Catalytic Asymmetric Synthesis of Axially Chiral Methylenecyclopropanes

Abstract

Atropisomeric compounds and 1,3-disubstituted allenes are the most common examples of axial chirality in organic chemistry. However, there are less explored classes of axially chiral molecules that may also hold significant value in asymmetric synthesis. Here, we report a catalytic asymmetric synthesis of axially chiral methylenecyclopropanes by a [2 + 1]-cycloaddition of an alkene and a vinylidene equivalent. Computational models provide a rationale for the origin of asymmetric induction and indicate that key elements of stereocontrol differ from catalytic enantioselective cyclopropanation reactions using carbenes. Methylenecyclopropanes participate in a broad range of axial-to-central chirality transfer reactions that take advantage of addition to the alkene or ring-opening of the strained three-membered ring.

Graphical Abstract

INTRODUCTION

Axially chiral compounds have unique functions in organic chemistry that cannot be readily replicated using compounds whose chirality arise solely from stereogenic centers (Figure 1A). For example, containing atropisomeric 2,2’-binaphthalenes are privileged substructures in chiral ligands¹ and organocatalysts.² Allenes can undergo axial-to-central chirality transfer reactions to generate useful unsaturated building blocks in highly enantioenriched form.³ There are also numerous natural products⁴ and pharmaceutical compounds⁵ that feature axial chirality.

Figure 1. Catalytic asymmetric synthesis of axially chiral methylenecyclopropanes.

A) Ligands, natural products, and pharmaceutical compounds featuring axial chirality. B) Additions of vinylidenes to symmetrical (Z)-alkenes generate axially chiral methylenecyclopropanes. C) Proposed stepwise mechanism for cyclopropanation involving a [2 + 2]-cycloaddition of a cobalt vinylidene and an alkene followed by C–C reductive elimination. D) Identification of an optimal PyBox ligand for the highly enantioselective reductive [2 + 1]-cycloaddition of 1,1-dichloroalkene 1 and cyclopentene (2).

Beyond atropisomeric compounds and allenes, there are also several other axially chiral structures that are currently underexplored in asymmetric synthesis. One such example is the methylenecycloalkane class of molecules,⁶ among which the smallest ring size, methylenecyclopropanes, possesses the greatest potential utility. The addition of a carbene to a symmetrical Z-alkene necessarily generates an achiral cyclopropane. However, a related addition of a vinylidene can generate an axially chiral product if the alkene substituents break the plane of symmetry. These methylenecyclopropanes display the unusual property of E/Z-enantiomerism in that E-to-Z isomerization of the alkene leads to an inversion in absolute configuration (Figure 1B).

Methylenecyclopropanes are versatile synthetic intermediates because they combine a reactive exocyclic alkene with a three-membered ring that has 39 kcal/mol of strain energy, approximately 10 kcal/mol higher than that of parent cyclopropane.⁷ As such, a broad scope of alkene additions and ring-opening reactions of methylenecyclopropanes have been developed.⁸ Despite the utility of these reactions, their application in axial-to-central chirality transfer processes has not been evaluated due to the requisite starting materials not being available. There is only one example of a catalytic [2 + 1]-cycloaddition of a vinylidene equivalent and an alkene to generate an axially chiral methylenecyclopropane.⁹ Due to the mechanistic constraints of the reaction, only norbornene derivatives could be used as the 2π component.

We are exploring an alternative strategy to access metal vinylidene species based on the reductive activation of 1,1-dichloroalkenes.¹⁰ Here, we report a highly enantioselective synthesis of axially chiral methylenecyclopropanes by a cobalt-catalyzed [2 + 1]-cycloaddition. The reaction is effective for acyclic and cyclic Z-alkenes and accommodates significant structural diversity in the vinylidene partner. In our proposed mechanism (Figure 1C), a low-valent Co(I) complex (I) activates the 1,1-dichloroalkene by oxidative addition. Subsequent reduction by Zn generates a Co=C=CHR intermediate (II), which adds to the alkene in a [2 + 2]-cycloaddition step. Formation of the intermediate alkene adduct III likely requires dissociation of Cl⁻ in order to avoid exceeding 18 valence electrons. Finally, the Co(III) metallacyclobutane (IV) undergoes reductive elimination to yield the methylenecyclopropane product. Models for the origin of asymmetric induction and applications of highly enantioenriched methylenecyclopropanes in axial-to-central chirality transfer processes are described.

