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Enantioselective Synthesis of (R)‑Sitagliptin via Phase-Transfer

Catalytic aza-Michael Addition
Daehyun Oh, Jaeyong Lee, Sehun Yang, So Hyun Jung, Mihyun Kim, Geumwoo Lee,*
and Hyeung-geun Park*
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ABSTRACT: The highly enantioselective synthesis of (R)-sitagliptin has been

achieved through a series of key steps, including the aza-Michael addition and
Baeyer−Villiger oxidation. The enantioselective aza-Michael addition involved the
Downloaded via 157.47.55.22 on December 22, 2024 at 02:50:08 (UTC).

reaction of tert-butyl β-naphthylmethoxycarbamate with (E)-1-(4-methoxyphenyl)-4-

(2,4,5-trifluorophenyl)but-2-en-1-one, utilizing a quinine-derived C(9)-urea ammo-
nium catalyst under phase-transfer catalytic conditions. The aza-Michael addition
successfully introduced chirality to the amine in (R)-sitagliptin with 96% ee. The
subsequent Baeyer−Villiger oxidation of the aza-Michael adduct led to the formation
of 4-methoxyphenyl ester. Hydrolysis and amide coupling were then employed to
construct the amide moiety. Further deprotections were performed to complete the
synthesis of (R)-sitagliptin (7 steps, 41%, 96% ee).

■ INTRODUCTION
Type 2 diabetes stands out as one of the most prevalent
amino acids, including the utilization of chiral starting
materials,5 chiral auxiliaries,4,6 biocatalysis,7 organocatalysis,8
diseases, with the quest for effective therapies being a central and transition-metal-based organometallic catalysis.9 While a
focus in the field of drug discovery.1 Dipeptidyl peptidase IV considerable number of synthetic examples have emerged
(DPP-4), a relatively recent target for therapeutic interventions through transition-metal-based catalysis, instances of organo-
in type 2 diabetes, has garnered significant attention.2 DPP-4 catalysis remain relatively scarce (Scheme 1). Herein, we
inhibitors serve as agents that elevate the levels of glucagon-like present an efficient synthetic methodology for (R)-sitagliptin
peptide-1 (GLP-1), thereby triggering insulin secretion and via enantioselective phase-transfer organocatalysis, which is a
lowering blood glucose levels.3 well-known economic and environmentally friendly green
Sitagliptin 1 is a widely prescribed oral antidiabetic chemistry that is beneficial for industrial processes.
medication that gained FDA approval in 2006 as the
pioneering DPP-4 inhibitor (see Figure 1).4 Since Merck
■ RESULTS AND DISCUSSION
In a previous study, we reported the highly enantioselective
conjugate addition of tert-butyl-N-alkoxycarbamates to a series
of cyclic α,β-unsaturated ketones, esters, and amides.10 The
versatile methodology has proven to be highly effective in the
synthesis of chiral cyclic 1,3-aminoalcohols, which serve as
essential chiral building blocks in the field of medicinal
chemistry. Our intention is to establish the synthesis of (R)-
sitagliptin via the enantioselective conjugate addition in the
Figure 1. Structure of (R)-sitagliptin 1. acyclic system. As depicted in the synthetic strategy (Scheme
2), the key intermediate 4 can be synthesized by the
first disclosed the synthetic pathway for (R)-sitagliptin in 2005,
numerous subsequent synthetic methods have been reported, Received: December 17, 2023
featuring adjustments to key intermediates and reaction Revised: February 7, 2024
conditions. These developments have unfolded over the past Accepted: March 8, 2024
few decades, driven by the immense commercial significance of Published: March 21, 2024
sitagliptin. The reported synthetic approaches can be
categorized based on the chiral induction strategy for β-
© 2024 The Authors. Published by
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Scheme 1. Enantioselective Synthesis of (R)-Sitagliptin by Organocatalysis

Scheme 2. Retrosynthetic Strategy of (R)-Sitagliptin

enantioselective aza-Michael addition of phenylketone 2 the best result (entry 12). In our attempts to test the
followed by the Baeyer−Villiger oxidation. Subsequent amide enantioselective Michael addition using representative sub-
coupling and deprotections lead to (R)-sitagliptin. Due to the strate 7a, we initially employed previously established reaction
low reactivities of the corresponding α,β-unsaturated ester and conditions involving aqueous KOH (1.2 equiv) in toluene,
amide, α,β-unsaturated phenylketone (2) was chosen as a along with catalyst 9 or 1012 (10 mol %) at room temperature
Michael acceptor. (Table 2).10 However, this resulted in the formation of a
First, we synthesized substrate 7 for the aza-Michael significant amount of the double bond migrated isomer of 7a,
addition (Scheme 3). Employing a Wittig coupling reaction both at room temperature and 0 °C, leading to a low chemical
between commercially available 2,4,5-trifluorophenylacetalde- yield and moderate enantioselectivity (entries 1 and 2).
hyde (5) and benzoylmethylenetriphenylphosphoranes (6a− Subsequently, we explored lower temperatures, specifically
h) afforded Michael acceptors 7a−h (52−84%) (Table 1).11 −20 °C, which led to the formation of the corresponding
Among the used solvents, dichloromethane showed the best addition adduct (11a) without isomerization of 7a, achieving a
chemical yield (entries 3 and 5−7) at 0 °C. No reaction high chemical yield and moderate enantioselectivity (entry 3,
proceeded at −20 °C, and the optimal temperature was 0 °C 84%, 87% ee). We observed that reducing the reaction
(entries 2−4). In the case of the functional group on the concentration provided benefits in terms of both chemical
phenyl ring, the electron-donating 4-methoxy group showed yield and enantioselectivity, with the optimal concentration
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Scheme 3. Synthetic Route of (R)-Sitagliptin Precursors

Table 1. Optimization of the Wittig Reaction for 7a Next, we decided to explore variations in the functional
groups attached to the benzoyl part of substrate 7a under the
optimized PTC conditions (Table 2, entry 5). As illustrated in
Scheme 4, among the various functional groups investigated,
the p-methoxy group (7f, 3.26 mmol, 1 g) exhibited the
highest level of enantioselectivity and chemical yield (11f, 94%,
96% ee). The presence of electron-withdrawing groups at the
temp. time yield
para-position may enhance the reactivity of the Michael
entry 6 (equiv) R solvent (°C) (h) (%)b acceptor, consequently leading to decreased enantioselectivity
1 6a (1.0) H DCM 25 12 35 due to an increase in noncatalytically mediated reactions.
2 6a (1.5) H DCM 25 12 42 Subsequently, we proceeded with the optimization of the
3 6a (1.5) H DCM 0 24 65 Baeyer−Villiger oxidation of 11f. In this regard, the Baeyer−
4 6a (1.5) H DCM −20 48 0 Villiger oxidation was systematically explored across diverse
5 6a (1.5) H Et2O 0 24 62 reaction conditions, employing m-CPBA as the oxidizing agent
6 6a (1.5) H THF 0 24 58 (Table 3).14 Almost no reaction was observed under acidic
7 6a (1.5) H DMF 0 24 47 conditions utilizing trifluoroacetic acid (TFA) and hexafluor-
8 6b (1.5) 4-F DCM 0 24 62 oisopropanol (HFIP) (entries 1 and 2). Nevertheless, under
9 6c (1.5) 3-F DCM 0 24 71 basic conditions employing NaHCO3 and with the main-
10 6d (1.5) 4-Cl DCM 0 24 52 tenance of neutrality through a phosphate buffer in the
11 6e (1.5) 4-Br DCM 0 24 58 presence of HFIP, the desired product was obtained in low
12 6f (1.5) 4-CH3O DCM 0 24 84 chemical yields (entries 3−5). Remarkably, the highest
13 6g (1.5) 3-CH3O DCM 0 24 72 chemical yield was successfully achieved under anhydrous
14 6h (1.5) 4-CH3 DCM 0 24 57 conditions utilizing 4 Å molecular sieves (entry 6, 90%).
a We finalized the synthesis of (R)-sitagliptin from compound
Reactions were performed with 1.0 or 1.5 equiv of Wittig reagents 6
under the given conditions. bIsolated yields. 12 (Scheme 5). The hydrolysis of 12 under alkaline
conditions, followed by amide coupling with the commercially
available triazole 13 in the presence of EDC, resulted in the
being 0.05 M (entries 3−6). Recognizing that the ratio of the formation of amide 14 (83% yield from 12). 8d The
organic phase to the water phase could impact both chemical hydrogenolysis of 14, utilizing Raney-Ni under atmospheric
yield and enantioselectivity in phase-transfer catalysis, we H2,15 produced carbamate 15 (75%) {[α]D23 = +22.0 (c 1.0,
experimented with varying the volume of toluene and water in CHCl3); Lit.8b R-15, [α]D23 = +23.2 (c 1.0, CHCl3)}. Lastly,
reactions at −40 °C. However, no significant variation in the deprotection of the N-Boc group under 0.5 N HCl/MeOH
enantioselectivity was observed (entries 7−9). In addition, acidic conditions successfully furnished the target compound
temperatures lower than −20 °C did not show a benefit in (R)-sitagliptin·HCl. The overall yield in 7 steps starting from
enantioselectivity (entries 5 and 7). Notably, there was also no compound 5 was 41%.
significant change in enantioselectivity with other various A plausible mechanism for the aza-Michael addition is
bases, although their chemical yields were lower compared to depicted in Figure 2 based on insights from density functional
aq. KOH (entries 10−12). In the case of quinidine-based theory (DFT) calculations.16 Initially, the carbamate anion
catalyst 10,13 the enantioselectivity was lower than that of (10) forms an ionic complex with the quaternary ammonium
quinine-based catalyst 9, with a significantly longer reaction cation or hydrogen bonding with the α−C−H of the
time (entry 13, 85%, −81% ee). The slow reaction rate may be ammonium cation of catalyst 9. Two notable π−π stacking
attributed to a less favorable binding conformation. interactions occur: one between the two phenyl groups of
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Table 2. Optimization of Reaction Conditiona

