N-TFA-Gly-Bt-based stereoselective synthesis of substituted 3-amino tetrahydro-2 h-pyran-2-ones via an organocatalyzed cascade process

Article abstract of DOI:10.1021/acs.joc.9b01488

Chiral-substituted 3-amino tetrahydro-2H-pyran-2-ones were prepared in excellent enantioselectivities (up to 99percent ee) via an organo-catalyzed cascade procedure with N-TFA-Gly-Bt and α,β-unsaturated aldehydes as the substrates. The corresponding tetra

Full text of DOI:10.1021/acs.joc.9b01488

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Note
N-TFA-Gly-Bt Based Stereoselective Synthesis of Substituted 3-Amino
Tetrahydro-2H-pyran-2-ones via an Organocatalyzed Cascade Process
Liuqing Han, Ke Li, Haitong Xu, Tao Mei, Yali Sun, Jingping Qu, and Yuming Song
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01488 • Publication Date (Web): 23 Jul 2019
Downloaded from pubs.acs.org on July 27, 2019
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N-TFA-Gly-Bt Based Stereoselective Synthesis of Substituted 3-
Amino Tetrahydro-2H-pyran-2-ones via an Organocatalyzed Cas-
cade Process
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Liuqing Han, Ke Li, Haitong Xu, Tao Mei, Yali Sun, Jing ping Qu, Yuming Song*
State Key Laboratory of Fine Chemicals, School of Chemical Engineering, Dalian University of Technology, Dalian 116024,
P. R. China.
Supporting Information
ABSTRACT: Chiral substituted 3-amino tetrahydro-2H-pyran-2-ones were prepared in excellent ees (up to 99% ee) via an organo-
catalyzed cascade procedure with N-TFA-Gly-Bt and α,β-unsaturated aldehydes as the substrates. The corresponding tetrahydro-
2H-pyran-2-ones can be used for further synthetic transformations that furnish chiral substituted 3-amino piperidin-2-ones with
high levels of stereoselectivity.
Chiral α-amino acids and their derivatives are among the most important building blocks for natural products, bioactive entities and
pharmaceuticals. Many drugs contain both natural and more importantly, unnatural α-amino acid fragments, meaning new method-
ologies for accessing α-amino acids are of utmost importance to both academic and pharmaceutical chemists.1-2 A wide variety of
asymmetric transformations have been developed for the synthesis of chiral α-amino acids with readily available pro-chiral or chiral
precursors,3-5 among which glycine and its derivatives, especially glycine imino esters, have been extensively studied and used for
the preparation of many non-natural amino acid derivatives as drug intermediates in multi- to several hundred kilogram quantities
(Fig. 1).6,7,8 It was assumed that the unique properties of the imino group should be responsible for the α-activation of glycine deriv-
atives, which could react with diverse electrophiles in enantioselective manners.9-11 Fantastic improvements with the imino activa-
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tion strategies using chiral aldehydes as the organocatalysts were achieved recently by Guo’s, Ouyang’s, Zhao’s and Yuan’s groups,
respectively: glycine esters without N-protection reacted with α,β-unsaturated ketones or aryl N-diphenylphosphinyl imines in ex-
cellent yields, drs and ees; similar glycine Schiff base intermediates, formed in situ during the reactions, were proposed to be the
active species. 12-13 Asymmetric reactions with other glycine derivatives as glycinate Schiff bases Ni(II) complexes,14 triketopipera-
zines15 and N,N-disubstituted glycinates 16 were also reported. However, except for some intramolecular procedures, 17-18 other gly-
cine derivatives with general nitrogen protections (amides, carbamates and sulfonamides) have not been extensively studied due to
poor reactivity. Hence, auxiliary strategies, and even chiral resolution methods are still needed for the preparation of some im-
portant intermediates. 19-23
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Fig 1 Representative unnatural amino acids and their derivatives.
As part of our continuous efforts to develop new methodologies for the asymmetric functionalization of α-amino carbonyl com-
pounds, we found that amino protections played decisive roles for the formation of enol intermediates, which reacted with α,β-
unsaturated aldehydes and afforded polysubstituted pyrrolidines with controlled stereochemistry in excellent ees.24 We envisioned
that efficient activations and good chiral inductions with non-imino glycine derivatives could be achieved through the regulation of
amino protections and carboxyl derivations. Asymmetric reactions between imino-glycine derivatives and α,β-unsaturated alde-
hydes were first developed by Belokon et al., wherein a chiral glycinate Schiff base Ni(II) complex reacted with substituted acrole-
ins under basic conditions to yield Michael addition products in excellent chiral induction (Scheme 1 A).25-26 An organocatalyzed
asymmetric version of this transformation with non-chiral Ni(II) complexes afforded Michael adducts in up to 95% ee (Scheme 1
B). 27 Other than the nickel complexes, free glycine ester Schiff bases are also good partners for Michael additions under chiral PTC
conditions and an optically pure bicyclic amino acid, which is the key intermediate for Telaprevir production was prepared in up to
93% ee. (Scheme 1 C).28-30 Asymmetric 1,3-dipolar cycloaddition of imino glycinates with methacrolein was discovered by Carret-
ero et al. and chiral pyrrolidines were prepared in good enantioselectivity (69% ee) (Scheme 1 D).31-32
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(A)
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(B)
(C)
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(D)
(E)
Scheme 1 Asymmetric reactions between glycine derivatives and α,β-unsaturated aldehydes
N-Acyl derivatives of benzotriazole (COBt) are known as powerful acylating agents and have found widespread application in
organic synthesis.33 Albeit the strong electron withdrawing properties of Bt group can significantly increase the acidity of hydrogen
atom in α-position, only a few researches focused on the α-functionalization of COBts.34-35 Katritzky et al. reported a fascinating
formation of polysubstituted 3,4-dihydropyran-2-ones or 1,3-dienes by intramolecular cyclization of lithium enolates of N-
acylbenzotriazoles to α,β-unsaturated carbonyl compounds in good yields and up to 20:1 drs.36 Barbas III et al. found the first or-
ganocatalyzed asymmetric α-functionalization of 4-nitro-benzyl COBt to yield the product with low chiral induction (20% ee). We
reported herein an efficient organocatalyzed asymmetric cascade reaction with N-TFA glycine Bt and α,β-unsaturated aldehydes as
the substrates affording chiral 3,4,6-trisubstituted tetrahydro-2H-pyran- 2-ones in up to 65% overall yield and 99% ee (Scheme 1 E).
