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1.
This review summarizes the advances in the catalytic enantioselective construction of vicinal quaternary carbon stereocenters, introduces major synthetic strategies and discusses their advantages and limitations, highlights the application of known protocols in the total synthesis of natural products, and outlines the synthetic opportunities.This review summarizes the advances in catalytic enantioselective construction of vicinal quaternary carbon stereocenters, introduces major synthetic strategies and discusses their advantages and limitations, and outlines the synthetic opportunities. 相似文献
2.
Caille S Crockett R Ranganathan K Wang X Woo JC Walker SD 《The Journal of organic chemistry》2011,76(13):5198-5206
An expeditious synthetic approach to chiral phenol 1, a key building block in the preparation of a series of drug candidates, is reported. The strategy includes a cost-effective and readily scalable route to cyclopentanone 3 from isobutyronitrile (10). The sterically hindered and enolizable ketone 3 was subsequently employed in a challenging Grignard addition mediated by LaCl(3)·2LiCl. A novel preparation of the lanthanide reagent required for this transformation is described. To complete the process, a highly enantioselective hydrogenation step afforded the target (1). The importance of the phenol group to the success of this asymmetric transformation is discussed. 相似文献
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4.
A direct vinylogous Michael reaction of γ-substituted deconjugated butenolides with nitroolefins has been developed with the help of a newly identified quinine-derived bifunctional catalyst, allowing the synthesis of densely functionalized products with contiguous quaternary and tertiary stereocenters in excellent yield with perfect diastereoselectivity (>20:1 dr) and high enantioselectivity (up to 99:1 er). 相似文献
5.
With the aid of an appropriate chiral catalyst, acyclic silyl ketene acetals react with anhydrides to furnish 1,3-dicarbonyl compounds that bear all-carbon quaternary stereocenters in good ee and yield. Mechanistic studies provide strong support for a catalytic cycle that involves activation of both the electrophile (anhydride --> acylpyridinium) and the nucleophile (silyl ketene acetal --> enolate). 相似文献
6.
Zhiyang Li Yichen Li Xingguang Li Mandi Wu Ming-Liang He Jianwei Sun 《Chemical science》2021,12(35):11793
A new catalytic asymmetric formal cross dehydrogenative coupling process for the construction of all-aryl quaternary stereocenters is disclosed, which provides access to rarely explored chiral tetraarylmethanes with excellent enantioselectivity. The suitable oxidation conditions and the hydrogen-bond-based organocatalysis have enabled efficient intermolecular C–C bond formation in an overwhelmingly crowded environment under mild conditions. para-Quinone methides bearing an ortho-directing group serve as the key intermediate. The precise loading of DDQ is critical to the high enantioselectivity. The chiral products have also been demonstrated as promising antiviral agents.A one-pot oxidation of racemic triarylmethanes to form para-quinone methides followed by enantioselective construction of all-aryl quaternary stereocenters has been developed.Cross dehydrogenative coupling (CDC) is a powerful tool to forge intermolecular C–C bonds from two C–H bonds without prefunctionalization.1 Specifically, the benzylic C–H bond is relatively prone to oxidation and thus it has evolved into a versatile arena for the implementation of this reaction, leading to efficient construction of various benzylic stereogenic centers. As a result, CDC has proved to be useful for the establishment of a wide range of 1,1-diaryl stereocenters (Scheme 1a).2 Recently, Liu and coworkers reported a elegant synthesis of enantioenriched triarylacetonitriles via in situ oxidation of α-diarylacetonitriles to para-quinone methides (p-QMs) followed by asymmetric nucleophilic addition with stereocontrol induced by a chiral phosphoric acid catalyst. This represents a rare example of formal CDC for the synthesis of 1,1,1-triarylalkanes (Scheme 1b).3 However, the establishment of tetraaryl-substituted carbon stereocenters by this approach remains unknown (Scheme 1c).Open in a separate windowScheme 1Catalytic asymmetric synthesis of chiral tetraarylmethanes.Distinct from the asymmetric synthesis of triaryl-substituted stereocenters,4 substantial steric hindrance in establishing tetraaryl-substituted quaternary stereocenters poses significant synthetic challenges.5–8 Indeed, even racemic or achiral syntheses of tetraarylmethanes have been an elusive topic of investigation in organic synthesis.6 In this context and in continuation of our effort in the studies of asymmetric reactions of para-quinone methides (p-QMs)9,10 as well as the synthesis of chiral tetraarylmethanes,8 