Facile construction of distal and diversified tertiary and quaternary stereocenters

Significance

The motivation driving the intensive efforts of synthetic chemists lies in the exploration of novel chiral pharmaceutical candidates. Especially, achieving efficient skeletal construction and introducing chiral diversity is a significant goal within the chemical society. However, existing methods for chiral induction primarily target specific sites. In this context, we have successfully developed an asymmetric chain-walking process, enabling the construction of multisite tertiary and quaternary stereocenters with high yields and enantioselectivity. Of particular importance is that this methodology can be compatible with various active pharmaceutical molecules, and the resulting products can undergo diverse derivative transformations. The successful transformation achieved with unparalleled aryl iodide coupling partners along with the successful gram-scale experiment makes this methodology highly promising for practical applications.

Abstract

Exploration of novel chiral pharmaceutical candidates is motivation to immersive efforts among synthetic chemists. Achieving skeletal construction and chiral diversity in a highly efficient manner is a momentous goal in the chemical society. Unfortunately, current methods for chiral induction focus primarily on a specific site. Herein, we realized the asymmetric chain-walking arylation of alkenyl alcohols for the construction of multisite tertiary and quaternary stereocenters in high yields and enantioselectivity. This new operation-friendly strategy carries substantial potential for future industrialization.

The chirality of molecules is a central concern in the drug discovery and development process. Introduction of a stereocenter on a molecule has shown a series of benefits including improved solubility, potency, on-target selectivity, and metabolic stability from additional binding to proteins at the active sites (1–11). Indeed, over 60% of top 200 selling small molecules in 2020 have at least one chiral center and the vast majority of these molecules been administrated in their enantiomerically pure form (Fig. 1A) (12). As a result, there is a strong demand for ever more efficient and applicable stereoselective processes to access chiral pharmaceuticals on a large scale. In such a situation, metal-catalyzed remote functionalization involving a chain-walking process has emerged as a transformative approach in the field of synthetic organic chemistry. This innovative approach leverages the unique capabilities to facilitate the precise installation of functional groups at remote, previously inaccessible positions. Moreover, the chain-walking strategy enhances the flexibility and selectivity of the catalytic pattern, allowing for the construction of complex molecular architectures with high stereochemical fidelity (13–17).

Fig. 1.

Relevance of drugs and multisite functionalization of unsaturated alcohols. (A) Drug molecules containing an aryl-substituted chiral center β, γ, or δ to a functional group. (B) Asymmetric arylation of unsaturated alcohols with aryl iodides for the construction of distal tertiary and quaternary stereocenters. (C) Proposed reaction pathway.

Carbonyl, an important class of functional group in organic synthesis, plays a vital role in the development of novel pharmaceuticals, agrochemicals, and materials. As a result, considerable efforts have been devoted in constructing a chiral center on a distal position of this functional group (18–24). While a β stereocenter could be readily established via conjugate addition of unsaturated carbonyl compounds (25–28), isomerization of allylic alcohol (29–31), C–H functionalization (32), and asymmetric hydrogenation of prochiral unsaturated carbonyl compounds (33–35), there are only few examples of chiral induction on the γ position (36–39). Furthermore, the construction of a chiral center on the δ position of a carbonyl group is particularly challenging, mainly for the saturated chain-like frameworks (40–44). Moreover, the vast majority of current methods only allowed for the chirality delivery on one specific site. Consequently, the development of a general and industrially friendly process to achieve distal multisite chirality is of great value to both the pharmaceutical industry and the chemical society as a whole. While significant contributions have been made by the Sigman group, the utilization of unstable diazonium salts (23) or the need of additional stoichiometric amounts of oxidants or oxygen gas with aryl boronic acids (24, 45–47) poses limitations on the widespread applicability of their approaches. This type of transformation is a powerful tool but has not been realized with aryl halides, practical coupling partners in industrial settings. As is well known, aryl iodides have been well recognized as incomparable coupling partners among their analogs or surrogates due to their stability, low toxicity, low cost, and industrial scalability (48–50). Herein, we report an asymmetric chain-walking arylation reaction of unsaturated alcohols with aryl iodides to achieve the ease of chiral and skeletal diversity construction (Fig. 1B). The importance of this work is due not only to its many advantages but also the fact that it embodies a solution to an extremely challenging problem that has yet to be solved.