Scheme 2 Amino protection screen
Our initial investigation started by using acylbenzotriazole 1 and 4-Br-cinnamaldehyde (2a) as the substrates with a traditional
(S)-diphenyl prolinol silyl ether (10% mol)/benzoic acid (10% mol)/CH2Cl2 system (Scheme 2). No reaction was observed with 1a
and 1b, which was attributed to the poor electron withdrawing properties of the protective groups. Replacing the protective group
with TFA (1c), to our delight, the reaction finished in 12 hours and a novel 3,4,6-trisubstituted-tetrahydro-2H-pyran-2-one (3a) was
obtained in excellent enantioselectivity (97% ee). Characteristic LCMS signals of Bromo containing components of the reaction
mixture indicated that there was predominately one product produced (dr>10:1, by LC normalization), though decomposed BtH
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was observed. The promising results promoted further optimization of the reaction with cinnamaldehyde (2b) as the standard sub-
strate (Table 1). Without any additive, the reaction afforded product in 23% yield and 80% ee (Table 1, entry 1). Remarkable im-
provements in both yields and ees were achieved with most of the acidic additives (Table 1, entries 2-7). Compared with HOAc,
MeSO3H, ArSO3H, TfOH and CF3CO2H, reaction with benzoic acid (BA) afforded the product in the highest yield and ee (36%
yield and 97% ee; Table 1, entry 7). Para-substitution of BA were further optimized and elevation of the yields was reached with Br,
I, -NMe2 and methyl substitutions (Table 1, entries 8-11); up to 59% yield and 97% ee were obtained with 4-Me-BA as the co-
catalyst (Table 1, entry 11). Additionally, other common solvents were also examined, and acetone was the best choice of solvent in
terms of yield and enantioselectivity (Table 1, entries 12-16).
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Table 1. Optimization of Reaction Conditionsa
Entry
1
Additive
None
Solvent
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
Yield (%)b
23
Ee (%)c
80
2
HOAc
36
93
3
BA
36
97
4
TFA
24
83
5
LABSA
TsOH
23
93
6
30
91
7
TfOH
18
95
8
4-Br-BA
4-I-BA
55
96
9
45
89
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16
4-N(CH3)2-BA
4-CH3-BA
4-CH3-BA
4-CH3-BA
4-CH3-BA
4-CH3-BA
4-CH3-BA
55
93
59
97
49
92
CH3CN
EtOAc
Me2CO
MIBK
53
92
55
96
61
97
42
97
a Reactions performed with 1c (0.5 mmol) and 2b (0.55 mmol) in 1 mL of solvent for 12h. b Isolated yield. c Determined by HPLC on chiral stationary
phase.
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After establishment of the optimal catalytic system, the substrate scope of the reaction were then examined. Various substituted
α,β-unsaturated aldehydes were well tolerated in this reaction, giving the products in low to moderate isolated yields (27-65%) and
good to excellent enantioselectivities (80-99% ee) (Table 2). As shown in Table 2, halogen-substituted cinnamaldehydes (2a, 2c,
2d, 2e) reacted with 1c to give the corresponding products with similar yields and enantioselectivities (58-65% yield and > 95% ee)
(Table 2, Entries 1,3-5). But unexpectedly, with 2-chloro cinnamaldehyde (2c) as the substrate, a 1:1 diastereomer mixture (at C-6
position) was obtained in a total 62% yield and 97/99% ees (Table 2, Entry 3). With 3-cyano substitution (2f), 3f was obtained in
the lowest ee (80%) (Table 2, Entry 6). Considering the result, that a slight ee decrease was also observed for 3-Cl substituted prod-
uct 3d, the enantioselectivity of the reaction seems more sensitive in comparison with the electron properties of para substitution.
Thus, we propose that the steric repulsion between substituted phenyl and bulky nucleophile might be responsible for the ees’
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erosion of both meta substituted substrates (A slightly deviation of the phenyl ring from the iminium plane was observed in report-
ed single crystal X-ray structures 37). Further evidence stems from the fact that para substituted cinnamaldehydes with both elec-
tron-withdrawing groups (-CN and -NO2) and electron-donating groups (-Ph, -OMe, -O-2-naphthyl) gave chiral tetrahydro-2H-
pyran-2-ones (3g-k) in 45-62% yields and 93-98% ees (Table 2, Entries7-11). (2E,4E)-5-(3,4dichlorophenyl)penta-2,4-dienal (2l)
reacted selectively following the same process with 1c to afford a chiral tetrahydro-2H-pyran-2-one (3l) in 51% yield and 86% ee
(Table 2, Entry 12). Disubstituted substrate 3,4-dichloro cinnaldehyde 2m gave the product 3m in the same ee (95%) as that of 3-
chloro cinnaldehyde 2d. Unlike meta mono substituted 2d and 2f, meta disubstituted substrates 2n and 2o produced the products 3n
and 3o in excellent ees (97 and 98% ee respectively), we envisioned that the ee erosion caused by one substituent oriented to the si-
face was neutralized by the other one, which further blocked re-face of the iminium intermediate (because of the rotatable single
bond between phenyl ring and the double bond). (Table 2, Entries 13-15). Varying phenyl group to furanyl, 54% yield and 95% ee
were achieved (Table 2, Entry 16). With 3-Ferrocenyl acrolein, 90% ee was achieved, but, however, only 27% yield was obtained
because of the poor stability of Fc fragment during column purification (Table 2, Entry 17). With crotonaldehyde as the substrate, a
complex mixture was obtained following current procedure (Table 2, Entry 18).
Table 2. Substrate Scope of α,β-Unsaturated aldehydesa
entry
2 (R=)
3
Yield (%)b
Ee (%)c
97
1
2
3
4
2a (4-Br-C6H4-)
2b (C6H5-)
3a
3b
3cd
3d
58
61
62
60
97
2c (2-Cl-C6H4-)
2d (3-Cl-C6H4-)
97/99
95
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2e (4-Cl-C6H4-)
2f (3-CN-C6H4-)
2g (4-CN-C6H4-)
2h (4-NO2-C6H4-)
2i (4-Ph-C6H4-)
2j (4-CH3O-C6H4-)
3e
3f
3g
3h
3i
65
62
62
53
45
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27
--
97
80
94
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98
86
95
97
98
95
90
--
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3j
2k(4-(2-naphthyl)O-C6H4-)
2l((E)-(3,4)Cl2C6H3-CH=CH-)
2m (3,4-Cl2C6H3-)
2n (3,5-Cl2C6H3-)
2o(3,5-(CF3)2C6H3-)
2p (2-Furanyl-)
3k
3l
3m
3n
3o
3p
3q
3r
2q (Ferrocenyl-)
2r (CH3-)e
a
b
c
Reactions were performed with 1c (0.5 mmol) and 2a–q (0.55 mmol) in 1 mL acetone. Isolated yield. Determined by HPLC on chiral stationary phase.
d
The two diasteromers (1:1) that configurationally differed at the 6 position were not separated since both isomers could be converted into one single prod-
uct after removing the Bt group via reduction. e The reaction mixture contains less desired diastereomers and more unknown byproducts.