entry base concn (M) solvent (PhCH3:H2O) temp. (°C) time (h) yield (%)b ee (%)c
1 KOH 0.15 8:1 25 1 50 83
2 KOH 0.15 8:1 0 1 71 85
3 KOH 0.15 8:1 −20 1 84 87
4 KOH 0.10 8:1 −20 2 96 92
5 KOH 0.05 8:1 −20 2 92 93
6 KOH 0.025 8:1 −20 5 85 92
7 KOH 0.05 8:1 −40 4 92 93
8 KOH 0.05 16:1 −40 4 92 93
9 KOH 0.05 32:1 −40 4 92 93
10 K2CO3 0.05 8:1 −20 48 75 92
11 Cs2CO3 0.05 8:1 −20 24 70 92
12 K3PO4 0.05 8:1 −20 4 81 92
13d KOH 0.05 8:1 −20 24 85 −81
a
Reactions were performed with 2.0 equiv of tert-butyl carbamate 8 and 1.2 equiv of base under the given conditions. bIsolated yields.
c
Enantiopurity was determined by high-performance liquid chromatography (HPLC) analysis using a chiral column (DAICEL Chiralpak AD-H).
d
Reactions were performed with catalyst 10, and the enantiomer of 11a was obtained.

Scheme 4. Substrate Optimization of aza-Michael Reactiona,b,c

a
Reactions were performed with 2.0 equiv of tert-butyl carbamates and 1.2 equiv of 50% KOH (aq.) under the given conditions. bIsolated yields.
c
Enantiopurity was determined by HPLC analysis using a chiral column (DAICEL Chiralpak AD-H) (see the Supporting Information).

(CF3)2Ph in catalyst 9 and the other between the quinoline These interactions collectively contribute to a more rigid
group of catalyst 9 and the β-naphthyl group of carbamate 8. conformation. Simultaneously, the enone (7f) engages in
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Table 3. Optimization of the Baeyer−Villiger Oxidationa The commercially available KOH pellet (99%) was ground to
prepare solid KOH as a powder form. 50% w/v aqueous KOH
was used as a stock solution. For the reactions that required
heating, a sand bath was used as a heat source. Organic
solvents were concentrated under reduced pressure using a
Büchi rotary evaporator. Phase-transfer catalysts (910) were
temp. time yield prepared according to the reported procedure. Thin layer
entry additive (°C) (h) (%)b chromatography (TLC) analyses were performed using
1 TFA (1 equiv) 25 24 trace precoated TLC plates (TLC Silica gel 60 F254). Flash column
2 HFIPc (40 equiv) 25 24 trace chromatography was carried out using E. Merck Silica gel 60
3 HFIP, phosphate buffer (pH: 7.6) 25 48 31 (0.040−0.063 mm). Hitachi (UV detector L-2130, Pump L-
4 HFIP, phosphate buffer (pH: 7.6) 40 48 17 2130, and software LaChrome 890-8800-12) was used for
5 NaHCO3 (2 equiv) 25 24 24 HPLC. The values of enantiomeric excess (ee) of chiral
6 NaHCO3 (2 equiv), 4 Å molecular 25 24 90 products were determined by HPLC using 4.6 mm × 250 mm
sieves Daicel Chiralpak AD-H. Nuclear magnetic resonance (1H
a
Reactions were performed with 1.5 equiv of m-CPBA. bIsolated NMR and 13C NMR) spectra were measured on JEOL JNM-
yields. c1,1,1,3,3,3-Hexafluoro-2-propanol. ECZ400s [400 MHz (1H), 101 MHz (13C)], Bruker AVANCE
500 [500 MHz (1H), 126 MHz (13C)], and 800 MHz Bruker
hydrogen bond interactions with the C(9) urea group of Avance III HD spectrometer [800 MHz (1H), 201 MHz
catalyst 9. In accordance with the experimental findings, the (13C)] using deuterated solvents and are reported in ppm
up-face of enone 7f remains accessible for the nucleophilic relative to CDCl3 (δ 7.24), CD3OD (δ 3.31), and DMSO-d6 (δ
carbamate N-anion (8) to approach, resulting in the formation 2.50) for 1H NMR and relative to the central CDCl3 (δ 77.23),
of the R-enantiomer of 11f. CD3OD (δ 49.0), and DMSO-d6 (δ 39.5) resonance for 13C
NMR. Coupling constants (J) in 1H NMR are reported in
■ CONCLUSIONS
We have successfully established an efficient synthetic pathway
hertz. Low-resolution mass spectra (LRMS) and high-
resolution mass spectra (HRMS) were measured on JEOL
for (R)-sitagliptin utilizing organocatalysis. The chirality of the JMS-700 spectrometers (double-focusing mass analyzer).
primary amine was effectively introduced through the aza- Melting points were measured on a Büchi B-540 melting
Michael addition of tert-butyl β-naphthylmethoxycarbamate point apparatus and are not corrected. Infrared (IR) spectra
(8) to (E)-1-(4-p-methoxyphenyl)-4-(2,4,5-trifluorophenyl)- were recorded on JASCO FT/IR-4200 spectrometers. Optical
but-2-en-1-one (7f), employing the quinine-derived bifunc- rotations were measured on a JASCO P-2000 digital
tional phase-transfer catalyst (9) (94% and 96% ee). polarimeter and calibrated with pure solvent as the blank.
Subsequent steps, including the Baeyer−Villiger oxidation, General Procedure for the Synthesis of α,β-Unsatu-
hydrolysis, and amide coupling, were instrumental in rated Phenylketones (7a). A mixture of 2-(2,4,5-
constructing the core structure of (R)-sitagliptin. The final trifluorophenyl)acetaldehyde (5) (0.90 g, 5.17 mmol) and 1-
stage of deprotections successfully completed the synthesis of phenyl-2-(triphenylphosphoranylidene)ethanone (6a) (2.95 g,
(R)-sitagliptin·HCl, achieved in a total of 7 steps with an 7.76 mmol) in methylene chloride (10 mL) of a round-bottom
overall yield of 41% and an enantiomeric purity of 96%. flask (50 mL) was stirred at 0 °C. After the reaction was

■ EXPERIMENTAL SECTION
General Information. All reagents purchased from
completed, the reaction mixture was diluted with ethyl acetate
(200 mL), washed with water (40 mL × 2), dried over
anhydrous magnesium sulfate, filtered, and concentrated in
commercial sources were used without further purification. vacuo. The residue was purified by column chromatography

Scheme 5. Finalization of the Synthesis of (R)-Sitagliptin

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Figure 2. Plausible mechanism of the aza-Michael addition of 7f by DFT calculations (gray: catalyst 9, yellow: carbamate 8, purple: substrate 7f;
oxygen: red, nitrogen: blue, fluoro: green).