RESULTS AND DISCUSSION

We began our studies by examining the cobalt-catalyzed reductive cyclopropanation of cyclopentene (2) using 1,1-dichloroalkene 1 as a model vinylidene partner (Figure 1D). An initial ligand screen revealed ^i-PrPyBox (4) (PyBox = pyridine–bis(oxazoline)) as being a promising candidate with regard to enantioselectivity. Other PyBox derivatives containing i-Bu (5), t-Bu (6), or Ph (7) substituents provided lower ee values. Reaction monitoring by ¹H NMR spectroscopy revealed that the relatively low yield of 3 using ligand 4 can be attributed to decomposition of the catalyst into a form that continues to consume the 1,1-dichloroalkene but no longer generates the desired methylenecyclopropane. It has been observed in related redox-active nitrogen donor ligands that 4-substitution of the pyridine ring can mitigate ligand decomposition pathways. Accordingly, PyBox derivatives containing either a methoxy group (8) or a t-Bu group (9) at the 4-position displayed improved yields, and 4-OMe derivative 8 was selected as the optimal ligand.¹¹ A moderate improvement in yield was observed using a ZnBr₂ Lewis acid additive.

The substrate scope of the axially chiral methylenecyclopropane synthesis is summarized in Figure 2. A broad range of electron-rich to electron-poor aryl substituents on the vinylidene component are tolerated. Functional groups used in cross-coupling reactions, such as aryl bromides (product 14) and boronate esters (product 12), do not undergo competing activation by the catalyst. Oxygen and nitrogen heterocycles (products 17–20) can be incorporated without significant reduction in yield. Branched alkenyl- and alkyl-substituted 1,1-dichloroalkenes (products 21 and 22) react efficiently with only a moderate decrease in ee. However, 1,1-dichloroalkenes containing linear alkyl groups provide lower levels of enantioselectivity. The absolute configuration of solid methylenecyclopropane 23 was established by X-ray crystallography.

Figure 2. Substrate scope studies.

Standard reaction conditions: 1,1-dichloroalkene (0.2 mmol), alkene (2.0 equiv), Co(dme)Br₂ (10 mol%), ^MeO,i-PrPyBox (8, 10 mol%), ZnBr₂ (1.0 equiv), Zn (3.0 equiv), NMP, 4 h, rt. ^a15 mol% instead of 10 mol % catalyst loading. ^bwithout ZnBr₂. ^cPhotoredox reduction: Ru(bpy)₃(PF₆)₂ (2 mol%), Hantzsch ester (1.5 equiv), K₃PO₄ (2.0 equiv), 450 nm LED.

Cyclic alkenes ranging from five- to eight-membered rings are effective reaction partners. Heteroatom substitution and elements of unsaturation do not negatively impact the yield or enantioselectivity of the reaction. Acyclic (Z)-alkenes are also viable substrates and produce cis-disubstituted methylenecyclopropanes (products 31 and 32) with no erosion to the trans diastereomer. To test the impact of ring-substitution, cyclopentenes containing substituents at the 4-position were examined (products 33–36). In cases where the substituent had significant steric bulk (e.g., CH₂OTBS, CO₂Me, and NPhth), the products were obtained with dr values greater than 20:1. The configuration of the major diastereomer for 36 was assigned by X-ray crystallography.

