Enantioselective Hashimoto catalyst

The intermolecular version of the above described reaction has also been reported [92]. In the first example the reaction of a rhodium catalyst carbonyl ylide with maleimide was studied. However, only low enantioselectivities of up to 20% ee were obtained [92]. In a more recent report Hashimoto et al. were able to induce high enantioselectivities in the intermolecular carbonyl ylide reaction of the... 

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. 

Asymmetric activation of the C—H bonds in benzyl silyl ethers was achieved by using Hashimoto s A-phthaloyl-based Rh2((5)-PTTL)4 catalyst (Figure 5.6) in high diastereoselectivities and enantioselectivities (Scheme 5.15). The well-established dirhodium tetraprolinates such as Rh2((5)-DOSP)4 and Rh2((R)-DOSP)4 catalysts, which generally are excellent catalysts for asymmetric C—H bond activation, were not suitable catalysts in these reactions. 

Later in 2005, Hashimoto [106] reported the asymmetric ring opening reaction of cyclohexane oxide with catalyst 30 and afforded the corresponding chlorohydrin in high yield and enantioselectivity (Scheme 31). 

Hashimoto has noted improved enantioselectivities for C-H insertion of indane and tetralin substrates using dirhodium tetrakis(N-phthaloyl-tert-butylleucinate)-based catalysts (Scheme 17.9) ]49]. In the best of these examples, 84% ee was obtained with 1,1-dimethyltetrahn 9 (5 equiv) and NsN=IPh. Despite the modest enantiomeric ex-... 

After completing his initial intramolecular cycloaddition, Hodgson utilized conditions that had been optimized for the intermolecular cycloaddition of DMAD with simple cyclic carbonyl ylides used by Hashimoto and co-workers (139). Hodgson et al. (140) found that the reaction indeed gave excellent overall chemical yield, but the enantioselectivity dropped to 1%, giving essentially a racemic mixture. It appeared that ee ratios were sensitive to the electronic nature of the dipole. Hodgson chose to screen several binaphthol derived rhodium catalysts of the type developed by McKervey and Pirrung, due in part to the reports of... 

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). 

Hashimoto and co-workers (206,207) recently published enantioselectivities of up to 92% ee in carbonyl ylide cycloadditions to acetylenic esters in the presence of a chiral rhodium catalyst (Scheme 11.58). 

Hashimoto and co-workers, on the other hand, studied the intramolecular reaction between cyclic carbonyl yield and dimethyl acetylenedicarboxylate (DMAD) (Equation (14)). With dirhodium(ii) tetrakis[A-benzene-fused phthaloyl-(A)-valinate] [Rh2(WBPTV)4] 104, high enantioselectivity (68-92% ee) was achieved over a range of diazo substrates.The high level of enantiocontrol provided conclusive evidence that chiral Rh(ii) catalyst is associated with the ylide in the cycloaddition step. 

Hashimoto has shown that the the valine-derived catalyst Rh2(S-BPTV)4 (5) is effective in intermolecular tandem cyclization/intermolecular cycloaddition resulting in the formation of 46 in 92% ee (Eq. (26) [10]. More recent studies have broadened the range of substrates that can be used in the reaction although the enantioselectivity is variable [38,39],... 

The synthesis of the tetrasubstituted dihydroquinoline portion of siomycin Di, which belongs to the thiostrepton family of peptide antibiotics, was achieved in the laboratory of K. Hashimoto. The Jacobsen epoxidation was utilized to introduce the epoxide enantioselectively at the C7-C8 position. The olefin was treated with 5 mol% of Jacobsen s manganese(lll)-salen complex (R =f-Bu) and 4% aqueous NaOCI solution in dichloromethane. To enhance the catalyst turnover, 50 mol% of 4-phenylpyridine-A/-oxide was added to the reaction mixture. The desired epoxide was obtained in 43% yield and with 91% ee. 

Intramolecular carbenoid C-H insertion has been a useful method for the construction of small to medium rings since the early 1980s, and these transformations can occur with good regio-, diastereo-, and enantioselectivity with appropriate choice of catalyst [6], Taber, Doyle, and Hashimoto have been key players in this area and have also developed a number of chiral catalysts for increasing levels of enantioin-duction. Many studies have been conducted concerning the effects of substrate conformation, sterics, stereoelectronics, and catalyst on the regioselectivity, diastereoselectivity, and enantioselectivity of the C-H insertion events, but these are outside the scope of this chapter. For detailed discussion, refer to the reviews cited in Sect. 1.3. 