The presence of the Bt–C–OCO fragment within the products allowed for further derivatization of 3 into a stereo-defined 3-
amino-piperidin-2-ones (Scheme 3). Facile aminolysis of 3i in NH3/MeOH at room temperature generated 6-hydroxyl-piperidin- 2-
one 4i, which undergoes a dehydroxyl/reduction process in a BF3OEt2/HSiEt3/CH2Cl2 system to afford 4-([1,1'-biphenyl]-4-yl)-3-
(2,2,2-trifluoroacetamido)-piperidin-2-one 5i in 80% yield and 97% ee. To verify the stereochemistry of 3c (diastereomer mixture
at C-6 position), following the same procedure, pure 5c was prepared with 3c in 70% yield and >99% ee without column purifica-
tion. Chiral 3-amino-4-aryl-2-piperidone derivatives, which were prepared by multi-step procedures with chiral auxiliaries,38-39 had
been used as phenylalanine isosteres in Renin inhibitors design.40
Scheme 3 Synthesis of chiral substituted 3-amino piperidin-2-ones
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The absolute configuration of 3q was confirmed by X-ray single crystal diffraction analysis (Supporting Information), namely,
with (S)-diphenyl prolinol silyl ether as the catalyst, trisubstituted chiral tetrahydro-2H-pyran-2-one obtained adopts a (3S,4S,6S)
configuration, and all bulky groups are in equatorial orientations. According to the above results, a proposed catalytic cycle was
shown in Scheme 4. As shown in the scheme, the TFA protection, together with a strong electron-withdrawing COBt group facili-
tates the formation of the active enol intermediate, which adopts a configuration constrained intermediate I-1 because of a possible
intramolecular hydrogen bond formed between Bt and N-H. Secondly, deprotonation of I-1 by A- formed during iminium active
intermediate formation, generates enolate anion, which forms a compact ion pair I-2 with iminium cation. The reaction occurs from
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37,
the si face of the enolate to the si face of the iminium ion that builds the absolute configurations of C-3 and C-4 simultaneously.
41
Finally, following an active amide hydrolyzation (I-3), lactonization and Bt substitution (I-4) procedure, the chiral 3,4,6-
trisubstituted tetrahydro-2H-pyran-2-one is formed and the labile hemi-amino acetal structure in favor of the Bt group opt for a
thermodynamic stable configuration.
Scheme 4 Proposed mechanism
In conclusion, an atom economical enantioselective organocatalysis has been developed for the synthesis of substituted 3-amino
tetrahydro-2H-pyran-2-ones from readily available N-TFA-Gly-Bt and α,β-unsaturated aldehydes. The reaction presumably pro-
ceeded via a Michael addition/amide hydrolyzation/lactonization/Bt substitution process. The high level of diastereoselectivity and
enantioselectivity might be determined by the compact ion pair I-2 formed during the reaction. Enantioenriched 3-amino-piperidin-
2-ones can be obtained following a one pot procedure without column purification. Extremely mild deprotection conditions for
trifluoroacetamide endows the current method excellent compatibility with sensitive substrates. Developing more practical, catalyt-
ic, and enantioselective processes for the α-functionalization of inactive carbonyl compounds are in progress.
EXPERIMENTAL SECTION
General Information. All solvents and reagents were used as received without further purification. α,β-Unsaturated aldehydes
1
1
were prepared according to reported procedures. The H and 13C{1H} NMR spectra were recorded at 400 MHz for H and at 101
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MHz for 13C. The chemical shifts (δ) for H and 13C are given in ppm relative to residual signals of the solvents (DMSO-d6 at 2.50
ppm 1H NMR, 39.5 ppm 13C{1H} NMR, Acetone-d6 at 2.05 ppm 1HNMR, 29.92 ppm, 206.68 ppm 13C{1H} NMR). Coupling con-
stants are given in Hz. The following abbreviations are used to indicate the multiplicity: s, singlet; d, doublet; t, triplet; q, quartet; m,
multiplet. Analytical thin layer chromatography (TLC) was performed on pre-coated silica gel plates. The products were purified by
flash chromatography on silica gel (200-300 mesh). Organic solutions were concentrated under reduced pressure using a rotary
evaporator. HPLC analyses on chiral stationary phase were performed on a DAICEL CHIRALPAK AD-H column with n-hexane/i-
PrOH (7/3) as the eluent. Optical rotations were reported as follows: [α] DT(c g/100 mL, solvent). HRMS (ESI or EI) was obtained
with a HRMS instrument (LTQ Orbitrap XL TM).
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Synthesis of TFANHCH2COBt (1c) To a stirring solution of glycine (10 g, 130 mmol) and CH3OH (100 mL) in a 250 mL round
bottom flask, was added Et3N (130 mmol, 18 mL) and ethyl trifluoroacetate (160 mmol, 19 mL) in sequence at room temperature.
After stirring vigorously for three days, the solvent was removed under reduced pressure, and the resulting residue was dissolved in
water (50 mL), acidified with concentrated aqueous hydrochloric acid until a pH of 2 was obtained. The mixture was then extracted
with ethyl acetate (30 mL × 2), and the organic layers were combined. The combined organic layers were washed with brine, dried
over anhydrous Na2SO4, and the solvent was removed under reduced pressure to provide TFANHCH2COOH as a white solid
(18.71 g, 84% yield). Thionyl chloride (4.8 g, 41 mmol) was added to the 1H-benzotriazole (10.4 g, 85 mmol) dissolved in anhy-
drous dichloromethane (100 mL), and the solution was stirred at room temperature for 30 min. After cooling to -10°C,
TFANHCH2COOH (5.0 g, 29 mmol) was added, and the mixture was stirred at 20°C for 2 h. The solvent was removed under re-
duced pressure, and the residue was dissolved in ethyl acetate (50 mL) followed by washing with saturated sodium carbonate (50
mL × 5) and brine (20 mL × 2) and drying with anhydrous Na2SO4. Evaporation of the solvent gave product 1c as a white solid (5.7
g, 72% yield). 1H NMR (400 MHz, DMSO-d6) δ 10.26 (t, J = 5.3 Hz, 1H), 8.23 (d, J = 8.3 Hz, 1H), 8.17 (d, J = 8.2 Hz, 1H), 7.77 (t,
J = 7.6 Hz, 1H), 7.61 (t, J = 7.7 Hz, 1H), 5.16 (d, J = 5.6 Hz, 2H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 167.4, 157.8 (q, J = 36.4
Hz), 145.7, 131.4, 130.9, 127.1, 120.6, 116.3 (q, J = 288.9 Hz), 114.0, 43.2. HRMS (ESI) m/z: [M-H+] Calcd for C10H6F3N4O2
271.0448; Found 271.0454..
