A versatile copper-catalyzed γ-C(sp³)−H lactonization of aliphatic acids

Abstract

Site-selective C(sp³)−H oxidation is of great importance in organic synthesis and drug discovery. γ-C(sp³)−H lactonization of free carboxylic acids provides the most straightforward means to prepare biologically important lactone scaffolds from abundant and inexpensive carboxylic acids; however, a versatile catalyst for this transformation with broad substrate scope remains elusive. Herein, we report a simple and yet broadly applicable and scalable γ-lactonization reaction of free aliphatic acids enabled by a copper catalyst in combination with inexpensive Selectfluor as the oxidant. This lactonization reaction exhibits compatibility with tertiary, benzylic, allylic, methylene, and primary γ-C−H bonds, affording access to a wide range of structurally diverse lactones such as spiro-, fused-, and bridged-lactones. Notably, exclusive γ-methylene C−H lactonization of cycloalkane carboxylic acids and cycloalkane acetic acids was observed, giving either fused- or bridged-γ-lactones that are difficult to access by other methods. δ-C−H lactonization was only favored in the presence of tertiary δ-C−H bond. The synthetic utility of this methodology was demonstrated by the late-stage functionalization of amino acids, drug molecules, and natural products, as well as a two-step total synthesis of (iso)mintlactones (the shortest synthesis reported to date).

Graphical Abstract

1. Introduction

Aliphatic carboxylic acids are ubiquitous and diverse starting materials in organic chemistry. Therefore, the ability to site-selectively functionalize multiple C−H bonds in this class of substrates could afford unprecedented disconnections and greatly expedite the synthesis of target molecules. Recently, the development of new ligands has facilitated the rapid development of carboxylic acid-directed β-C−H functionalizations for the construction of diverse C−C and C−Y (Y = heteroatom) bonds^1–4. However, distal γ-methylene C−H activation via C−H palladation remains limited to cycloalkane or dicarboxylic acids^4–6. Radical-mediated C(sp³)−H functionalization offers a complementary strategy to functionalize γ-methylene C−H bonds in aliphatic amides via 1,5-hydrogen atom transfer (1,5-HAT) from amidyl radicals (Scheme 1A)^7–12. However, extending these HAT strategies to free carboxylic acid substrates is very challenging due to the propensity of alkyl carboxylate radicals to undergo decarboxylative fragmentation. As such, the development of a general and practical γ-C−H functionalization of free carboxylic acids remains a fundamental chemical challenge.

Scheme 1.

C(sp³)−H lactonization of free carboxylic acids

Due to the abundance of lactone motifs among natural products, pharmaceuticals, and agrochemical compounds^13–15, the development of practical C(sp³)−H lactonization reactions of free carboxylic acids has been pursued since the 1980s (Scheme 1B)¹⁶. Although benzylic γ-lactonizations using catalytic copper have been developed, these protocols lack applicability to a more general scope of aliphatic carboxylic acids¹⁷. Platinum-catalyzed γ-lactonizations of aliphatic acids have also been investigated, but with limited scope and low yields^18,19. Recently, a palladium-catalyzed γ-methylene C−H lactonization was realized, but its scope was limited to dicarboxylic acids⁴. So far, the γ-methylene C−H lactonization of simple aliphatic acids has only been demonstrated using biomimetic catalyst systems, wherein tetraaza ligand-supported iron- or manganese-oxo species are directed to perform 1,7-HAT processes^20–24. Thus, a simple and widely applicable metal catalyst for γ-methylene C−H lactonization remains to be developed. A key trend in the development of green and sustainable chemistry is the reduction of reliance on precious metals such as platinum and palladium. Using inexpensive and sustainable earth-abundant first-row transition metals such as copper as alternatives to precious metals in lactonization reaction is highly desirable^25,26.

