Copper Hydride Catalyzed Enantioselective Synthesis of Axially Chiral 1,3-Disubstituted Allenes

Abstract

The general enantioselective synthesis of axially chiral disubstituted allenes from prochiral starting materials remains a long-standing challenge in organic synthesis. Here, we report an efficient enantio- and chemoselective copper hydride catalyzed semireduction of conjugated enynes to furnish 1,3-disubstituted allenes using water as the proton source. This protocol is sufficiently mild to accommodate an assortment of functional groups including keto, ester, amino, halo, and hydroxyl groups. Additionally, applications of this method for the selective synthesis of monodeuterated allenes and chiral 2,5-dihydropyrroles are described.

Allenes form a distinctive class of compounds capable of exhibiting axial chirality. They are represented in over 2,900 natural metabolites and synthetic compounds, and have been studied with regard to biological activity for over 40 years.¹ The introduction of allenes into steroids, prostaglandins, carbacyclins, and unnatural amino acids and nucleosides has been shown to increase the metabolic stability, bioavailability, and potency of these bioactive compounds.² Additionally, these cumulated dienes have found use in molecular materials and as synthetic intermediates in complex chemical syntheses as substrates due to their substituent-loading capability and enhanced reactivity under mild reaction conditions. Their tranformation often takes advantage of axial-to-central chirality transfer to generate one or more new stereogenic centers.³ Finally, chiral allenes have also been explored in asymmetric autocatalysis and as ligands for the development of enantioselective transformations.⁴⁻⁶

While the utility of chiral allenes has been widely explored, the selective synthesis of these valuable materials still remains a challenge in organic synthesis.^3a,7 Traditional approaches to access enantioenriched allenes most commonly start from chiral, enantioenriched precursors wherein the allene product is generated through nucleophilic displacement, rearrangement, or elimination with central-to-axial chirality transfer (Figure 1) or through resolution of racemic allenes. More recently, several methods have employed achiral or racemic starting materials in catalytic asymmetric versions of these reactions to access the desired product using catalysts bearing chiral ligands. However, the majority of these reports target the synthesis of tri- or tetrasubstituted allenes.⁸

Figure 1.

Synthetic strategies for the construction of enantioenriched allenes and representative examples of valuable 1,3-disubstituted allenes.

The direct catalytic conversion of prochiral 1,3-enynes to enantioenriched allenes has become a practical synthetic strategy in recent years, owing to the accessibility of these substrates.⁹ Early reports by Hayashi describe the direct catalytic and enantioselective conversion of 1,3-enynes to boryl, silyl, or aryl allenes via palladium or rhodium catalysis.^8a−8d Since then, methods detailing the stereoselective transformations of enynes, including reports by Loh, Feng, Tang, Sun, and Malcolmson, have provided novel routes to enantioenriched allenes containing esters, lactones, or amines.^{8g,8l,8n,8p,10}

The LCuH-catalyzed hydrofunctionalization of 1,3-enynes to access enantioenriched allenes was first reported by the Hoveyda group wherein trisubstituted allenyl boronate derivatives are generated in high yield and enantioselectivity (Scheme 1a).¹¹ Shortly thereafter, the Ge and Engle groups independently disclosed their own reports of enyne hydroboration, followed by Ge’s report of the catalytic asymmetric hydroarylation of enynes to provide access to quinoline-substituted allenes.¹²⁻¹⁴

Scheme 1. Precedent for the Proposed Asymmetric LCuH-Catalyzed Semi-reduction of 1,3-Enynes.

Despite these recent advances, fewer reports describe the catalytic synthesis of enantioenriched 1,3-disubstituted allenes from prochiral or racemic precursors.^10,15−21 While these methods have offered elegant and innovative routes to this class of allenes, the vast majority of them provide access to a limited scope of products including allenyl esters,^16,18 alcohols,¹⁹ and amines.^10,16,20 This modest scope is perhaps due to difficulty in controlling the stereochemical outcome of a three-carbon axis of chirality possessing two hydrogen substituents without an additional functional group handle. Consequently, there persists an unmet need for a general strategy to access a broad range of 1,3-disubstituted axially chiral allenes.

In the course of our ongoing studies on the hydroalkylation of 1,3-enynes with imines, we serendipitously discovered an alternative strategy for the synthesis of 1,3-disubstituted allenes (Scheme 1b). Analogous to our previous report on the hydroalkylation of conjugated enynes with ketones,²² enantioenriched allenyl copper intermediates 2 are generated via hydrocupration of an achiral 1,3-enyne starting material (1). However, trapping of the allenyl copper species 2 directly with a proton, instead of a ketone (which favors the alternative S_E2′ reaction pathway to yield γ-adduct 3), would provide access to axially chiral 1,3-disubstituted allenes (4). Potential challenges in developing this reaction include avoiding the unproductive silylation of the protonating reagent,²³ controlling the regioselectivity²⁴ and enantioselectivity of the process, and preventing further reduction of the allene product in the presence of the copper hydride catalyst. To date, the semireduction of 1,3-enynes to enantioenriched disubstituted allenes has only been demonstrated with the stoichiometric use of chiral metal reducing agents.²⁵ Herein, we report the asymmetric catalytic semireduction of 1,3-enynes to furnish axially chiral allenes enabled by CuH-catalysis.

