Cu(i)-catalyzed enantioselective and stereospecific borylative annulation of cyclic 1,3-dione-tethered 1,3-enynes

Abstract

A copper(i)-catalyzed, highly enantioselective, and diastereoselective borylative cyclization of prochiral cyclic 1,3-dione-tethered 1,3-enynes is reported. This stereospecific transformation exhibits a broad substrate scope, enabling access to bicyclic organoboron products containing four contiguous stereocenters with excellent enantioselectivity. Notably, the reaction rate is significantly influenced by the substrate's stereochemistry, with the (Z)-isomer undergoing borylative cyclization much faster than the (E)-isomer due to reduced steric interactions during C–C bond formation. Furthermore, treatment of the resulting products with sodium perborate yields the corresponding alcohols without compromising enantiomeric excess.

A copper(i)-catalyzed, highly enantioselective, and diastereoselective borylative cyclization of prochiral cyclic 1,3-dione-tethered 1,3-enynes is reported.

Introduction

Conjugated enynes are highly reactive and valuable substrates in modern organic chemistry, widely utilized in the synthesis of complex aromatic molecules and materials.¹ While 1,3-enyne motifs can be readily accessed through several efficient methods, the catalytic cross-coupling of terminal alkynes stands out as the most convenient approach.² Recently, copper-catalyzed hydro- and borofunctionalizations, multicomponent reactions, radical functionalizations, and cyclizations of these π-systems have garnered significant attention from organic and medicinal chemists.³ Among these methods, enantioselective Cu-catalyzed borylation of 1,3-enynes has also emerged as an elegant strategy, providing access to a diverse range of chiral organoboranes.⁴ The resulting C–B bonds can be conveniently converted into C–C, C–O, and C–N bonds through stereospecific 1,2-migration.⁵ However, achieving asymmetric chemo- and regioselective borylative difunctionalization of 1,3-enynes remains highly challenging due to the presence of multiple reactive sites.

In general, two pathways are possible for 1,3-enynes during hydro- or borofunctionalization. The reaction at the olefin can yield propargyl or allene products via the ene-pathway (Scheme 1a), whereas the reaction at the alkyne results in diene products through the yne-pathway.³ In 2011, Ito and co-workers reported that the regioselectivity of borocupration is influenced by the nature of the ligand employed in the reaction and steric hindrance around the olefinic functionality of the enyne.⁶ The first enantioselective Cu-catalyzed borylative 1,2-difunctionalization of 1,3-enynes was reported by the Hoveyda group in 2014 via the ene-pathway (Scheme 1b).⁷ The borocupration of 1,3-enynes enables the formation of a chiral allenylcopper complex, which is readily captured by aldehydes to provide propargylated products with excellent diastereo- and enantioselectivities. In light of this report, Yin and co-workers disclosed similar consecutive protocols on ketones.⁸ Later, Procter and co-workers disclosed a highly enantio- and diastereoselective borylative 1,2-coupling of 1,3-enynes with imines to provide chiral homopropargyl amines with excellent diastereo- and enantioselectivity.⁹ Recently, Yun and co-workers reported a highly enantioselective 1,2-borylation/conjugate addition with β-substituted alkylidene malonates, enabling organoboranes bearing adjacent stereocentres.¹⁰ In 2020, Hu, Wang, Liao, and co-workers developed a cooperative Cu/Pd-catalyzed 1,4-boroarylation, wherein arylation occurs via transmetalation with palladium to access chiral tri- and tetra-substituted allenes.¹¹ Shortly thereafter, Xu et al. reported the 1,4-boroprotonation of trifluoromethyl-substituted conjugated enynes to access enantioenriched homoallenyboronates.¹² Similarly, CuH-catalyzed hydrofunctionalization of 1,3-enynes also allows the generation of chiral allenylcopper intermediates, which are readily captured by various electrophiles to yield the corresponding propargylic products and allenes with excellent stereoselectivities.^13,14 Among these elegant methods, 1,2-borofunctionalization is generally limited to terminal 1,3-enynes, with only two reports^9,10 exploring internal enynes due to their lower reactivity and other challenges related to regioselectivity and stereoselectivity. Here, E/Z-selectivity of the double bond controls the diastereoselectivity of the corresponding product in a stereospecific manner.

Scheme 1. Cu(i)-catalyzed borylative functionalization of 1,3-enyes.