General Procedure for the synthesis of 3: To a solution of (S)-Jorgensen-Hayashi catalyst (0.05 mmol, 10% mol) in dry acetone
(1 mL), was added p-methylbenzoic acid (0.05 mmol, 10% mol). The reaction mixture was stirred at room temperature for 30 min.
Then 2a-q (0.5 mmol) and 1c (0.55 mmol, 1.1 eq) were added and the reaction mixture was stirred overnight. The crude residue
was purified by column chromatography to afford the chiral product 3a-q.
(3S,4S,6S)-3-N-TFA-6-(1H-benzo[d][1,2,3]triazol-1-yl)-4-(4-bromophenyl)-tetrahydro-2H-pyran-2-one (3a). Following the
general procedure, 3a was prepared from 2a as white solid (140.4 mg, 58%). 1H NMR (400 MHz, DMSO-d6) δ 9.96 (d, J = 8.5 Hz,
1H), 8.17 (d, J = 8.3 Hz, 1H), 8.10 (d, J = 8.3 Hz, 1H), 7.70 (t, J = 7.5 Hz, 1H), 7.58 (d, J = 7.4 Hz, 3H), 7.52 (t, J = 7.6 Hz, 1H),
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7.42 (d, J = 8.1 Hz, 2H), 5.45–5.34 (m, 1H), 4.07 (m, 1H), 3.33–3.23 (m, 1H), 3.15–3.02 (m, 1H). 13C{1H} NMR (101 MHz,
DMSO-d6) δ 167.3, 156.4 (q, J = 37.37 Hz), 145.1, 139.8, 132.7, 131.5, 130.0, 128.5, 125.0, 120.6, 119.5, 115.6 (q, J = 289.87 Hz),
111.2, 82.2, 53.3, 38.2, 32.1. Mp 145.2-146.0oC. [α]D13 60 (c 0.10, acetone). HRMS (ESI) m/z: [M+H]+ Calcd for C19H15BrF3N4O3
483.0274; Found 483.0277.
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cedure, 3b was prepared from 2b as white amorphous solid (123 mg, 61%). 1H NMR (400 MHz, DMSO-d6) δ 9.92 (d, J = 8.5 Hz,
1H), 8.15 (d, J = 8.3 Hz, 1H), 8.10 (d, J = 8.3 Hz, 1H), 7.68 (t, J = 7.5 Hz, 1H), 7.56– 7.47 (m, 2H), 7.45 (d, J = 7.4 Hz, 2H), 7.35 (t,
J = 7.3 Hz, 2H), 7.27 (t, J = 6.9 Hz, 1H), 5.39 (dd, J = 11.6, 9.0 Hz, 1H), 4.07 (m,1H), 3.33–3.22 (m, 1H), 3.15–3.01 (m, 1H).
13C{1H} NMR (101 MHz, DMSO-d6) δ 167.5, 156.4 (q, J = 37.37 Hz), 145.2, 140.4, 132.8, 128.5, 128.4, 127.6, 127.4, 124.9, 119.4,
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115.6 (q, J = 289.87 Hz), 111.2, 82.3, 53.5, 38.5, 32.4. [α]D -2.8 (c 0.32, acetone). HRMS (ESI) m/z: [M+H]+ Calcd for
C19H16F3N4O3 405.1169; Found 405.1169.
(3S,4S,6(R,S))-3-N-TFA-6-(1H-benzo[d][1,2,3]triazol-1-yl)-4-(2-chlorophenyl)-tetrahydro-2H-pyran-2-one (3c). Following
the general procedure, 3c was prepared from 2c as white solid (135 mg, 62%, diastereomer mixture). 1H NMR (400 MHz, DMSO-
d6) δ 10.16 (d, J = 7.3 Hz, 1H), 8.23 (d, J = 8.4 Hz, 1H), 8.17 (dd, J = 8.3, 2.1 Hz, 1H), 7.89 (d, J = 7.4 Hz, 1H), 7.70 (dd, J = 15.1,
7.1 Hz, 1H), 7.58–7.39 (m, 4H), 7.3–7.29 (m, 1H), 5.59 (dd, J = 11.5, 8.5 Hz, 1H), 4.68 (m, 1H), 3.67 (m, 1H), 2.98 (m, 1H).
13C{1H} NMR (101 MHz, DMSO-d6) δ 167.2, 156.5 (q, J = 37.37 Hz), 145.6, 137.6, 133.4, 132.0, 129.4, 129.0, 128.5, 127.8, 125.0,
119.6, 115.6 (q, J = 289.87 Hz), 111.2, 84.8, 54.5, 36.6, 32.0.
1H NMR (400 MHz, DMSO-d6) δ10.06 (d, J = 8.3 Hz, 1H), 8.17 (dd, J = 8.3, 2.1 Hz, 1H), 8.10 (d, J = 8.4 Hz, 1H), 7.70 (dd, J =
15.1, 7.1 Hz, 2H), 7.58–7.39 (m, 4H), 7.37 –7.29 (m, 1H), 5.15–5.01 (m, 1H), 4.49–4.33 (m, 1H), 3.33–3.21 (m, 1H), 2.69 (m, 1H).
13C{1H} NMR (101 MHz, DMSO-d6) δ 166.4, 156.5 (q, J = 37.37 Hz), 145.2, 137.4, 132.7, 129.6, 129.1, 128.8, 128.4, 127.6, 124.9,
119.4, 115.6 (q, J = 289.87 Hz), 111.1, 82.2, 52.2, 35.2, 31.9.
HRMS (ESI) m/z: [M+H]+ Calcd for C19H15ClF3N4O3 439.0779; Found 439.0770.
(3S,4S,6S)-3-N-TFA-6-(1H-benzo[d][1,2,3]triazol-1-yl)-4-(3-chlorophenyl)-tetrahydro-2H-pyran-2-one (3d). Following the
general procedure, 3d was prepared from 2d as white solid (131.4 mg, 60%). 1H NMR (400 MHz, DMSO-d6) δ 9.97 (d, J = 7.9 Hz,
1H), 8.17 (d, J = 8.2 Hz, 1H), 8.11 (d, J = 8.2 Hz, 1H), 7.70 (t, J = 7.1 Hz, 1H), 7.59 (s, 2H), 7.52 (t, J = 7.2 Hz, 1H), 7.38 (d, J =
10.4 Hz, 3H), 5.63–5.25 (m, 1H), 4.07 (m, 1H), 3.31 (m, 1H), 3.11 (m, 1H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 167.3, 156.4 (q,
J = 37.37 Hz), 145.2, 142.8, 133.2, 132.8, 130.3, 128.4, 127.5, 127.5, 126.7, 124.9, 119.5, 115.6 (q, J = 288.86 Hz), 111.2, 82.2,
53.2, 38.4, 31.9. Mp 175.8-176.4oC. [α]D13 22.0 (c 0.30, acetone). HRMS (ESI) m/z: [M+H]+ Calcd for C19H15ClF3N4O3 439.0779;
Found 439.0783.
