Direct construction of d3-methylated all-carbon quaternary stereocenters through carbene-catalyzed desymmetrization
Abstract
The construction of d3-methylated all-carbon quaternary stereocenters has been successfully developed via carbene-catalyzed desymmetrization of prochiral d3-methylated oxindolyl 1,3-diketones. Three new stereogenic centers were efficiently constructed with satisfactory outcomes. Diverse spiro-polycyclic molecules with a d3-methylated all-carbon quaternary stereocenter were generated in good to excellent yields with good to excellent diastereoselectivities and excellent enantioselectivities. This reaction features a broad substrate scope, good functional-group tolerance, and easy scale-up.
Keywords
As a result of the unique nature of deuterium, deuterium-labeled organic compounds have been widely used in organic chemistry[1,2], pharmaceuticals[3-5], and materials[6-10]. In the field of medicinal chemistry, replacing a hydrogen atom of a bioactive molecule with a deuterium atom can significantly improve the pharmacokinetics, biological activities, and stability of chemically unstable stereoisomers while also reducing toxicities[11-14]. Furthermore, due to the well-known “magic methyl effect”[15-18], the synthesis and application of d3-methylated organic molecules have received continuous interest. And several d3-methylated organic molecules have become marketed drugs or are currently undergoing clinical trials [Figure 1]. For example, Austedo, with two CD3 groups, as the first deuterated drug, is applied in the treatment of symptoms of Huntington’s disease[19,20]. Donafenib, as an orally available multikinase inhibitor, was approved by the NMPA in 2021 for treating liver cancer[21]. CTP-518 (d15-Atazanavir) displays an average 52% increase in half-life compared to atazanavir[22]. CTP-499 (d5-Pentoxifylline) exhibits antifibrogenic, antioxidative, and anti-inflammatory activities, with higher plasma concentrations and related major metabolites compared to regular Pentoxifylline[23,24]. Despite these advancements, the asymmetric construction of chiral organic molecules with d3-methylated all-carbon quaternary stereocenters remains underdeveloped. However, methylated all-carbon quaternary stereocenters have been widespread in natural products and biological molecules, offering a diverse set of promising biological activities[25].
Figure 1. Asymmetric desymmetrization of d3-methylated cyclic 1,3-diketones; (a) Representative examples containing CD3; (b) Naturally occurring and biologically active molecules with methylated all-carbon quaternary stereocenters; (c) This work: NHC-catalyzed asymmetric desymmetrization of d3-methylated 1,3-diketones.
N-heterocyclic carbene (NHC) catalysis, as one of the most efficient methods of asymmetric catalysis, has been widely used in the construction of diverse chiral molecules[26-39]. Among them, carbene-catalyzed desymmetrization of 1,3-diketones has been recognized as one of the most powerful strategies for the construction of chiral centers, especially chiral all-carbon quaternary centers[40-47]. Although NHC catalysis has shown potential applications in the construction of deuterated organic molecules[48-51], the application of NHC catalysis to construct chiral deuterated organic molecules remains underdeveloped. As part of our ongoing interest in organocatalysis[51-56], we designed novel prochiral d3-methylated oxindolyl 1,3-diketones for the asymmetric construction of d3-methylated all-carbon quaternary stereocenters based on NHC-catalyzed asymmetric desymmetrization. These readily available prochiral d3-methylated oxindolyl 1,3-diketones could react with unsaturated acyl triazolium intermediates[57] obtained from bromoenals with NHC to construct spiro-polycyclic molecules with a d3-methylated all-carbon quaternary stereocenter with excellent outcomes. Notably, spirocyclic and oxindole moieties of the products are proven among the most important scaffolds in natural products and bioactive molecules[58-61].