To the best of our knowledge, there are no intramolecular cyclizations reported via Cu-catalyzed borylative 1,2-difunctionalization of 1,3-enynes with internal electrophiles. Based on our interest in the area of enantioselective Cu-catalysis,¹⁵ herein, we report a stereospecific annulation of 1,3-enyne-tethered cyclic 1,3-enones (Scheme 1c). This work describes an unprecedented intramolecular Cu(i)-catalyzed borylative difunctionalization of 1,3-enynes, delivering products with excellent diastereo- and enantioselectivity. The E/Z configuration of the substrates significantly influences the reaction rate and diastereoselectivity of products. We envisioned that stereospecific syn-addition of a borylcopper(i) intermediate on the double bond of (Z/E)-1 could provide intermediate A/B. Subsequent intramolecular nucleophilic attack of organocuprate A/B could afford the corresponding product anti-2 or syn-2, respectively with the retention of the configuration at the C–B bond. Notably, the reaction proceeds through highly regioselective 1,2-borocupration on the double bond adjacent to the sterically demanding quaternary prochiral center.

Results and discussion

We began our investigation on Cu(i)-catalyzed borylative cyclization of Z-selective 1,3-enyne 1a as a model substrate in the presence of bis(pinacolato)diboron as the borylation source with various chiral bidentate phosphine ligands (Table 1). The reaction was initially conducted with 2.5 mol% of Cu(CH₃CN)₄PF₆, 5 mol% of ligand, and 2.0 equivalents of base in THF at −78 °C for 2 hours. Notably, the BINAP ligands provided the desired product anti-2a in moderate yield with enantioselectivity ranging from 37% to 92%, whereas SEGPHOS ligands resulted in only trace amounts of the product (entries 1–5). In addition, the BDPP ligand L6, DUPHOS ligand L7, BIPHEP ligand L8, and iPr-BPE ligand L9 proved ineffective in the model reaction, resulting in no product formation. Fortunately, the reaction with (S,S)-Ph-BPE ligand L10 afforded 2a in high yield with excellent enantioselectivity (>99% ee). The exclusive diastereoselectivity suggests that the borylative cyclization of (Z)-1a proceeds with high stereocontrol. The relative stereochemistry of anti-2a was confirmed by single crystal X-ray diffraction analysis (see Table 2).¹⁶

Table 1. Optimization of reaction conditions^a,b,c,d.

Entry	Ligand	Yield [%]	2a (ee)
1	(R)-SEGPHOS, L1	<5	—
2	(S)-BINAP, L2	54	92%
3	(R)-Tol-BINAP, L3	36	69%
4	(S)-DM-SEGPHOS, L4	<5	—
5	(R)-DM-BINAP, L5	31	37%
6	(S,S)-BDPP, L6	<5	—
7	(R,R)-Me-DUPHOS, L7	—	—
8	(R)-Cl-MeO-BIPHEP, L8	—	—
9	(S,S)-iPr-BPE, L9	—	—
10	(S,S)-Ph-BPE-L10	82%	>99%

^aReaction conditions: 1a (50 mg, 0.2 mmol), B₂(pin)₂ (60 mg, 0.24 mmol), Cu(CH₃CN)₄PF₆ (1.9 mg, 2.5 mol%), ligand (5.0 mol%), ^tBuOH (38 μL, 0.4 mmol), LiO^tBu (36 μL, 0.4 mmol, 1.0 M THF solution), in THF solvent (3 mL, 0.1 M).

^bIsolated yields.

^cEnantiomeric ratio (er) was determined by HPLC analysis using a chiral stationary phase.

^d>20 : 1 dr was observed from ¹H NMR analysis.

Table 2. Substrate scope of (Z)-isomer^a,b,c,d.

^aReaction conditions: 1 (0.3 mmol), B₂(pin)₂ (91 mg, 0.36 mmol), Cu(CH₃CN)₄PF₆ (2.8 mg, 2.5 mol%), (S,S)-Ph-BPE (7.6 mg, 5.0 mol%), ^tBuOH (57 μL, 0.6 mmol), LiO^tBu (54 μL, 0.6 mmol, 1.0 M THF solution), in THF solvent (3 mL, 0.1 M).

^bIsolated yields after column chromatography.

^cEnantiomeric ratio (er) was determined by chiral HPLC analysis.

^d>20 : 1 dr was observed (unless otherwise mentioned) through ¹H NMR analysis of a crude reaction mixture. SM = Starting material.

Under standard conditions, the borylative cyclization of 1,3-enyne (Z)-1a proceeded with complete anti-selectivity, affording the bicyclic product 2a in 82% yield with >99% enantioselectivity (Scheme 2). In contrast, the reaction of 1,3-enyne (E)-1a yielded the syn-selective bicyclic product 2a with moderate yield and 92% enantioselectivity. Besides, prolonging the reaction time did not enhance the conversion, and over 35% of the starting material (E)-1a remained unreacted in both cases. The reaction rates and syn/anti selectivity of the reaction were significantly influenced by the E or Z configuration of the 1,3-enyne substrates.¹⁷ Notably, the borylative cyclization of (Z)-1a proceeded much faster than that of (E)-1a, affording the desired product in high yield with exclusive enantioselectivity. This enhanced reactivity is likely attributed to reduced steric interaction between the Bpin and alkyne groups in Int-A compared to Int-B during C–C bond formation (see Scheme 1c).

