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Article

Ru(II)-Catalyzed Asymmetric Transfer Hydrogenation of α-Alkyl-β-Ketoaldehydes via Dynamic Kinetic Resolution

by
Daiene P. Lapa
,
Leticia H. S. Araújo
,
Sávio R. Melo
,
Paulo R. R. Costa
* and
Guilherme S. Caleffi
*
Laboratório de Química Bioorgânica, Instituto de Pesquisas de Produtos Naturais Walter Mors, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
*
Authors to whom correspondence should be addressed.
Molecules 2024, 29(14), 3420; https://doi.org/10.3390/molecules29143420 (registering DOI)
Submission received: 22 June 2024 / Revised: 14 July 2024 / Accepted: 17 July 2024 / Published: 21 July 2024
(This article belongs to the Special Issue Recent Advances of Catalytic Asymmetric Synthesis)
Browse Figures
Versions Notes

Abstract

:
The (R,R)-Teth-TsDPEN-Ru(II) complex promoted the one-pot double C=O reduction of α-alkyl-β-ketoaldehydes through asymmetric transfer hydrogenation/dynamic kinetic resolution (ATH-DKR) under mild conditions. In this process, ten anti-2-benzyl-1-phenylpropane-1,3-diols (85:15 to 92:8 dr) were obtained in good yields (41–87%) and excellent enantioselectivities (>99% ee for all compounds). Notably, the preferential reduction of the aldehyde moiety led to the in situ formation of 2-benzyl-3-hydroxy-1-phenylpropan-1-one intermediates. These intermediates played a crucial role in enhancing both reactivity and stereoselectivity through hydrogen bonding.

1. Introduction

The 2-alkyl-1-phenylpropane-1,3-diols are structural motifs containing two adjacent stereocenters that are prevalent in various natural products. Notable examples include the lignans (−)-podophyllotoxin (1) and (−)-sesaminone (2), as well as the flavonoid (+)-homoferrugenone (3) (Figure 1) [1,2,3].
In the pursuit of synthetic strategies to access these key intermediates in natural products synthesis, transition metal (TM)-catalyzed asymmetric hydrogenation (AH) of α-alkyl-β-ketoesters stands out as a straightforward approach. This method allows for the creation of two contiguous stereocenters in one single step through a dynamic kinetic resolution (DKR) [4,5,6]. However, the α-alkyl-β-ketoesters pose challenges in TM-AH-DKR reactions when compared to cyclic β-ketoesters or acyclic α-heteroatom-substituted β-ketoesters. These challenges arise due to their low racemization rates and poor stereorecognition of the α-alkyl substituents [7,8,9,10].
To selectively obtain anti-α-alkyl-β-hydroxyesters (83:17 to 96:4 dr and 63 to >99% ee), chiral ferrocenyl-based tridentate ligands−Ir(I) complexes were developed. These complexes were employed under 10–40 atm of H2 with t-BuOK or NaOAc as the base in three seminal works [7,8,9]. More recently, a DIPSkewphos/3-AMIQ−Ru(II) catalyst, in combination with t-BuOK, efficiently promoted the AH-DKR of α-alkyl-β-ketoesters under 10 atm of H2. This method yielded anti-α-alkyl-β-hydroxyesters with high stereoselectivities (94:6 to >99:1 dr and 98 to >99% ee) (Scheme 1a) [10].
Despite the efficiency of the three previous works in synthesizing α-alkyl-β-hydroxyesters with high stereoselectivities, an additional ester reduction step would be required to obtain the 2-alkyl-1-phenylpropane-1,3-diols (Figure 1). Therefore, we wondered if these intermediates could be obtained in a straightforward and practical manner.
In this context, the asymmetric transfer hydrogenation (ATH) reactions emerge as interesting alternatives to the AH methods, particularly in the synthesis of natural products and pharmaceuticals [11,12,13]. Unlike AH, ATH avoids the use of hazardous pressurized H2 gas and high-pressure equipment. Instead, formic acid/triethylamine mixtures or sodium formate serve as hydrogen sources [14]. Noyori–Ikariya-type complexes play a pivotal role in ATH, efficiently promoting the reduction of a wide range of ketones, including substrates with labile α- and β-stereocenters. This process results in enantiomerically pure products containing up to three contiguous stereocenters through dynamic kinetic resolution (DKR). Notably, these phosphine-free catalysts are easy to handle, exhibit stability against air and moisture exposure, and remain compatible with both protic and aprotic organic solvents, as well as polar functionalities of the substrate [6,15,16,17].
In 2019, Ratovelomanana-Vidal et al. [18] reported the Rh(III)-catalyzed ATH-DKR of 3-formyl-chromones (6) using formic acid/triethylamine as hydrogen source (Scheme 1b). The substrate’s three unsaturated bonds were reduced in a one-pot reaction by the Rh(III)-tethered Noyori–Ikariya-type catalyst [19], yielding cis-3-(hydroxymethyl)chroman-4-ols (7) with high diastereo- and enantioselectivities (92:8 to 98:2 dr and 97 to >99% ee). Remarkably, monitoring studies showed that the aldehyde moiety is the first of the three unsaturated bonds to be reduced.
In subsequent years, Wills et al. [20] reported the Ru(II)-catalyzed ATH of three chalcones (8), leading to the enantioselective synthesis of 1,3-diarylpropan-2-ols (9) through a one-pot C=C/C=O reduction sequence (Scheme 1c). Our group expanded the reaction scope to include 27 additional examples using sodium formate as the hydrogen source in water [21]. Furthermore, we demonstrated the applicability of the chiral 1,3-diarylpropan-2-ols (9) obtained in the total synthesis of two flavans: the antiviral (S)-BW683C and the natural flavan (S)-tephrowatsin E.
Building upon the success of using ATH of chalcones (8) as a strategy to obtain 1,3-diarylpropan-2-ols (9) [21], we envisioned that acyclic α-benzyl-β-ketoaldehydes (rac)-10 would undergo a one-pot double C=O reduction under ATH-DKR conditions promoted by Noyori–Ikariya-type catalysts. This transformation would afford 2-benzyl-1-phenylpropane-1,3-diols (12) with two contiguous stereocenters, exhibiting high diastereo- and enantioselectivities (Scheme 1d). The expected preferential reduction of the aldehyde group [18] would yield 2-benzyl-3-hydroxy-1-phenylpropan-1-one intermediates (11), potentially enhancing substrate reactivity and/or stereorecognition of the α-alkyl substituents by the chiral complex through hydrogen bonding. These effects have been increasingly explored in ATH-DKR of ketones bearing hydrogen bonding donors promoted by Noyori–Ikariya-type catalysts [21,22,23,24,25,26,27,28,29].