The reaction of (Z)-2-bromo-3-phenylacrylaldehyde 2a and prochiral 2-(methyl-d3)-2-[(1-methyl-2-oxoindolin-3-yl)methyl]-1H-indene-1,3(2H)-dione 1a was initially selected to optimize reaction conditions. The key results are summarized in Figure 2. As expected, the desired chiral d3-methylated product 3a’ could be found when aminoindanol-derived triazolium precatalyst NHC A was used in the presence of K2CO3 in toluene at room temperature. Notably, due to unavoidable release of CO2 for product 3a’ during the reaction process and in the following purification step, one more decarbonation operation, adding SiO2 to the reaction system under 70 oC for 10 h, was further performed. Accordingly, the asymmetrical d3-methylated product 3a was generated smoothly in 70% yield with 3:1 dr and 80% ee (Entry 1) [Figure 2]. Subsequently, base screening showed that sodium acetate was the best base, leading to the formation of the product 3a in excellent yield (90%) with good diastereoselectivity (13:1 dr) and excellent enantioselectivity (95% ee) (Entries 2-4). Next, several NHC catalysts were examined (Entries 5-8). All selected NHC catalysts could promote reaction smoothly, with NHC precatalyst C bearing a NO2 substituent on the indane moiety proving to be the better choice to deliver the product 3a in both excellent yield (90%) with enantioselectivity (> 99% ee) and good diastereoselectivity (13:1 dr). Several solvents were then investigated to further improve the diastereoselectivity (Entries 9-14). The excellent diastereoselectivity (> 20:1) was realized with both excellent yield (95%) and enantioselectivity (> 99) by using mesitylene as the solvent (Entry 14). In the absence of the catalyst, no reaction occurred (Entry 15). The absolute configuration of products 3 was determined via X-ray structural analysis of 3 h.
Figure 2. Optimized conditions[a]. [a] Standard condition: 1a (0.1 mmol), 2a (1.2 equiv), NHC.HX (10 mol%), solvent (0.1 M), 30 °C, and 24 h, then SiO2, 70 °C, and 10 h; [b] Yield of the product 3a after column chromatography; [c] Determined via 1H NMR spectroscopy; [d] Determined by chiral HPLC, % ee = (R-S) / (R + S) * 100.
After successfully establishing the optimal conditions, the substrate scope of this desymmetrization strategy for enals was then evaluated by using 1a as a model substrate [Figure 3]. For bromoenals with aromatic rings bearing electron-donating groups (such as Me, MeO) or electron-withdrawing groups (such as F, Cl, Br, and NO2), all the reactions proceeded smoothly to form the d3-methylated products 3b-i in excellent yields (90%-94%) with good to excellent diastereoselectivities (16:1 dr-> 20:1 dr values) and excellent enantioselectivities (> 99% ee values for all the cases).
Figure 3. Scope of Reactions.
Bromoenals bearing naphthalene or heteroaromatic rings (2-furyl and 2-thienyl) did not influence the efficiency, affording the corresponding d3-methylated products 3j-l with good to excellent outcomes (90%-97% yields, 11:1-> 20:1 dr values and > 99% values for all the cases). Subsequently, the generation of trideuteromethyl oxindolyl 1,3-diketones 2 was evaluated. For trideuteromethyl oxindolyl 1,3-diketones, several substituents at the 4-, 5-, 6-, and 7-positons on the oxindole ring were also compatible with the reaction to generate the d3-methylated products 3m-3q in excellent yields (94%-97%) with good to excellent diastereoselectivities (10:1-> 20:1 dr values) and excellent enantioselectivities (> 99% ee values). Substrates with N-benzyl and N-allyl groups reacted efficiently to form d3-methylated products 3r and 3s in 94% and 87% yields with 17:1 dr, > 20:1 dr values and > 99%, 96% ee values, respectively. Unfortunately, β-alkyl-substituted enals failed to deliver the product in our reaction.
After successfully documenting the synthesis of trideuteromethyl molecules with three stereogenic centers under NHC organocatalysis, to further evaluate the scope and limitations of this strategy, other alkyl groups were introduced into the prochiral substrates [Figure 4]. The CD3 group can be replaced with a methyl group, with the corresponding product 4a formed in 96% yield with 13:1 dr and > 99% ee. Compound 1 with a propyl group also works efficiently to result in the product 4b in 87% yields with > 20:1 dr and > 99% ee. Notably, the substrates with functional groups, such as allyl, propargyl, and NO2 substituted benzyl and acetylethoxy groups, were also compatible with this transformation, resulting in the formation of products 4c-f in excellent yields (90%-97%) with excellent diastereoselectivities (> 20:1 dr values) and enantioselectivities (> 99% ee values).