(silica gel, hexane/ether/dichloromethane = 12:1:1) to afford 129.3, 127.4, 124.8, 124.7, 124.7, 123.0, 122.0, 119.9, 118.0,
7a (928 mg, 3.36 mmol, 65% yield) as a white solid. 116.9, 114.9, 114.9, 101.0, 70.2, 57.3, 55.1, 54.1, 36.8, 31.4,
General Procedure for the Enantioselective Phase- 28.1, 25.4, 23.6, 22.4 ppm; IR (neat) 1542, 1508, 1280 cm−1;
Transfer Catalytic aza-Michael Reaction (11a). To a HRMS (FAB) m/z: [M + H]+ calcd for [C38H34F12N4O2]+
solution of tert-butyl β-naphthylmethoxycarbamate (8) (26.8 ([M + H]+) 805.2406; found 805.2421. [α]D20 = −2.21 (c 1.0,
mg, 0.097 mmol, 2.0 equiv) and cinchona-derived chiral CH3OH).
bifunctional tetraalkylammonium bromide (9) (4.33 mg, 0.005 Analytical Data. (E)-1-Phenyl-4-(2,4,5-trifluorophenyl)-
mmol, 10 mol %) in toluene (950 μL, 0.05 M) of a round- but-2-en-1-one (7a). Following the general procedure (2),
bottom flask (5 mL) was added (E)-1-phenyl-4-(2,4,5- molecule 7a was obtained as a white solid (mp 74 °C, 928 mg,
trifluorophenyl)but-2-en-1-one (7a) (15 mg, 0.049 mmol, 1.0 65% yield); 1H NMR (400 MHz, CDCl3) δ 7.89 (dd, J = 8.2,
equiv) at −20 °C. Then, 50% w/v aqueous KOH (6.59 μL, 1.4 Hz, 2H), 7.54−7.58 (m, 1H), 7.46 (t, J = 7.5 Hz, 2H),
0.059 mmol, 1.2 equiv) and water (23.09 μL) were added to 6.84−7.11 (m, 4H), 3.59 (d, J = 6.9 Hz, 2H) ppm; 13C NMR
the reaction mixture and stirred until the starting material (101 MHz, CDCl3) δ 190.4, 144.5, 137.6, 137.5, 133.1, 128.7,
disappeared at −20 °C. After the reaction was completed, the 128.6, 127.5, 118.5, 118.3, 105.8, 105.6, 31.5 ppm; IR (neat)
reaction mixture was diluted with ethyl acetate (10 mL), 1673, 1623 cm−1; HRMS (FAB) m/z: [M + H]+ calcd for
washed with water (5 mL × 2), dried over anhydrous [C16H12F3O]+ ([M + H]+) 277.0840; found 277.0836.
magnesium sulfate, filtered, and concentrated in vacuo. The (E)-1-(4-Fluorophenyl)-4-(2,4,5-trifluorophenyl)but-2-en-
residue was purified by column chromatography (silica gel, 1-one (7b). Following the general procedure (2), molecule 7b
hexane: EtOAc = 10:1) to afford 11a (18.3 mg, 0.033 mmol, was obtained as a white solid (mp 46 °C, 99.2 mg, 62% yield);
1
92% yield) as a white solid [α]D20 = +3.64 (c 1.0, CHCl3). The H NMR (400 MHz, CDCl3) δ 7.92 (td, J = 5.9, 2.6 Hz, 2H),
enantioselectivity was determined by chiral HPLC analysis 6.91−7.15 (m, 5H), 6.82−6.85 (m, 1H), 3.59 (d, J = 6.6 Hz,
(DAICEL Chiralpak AD-H, hexane: ethanol = 95:5, flow rate 2H) ppm; 13C NMR (101 MHz, CDCl3) δ 188.6, 167.0, 164.5,
= 1.0 mL/min, 23 °C, λ = 250 nm), retention time: minor 157.1, 154.7, 144.7, 133.9, 131.3, 131.2, 127.0, 118.5, 118.3,
isomer 8.38 min, major isomer 11.79 min, 93% ee. 116.0, 115.8, 106.1, 105.9, 105.8, 105.6, 31.5 ppm; IR (neat)
Procedure for the Preparation of Phase-Transfer 1673 cm−1; HRMS (FAB) m/z: [M + H]+ calcd for
Catalyst (10). Under an argon atmosphere, urea10 (2 g, [C16H11F4O]+ ([M + H]+) 295.0746; found 295.0740.
3.46 mmol, 1.0 equiv) was dissolved in tetrahydrofuran (17 (E)-1-(3-Fluorophenyl)-4-(2,4,5-trifluorophenyl)but-2-en-
mL) of a round-bottom flask (100 mL); then, 2,4-bis- 1-one (7c). Following the general procedure (2), molecule 7c
(trifluoromethyl)benzyl bromide (778 μL, 4.15 mmol, 1.2 was obtained as a brown solid (mp 45 °C, 120 mg, 71% yield);
1
equiv) was added. The mixture was stirred at 60 °C for 24 h. H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 7.8 Hz, 1H), 7.58
After the reaction was finished, the mixture was concentrated (dt, J = 9.5, 2.1 Hz, 1H), 7.44 (td, J = 8.0, 5.5 Hz, 1H), 7.23−
under reduced pressure. After purification of the residue by 7.28 (m, 1H), 6.92−7.13 (m, 3H), 6.81 (d, J = 15.6 Hz, 1H),
column chromatography on silica gel with hexane-ethyl acetate 3.60 (d, J = 6.9 Hz, 2H) ppm; 13C NMR (101 MHz, CDCl3) δ
(5:1 to EtOAc only) to ethyl acetate-methanol (EtOAc only to 189.0, 164.1, 161.7, 145.4, 139.7, 139.7, 130.4, 130.4, 127.0,
8:1), molecule 10 was obtained as a white solid (mp 158−162 124.3, 120.2, 120.0, 118.5, 118.5, 118.3, 118.3, 115.4, 115.3,
°C, 642.9 mg, 21% yield); 1H NMR (400 MHz, CD3OD) δ 106.1, 105.9, 105.8, 105.6, 31.6 ppm; IR (neat) 1674, 1626