2. Results and Discussion

To the best of our knowledge, there are no reports in the literature regarding the synthesis of α-benzyl-β-ketoaldehydes (rac)-10. Therefore, we developed a synthetic route, as outlined in Table 1. The initial step involves an aldol condensation between commercially available acetophenones and aldehydes, using KOH as the base at room temperature (rt) in a mixture of MeOH and H2O [30]. The reactions proceeded for 2 to 27 h, monitored by TLC analysis until complete consumption of the acetophenones. Consequently, chalcones 8a–j were obtained with yields ranging from 65% to 96%. Then, the chalcones 8a–j underwent catalytic hydrogenation using 10% Pd/C in AcOEt at room temperature for 1 to 5 h [31]. The resulting dihydrochalcones 13a–j were obtained in 37 to 96% yield after purification (Table 1).
Then, the formylation of the dihydrochalcones 13a–j was achieved through reaction with N,N-dimethylformamide dimethyl acetal (DMF-DMA), followed by hydrolysis of the crude products to yielded α-benzyl-β-ketoaldehydes (rac)-10 (Table 1) [32]. During the optimization process (Table S1), we observed that increasing the solvent polarity—from toluene (PhMe) to dimethyl sulfoxide (DMSO)—resulted in higher conversions of 13 [23]. Additionally, lowering the reaction temperature from 110 to 60 °C was necessary to prevent product degradation. Consequently, reaction times ranging from 42 to 120 h were required to achieve complete conversion of 13, as confirmed by TLC analysis (Table 1). After work-up, the reaction crudes were directly used in the subsequent step without further purification.
Notably, initial attempts to promote the hydrolysis of enaminone 14 using 5% HCl aqueous [33] or 25% NaOH [34] resulted in the cleavage of the C=C bond, exclusively affording the dihydrochalcones under acid hydrolysis or in 38% yield under basic conditions (Table S2). Control experiments confirmed that the cleavage occurred at the enaminone 14 intermediate and not at the β-ketoaldehyde 10 (Figures S1 and S2) [33,35]. Subsequently, we discovered that milder acid conditions—specifically, acetic acid at room temperature for 1.5 h—proved optimal. This led to the formation of the tautomeric keto-enol mixtures (10/15) in yields ranging from 49% to 91% (Table 1).
The α-benzyl-β-ketoaldehyde 10j was chosen as the substrate for optimizing the ATH-DKR reactions due to its methylenedioxy substituent at ring A. This electron-donating group is commonly found in natural products (Figure 1). The evaluated reaction conditions are listed in Table 2.
We initiated our evaluations using sodium formate as the hydrogen source in a biphasic DCE/H2O mixture. This choice was based on previous reports of faster rates and higher turnover numbers under near-neutral initial conditions in ATH of challenging ketones using Noyori–Ikariya-type catalysts (A–I) (Table 2, entry 1) [23,36,37,38,39,40]. Additionally, we opted for Will’s 3-C-tethered-Ru(II) catalyst, (R,R)-D, due to its robustness, which often leads to enhanced reactivity and enantioselectivity compared to first-generation catalysts [17,41]. Then, after 16 h at room temperature using 2 mol% of (R,R)-D and 10 mol% of the phase transfer catalyst CTAB, the starting α-benzyl-β-ketoaldehyde 10j was completely converted into the intermediate ketone 11j. However, no reduction to the desired product 12j was observed.
Subsequently, in our quest for higher conversions and stereoselectivities potentially enhanced by the intermediate ketone 11j, which bears a β-substituted with a hydrogen bond donor hydroxyl group, we evaluated the use of the aprotic DCE as the sole solvent (Table 2, entry 2). Due to solubility issues with sodium formate, we resorted to a formic acid/triethylamine mixture (5:4) as the hydrogen source. Unfortunately, no reduction of the ketone 11j was observed under these conditions either.
Further exploration of aprotic solvents revealed that decreasing solvent polarity was beneficial for both enhancing the reduction of intermediate 11j and improving the stereoselectivity of the reaction (Table 2, entries 3–6). Remarkably, using toluene as the solvent resulted in an 11j/12j ratio of 44:56, with the anti-(1R,2R)-12j diol obtained in higher diastero- and enantioselectivity (anti/syn 92:8, >99% ee) (Table 2, entry 6). The absolute configuration was assigned by comparing optical rotation data from literature (Figure S3) [42].
To enhance the conversion of compound 11j into anti-12j diastereoisomer, we raised the reaction temperature from room temperature (rt) to 45 °C. This change led to a substantial conversion of the intermediate ketone 11j (11j/12j 7:93) (Table 2, entry 7). However, the higher yield of 12j at 45 °C was accompanied by a decrease in the diastereoselectivity (anti/syn 87:13).
We also evaluated other catalysts, including Ru(II), Rh(III), and Ir(III)-Noyori–Ikariya types, at 45 °C (Table 2, entries 8–13). Unfortunately, these catalysts showed minimal or no conversion of intermediate 11j. To mitigate the negative impact of higher temperature on stereoselectivity in the of the (R,R)-D catalyzed ATH-DKR, we explored the use of copper(II) triflate or triflic acid as additives (Table 2, entries 14–15) [23,36]. Regrettably, none of these additives significantly improved the previously observed anti/syn ratio (Table 2, entry 7).
Finally, by increasing the catalyst loading, from 2 to 4 mol% at rt, we achieved a substantial improvement in the conversion of 11j into 12j. This yielded the diol 12j with a good yield (75%) and maintained excellent stereoselectivity (anti/syn 92:8, >99% ee) (Table 2, entry 16). Notably, extending the reaction time from 16 to 24 h at rt did not further enhance the conversion of the remaining 11j (Table 2, entry 17).
The scope of the one-pot double C=O reduction of α-benzyl-β-ketoaldehydes (rac)-10, promoted by the (R,R)-D catalyst, was evaluated using the optimal conditions (Scheme 2). Ten (1R,2R)-2-benzyl-1-phenylpropane-1,3-diols were obtained in yields ranging from 41% to 87%, demonstrating viability of the dynamic kinetic resolution (DKR) process even under mild reaction conditions for these challenging acyclic α-alkyl-β-ketoaldehydes substrates. Complete conversion of the starting materials 10 was observed in all cases. However, the ratio between the ketone intermediate 11 and the diol 12 was influenced by the substituents.
Generally, substrates with no substituents at the A-ring showed higher conversion of the intermediate ketone 11 compared to substrates substituted with bromine, methoxy, and methylenedioxy groups. The deactivating effect of the electron-donating methoxy group, conjugated at the para-position of the A-ring with the carbonyl group, was particularly remarkable. In this case, an increase in the catalyst loading was necessary to obtain the diol 12g with good yield (69%). Additionally, fluorine groups at meta- and ortho-positions of the B-ring resulted in a slight decrease in the ketone 11 reactivity compared to fluorine and other groups at the para-position of the ring. On the other hand, the electron-withdrawing chlorine substituent resulted in the higher conversion of the intermediate ketone 11.
The anti-diastereoisomers were the major products in all examples, with ratios varying from 85:15 to 92:8 anti/syn, demonstrating good stereorecognition the α-alkyl substituents by the (R,R)-D catalyst. Notably, excellent enantioselectivities (>99% ee) were found for all examples, regardless of the stereoelectronic effect of the substituent.
The enhancement of the substrate reactivity and stereorecognition by the chiral complex through in situ formation of the intermediate’s (11) hydrogen bonding donor group was supported by control experiments (Scheme 3).
These experiments were conducted under two conditions previously evaluated for the α-benzyl-β-ketoaldehyde (rac)-10j, using 2 mol% of (R,R)-D at 45 °C or 4 mol% of (R,R)-D at room temperature (Scheme 3a; Table 2, entries 8 and 16). When the α-benzyl-β-ketoester (rac)-4a underwent the Ru(II)-catalyzed ATH-DKR at 45 °C, only 64% conversion was observed (Scheme 3b), in sharp contrast to the 94% of conversion of the intermediate (rac)-11j under the same conditions (Scheme 3a).
Furthermore, the role of a hydrogen bond donor in these acyclic α-alkyl substrates also proved to be crucial for the catalyst stereorecognition. The ATH-DKR of (rac)-4a resulted in significantly lower levels of diastereo- and enantioselectivity (67:33 anti/syn, 83% ee) compared to (rac)-10j (87:13 anti/syn, >99% ee). Notably, the in situ formation of the (rac)-11j played a key role in improving the reaction’s stereoselectivity (92:8 anti/syn, >99% ee) compared to using (rac)-11j as the starting material (73:27 anti/syn, 98% ee) (Scheme 3).
To demonstrate the feasibility of the developed Ru(II)-catalyzed ATH-DKR of α-benzyl-β-ketoaldehydes, the reaction was scaled up 10-fold, from 0.1 to 1 mmol (Scheme 4a). After 16 h at rt, the 2-benzyl-1-phenylpropane-1,3-diol 12j was obtained with the same yield (75%, 228 mg) and stereoselectivity observed previously.
Subsequently, the utility of the enantiomer-enriched 2-benzyl-1-phenylpropane-1,3-diol 12j was demonstrated in the synthesis of the oxetane 17 (Scheme 4b). Oxetanes are strained cyclic ethers found in the structures of several natural products. They are considered stable motifs for medicinal chemistry and serve as key reactive intermediates in organic synthesis [43]. The regioselective tosylation of the primary hydroxyl group in 12j yielded intermediate (R,R)-16 in 65% yield, with a slight improvement in the diastereoisomeric ratio (97:3 anti/syn) and no erosion of the optical purity after purification (>99% ee). Finally, an intramolecular O-nucleophilic substitution triggered by n-BuLi exclusively afforded trans-(2R,3R)-3-benzyl-2-phenyloxetane 17 in good yield (57%) and >99% ee.

3. Materials and Methods

3.1. General Information

All commercial reagents and solvents were purchased from Sigma-Aldrich (St. Louis, MO, USA), Ambeed (Arlington Heights, IL, USA), Biograde (Anápolis, GO, Brazil), Tedia (Fairfield, OH, USA), TCI (Portland, OR, USA), Oakwood Chemical (Estill, SC, USA), or Acros Organics (Geel, Belgium) and used without further purification. All reactions that required heating were performed using an oil bath. Analytical thin layer chromatography (TLC) was performed on 0.25 mm silica gel 60 F254 SiliCycle (Quebec, QC, Canada) plates and visualized under UV light (254 nm or 365 nm) or by staining with vanillin/H2SO4. Preparative TLC was performed on 20 × 20 cm glass backed plates bearing a 0.5 mm layer of silica gel 60 F254 (Macherey-Nagel; Düren, Germany). Flash column chromatography was performed on silica gel 60 (230–400 mesh) SiliCycle (Quebec, QC, Canada). High-performance liquid chromatography (HPLC) analyses were carried out on a Shimadzu (Kyoto, Japan) LC-20AT liquid chromatograph equipped with an SPD-M20A diode array detector, and retention times (tR) are expressed in minutes. NMR spectra were recorded on Varian Unity (Palo Alto, CA, USA) 400 or 500 MHz instruments at 25 °C. Chemical shifts are expressed in ppm relative to TMS (Me4Si) or deuterated solvent (CDCl3, DMSO-d6, (CD3)2CO) and the coupling constants are expressed in Hz. High-resolution mass spectra (HRMS) were obtained with a Bruker solariX XR mass spectrometer (Billerica, MA, USA) with Electrospray Ionization (ESI) source coupled to a Fourier Transform–Ion Cyclotron Resonance (FT-ICR) mass analyzer.