Results

In our study, (E)-1-cyclohexylpent-2-en-1-ol and 4-iodoanisole were employed as the model substrates for reaction conditions optimization (SI Appendix, Tables S1–S3). Our initial efforts on palladium salt screening indicated that PdCl₂ provided high enantioselectivity (4.6/95.4 e.r.) in the presence of the chiral ligand L3 while exhibiting low reactivity (23% yield). Since carboxylic acids have been reported to remarkably enhance the reaction activity and increase the product output (51), a series of acids were then studied. Delightfully, aryl acids, especially those with an electron-withdrawing substituent, exhibited a positive effect on the catalytic efficiency with 4-nitrobenzoic acid providing the desired product in 68% yield and 2.7/97.3 e.r. (SI Appendix, Table S4http://www.pnas.org/lookup/doi/10.1073/pnas.2408541121#supplementary-materials). Following this, a series of ligands with a similar skeleton were investigated but failed to show any improvement. Gratifyingly, by increasing the catalyst loading to 7 mol%, the yield was increased to 80% with maintained enantioselectivity (2.7/97.3 e.r.). Higher loading of the palladium catalyst did not significantly improve the yield of this transformation.

With an optimized protocol obtained, a wide range of aryl iodides bearing an electron-donating substituent were then evaluated (Fig. 2). In most cases (3aa-3ja, 3la), reactions proceeded smoothly to provide the corresponding products in excellent enantioselectivity and satisfactory yields. Notably, aryl iodide with a substituent located in the ortho position (3ka) afforded the desired product, albeit with slightly decreased enantioselectivity (8.9/91.1 e.r.) Additionally, heteroaromatic substrates were tolerated under the reaction conditions to form the corresponding products (3ma and 3na).

Fig. 2.

Substrate scope of aryl iodides bearing an electron-donating group. Conditions: 1 (0.3 mmol), 2 ( trans-configuration. 0.2 mmol), L3 (7.7 mol%), PdCl₂ (7 mol%), Cs₂CO₃ (2 eq), 4-NO₂PhCOOH (50 mol%), DME (2 mL), 60 °C, 24 h, unless otherwise noted. Isolated yields. The e.r. values were determined by HPLC using chiral columns. ^a90 °C. ^b5 mol% catalyst loading.

Next, we surveyed the scope with respect to the alkenol coupling partners (Fig. 2). Alkenols were found to be compatible, delivering corresponding products with high enantioselectivity and moderate to excellent yields (3ab-3ah). It is worth noting that when alkenols bearing a primary alcohol moiety were used (3ab, 3af, 3ah, 3jh, 3oh, and 3hh), the amount of catalyst could be reduced to 5 mol%, and the target aldehyde products could still be obtained with excellent yields and enantioselectivity.

Surprisingly, under the optimal reaction conditions established above, aryl iodides bearing an electron-withdrawing group experienced poor conversion of alkenol due to undesired homocoupling and dehalogenation side reactions, resulting in no product formation at all. To our delight, by rescreening the previous conditions, electron-deficient substrates were finally able to produce the corresponding target products at very satisfactory results with DCE and 2,4-dimethoxybenzoic acid as the solvent and acid, respectively (SI Appendix, Table S5). As shown in Fig. 3, aryl iodides bearing an electron-withdrawing group were well tolerated. Notably, halogen atoms, especially bromo (3ra and 3ua), were also well compatible with the reaction system, allowing for further manipulation of the initial products. It is also worth mentioning that primary alcohols reacted very smoothly with reduced catalyst loading, resulting in the formation of desired aldehyde products in good yields and enantioselectivity (3sh, 3wh, 3xh, 3vh, and 3zh).

Fig. 3.

