Source: https://pubs.rsc.org/en/content/articlehtml/2019/sc/c8sc05702h
Timestamp: 2019-04-24 06:25:22+00:00

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Chiral cyclopentadienyl RhIII complexes efficiently catalyze enantioselective cyclopropanations of electron-deficient olefins with N-enoxysuccinimides as the C1 unit. Excellent asymmetric inductions and high diastereoselectivities can be obtained for a wide range of substrate combinations. The reaction proceeds under mild conditions without precautions to exclude air and water. Moreover, the synthetic utility of the developed method is demonstrated by concise syntheses of members of the oxylipin natural products family and the KMO inhibitor UPF-648.
Fig. 1 Catalytic methods for the selective cyclopropanation of electron-deficient olefins.
Herein, we report a highly enantioselective alkenyl C–H bond functionalization providing access to chiral cyclopropanes under mild conditions.
The envisioned enantioselective cyclopropanation was investigated with N-enoxyphthalimide 1 and ethyl acrylate (Table 1). Rh1 featuring our simplest first generation Cpx design13b provided desired cyclopropane 4aa in 71% yield, >20 : 1 trans/cis ratio and 93.5 : 6.5 er (entry 1). Increasing of the size of the backwall using a diphenyl acetal (Rh2) or a silyl bridge (Rh3) reduced the enantioselectivity (entries 2 and 3). Complex Rh4 with a trisubstituted TMS-bearing Cpx ligand13g was as well inferior (entry 4). Binaphthyl-derived ligands (Rh5–Rh8)13c are not suited and gave a general poor performance concerning yield, diastereo- and enantioselectivity (entries 5–8). Moreover, usage of Rh9 with a cyclopentyl-backbone Cpx ligand13f formed cyclopropane 4aa in negligible amounts (entry 9). The solvent has a large influence. Replacement of TFE by either ethanol or HFIP gave dramatically lower yields (entries 10 and 11). A lower reaction temperature (0 °C) caused a sluggish reaction with no discernible increase in enantioselectivity (entry 12), whereas heating to 50 °C triggered slight erosion in yield and selectivity (entry 13). A short premixing period between the rhodium catalyst and the oxidant increased the yield to 76% while maintaining an enantiomeric ratio of 93.5 : 6.5 (entry 14). The nature of the imide of the oxidizing directing group was important. A range of other oxidizing directing group Rox failed to provide the desired reactivity which was attributed to poor solubility. However, replacement of 1 by enoxysuccinimide 2a resulted in a cleaner and faster reaction, giving 4aa in 78% isolated yield with an improved excellent enantioselectivity of 97 : 3, although with a lower diastereoselectivity of 4 : 1 (entry 15).
a 0.05 mmol 1, 0.055 mmol 3a, 2.5 μmol Rh, 2.5 μmol (BzO)2, 0.2 M in the indicated solvent and temperature for 16 h. b Isolated yield. c dr determined by 1H-NMR of the crude product. d er determined by HPLC analysis with a chiral stationary phase. e (BzO)2 and Rh were premixed for 2 min. f With 2a instead of 1.
With the optimized conditions, the scope of the reaction was investigated (Scheme 1). A variety of acrylic esters were tested. Commonly used methyl, ethyl, butyl and benzyl esters gave the cyclopropane products with good yields, >95 : 5 er and useful diastereomeric ratios between 4 : 1 and 6 : 1. Notably, tert-butyl acrylate provided in all aspects superior results, giving 4ae in 85% yield with >20 : 1 dr and 97 : 3 er. Moreover, acrylamide derivatives, exemplified with morpholine 3f reacted smoothly, giving 4af in excellent dr and suitable yields and enantioselectivity. In particular, Weinreb acrylamide proved to be well suited, giving cyclopropane 4ag in 75% yield with >20 : 1 dr and 97 : 3 er. Surprisingly, both acrolein and MVK acceptors gave high yields of the corresponding cyclopropanes 4ah and 4ai, maintaining high levels of enantioselectivity. However, due to their small size, the diastereomeric ratio was with 1.6 : 1, respectively 2 : 1 lower. Interestingly, the cis-products were formed in approximately the same enantioselectivity. Besides MVK, similar reactivity was observed for longer chain vinyl ketone giving 4aj. Considering the dearth of methods for enantiopure cis-cyclopropanes from electron-poor olefins,18 this observation could be a starting point in the development of an enantioselective cis-selective variant. Heteroatom-based Michael acceptor such as phenyl vinyl sulfone/selenone or ethenesulfonyl fluoride did not undergo cyclopropanation. Acrylates with α or β-substitution were not reactive acceptors with the current catalytic system.