3.2. General Procedure for the Synthesis of Compounds 8a–j

A mixture of the appropriate acetophenone (1 equiv., 6 mmol) and KOH (7.5 equiv., 45 mmol) in MeOH/H2O (2:1, 36 mL) was magnetically stirred at rt for 10 min. The resulting solution was treated with the corresponding benzaldehyde (2.0 equiv., 6 mmol) and then stirred 2–27 h at rt, until the total consumption of acetophenone, indicated by TLC analysis. After completing the reaction, it was acidified to pH = 7 under an ice bath. Saturated sodium bisulfite solution (200 mL) was added, and the mixture was stirred for 40 min. After, the mixture was diluted with EtOAc (50 mL), washed with H2O (3 × 50 mL) and brine (1 × 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel (EtOAc/hexane, 5:95), yielding the pure product (see Supplementary Materials for NMR spectra).
(E)-chalcone (8a): Synthesized in a 6 mmol scale and purified by recrystallization from chloroform/hexane. Pale yellow solid, 1067.6 mg, 85% yield. 1H NMR (500 MHz, CDCl3) δ 8.02 (d, J = 7.1 Hz, 2H), 7.81 (d, J = 15.8 Hz, 1H), 7.67–7.62 (m, 2H), 7.58 (t, J = 7.4 Hz, 1H), 7.55–7.48 (m, 3H), 7.41 (dd, J = 5.1, 1.9 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 190.6, 144.8, 138.2, 134.9, 132.8, 130.6, 129.0, 128.6, 128.5, 128.5, 122.1. Spectroscopic data were consistent with those reported in the literature [44].
(E)-3-(4-methoxyphenyl)-1-phenylprop-2-en-1-one (8b): Synthesized in a 5 mmol scale and purified by recrystallization from chloroform/hexane. Pale yellow solid, 796.4 mg, 67% yield. 1H NMR (500 MHz, CDCl3) δ 8.01 (d, J = 6.9 Hz, 2H), 7.79 (d, J = 15.6 Hz, 1H), 7.60 (d, J = 8.7 Hz, 2H), 7.56 (d, J = 7.5 Hz, 1H), 7.49 (t, J = 7.5 Hz, 2H), 7.41 (d, J = 15.7 Hz, 1H), 6.94 (d, J = 8.9 Hz, 2H), 3.85 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 190.6, 161.7, 144.7, 138.5, 132.6, 130.3, 128.6, 128.4, 127.6, 119.8, 114.4, 55.4. Spectroscopic data were consistent with those reported in the literature [44].
(E)-1-phenyl-3-(4-(trifluoromethyl)phenyl)prop-2-en-1-one (8c): Synthesized in a 6 mmol scale and purified by recrystallization from H2O/MeOH. White solid, 1017.6 mg, 61% yield. 1H NMR (500 MHz, CDCl3) δ 8.03 (d, J = 7.0 Hz, 2H), 7.80 (d, J = 15.9 Hz, 1H), 7.73 (d, J = 8.2 Hz, 2H), 7.67 (d, J = 8.5 Hz, 2H), 7.60 (d, J = 15.9 Hz, 2H), 7.54–7.49 (m, 2H). 13C NMR (126 MHz, CDCl3) δ 190.0, 142.7, 138.3, 137.8, 131.9 (q, J = 32.8 Hz), 131.8, 128.7, 128.6, 128.5, 125.9 (q, J = 3.9 Hz), 124.3 (q, J = 272.2 Hz), 124.2. Spectroscopic data were consistent with those reported in the literature [44].
(E)-3-(4-fluorophenyl)-1-phenylprop-2-en-1-one (8d): Synthesized in a 5 mmol scale and purified by column chromatography on silica gel (EtOAc/hexane, 10:90). White solid, 940 mg, 83% yield. 1H NMR (500 MHz, CDCl3) δ 8.02 (dd, J = 8.4, 1.3 Hz, 2H), 7.78 (d, J = 15.8 Hz, 1H), 7.64 (dd, J = 8.4, 5.3 Hz, 2H), 7.59 (t, J = 7.4 Hz, 1H), 7.51 (t, J = 7.6 Hz, 2H), 7.46 (d, J = 15.8 Hz, 1H), 7.11 (t, J = 8.7 Hz, 2H). 13C NMR (126 MHz, CDCl3) δ 190.3, 164.1 (d, J = 251.8 Hz), 143.5, 138.2, 132.8, 131.2 (d, J = 3.3 Hz), 130.4 (d, J = 8.6 Hz), 128.7, 128.5, 121.8, 121.8, 116.2, 116.1 (d, J = 21.9 Hz). Spectroscopic data were consistent with those reported in the literature [45].
(E)-3-(3-fluorophenyl)-1-phenylprop-2-en-1-one (8e): Synthesized in a 6 mmol scale and the crude material was used in the next step without purification. White solid. 1H NMR (500 MHz, CDCl3) δ 8.02 (dd, J = 8.4, 1.3 Hz, 2H), 7.75 (d, J = 15.8 Hz, 1H), 7.59 (t, J = 7.4 Hz, 1H), 7.54–7.48 (m, 3H), 7.42–7.31 (m, 3H), 7.13–7.06 (m, 1H). 13C NMR (126 MHz, CDCl3) δ 190.1, 163.1 (d, J = 247.0 Hz), 143.3, 137.9, 137.2 (d, J = 7.6 Hz), 133.0, 130.5 (d, J = 8.1 Hz), 128.7, 128.5, 124.6, 124.5, 123.2, 117.4 (d, J = 21.5 Hz), 114.5 (d, J = 21.9 Hz). Spectroscopic data were consistent with those reported in the literature [44].
(E)-3-(2-fluorophenyl)-1-phenylprop-2-en-1-one (8f): Synthesized in a 6 mmol scale and the crude material was used in the next step without purification. Pale yellow solid. 1H NMR (500 MHz, CDCl3) δ 8.02 (d, J = 7.1 Hz, 2H), 7.90 (d, J = 15.9 Hz, 1H), 7.67–7.61 (m, 2H), 7.58 (t, J = 7.3 Hz, 1H), 7.50 (t, J = 7.6 Hz, 2H), 7.40–7.34 (m, 1H), 7.19 (t, J = 7.6 Hz, 1H), 7.15–7.09 (m, 1H). 13C NMR (126 MHz, CDCl3) δ 190.5, 161.7 (d, J = 254.2 Hz), 138.0, 137.5 (d, J = 2.4 Hz), 132.9, 131.9 (d, J = 8.6 Hz), 129.8 (d, J = 2.9 Hz), 128.7, 128.6, 124.6 (d, J = 7.6 Hz), 124.5 (d, J = 1.9 Hz), 123.0 (d, J = 11.4 Hz), 116.3 (d, J = 21.9 Hz). Spectroscopic data were consistent with those reported in the literature [46].
(E)-1-(4-methoxyphenyl)-3-phenylprop-2-en-1-one (8g): Synthesized in a 6 mmol scale and purified by recrystallization from chloroform/hexane. White solid, 1155.4 mg, 81% yield. 1H NMR (500 MHz, CDCl3) δ 8.04 (d, J = 9.0 Hz, 2H), 7.80 (d, J = 15.6 Hz, 1H), 7.64 (d, J = 9.6 Hz, 2H), 7.54 (d, J = 15.7 Hz, 1H), 7.44–7.39 (m, 3H), 6.98 (d, J = 9.0 Hz, 2H), 3.88 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 188.7, 163.4, 144.0, 135.1, 131.1, 130.8, 130.3, 128.9, 128.4, 121.9, 113.9, 55.5. Spectroscopic data were consistent with those reported in the literature [44].
(E)-1-(4-bromophenyl)-3-phenylprop-2-en-1-one (8h): Synthesized in a 6 mmol scale. White solid, 1722.5 mg, quantitative yield. 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 8.6 Hz, 2H), 7.81 (d, J = 15.7 Hz, 1H), 7.64 (d, J = 8.6 Hz, 4H), 7.47 (d, J = 15.7 Hz, 1H), 7.44–7.38 (m, 3H). 13C NMR (101 MHz, CDCl3) δ 189.4, 145.4, 136.9, 134.7, 131.9, 130.8, 130.0, 129.0, 128.5, 127.9, 121.5. Spectroscopic data were consistent with those reported in the literature [47].
(E)-1-(4-chlorophenyl)-3-(4-fluorophenyl)prop-2-en-1-one (8i): Synthesized in a 5 mmol scale and purified by recrystallization from chloroform/hexane. White solid, 841.1 mg, 65% yield. 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 8.6 Hz, 2H), 7.78 (d, J = 15.7 Hz, 1H), 7.64 (dd, J = 8.9, 5.3 Hz, 2H), 7.48 (d, J = 8.6 Hz, 2H), 7.41 (d, J = 15.7 Hz, 1H), 7.12 (t, J = 8.6 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 189.0, 164.2 (d, J = 252.2 Hz), 144.0, 139.3, 136.4, 131.0 (d, J = 3.4 Hz), 130.4 (d, J = 8.8 Hz), 129.9, 129.0, 121.2, 116.2 (d, J = 21.7 Hz). Spectroscopic data were consistent with those reported in the literature [48].
(E)-1-(benzo[d][1,3]dioxol-5-yl)-3-(4-fluorophenyl)prop-2-en-1-one (8j): Synthesized in a 5 mmol scale and purified by recrystallization from chloroform/hexane. White crystalline solid, 1154.3 mg, 85% yield. 1H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 15.7 Hz, 1H), 7.67–7.58 (m, 3H), 7.52 (d, J = 1.8 Hz, 1H), 7.41 (d, J = 15.6 Hz, 1H), 7.10 (t, J = 8.6 Hz, 2H), 6.89 (d, J = 8.1 Hz, 1H), 6.06 (s, 2H). 13C NMR (101 MHz, CDCl3) δ 188.0, 164.0 (d, J = 251.4 Hz), 151.7, 148.3, 142.9, 132.9, 131.2 (d, J = 3.4 Hz), 130.2 (d, J = 8.8 Hz), 124.6, 121.4, 116.1 (d, J = 21.7 Hz), 108.4, 107.9, 101.9. Spectroscopic data were consistent with those reported in the literature [49].