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(3S,4S,6S)-3-N-TFA-6-(1H-benzo[d][1,2,3]triazol-1-yl)-4-(4-chlorophenyl)- tetrahydro-2H-pyran-2-one (3e). Following the
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general procedure, 3e was prepared from 2e as white solid (142 mg, 65%). H NMR (400 MHz, DMSO-d6) δ 9.95 (d, J = 8.6 Hz,
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1H), 8.17 (d, J = 8.3 Hz, 1H), 8.10 (d, J = 8.4 Hz, 1H), 7.70 (t, J = 7.6 Hz, 1H), 7.57 (t, J = 5.1 Hz, 1H), 7.53 (d, J = 7.6 Hz, 1H),
7.51–7.43 (m, 4H), 5.39 (dd, J = 12.0, 8.8 Hz, 1H), 4.08 (m, 1H), 3.27 (m, 1H), 3.09 (m, 1H). 13C{1H} NNMR (101 MHz, DMSO-
d6) δ 167.3, 156.4 (q, J = 37.37 Hz), 145.2, 139.3, 132.7, 132.1, 129.6, 128.5, 128.4, 124.9, 119.5, 115.6 (q, J = 288.86 Hz), 111.2,
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82.2, 53.3, 38.1, 32.1. Mp 234.4-234.5oC. [α]D -4.4 (c 0.25, acetone). HRMS (ESI) m/z: [M+H]+: Calcd for C19H15ClF3N4O3
439.0779; Found 439.0780.
(3S,4S,6S)-3-N-TFA-6-(1H-benzo[d][1,2,3]triazol-1-yl)-4-(3-cyanopheny)-tetrahydro-2H-pyran-2-one (3f). Following the
general procedure, 3f was prepared from 2f as white amorphous solid (134 mg, 62%). 1H NMR (400 MHz, DMSO-d6) δ 10.01 (d, J
= 7.9 Hz, 1H), 8.17 (d, J = 8.3 Hz, 1H), 8.12 (d, J = 8.3 Hz, 1H), 8.01 (s, 1H), 7.77 (t, J = 7.9 Hz, 2H), 7.74–7.68 (m, 1H), 7.65 (m,
1H), 7.59 (t, J = 7.7 Hz, 1H), 7.52 (t, J = 7.5 Hz, 1H), 5.53–5.40 (m, 1H), 4.11 (m, 1H), 3.38 (m, 1H), 3.13 (m, 1H). 13C{1H}
NNMR (101 MHz, DMSO-d6) δ 167.2, 156.4 (q, J = 36.36 Hz), 145.2, 141.9, 133.2, 132.8, 131.4, 131.3, 129.8, 128.4, 124.7,
119.5, 118.7, 115.6 (q, J = 289.87 Hz), 111.6, 111.1, 82.1, 53.1, 38.4, 31.8. [α]D14 11.3 (c 0.31, acetone). HRMS (ESI) m/z: [M+H]+
Calcd for C20H15F3N5O3 430.1122; Found 430.1117.
(3S,4S,6S)-3-N-TFA-6-(1H-benzo[d][1,2,3]triazol-1-yl)-4-(4-cyanopheny)-tetrahydro-2H-pyran-2-one (3g). Following the
general procedure, 3g was prepared from 2g as white amorphous solid (133 mg, 62%). 1H NMR (400 MHz, DMSO-d6) δ 9.98 (d, J
= 8.6 Hz, 1H), 8.17 (d, J = 8.3 Hz, 1H), 8.11 (d, J = 8.3 Hz, 1H), 7.89 (d, J = 8.1 Hz, 2H), 7.70 (dd, J = 17.0, 7.9 Hz, 3H), 7.61 (t, J
= 5.1 Hz, 1H), 7.53 (t, J = 7.7 Hz, 1H), 5.48 (dd, J = 12.1, 8.8 Hz, 1H), 4.20 (m, 1H), 3.38–3.34 (m, 1H), 3.14 (m, 1H). 13C{1H}
NNMR (101 MHz, DMSO-d6) δ 167.1, 156.4 (q, J = 36.36 Hz), 145.9, 145.1, 132.7, 132.5, 128.9, 128.4, 124.9, 119.4, 118.6, 115.5
(q, J = 289.87 Hz), 111.1, 110.4, 82.1, 52.9, 38.8, 31.8. [α]D 36.7 (c 0.27, acetone). HRMS (ESI) m/z: [M+H]+ Calcd for
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C20H15F3N5O3 430.1122; Found 430.1113.
(3S,4S,6S)-3-N-TFA-6-(1H-benzo[d][1,2,3]triazol-1-yl)-4-(4-nitrophenyl)-tetrahydro-2H-pyran-2-one (3h). Following the
general procedure, 3h was prepared from 2h as white solid (120 mg, 53%). 1H NMR (400 MHz, DMSO-d6) δ 10.02 (d, J = 8.2 Hz,
1H), 8.27 (d, J = 8.5 Hz, 2H), 8.19 (d, J = 12.4 Hz, 1H), 8.11 (d, J = 8.3 Hz, 1H), 7.81–7.72 (m, 3H), 7.62 (t, J = 5.0 Hz, 1H), 7.53
(t, J = 7.6 Hz, 1H), 5.52 (dd, J = 11.6, 8.3 Hz, 1H), 4.27 (m 1H), 3.33–3.26 (m, 1H), 3.16 (m, 1H). 13C{1H} NNMR (101 MHz,
DMSO-d6) δ 167.0, 156.4 (q, J = 37.37 Hz), 148.0, 146.9, 145.1, 132.7, 129.2, 128.5, 124.9, 123.7, 119.5, 115.5 (q, J = 288.86 Hz),
111.1, 82.2, 52.9, 38.6, 31.8. Mp 117.7-119.4oC. [α]D 27.3 (c 0.22, acetone). HRMS (ESI) m/z: [M+H]+ Calcd for C19H15F3N5O5
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450.1020; Found 450.1018.