As is the case with other axially chiral compounds, methylenecyclopropanes containing arenes on both sides of the chiral axis display large optical rotations. For example, product 25, derived from 1,4-dihydronaphthalene, has a specific rotation of −592°, which is the highest value observed among the products shown in Figure 2.

Under standard reaction conditions, 2,4-dihydrofuran (37) did not form a methylenecyclopropane product but instead generated homoallylic alcohol 38 in 56% yield and 94% ee. Based on our previous studies,¹² we hypothesized that product 38 arose from a Lewis-acid promoted β-alkoxide elimination that outcompeted the desired C–C reductive elimination. To circumvent this process, it was necessary to identify a reductant that would avoid the formation of a Lewis acidic byproduct. To that end, photoredox conditions using Ru(bpy)₃²⁺ as a photocatalyst and Hantzsch Ester as a terminal reductant yielded methylenecyclopropane 39 with minimal competing formation of 38.

Because of the unusual nature of the axial chirality featured in the methylenecyclopropane products, it was of interest to understand the origin of asymmetric induction. The stereochemical features of the putative cobalt vinylidene intermediate are shown in Figure 3C. The i-Pr substituents of the ligand occupy opposing quadrants (B and D), and the vinylidene substituent is oriented above the plane of the PyBox ligand in quadrants C and D. Quadrant A is the most sterically accessible, and attack of the alkene along this trajectory leads to the experimentally observed major enantiomer of the product (Figure 3B). According to DFT models, quadrant C is the next most favorable trajectory and generates the minor enantiomer (Figure 3A). Approach of the alkene in the quadrant occupied by the i-Pr group but away from the vinylidene substituent is slightly less favorable (quadrant B), and quadrant D represents the doubly disfavored trajectory. The transition states corresponding to quadrants A and D lead to the major enantiomer of the methylenecyclopropane, while those corresponding to quadrants B and C lead to the minor enantiomer.

Figure 3. Origin of asymmetric induction.

A) Calculated [2 + 2]-cycloaddition barriers for the four diastereomeric transition states (M06-L/6–311G(d,p)). B) Transition structure for the most favorable [2 + 2]-cycloaddition. C) Quadrant diagram for the four possible approaches of the alkene. D) Comparing enantioselectivity and stereochemical models for Z-, E-, and terminal alkenes.

To probe the validity of this model, we also examined whether other classes of alkenes would follow the same principles of enantioinduction (Figure 3D). (E)-3-Hexene generates methylenecyclopropane 40 with high enantioselectivity (98% ee). Product 40 is not an axially chiral compound but instead possesses two stereogenic centers with no stereochemistry at the alkene. Asymmetric induction can be rationalized by a similar set of steric factors as described for Z-alkenes. A terminal alkene reacts to yield two diastereomeric products with Z-41 being favored over E-41 in a 3:1 ratio. The Z-41 diastereomer is formed in low ee, and the E-41 diastereomer is formed in high ee. In considering the stereochemical model, Z-41 would be generated from a transition state in which the alkene substituent is oriented toward the planar portion of the PyBox ligand and would not experience significant interactions with the ligand i-Pr groups. On the other hand, the E-41 diastereomer follows the same model as the Z and E internal alkene cases.

Axially chiral methylenecyclopropanes can serve as versatile intermediates to access a broad range of derivatives through axial-to-central chirality transfer processes. There are two elements of stereocontrol that underly the reactions shown in Figure 4. First, attack on the exocyclic alkene occurs reliably on the convex face of the [n.1.0]-bicyclic framework. Second, oxidative addition reactions are selective for the less hindered C–C bond that is not shielded by the vinylidene substituent. Each of the examples shown in Figure 4B take advantage of one of these two features.

Figure 4. Axial-to-central chirality transfer processes.

