Asymmetric Multi-component Trifunctionalization Reactions with α-Halo Rh-Carbenes

doi:10.21203/rs.3.rs-5048262/v1

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Asymmetric Multi-component Trifunctionalization Reactions with α-Halo Rh-Carbenes

https://doi.org/10.21203/rs.3.rs-5048262/v1

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Multi-component multi-functionalization reactions involving active intermediates are powerful tools for rapidly generating a wide array of compounds. Metal carbynoids, with their distinct reactivity, hold great promise for developing new synthetic methodologies. However, their application in catalytic transfer reactions has been hindered by the limited availability of suitable precursors. In this study, we investigate the catalytic potential of α-halo Rh-carbenes, leveraging the concept of metal carbynoids in multi-functionalization reactions. Through a chiral phosphoric acid-catalyzed asymmetric trifunctionalization, we have developed an innovative method for synthesizing a variety of chiral α-cyclic ketal β-amino esters with high yields and excellent enantioselectivity. Our extensive experimental and computational studies reveal that α-halo Rh-carbenes exhibit carbynoid properties, which facilitate the transformation into functionalized Fischer-type Rh-carbenes through the decomposition of the C-halo bond.

Physical sciences/Chemistry/Organic chemistry

Physical sciences/Chemistry/Chemical synthesis

α-Halo Metal Carbenes

Multi-component Reactions

Asymmetric Trifunctionalization

Metal carbynoids

Multi-functionalization reactions^1–6 involving multiple components^7–13 with active intermediates are vital tools in synthetic and medicinal chemistry. These reactions offer a more efficient method for constructing multiple chemical bonds by combining three or more starting materials with a single operational step and enable the rapid exploration of diverse chemical spaces, offering efficient pathways to structurally varied compounds with a wide spectrum of biological activities^14–18. Metal carbynoids^19–23, which exhibit both carbene and carbon cation properties, can form up to three sigma bonds on a single carbon. This unique reactivity endows them with immense potential for pioneering new synthetic methodologies and facilitating the synthesis of intricate molecules^24–26.

In recent years, Suero group have reported a series of investigations using hypervalent iodine Rh-carbenes as metal carbynoids. These studies focused on cycloaddition reactions with unsaturated olefins and acetylenes to generate allyl structural units, cyclopropenes, and cyclopropyl-fused lactones^27–29. In 2023, our group reported the first asymmetric trifunctionalization reactions using the same reagents to generate optically pure β-amino esters³⁰. Recently, sulfonium Rh-carbenes have been utilized as metal carbynoids in two distinct applications: Han's group employed them for synthesizing imidazo N-heterocycles through [2 + 1 + 2] cycloadditions³¹, while the Alcarazo group used them for a ring expansion process that transforms indenes into naphthalenes³². However, the utilization of these active intermediates in catalytic transfer reactions remains largely unexplored. This is primarily due to the limited availability of suitable precursors^33–35, and addressing this limitation could unlock new possibilities in the development of efficient and innovative synthetic strategies.

α-Halo metal carbenes, developed by Bonge-Hanson's group^36–42, have proven effective in various metal-catalyzed reactions, including X-H insertion^37–38, cyclopropanation^36,42 and serve as C1 synthons in carbon atom insertion reactions^39,41 for skeletal editing^43–45. However, their potential as metal carbynoid precursors in catalytic reactions, especially in enantioselective transformations, remains untapped. This is primarily due to the significant challenge posed by the lower departure capability of the C-X bond compared to C-I^III / C-S⁺ bonds, as well as the necessity for precise control over newly formed multiple active intermediates. Furthermore, it is essential to address and overcome the adverse effects of liberated acid (HBr or HCl) on enantioselective control within the chiral acid control system.

Building upon our previous research on selective metal carbene multi-functionalization via ylide trapping process^46–50, in this study, we present a chiral phosphoric acid catalyzed asymmetric trifunctionalization reaction employing α-halo Rh-carbenes as carbynoids with diols and imines (Scheme 1C). This method offers a rapid and efficient pathway to a diverse array of chiral α-cyclic ketal β-amino esters, which are of significant interest due to their wide ranging biological activities^51–54, in high yields and exceptional enantioselectivities. The mechanism of this reaction has been elucidated through a comprehensive analysis combining experimental and computational studies.