3.3. General Procedure for the Synthesis of Compounds 13a–j

To a solution of the corresponding chalcone 8a–j (1.0 equiv.) in EtOAc (0.083 M) was added 10% Pd/C (2–8% m/m in Pd/chalcone ratio) and stirred under hydrogen atmosphere at rt for 1–4.5 h, until the total consumption of starting material, indicated by TLC analysis. Upon completion, the mixture was diluted with EtOAc (40 mL), vacuum-filtered through a pad of Celite/Silica, and the solvent was removed under reduced pressure. The obtained crude was purified by flash chromatography on a silica gel (EtOAc/hexane, 5:95), to afford the dihydrochalcones 13a–j.
1,3-diphenylpropan-1-one (13a): Synthesized in a 4.1 mmol scale and purified by column chromatography on silica gel (EtOAc/hexane, 5:95). White solid, 927.1 mg, 87% yield. 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 7.1 Hz, 2H), 7.56 (t, J = 7.4 Hz, 1H), 7.45 (t, J = 7.6 Hz, 2H), 7.34–7.23 (m, 4H), 7.21 (t, J = 7.0 Hz, 1H), 3.31 (t, J = 7.5 Hz, 2H), 3.07 (t, J = 8.2 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 199.2, 141.3, 136.8, 133.1, 128.6, 128.5, 128.4, 128.0, 126.1, 40.4, 30.1. Spectroscopic data were consistent with those reported in the literature [50].
3-(4-methoxyphenyl)-1-phenylpropan-1-one (13b): Synthesized in a 3.5 mmol scale and purified by column chromatography on silica gel (EtOAc/hexane, 10:90). Pale beige solid, 443.3 mg, 53% yield. 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 7.0 Hz, 2H), 7.56 (t, J = 7.4 Hz, 1H), 7.46 (t, J = 7.9 Hz, 2H), 7.18 (d, J = 8.8 Hz, 2H), 6.85 (d, J = 8.8 Hz, 2H), 3.79 (s, 3H), 3.31–3.24 (m, 2H), 3.02 (t, J = 7.6 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 199.4, 158.0, 136.9, 133.3, 133.0, 129.4, 128.6, 128.0, 113.9, 55.3, 40.7, 29.3. Spectroscopic data were consistent with those reported in the literature [51].
1-phenyl-3-(4-(trifluoromethyl)phenyl)propan-1-one (13c): Synthesized in a 3.7 mmol scale and purified by column chromatography on silica gel (EtOAc/hexane, 7:93). White solid, 685.8 mg, 67% yield. 1H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 7.1 Hz, 2H), 7.57 (d, J = 7.9 Hz, 3H), 7.49 (t, J = 7.5 Hz, 2H), 7.40 (d, J = 8.3 Hz, 2H), 3.35 (t, J = 7.3 Hz, 2H), 3.16 (t, J = 7.5 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 198.6, 145.5, 136.7, 133.3, 128.8, 128.7, 128.6 (q, J = 24.6 Hz), 128.0, 125.4 (q, J = 3.9 Hz), 124.3 (q, J = 271.8 Hz), 39.8, 29.8. Spectroscopic data were consistent with those reported in the literature [52].
3-(4-fluorophenyl)-1-phenylpropan-1-one (13d): Synthesized in a 4.16 mmol scale and purified by column chromatography on silica gel (EtOAc/hexane, 5:95). White solid, 615.3 mg, 65% yield. 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 7.1 Hz, 2H), 7.55 (t, J = 7.4 Hz, 1H), 7.45 (t, J = 7.5 Hz, 2H), 7.20 (dd, J = 8.8, 5.4 Hz, 2H), 6.97 (t, J = 8.8 Hz, 2H), 3.27 (t, J = 7.4 Hz, 2H), 3.04 (t, J = 7.6 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 199.0, 161.4 (d, J = 243.8 Hz), 136.9 (d, J = 3.4 Hz), 136.8, 133.1, 129.8 (d, J = 7.6 Hz), 128.6, 128.0, 115.2 (d, J = 21.0 Hz), 40.4, 29.2. Spectroscopic data were consistent with those reported in the literature [51].
3-(3-fluorophenyl)-1-phenylpropan-1-one (13e): Synthesized in a 6 mmol scale from the crude material of the previous step. Purified by column chromatography on silica gel (EtOAc/hexane, 3:97). White solid, 1077.7 mg, 79% yield (two steps). 1H NMR (400 MHz, CDCl3) δ 7.95 (dd, J = 8.4, 1.3 Hz, 2H), 7.55 (t, J = 7.4 Hz, 1H), 7.45 (t, J = 7.5 Hz, 2H), 7.26–7.21 (m, 1H), 7.02 (d, J = 8.3 Hz, 1H), 6.95 (d, J = 9.9 Hz, 1H), 6.89 (t, J = 7.9 Hz, 1H), 3.29 (t, J = 7.8 Hz, 2H), 3.06 (t, J = 7.6 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 198.8, 162.9 (d, J = 245.8 Hz), 143.9 (d, J = 7.3 Hz), 136.8, 133.2, 130.0, 129.9 (d, J = 8.4 Hz), 128.7, 128.0, 124.1, 115.3 (d, J = 20.9 Hz), 113.0 (d, J = 20.9 Hz), 40.0, 29.7. Spectroscopic data were consistent with those reported in the literature [53].
3-(2-fluorophenyl)-1-phenylpropan-1-one (13f): Synthesized in a 6 mmol scale from the crude material of the previous step. Purified by column chromatography on silica gel (EtOAc/hexane, 3:97). White solid, 503.8 mg, 37% yield (two steps). 1H NMR (500 MHz, CDCl3) δ 7.95 (dd, J = 8.5, 1.3 Hz, 2H), 7.54 (t, J = 7.4 Hz, 1H), 7.47–7.40 (m, 2H), 7.29–7.24 (m, 1H), 7.21–7.15 (m, 1H), 7.06 (t, J = 8.1 Hz, 1H), 7.04–6.99 (m, 1H), 3.32–3.27 (m, 2H), 3.09 (t, J = 7.7 Hz, 2H). 13C NMR (126 MHz, CDCl3) δ 199.0, 161.3 (d, J = 244.6 Hz), 136.8, 130.9 (d, J = 5.2 Hz), 128.6, 128.1 (d, J = 15.7 Hz), 128.0 (d, J = 8.6 Hz), 124.1 (d, J = 3.8 Hz), 115.3 (d, J = 21.9 Hz), 38.9, 24.0. Spectroscopic data were consistent with those reported in the literature [51].
1-(4-methoxyphenyl)-3-phenylpropan-1-one (13g): Synthesized in a 4.3 mmol scale and purified by column chromatography on silica gel (EtOAc/hexane, 10:90). Pale yellow solid, 1063.1 mg, 92% yield. 1H NMR (500 MHz, CDCl3) δ 7.93 (d, J = 9.0 Hz, 2H), 7.32–7.27 (m, 2H), 7.25 (d, J = 6.6 Hz, 2H), 7.22–7.17 (m, 1H), 6.91 (d, J = 9.0 Hz, 2H), 3.85 (s, 3H), 3.24 (s, 2H), 3.05 (s, 2H). 13C NMR (126 MHz, CDCl3) δ 197.8, 163.5, 141.5, 130.3, 130.0, 128.5, 128.4, 126.1, 113.7, 55.5, 40.1, 30.3. Spectroscopic data were consistent with those reported in the literature [50].
1-(4-bromophenyl)-3-phenylpropan-1-one (13h): Synthesized in a 4.22 mmol scale and filtrated with vacuum pump. White solid, 1111.5 mg, 91% yield. 1H NMR (500 MHz, CDCl3) δ 7.81 (d, J = 8.7 Hz, 2H), 7.58 (d, J = 8.7 Hz, 2H), 7.33–7.17 (m, 5H), 3.26 (t, J = 7.2 Hz, 2H), 3.06 (t, J = 7.3 Hz, 2H). 13C NMR (126 MHz, CDCl3) δ 198.2, 141.0, 135.6, 132.0, 129.6, 128.6, 128.4, 128.2, 126.2, 40.4, 30.0. Spectroscopic data were consistent with those reported in the literature [51].
1-(4-chlorophenyl)-3-(4-fluorophenyl)propan-1-one (13i): Synthesized in a 3.17 mmol scale and purified by column chromatography on silica gel (EtOAc/hexane, 10:90). White solid, 640.1 mg, 77% yield. 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 8.7 Hz, 2H), 7.41 (d, J = 8.7 Hz, 2H), 7.19 (dd, J = 8.7, 5.4 Hz, 2H), 6.97 (t, J = 8.7 Hz, 2H), 3.24 (t, J = 7.8 Hz, 2H), 3.03 (t, J = 7.5 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 197.75, 161.45 (d, J = 244.0 Hz), 139.6, 136.7 (d, J = 3.2 Hz), 135.1, 129.8 (d, J = 7.8 Hz), 129.4, 128.9, 115.3 (d, J = 21.2 Hz), 40.4, 29.2. Spectroscopic data were consistent with those reported in the literature [54].
1-(benzo[d][1,3]dioxol-5-yl)-3-(4-fluorophenyl)propan-1-one (13j): Synthesized in a 4.2 mmol scale and purified by column chromatography on silica gel (EtOAc/hexane, 10:90). White solid, 1145.6 mg, 88% yield. 1H NMR (400 MHz, CDCl3) δ 7.54 (d, J = 8.2 Hz, 1H), 7.43 (s, 1H), 7.23–7.14 (m, 2H), 6.96 (t, J = 8.8 Hz, 2H), 6.83 (d, J = 8.2 Hz, 1H), 6.03 (s, 2H), 3.19 (t, J = 7.3 Hz, 2H), 3.01 (t, J = 7.6 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 197.1, 161.4 (d, J = 243.8 Hz), 151.8, 148.2, 136.9 (d, J = 3.1 Hz), 131.7, 129.8 (d, J = 8.0 Hz), 124.2, 115.2 (d, J = 21.0 Hz), 107.9, 107.8, 101.8, 40.1, 29.5. Spectroscopic data were consistent with those reported in the literature [55].

3.4. Method for the Synthesis of Compound 4a

To a solution of methyl 3-(benzo[d][1,3]dioxol-5-yl)-3-oxopropanoate (1.0 equiv, 1110 mg, 5 mmol) in dimethylformamide (12.5 mL) was added K2CO3 (1.0 equiv, 570 mg, 5 mmol) and 1-(bromomethyl)-4-fluorobenzene (1.0 equiv, 0.62 mL, 5 mmol) and was stirred 24 h at 60 °C. Subsequently, the reaction was diluted with EtOAc (75 mL), washed with H2O (7 × 75 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The obtained crude was purified by flash chromatography on a silica gel (EtOAc/hexane/DCM, 1:6:1), yielding the pure product 4a
methyl 3-(benzo[d][1,3]dioxol-5-yl)-2-(4-fluorobenzyl)-3-oxopropanoate (4a): White solid, 907.7 mg, 55% yield. 1H NMR (500 MHz, DMSO-d6) δ 7.62 (dd, J = 8.3, 1.8 Hz, 1H), 7.42 (d, J = 1.8 Hz, 1H), 7.27 (dd, J = 8.8, 5.5 Hz, 2H), 7.08–6.99 (m, 3H), 6.13 (s, 2H), 4.98 (t, J = 7.6 Hz, 1H), 3.54 (s, 3H), 3.14 (dd, J = 7.6, 2.8 Hz, 2H). 13C NMR (126 MHz, DMSO-d6) δ 193.3, 170.0, 161.4 (d, J = 242.2 Hz), 152.6, 148.5, 134.7, 131.4 (d, J = 8.1 Hz), 130.9 (d, J = 3.3 Hz), 125.9, 115.1 (d, J = 21.5 Hz), 108.6, 108.2, 102.7, 54.2, 52.6, 34.0. HRMS (ESI) [M + H]+ calc. For C18H16FO5+ = 331.0976; found = 331.0972.