(3S,4S,6S)-3-N-TFA-6-(1H-benzo[d][1,2,3]triazol-1-yl)-4-([1,1'-biphenyl]-4-yl)tetrahydro-2H-pyran-2-one (3i). Following the
general procedure, 3i was prepared from 2i as white solid (107 mg, 45%). 1H NMR (400 MHz, DMSO-d6) δ 9.98 (d, J = 8.5 Hz,
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1H), 8.16 (d, J = 8.3 Hz, 1H), 8.11 (d, J = 8.3 Hz, 1H), 7.68 (m, 5H), 7.59 (t, J = 4.9 Hz, 1H), 7.54 (d, J = 8.1 Hz, 2H), 7.49 (d, J =
7.6 Hz, 1H), 7.44 (t, J = 7.5 Hz, 2H), 7.33 (t, J = 7.2 Hz, 1H), 5.44 (dd, J = 11.6, 9.0 Hz, 1H), 4.15 (m, 1H), 3.31 (m, 1H), 3.13 (m,
1H). 13C{1H} NNMR (101 MHz, DMSO-d6) δ 167.5, 156.5 (q, J = 36.36 Hz), 145.2, 139.7, 139.6, 139.2, 132.8, 128.9, 128.4,
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128.3, 127.5, 126.8, 126.6, 124.9, 119.5, 115.7 (q, J = 289.87 Hz), 111.2, 82.3, 53.5, 38.2, 32.4. Mp 211.0-212.9oC. [α]D 5.9 (c
0.29, acetone). HRMS (ESI) m/z: [M+H]+ Calcd for C25H20F3N4O3+ 481.1482; Found 481.1489.
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(3S,4S,6S)-3-N-TFA-6-(1H-benzo[d][1,2,3]triazol-1-yl)-4-(4-methoxyphenyl)tetrahydro-2H-pyran-2-one (3j). Following the
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general procedure 3j was prepared from 2j as white solid (121 mg, 56%). H NMR (400 MHz, DMSO-d6) δ 9.91 (d, J = 8.6 Hz,
1H), 8.17 (d, J = 8.3 Hz, 1H), 8.11 (d, J = 8.3 Hz, 1H), 7.70 (t, J = 7.6 Hz, 1H), 7.54 (m, 2H), 7.38 (d, J = 8.5 Hz, 2H), 6.93 (d, J =
8.5 Hz, 2H), 5.34 (dd, J = 11.6, 8.9 Hz, 1H), 4.03 (m, 1H), 3.74 (s, 3H), 3.30–3.21 (m, 1H), 3.07 (m, 1H). 13C{1H} NNMR (101
MHz, DMSO-d6) δ 167.6, 158.5, 156.4 (q, J = 37.37 Hz), 145.2, 132.8, 132.3, 128.7, 128.4, 124.9, 119.4, 115.6 (q, J = 288.86 Hz),
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113.9, 111.2, 82.3, 55.1, 53.7, 37.8, 32.6. Mp 168.2-170.3oC. [α]D 6.6 (c 0.35, acetone). HRMS (ESI) m/z: [M+H]+ Calcd for
C20H18F3N4O4 435.1275; Found 435.1272.
(3S,4S,6S)-3-N-TFA-6-(1H-benzo[d][1,2,3]triazol-1-yl)-4-(4-(naphthalen-2-yloxy)phenyl)tetrahydro-2H-pyran-2-one
(3k).
Following the general procedure 3k was prepared from 2k as white solid (140 mg, 51%). 1H NMR (400 MHz, DMSO-d6) δ 9.95 (d,
J = 8.7 Hz, 1H), 8.16 (d, J = 8.4 Hz, 1H), 8.10 (d, J = 8.4 Hz, 1H), 7.94 (d, J = 8.6 Hz, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.74–7.65 (m,
2H), 7.58 (s, 1H), 7.53–7.39 (m, 5H), 7.28 – 7.26 (d, J = 8.0 Hz, 2H), 7.10 (d, J = 8.6 Hz, 2H), 5.40 (dd, J = 12.0, 8.8 Hz, 1H),
4.14–4.00 (m, 1H), 3.32 (m, 1H), 3.14 (m 1H). 13C{1H} NNMR (101 MHz, DMSO-d6) δ 167.5, 156.4 (q, J = 37.37 Hz), 155.6,
154.9, 145.2, 135.8, 133.9, 132.8, 130.1, 129.7, 129.5, 128.4, 127.7, 126.9, 126.7, 124.9, 124.8, 119.5, 119.3, 115.7 (q, J = 288.86
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Hz), 113.1, 111.2, 82.3, 53.7, 38.1, 32.1. Mp 112.6-113.4oC. [α]D 49.6 (c 0.25, acetone). HRMS (ESI) m/z: [M+H]+ Calcd for
C29H22F3N4O4 547.1588; Found 547.1587.
(3S,4S,6S)-3-N-TFA-6-(1H-benzo[d][1,2,3]triazol-1-yl)-4-(3,4-dichlorostyryl)-tetrahydro-2H-pyran-2-one (3l). Following the
general procedure 3l was prepared from 2l as white solid (127 mg, 51%). 1H NMR (400 MHz, DMSO-d6) δ 10.03 (d, J = 8.1 Hz,
1H), 8.16 (d, J = 8.4 Hz, 1H), 8.07 (d, J = 8.2 Hz, 1H), 7.74–7.66 (m, 2H), 7.61 (d, J = 8.3 Hz, 1H), 7.55 – 7.47 (m, 2H), 7.39 (d, J
= 8.1 Hz, 1H), 6.55 (d, J = 15.8 Hz, 1H), 6.44 (dd, J = 15.9, 8.4 Hz, 1H), 5.19–4.92 (m, 1H), 3.54 (m,1H), 3.21 (m, 1H), 2.85 (m,
1H). 13C{1H} NNMR (126 MHz, DMSO-d6) δ 166.9, 156.4 (q, J = 37.37 Hz), 145.1, 137.3, 132.6, 131.7, 131.4, 130.8, 129.9,
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129.3, 128.5, 127.8, 126.3, 124.9, 119.5, 115.7 (q, J = 288.86 Hz), 111.0, 81.9, 52.0, 37.1, 30.7. Mp 177.7-179.1oC. [α]D 4.3 (c
0.30, acetone). HRMS (ESI) m/z: [M+H]+ Calcd for C21H16Cl2F3N4O3 499.0546; Found 499.0541.
(3S,4S,6S)-3-N-TFA-6-(1H-benzo[d][1,2,3]triazol-1-yl)-4-(3,4-dichlorophenyl)-tetrahydro-2H-pyran-2-one (3m). Following
the general procedure 3m was prepared from 2m as white solid (105 mg, 44%). 1H NMR (400 MHz, DMSO-d6) δ 10.01 (d, J = 8.6
Hz, 1H), 8.18 (d, J = 8.4 Hz, 1H), 8.13 (d, J = 8.4 Hz, 1H), 7.81 (s, 1H), 7.76–7.61 (m, 3H), 7.54 (t, J = 7.6 Hz, 1H), 7.46 (dd, J =
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8.4, 1.9 Hz, 1H), 5.46 (dd, J = 12.1, 8.7 Hz, 1H), 4.18–4.06 (m, 1H), 3.34 (m, 1H), 3.14 (m, 1H). 13C{1H} NNMR (101 MHz,
DMSO-d6) δ 167.1, 156.5 (q, J = 36.36 Hz), 145.2, 141.4, 132.8, 131.2, 130.6, 130.1, 129.8, 128.4, 128.4, 124.9, 119.4, 115.6 (q, J
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= 288.86 Hz), 111.1, 82.1, 53.1, 38.0, 31.8. Mp 226.2-228.4oC. [α]D 43.3 (c 0.30, acetone). HRMS (ESI) m/z: [M+H]+ Calcd for
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C19H14Cl2F3N4O3 473.0390; Found 473.0384.