Figure 4. Scope of reactions. The reaction conditions are the same in Figure 2, Entry 14.
To show the practicality of our method, a gram-scale reaction was carried out [Figure 5]. Pleasingly, with the use of 1.0 gram of prochiral substrate 2a under the standard conditions, the reaction worked efficiently to afford 1.23 grams of the product 3a (97% yield) without any erosion of dr value and ee value.
Figure 5. Gram-scale synthesis.
To show further potential applications of this method, the synthetic transformation was performed, as shown in Figure 6. One-pot ring-opening of intermediate 3a’ could give the molecules five stereogenic centers. Treatment of intermediate 3a’ with nucleophiles such as methanol, benzyl mercaptan, and benzylamine at room temperature led to the formation of ring-opening products 5-7 in good yields and without any erosion of dr values and ee values.
Figure 6. One pot process to ring-opening products.
On the basis of previous reports and current results[46], a plausible mechanism is depicted in Figure 7. The process begins with the addition of carbene to bromoenal 1a, followed by debromination to give α, β-unsaturated acyl azolium I. Deprotonation of trideuteromethyl oxindolyl 1,3-diketones 2a results in the formation of intermediate II, which undergoes Michael addition to intermediate I to form intermediate III. Then, intramolecular cyclization of intermediate III could generate intermediate IV, which undergoes intramolecular lactonization to give 3a’ and regenerate free carbene. Subsequently, treatment of 3a’ with acidic SiO2 affords the final product 3a via a decarbonation process.
Figure 7. Proposed mechanism.
In summary, we have successfully established an efficient strategy for the asymmetric construction of spiro-polycyclic molecules with a d3-methylated all-carbon quaternary stereocenter under carbene organocatalysis. This versatile and practical asymmetric desymmetrization features a broad substrate scope, good functional-group tolerance, and can be easily scaled-up. Notably, this strategy enables the efficient construction of three stereogenic centers, including two quaternary centers. Further investigations and explorations of this catalytic process and the resulting enantioenriched d3-methylated molecules are currently underway in our laboratory.
DECLARATIONS
Authors’ contributionsDesigning the experiments, writing the manuscript, and being responsible for the whole work: Fu Z, Zhang X
Performing the experiments: Guo J, Zhang Y
Synthesizing the substrates: Guo J, Zhang Y
Availability of data and materialsDetailed experimental procedures and spectroscopic data were published as Supplementary Materials in the journal.
Financial support and sponsorshipWe acknowledge the financial support by the Ningbo Natural Science Foundation (202003N4063) and the General Program of Chongqing Natural Science Foundation Project (cstc2020jcyj-msxmX0712).
Conflicts of interestAll authors declared that there are no conflicts of interest.
Ethical approval and consent to participateNot applicable.
Consent for publicationNot applicable.
Copyright© The Author(s) 2023.
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Guo J, Zhang Y, Zhang X, Fu Z. Direct construction of d3-methylated all-carbon quaternary stereocenters through carbene-catalyzed desymmetrization. Chem Synth 2023;3:34. http://dx.doi.org/10.20517/cs.2023.04
AMA Style
Guo J, Zhang Y, Zhang X, Fu Z. Direct construction of d3-methylated all-carbon quaternary stereocenters through carbene-catalyzed desymmetrization. Chemical Synthesis. 2023; 3(4): 34. http://dx.doi.org/10.20517/cs.2023.04
Chicago/Turabian Style
Guo, Jingcheng, Ye Zhang, Xiaoxiang Zhang, Zhenqian Fu. 2023. "Direct construction of d3-methylated all-carbon quaternary stereocenters through carbene-catalyzed desymmetrization" Chemical Synthesis. 3, no.4: 34. http://dx.doi.org/10.20517/cs.2023.04
ACS Style
Guo, J.; Zhang Y.; Zhang X.; Fu Z. Direct construction of d3-methylated all-carbon quaternary stereocenters through carbene-catalyzed desymmetrization. Chem. Synth. 2023, 3, 34. http://dx.doi.org/10.20517/cs.2023.04
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