In our initial investigation, we tested various carbynoid precursors 1 with different types of leaving groups, including α-halodiazo esters, hypervalent iodine diazo reagents, and α-diazo sulfonium salts. These reactions were conducted with diol 2a and imine 3a in CH₂Cl₂ at 0 ^oC in the presence of a Rh₂(OAc)₄ catalyst. We were pleased to observe that the reaction proceeded smoothly, with the bromo diazo ester 1a providing the highest yield of 67%. Interestingly, the chloro diazo ester 1Ia also gave a satisfactory yield of 53%. The yield was further improved to 78% when 3.0 equivalents of 1a were used. Subsequently, we evaluated the performance of various commercially available transition metal catalysts to optimize the reaction conditions. Notably, both Rh₂(esp)₂ and Rh₂(Oct)₄ delivered promising outcomes, yielding the product at 69% and 67%, respectively. Conversely, Cu(MeCN)₄PF₆ and AgOTf, renowned for their efficacy in metal carbene transformations, proved unsuitable, failing to yield any desired product. Additionally, while [Pd(allyl)Cl]₂ did afford the desired product with a diminished yield of 32%. Encouraged by this preliminary result, we later employed chiral phosphoric acid 4 for enantiocontrol. We were pleased to discover that the anticipated chiral β-amino esters could be obtained in a 70% yield, albeit with <5% ee, utilizing 5.0 mol% of chiral phosphoric acid 4a. Subsequently, we explored various types of chiral phosphoric acid, ranging from 4b to 4f. The enantioselectivity experienced an enhancement upon employing spirol-type chiral phosphoric acid 4d, resulting in the delivery of the desired product 5a in an 84% yield with 40% ee. Considering the potential activation of the imine by the release of HBr during the reaction process, subsequently impacting the asymmetric control of the reaction, we systematically explored a variety of bases. Gratifyingly, the addition of Cs₂CO₃as an additive led to a significant enhancement in enantioselectivity control, culminating in the delivery of the desired product 5a with high 88% yield and excellent 92% ee. Notably, using a smaller amount of Cs₂CO₃ resulted in a lower isolated yield and enantiomeric excess, indicating that the base additive is crucial for controlling the selectivity of the reaction.

With optimized reaction conditions in hand, we expanded the applicability of the protocol to encompass various imines, diols, and diverse diazo esters (Scheme 1). Initially, we examined the substrate scope of imines 3 alongside diazo compound 1a and diol 2a. Impressively, a wide array of functional groups on the aryl rings of the imines exhibited excellent tolerance, leading to the formation of Mannich-type addition products 5 with exceptional enantioselectivity and yields ranging from good to high. Specifically, imines 3 featuring benzaldehyde units at different positions, encompassing both electron-neutral and electron-withdrawing groups, yielded the desired products 5a-5m in yields ranging from 70% to 92% with high 84-96% ee. Moreover, imines bearing various substituents on the aniline unit (Ar), such as hydrogen, halogen, and methoxy groups, demonstrated outstanding reactivity, yielding products 5n-5t with yields ranging from 70% to 93% and 84-93% ee. Smooth reactions were also observed for imines derived from 2-thiophene and 1-naphthaldehyde, providing products 5u and 5v, respectively, in good yields and with high enantiomeric excesses of 90-91%. In addition to imines derived from aromatic aldehydes, those derived from cinnamaldehyde and ethyl glyoxalate emerged as practical reagents for this reaction, yielding the respective products 5w and 5x in good yields, albeit with slightly lower of 78-84% ee. The stereochemistry of 5n was determined as S by single crystal X-ray diffraction analysis, while the stereochemistry of other compounds was tentatively assigned by analogy.

Subsequently, a diverse array of diols was examined under the current reaction conditions, yielding the corresponding products smoothly. Diols with varying chain lengths exhibited robust performance, yielding β-amino esters bearing diverse cyclic ketal ring sizes 5ba-5bc in yields ranging from 73% to 91% with high 80-93% ee. Furthermore, diols featuring alkene groups capable of undergoing cyclopropanation with carbene complex^37-40 were also well tolerated in this transformation, yielding the target products 5bd-5be in good yields of 74-85% with good 88-96% ee. Moreover, reactions involving substituted diols and diols containing nitrogen atoms proceeded smoothly, yielding products 5bf-5bi in yields of 76-88% with remarkable enantiomeric excesses of 83-94%. Gratifying, naturally derived diols containing secondary and tertiary alcohols, such as Pinanediol, Ribofuranose and Mannitol, afforded the desired products 5bj-5bl in high yields ranging from 89% to 93%. Finally, various ester groups of the diazo reagents were explored, all of which successfully provided the desired products 5ca-5ce in good yields of 50-81% with enantiomeric excesses of 82-92%, even with bulky ^tBu ester groups. Additionally, a variety of naturally occurring alcohol-derived diazo reagents, including Geraniol, Epiandrosterone, and L(-)-Borneol were investigated, yielding their respective products 5cf-5ch in high yields of 82-90% with excellent stereoselectivity (88% ee or >20:1 dr).