3.5. General Procedure for the Synthesis of Compounds 10/15a–j

To a solution of the corresponding dihydrochalcones 13a–j (1.0 equiv.) in DMSO (0.196 M) was added N,N-dimethylformamide dimethyl acetal (DMF-DMA, 5.0 equiv.) and stirred at rt for 10 min. Then, the reaction mixture was heated to 60 °C and stirred for 42–120 h, until the total consumption of starting material, indicated by TLC analysis. After this time, the mixture was cooled to rt and a solution acetic acid/H2O (1:1, 0.24 M) was added, allowed to stir at rt for 1.5 h. Subsequently, the reaction was diluted with EtOAc (75 mL), washed with H2O (7 × 75 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The obtained crude was purified by flash chromatography on a silica gel (EtOAc/hexane gradient, 10:90−15:85) to afford a mixture of tautomers keto-enol 10/15a–j.
2-benzyl-3-hydroxy-1-phenylprop-2-en-1-one (15a): Synthesized in a 4.22 mmol scale and purified by column chromatography on silica gel (EtOAc/hexane, 10:90−15:85) to afford a mixture of tautomers keto-enol. White solid, 707 mg, 70% yield. 1H NMR (500 MHz, CDCl3) δ 8.67 (d, J = 4.0 Hz, 1H), 7.90–7.10 (m, 10H), 3.70 (s, 2H). 13C NMR (126 MHz, CDCl3) δ 188.5, 184.6, 140.5, 133.9, 130.9, 128.7, 128.4, 128.1, 127.7, 126.4, 110.2, 33.5. HRMS (ESI) [M + H]+ calc. For C16H15O2+ = 239.1067; found = 239.1064.
2-(4-methoxybenzyl)-3-oxo-3-phenylpropanal (10b): Synthesized in a 1.79 mmol scale and purified by column chromatography on silica gel (EtOAc/hexane, 10:90−15:85) to afford a mixture of tautomers keto-enol. Beige solid, 378.23 mg, 79% yield. 1H NMR (500 MHz, CDCl3) δ 9.69 (d, J = 2.8 Hz, 1H), 7.90–6.75 (m, 9H), 4.65 (td, J = 7.2, 2.8 Hz, 1H), 3.69 (s, 3H), 3.27 (d, J = 7.1 Hz, 2H). 13C NMR (126 MHz, CDCl3) δ 197.9, 195.8, 158.5, 136.4, 133.9, 130.0, 129.5, 128.9, 128.7, 114.1, 63.1, 55.2, 32.7. HRMS (ESI) [M + H]+ calc. For C17H17O3+ = 269.1172; found = 269.1170.
3-hydroxy-1-phenyl-2-(4-(trifluoromethyl)benzyl)prop-2-en-1-one (15c): Synthesized in a 2.31 mmol scale and purified by column chromatography on silica gel (EtOAc/hexane, 10:90−15:85) to afford a mixture of tautomers keto-enol. Pale beige solid, 506.18 mg, 71% yield. 1H NMR (500 MHz, CDCl3) δ 8.63 (s, 1H), 7.52 (d, J = 8.2 Hz, 2H), 7.48–7.41 (m, 3H), 7.38 (t, J = 7.3 Hz, 2H), 7.20 (d, J = 8.6 Hz, 2H), 3.75 (s, 2H). 13C NMR (126 MHz, CDCl3) δ 187.3, 185.8, 144.6, 135.5, 131.1, 128.9 (d, J = 32.9 Hz), 128.5, 128.3, 127.5, 125.1 (q, J = 3.8 Hz), 124.1 (q, J = 271.8 Hz), 109.6, 33.5. HRMS (ESI) [M + H]+ calc. For C17H14F3O2+ = 307.0940; found = 307.0934.
2-(4-fluorobenzyl)-3-oxo-3-phenylpropanal (10d): Synthesized in a 2.7 mmol scale and purified by column chromatography on silica gel (EtOAc/hexane, 10:90−15:85) to afford a mixture of tautomers keto-enol. Pale beige solid, 412.3 mg, 49% yield. 1H NMR (400 MHz, (CD3)2CO) δ 9.81 (d, J = 1.9 Hz, 1H), 8.03–6.97 (m, 9H), 5.09 (td, J = 7.1, 1.9 Hz, 1H), 3.43–3.24 (m, 2H). 13C NMR (101 MHz, (CD3)2CO) δ 197.6, 195.4, 161.5 (d, J = 243.0 Hz), 136.8, 134.5 (d, J = 3.4 Hz), 133.7, 130.9, 130.8, 128.8, 128.6, 114.9 (d, J = 21.4 Hz), 62.3, 31.5. HRMS (ESI) [M + H]+ calc. For C16H14FO2+ = 257.0972; found = 257.0970.
2-(3-fluorobenzyl)-3-oxo-3-phenylpropanal (10e): Synthesized in a 4.48 mmol scale and purified by column chromatography on silica gel (EtOAc/hexane, 10:90−15:85) to afford a mixture of tautomers keto-enol. White solid, 743 mg, 65% yield. 1H NMR (500 MHz, (CD3)2CO) δ 9.83 (d, J = 1.8 Hz, 1H), 8.05–6.85 (m, 9H), 5.15 (td, J = 7.1, 1.8 Hz, 1H), 3.40 (dd, J = 14.2, 6.8 Hz, 1H), 3.32 (dd, J = 14.2, 7.5 Hz, 1H). 13C NMR (126 MHz, (CD3)2CO) δ 197.4, 195.2, 162.8 (d, J = 242.7 Hz), 144.3 (d, J = 7.2 Hz), 136.7, 133.7, 130.4, 129.7 (d, J = 9.1 Hz), 128.7, 128.1, 124.4, 115.0 (d, J = 21.0 Hz), 112.2 (d, J = 21.0 Hz), 62.0, 31.9. HRMS (ESI) [M + H]+ calc. For C16H14FO2+ = 257.0972; found = 257.0969.
2-(2-fluorobenzyl)-3-oxo-3-phenylpropanal (10f): Synthesized in a 2.03 mmol scale and purified by column chromatography on silica gel (EtOAc/hexane, 10:90−15:85) to afford a mixture of tautomers keto-enol. Pale yellow solid, 296.7 mg, 57% yield. 1H NMR (400 MHz, CDCl3) δ 9.75 (d, J = 2.5 Hz, 1H), 7.99–6.94 (m, 9H), 4.80 (td, J = 7.1, 2.6 Hz, 1H), 3.44 (dd, J = 14.2, 7.5 Hz, 1H), 3.32 (dd, J = 14.2, 6.8 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 197.2, 195.4, 161.2 (d, J = 244.9 Hz), 136.2, 134.0, 131.7 (d, J = 4.6 Hz), 128.9, 128.8, 128.7, 124.6, 124.4, 124.3, 124.3, 115.4 (d, J = 21.7 Hz), 61.1, 27.3. HRMS (ESI) [M + H]+ calc. For C16H14FO2+ = 257.0972; found = 257.0970.
2-benzyl-3-(4-methoxyphenyl)-3-oxopropanal (10g): Synthesized in a 2.51 mmol scale and purified by column chromatography on silica gel (EtOAc/hexane, 10:90−15:85) to afford a mixture of tautomers keto-enol. Yellow solid, 392.2 mg, 58% yield. 1H NMR (500 MHz, CDCl3) δ 9.71 (d, J = 2.9 Hz, 1H), 7.94–6.82 (m, 9H), 4.62 (td, J = 7.0, 2.9 Hz, 1H), 3.84 (s, 3H), 3.34 (dd, J = 7.0, 1.8 Hz, 2H). 13C NMR (126 MHz, CDCl3) δ 197.9, 193.7, 164.2, 140.7, 131.2, 129.5, 128.9, 128.7, 126.8, 114.1, 62.7, 55.4, 33.5. HRMS (ESI) [M + H]+ calc. For C17H17O3+ = 269.1172; found = 269.1169.
2-benzyl-3-(4-bromophenyl)-3-oxopropanal (10h): Synthesized in a 3.80 mmol scale and purified by column chromatography on silica gel (EtOAc/hexane, 10:90−15:85) to afford a mixture of tautomers keto-enol. Pale beige solid, 818.5 mg, 68% yield. 1H NMR (500 MHz, CDCl3) δ 9.71 (s, 1H), 7.72–7.05 (m, 9H), 4.60 (td, J = 7.2, 2.7 Hz, 1H), 3.34 (d, J = 7.6 Hz, 2H). 13C NMR (126 MHz, CDCl3) δ 197.3, 194.6, 140.2, 137.3, 132.2, 130.1, 129.4, 128.8, 128.0, 127.0, 62.9, 33.6. HRMS (ESI) [M + H]+ calc. For C16H14BrO2+ = 317.0172; found = 317.0169.
3-(4-chlorophenyl)-2-(4-fluorobenzyl)-3-oxopropanal (10i): Synthesized in a 2.44 mmol scale and purified by column chromatography on silica gel (EtOAc/hexane, 10:90−15:85) to afford a mixture of tautomers keto-enol. Pale yellow solid, 412.5 mg, 58% yield. 1H NMR (400 MHz, CDCl3) δ 9.69 (d, J = 2.6 Hz, 1H), 7.80–6.85 (m, 8H), 4.61 (td, J = 7.1, 2.7 Hz, 1H), 3.31 (d, J = 7.2 Hz, 2H). 13C NMR (126 MHz, (CD3)2CO) δ 197.5, 194.6, 161.6 (d, J = 242.7 Hz), 139.5, 135.4, 134.4 (d, J = 2.9 Hz), 130.9, 130.4, 129.0, 115.0 (d, J = 21.5 Hz), 62.1, 31.5. HRMS (ESI) [M + H]+ calc. For C16H13ClFO2+ = 291.0583; found = 291.0580.
1-(benzo[d][1,3]dioxol-5-yl)-2-(4-fluorobenzyl)-3-hydroxyprop-2-en-1-one (15j): Synthesized in a 1.67 mmol scale and purified by column chromatography on silica gel (EtOAc/hexane, 10:90−15:85) to afford a mixture of tautomers keto-enol. White solid, 454.7 mg, 91% yield. White solid. 1H NMR (500 MHz, CDCl3) δ 8.56 (d, J = 4.7 Hz, 1H), 7.12–7.05 (m, 2H), 7.03 (dd, J = 8.1, 1.8 Hz, 1H), 7.01–6.95 (m, 3H), 6.77 (d, J = 8.0 Hz, 1H), 6.00 (s, 2H), 3.70 (s, 1H). 13C NMR (126 MHz, CDCl3) δ 187.0, 184.7, 161.6 (d, J = 245.1 Hz), 150.1, 147.8, 136.1 (d, J = 3.3 Hz), 129.5, 129.4, 129.4, 123.0, 115.5 (d, J = 21.0 Hz), 109.7, 108.2, 108.1, 101.6, 33.1. HRMS (ESI) [M + H]+ calc. For C17H14FO4+ = 301.0871; found = 301.0868.