8.78 (d, J = 4.1 Hz, 1H), 8.23 (d, J = 8.2 Hz, 1H), 8.17 (s, cm−1; HRMS (EI) m/z: [M]+ calcd for [C16H10F4O]+ ([M]+)
1H), 8.13 (d, J = 8.2 Hz, 1H), 7.94−7.99 (m, 3H), 7.81 (d, J = 294.0667; found 294.0662.
4.1 Hz, 1H), 7.71 (s, 1H), 7.48 (dd, J = 9.4, 2.5 Hz, 1H), 7.43 (E)-1-(4-Chlorophenyl)-4-(2,4,5-trifluorophenyl)but-2-en-
(s, 1H), 6.47 (d, J = 9.6 Hz, 1H), 5.77−5.85 (m, 1H), 5.24− 1-one (7d). Following the general procedure (2), molecule 7d
5.36 (m, 4H), 5.10−5.12 (m, 1H), 4.05 (s, 5H), 3.78−3.84 was obtained as a brown solid (mp 46 °C 93 mg, 52% yield);
1
(m, 1H), 3.49 (s, 1H), 2.75 (s, 1H), 2.09−2.16 (m, 1H), 1.95 H NMR (400 MHz, CDCl3) δ 7.83 (dt, J = 8.7, 2.2 Hz, 2H),
(s, 2H), 1.83 (s, 1H), 1.39 (s, 1H), 1.21−1.28 (m, 1H) ppm; 7.43 (dt, J = 8.8, 2.2 Hz, 2H), 6.91−7.11 (m, 3H), 6.82 (d, J =
13
C NMR (101 MHz, CD3OD) δ 159.3, 154.6, 147.3, 144.2, 15.6 Hz, 1H), 3.59 (d, J = 6.4 Hz, 2H) ppm; 13C NMR (101
141.1, 137.9, 136.4, 133.1, 132.7, 131.9, 131.6, 130.7, 129.9, MHz, CDCl3) δ 189.0, 157.2, 157.1, 154.7, 150.3, 148.2, 148.2,
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148.1, 148.1, 147.9, 147.8, 145.1, 139.5, 135.9, 130.0, 129.1, enantioselectivity was determined by chiral HPLC analysis
127.0, 121.2, 121.1, 121.0, 120.9, 118.5, 118.4, 118.3, 118.3, (DAICEL Chiralpak AD-H, hexane: ethanol = 95:5, flow rate
106.1, 105.9, 105.8, 105.6, 31.5 ppm; IR (neat) 1672 cm−1; = 1.0 mL/min, 23 °C, λ = 250 nm), retention time: minor
HRMS (FAB) m/z: [M + H]+ calcd for [C16H11ClF3O]+ ([M isomer 6.06 min, major isomer 6.58 min, 93% ee, [α]D20 =
+ H]+) 311.0451; found 311.0441. +3.64 (c 1.0, CHCl3).
(E)-1-(4-Bromophenyl)-4-(2,4,5-trifluorophenyl)but-2-en- (R)-tert-Butyl-(4-(4-Fluorophenyl)-4-oxo-1-(2,4,5-
1-one (7e). Following the general procedure (2), molecule 7e trifluorophenyl)butan-2-yl)(naphthalen-2-ylmethoxy)-
was obtained as a white solid (mp 44 °C, 118 mg, 58% yield); carbamate (11b). Following the general procedure (3),
1
H NMR (400 MHz, CDCl3) δ 7.75 (dt, J = 9.0, 2.1 Hz, 2H), molecule 11b was obtained as a white solid (mp 95 °C, 27
7.60 (dt, J = 9.0, 2.1 Hz, 2H), 6.91−7.11 (m, 3H), 6.81 (d, J = mg, 92% yield); 1H NMR (400 MHz, CDCl3) δ 7.79−7.85 (m,
15.1 Hz, 1H), 3.59 (d, J = 6.4 Hz, 2H) ppm; 13C NMR (101 3H), 7.76 (s, 1H), 7.69 (dd, J = 8.7, 5.5 Hz, 2H), 7.47−7.51
MHz, CDCl3) δ 189.2, 145.2, 136.3, 132.0, 130.1, 128.2, 126.9, (m, 3H), 7.14 (q, J = 8.7 Hz, 1H), 6.97 (t, J = 8.5 Hz, 2H),
118.5, 118.4, 118.3, 118.2, 106.1, 105.9, 105.8, 105.6, 31.6 6.84 (td, J = 9.6, 6.9 Hz, 1H), 5.03 (d, J = 11.0 Hz, 1H), 4.87
ppm; IR (neat) 1672, 1622 cm−1; HRMS (FAB) m/z: [M + (d, J = 10.5 Hz, 1H), 4.83−4.90 (m, 1H), 3.15 (dd, J = 17.2,
H]+ calcd for [C16H11BrF3O]+ ([M + H]+) 354.9945; found 6.2 Hz, 1H), 2.84−2.99 (m, 3H), 1.39 (s, 9H) ppm; 13C NMR
354.9942. (101 MHz, CDCl3) δ 195.7, 167.1, 164.5, 156.6, 133.5, 133.4,
(E)-1-(4-Methoxyphenyl)-4-(2,4,5-trifluorophenyl)but-2- 133.2, 130.7, 130.6, 128.6, 128.4, 128.1, 127.8, 127.1, 126.5,
en-1-one (7f). Following the general procedure (2), molecule 126.4, 121.8, 121.6, 119.5, 119.4, 119.3, 119.2, 115.8, 115.6,
7f was obtained as a white solid (mp 88 °C, 1.33 g, 84% yield); 105.5, 105.3, 105.2, 105.0, 82.0, 77.9, 56.4, 41.3, 30.6, 28.2,
1
H NMR (400 MHz, CDCl3) δ 7.90 (dt, J = 9.5, 2.5 Hz, 2H), 27.7 ppm; IR (neat) 1689, 1598 cm−1; HRMS (FAB) m/z: [M
6.85−7.08 (m, 6H), 3.87 (s, 3H), 3.58 (d, J = 6.9 Hz, 2H) + H]+ calcd for [C32H30F4NO4]+ ([M + H]+) 568.2111; found
ppm; 13C NMR (101 MHz, CDCl3) δ 188.6, 163.6, 143.5, 568.2133. The enantioselectivity was determined by chiral
131.0, 130.5, 127.2, 118.5, 118.4, 118.3, 118.2, 113.9, 106.0, HPLC analysis (DAICEL Chiralpak AD-H, hexane: ethanol =
105.8, 105.7, 105.5, 77.4, 77.1, 76.8, 55.6, 31.5 ppm; IR (neat) 95:5, flow rate = 1.0 mL/min, 23 °C, λ = 250 nm), retention
1668, 1621 cm−1; HRMS (FAB) m/z: [M + H]+ calcd for time: minor isomer 5.73 min, major isomer 6.74 min, 94% ee,
[C17H14F3O2]+ ([M + H]+) 307.0946; found 307.0951. [α]D20 = −39.10 (c 1.0, CHCl3).
(E)-1-(3-Methoxyphenyl)-4-(2,4,5-trifluorophenyl)but-2- (R)-tert-Butyl-(4-(3-Fluorophenyl)-4-oxo-1-(2,4,5-
en-1-one (7g). Following the general procedure (2), molecule trifluorophenyl)butan-2-yl)(naphthalen-2-ylmethoxy)-