Scheme 1 Suitable acceptors for the enantioselective cyclopropanation. Reaction conditions: 0.10 mmol 2a, 5.0 μmol Rh1, 5.0 μmol (BzO)2, 0.12 mmol 2, 0.2 M in TFE at 23 °C for 16 h; isolated yields; dr determined by 1H-NMR of the crude product; er determined by HPLC analysis with a chiral stationary phase.
The range of suitable enoxy-succinimides was investigated (Table 2). We first evaluated variations of the steric and electronic properties of the aryl-substituted enoxy-succinimides. Electron-donating and withdrawing groups in the para position were found to have very little influence on the reaction outcome, providing high yields and enantioselectivities of the corresponding cyclopropanes 4 (entries 1–4). Along the same lines, meta- (2f) and ortho- (2g) substitution as well as heteroaryl (2i) and condensed aromatic substituent (2h) were tolerated well. Due to limited solubility in TFE, substrates having a naphthyl- (2h) or chloroarene substituent (2e) required longer reaction times. Attractively, besides aryl-substituted enoxy-succinimides, the cyclopropanation worked very well with dienenoxy substrates such as 2j and 2k giving enone products 4je and 4ke in an excellent er of 96 : 4. Notably, no competing Diels–Alder cycloaddition between the electron-rich diene and the acrylate acceptor was observed under the reaction conditions. Moreover, the reactivity, diastereo- and enantioselectivity were excellent for alkyl substituents, leading to functionalized cyclopropanes 4le and 4me (entries 11 and 12).
a 0.10 mmol 2, 5.0 μmol Rh1, 5.0 μmol (BzO)2, 0.12 mmol 3e, 0.20 mmol CsOAc, 0.2 M in TFE at 23 °C for 16 h. b Isolated yield. c Determined by 1H-NMR of the crude product. d Determined by HPLC analysis with a chiral stationary phase. e For 40 h. f For 56 h.
Scheme 2 Synthetic application of the enantioselective cyclopropanation in the formal synthesis of members of oxylipin natural products family.
UPF-648, a potent inhibitor (IC50 = 40 nM) for kynurenine 3-monooxygenase (KMO),25,26 was identified as another attractive target. Inhibition of KMO has therapeutic potential for several neurodegenerative disorders, including Huntington's disease.27 The two reported syntheses of UPF-648 are long and use a stoichiometric chiral auxiliary28 or involve a resolution.29 Therefore, a short catalytic enantioselective route represents significant synthetic value. Our synthesis starts with a gold-catalyzed addition of N-hydroxy succinimide to 3,4-dichloro phenyl acetylene (9) affording N-enoxysuccinimide 2o in 53% yield (Scheme 3). The enantioselective cyclopropanation was conducted without any precaution to exclude moisture or oxygen, giving cyclopropane 4oe in 80% yield and 95 : 5 er. Alternatively, application of our recently developed in situ CpxRh catalyst preparation13g provided 4oe in 76% yield and 94.5 : 4.5 er. Cleavage of the tert-butyl ester gave UPF-648 ester. A subsequent recrystallization increased its optical purity to 99 : 1 er. Overall, UPF-648 could be synthesized in 3 steps in a catalytic enantioselective fashion with an overall yield of 39%.
Scheme 3 Synthetic application of the enantioselective cyclopropanation in the formal synthesis of the KMO inhibitor UPF-648.
In summary, we have developed a highly enantioselective and diastereoselective cyclopropanation of electron-deficient olefins using enoxysuccinimides as the one-carbon component. The transformation is catalyzed by chiral CpxRhIII complexes and operates under mild and open-flask reaction conditions. We applied the transformation as a key step in the synthesis of the oxylipin family of natural products and the kynurenine 3-monooxygenase inhibitor UPF-648, showcasing its synthetic utility.
This work is supported by the Swiss National Science Foundation (no. 157741).
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