we envisioned that suitable oxidation of racemic triarylmethane 1 is expected to generate triarylmethyl cation IM1 (Scheme 1c). With one aryl group as para-hydroxyphenyl, this cation could be stabilized in the form of p-QM IM2. Subsequent asymmetric nucleophilic addition by another electron-rich arene to the p-QM intermediate is expected to generate chiral tetraarylmethanes 2. The challenges associated with this one-pot process mainly include the compatibility problem between the oxidative condition and the catalytic asymmetric system in order to achieve both high efficiency and enantioselectivity.We commenced our study with racemic triarylmethane 1a as the model substrate. The initial study was directed to the search for a suitable oxidant to mildly generate the p-QM intermediate (11 At room temperature, the use of superstoichiometric amounts of Ag2O or benzoquinone was completely ineffective (entries 1 and 2). Similarly, the reaction did not proceed using oxygen as the oxidant in combination with catalyst Mn(acac)3 (entry 3). Subsequently, considerable efforts were devoted to screening many other oxidation systems, almost all of which were completely incapable for this oxidation (entries 4–8). However, eventually we were delighted to identify DDQ as the superior oxidant, leading to complete and clean conversion to the desired QM at room temperature (entry 9). In contrast, a combination of catalytic DDQ with 5 equivalents of MnO2 gave only 60% conversion (entry 10).Evaluation of oxidants
Open in a separate windowWe next set out to evaluate the key C–C bond formation step (12,13 After oxidation, the nucleophile and catalyst were added to the reaction mixture. The reaction with catalyst (R)-A1 proceeded smoothly at room temperature to form the desired product 2a in 90% yield, but unfortunately in a racemic form (entry 1). Next, a range of chiral phosphoric acids were screened. To our delight, the BINOL-derived TRIP catalyst, (R)-A4, provided excellent enantioselectivity (93% ee, entry 4). However, those with H8BINOL- and SPINOL-derived catalysts (B and C) bearing the same 2,4,6-triisopropylphenyl substituents proved to be inferior. Finally, a slightly modified acid A5 was found to be the best (95% ee, entry 7). Decreasing the temperature to 0 °C improved the result (97% ee, entry 8). However, no further improvement was observed at a lower temperature. While DCM was comparable to DCE, other solvents (e.g., EtOAc and Et2O) significantly affected the enantioselectivity. Varying the concentration led to no improvement (entries 9–13). Finally, the catalyst loading could be reduced to 7.5 mol% without erosion in yield or enantioselectivity (entry 14). Notably, during the course of our study, the enantioselectivity was found to be sensitive to the amount of DDQ when it was used in excess. For example, with 1.5 equivalents of DDQ (entry 15), the enantioselectivity decreased to 51% ee. However, with 0.8 equivalents, the selectivity remained excellent, albeit with reduced yield. These results suggest that the excessive DDQ might be detrimental to stereocontrol. Unfortunately, this feature also prevented the two-step protocol from merging into one operation. The catalyst has to be added after complete consumption of DDQ to ensure high enantioselectivity (entry 17). Moreover, although the oxidation step was relatively fast (∼30 min) based on TLC analysis, keeping this mixture under stirring for an additional 4 h before adding the acid catalyst was critical to achieve high enantioselectivity, which is likely to ensure complete consumption of DDQ or precipitation of its reduced form DDQH2 from the solution (entry 18).Condition optimizationa
Open in a separate windowaReaction conditions: 1a (0.025 mmol), 3a (0.05 mmol), catalyst (10 mol%), DCE (0.5 mL). Yield is based on analysis of the 1H NMR spectroscopy of the crude reaction mixture using CH2Br2 as an internal standard.
Open in a separate windowWith the optimized conditions (entry 14, Scheme 2). A wide range of diversely-substituted triarylmethanes participated in this process with good to excellent efficiency and enantioselectivity. In addition to OMe, other alkoxy groups (e.g., OBn and OAllyl, 2k–l), protected amine groups (e.g., sulfonamides, 2m–o), and even fluorine (2p–q) can serve as an effective directing group when they are present at the ortho position. Moreover, as shown in the case of 2f, the observed good enantioselectivity indicated that the directing ability of alkoxy and fluorine groups is remarkably different. The incorporation of a heterocycle, such as thiophene (2g), did not interfere with the reactivity or enantiocontrol. Some other pyrroles, including 2,4-dimethyl pyrrole (2x), were also good nucleophiles. 