7g was obtained as a colorless oil (127 mg, 72% yield); 1H carbamate (11c). Following the general procedure (3),
NMR (400 MHz, CDCl3) δ 7.42−7.46 (m, 2H), 7.36 (t, J = molecule 11c was obtained as a white solid (mp 81 °C, 25
7.8 Hz, 1H), 6.91−7.13 (m, 4H), 6.82−6.89 (m, 1H), 3.85 (s, mg, 85% yield); 1H NMR (400 MHz, CDCl3) δ 7.78−7.85 (m,
3H), 3.59 (d, J = 6.4 Hz, 2H) ppm; 13C NMR (100 MHz, 3H), 7.76 (s, 1H), 7.43−7.52 (m, 5H), 7.29 (td, J = 7.9, 5.6
CDCl3) δ 190.1, 160.0, 144.5, 139.0, 129.7, 127.5, 121.2, Hz, 1H), 7.10−7.22 (m, 2H), 6.84 (td, J = 9.6, 6.6 Hz, 1H),
119.6, 118.5, 118.3, 112.9, 106.0, 105.8, 105.8, 105.6, 77.4, 5.03 (d, J = 10.5 Hz, 1H), 4.87 (d, J = 10.5 Hz, 1H), 4.84−
77.1, 76.8, 55.5, 31.5 ppm; IR (neat) 1672, 1624 cm−1; HRMS 4.91 (m, 1H), 3.20 (dd, J = 16.9, 6.4 Hz, 2H), 2.84−2.99 (m,
(FAB) m/z: [M + H]+ calcd for [C17H14F3O2]+ ([M + H]+) 3H), 1.40 (s, 9H) ppm; 13C NMR (101 MHz, CDCl3) δ 196.1,
307.0946; found 307.0942. 164.1, 161.6, 156.5, 138.6, 133.4, 133.3, 133.2, 130.4, 130.3,
(E)-1-(p-Tolyl)-4-(2,4,5-trifluorophenyl)but-2-en-1-one 128.6, 128.4, 128.1, 127.8, 127.0, 126.5, 126.4, 123.8, 121.8,
(7h). Following the general procedure (2), molecule 7h was 121.7, 121.6, 121.5, 120.4, 120.2, 119.5, 119.4, 119.3, 119.2,
obtained as a white solid (mp 85 °C, 95 mg, 57% yield); 1H 114.9, 114.6, 105.5, 105.3, 105.2, 105.0, 82.1, 78.0, 56.5, 41.5,
NMR (400 MHz, CDCl3) δ 7.80 (d, J = 7.8 Hz, 2H), 7.26 (d, J 30.7, 28.2 ppm; IR (neat) 1705, 1589 cm−1; HRMS (CI) m/z:
= 6.9 Hz, 2H), 6.85−7.08 (m, 4H), 3.58 (d, J = 6.4 Hz, 2H), [M + H]+ calcd for [C32H30F4NO4]+ ([M + H]+) 568.2015;
2.40 (s, 3H) ppm; 13C NMR (101 MHz, CDCl3) δ 189.9, found 568.2103. The enantioselectivity was determined by
144.0, 135.0, 129.4, 128.8, 127.5, 121.5, 121.4, 121.3, 121.2, chiral HPLC analysis (DAICEL Chiralpak AD-H, hexane:
118.5, 118.4, 118.3, 118.2, 106.0, 105.8, 105.7, 105.5, 77.4, ethanol = 95:5, flow rate = 1.0 mL/min, 23 °C, λ = 250 nm),
77.1, 76.8, 31.5, 21.8 ppm; IR (neat) 1671, 1616 cm−1; HRMS retention time: minor isomer 5.71 min, major isomer 6.31 min,
(FAB) m/z: [M + H]+ calcd for [C17H14F3O]+ ([M + H]+) 95% ee, [α]D20 = +7.30 (c 1.0, CHCl3).
291.0997; found 291.1000. (R)-tert-Butyl-(4-(4-Chlorophenyl)-4-oxo-1-(2,4,5-
(R)-tert-Butyl-(Naphthalen-2-ylmethoxy)(4-oxo-4-phenyl- trifluorophenyl)butan-2-yl)(naphthalen-2-ylmethoxy)-
1-(2,4,5-trifluorophenyl)butan-2-yl)carbamate (11a). Fol- carbamate (11d). Following the general procedure (3),
lowing the general procedure (3), molecule 11a was obtained molecule 11d was obtained as a white solid (mp 92 °C, 25
as a white solid (mp 85 °C, 27 mg, 92% yield); 1H NMR (400 mg, 88% yield); 1H NMR (400 MHz, CDCl3) δ 7.78−7.84 (m,
MHz, CDCl3) δ 7.73−7.85 (m, 6H), 7.47−7.54 (m, 4H), 3H), 7.75 (s, 1H), 7.60 (d, J = 8.7 Hz, 2H), 7.47−7.53 (m,
7.34−7.38 (m, 2H), 7.11−7.18 (m, 1H), 6.84 (td, J = 9.6, 6.6 3H), 7.27 (d, J = 8.7 Hz, 2H), 7.11−7.17 (m, 1H), 6.84 (td, J
Hz, 1H), 5.05 (d, J = 10.5 Hz, 1H), 4.86−4.94 (m, 2H), 3.25 = 9.6, 6.7 Hz, 1H), 5.03 (d, J = 10.5 Hz, 1H), 4.87 (d, J = 11.0
(dd, J = 16.9, 5.9 Hz, 1H), 3.07 (dd, J = 17.2, 7.1 Hz, 1H), Hz, 1H), 4.83−4.90 (m, 1H), 3.14 (dd, J = 17.4, 6.4 Hz, 1H),
2.86−2.99 (m, 2H), 1.39 (s, 9H) ppm; 13C NMR (101 MHz, 2.84−2.97 (m, 3H), 1.40 (s, 9H) ppm; 13C NMR (101 MHz,
CDCl3) δ 197.4, 156.5, 136.6, 133.4, 133.3, 133.2, 128.7, CDCl3) δ 196.1, 156.6, 147.7, 145.5, 139.7, 134.8, 133.4,
128.6, 128.4, 128.1, 128.0, 127.8, 127.1, 126.5, 126.4, 121.9, 133.3, 133.2, 129.4, 128.9, 128.6, 128.4, 128.1, 127.8, 127.1,
121.8, 121.7, 121.7, 119.5, 119.4, 119.3, 119.2, 105.5, 105.3, 126.5, 126.4, 121.7, 121.6, 119.5, 119.4, 119.3, 119.2, 105.5,
105.2, 105.0, 81.9, 78.0, 56.6, 41.5, 30.6, 28.2 ppm; IR (neat) 105.3, 105.2, 105.0, 82.0, 77.9, 56.4, 41.3, 30.7, 28.2 ppm; IR
1706, 1520 cm−1; HRMS (FAB) m/z: [M + H]+ calcd for (neat) 1689, 1589 cm−1; HRMS (FAB) m/z: [M + H]+ calcd
[C32H31F3NO4]+ ([M + H]+) 550.2205; found 550.2193. The for [C32H30ClF3NO4]+ ([M + H]+) 584.1815; found 584.1823.
15334 https://doi.org/10.1021/acsomega.3c10080
ACS Omega 2024, 9, 15328−15338
ACS Omega http://pubs.acs.org/journal/acsodf Article