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(3S,4S,6S)-3-N-TFA-6-(1H-benzo[d][1,2,3]triazol-1-yl)-4-(3,5-dichlorophenyl)-tetrahydro-2H-pyran-2-one (3n). Following
the general procedure 3n was prepared from 2n as white solid (115 mg, 49%). 1H NMR (400 MHz, DMSO-d6) δ 9.98 (d, J = 8.2 Hz,
1H), 8.12 (dd, J = 19.0, 8.2 Hz, 2H), 7.68-7.62 (m, 2H), 7.51 (dd, J = 15.2, 7.9 Hz, 4H), 5.51–5.39 (dd, J = 12.1, 8.7 Hz, 1H), 4.05
(m, 1H), 3.38 (m, 1H), 3.10 (m, 1H). 13C{1H} NNMR (101 MHz, DMSO-d6) δ 167.6, 156.9 (q, J = 37.37 Hz), 145.6, 144.9, 134.6,
133.2, 128.9, 127.7, 127.3, 125.4, 119.9, 115.6 (q, J = 288.86 Hz), 111.6, 82.5, 53.5, 38.8, 32.0. Mp 235.0-236.6oC. [α]D14 30.0 (c
0.30, acetone). HRMS (ESI) m/z: [M+H]+ Calcd for C19H14Cl2F3N4O3 473.0390; Found 473.0394.
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(3S,4S,6S)-3-N-TFA-6-(1H-benzo[d][1,2,3]triazol-1-yl)-4-(3,5-bis(trifluoromethyl)-henyl)tetrahydro-2H-pyran-2-one
(3o).
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Following the general procedure 3o was prepared from 2o as white solid (148 mg, 55%). H NMR (400 MHz, DMSO-d6) δ 10.03
(d, J = 8.6 Hz, 1H), 8.18 (s, 3H), 8.14 (d, J = 8.4 Hz, 1H), 8.06 (s, 1H), 7.71 (dd, J = 14.6, 6.7 Hz, 2H), 7.54 (t, J = 7.6 Hz, 1H),
5.56 (dd, J = 11.8, 9.0 Hz, 1H), 4.27 (dd, J = 19.8, 8.5 Hz, 1H), 3.47 (m, 1H), 3.30–3.20 (m, 1H). 13C{1H} NNMR (101 MHz,
DMSO-d6) δ167.0, 156.4 (q, J = 37.37 Hz ), 145.2, 143.4, 132.7, 130.4 (q, J = 33.33 Hz), 129.08, 128.5, 124.8 (q, J = 37.37 Hz),
121.9, 121.4, 119.5, 115.5 (q, J = 288.86 Hz), 111.1, 82.0, 52.9, 38.6, 31.1. Mp 221.6-223.0oC. [α]D14 42.4 (c 0.34, acetone). HRMS
(ESI) m/z: [M+H]+ Calcd for C21H14F9N4O3 541.0917; Found 541.0911.
(3S,4R,6S)-3-N-TFA-6-(1H-benzo[d][1,2,3]triazol-1-yl)-4-(furan-2-yl)tetrahydro-2H-pyran-2-one (3p). Following the general
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procedure 3p was prepared from 2p as white solid (106.4 mg, 54%). H NMR (400 MHz, DMSO-d6) δ 10.04 (d, J = 8.5 Hz, 1H),
8.16 (d, J = 8.4 Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.69 (t, J = 7.7 Hz, 1H), 7.63 (d, J = 1.2 Hz, 1H), 7.54–7.43 (m, 2H), 6.43 (dd, J
= 3.2, 1.9 Hz, 1H), 6.35 (d, J = 3.2 Hz, 1H), 5.29 (dd, J = 11.6, 8.5 Hz, 1H), 4.20 (m, 1H), 3.30 (m, 1H), 3.05 (m, 1H). 13C{1H}
NNMR (101 MHz, DMSO-d6) δ 166.8, 156.4 (q, J = 37.37 Hz), 153.1, 145.2, 142.8, 132.7, 128.5, 125.0, 119.5, 115.7 (q, J =
288.86 Hz), 111.1, 110.5, 106.7, 81.9, 51.9, 32.8, 30.1. Mp 191.9-193.1oC. [α]D13 -1.3 (c 0.23, acetone). HRMS (ESI) m/z: [M+H]+
Calcd for C17H14F3N4O4 395.0962; Found 395.0963.
(3S,4S,6S)-3-N-TFA-6-(1H-benzo[d][1,2,3]triazol-1-yl)-4-(ferrocenyl)tetrahydro-2H-pyran-2-one (3q). Following the general
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procedure 3q was prepared from 2q as white solid (69 mg, 27%). H NMR (400 MHz, Acetone-d6) δ 8.95 (d, J = 8.5 Hz, 0.5H),
8.13 (d, J = 8.3 Hz, 1H), 8.04 (d, J = 8.3 Hz, 1H), 7.68 (t, J = 7.7 Hz, 1H), 7.53 (t, J = 7.7 Hz, 1H), 7.46 (t, J = 4.9 Hz, 1H), 4.89–
4.76 (m, 1H), 4.37 (d, J = 30.6 Hz, 2H), 4.25 (s, 5H), 4.19 (d, J = 12.6 Hz, 2H), 3.90–3.77 (m, 2H), 3.33 (m, 1H). 13C{1H} NNMR
(101 MHz, Acetone-d6) δ 166.7, 157.0 (q, J = 36.36 Hz), 146.2, 133.4, 128.6, 125.0 119.9, 116.3 (q, J = 287.85 Hz), 111.1, 88.3,
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83.2, 69.1, 68.8, 68.3, 68.0, 65.4, 55.6, 34.2, 32.0. Mp 150.0-151.1oC. [α]D13 -1.3 (c 0.23, acetone). HRMS (ESI) m/z: [M+H]+
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Calcd for C23H20F3FeN4O3 513.0831; Found 513.0834.