Herein, we report a versatile and scalable γ-lactonization of abundant free carboxylic acids using a copper catalyst and Selectfluor as the sole oxidant, affording structurally diverse spiro-, fused-, or bridged-lactones (Scheme 1C). Tertiary, benzylic, allylic, methylene, and primary C−H bonds were all compatible with this protocol, as demonstrated by the late-stage lactonizations of amino acids (leucine, norvaline, homophenylalanine, β-homophenylalanine, and tert-leucine), drug molecules (pregabalin and gabapentin), and natural products (isosteviol). Notably, exclusive γ-methylene C−H lactonizations of cycloalkane carboxylic acids and cycloalkane acetic acids were observed, providing access to either fused- or bridged-γ-lactones that are difficult to access by other methods. δ-C−H lactonization was only favored in the presence of tertiary δ-C−H bond. The wider synthetic applications of this methodology were demonstrated by a two-step total synthesis of mintlactone and isomintlactone through a Wittig-Horner reaction and subsequent γ-lactonization.

2. Results and Discussion

Non-directed HAT-mediated radical C(sp³)−H functionalization has attracted significant attention recently²⁷. However, selectivity in these non-directed HAT reactions is usually a function of the strengths of the different C−H bonds among the substrate, with the functionalization of weaker benzylic and tertiary C−H bonds favored over stronger secondary or primary C−H bonds. We envisioned that we could achieve a formally directed radical γ-C−H lactonization reaction by combining a non-directed radical C−H abstraction process with a subsequent intramolecular carbocationic cyclization. Due to kinetic and thermodynamic factors, trapping the carbocationic intermediate (generated by oxidation of the initial carbon radical) with a pendant carboxylic acid would favor the formation of five-membered products, thereby enhancing the site selectivity of the lactonization for methylene and primary C−H bonds at γ sites. Unlike previously reported oxidations of amino acids with biomimetic iron and manganese catalysts, where the γ-selectivity is primarily influenced by the acid-directed 1,7-HAT step, the selectivity of this approach is determined by a combination of the characteristics of the γ-C−H bonds and the geometry of the lactonization transition states.

In order to realize this sequential process involving radical C−H abstraction, carbocation formation, and cyclization, we began our investigation on the lactonization of carboxylic acids using 4-methylpentanoic acid 1a as a model substrate. Taking inspiration from the Kharasch−Sosnovsky reaction, which uses a copper catalyst and a peroxide for allylic C−H abstraction²⁸, we extensively surveyed various metal catalysts and oxidants for activity in the desired lactonization reaction (see Table S1−S5). These studies revealed that a combination of Cu(CH₃CN)₄PF₆ (10 mol%) and Selectfluor (2.0 equiv) was the most efficient system for promoting the HAT and subsequent γ-lactonization steps, delivering the desired γ-lactone 2a in 90% isolated yield²⁹. Notably, Cu(I) catalyst, Cu(CH₃CN)₄PF₆ (US$2 per gram), and Selectfluor (US$1 per gram) are inexpensive and Selectfluor is a non-explosive, non-toxic, and easily-handled electrophilic fluorinating reagent. This same catalyst was previously used for Ritter-type tertiary C−H amination reactions³⁰. The Cu(II) catalyst, Cu(OAc)₂, was also effective in the lactonization reaction to provide the desired product in 77% ¹H NMR (nuclear magnetic resonance) yield (see Table S6). Interestingly, Pd(CH₃CN)₂Cl₂ (3 mol%) also exhibited comparably good reactivity, affording the product in 71% ¹H NMR yield, while also avoiding the formation of β-functionalized products¹. The fluorinated alcohol solvent HFIP was essential for the observed reactivity probably due to its ability to stabilize transient radical intermediates³¹. The lactonization of the corresponding ethyl ester of 1a provided the same γ-lactone product 2a, indicating that a 1,5-HAT process initiated by a carboxylate radical is unlikely. Furthermore, this observation suggests that our catalyst system may be broadly compatible with ester substrates, thus facilitating more efficient syntheses in cases where the corresponding acids are not easily accessible (Scheme 2B). Based on previous literatures and our experimental results, we propose that γ-lactonization of acids proceeds via the Cu(I)/Cu(II) catalytic cycle (See Scheme S1 in SI). First, Cu(I) catalyst is oxidized by Selectfluor oxidant to form Cu(II), which concomitantly generates the nitrogen-centered radical cation (Selectfluor radical dication) responsible for the non-directed radical C−H abstraction.²⁹ Next, electrophilic HAT of aliphatic acids produces an initial carbon radical int-I, which is subsequently oxidized by Cu(II) to form a carbocationic intermediate int-II. The favored γ-carbocation formation may be due to carbocation migration, as evidenced by the formation of an alkyl-shifted γ-lactone product when the γ position of the aliphatic acid is blocked. Finally, trapping the int-II with a pendant carboxylic acid yields a kinetically and thermodynamically favored five-membered γ-lactone product. The stoichiometry of Selectfluor oxidant is required to drive Cu(I)/Cu(II) catalytic cycle.

