Organocatalytic asymmetric formal oxidative coupling for the construction of all-aryl quaternary stereocenters

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

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

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 optimization^a

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

Open in a separate window^aReaction 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.

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

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 (