Substrate scope of aryl iodides bearing an electron-withdrawing group. Conditions: 1 (0.3 mmol), 2 (trans-configuration. 0.2 mmol), L3 (7.7 mol%), PdCl₂ (7 mol%), Cs₂CO₃ (2 eq), 2,4-Dimethoxybenzoic acid (50 mol%), DCE (2 mL), 60 °C, 24 h, unless otherwise noted. Isolated yields. The e.r. values were determined by HPLC using chiral columns. ^a5 mol% catalyst loading.

Then, we investigated the reactivity of alkenol substrates with varied chain length between the double bond and the hydroxyl group in this reaction (Fig. 4). Interestingly, when a homoallylic primary alcohol (2i) was used as a substrate, the reactivity and enantioselectivity were significantly higher than when an allylic primary alcohol (2h) was employed, indicating that double bond migration is an easily achievable process in this catalytic system. Both cis- and trans-alkenols were compatible with this catalytic system, and products (3ai, 3ei, and 3oi) were obtained with excellent yields and enantioselective ratios. As expected, secondary alcohol was also tolerated and delivered the corresponding ketone products in good results (3aj, 3cj, 3qj, and 3tj). When it came to alkenols with three carbons between the double bond and the hydroxyl group, the catalytic system still demonstrated good applicability, and excellent results were obtained utilizing PdI₂ as a catalyst.

Fig. 4.

Enantioselective construction of remote chirogenic centers. Conditions: 1 (0.3 mmol), 2 (trans-configuration unless otherwise noted. 0.2 mmol), L3 (5.5 mol%), PdCl₂ (5 mol%), Cs₂CO₃ (2 eq), 60 °C, 24 h, unless otherwise noted. Isolated yields. The e.r. values were determined by HPLC using chiral columns. ^aConditions: 4-NO₂PhCOOH (50 mol%), DME (2 mL). ^bConditions: 3,4-Di-MeOPhCOOH (50 mol%), DCE (2 mL). ^cConditions: (cis)-alkenols were used. PdI₂ was used instead of PdCl₂ with acid. ^dConditions: 4-NO₂PhCOOH (50 mol%), DME (2 mL), 90 °C, 10 mol% catalyst loading. ^eConditions: 3,4-Di-MeOPhCOOH (50 mol%), DCE (2 mL), 90 °C, 10 mol% catalyst loading. ^f(cis)-alkenyl alcohols (2p and 2q) were used. Oct = n-Octyl.

To broaden the applicability of this approach, we then turned our attention to the more challenging trisubstituted alkenes. In the form of 1,1,2-substitution, the alkenols are faced with excessive steric hindrance (Fig. 4). To our delight, aryl iodides bearing a substituent at the meta or para position underwent this transformation smoothly, yielding the desired products with good yields and enantioselectivity, regardless of the presence of an electron-withdrawing or electron-donating substituent, or a mono- or di-substituted aromatic ring (3ak, 3ck, 3lk, 3ok, 3qk, 3yk, 3ao, 3ap, 3aq, and 3ar). The resulting products are of great significance due to the formation of a quaternary stereocenter from 1,1,2-trisubstituted alkenes. Consequently, this methodology is incomparably powerful in constructing diversified molecules.

To gain some insight into the catalytic pathway, deuterium-labeled substrate (2i-d) was prepared and subjected into the optimized conditions. The results indicated that the substrate (2i-d) underwent a Heck-type process followed by subsequent double bond migration to generate the enol intermediate (int-1), which directly experienced keto-enol tautomerism to deliver the target product (3ai-d), rather than double bond reinsertion followed by β-H elimination as reported in the literature (Fig. 5A) (52). Furthermore, in order to investigate how double bond migration affects an existing stereocenter, chiral-2n with a chiral center in the middle of the double bond and the hydroxyl group were synthesized and subjected to this catalytic system (Fig. 5B). According to the obtained results, it is believed that chirality is maintained throughout the whole pathway, suggesting that the [PdH] species is in a nondissociated mode with the double bond during the process of double bond migration to some extent. On the basis of these observations, a plausible reaction pathway is proposed (Fig. 1C). Oxidative addition of a palladium(0) species with an aryl iodide in the presence of the chiral ligand generates the palladium(II) intermediate A which then undergoes syn-migratory insertion to afford the intermediate B. The palladium(II) species on this intermediate migrates through the chain to give rise to intermediate C via a nondissociative iterative β-hydride elimination/migratory insertion process. The desired product 3 is finally formed via ligand dissociation followed by subsequent tautomerization of intermediate C (53).