We began our studies utilizing 1,2-bis((2S,5S)-2,5-diphenylphospholano)ethane [(S,S)-Ph-BPE] in combination with Cu(OAc)₂ and dimethoxy(methyl)silane (DMMS) to generate a chiral LCuH complex previously shown to engage 1,3-enyne 1a (Table 1).²² At room temperature with t-BuOH as the proton source, the complete consumption of 1a occurred yielding a complex mixture consisting primarily of products from the unselective hydrogenation of the desired product, allene 4a (entry 1). Decreasing the reaction temperature to −10 °C slowed the over-reduction and provided 4a in 34% yield and 60:40 enantiomeric ratio (er) (entry 2). A subsequent screen of several ethereal solvents indicated that both chemo- and enantioselectivity were enhanced by replacing THF with 1,2-dimethoxyethane (DME) (entries 3–5).

Table 1. Reaction Optimization^a.

entry	T (°C)	solvent	proton source	silane	% conv	% yieldb	erc
1	23	THF	t-BuOH (1.5 equiv)	DMMS	100	0	–
2	–10	THF	t-BuOH (1.5 equiv)	DMMS	100	34	60:40
3	–10	MTBEd	t-BuOH (1.5 equiv)	DMMS	64	36	87:13
4	–10	1,4-Dioxane	t-BuOH (1.5 equiv)	DMMS	67	26	92:8
5	–10	DME	t-BuOH (1.5 equiv)	DMMS	50	36	96:4
6	–10	DME	i-PrOH (1.5 equiv)	DMMS	100	68	99:1
7	–10	DME	i-PrOH (1.1 equiv)	DMMS	100	90	99:1
8	–10	DME	H2O (0.55 equiv)	DMMS	100	90	>99:1
9e	–10	DME	H2O (0.52 equiv)	TMCTS	100	90f	>99:1

^aConditions: Reactions were carried out under a N₂ atmosphere. 0.2 mmol enyne (1 equiv), copper(II) acetate (3 mol %), (S,S)-Ph-BPE (3.3 mol %), silane (4 equiv) in solvent (0.4 mL).

^bYield was determined by ¹H NMR spectroscopy of the crude reaction mixture, using mesitylene as an internal standard.

^cEnantiomeric ratio was determined by GC analysis, and the absolute configuration of 4a was determined by analogy to desilylated 4f (see the Supporting Information for more details).

^dMTBE = methyl tert-butyl ether.

^eReaction was run with 1 mol % copper(II) acetate and 1.1 mol % (S,S)-Ph-BPE over 16.5 h instead.

^fReported as an average of two isolated yields.

The use of a sterically less hindered proton source, i-PrOH, provided improved conversion and enantiomeric ratio of product 4a. Moreover, we found that by decreasing the quantity of i-PrOH to 1.1 equiv minimized the amount of overreduction that was observed (entries 6–7). As the use of a less hindered proton source proved beneficial for both yield and er, we next examined the use of H₂O (0.55 equiv) which resulted in the efficient delivery of both protons in the enyne semireduction (entry 8). Further, we found that substituting DMMS with 0.5 equiv of 2,4,6,8-tetramethylcyclotetrasiloxane (TMCTS) and decreasing the catalyst loading to 1 mol % provided improved reaction conditions for the enantioselective semireduction of 1,3-enyne 1a affording the desired product (R)-4a in 90% isolated yield and >99:1 er (entry 9).

Next, we surveyed the generality of the LCuH-catalyzed asymmetric semireduction of an assortment of terminal 1,3-enynes (Table 2).²⁶ Unfunctionalized substrates are efficiently converted to the corresponding allenes in good yield and exceptional er (4a–c). Enynes bearing a variety of functional groups are tolerated under the reaction conditions including potentially reducible groups such as alkyl chlorides (4d) and ketones (4e) as well as ethers (4f, 4i), amines (4j, 4l), and various heterocycles (4i, 4k, 4n, 4o). Substrates containing unprotected alcohols are not only tolerated, but the unhindered primary alcohol of enyne 1g, itself, serves as a proton source in the reduction, permitting the use of only 0.25 equiv of H₂O additive to furnish allene 4g. The reactivity and selectivity of the sterically more encumbered enyne 1h, bearing an unprotected propargylic alcohol, were unaffected, providing allenyl alcohol 4h with 88% yield and >99:1 er. While substrates containing free N–H bonds react with a high yield, the allene products are produced with a diminished er (4m, n). In the case of 1n it was demonstrated that the use of the protected variant, 1o, provided significantly improved results (4o). Finally, this protocol exhibits excellent catalyst control in the semireduction of chiral enyne 1p to furnish either diastereomer of allene 4p depending on the enantiomer of ligand used.

