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Page 2 of 11 Guo et al. Chem Synth 2023;3:34 https://dx.doi.org/10.20517/cs.2023.04

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 d -methylated organic molecules have received continuous interest. And several d -
3
3
methylated organic molecules have become marketed drugs or are currently undergoing clinical trials
[Figure 1]. For example, Austedo, with two CD groups, as the first deuterated drug, is applied in the
3
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 . CTP-518 (d -Atazanavir) displays an
[21]
15
[22]
average 52% increase in half-life compared to atazanavir . CTP-499 (d -Pentoxifylline) exhibits
5
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 d -methylated all-carbon quaternary stereocenters
3
remains underdeveloped. However, methylated all-carbon quaternary stereocenters have been widespread
[25]
in natural products and biological molecules, offering a diverse set of promising biological activities .
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 d -methylated oxindolyl 1,3-diketones
3
for the asymmetric construction of d -methylated all-carbon quaternary stereocenters based on NHC-
3
catalyzed asymmetric desymmetrization. These readily available prochiral d -methylated oxindolyl 1,3-
3
diketones could react with unsaturated acyl triazolium intermediates obtained from bromoenals with
[57]
NHC to construct spiro-polycyclic molecules with a d -methylated all-carbon quaternary stereocenter with
3
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-d )-2-[(1-methyl-2-
3
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 d -methylated product 3a’ could
3
be found when aminoindanol-derived triazolium precatalyst NHC A was used in the presence of K CO in
3
2
toluene at room temperature. Notably, due to unavoidable release of CO for product 3a’ during the
2
reaction process and in the following purification step, one more decarbonation operation, adding SiO to
2
the reaction system under 70 C for 10 h, was further performed. Accordingly, the asymmetrical d -
o
3
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 NO substituent on the indane moiety
2
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.