The enantioselectivity was determined by chiral HPLC analysis = 1.0 mL/min, 23 °C, λ = 250 nm), retention time: minor
(DAICEL Chiralpak AD-H, hexane: ethanol = 95:5, flow rate isomer 5.12 min, major isomer 6.20 min, 91% ee, [α]D20 =
= 1.0 mL/min, 23 °C, λ = 250 nm), retention time: minor −28.60 (c 1.0, CHCl3).
isomer 6.21 min, major isomer 7.04 min, 94% ee, [α]D20 = (R)-tert-Butyl-(naphthalen-2-ylmethoxy)(4-oxo-4-(p-
−3.12 (c 1.0, CHCl3). tolyl)-1-(2,4,5-trifluorophenyl)butan-2-yl)carbamate (11h).
(R)-tert-Butyl-(4-(4-Bromophenyl)-4-oxo-1-(2,4,5- Following the general procedure (3), molecule 11h was
trifluorophenyl)butan-2-yl)(naphthalen-2-ylmethoxy)- obtained as a white solid (mp 73 °C, 26 mg, 89% yield); 1H
carbamate (11e). Following the general procedure (3), NMR (400 MHz, CDCl3) δ 7.78−7.85 (m, 3H), 7.76 (s, 1H),
molecule 11e was obtained as a white solid (mp 95 °C, 25 7.66 (d, J = 8.2 Hz, 2H), 7.47−7.53 (m, 3H), 7.11−7.17 (m,
mg, 90% yield); 1H NMR (400 MHz, CDCl3) δ 7.77−7.84 (m, 3H), 6.83 (td, J = 9.7, 6.6 Hz, 1H), 5.04 (d, J = 10.5 Hz, 1H),
3H), 7.74 (s, 1H), 7.47−7.53 (m, 5H), 7.43 (dt, J = 8.8, 1.9 4.86 (d, J = 10.5 Hz, 1H), 3.25 (dd, J = 16.9, 5.9 Hz, 1H), 3.06
Hz, 2H), 7.11−7.17 (m, 1H), 6.84 (td, J = 9.6, 6.6 Hz, 1H), (dd, J = 16.9, 6.9 Hz, 1H), 2.85−2.98 (m, 2H), 2.38 (s, 3H),
5.03 (d, J = 10.5 Hz, 1H), 4.87 (d, J = 10.5 Hz, 1H), 4.83− 1.39 (s, 9H) ppm; 13C NMR (101 MHz, CDCl3) δ 197.0,
4.90 (m, 1H), 3.14 (dd, J = 17.2, 6.2 Hz, 1H), 2.83−2.97 (m, 156.5, 144.2, 134.2, 133.4, 133.2, 129.4, 128.5, 128.4, 128.2,
3H), 1.40 (s, 9H) ppm; 13C NMR (101 MHz, CDCl3) δ 196.2, 127.8, 127.0, 126.4, 126.3, 112.2, 112.1, 112.0, 81.9, 78.1, 56.6,
156.6, 150.2, 147.7, 135.2, 133.4, 133.3, 133.2, 131.9, 129.5, 41.3, 30.6, 28.2, 21.7 ppm; IR (neat) 1706, 1607 cm−1; HRMS
128.6, 128.5, 128.4, 128.1, 127.8, 127.1, 126.5, 126.4, 121.7, (FAB) m/z: [M + H]+ calcd for [C33H33F3NO4]+ ([M + H]+)
121.6, 119.5, 119.2, 105.5, 105.3, 105.2, 105.0, 82.0, 77.9, 56.4, 564.2362; found 564.2345. The enantioselectivity was
41.3, 30.7, 28.2 ppm; IR (neat) 1706, 1585 cm−1; HRMS determined by chiral HPLC analysis (DAICEL Chiralpak
(FAB) m/z: [M + H]+ calcd for [C32H30BrF3NO4]+ ([M + AD-H, hexane: 2-propanol = 98:2, flow rate = 1.0 mL/min, 23
H]+) 628.1310; found 628.1287. The enantioselectivity was °C, λ = 254 nm), retention time: minor isomer 15.54 min,
determined by chiral HPLC analysis (DAICEL Chiralpak AD- major isomer 28.92 min, 92% ee, [α]D20 = −24.43 (c 1.0,
H, hexane: ethanol = 95:5, flow rate = 1.0 mL/min, 23 °C, λ = CHCl3).
250 nm), retention time: minor isomer 6.85 min, major isomer (R)-4-Methoxyphenyl-3-((tert-butoxycarbonyl)-
7.67 min, 89% ee, [α]D20 = −5.64 (c 1.0, CHCl3). (naphthalen-2-ylmethoxy)amino)-4-(2,4,5-trifluorophenyl)-
(R)-tert-Butyl-(4-(4-Methoxyphenyl)-4-oxo-1-(2,4,5- butanoate (12). In a one-neck round-bottom flask, (R)-tert-
trifluorophenyl)butan-2-yl)(naphthalen-2-ylmethoxy)- butyl-(4-(4-methoxyphenyl)-4-oxo-1-(2,4,5-trifluorophenyl)-
carbamate (11f). Following the general procedure (3), butan-2-yl)(naphthalen-2-ylmethoxy)carbamate (11f) (238
molecule 11f was obtained as a white solid (mp 88 °C, 1.77 mg, 0.41 mmol) and sodium bicarbonate (69 mg, 0.82
g, 94% yield); 1H NMR (400 MHz, CDCl3) δ 7.79−7.85 (m, mmol, 2 equiv) were dissolved in dichloromethane (2 mL)
3H), 7.77 (s, 1H), 7.71−7.73 (m, 2H), 7.47−7.53 (m, 3H), under an argon atmosphere and stirred for 10 min. m-
7.11−7.18 (m, 1H), 6.79−6.87 (m, 3H), 5.04 (d, J = 10.6 Hz, Chloroperoxybenzoic acid (138 mg, 0.62 mmol) in dichloro-
1H), 4.87 (d, J = 10.6 Hz, 1H), 4.88−4.93 (m, 1H), 3.84 (s, methane (2 mL) was dried with the excess amount of 4 Å
3H), 3.20 (dd, J = 16.9, 6.2 Hz, 1H), 3.01 (dd, J = 17.0, 7.4 molecular sieves and slowly added to the reaction mixture at 0
Hz, 1H), 2.85−2.96 (m, 2H), 1.39 (s, 9H) ppm; 13C NMR °C. The reaction was stirred for 24 h at room temperature until
(101 MHz, CDCl3) δ 195.8, 163.6, 156.5, 133.5, 133.4, 133.2, the TLC analysis showed that the reaction was complete. After
130.4, 129.7, 128.5, 128.4, 128.2, 127.8, 127.1, 126.4, 126.3, completion of the reaction, the residue was diluted with
122.0, 121.9, 121.8, 121.8, 121.7, 119.5, 119.4, 119.3, 119.2, dichloromethane (30 mL), quenched with sodium sulfite
113.8, 105.4, 105.2, 105.1, 105.0, 81.9, 78.0, 56.7, 55.6, 41.1, solution (10 mL), and extracted. The organic phase was
30.6, 28.2 ppm; IR (neat) 1707, 1601 cm−1; HRMS (FAB) m/ washed with sodium bicarbonate solution (10 mL) and brine
z: [M + H]+ calcd for [C33H33F3NO5]+ ([M + H]+) 580.2311; (5 mL), dried over anhydrous MgSO 4 , filtered, and
found 580.2316. The enantioselectivity was determined by concentrated in vacuo. The residue was purified by column
chiral HPLC analysis (DAICEL Chiralpak AD-H, hexane: chromatography (silica gel, hexane/ethyl acetate = 10:1) to
ethanol = 95:5, flow rate = 1.0 mL/min, 23 °C, λ = 250 nm), afford compound 12 as a colorless oil (219 mg, 90% yield); 1H
retention time: minor isomer 10.44 min, major isomer 11.84 NMR (400 MHz, CDCl3) δ 7.87−7.82 (m, 4H), 7.59 (d, J =
min, 96% ee, [α]D20 = −14.92 (c 1.0, CHCl3). 8.7 Hz, 1H), 7.50 (td, J = 6.4, 3.4 Hz, 2H), 7.10 (q, J = 8.7 Hz,
(R)-tert-Butyl-(4-(3-Methoxyphenyl)-4-oxo-1-(2,4,5- 1H), 6.96−6.81 (m, 5H), 5.15 (d, J = 10.1 Hz, 1H), 4.96 (d, J
trifluorophenyl)butan-2-yl)(naphthalen-2-ylmethoxy)- = 9.6 Hz, 1H), 4.89−4.82 (m, 1H), 3.76 (s, 3H), 3.02−2.89
carbamate (11g). Following the general procedure (3), (m, 3H), 2.80 (dd, J = 15.1, 5.9 Hz, 1H), 1.39 (s, 9H) ppm;
13
molecule 11g was obtained as a colorless oil (27 mg, 94% C NMR (101 MHz, CDCl3) δ 170.0, 157.4, 156.5, 144.1,
yield); 1H NMR (400 MHz, CDCl3) δ 7.79−7.85 (m, 3H), 133.4, 133.3, 133.0, 128.5, 128.4, 128.2, 127.8, 126.9, 126.4,
7.76 (s, 1H), 7.46−7.53 (m, 3H), 7.38 (s, 1H), 7.22−7.28 (m, 126.3, 122.3, 121.3, 121.2, 121.1, 121.0, 119.7, 119.6, 119.5,
3H), 7.05−7.17 (m, 2H), 6.84 (td, J = 9.7, 6.4 Hz, 1H), 5.04 119.4, 114.5, 105.6, 105.4, 105.3, 105.1, 82.1, 78.5, 57.4, 55.7,
(d, J = 10.1 Hz, 1H), 4.88−4.94 (m, 1H), 3.80 (s, 3H), 3.27 37.9, 30.7, 28.2 ppm; IR (neat) 1647, 1622 cm−1; HRMS
(dd, J = 16.9, 6.4 Hz, 1H), 3.07 (dd, J = 16.9, 6.9 Hz, 1H), (FAB) m/z: [M-Boc + H]+ calcd for [C28H25F3NO4]+ ([M-
2.85−3.10 (m, 2H), 1.39 (s, 9H) ppm; 13C NMR (101 MHz, Boc + H]+) 496.1736; found 496.1739 [α]D20 = +6.88 (c 1.0,
CDCl3) δ 197.1, 159.8, 156.5, 138.1, 133.4, 133.3, 133.2, CHCl3).
129.7, 128.5, 128.4, 128.1, 127.8, 127.0, 126.4, 126.3, 120.7, (R)-3-((tert-Butoxycarbonyl)(naphthalen-2-ylmethoxy)-
120.0, 112.1, 82.0, 78.0, 56.6, 55.5, 41.4, 30.7, 28.2 ppm; IR amino)-4-(2,4,5-trifluorophenyl)butanoic Acid (4). (R)-4-
(neat) 1748, 1706 cm−1; HRMS (FAB) m/z: [M + H]+ calcd Methoxyphenyl-3-((tert-butoxycarbonyl)(naphthalen-2-
for [C33H33F3NO5]+ ([M + H]+) 580.2311; found 580.2317. ylmethoxy)amino)-4-(2,4,5-trifluorophenyl)butanoate (12)
The enantioselectivity was determined by chiral HPLC analysis (214 mg, 0.36 mmol) was dissolved in tetrahydrofuran (1.2
(DAICEL Chiralpak AD-H, hexane: ethanol = 95:5, flow rate mL, 0.3 M), and KOH (1 M in water, 1.1 mL, 3 equiv) was
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ACS Omega http://pubs.acs.org/journal/acsodf Article