Table 2. Substrate Scope of the LCuH-Catalyzed Asymmetric Semi-reduction of 1,3-Enynes to Allenes^a.

^aReactions were carried out under a N₂ atmosphere at −10 °C. Isolated yields and enantiomeric ratios are reported as an average of two independent runs.

^bYield was determined by ¹H NMR spectroscopy using mesitylene as an internal standard due to the volatility of the product.

^cWith 0.25 equiv of H₂O instead.

^dYield and diastereomeric ratio reported for a single run.

Our initial efforts to effect the asymmetric semireduction of internal 1,3-enyne substrates proved considerably more challenging. This difficulty was presumably due, in part, to an increased energetic barrier to hydrocupration, resulting in low conversion (possibly owing to unproductive silylation of the proton source) as well as, in some cases, competitive overreduction of the initially formed allene products.²⁷ To ameliorate these issues, we found that the utilization of a protocol with the slow addition of water was essential (Table 3). The reaction of ester-containing enyne 1q occurred in moderate yield, largely due to competitive overreduction of the desired product, 4q. The antifungal antibiotic Terbinafine (1r) was cleanly transformed to 4r in 68% yield and 99:1 er, although it necessitated an increase in H₂O and TMCTS loading.²⁸ The direct conversion of fatty acid natural product 1s to laballenic acid (4s), a seed oil natural product isolated from the Leonitis nepetaefolia plant, could also be accomplished.²⁹⁻³² The in situ protection of carboxylic acid 1s with DMMS (to furnish the corresponding silyl ester) at room temperature was carried out, followed by slow addition of water at −10 °C to deliver laballenic acid in 50% yield and 93:7 er.

Table 3. Select Examples of the LCuH-Catalyzed Asymmetric Semi-reduction of Internal Enynes to Allenes^a.

^aReactions were carried out under a N₂ atmosphere at −10 °C, and H₂O was added over a 16 h time period. Isolated yields and enantiomeric ratios are reported as an average of two independent runs.

^bReaction required a 1 h prestir at room temperature prior to addition of water at −10 °C.

Based on previous mechanistic studies and DFT calculations,^11,22 we propose the following mechanism detailed in Figure 2. After generation of the chiral LCuH complex I, enantioselective hydrocupration of enyne II affords a chiral propargylic copper species (III). This undergoes a stereospecific 1,3-isomerization to yield allenyl copper intermediate V. Next intermediate V is protonated to furnish the final product, allene VI. σ-Bond metathesis between VII and silane (VIII) results in the formation of silanol IX and regeneration of I. As less than a full equivalent of water is utilized in this process, we propose that silanol IX can also facilitate proto-demetalation, producing siloxane X.

Figure 2.

Proposed catalytic cycle for the LCuH-catalyzed conversion of 1,3-enynes to allenes.

Two examples demonstrating further applications of this methodology are depicted in Scheme 2. The incorporation of deuterium into molecular scaffolds is pervasive not only in the pharmaceutical industry, due to the enhanced metabolic stability and safety imparted by corresponding deutero-analogs, but also in mechanistic studies and protein crystallography.³³ Substitution of H₂O for D₂O selectively delivers enantioenriched monodeuterated products, as exhibited in the conversion of enyne 1t to allene 5 with 98:2 D/H incorporation (Scheme 2a). This protocol represents a new strategy for the deuterium labeling of allenes, employing an affordable, easy to handle, and abundant deuterium source.

Scheme 2. Applications of the LCuH-Catalyzed Asymmetric Reduction for Deuterium Incorporation and Heterocycle Synthesis.

Additionally, enantioenriched allenyl alcohols and amines are known to serve as valuable synthetic intermediates toward the production of chiral heterocycles including dihydrofurans and dihydropyrroles.^3h,34,35 Taking advantage of the highly selective nature of gold-catalyzed cycloisomerization chemistry, α-aminoallene 4l furnished 2,5-dihydropyrrole 6 with complete axial-to-point chirality transfer (Scheme 2b).^36,37

In summary, we have developed a LCuH-catalyzed asymmetric semireduction of 1,3-enynes to supply highly enantioenriched 1,3-disubstituted allenes in up to 98% yield and >99:1 er. This chemistry benefits from the functional group tolerance afforded by the mild reducing nature of LCuH catalysts and employs only a 1–2 mol % catalyst loading. Moreover, the utilization of substoichiometric quantities of H₂O as the proton source and TMCTS as the hydride source provides an efficient protocol for the hydrogenation of terminal 1,3-enynes. The reduction of internal conjugated enynes is enabled via slow addition of water and has been demonstrated through the late-stage derivatization of antibiotic Terbinafine and the synthesis of the seed oil natural product, laballenic acid. Furthermore, this protocol provides an efficient synthetic route for the construction of deutero-allenes as well as aza-heterocycles.

Supporting Information Available

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.9b07582.

• General procedural information and characterization data (PDF)

• NMR spectra (PDF)

• SFC, GC, and HPLC traces (PDF)

The authors declare no competing financial interest.