Next, we focused on establishing the catalytic asymmetric version of this transformation using chloro diazo esters as metal carbynoid precursors. Under optimized conditions, a wide range of imines with varying electronic properties and substitution patterns, as well as diols, were evaluated. This led to the formation of the desired products 5 in 58-80% yield with high 80-92% ee. Alkene groups present in both diols and diazo esters were well-tolerated, yielding compounds 5bd and 5cf in good yields with enantiomeric excesses exceeding 91%. These results indicate that chloro diazo esters can also serve as practical carbynoid precursors in multicomponent reactions.

To further demonstrate the effectiveness of α-halo Rh-carbenes as metal carbynoids, we explored different nucleophiles. Monoalcohols were well-tolerated under the standard reaction conditions, yielding the desired uncyclic β-amino esters 6a and 6b with good yields and excellent enantiomeric excesses of 92% and 87%, respectively. Additionally, carbamates with Cbz and Boc protecting groups also performed well, resulting in the desired products 6c and 6d with excellent enantiomeric excesses of 99% and 91% and good yields.

To gain insight into the mechanism underlying this trifunctionalization reaction, we conducted several control experiments. Using diol 2bm, the desired product 5bm was obtained in 40% yield with a high enantiomeric excess of 90%, while the typical ylide trapping product 7 was also detected in 36% yield (Scheme 3a). When isolated 7 was treated under standard conditions, no cycloaddition product 5bm was observed (Scheme 3b), suggesting that the C-Br bond is broken before the addition step. Next, we observed no reaction between the insertion product 8 and imine 3a under standard reaction conditions (Scheme 3c), suggesting that a stepwise pathway is not a viable mechanism for this reaction. Then we introduced Rh₂(R-PTTL)₄ as the chiral catalyst along with racemic phosphoric acid, yielding the corresponding product 5n in a high yield of 78%, but with enantioselectivity below 5%. In contrast, using CPA (S)-4d led to a good yield of 76% with a high 87% ee (Scheme 3d). Similarly, when CPA (R)-4d was used as the chiral catalyst in combination with achiral Rh₂(OAc)₄, the desired isomer was smoothly generated in a good yield of 84% with -88% ee. Furthermore, we observed a linear correlation between the enantiopurities of the products 5a and their corresponding catalysts (S)-4d, indicating that a single chiral phosphoric acid (CPA) catalyst is involved in each enantioselective transition state (Scheme 3e). We later observed that CPA can react with Cs₂CO₃ under standard reaction conditions to form the cesium salt CP-Cs, with a calculated Gibbs free energy change (ΔG) of -26.1 kcal/mol. The CP-Cs salt can be acidified by HBr, converting it back to CPA, with a ΔG of -25.1 kcal/mol (Scheme 3f). When CP-Cs is employed as a chiral catalyst in trifunctionalization reactions in combination with Rh₂(OAc)₄, the desired products 5a and 5g can be obtained in high yields, achieving excellent 90% and 93% ee, respectively (Scheme 3g).