Fig. 5.

Mechanistic investigation. (A) Deuteration experiment. (B) Chirality retaining experiment.

To demonstrate the potential utility of this protocol, the asymmetric chain-walking Heck arylation was carried out on a gram scale, and the corresponding arylated product was further converted to several important chiral products with diversified functional groups (Fig. 6). Additionally, several aryl iodides derived from drugs and natural products were synthesized and exposed to this reaction system. In all cases, the products were obtained with satisfactory results, indicating that this methodology has good functional group compatibility and potential applicability to be developed into practical applications.

Fig. 6.

Derivatization of the chiral product and application of substrates with the structure of drugs or natural products. i) Standard conditions. ii) NaBH₄ (1.0 eq), EtOH, rt, 2 h, then PPh₃ (1.5 eq), CCl₄/CBr₄, DCM, rt, 18 h. iii) NH₂OH·HCl (1.2 eq), NaOAc (1.5 eq), MeOH, 50 °C, 2 h, then SnCl₂, MeCN, 80 °C, 4 h. iv) Oxone (1.5 eq), EtOH, rt, 18 h. v) CH₃PPh₃Br, n-BuLi, THF, 0 °C, then rt, 4 h. vi) NaBH₄ (1.0 eq), EtOH, rt, 2 h. ^aDetermined by corresponding aldehyde. Conditions: NaIO₄ (2.2 eq), OsO₄ (4 %), H₂O, EtOAc, rt, 2 h. Reaction Conditions for natural structures: aryl iodide (0.1 mmol), alkenol (0.15 mmol), L3 (11 mol%), PdCl₂ (10 mol%), Cs₂CO₃ (2 eq), 24 h, unless otherwise noted. ^b3,4-Di-MeOPhCOOH (50 mol%), DCE (1 mL), 60 °C. ^c4-NO₂PhCOOH (50 mol%), DME (1 mL), 90 °C.

Conclusion

In conclusion, we are here disclosing an efficient asymmetric chain-walking Heck arylation of alkenols using cheap and readily available aryl iodides as starting materials. This approach is widely applicable to alkenols with diversified structures, including primary or secondary alkenols, alkenols of different chain lengths, and trisubstituted alkenols. The ease of skeleton construction and chiral diversity grant this method a unique edge compared to currently reported methods. Mechanistic studies have shown that the chain-walking process does not destroy the encountered chiral centers, which is a great advantage for the derivation of chiral compounds under this catalytic system. Moreover, the molecular structures of drugs and natural products are also compatible, implying that this strategy is a very promising tool for drug improvement and modification.

Materials and Methods

General Procedure for the Aryl Iodides Bearing Electron-Donating Groups.

1 (0.3 mmol, 1.5 eq), L3 (0.015 mmol, 7.7 mol%), PdCl₂ (0.014 mmol, 7 mol%), Cs₂CO₃ (0.4 mmol, 2 eq), and 4-Nitrobenzoic acid (0.1 mmol, 50 mol%) was added to a Schlenk tube equipped with a magnetic stirrer. A solution of 2 (0.2 mmol, 1.0 eq) in degassed DME (2 mL) was introduced through syringe, and the tube was sealed. The Schlenk tube was removed from the glovebox and degassed by a freeze–pump–thaw cycle. The solution was allowed to stir for 1 h at rt under a N₂ atmosphere. The resulting solution was then allowed to stir at 60 °C for 24 h. Upon completion, the mixture was diluted with EtOAc and filtered through a celite pad. The filtrate was evaporated under reduced pressure and the crude mixture was purified by column chromatography using silica (200 to 300 mesh size) and hexane/ethyl acetate as the eluent. Operations for other different types of substrates can be found in SI Appendix.

Supplementary Material

Appendix 01 (PDF)