Scheme 2.

Gram-scale lactonization and its synthetic application

With the optimal reaction conditions in hand, we next evaluated the scope of the γ-C(sp³)−H lactonization reaction (Table 1). A wide range of free carboxylic acids containing tertiary, benzylic, allylic, methylene, and primary C−H bonds at γ-positions were all compatible under these conditions, affording spiro-, fused-, and bridged-lactones in moderate to excellent yields (24−99%). Among these substrates, the late-stage functionalization of amino acids (1d, 1s, 1t, 1al, and 1be) and complex bioactive molecules (1l, 1ar, and 1bd) was also demonstrated. In contrast to cyclometalation strategies, where reactivity is constrained by the substituents on the substrates because of the Thorpe-Ingold effect, in this copper-catalyzed γ-lactonization reaction, aliphatic carboxylic acids bearing α-quaternary, tertiary, or secondary centers were all reactive substrates. Cu(CH₃CN)₄PF₆ was generally the optimal catalyst, but in some cases (1f−h, 1n, 1aj, and 1ak), Pd(CH₃CN)₂Cl₂ (3 mol%) displayed comparably high reactivity and good site-selectivity. The formation of Selectfluor radical dication by Pd(II) and Selectfluor has been reported³². Lactonization of tertiary γ-C−H bonds generally afforded the desired lactone products (2a−i) in modest to good yields (47−98%) with exclusive γ-site-selectivity, including biologically valuable fused-lactones (2e), spiro-lactones (2f−h) and bridged-lactones (2i). δ-C−H lactonization was favored in the presence of tertiary δ-C−H bond (2j−n). Among these, a variety of functional groups such as hydroxy (2b), chloro (2c), phthalimide (2d and 2l), and carboxyl (2k) were all well-tolerated, potentially serving as useful synthetic handles for subsequent derivatization. Benzylic γ-lactonization generally proceeded well (1o−ac) using copper catalyst loadings as low as 3 mol%, delivering benzo-fused γ-lactones in yields ranging from modest to excellent (32−98%). The formation of phthalides (2x−ac) and 3-isochromanone (2ad) via lactonization was extremely valuable due to the abundance of these motifs among natural products and biologically important molecules¹⁴. The γ-lactonization of aliphatic acids containing a substituent at the β-position (1t and 1w) gave the desired products with high diastereoselectivity (16/1 and > 20/1, respectively). Notably, this protocol was compatible with challenging electron-deficient arenes such as pyridines containing an electron-withdrawing group (2x and 2y), which were unreactive in previous reports due to their tendency to poison the metal catalyst by coordination. A wide range of substituents, such as fluoro (2p), chloro (2q and 2y), ketone (2r), carboxyl (2r), trifluoromethyl (2x), and strained cyclobutyl (2u), was well tolerated, with chloro serving as a useful handle for further synthetic elaboration. It is noteworthy that polar functional groups, including nitro, primary amine, and simple pyridine, are not compatible with the current conditions (see Table S7). Allylic γ-lactonization consistently afforded β-alkylidene-γ-lactone (2ae) and butenolide (2af) in synthetically useful yields (38% and 55%, respectively), with the olefin remaining intact in the presence of the electrophilic F⁺ reagent. While methylene lactonization of acyclic aliphatic acids (1ag−an) generally provided a mixture of γ- and δ-lactones in moderate yields (35−57%), the lactonization of cyclic substrates (1ao−bd) delivered fused-lactones (2ao−at) and bridged-lactones (2au−bd) with exclusive γ-selectivity in modest to good yields (30−71%), presumably due to a more restricted geometry in the lactonization transition state. Notably, the single-step preparation of bicyclo[3.2.1] and bicyclo[2.2.1] lactones from parent carboxylic acids was extremely valuable (2au−bd), providing strategic retrosynthetic disconnections that are otherwise difficult to achieve using traditional methods. The biologically important isoxazoline moiety was also well tolerated (2at). This reaction’s exquisite site-selectivity was highlighted in the selective late-stage γ-lactonization of isosteviol, a diterpene metabolite, which contains two tertiary, nine secondary, and three primary carbons. Free carboxylic acids containing less reactive primary γ-C−H bonds (1be and 1bf) also successfully underwent lactonization under the optimal reaction conditions.