4,7-Dihydro-1H-indole also reacted smoothly to form the product 2v. Subsequent oxidation by DDQ could easily afford the indole-substituted tetraarylmethane 2weqn (1). Unfortunately, pyrroles with carbonyl substituents and other electron-rich arenes, such as indole, furan, 2-naphthol, and 1,3,5-trimethoxybenzene, were not reactive under the standard conditions (0 °C). At room temperature, indole could react to form the desired product 2y, but in only 21% ee, while the others remain unreactive.1Open in a separate windowScheme 2Reaction scope. Reaction scale: 1 (0.25 mmol), DDQ (0.25 mmol), DCE (5.0 mL), rt, 5 h; then 3 (0.50 mmol), (R)-A5 (18.8 μmmol), 0 °C, 3 h. Isolated yield is provided. The ee value was determined by chiral HPLC analysis. aRun at −20 °C for 12 h after catalyst addition. bRun at rt for 24 h after catalyst addition.The standard protocol could be scaled to 1.25 mmol without erosion in efficiency or enantiocontrol (Scheme 3). Moreover, the directing groups, such as the para-hydroxy group, could be easily converted or removed. For example, after triflation of the phenol unit in 2d, the triflate 3 could easily participate in coupling reactions to form the arylation, reduction, and allylation products 4–6. The high enantiopurity remained essentially intact.Open in a separate windowScheme 3Product transformations. [a] Tf2O, Et3N, DCM, 0 °C to rt; [b] PhB(OH)2, Pd(OAc)2, BrettPhos, K3PO4, tBuOH, 85 °C; [c] Et3SiH, Pd(OAc)2, dppp, DMF, 60 °C; [d] AllylBpin, Pd(OAc)2, BrettPhos, K3PO4, tBuOH, 85 °C.To understand the reaction mechanism, we carried out some control experiments. First, the intermediate QM, though unstable and easy to undergo addition, was obtained by careful isolation from the oxidation step in the presence of molecular sieves (Scheme 4a). Next, in the absence of DDQ, the standard reaction between QM and 2-methylpyrrole proceeded with high efficiency and excellent enantioselectivity (97% ee, Scheme 4b). However, with DDQ as an additive, the enantioselectivity decreased to 44% ee, which confirmed that it is detrimental to enantiocontrol.14 The methylated substrate 1a-Me was also examined. The desired tetraarylmethane 2a-Me was successfully formed, but in an almost racemic form (Scheme 4c). In this case, the corresponding oxonium cation served as an activated intermediate, rather than p-QM. This result indicated that the free hydroxyl group in the standard substrates is not necessary for DDQ oxidation, but the resulting p-QM intermediate is essential for excellent enantiocontrol.Open in a separate windowScheme 4Mechanistic study.Finally, the substrates bearing other ortho-substituents in place of the ortho-methoxyl group were examined. With ortho-methyl and ethyl groups (1r–s), low enantioselectivies were obtained in spite of excellent yields. In particular, the ethyl group has a similar size to the methoxyl group, but does not provide hydrogen bonding interactions. The dramatically low ee (17% ee) for this case provided strong evidence that steric hindrance is not key to the excellent asymmetric induction for 1a. Furthermore, substrate 1t (with ortho-OiPr) also provided a lower ee (72% ee) than 1a. These results suggested that it is the hydrogen bonding interaction with the ortho-directing group, not the steric or electronic effect, that leads to the excellent enantiocontrol in the standard protocol.8We also randomly selected a few of our products to test their potential antiviral activities in Rhabdomyosarcoma (RD) cells, which are commonly used to investigate enterovirus A71 (EV-A71) infections. Our compounds showed relatively high CC50 measured by MTT assay, indicating low cell toxicity (Fig. 1). Quantitation of viral genome RNA in the secreted virions showed potent inhibition of virus replication with IC50 ranging from 0.20 to 1.24 μM, indicating a high selectivity index (Compound CC50 (μM) IC50 (μM) Selectivity indexb 2k 29.3 0.20 148.5 2u 33.2 0.24 138.3 2r 28.2 1.24 22.7
Entry | [O] | Conv. (%) |
---|---|---|
1 | Ag2O (5.0 equiv.) | 0 |
2 | Benzoquinone (1.5 equiv.) | 0 |
3 | Mn(acac)3 (10 mol%), O2 (1 atm) | 0 |
4 | KBr (1.2 equiv.), Oxone (1.2 equiv.) | 0 |
5 | K3Fe(CN)6 (1.5 equiv.) | 0 |
6 | AIBN (0.5 equiv.), TBHP (3.0 equiv.) | 0 |
7 | FeCl3 (10 mol%), TBHP (3.0 equiv.) | 0 |
8 | TEMPO (3.0 equiv.) | 0 |
9 | DDQ (1.0 equiv.) | 100 |
10 | DDQ (20 mol%), MnO2 (5.0 equiv.) | 60 |
Entry | CPA | Temp. | Yield 2a (%) | ee (%) |
---|---|---|---|---|
1 | (R)-A1 | rt | 90 | 0 |
2 | (R)-A2 | rt | 95 | 47 |
3 | (R)-A3 | rt | 92 | 49 |
4 | (R)-A4 | rt | 96 | 93 |
5 | (R)-B | rt | 93 | 65 |
6 | (R)-C | rt | 91 | 9 |
7 | (R)-A5 | rt | 95 | 95 |
8 | (R)-A5 | 0 °C | 95 | 97 |
Change from the entry 8 | |||
9 | EtOAc as solvent | >95 | 41 |
10 | Et2O as solvent | 88 | 70 |
11 | DCM as solvent | >95 | 93 |
12 | c = 0.1 M | 96 | 95 |
13 | c = 0.025 M | 95 | 93 |
14 | 7.5 mol% of (R)-A5 | 95 | 97 |
15 | 1.5 equiv. of DDQ | 94 | 51 |
16 | 0.8 equiv. of DDQ | 77 | 96 |
17 | Mix all together at the beginning | 47 | 62 |
18 | 1 h (not 5 h) for the first step | 95 | 81 |