Later, a density functional theory (DFT) using the quantum mechanics/molecular mechanics (QM/MM) methodology (two-layer ONIOM)^55-57 was conducted to elucidate the mechanism of Rh/CPA cooperatively catalyzed trifunctionalization with bromo diazo esters 1a and the origin of its stereoselectivity. As depicted in Figure 1, the free energy profile for Rh₂(OAc)₄ and CPA cooperatively catalyzed reaction starts from the carbynoid complex Cat-Rh, which is formed by the reaction between the substrate 1 and Rh₂(OAc)₄through extruding N₂. The metal-alkyl intermediate IM1 (-4.9 kcal/mol) is formed following the addition of alcohol 2 with metal-carbynoid via TS1 (2.1 kcal/mol). The tautomeric isomer enol-intermediate IM1-iso is calculated with unfavorable energy about 18.0 kcal/mol. Based on IM1, the subsequent reaction between the ylide and electrophile involves pathway A (in red) and pathway B (in blue). In pathway A, IM1 is converted to a new carbene A-IM2 (-21.8 kcal/mol) through the dissociation of HBr. With the assistant of another alcohol 2, the intramolecular nucleophilic addition from the A-IM2 occurs through the transition state TS2 (-10.8 kcal/mol) to form the intermediate A-IM3 (-15.0 kcal/mol) or the enol-intermediate A-IM3-iso (-16.9 kcal/mol). Computational result show that the enol-intermediate A-IM3-iso is in favor. Next, the enol-intermediate A-IM3-iso interacts with imine and CPA to form more stable interaction A-IM4 (-41.0 kcal/mol), which is exergonic by 24.1 kcal/mol. The enantioselective S- and R- products are obtained via the transition state A-TS3_S (-42.5 kcal/mol) and A-TS3_R (-40.1 kcal/mol). Then the A-PC can undergo ligand exchange with the substrate 1 to produce the final product 5, regenerating the carbynoid complex Cat-Rh. The whole process for producing 5 is exergonic by 54.4 kcal/mol. Alternatively, the ylide IM1 directly interacts with imine and CPA to results in the intermediate B-IM2 (-38.3 kcal/mol) (pathway B). Afterwards, the bromine product in S- and R- configuration might be formed through the transition state B-TS3_S (-39.0 kcal/mol) and B-TS3_R (-36.4 kcal/mol). Subsequently, regeneration of Cat-Rh through the substrate exchange between substrate, product and CPA, which is also an exergonic process (-53.6 kcal/mol). Comparing with the enantioselective transition states in pathway A, the energy barrier of A-TS3_Sis lower than that of B-TS3_S in pathway B by 3.5 kcal/mol, implying the bromine product is less favourable to form. In addition, the CP-Cs catalysis mechanism is considered. The A-IM3-iso and imine combine with CP-Cs to generate the intermediate A-IM4’ (-39.5 kcal/mol), however, the free energy of A-IM4’ is 1.5 kcal/mol higher than that of A-IM4, indicating that the CP-Cs catalysis mechanism is less favoured than the pathway A of the CPA mechanism. To sum up, these calculations indicate that the formation of the enantioselective S-product 5 is more competitive when catalyzed by the CPA mechanism.

To uncover the origin of enantioselectivity control, independent gradient model based on Hirshfeld partition (IGMH) analysis was used to evaluate noncovalent interactions on the structures of A-TS3_S and A-TS3_R. As shown in the Figure 2, many kinds of interaction between the fragment A (CPA and Rh₂(OAc)₄)and fragment B (imine and enol). One more C-H···O interaction exit in A-TS3_S than that in A-TS3_R(b),and the C-H···O distance between H atom of imine and O atom of Rh₂(OAc)₄ in A-TS3_S is shorter than that in A-TS3_R(A-TS3_S, 1.940 Å vs A-TS3_R, 2.003 Å) (b²), which reflects a significant C-H···O interaction in A-TS3_S. Moreover, the green isosurface (C-H···π interactions) between the phenanthrene of CPA and the fragment B in A-TS3_S is larger than that in A-TS3_R(c), indicating a stronger C-H···π interaction in A-TS3_S. Furthermore, the dispersion interactions are observed not only between the H atom of imine and the methyl of Rh₂(OAc)₄(e¹)but also between the benzene group of imine and the phenanthrene of CPA (e²). The isosurface (e¹and e²) is shown wider in A-TS3_S than that in A-TS3_R. These dispersion interactions are also in favor of the enantioselectivity. Therefore, these noncovalent interactions play a pivotal role in the enantioselectivity control.

Based on the insights from control reactions and previous studies, we proposed a plausible reaction mechanism, as illustrated in Scheme 4. Initially, the diazo compound 1 decomposes in the presence of a rhodium catalyst to form a carbynoid intermediate A. This intermediate then undergoes a nucleophilic attack by diol 2, resulting in the formation of ylide B. Ylide B subsequently transforms into a Fischer-type alkoxy-Rh-carbene C through the cleavage of the C-Br bond and the release of HBr. The newly formed carbene species C can then react intramolecularly with the alcohol, leading to the formation of cyclic ylide D, which exists in equilibrium with its enolate forms E. This active intermediate E is intercepted by chiral CPA 4 activated imine 3, leading to the formation of Mannich-type products 5 and the regeneration of the catalysts. Meanwhile, CPA can be converted to CP-Cs in the presence of Cs₂CO₃, and the CP-Cs salt can subsequently be acidified by the released HBr to regenerate CPA. Alternatively, byproduct 7 can be formed when electrophilic imines 3 react with enolate intermediate F, which is in equilibrium with ylide intermediate B.