Table 1.

Substrate scope of the lactonization of free carboxylic acids^a,b

^aConditions: Substrate 1a−bf (0.1 mmol), Cu(CH₃CN)₄PF₆ (3−10 mol%), Selectfluor (2.0 equiv), HFIP (1.0 mL), 90−120 °C, 12 h.

^bIsolated yields.

^cPd(CH₃CN)₂Cl₂ (3 mol%) and Li₂CO₃ (1.0 equiv) instead of Cu(CH₃CN)₄PF₆ (10 mol%).

To demonstrate the scalability of this protocol, a gram-scale γ-lactonization of 1-methyl-1-cyclohexanecarboxylic acid 1av with 3 mol% copper catalyst was conducted, delivering the γ-lactone product 2av in 63% yield (Scheme 2A). The γ-lactone products served as versatile linchpins to install hydroxyl, iodo, or phenyl groups at the γ-position by ring-opening reactions (Scheme 2A): (1) mild hydrolysis of 2av gave the γ-hydroxyl acid 3a in high yield (80%); (2) opening the γ-lactone in the presence of NaI and TMSCl delivered the trans-γ-iodinated aliphatic acid 3b in useful yield (63%), a versatile intermediate for further elaboration; (3) a Friedel-Crafts reaction between γ-lactone 2av and benzene using the Lewis acid AlCl₃ forged a new C−C bond at the γ-position of the parent acid 1av as a trans-diastereomer in good yield (71%). Given the power of this methodology for the construction of diverse lactone scaffolds, we embarked on a two-step total synthesis of mintlactone and isomintlactone via a Wittig-Horner reaction and subsequent γ-lactonization (Scheme 2B). (–)-Mintlactone and (+)-isomintlactone, two natural monoterpenic lactones found in the essential oil of several Mentha species, have been the target of numerous synthesis campaigns³³. Our synthesis began with a Wittig-Horner reaction of 4-methylcyclohexanone for the preparation of the γ-lactonization precursor ester 1bg. Because our methodology is compatible with ester substrates, the copper-catalyzed γ-lactonization was then performed under the standard conditions to give (±)-isomintlactone 2bg and (±)-mintlactone 2bg’ in 43% and 21% yield, respectively, completing the total synthesis in two steps, the shortest total synthesis to date.

3. Conclusion

In conclusion, we have developed a versatile site-selective γ-lactonization protocol using an inexpensive copper catalyst and Selectfluor. The selectivity of non-directed HAT reactions is governed by the strengths of the different C−H bonds among the substrates. This work demonstrates that γ-selectivity can be achieved through C−H abstraction and subsequent intramolecular cyclization to form a kinetically and thermodynamically favored five-membered lactone. We envision that this strategy could potentially be applied to other substrates bearing nucleophilic heteroatom, such as amides, amines, or alcohols, for the construction of lactams, pyrrolidines, and tetrahydrofurans.

4. Experimental Section

General procedure for the γ-C(sp³)−H lactonization

Into a culture tube, Cu(CH₃CN)₄PF₆ (10 mol%, 3.7 mg), Selectfluor (2.0 equiv, 70.8 mg), and aliphatic carboxylic acid 1 (0.1 mmol) were weighed in air in this order and a magnetic stir bar was added. Then HFIP (1.0 mL) was added. The reaction mixture was stirred at rt for 3 min, and then heated to 100 °C for 12 h (600 rpm). After being allowed to cool to room temperature, the mixture was diluted with DCM, filtered through a Celite plug, and concentrated in vacuo. The crude mixture was purified by pTLC or column chromatography to afford the lactone product.