valine readily forms imines with carbonyl compounds which are used for the highly efficient alkylations of their azaenolates (Sections D.1.1.1.4.1D.1.5.2.4.). All these derivatives can be obtained by the standard methods described in Houben-Weyl3. 

Metal catalyzed enantioselective C-H insertions of carbenes have so far not been studies in great detail. Copper catalysts are of no use for this type of reaction, rhodium(Il) catalysts, however, allow intramolecular C-H insertions, for example, in the alkyl group of diazoacetates with longer chains. The formation of five-membered rings such as y-lac-tones is favored. [Rh2(55-mepy)4] affords... 

Bis(methoxycarbonyl)(phenyliodinio)methanide (778), the most common iodonium ylide derived from malonate methyl ester, has found synthetic applications in the C—H insertion reactions [1044-1048] and the cyclopropanation of alkenes [1049-1055], including enantioselective cyclopropanations in the presence of chiral rhodium complexes [1056-1058], Representative examples of these reactions are shown in Scheme 3.306 and include the BFs-catalyzed bis(carbonyl)alkylation of 2-alkylthiophenes 777 [1045] and the optimized procedure for rhodium-catalyzed cyclopropanation of styrene 779 [1052]. 

Davies and Venkataramani [47a] have used similar catalysts to generate chiral rhodium carbenoids from diazoesters under KR conditions. Among many examples of enantioselective C—H insertions, one case of enantiodivergent RRM was documented using individual enantiomers as substrates. However, the reactions with racemic substrates were limited to simple KR conditions (excess racemic substrate). Application of this stereodivergent Rh-catalysed cyclopropanation towards... 

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