Asymmetric Synthesis of 1-Tetralones Bearing A Remote Quaternary Stereocenter through Rh-Catalyzed C−C Activation of Cyclopentanones

Abstract

Herein, we describe the preparation of 1-tetralones bearing a remote quaternary stereocenter in a highly enantioselective manner. A sequence of Pd-catalyzed asymmetric 1,4-addition and Rh-catalyzed enantiospecific C−C/C−H activation delivers diverse 1-tetralones with a C4 quaternary stereocenter, which are prepared in good overall yields and high enantioselectivity.

Graphical Abstract

Summary

Here, 1-tetralones bearing a remote quaternary stereocenter can be constructed through a combination of Pd-catalyzed asymmetric conjugate addition and Rh-catalyzed enantiospecific C−C/C−H bond re-organization from readily available cyclopentenones and arylboronic acids. The transformation features the conversion of an easily-forming proximal stereocenter to a remote one, which could have broad implications on the construction of remote quaternary stereocenters.

All-carbon quaternary stereocenters commonly exist in natural products and bioactive molecules.¹ The construction of all-carbon quaternary centers with control of absolute stereochemistry has been an ongoing challenge and received substantial attention from the synthetic community.² To date, a range of catalytic methods have been developed for enantioselective formation of all-carbon quaternary centers.^1,2 However, most of these approaches require the presence of an adjacent reactive functional group. For example, numerous innovative approaches have been made available to introduce quaternary centers α or β to carbonyl groups via asymmetric catalysis (Scheme 1a).^3,4 On the other hand, few strategies are available to construct remote quaternary centers in an enantioselective manner due to the lack of reactive sites and controlling handles.⁵

Scheme 1.

(a) Common strategies for construction of quaternary all-carbon stereocenters; (b) Representative 1-tetralones with a C4 quaternary stereocenter in natural products and advanced intermediate; (c) C−C/C−H bond re-organization in 3-arylcyclopentanones; (d) This work: Construction of a remote quaternary stereocenter

On the other hand, carbon−carbon bond (C−C) activation reactions catalyzed by transition metals allow for deconstructive rearrangement of carbon skeletons, thereby enabling new strategic bond disconnections for constructing complex molecules.^6,7 This inspired us to examine a distinct approach for installing remote chiral all-carbon quaternary centers, which involves first introducing the stereocenter at an adjacent position, e.g. β to carbonyl, and then transporting it to a distal position via C−C activation. In this context, 1-tetralones bearing a C4 quaternary center have been found in many bioactive compounds and often serve as important synthetic intermediates (Scheme 1b);⁸ however, they are nontrivial to prepare asymmetrically. Recently we developed a general and catalytic method for converting 3-arylcyclopentanones to 1-tetralones via Rh-catalyzed C−C activation followed by intramolecular C−H functionalization (Scheme 1c).^9,10 In this transformation, the β stereocenter in the cyclopentanone substrate is transferred to the C4 stereocenter in the 1-tetralone product through bond re-organization. Thus, if enantioenriched cyclopentanones that contain a β quaternary stereocenter could be used as substrates, a convenient enantioselective preparation of 1-tetralones bearing a C4 quaternary center would be realized. Here, we describe the development of a catalytic C−C activation approach for constructing remote all-carbon quaternary centers in 1-tetralones (Scheme 1d).