3.6. General Procedure for the Synthesis of Compounds 12a–j and 5a

A mixture of tautomers keto-enol 10/15a–j (1.0 equiv., 0.06 mmol), (R,R)-D (0.0024 mmol, 4 mol%), formic acid/triethylamine mole ratio (5:4) in toluene (0.25 M) was stirred under argon at rt for 16 h. Following this, the reaction was diluted with EtOAc (20 mL), dried over anhydrous Na2SO4, filtered over a pad of silica gel, and concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography (PTLC), resulting in the isolation of products 12a–j.
(1R,2R)-2-benzyl-1-phenylpropane-1,3-diol (12a): Purified by preparative TLC (DCM/petroleum ether/EtOAc, 2:5:2, 100 mL). White waxy solid, 9.74 mg, 0.06 mmol, 67% yield (containing 9% of the diastereoisomer, 61% corrected yield). Enantiomeric excess (>99% ee), was determined by HPLC analysis using a Phenomenex LC column 250 × 4.6 mm—Lux 5 µm Amylose-2, 90:10 hexane/iPrOH, flow rate 1 mL/min, at 208 nm (RTmaj = 10.399, RTmin = 16.160). Specific rotation: α D 25 = + 1.17   c   0.1 , M e O H ; + 3.96   c   0.2 , C H C l 3 .  1H NMR (500 MHz, (CD3)2CO) δ 7.40 (d, J = 6.7 Hz, 2H), 7.35 (t, J = 7.6 Hz, 2H), 7.29–7.23 (m, 3H), 7.23–7.15 (m, 3H), 4.82 (t, J = 5.0 Hz, 1H), 4.70 (d, J = 4.5 Hz, 1H), 3.86 (t, J = 5.1 Hz, 1H), 3.69 (d, J = 10.8 Hz, 1H), 3.52–3.43 (m, 1H), 2.75–2.63 (m, 2H), 2.14–2.08 (m, 1H). 13C NMR (126 MHz, (CD3)2CO) δ 144.7, 141.2, 129.1, 128.2, 127.9, 126.8, 126.4, 125.7, 75.2, 61.2, 49.5, 34.1. HRMS (ESI) [M + Na]+ calc. For C16H18NaO2+ = 265.1199; found = 265.1197.
(1R,2R)-2-(4-methoxybenzyl)-1-phenylpropane-1,3-diol (12b): Purified by preparative TLC (DCM/petroleum ether/EtOAc, 2:5:2, 100 mL). Dark gray waxy solid, 12.5 mg, 0.06 mmol, 76% yield (containing 13% of the diastereoisomer, 66% corrected yield). Enantiomeric excess (>99% ee), was determined by HPLC analysis using a Phenomenex LC column 250 × 4.6 mm—Lux 5 µm Amylose-2, 85:15 hexane/iPrOH, flow rate 1 mL/min, at 278 nm (RTmaj = 10.325, RTmin = 18.241). Specific rotation: α D 25 = + 1.58   c   0.1 , M e O H .  1H NMR (400 MHz, CDCl3) δ 7.41–7.27 (m, 5H), 7.05 (d, J = 8.7 Hz, 2H), 6.81 (d, J = 8.7 Hz, 2H), 4.76 (d, J = 6.2 Hz, 1H), 3.77 (s, 3H), 3.75–3.72 (m, 1H), 3.57 (dd, J = 11.1, 5.5 Hz, 1H), 2.66 (dd, J = 13.9, 5.8 Hz, 1H), 2.55 (dd, J = 13.9, 9.3 Hz, 1H), 2.48 (s, 1H), 2.12–2.01 (m, 1H). 13C NMR (126 MHz, (CD3)2CO) δ 158.0, 144.7, 132.8, 129.9, 127.9, 126.8, 126.4, 113.6, 75.2, 61.2, 54.5, 49.6, 33.2. HRMS (ESI) [M + Na]+ calc. For C17H20NaO3+ = 295.1305; found = 295.1303.
(1R,2R)-1-phenyl-2-(4-(trifluoromethyl)benzyl)propane-1,3-diol (12c): Purified by preparative TLC (DCM/petroleum ether/EtOAc, 1:3:1, 100 mL). Colorless oil, 13.7 mg, 0.06 mmol, 73% yield (containing 9% of the diastereoisomer, 66% corrected yield). Enantiomeric excess (>99% ee), was determined by HPLC analysis using a Phenomenex LC column 250 × 4.6 mm—Lux 5 µm Amylose-2, 95:5 hexane/iPrOH, flow rate 1 mL/min, at 208 nm (RTmaj = 12.846, RTmin = 20.204). Specific rotation: α D 25 = + 1.39   c   0.1 , M e O H .  1H NMR (500 MHz, (CD3)2CO) δ 7.60 (d, J = 7.8 Hz, 2H), 7.43 (d, J = 7.8 Hz, 2H), 7.39 (d, J = 7.0 Hz, 2H), 7.33 (t, J = 7.6 Hz, 2H), 7.24 (t, J = 7.3 Hz, 1H), 4.81 (t, J = 5.1 Hz, 1H), 4.72 (s, 1H), 3.89 (s, 1H), 3.68 (d, J = 10.9 Hz, 1H), 3.48–3.40 (m, 1H), 2.80 (d, J = 7.5 Hz, 2H), 2.19–2.10 (m, 1H). 13C NMR (126 MHz, (CD3)2CO) δ 146.2, 144.4, 129.8, 128.0, 127.0 (q, J = 86.4 Hz), 126.9, 126.4, 125.0 (q, J = 3.8 Hz), 124.7 (q, J = 270 Hz), 74.7, 60.7, 49.3, 33.9. HRMS (ESI) [M + FA − H]− calc. For C18H18F3O4− = 355.1163; found = 355.1162.
(1R,2R)-2-(4-fluorobenzyl)-1-phenylpropane-1,3-diol (12d): Purified by preparative TLC (DCM/petroleum ether/EtOAc, 1:3:1, 100 mL). Colorless oil, 13.6 mg, 0.06 mmol, 87% yield (containing 12% of the diastereoisomer, 77% corrected yield). Enantiomeric excess (>99% ee), was determined by HPLC analysis using a Phenomenex LC column 250 × 4.6 mm—Lux 5 µm Amylose-2, 90:10 hexane/iPrOH, flow rate 1 mL/min, at 267 nm (RTmaj = 9.123, RTmin = 14.316). Specific rotation: α D 25 = + 1.51   c   0.1 , M e O H .  1H NMR (400 MHz, CDCl3) δ 7.41–7.34 (m, 4H), 7.33–7.27 (m, 1H), 7.10 (dd, J = 8.8, 5.4 Hz, 2H), 6.95 (t, J = 8.8 Hz, 2H), 4.78 (d, J = 6.2 Hz, 1H), 3.77 (dd, J = 11.1, 2.7 Hz, 1H), 3.57 (dd, J = 11.0, 5.4 Hz, 1H), 2.70 (dd, J = 13.9, 6.0 Hz, 1H), 2.61 (dd, J = 13.8, 9.2 Hz, 1H), 2.13–2.02 (m, 1H). 13C NMR (126 MHz, (CD3)2CO) δ 161.2 (d, J = 241.3 Hz), 144.6, 137.1 (d, J = 3.3 Hz), 130.7 (d, J = 8.1 Hz), 127.9, 126.8, 126.4, 114.7 (d, J = 21.0 Hz), 74.9, 60.9, 49.5, 33.3. HRMS (ESI) [M + FA − H]− calc. For C17H18FO4− = 305.1195; found = 305.1194.
(1R,2R)-2-(3-fluorobenzyl)-1-phenylpropane-1,3-diol (12e): Purified by preparative TLC (DCM/petroleum ether/EtOAc, 1:3:1, 100 mL). Dark gray waxy solid, 8.5 mg, 0.06 mmol, 54% yield (containing 9% of the diastereoisomer, 49% corrected yield). Enantiomeric excess (>99% ee), was determined by HPLC analysis using a Phenomenex LC column 250 × 4.6 mm—Lux 5 µm Amylose-2, 90:10 hexane/iPrOH, flow rate 1 mL/min, at 263 nm (RTmaj = 10.485, RTmin = 14.573). Specific rotation: α D 25 = + 1.48   c   0.1 , M e O H .  1H NMR (400 MHz, (CD3)2CO) δ 7.42–7.18 (m, 6H), 7.10–6.85 (m, 3H), 4.80 (t, J = 5.0 Hz, 1H), 4.70 (d, J = 4.6 Hz, 1H), 3.88 (t, J = 4.9 Hz, 1H), 3.73–3.62 (m, 1H), 3.45 (m, 1H), 2.72 (d, J = 7.8 Hz, 2H), 2.10 (m, 1H). 13C NMR (126 MHz, (CD3)2CO) δ 205.4, 162.8 (d, J = 243.2 Hz), 144.5, 144.2 (d, J = 7.2 Hz), 129.9 (d, J = 8.6 Hz), 128.0, 126.9, 126.4, 125.1, 115.7 (d, J = 21.0 Hz), 112.4 (d, J = 21.5 Hz)., 74.8, 60.9, 49.3, 33.9, 28.8. HRMS (ESI) [M + Na]+ calc. For C16H17FNaO2+ = 283.1105; found = 283.1102.
(1R,2R)-2-(2-fluorobenzyl)-1-phenylpropane-1,3-diol (12f): Purified by preparative TLC (DCM/petroleum ether/EtOAc, 1:3:1, 100 mL). Brown oil, 11.7 mg, 0.06 mmol, 74% yield (containing 14% of the diastereoisomer, 64% corrected yield). Enantiomeric excess (>99% ee), was determined by HPLC analysis using a Phenomenex LC column 250 × 4.6 mm—Lux 5 µm Amylose-2, 90:10 hexane/iPrOH, flow rate 1 mL/min, at 209 nm (RTmaj = 10.603, RTmin = 15.706). Specific rotation: α D 25 = + 1.21   c   0.1 , M e O H .  1H NMR (400 MHz, (CD3)2CO) δ 7.43–7.18 (m, 7H), 7.15–6.99 (m, 2H), 4.82 (t, J = 5.0 Hz, 1H), 4.72 (d, J = 4.5 Hz, 1H), 3.88 (t, J = 4.9 Hz, 1H), 3.75–3.62 (m, 1H), 3.53–3.40 (m, 1H), 2.72 (d, J = 6.2 Hz, 2H), 2.21–2.09 (m, 1H). 13C NMR (101 MHz, (CD3)2CO) δ 161.3 (d, J = 243.6 Hz), 144.4, 131.7 (d, J = 5.0 Hz), 127.9, 127.8 (d, J = 4.8 Hz), 126.9, 126.4, 126.1, 124.0 (d, J = 3.5 Hz), 115.0 (d, J = 22.4 Hz), 75.2, 61.2, 47.9, 27.4. HRMS (ESI) [M + Na]+ calc. For C16H17FNaO2+ = 283.1105; found = 283.1103.
(1R,2R)-2-benzyl-1-(4-methoxyphenyl)propane-1,3-diol (12g): Purified by preparative TLC (DCM/petroleum ether/EtOAc, 2:5:2, 100 mL). Colorless oil, 17.6 mg, 0,094 mmol, 69% yield (containing 20% of the diastereoisomer, 55% corrected yield). Enantiomeric excess (>99% ee), was determined by HPLC analysis using a Phenomenex LC column 250 × 4.6 mm—Lux 5 µm Amylose-2, 85:15 hexane/iPrOH, flow rate 1 mL/min, at 276 nm (RTmaj = 11.265, RTmin = 17.587). Specific rotation: α D 25 = + 1.21   c   0.1 , M e O H .  1H NMR (500 MHz, (CD3)2CO) δ 7.31 (d, J = 8.6 Hz, 2H), 7.25 (m, 2H), 7.19–7.14 (m, 3H), 6.90 (d, J = 8.7 Hz, 2H), 4.75 (d, J = 6.4 Hz, 1H), 4.64 (s, 1H), 3.88 (s, 1H), 3.78 (s, 3H), 3.68 (dd, J = 10.7, 3.9 Hz, 1H), 3.46 (dd, J = 10.7, 5.4 Hz, 1H), 2.65 (dd, J = 13.5, 5.6 Hz, 1H), 2.56 (dd, J = 13.6, 9.2 Hz, 1H), 2.04 (s, 1H). 13C NMR (126 MHz, (CD3)2CO) δ 158.8, 141.2, 136.5, 129.0, 128.1, 127.6, 125.7, 113.3, 75.1, 61.4, 54.6, 49.5, 34.1. HRMS (ESI) [M + Na]+ calc. For C17H20NaO3+ = 295.1305; found = 295.1302.
(1R,2R)-2-benzyl-1-(4-bromophenyl)propane-1,3-diol (12h): Purified by preparative TLC (DCM/petroleum ether/EtOAc, 1:3:1, 100 mL). Colorless oil, 12.7 mg, 0.06 mmol, 66% yield (containing 12% of the diastereoisomer, 58% corrected yield). Enantiomeric excess (>99% ee), was determined by HPLC analysis using a Phenomenex LC column 250 × 4.6 mm—Lux 5 µm Amylose-2, 95:5 hexane/iPrOH, flow rate 1 mL/min, at 222 nm (RTmaj = 19.504, RTmin = 26.438). Specific rotation: α D 25 = + 1.14   c   0.1 , M e O H .  1H NMR (400 MHz, CDCl3,) δ 7.48 (d, J = 8.4 Hz, 2H), 7.33–7.19 (m, 5H), 7.14 (d, J = 8.8 Hz, 2H), 4.74 (d, J = 5.9 Hz, 1H), 3.73 (d, J = 10.6 Hz, 1H), 3.57 (dd, J = 11.1, 5.3 Hz, 1H), 2.73 (dd, J = 13.7, 5.9 Hz, 1H), 2.62 (dd, J = 14.0, 9.3 Hz, 1H), 2.10–1.95 (m, 1H). 13C NMR (101 MHz, (CD3)2CO) δ 144.0, 140.9, 130.9, 129.2, 128.6, 128.4, 125.7, 120.1, 74.2, 61.0, 49.3, 34.0. HRMS (ESI) [M + H]+ calc. For C16H18BrO2+ = 321.0485; found = 321.0306.
(1R,2R)-1-(4-chlorophenyl)-2-(4-fluorobenzyl)propane-1,3-diol (12i): Synthesized in a 0.06 mmol scale and purified by preparative TLC (DCM/petroleum ether/EtOAc, 1:3:1, 100 mL). Colorless oil, 13 mg, 73% yield (containing 11% of the diastereoisomer, 65% corrected yield). Enantiomeric excess (>99% ee), was determined by HPLC analysis using a Phenomenex LC column 250 × 4.6 mm—Lux 5 µm Amylose-2, 95:5 hexane/iPrOH, flow rate 1 mL/min, at 222 nm (RTmaj = 16.478, RTmin = 21.835). Specific rotation: α D 25 = + 1.09   c   0.1 , M e O H .  1H NMR (400 MHz, CDCl3) δ 7.37–7.24 (m, 4H), 7.09 (dd, J = 8.8, 5.4 Hz, 2H), 6.95 (t, J = 8.8 Hz, 2H), 4.74 (d, J = 5.9 Hz, 1H), 3.73 (dd, J = 10.9, 2.8 Hz, 1H), 3.55 (dd, J = 10.9, 5.3 Hz, 1H), 2.70 (dd, J = 13.9, 6.2 Hz, 1H), 2.61 (dd, J = 13.9, 9.2 Hz, 1H), 2.05–1.94 (m, 1H). 13C NMR (126 MHz, (CD3)2CO) δ 161.1 (d, J = 241.8 Hz), 143.5, 136.9, 132.0, 130.7 (d, J = 7.6 Hz), 128.1, 127.9, 114.7 (d, J = 21.5 Hz), 74.1, 60.7, 49.4, 33.1. HRMS (ESI) [M + Na]+ calc. For C16H16ClFNaO2+ = 317.0715; found = 317.0713.
(1R,2R)-1-(benzo[d][1,3]dioxol-5-yl)-2-(4-fluorobenzyl)propane-1,3-diol (12j): Purified by preparative TLC (DCM/petroleum ether/EtOAc, 1:2:1, 100 mL). Colorless oil, 15.4 mg, 0.067 mmol, 75% yield (containing 8% of the diastereoisomer, 69% corrected yield). Enantiomeric excess (>99% ee), was determined by HPLC analysis using a Phenomenex LC column 250 × 4.6 mm—Lux 5 µm Amylose-2, 85:15 hexane/iPrOH, flow rate 1 mL/min, at 286 nm (RTmaj = 12.147, RTmin = 20.759). Specific rotation: α D 25 = + 0.69   c   0.1 , M e O H .  1H NMR (500 MHz, (CD3)2CO) δ 7.21 (dd, J = 8.7, 5.5 Hz, 2H), 7.01 (t, J = 8.9 Hz, 2H), 6.91 (d, J = 1.8 Hz, 1H), 6.85–6.78 (m, 2H), 5.97 (s, 2H), 4.71 (t, J = 4.3 Hz, 1H), 4.64 (d, J = 4.4 Hz, 1H), 3.68 (dt, J = 10.6, 4.5 Hz, 1H), 3.45 (dt, J = 10.5, 5.1 Hz, 1H), 2.69–2.57 (m, 2H), 2.04–1.97 (m, 1H). 13C NMR (126 MHz, (CD3)2CO) δ 161.2 (d, J = 241.3 Hz), 147.6, 146.5, 138.7, 137.1, 130.7 (d, J = 8.1 Hz), 119.7, 114.7 (d, J = 21.0 Hz), 107.5, 106.7, 100.9, 75.0, 61.0, 49.5, 33.2. HRMS (ESI) [M + Na]+ calc. For C17H17FNaO4+ = 327.1003; found = 327.1001.
methyl (2S,3R)-3-(benzo[d][1,3]dioxol-5-yl)-2-(4-fluorobenzyl)-3-hydroxypropanoate (5a): Purified by preparative TLC (DCM/petroleum ether/EtOAc, 1:5:1, 100 mL). White solid, 18.3 mg, 0.1 mmol, 55% yield. Enantiomeric excess (82% ee), was determined by HPLC analysis using a Phenomenex LC column 250 × 4.6 mm—Lux 5 µm Amylose-2, 60:40 hexane/iPrOH, flow rate 1 mL/min, at 283 nm (RTmaj = 6.408, RTmin = 8.837). Specific rotation: α D 25 = + 0.75   c   0.1 , M e O H .  1H NMR (500 MHz, (CD3)2CO) δ 7.12–7.06 (m, 2H), 7.00–6.94 (m, 3H), 6.90 (d, J = 6.4 Hz, 1H), 6.82 (d, J = 7.9 Hz, 1H), 6.00 (s, 2H), 4.76 (dd, J = 8.7, 4.6 Hz, 1H), 4.55 (d, J = 4.6 Hz, 1H), 3.49 (s, 3H), 3.01–2.93 (m, 1H), 2.75–2.66 (m, 1H), 2.48 (dd, J = 13.6, 4.3 Hz, 1H). 13C NMR (126 MHz, (CD3)2CO) δ 205.3, 173.6, 161.4 (d, J = 242.2 Hz), 147.9, 147.2, 137.0, 135.3, 130.4 (d, J = 8.1 Hz), 120.5, 114.8 (d, J = 21.0 Hz), 107.7, 106.8, 101.1, 75.1, 56.3, 50.5, 34.4. HRMS (ESI) [M + Na]+ calc. For C18H17FNaO5+ = 355.0952; found = 355.0949.