added to the reaction mixture and stirred for room concentrated in vacuo. The residue was purified by silica gel
temperature. The reaction was stirred for 3 h until the TLC column chromatography (Hx:EtOAc = 1:1) to afford molecule
analysis showed that the reaction was complete. After 15 as a white solid (mp 192 °C, 57 mg, 75% yield); 1H NMR
completion of the reaction, the residue was diluted with (400 MHz, CDCl3) δ 7.02−7.09 (m, 1H), 6.82−6.91 (m, 1H),
ethyl acetate (30 mL), washed with ammonium chloride 5.25−5.25 (m, 1H), 4.98−5.10 (m, 1H), 4.91 (s, 1H), 3.95−
solution (15 mL), dried over anhydrous MgSO4, filtered, and 4.25 (m, 5H), 2.61−2.95 (m, 4H), 1.34 (s, 9H) ppm; 13C
concentrated in vacuo. The residue was purified by column NMR (201 MHz, CDCl3) δ 169.9, 169.5, 156.1 (dd, J = 243.2,
chromatography (silica gel, hexane/ethyl acetate = 1:1 to ethyl 6.4 Hz), 155.2, 150.2, 148.9 (dt, J = 250.6, 13.1 Hz) 146.7 (dd,
acetate only) to afford compound 4 as a yellow sticky caramel J = 244.8, 11.1 Hz), 143.7 (q, J = 41.3 Hz), 143.5 (q, J = 42.9
(172 mg, 98% yield); 1H NMR (400 MHz, CDCl3) δ 7.82− Hz), 119.1 (t, J = 16.7 Hz), 118.2 (qd, J = 270.2, 9.5 Hz),
7.86 (m, 4H), 7.53−7.56 (m, 1H), 7.47−7.51 (m, 2H), 6.81− 105.42 (dd, J = 27.8, 21.5 Hz), 79.9, 79.7, 60.4, 48.4, 48.2,
7.08 (m, 2H), 5.10 (d, J = 9.6 Hz, 1H), 4.90 (d, J = 9.6 Hz, 43.6, 43.2, 42.6, 41.8, 39.3, 38.1, 36.8, 33.0, 29.7, 28.2 ppm; IR
1H), 4.70−4.77 (m, 1H), 2.79−2.91 (m, 3H), 2.55−2.60 (m, (neat) 1679, 1670 cm−1; HRMS (FAB) m/z: [M + H]+ calcd
1H), 1.40 (s, 9H) ppm; 13C NMR (101 MHz, CDCl3) δ 176.5, for [C21H24F6N5O3]+ ([M + H]+) 508.1783; found 508.1797.
157.6, 157.5, 156.6, 155.2, 155.1, 148.0, 147.8, 147.7, 145.4, [α]D20 = +22.0 (c 1.0, CHCl3).
145.4, 145.3, 145.2, 133.4, 133.2, 132.9, 128.4, 128.3, 128.1, The analytical data obtained for compound 15 were found
127.8, 126.9, 126.4, 126.3, 121.2, 121.1, 119.5, 119.4, 105.5, to be in agreement with those for the sample reported in the
105.3, 105.2, 105.0, 82.2, 78.5, 56.8, 37.2, 30.7, 28.1 ppm; IR literature.8d
(neat) 1714 cm−1; HRMS (CI) m/z: [M + H]+ calcd for (R)-Sitagliptin·HCl (1). (R)-tert-Butyl-(4-oxo-4-(3-(trifluor-
[C26H27F3NO5]+ ([M + H]+) 490.1836; found 490.1837. omethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-
[α]D20 = −1.52 (c 1.0, CHCl3). 1-(2,4,5-trifluorophenyl)butan-2-yl)carbamate (15) (60 mg,
tert-Butyl-(R)-(naphthalen-2-ylmethoxy)(4-oxo-4-(3-(tri- 0.12 mmol) was dissolved in 0.5 M HCl in methanol (3 mL)
fluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin- and stirred at room temperature. The reaction was stirred for 3
7(8H)-yl)-1-(2,4,5-trifluorophenyl)butan-2-yl)carbamate h until the TLC analysis showed that the reaction was
(14). 3-(Trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo- complete. After completion of the reaction, the residue was
[4,3-a]pyrazine hydrochloride (156 mg, 0.53 mmol, 1.5 solidified with diethyl ether and hexane to afford sitagliptin (1)
equiv), EDC·HCl (114 mg, 0.74 mmol, 2.1 equiv), and hydrochloride as a white solid (mp 171 °C, 26 mg, 92% yield);
1
DMAP (180 mg, 1.48 mmol, 4.2 equiv) were dissolved in H NMR (500 MHz, DMSO-d6) δ 8.36 (s, 3H, NH3), 7.57−
dichloromethane (5 mL) under an argon atmosphere. A 7.63 (m, 1H), 7.46−7.53 (m, 1H), 4.81−4.99 (m, 2H), 4.25−
solution of (R)-3-((tert-butoxycarbonyl)((4-nitrobenzyl)oxy)- 4.27 (m, 1H), 3.85−4.16 (m, 3H), 3.70−3.76 (m, 1H), 2.76−
amino)-4-(2,4,5-trifluorophenyl)butanoic acid (4) (172 mg, 3.12 (m, 4H) ppm; 13C NMR (126 MHz, DMSO-d6) δ 168.7,
0.35 mmol) in dichloromethane (5 mL) was added dropwise 156.2 (dd, J = 243.5, 11.4 Hz) 150.8, 150.7, 148.4 (dt, J =
to the reaction mixture at room temperature. The reaction was 247.3, 13.6 Hz), 145.9 (dd, J = 242.0, 9.9 Hz), 142.5 (q, J =
stirred for 16 h until the TLC analysis showed that the reaction 38.8 Hz), 142.4 (q, J = 39.2 Hz), 120.1 (ddd, J = 18.3, 5.7, 4.2
was complete. After completion of the reaction, the residue Hz), 119.8 (dd, J = 19.5, 6.3 Hz), 118.4 (q, J = 270.1 Hz),
was quenched with 1 N HCl and acidified to pH = 2. The 105.9 (dd, J = 29.1, 21.3 Hz), 47.8, 47.7, 43.5, 43.0, 41.7, 41.0,
residue was extracted with dichloromethane (20 mL × 2), 38.5, 37.5, 34.5, 34.2, 30.9, 30.8 ppm; IR (neat) 1745, 1707
dried over anhydrous Na2SO4, filtered, and concentrated in cm−1; HRMS (EI) m/z: [M]+ calcd for [C16H15F6N5O]+
vacuo. The residue was purified by column chromatography ([M]+) 407.1179; found 407.1175. [α]D20 = −21.6 (c 0.7,
(silica gel, hexane/ethyl acetate = 1:1) to afford compound 14 CH3OH).
as a white solid (mp 84 °C, 198 mg, 85% yield); 1H NMR Computational Method. To suggest a plausible transition
(400 MHz, CD3OD) δ 7.77−7.87 (m, 4H), 7.43−7.56 (m, state, calculations were carried out using the Jaguar v10.7 of
3H), 7.15−7.28 (m, 1H), 7.03 (m, 1H), 4.69−5.03 (m, 5H), the Schrodinger Suite with density-functional theory. All of the
3.85−4.27 (m, 3H), 3.58 (br s, 1H), 2.46−2.99 (m, 4H), 1.32 initial geometries of each species were optimized to respective
(d, J = 8.2 Hz, 9H) ppm; 13C NMR (101 MHz, CD3OD) δ minimum energy geometries using our previous method. DFT
170.1, 169.9, 157.7, 156.7, 151.1, 150.7, 150.1, 128.0, 127.8, calculations of the species using the B3LYP-D3 functional and
127.4, 126.3, 126.2, 122.0, 119.4, 119.1, 105.2, 104.9, 104.7, 6-31++G(d,p) basis set optimized individual molecules. After
81.8, 77.5, 56.9, 43.3, 43.1, 41.9, 41.1, 38.6, 38.3, 37.9, 37.7, combining the catalyst with enone 7 and carbamate 8, the
35.5, 30.4, 27.0 ppm; IR (neat) 1748, 1706 cm−1; HRMS relaxed coordinate scan was conducted in order to examine the
(FAB) m/z: [M + H]+ calcd for [C32H32F6N5O4]+ ([M + H]+) best dihedral angle of the catalysts N63-C61-C66-C71
664.2358; found 664.2363. [α]D20 = −7.08 (c 1.0, CHCl3). (−06.121 to −136.121 with 5 increments of 9 steps) to
(R)-tert-Butyl-(4-oxo-4-(3-(trifluoromethyl)-5,6-dihydro- make pi−pi interactions. The most stable complex chosen from
[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-1-(2,4,5- the scan was more optimized under the functional ωB97X-D
trifluorophenyl)butan-2-yl)carbamate (15). To a solution of method with the basis set 6-31++G(d,p) at the gas phase.
tert-butyl-(R)-(naphthalen-2-ylmethoxy)(4-oxo-4-(3-(trifluor-
omethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-
1-(2,4,5-trifluorophenyl)butan-2-yl)carbamate (14) (100 mg,
0.15 mmol, 1 equiv) in EtOAc (1.5 mL) was added a catalytic
■
*
ASSOCIATED CONTENT
sı Supporting Information