Scheme 2. Comparative study of reaction rates.

Later, the scope of the borylative cyclization in the presence of B₂pin₂ was explored using various prochiral (Z)-selective 1,3-enyne-tethered cyclic 1,3-diones 1 under optimized reaction conditions, unless otherwise specified for the Z/E ratio of the substrate. Our initial investigation focused on phenyl-substituted enynes with various substituents at the all-carbon prochiral center, and the results are summarized in Table 2. Substrates bearing sterically diverse alkyl groups and a cinnamyl group at the quaternary center were well-tolerated, undergoing borylative enantioselective desymmetrization to afford the corresponding products 2a–2e in 67–82% yield with excellent enantioselectivity. Next, a range of benzyl groups with electronically and sterically tuned substituents at the prochiral center were evaluated. These 1,3-enyne-tethered cyclopenta-1,3-diones proved to be highly suitable, delivering bicyclo[3.3.0]octane products 2f–2v in good yields with uniformly >99% ee across all cases. Particularly, the reaction was carried out on the substrates as an inseparable mixture of (Z/E)-isomers, with the major (Z)-1,3-enyne predominantly yielding the corresponding products anti-2n and anti-2p, along with trace amounts of syn-products derived from the (E)-isomer. Beyond benzyl groups, a similar range of yields and enantioselectivities was observed with other substituents, including 1-naphthyl and thiophen-2-ylmethylene groups at the quaternary prochiral center, furnishing products 2w and 2x, respectively. Next, the generality of the present approach was evaluated using Z-selective enyne-tethered cyclohexa-1,3-diones under standard conditions, which provided the corresponding products 2y–2ac in comparable yields and enantioselectivities. However, the cycloheptane-1,3-dione substrate failed to afford the desired product (2ad), and most of the starting material was recovered. The absolute stereochemistry of the bicyclic ketone anti-2o was unambiguously established by single-crystal X-ray diffraction analysis.¹⁶ The stereochemical assignments of the remaining products were assumed by analogy.

Next, we explored the scope of 1,3-enynes bearing various aromatic substituents (Table 3). The reaction was carried out on a mixture of (Z/E)-isomers under standard conditions, yielding product anti-2 predominantly from (Z)-1,3-enyne as the major diastereomer due to its higher reaction rate. Only trace amounts of the syn-product 2 (<5% yield) were identified from (E)-1 in a few examples, highlighting the strong stereochemical influence on the reaction outcome. The transformation proceeded with good diastereoselectivity, and excellent enantioselectivity. Aromatic 1,3-enynes with diverse substituents, regardless of their electronic properties, were well-tolerated under the standard conditions. Substituents such as alkyl, alkoxy, and halogen groups at the para-, meta-, or ortho-positions of the phenyl ring afforded the corresponding products (2ae–2ao) in moderate yields with excellent enantioselectivity (97–99% ee). Additionally, 9-phenanthryl and 1-cyclohexenyl groups on 1,3-enynes were readily converted into the desired products (2ap and 2aq) in good yields with >99% enantioselectivity. Unfortunately, 3-enyne substrates bearing aliphatic substituents failed to afford the desired products, and most of the starting material was recovered (entries 2ar and 2as).

Table 3. Substrate scope of the (Z/E)-isomer^a,b,c,d,e.

^aReaction conditions same as in Table 2.

^bIsolated yields of the major product anti-2.

^cDiastereoselectivity was observed to be >20 : 1 for the major isomer, which was confirmed by ¹H NMR analysis.

^dUnable to find the ratio of major and minor products in the crude ¹H NMR analysis.

^eEnantioselectivity of the major isomer. SM = starting material.

The enantioselective desymmetrization of α,α-disubstituted 1,3-indandione (Z/E)-3a (dr = 2.5 : 1) proceeded efficiently under the optimized reaction conditions, affording the desired product 4a as a mixture of inseparable diastereomers in a 1.5 : 1 ratio with a 71% yield (Scheme 3). Subsequent oxidation of the Bpin group using NaBO₃·4H₂O yielded the corresponding alcohols anti-5a (56%) and syn-5a (35%) as separable diastereomers, which were easily purified via simple column chromatography. It is interesting to observe that the (E)-isomer of the 1,3-indandione substrate reacts just as effectively as the (Z)-isomer.