3.7. Method for the Synthesis of Compound 16

To a solution of 2-benzyl-1-phenylpropane-1,3-diol (12j) (1.0 equiv, 55.72 mg, 0.183 mmol) in dichloromethane (3 mL, 0.061 M) was added tosyl chloride (3.0 equiv, 104.67 mg, 0.549 mmol), triethylamine (3.4 equiv, 86.7 µL, 0.622 mmol), and 4-dimethylaminopyridine (15 mol%, 3.35 mg, 0.027 mmol) at 0 °C. The mixture was stirred for 20 h at rt, followed by evaporation of the solvent under reduced pressure. The crude was diluted with EtOAc (50 mL), extracted with NH4Cl saturated solution (2 × 50 mL) and H2O (3 × 50 mL). The combined organic phases were dried with anhydrous Na2SO4, filtered and evaporated. The product was purified by PTLC (dichloromethane/petroleum ether/EtOAc, 1:4:1, 100 mL) to 65% yield the desired product 16.
(2R,3R)-3-(benzo[d][1,3]dioxol-5-yl)-2-(4-fluorobenzyl)-3-hydroxypropyl 4-methylbenzenesulfonate (16): Colorless oil, 54.5 mg, 0.183 mmol, 65% yield (containing 3% of the diastereoisomer, 63% corrected yield). Enantiomeric excess (>99% ee), was determined by HPLC analysis using a Phenomenex LC column 250 × 4.6 mm—Lux 5 µm Amylose-2, 20:80 hexane/iPrOH, flow rate 1 mL/min, at 207 nm (RTmaj = 7.822, RTmin = 17.078). Specific rotation: α D 25 = − 0.44   c   0.1 , M e O H .  1H NMR (500 MHz, CDCl3) δ 7.76 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 7.9 Hz, 2H), 6.93–6.83 (m, 4H), 6.80–6.70 (m, 3H), 5.96 (s, 2H), 4.57 (d, J = 8.1 Hz, 1H), 4.32 (dd, J = 9.5, 3.8 Hz, 1H), 3.81 (dd, J = 9.7, 3.2 Hz, 1H), 2.50–2.44 (m, 4H), 2.41 (dd, J = 13.6, 5.3 Hz, 1H), 2.06 (s, 1H). 13C NMR (126 MHz, CDCl3) δ 161.4 (d, J = 244.6 Hz), 148.1, 147.4, 144.9, 136.1, 134.6 (d, J = 3.3 Hz), 132.6, 130.3 (d, J = 8.1 Hz), 129.8, 128.0, 120.2, 115.2 (d, J = 21.0 Hz), 108.2, 106.6, 101.2, 73.0, 68.1, 47.7, 32.3, 21.6. HRMS (ESI) [M + FA − H]− calc. For C25H24FSO8− = 503.1176; found = 503.1181.

3.8. Method for the Synthesis of Compound 17

To a solution of intermediate 16 (1.0 equiv, 37.42 mg, 0.082 mmol) in anhydrous tetrahydrofuran (0.6 mL, 0.137 M) was added 2.5 M n-BuLi (30 µL, 0.082 mmol) at 0 °C under Ar atmosphere for 10 min. The reaction was heated to 60 °C and stirred for 22 h. Then, the phase aqueous was extracted with EtOAc (5 × 25 mL). The combined organic phases were dried with anhydrous Na2SO4, filtered, and evaporated. The product was purified by PTLC (dichloromethane/petroleum ether/EtOAc, 1:7.5:1, 100 mL) to 57% yield the desired product 17.
5-((2R,3R)-3-(4-fluorobenzyl)oxetan-2-yl)benzo[d][1,3]dioxole (17): Pale yellow oil, 25.9 mg, 0.082 mmol, 57% yield. Enantiomeric excess (>99% ee), was determined by HPLC analysis using a Phenomenex LC column 250 × 4.6 mm—Lux 5 µm Amylose-2, 90:10 hexane/iPrOH, flow rate 1 mL/min, at 288 nm (RTmaj =15.557, RTmin = 14.480). Specific rotation: α D 25 = + 2.22   c   0.1 , M e O H .  1H NMR (500 MHz, (CD3)2CO) δ 7.30 (dd, J = 8.5, 5.8 Hz, 2H), 7.06 (t, J = 8.9 Hz, 2H), 6.85 (d, J = 1.6 Hz, 1H), 6.80–6.73 (m, 2H), 6.00 (s, 2H), 5.40 (d, J = 6.0 Hz, 1H), 4.68–4.63 (m, 1H), 4.47 (t, J = 6.3 Hz, 1H), 3.18–3.12 (m, 1H), 3.12–3.09 (m, 2H). 13C NMR (126 MHz, (CD3)2CO) δ 161.5 (d, J = 242.2 Hz), 147.8, 147.2, 137.3, 135.4 (d, J = 3.3 Hz), 130.3 (d, J = 8.1 Hz), 118.8, 115.0 (d, J = 21.5 Hz), 107.7, 105.8, 101.1, 87.6, 72.3, 45.9, 37.8. HRMS (ESI) [M + Na]+ calc. For C17H15FNaO3+ = 309.0897; found = 309.0894.