A) Axially chiral methylenecyclopropanes can undergo alkene addition, ring-opening, and ring-expansion reactions with preservation of enantiomeric excess. B) Reaction conditions (see Supporting Information for details): (a) Pd/C (10% wt), H₂ (1 atm); (b) Co(acac)₂ (10 mol%), XantPhos (20 mol%), Ph₂SiH₂; (c) OsO₄ (5 mol%), NMO; (d) (^t-BuPDI)CoBr₂ (10 mol%), CH₂Br₂; (e) 5,5-dimethyl-1-pyrroline N-oxide, 80 °C; (f) PdCl₂ (5 mol%), CuCl, CO (1 atm), O₂ (1 atm), MeOH; (g) Pd(PPh₃)₄ (3 mol%), Bu₃SnH; (h) Pd(t-Bu₃P)₂ (5 mol%); (i) m-CPBA (ee in parentheses is following crystallization); (j) Co₂(CO)₈, 90 °C.

The Pd-catalyzed hydrogenation of 3 occurs selectively on the convex face, affording the all-cis trisubstituted cyclopropane 42 as a single diastereomer. Cyclopropanes in which all three carbons are substituted on the same face are rare and may serve as novel three-dimensional building blocks in medicinal chemistry. Product 42 is achiral due to its plane of symmetry. However, related hydrosilylation¹⁴ and dihydroxylation reactions produce new exocyclic stereogenic centers in high fidelity (products 43 and 44). Similarly, cycloadditions of the exocyclic alkene proceed with high diastereoselectivity to generate sp³-rich spiro-bicyclic products with complete preservation of enantiomeric excess (products 45 and 46).

Ring-opening processes involving the net hydrofunctionalization¹⁵ or difunctionalization¹⁶ of the cyclopropane C–C bond can also be carried out with minimal erosion in optical purity (products 47 and 48). In both cases, the proposed mechanism entails an initial hydrometallation or carbometallation of the alkene followed by β-carbon elimination to open the three-membered ring. Thus, the transfer of chirality relies on the same principle of convex face attack as the alkene addition reactions. A methylenecyclopropane could also be isomerized to the skipped diene product 49 using (t-Bu₃P)₂Pd as a catalyst.

The reaction of methylenecyclopropane 3 with mCPBA yielded cyclobutanone 50 via spontaneous rearrangement of a putative spiro-epoxide intermediate.¹⁷ There is moderate erosion in the enantiomeric excess during this process, presumably due to the formation of a carbocation intermediate. However, the diastereoselectivity of the rearrangement is high, and the ee of cyclobutanone 50 could be upgraded by crystallization. Finally, insertion of CO into the cyclopropane ring was carried out with Co₂(CO)₈ (product 51), and the alkene stereochemistry of the benzylidene group is consistent with insertion into the less hindered C–C bond. The small loss in ee may be due to competing pathways for this reaction: direct C–C insertion vs. addition to the alkene followed by a cyclopropyl-to-homoallyl rearrangement.¹⁸

CONCLUSIONS

A cobalt-catalyzed reductive [2 + 1]-cycloaddition of alkenes and 1,1-dichloroalkenes provides access to axially chiral methylenecyclopropanes with ee values up to 99%. Of particular note, methylenecyclopropanes possess 39 kcal/mol of ring-strain energy yet are stable under the catalytic conditions and can be accessed without the use of energetic carbene precursors such as diazoalkanes. DFT models reveal that it is not discrimination between two prochiral faces of the alkene but rather control over the alkene approach relative to the vinylidene substituent that determines the stereochemical outcome. The methylenecyclopropanes generated in this reaction participate in a broad range of alkene addition, ring-opening, and ring-expansion processes that transfer axial chirality to central chirality in high fidelity. One application of this reaction is in the synthesis of all-cis trisubstituted cyclopropanes with unique geometric properties that may prove valuable in medicinal chemistry. Generalization of this asymmetric vinylidene transfer strategy to the formation of other axially chiral products is the subject of ongoing investigation.

Supplementary Material

ASSOCIATED CONTENT

Supporting Information

The supporting information is available free of charge at https://pubs.acs.org

Experimental details, characterization data, and computational details (PDF)