Scheme 3. Borylative cyclization of 1,3-indandiones.

For ease of handling, we performed a one-pot borylative cyclization/oxidation of 1,3-indandiones under standard reaction conditions, followed by the sequential addition of NaBO₃·4H₂O (Table 4). We briefly screened this reaction with substrates featuring various benzyl groups at the prochiral quaternary center, yielding separable diastereomeric products anti-5 and syn-5. Electronically diverse substituents on the benzyl group provided high yields and excellent enantioselectivities (5a–5d). However, a sterically demanding ortho-substituted benzyl group resulted in only a trace amount of syn-product from the (E)-isomer and predominantly anti-5e from the (Z)-isomer.

Table 4. One-pot borylative cyclization/oxidation of 1,3-indandiones^a,b,c,d.

^aReaction conditions: Same as in Table 2 and then NaBO₃·4H₂O (150 mg, 1.5 mmol, 5.0 equiv.) was added in the same reaction.

^bIsolated yields of respective diastereomers.

^cEnantiomeric excess (ee) was determined by chiral HPLC analysis.

^dThe dr was observed from ¹H NMR analysis of the crude reaction mixture. SM = starting material.

Gram-scale reactions using (Z)-1a and (Z)-1y were carried out with reduced catalyst loading under standard conditions, affording the desired products anti-2a and anti-2y, respectively, without any significant loss in yield or enantioselectivity (Scheme 4a). The one-pot borylative cyclization, followed by the sequential addition of the mild oxidizing agent sodium perborate, afforded the corresponding alcohol 6 in a similar yield with exclusive enantioselectivity (Scheme 4b). Interestingly, the reaction with the strong oxidizing agent sodium periodate also afforded alcohol 6 in high yield, instead of undergoing boronic ester hydrolysis (Scheme 4c). The Pd/C-catalyzed hydrogenolysis of compound 2a successfully reduces the triple bond, providing bicyclic ketone 7 in 88%yield. The Fischer cyclization of compound 2y with phenylhydrazine furnished a highly functionalized tetracyclic fused indole 8 in 72% yield. Subsequent oxidation of 8 with sodium perborate afforded the corresponding alcohol 9 in 84% yield. Interestingly, direct oxidation of 2y with sodium perborate yielded alcohol 10, which upon Dess–Martin periodinane (DMP) oxidation provided the α-alkynyl enone 11via sequential alcohol oxidation and tert-alcohol elimination in good yield. This highly reactive, fused, electron-deficient enyne 11 serves as a promising intermediate for diverse cycloaddition reactions. In addition, Au(i)-catalyzed hydration of enyne 11 in methanol afforded arylketone 12 in 57% yield.

Scheme 4. Large-scale reactions and further transformations.

Based on the proposed copper catalytic cycle, the ligated copper alkoxide complex LnCuOtBu is generated in situ in the presence of a chiral ligand and base (Scheme 5). This complex undergoes σ-bond metathesis with a diboron reagent, yielding the LnCu–Bpin species. The enantioselective and regioselective 1,2-syn-addition of LnCu–Bpin to the 1,3-enyne-tethered cyclic-1,3-dione 1a leads to the formation of a propargylic copper intermediate A. This intermediate exists in equilibrium with an axially chiral allenyl–copper intermediate B via a stereospecific isomerization. Subsequent desymmetrization through annulation of propargylic intermediate A furnishes the desired product 2a, while the catalytic cycle is completed by regenerating LnCu–OtBu via a copper alkoxide intermediate C in the presence of a base.

Scheme 5. Plausible reaction mechanism.

Conclusions

In summary, we have developed a stereospecific, enantioselective copper(i)-catalyzed borylative cyclization of prochiral 1,3-enyne-tethered cyclic-1,3-diones with excellent diastereoselectivity. This asymmetric desymmetrization reaction efficiently delivers highly functionalized chiral octahydropentalenes bearing four contiguous stereocenters. Notably, the use of a BPE-ligand resulted in >99% ee for most examples. Additionally, (Z)-1,3-enyne substrates react more rapidly than their (E)-isomers, affording borylation products in high yields under standard reaction conditions. Ongoing studies in our laboratory are focused on further Cu(i)-catalyzed stereoselective transformations.

Author contributions

G. R. and V. B. P. performed the experiments and analyzed the experimental data; J. B. N. conducted the single X-ray crystallographic analysis; R. C. designed and supervised the project and wrote the manuscript with the assistance of co-authors.

Conflicts of interest

There are no conflicts to declare.

Data availability

The data supporting this article have been included as part of the ESI.†