Among various conjugate addition methods,^4,11 the palladium-catalyzed 1,4-arylation, pioneered by Lu, Stoltz, Minnaard etc., excel at constructing quaternary stereocenters at ketone β-positions,^12–16 which became our first choice to prepare cyclopentanones bearing a β quaternary center. While cyclohexenones have been extensively explored as substrates in these reactions, only a few examples are known for five-membered substrates, which are mainly restricted to 3-methyl-1-cyclopentenone.¹⁷ Thus, the first objective of this approach is to develop an efficient condition that can prepare 3,3-disubstituted cyclopentanones in high yields and high enantioselectivity. Towards the end, 3-ethyl-2-cyclopentenone (1a) and phenylboronic acid were chosen as the model substrates (Table 1). Under the previously reported conditions by Stoltz,¹³ the desired product (2a) was indeed obtained in a good level of enantiomeric ratio (er) albeit in moderate yields (entries 1 and 2). The enantioselectivity was further improved to 97.0:3.0 er by lowering the reaction temperature; however, the yield dropped significantly (entry 3). After careful examination of various reaction parameters, it was ultimately found that higher concentration was important to afford both high yield and excellent enantioselectivity, even at ambient temperature (entry 4). Finally, iterative addition of phenylboronic acid further improved reaction efficiency without compromising the er, probably through suppressing the undesired reactions such as homo-coupling (entry 5).^5a,15,16b Meanwhile, the Minnaard’s conditions were also effective, affording the product in 87% yield and 96.5:3.5 er. (see supporting information, Table S2).^14b

Table 1.

Optimization of conditions in the Pd-catalyzed asymmetric 1,4-addition

entry	conc. of 1a	temp (°C)	yield (%)a	erb
1	0.25 M	60 °C	69%	95.5:4.5
2c	0.25 M	40 °C	74%	94.5:5.5
3	0.25 M	rt	53%	97.0:3.0
4	0.5 M	rt	86%	97.0:3.0
5 d	0.5 M	rt	95%	97.0:3.0

^aIsolated yield.

^bDetermined by HPLC analysis using commercial chiral columns.

^c5 equiv. of H₂O and 30 mol% of NH₄PF₆ were used as additives.

^dAddition of PhB(OH)₂ at 3 h intervals. For details, see Supporting Information.

The conditions in entry 5 (Table 1) were employed in the synthesis of enantioenriched cyclopentanone substrates (Table 2). The scope of the asymmetric conjugate addition was first investigated using different arylboronic acids. The reaction of 1a with 4-methylphenylboronic acid gave comparable enantioselectivity to that of phenylboronic acid but with reduced yield. In general, decreased yield and enantioselectivity were observed when using substituted arylboronic acids. This issue could be partially relieved by increasing the reaction temperature to 60 °C and loading more catalyst (to 10 mol%), as illustrated in the case of 2c and 2g (for more details, see Supporting Information). Of note, this high temperature was supposed to be necessary to increase the solubility of arylboronic acid, which was often observed as an untransparent mixture at room temperature. Under the modified conditions, cyclopentanones bearing electron-rich (2c, 2d) or electro-poor aryl groups (2e-2h) could be obtained in good to excellent yields and excellent er. A wide range of functional groups on the aromatic ring were tolerated, including ether (2c), 4-chloro (2e), 4-fluoro (2f), trifluoromethyl (2g) and ester (2h). The meta-substituted arylboronic acid also proved to be a competent substrate, providing the adduct (2i) without diminishing the enantioselectivity.¹⁸ In addition, cyclopentenones bearing other β-alkyl substituents, including butyl, cyclohexyl, and an ester-substituted alkyl chain, also delivered the desired arylation products (2j-2l) in good yields and excellent er. Note that elevating the reaction temperature to 60 °C was essential for cyclopentenones possessing either a branched cyclohexyl group (2k) or an ester-substituted alkyl chain (2l).

Table 2.

Substrate preparation via the Pd-catalyzed asymmetric 1,4-addition

Condition: cyclopentenone substrate (0.5 mmol), arylboronic acid (1.0 mmol), Pd(TFA)₂ (0.05 mmol), (S)-t-BuPyOX (0.06 mmol) in 1 mL of 1,2-dichloroethane for 24 h. All yields are isolated yields. Enantiomeric ratios were determined by HPLC analysis using commercial chiral columns.

^aThe reaction was carried out at 60 °C.

^b10 mol% Pd(TFA)₂ and 12 mol% (S)-t-BuPyOX were used.