A number of groups have successfully synthesized dihydrobenzofurans (51) in high enantioselectivity, but the right combination of catalyst and substrate needs to be used [64-66], In all cases, ortfto-substituted benzene rings are the precursors for the C-H insertion events. Davies [64] and Hashimoto [66] both used diazoesters 50 as the carbenoid source (Scheme 11). Davies prolinate catalyst Rh2(S,-DOSP)4 (26) was found to give high enantioselectivity for insertion into methine C-H bonds (up to 94% ee), but selectivity was low for methylene sites. 

Hashimoto and coworkers have reported a highly diastereo- and enantioselective synthesis of 1,2-disubstituted cyclopentanes 53 that also avoids competing 1,2 hydride migration with appropriate choice of catalyst (Fig. 4) [68], Phthalimide-based Rh2(5-PTTL)4 (29a) was found to be the optimal catalyst for insertion into the benzylic position of the precursors to 53, and was effective for both electron poor and electron rich systems. The diastereoselectivity for the 1,2 cis product was excellent as long as the reaction was conducted at -78 °C, and enantioselectivities of up to 95% were achieved. An additional example demonstrated that insertion into a fully aliphatic position could also proceed with high ee (94%), but the resulting product was the trans diastereomer. 

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. 

Hu and coworkers utilized a very similar cyclization precursor 181 in 2005, with the main differences being the lack of a second acceptor group on the diazo and the protecting group on the nitrogen atom. They also chose to screen not the phthalim-ide-based catalysts, but the prolinates and carboxamidates, and Rh2(5S-MEOX)4 (28c) provided the best enantioselectivity, but still only 46% ee. After two recrystallizations of the final product, the enantiomeric purity was increased to 88% ee, but Hashimoto s protocol was clearly superior. 

Hashimoto and coworkers [69] have recently begun to explore the use of chiral rhodium catalysts in the intramolecular dipolar cycloadditirai reactions of indoles, and have applied their methodology to the synthesis of the Aspidosperma ring system. Thus, the cycloaddition of the cyclopropyl carbonyl ylides derived from cyclopropyl diazo-5-imido-3-ketoesters 135 upon treatment with dirhodium (11) tetrakis[Af-tetrachlorophthaloyl-(5)-ferf-leucinate] gave cycloadducts 136 along with the spiro[2.3]hexanes 137 in only moderate yields (Scheme 34). Although the reaction proceeds with exclusive endo diastereoselectivity, only moderate enantioselectivities of up to 66% enantiomeric excess (ee) could be obtained. 

In 2005, the Davies group discovered that the generally reliable catalyst Rh2(DOSP)4 failed to induce high levels of chiral control when benzyl silyl ether derivatives 37 were employed as reaction components. Fortunately, Hashimoto s Rh2(iS-PTTL)4 catalyst showed a superb performance, delivering C—H bond functionalization products 38 in prominent levels of diastereo-and enantioselectivity (up to >95% de and 98% ee) (Scheme 1.11). 

In 2002, Hashimoto and co-workers developed a new chiral Rh" catalyst Rh2(iS-TCPTTL)4 for this process (Scheme 1.35). By tuning the electronic property of the catalyst, they found that this amidation reaction of a variety of substrates 99 bearing either a benzylic C—H bond or an allylic C—H bond could proceed smoothly with moderate to good enantioselectivity. 

Hashimoto and co-workers have shown the enantioselective 1,3-dipolar cycloaddition of the ester-derived carbonyl ylides using chiral dirhodium(II) carboxylates [110]. The ester-derived carbonyl ylide from the a-diazo ketone 98 in the presence (1 mol%) of Rh2(S-PTTL)4 99 as the catalyst afforded the cycloadduct 100 with 93% ee (Scheme 30). 

Hashimoto and coworkers accomplished the immobilization of chiral dirhodium (II) catalyst on a polystyrene-based copolymer. The polymer catalyst (55), which was packed in a gravity fed column, was successfully applied in a domino carbonyl ylide formation - dipolar cydoaddition under continuous-flow conditions (Scheme 7.39). The desired bicyclic adduct was obtained in high yield and high levels of asymmetric induction (up to 99% ee). The flow reactor was demonstrated by the retention of activity and enantioselectivity even after 60 h with a low metal leaching level (2.1 ppm) [146]. 

In 1999, Hashimoto and coworkers demonstrated the first successM examples of the intermolecular cycloadditions of carbonyl ylides derived from a-diazo ketones with dimethyl acetylenedicarboxylate (DMDA) using fV-benzene-fitsed phthaloyl-(5)-valine-derived Rh catalyst, Rh2(5-BTPV)4 with high enantioselectivity (up to 92% ee) (Scheme 7.21) [57]. 

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