Subsequently, we conducted a mmol-scale reaction, which showed no adverse effect on the yield and stereoselectivity of product 5g. After simple crystallization, the enantiomeric excess of the product improved further to 99% (Scheme 5a). We then explored further transformations of the readily produced β-amino esters using commercially available reagents (Scheme 5b). The ester group was reduced to a hydroxyl group by LiAlH₄, producing amino alcohol which underwent cyclization with I₂/PPh₃, resulting in the formation of optically pure spiroazetidine 9 in 63% yield. Additionally, The PMP group on the nitrogen could be removed by treatment with CAN to generate the free amine, which was subsequently protected with Boc₂O under basic conditions, yielding compound 10 in a good 72% yield with 99% ee. Intramolecular amidation of compound 5a using LiHMDS yielded spirolactam 11 in high 91% yield and with 92% ee. Notably, the Suzuki coupling reaction was also compatible with this skeleton, producing compound 12 in 90% yield with 90% ee.

In summary, we have developed an efficient chiral phosphoric acid-catalyzed asymmetric three-component reaction that employs α-halo Rh-carbenes as carbynoids in conjunction with diols and imines. This method enables the synthesis of a wide range of α-cyclic ketal β-amino esters with broad substrate scope, high yields, and excellent enantioselectivities under mild conditions. Mechanistic studies demonstrate that the reaction's success hinges on the in situ formation of functionalized Fischer-type alkyloxy Rh-carbenes, with cesium carbonate playing a critical role in achieving precise enantioselective control. The origins of the high enantioselectivity have been further clarified through DFT calculations. Ongoing research in our laboratory is focused on extending this reaction to higher-order multicomponent systems (four or more components) and exploring its potential applications in biological activity testing.

Data availability

The data supporting the findings of this study are available within the paper and its Supplementary Information. Crystallographic data for the structures reported in this Article have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers CCDC2298129 (5n). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/.

Acknowledgements

Support for this research from the National Natural Science Foundation of China (92256301, 92056201), the National Key Research and Development Program of China (2023YFC3404500), Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery (2023B1212060022), Natural Science Foundation of Guangdong Province (2023A1515011486) and Key-Area Research and Development Program of Guangdong Province (2022B1111050003, 2022B1111070004) are greatly acknowledged.

Author contributions

Qian, Y. and Hu, W. designed the experiments and analyzed the data. Yang, X. performed the experiments and analyzed the data. Zhou, X. performed the theoretical calculations. Qian, Y. and Hu, W. wrote the manuscript. Qian, Y. and Hu, W. conceived and supervised the project. All authors discussed the results and commented on the article.

Competing interests

The authors declare no competing interests.

Additional information

Supplementary information The online version contains supplementary material available at https://doi.org

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General procedure for the asymmetric trifunctionalization Reaction

In a 10-mL oven-dried vial equipped with a magnetic stirring bar, 3 (0.10 mmol, 1.0 equiv.), 2 (0.30 mmol, 3.0 equiv.), Cs₂CO₃(0.3 mmol, 3.0 equiv.), Rh₂(OAc)₄ (2.0 mol%), CPA 4d (5.0 mol %) and 4 Å MS (150 mg) were combined in CH₂Cl₂ (1.5 mL). The cooled solution of diazo compound 1 or 1Ⅰ (0.30 mmol, 3.0 equiv.) in CH₂Cl₂ (1.5 mL) was added to this mixture via a syringe pump in 0.5 h under a nitrogen atmosphere at 0 ℃, and the reaction was running for 4 h under these conditions. Upon complete consumption of the starting material (monitored by TLC), the crude reaction mixture was then concentrated under vacuum, and the product was purified by column chromatography on silica gel to give the corresponding products in good to high yields. The enantioselectivity was determined by chiral HPLC analysis.

Tables 1 to 3 are available in the Supplementary Files section

Schemes 1-5 are available in the Supplementary Files section.

There is NO Competing Interest.

20230925yxyauto.cif
cif file for compound 5n
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Asymmetric Multi-component Trifunctionalization Reactions with α-Halo Rh-Carbenes

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