amount of acetone-washed (5 × 1 mL) Raney-Ni (4200; slurry The Supporting Information is available free of charge at
in water; active catalyst; Sigma-Aldrich). The reaction mixture https://pubs.acs.org/doi/10.1021/acsomega.3c10080.
was stirred under a hydrogen atmosphere at room temperature.
After stirring for 2 h, the reaction mixture was filtered through Spectral data of all new compounds including 1H,
13
celite pad and washed with EtOAc. The filtrate was C{1H} NMR spectra, HPLC analysis graphs under

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ACS Omega http://pubs.acs.org/journal/acsodf Article

optimized conditions, and computational data for (6) (a) Subbaiah, C. S.; Haq, W. Efficient stereocontrolled synthesis
Michael addition to 7f (PDF) of sitagliptin phosphate. Tetrahedron: Asymmetry 2014, 25, 1026.
(b) Dey, S.; Sudalai, A. A concise enantioselective synthesis of (R)-

■ AUTHOR INFORMATION
Corresponding Authors
selegiline, (S)-benzphetamine and formal synthesis of (R)-sitagliptin
via electrophilic azidation of chiral imide enolates. Tetrahedron:
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Geumwoo Lee − Research Institute of Pharmaceutical Sciences Secen, H.; Sahin, M. F.; Altundas, R.; Kara, Y. Novel and
and College of Pharmacy, Seoul National University, Seoul enantioselective syntheses of (R)- and (S)-3-hydroxy-4-(2,4,5-
08826, Republic of Korea; Email: [email protected] trifluorophenyl)butanoic acid: a synthon for sitagliptin and its
Hyeung-geun Park − Research Institute of Pharmaceutical derivatives. Tetrahedron 2012, 68, 2607. (d) Lin, K.; Cai, Z.; Zhou,
Sciences and College of Pharmacy, Seoul National University, W. Practical and economical approach to synthesize sitagliptin. Synth.
Commun. 2013, 43, 3281−3286. (e) Kang, S. K.; Cho, G. H.; Leem,
Seoul 08826, Republic of Korea; orcid.org/0000-0002-
H. J.; Soh, B. K.; Sim, J.; Suh, Y.-G. A highly stereoselective and
9645-8221; Phone: +82-2-880-7821; Email: hgpk@ efficient synthesis of enantiomerically pure sitagliptin. Tetrahedron:
snu.ac.kr; Fax: +82-2-872-9129 Asymmetry 2017, 28, 34−40. (f) Gutierrez, O.; Metil, D.; Dwivedi, N.;
Authors Gudimalla, N.; Chandrashekar, E. R. R.; Dahanukar, V. H.;
Bhattacharya, A.; Bandichhor, R.; Kozlowski, M. C. Practical,
Daehyun Oh − Research Institute of Pharmaceutical Sciences
Asymmetric Route to Sitagliptin and Derivatives: Development and
and College of Pharmacy, Seoul National University, Seoul Origin of Diastereoselectivity. Org. Lett. 2015, 17, 1742−1745.
08826, Republic of Korea (7) Savile, C. K.; Janey, J. M.; Mundorff, E. C.; Moore, J. C.; Tam,
Jaeyong Lee − Research Institute of Pharmaceutical Sciences S.; Jarvis, W. R.; Colbeck, J. C.; Krebber, A.; Fleitz, F. J.; Brands, J.;
and College of Pharmacy, Seoul National University, Seoul et al. Biocatalytic Asymmetric Synthesis of Chiral Amines from
08826, Republic of Korea Ketones Applied to Sitagliptin Manufacture. Science 2010, 329, 305.
Sehun Yang − Research Institute of Pharmaceutical Sciences (8) (a) Dey, S.; Gadakh, S. K.; Ahuja, B. B.; Kamble, S. P.; Sudalai,
and College of Pharmacy, Seoul National University, Seoul A. Pd-catalyzed reductive cleavage of Nsingle bondN bond in
08826, Republic of Korea dibenzyl-1-alkylhydrazine-1,2-dicarboxylates with PMHS: application
So Hyun Jung − Research Institute of Pharmaceutical Sciences to a formal enantioselective synthesis of (R)-sitagliptin. Tetrahedron
and College of Pharmacy, Seoul National University, Seoul Lett. 2016, 57, 684−687. (b) Bae, H. Y.; Kim, M. J.; Sim, J. H.; Song,
08826, Republic of Korea C. E. Direct Catalytic Asymmetric Mannich Reaction with
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2718-5637 Asymmetric Synthesis of Sitagliptin Phosphate Monohydrate.
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https://pubs.acs.org/10.1021/acsomega.3c10080 T.; Nishibayashi, K.; Kobayashi, Y.; Pápai, I.; Takemoto, Y.
Mechanistic Insight into Asymmetric Hetero-Michael Addition of
Notes α,β-Unsaturated Carboxylic Acids Catalyzed by Multifunctional
The authors declare no competing financial interest. Thioureas. J. Am. Chem. Soc. 2018, 140, 12216−12225.
(9) (a) Hansen, K. B.; Balsells, J.; Dreher, S.; Hsiao, Y.; Kubryk, M.;

■ ACKNOWLEDGMENTS
This research was supported by Basic Science Research
Palucki, M.; Rivera, N.; Steinhuebel, D.; Armstrong, J. D., III; Askin,
D.; Grabowski, E. J. First Generation Process for the Preparation of
the DPP-IV Inhibitor Sitagliptin. Org. Process Res. Dev. 2005, 9, 634−
Program through the National Research Foundation of 639. (b) Hansen, K. B.; Hsiao, Y.; Zu, F.; Rivera, N.; Clausen, A.;
Korea (NRF) funded by the Ministry of Education (NRF- Kubryk, M.; Krska, S.; Rosner, T.; Simmons, B.; Balsells, J.; Ikemoto,
2022R1A6A1A03046247) and the BK21 Plus Program in N.; Sun, Y.; Spindler, F.; Malan, C.; Grabowski, E. J. J.; Armstrong, J.
2023. D., III Highly Efficient Asymmetric Synthesis of Sitagliptin. J. Am.
Chem. Soc. 2009, 131, 8798−8804. (c) Bao, H.; Bayeh, L.; Tambar, U.
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