These cyclopentanones with a β-quaternary stereocenter were then subjected to the Rh-catalyzed C−C/C−H re-organization reaction (Table 3). Under our previously reported conditions,^9a various 1-tetralones were obtained in good yields with moderate to high regioselectivity (1-tetralone versus 1-indanone). Generally, substrates with a strong electron-donating (3c) or electron-withdrawing group (3e, 3g and 3h) showed excellent regioselectivity (>10:1, rr = major: minor) favoring the desired 1-tetralone, while substrates bearing electron-neutral aryl group (3a, 3b and 3d) delivered the product in moderate yields and moderate regioselectivity. Substitution at the meta position (3i) was also tolerated. Compared to the prior cyclopentanone substrates with a β tertiary center,^9a significantly higher reactivity was observed for these with a β quaternary center as no additional 2-aminopyridine (previously 50 mol%) or higher reaction temperature (previously 150 °C) was needed for electronically or sterically biased substrates.^9a The enhanced reactivity could likely be explained by the Thorpe–Ingold effect,¹⁹ where the quaternary stereocenter promotes intramolecular cyclization. In addition to the arene moiety, the effect of the β-alkyl substituents on the C−C activation reaction was also evaluated. The use of butyl (3j), cyclohexyl (3h), and 2-methoxycarbonylethyl (3k) substituents all led to higher yields than the standard ethyl substrate (3a). In particular, bulky cyclohexyl group rendered the reaction with excellent regioselectivity (3k). In all cases, the enantiomeric ratio of the quaternary stereocenters were fully retained (>99% es) to be incorporated in 1-tetralones through this transformation. Besides, the enantiomeric ratio of the minor 1-indanone product 3j’ also remained the same, as exemplified in the reaction of 2j (>99% es, see Supporting Information for details).

Table 3.

Scope of Rh-catalyzed C−C/C−H activation

Condition: substrates 2a-2l (0.2 mmol), [Rh(C₂H₄)₂Cl]₂ (5 mol%), IMes (10 mol%), 2-aminopyridine (25 mol%), TsOH.H₂O (10 mol%), H₂O (50 mol%) in 0.4 mL of 1,4-dioxane at 140 °C for 48 h. Isolated yields for the 1-tetralone product were reported. The regioselective ratios (rr) of C−C activation were determined by ¹H NMR using 1,1,2,2-tetrachloroethane as the internal standard. Enantiomeric ratios were determined by HPLC analysis using commercial chiral columns. Enantiospecificity (es) were calculated based on the er of 2a-2l.

To demonstrate the practicability of this strategy, gram-scale reactions were carried out (Scheme 2a). On a 10 mmol scale, the Pd-catalyzed asymmetric 1,4-addition gave 2a in 97% yield and 97.0:3.0 er. The following Rh-catalyzed C–C activation was also scalable even with a lower catalyst loading, while the regioselectivity was slightly decreased. In addition, the 1-tetralone product (3a) could be conveniently transformed to an interesting tetracycle (4a) in 96% yield through Fischer indole synthesis. Alternatively, it could be converted to a trisubstituted alkene (5a) via a palladium-catalyzed carbene coupling reaction with 4-bromotoluene through the formation of the corresponding N-tosylhydrazone (Scheme 2b).²⁰

Scheme 2.

Gram-scale synthesis and synthetic applications

In summary, we have demonstrated a unique approach to access enantioenriched 1-tetralones with an all-carbon quaternary stereocenter that is remote from the carbonyl moiety. Through a two-step sequence of Pd-catalyzed asymmetric conjugate addition and Rh-catalyzed C−C activation, chiral 1-tetralones have been obtained in good overall yields and excellent enantioselectivity from readily available cyclopentenones and arylboronic acids. The scalability and chemoselectivity could make this method attractive for complex molecule synthesis. While the current scope is limited to 1-tetralone products, the strategy–that is forming a proximal stereocenter with established methods and then transporting it to a distal position–could have broad implications beyond this work.

Biographies

Shusuke Ochi

Ying Xia

Guangbin Dong