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Synthesis of chiral substituted 3-amino piperidin-2-ones (5i): Into a 25 mL round bottom flask were placed 3i (66 mg, 0.14
mmol) and a solution of NH3/CH3OH (2 M, 5 mL). The mixture was stirred at room temperature for 2h, then the solvent was re-
moved under reduced pressure to provide crude 4i, which was re-dissolved in 5 mL CH2Cl2. The solution was cooled to −10 ℃,
Et3SiH (9.3 mmol, 1.5 mL) and BF3OEt2 (8 mmol, 1 mL) were added dropwise in sequence. After the consumption of the starting
material (monitored by TLC), the reaction was quenched with saturated aqueous Na2CO3 (20 mL). The organic layer was separated,
and the aqueous layer was extracted with ethyl acetate (10 mL × 3). The combined organic extracts were dried over Na2SO4. After
removal of solvent the residue was chromatographed on silica gel (CH2Cl2/CH3OH=50/1) to give 5i (40 mg, 0.11 mmol) as a white
solid in 80% yield and 97% ee. 1H NMR (400 MHz, DMSO-d6) δ 9.50 (d, J = 8.8 Hz, 1H), 7.90 (s, 1H), 7.65 (d, J = 7.3 Hz, 2H),
7.60 (d, J = 8.2 Hz, 2H), 7.45 (t, J = 7.6 Hz, 2H), 7.38–7.32 (m, 3H), 4.43 (dd, J = 11.4, 9.0 Hz, 1H), 3.32–3.16 (m, 3H), 2.27 (qd, J
= 12.8, 5.8 Hz, 1H), 1.95 (t, J = 12.5 Hz, 1H). 13C{1H} NNMR (101 MHz, DMSO-d6) δ167.8, 156.1 (q, J = 36.36 Hz), 141.2,
139.7, 138.4, 128.9, 127.9, 127.3, 126.5, 126.4, 115.8 (q, J = 289.87 Hz), 54.9, 42.7, 40.6, 29.1. Mp 202.5-204.5oC. [α]D13 -71.2 (c
0.38, CH3OH). HRMS (ESI) m/z: [M+H]+ Calcd for C19H18F3N2O2 363.1315; Found 363.1310.
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Synthesis of chiral substituted 3-amino piperidin-2-ones (5c): Into a 25 mL round bottom flask were placed 3c (80 mg, 0.18
mmol) and a solution of NH3/CH3OH (2 M, 5 mL). The mixture was stirred at room temperature for 2h, then the solvent was re-
moved under reduced pressure to provide crude 4c, which was re-dissolved in 5 mL CH2Cl2. The solution was cooled to −10 ℃,
Et3SiH (9.3 mmol, 1.5 mL) and BF3OEt2 (8 mmol, 1 mL) were added dropwise in sequence. After the consumption of the starting
material (monitored by TLC), the reaction was quenched with saturated aqueous Na2CO3 (20 mL). The organic layer was separated,
and the aqueous layer was extracted with ethyl acetate (10 mL × 3). The combined organic extracts were dried over Na2SO4. After
removal of solvent the residue was washed with minimum amount of dichloromethane to afford pure 5c as a white powder (40 mg)
in 70% yield and ˃ 99% ee. 1H NMR (400 MHz, CDCl3) δ 7.38 (d, J = 8.0 Hz, 1H), 7.31 (dt, J = 15.1, 6.8 Hz, 2H), 7.24–7.19 (m,
1H), 7.00 (d, J = 8.5 Hz, 1H), 6.42 (s, 1H), 4.72–4.57 (m, 1H), 3.86 (m, 1H), 3.63–3.51 (m, 1H), 3.51–3.42 (m, 1H), 2.21 (m, 2H).
13C{1H} NNMR (101 MHz, CDCl3) δ 169.3, 157.6 (q, J = 38.38 Hz), 137.3, 133.9, 129.9, 128.8, 127.6, 127.5, 115.6 (q, J =
13
289.87 Hz), 55.0, 41.3, 40.0, 28.9. Mp 189.4-190.4oC. [α]D -71.2 (c 0.38, CH3OH). HRMS (ESI) m/z: [M+H]+ Calcd for
C13H13ClF3N2O2 321.0612; Found 321.0607..
Deprotection procedure: method A: To a 25 mL round bottom flask, was added 5i (80 mg, 0.22 mmol, 96% ee), K2CO3 (3
equiv.), methanol (3 mL) and H2O (0.5 mL). The resulting solution was stirred at 70℃ for 12 hours. After cooling to room tempera-
ture and removing solvent, the reaction was diluted with dichloromethane (80 mL), washed with brine (10 mL × 2) and dried over
anhydrous Na2SO4. Evaporation of the solvent gave (3S,4S)-4-([1,1'-biphenyl]-4-yl)-3-aminopiperidin-2-one as a white solid (40
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mg, 67% yield, 83% ee). Method B: 5i (10 mg, 0.028 mmol) was dissolved in CH3OH (0.6 mL) and concentrated HCl (0.5
mL).The resulting solutions were then stirred at 70℃ for 5 hours. After cooling to room temperature and removing solvent, the
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mixture was extracted with dichloromethane (3 mL × 3) and saturated sodium bicarbonate (4 mL). The combined organic layers
were washed with brine, dried (Na2SO4) and the solvent was removed under reduced pressure to provide (3S,4S)-4-([1,1'-biphenyl]-
4-yl)-3-aminopiperidin-2-one (˃99% ee).
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1HNMR (400 MHz, MeOD) δ 7.66-7.60 (m, 4H), 7.43 (dd, J = 15.4, 7.7 Hz, 4H), 7.38–7.30 (m, 1H), 3.66 (d, J = 10.6 Hz, 1H),
3.51-3.36 (m, 2H), 2.96 (t, J = 10.3Hz, 1H), 2.21 (m 1H), 2.01 (d, J = 13.5Hz, 1H). 13C{1H} NNMR (101 MHz, MeOD) δ 173.4,
141.2, 140.5, 139.9, 128.4, 127.4, 127.0, 126.9, 126.4, 55.7, 45.9, 40.9, 29.1. HRMS (EI) m/z: [M] + Calcd for C17H18N2O 266.1419;
Found 266.1422.
SUPPORTING INFORMATION
1HNMR and 13CNMR spectra; HPLC for all new compounds and X-ray Crystallographic Data of 3q.
ACCESSION CODES
CCDC 1912111 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from
http://www.ccdc.cam.ac.uk/data_request/cif, by contacting data_ request@ccdc.cam.ac.uk, or by contacting The Cambridge Crystallo-
graphic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
* E-mail: song-ym@dlut.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work was financially supported by the Natural Science Foundation of Liaoning Province (No. ZX20160447). We thank Mr. Zuoquan
Wang, Dr. Hengyuan Lang, Prof. Baomin Wang, Prof. Yi Luo, Prof. Yuhan Zhou, and Prof. Ying Peng for valuable discussions. The au-
thors would also like to thank Dr. Huihui Wan at the Analytical Center of the Dalian University of Technology for assistance obtaining
LC-MS data.
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