4. Conclusions

In our pursuit of developing methods to obtain 2-alkyl-1-phenylpropane-1,3-diols, we present in this study the teth-TsDPEN-Ru(II)-catalyzed [(R,R)-D] one-pot double C=O reduction of α-benzyl-β-ketoaldehydes (10) through ATH-DKR under mild conditions. Initially, ten α-benzyl-β-ketoaldehydes (10) were synthesized as tautomeric keto-enol mixtures in a four-step sequence using commercially available acetophenones and benzaldehydes. These compounds were then subjected to ATH-DKR reactions.
The optimal conditions of the ATH-DKR were determined through careful optimization, considering various factors such as solvents, hydrogen sources, catalysts, additives, temperatures, and reaction times. In this process, ten anti-2-benzyl-1-phenylpropane-1,3-diols (12) (85:15 to 92:8 dr) were obtained with good yields (41–87%) and excellent enantioselectivities (>99% ee for all compounds). The reaction employed 4 mol% of (R,R)-D and formic acid/triethylamine mixture (5:4) as the hydrogen source in toluene at room temperature. Notably, the preferential reduction of the aldehyde moiety led to the in situ formation of 2-benzyl-3-hydroxy-1-phenylpropan-1-one intermediates (11). Control experiments confirmed that these intermediates (11) played a crucial role in enhancing both reactivity and stereoselectivity through hydrogen bonding. Finally, scale-up and functionalization experiments on the enantioenriched (1R,2R)-12j demonstrated the feasibility of the developed method.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules29143420/s1, Table S1. Optimization of the reaction conditions for the synthesis of the enaminone 14j; Table S2. Optimization of the conditions for the hydrolysis of enaminone 14j; Figure S1. Control experiment 1. Figure S2. Control experiment 2. Figure S3. Absolute configuration assignment. NMR spectra of the synthetized compounds 8a–j, 13a–j, 12a–j, 10/15a–j, 4a, 5a, 16, 17. Chromatograms of compounds 12a–j, 5a, 16, 17.

Author Contributions

Conceptualization, P.R.R.C. and G.S.C.; Data curation, D.P.L. and G.S.C.; Formal analysis, D.P.L. and G.S.C.; Funding acquisition, P.R.R.C.; Investigation, D.P.L., L.H.S.A. and S.R.M.; Methodology, D.P.L. and G.S.C.; Project administration, P.R.R.C. and G.S.C.; Resources, P.R.R.C.; Supervision, P.R.R.C. and G.S.C.; Visualization, G.S.C.; Writing—original draft, G.S.C.; Writing—review and editing, D.P.L., P.R.R.C. and G.S.C. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by Conselho Nacional de Desenvolvimento Científico e Tecnológico (grant numbers PQ-SR 313346/2022-4; GD 161313/2021-3) and Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (grant numbers CNE E-26/201.179/2021, PDR10 E-26/206.050/2022, IC E-26/200.267/2022). The APC was funded by Coordenacão de Aperfeiçoamento de Pessoal de Nível Superior−Brasil (CAPES), Finance Code 001.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data are contained within the article and Supplementary Materials.

Acknowledgments

We are grateful to Monica C. Padilha from the Laboratory for the Support of Technological Development (LADETEC) at the Federal University of Rio de Janeiro (UFRJ) for conducting the high-resolution mass spectrometry (HRMS) analyses.

Conflicts of Interest

The authors declare no conflicts of interest.

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Molecules 29 03420 g001
Figure 1. 2-alkyl-1-phenylpropane-1,3-diols highlighted in the structure of natural products.
Figure 1. 2-alkyl-1-phenylpropane-1,3-diols highlighted in the structure of natural products.
Molecules 29 03420 g001
Molecules 29 03420 sch001
Scheme 1. (a) Enantioselective synthesis of anti-α-alkyl-β-hydroxyesters (5) through AH-DKR; (b) Enantioselective synthesis of cis-3-(Hydroxymethyl)chroman-4-ols (7); (c) 1,3-diarylpropan-2-ols (9); and (d) 2-benzyl-1-phenylpropane-1,3-diols (12) through ATH-DKR.
Scheme 1. (a) Enantioselective synthesis of anti-α-alkyl-β-hydroxyesters (5) through AH-DKR; (b) Enantioselective synthesis of cis-3-(Hydroxymethyl)chroman-4-ols (7); (c) 1,3-diarylpropan-2-ols (9); and (d) 2-benzyl-1-phenylpropane-1,3-diols (12) through ATH-DKR.
Molecules 29 03420 sch001
Molecules 29 03420 sch002
Scheme 2. Scope of the one-pot double C=O reduction of α-benzyl-β-ketoaldehydes (rac)-10 under ATH-DKR conditions catalyzed by (R,R)-D.
Scheme 2. Scope of the one-pot double C=O reduction of α-benzyl-β-ketoaldehydes (rac)-10 under ATH-DKR conditions catalyzed by (R,R)-D.
Molecules 29 03420 sch002
Molecules 29 03420 sch003
Scheme 3. Control experiments using different substrates (a) (rac)-10j, (b) (rac)-4a, and (c) (rac)-11j.
Scheme 3. Control experiments using different substrates (a) (rac)-10j, (b) (rac)-4a, and (c) (rac)-11j.
Molecules 29 03420 sch003
Molecules 29 03420 sch004
Scheme 4. Scale-up (a) and synthetic application (b) experiments.
Scheme 4. Scale-up (a) and synthetic application (b) experiments.
Molecules 29 03420 sch004
Table 1. Synthesis of the α-benzyl-β-ketoaldehydes (rac)-10 from chalcones (8).
Table 1. Synthesis of the α-benzyl-β-ketoaldehydes (rac)-10 from chalcones (8).
Molecules 29 03420 i001
EntryStructure8 aR1R2R313 bYield (%) c10 d10:15 eYield (%) f
1Molecules 29 03420 i0028aHHH13a8710a4:9670
28bHHOMe13b5310b48:5279
38cHHCF313c6710c0:10071
48dHHF13d6510d15:8549
58eHFH13e7910e12:8865
68fFHH13f3710f24:7657
7Molecules 29 03420 i0038gOMe--13g9210g33:6758
88hBr--13h9110h37:6368
9Molecules 29 03420 i0048iClHF13i7710i53:4758
108jOCH2OF13j8810j50:5091
a Obtained in a 6 mmol scale from the aldol condensation between the corresponding commercial acetophenones and aldehydes using KOH (7.5 equiv) in MeOH/H2O (1:1), rt, 2–27 h (65–96% yield). b Obtained in a 3–6 mmol scale. c Isolated yield after purification by column chromatography. d Obtained as a tautomeric keto-enol mixture (10/15) in a 1.7–4.5 mmol scale. e Determined by analysis of the 1H NMR spectrum of the isolated products. f Isolated yield of tautomeric keto-enol mixture (10/15) after purification by column chromatography.
Table 2. Optimization of the conditions for the ATH-DKR of (rac)-10j a.
Table 2. Optimization of the conditions for the ATH-DKR of (rac)-10j a.
Molecules 29 03420 i005
Entry[H] Source
(Ratio) b		(R,R)-C-I (mol%)Solvent cAdd. dT (°C)t (h)11j/12j e12j
anti/syn e		Yield (%) fee (%) g
1HCO2NaD (2)DCE/H2OCTABrt16>99:1ndndnd
2HCO2H/Et3N (5:4)D (2)DCE-rt16>99:1ndndnd
3HCO2H/Et3N (5:4)D (2)MeCN-rt1668:32 84:16nd nd
4HCO2H/Et3N (5:4)D (2)THF-rt1662:3893:729>99
5HCO2H/Et3N (5:4)D (2)EtOAc-rt1654:4692:83698
6HCO2H/Et3N (5:4)D (2)PhMe-rt1644:5692:847>99
7HCO2H/Et3N (5:4)D (2)PhMe-45167:9387:1392>99
8HCO2H/Et3N (5:4)C (2)PhMe-451685:1559:41ndnd
9HCO2H/Et3N (5:4)E (2)PhMe-451695:5ndndnd
10HCO2H/Et3N (5:4)F (2)PhMe-451693:7ndndnd
11HCO2H/Et3N (5:4)G (2)PhMe-4516>99:1ndndnd
12HCO2H/Et3N (5:4)H (2)PhMe-4516>99:1ndndnd
13HCO2H/Et3N (5:4)I (2)PhMe-4516>99:1ndndnd
14HCO2H/Et3N (5:4)D (2)PhMeCu(OTf)245166:9488:1292>99
15HCO2H/Et3N (5:4)D (2)PhMeTfOH45164:9685:1590>99
16HCO2H/Et3N (5:4)D (4)PhMe-rt1619:8192:875>99
17HCO2H/Et3N (5:4)D (4)PhMe-rt2420:8090:10ndnd
a All reactions were carried out on a 0.085 mmol scale using (R,R)-C-I, HCO2Na or HCO2H/Et3N as [H] source in the quantities indicated in each case. b HCO2Na (6 equiv.) and to F/T 7.6 and 6.1 equivalents of each were used, respectively. c At 0.25 M, using the pure solvent or in a 1:1 mixture with water. d Using the additives: 20 mol% of CTAB (cetyltrimethylammonium bromide), 4 mol% of Cu(OTf)2 (copper(II) triflate), or 4 mol% of TfOH (triflic acid). e Ratios determined by analysis of the 1H NMR spectrum of the crude mixture; full conversion of (rac)-10j was observed in all tests. f Isolated yield for the anti/syn mixture of 12j after preparative TLC. g Determined by HPLC analysis using chiral stationary phase column, for the major diastereoisomer. nd: not determined.
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Lapa, D.P.; Araújo, L.H.S.; Melo, S.R.; Costa, P.R.R.; Caleffi, G.S. Ru(II)-Catalyzed Asymmetric Transfer Hydrogenation of α-Alkyl-β-Ketoaldehydes via Dynamic Kinetic Resolution. Molecules 2024, 29, 3420. https://doi.org/10.3390/molecules29143420

AMA Style

Lapa DP, Araújo LHS, Melo SR, Costa PRR, Caleffi GS. Ru(II)-Catalyzed Asymmetric Transfer Hydrogenation of α-Alkyl-β-Ketoaldehydes via Dynamic Kinetic Resolution. Molecules. 2024; 29(14):3420. https://doi.org/10.3390/molecules29143420

Chicago/Turabian Style

Lapa, Daiene P., Leticia H. S. Araújo, Sávio R. Melo, Paulo R. R. Costa, and Guilherme S. Caleffi. 2024. "Ru(II)-Catalyzed Asymmetric Transfer Hydrogenation of α-Alkyl-β-Ketoaldehydes via Dynamic Kinetic Resolution" Molecules 29, no. 14: 3420. https://doi.org/10.3390/molecules29143420

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