Dual-reagent organophosphine catalyzed asymmetric Mannich reactions of isocyanoacetates with N-Boc-aldimines

Article abstract of DOI:10.1016/j.tet.2017.08.031

A combination of an amino-acid derived chiral phosphine catalyst and methyl acrylate has been employed to catalyze the direct Mannich reaction of α-aryl isocyanoacetate and N-Boc-aldimines efficiently. The loading of the catalyst could be as low as 0.5 mol% without compromise on the yield and enantioselectivity and the corresponding chiral adducts were obtained in excellent yields (up to 98%) and good enantioselectivities (up to 95%).

Full text of DOI:10.1016/j.tet.2017.08.031

Accepted Manuscript
Dual-reagent organophosphine catalyzed asymmetric Mannich reactions of
isocyanoacetates with N-Boc-aldimines
Xiong Ji, Wei-Guo Cao, Gang Zhao
PII:
S0040-4020(17)30869-4
10.1016/j.tet.2017.08.031
TET 28925
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 30 June 2017
Revised Date: 14 August 2017
Accepted Date: 18 August 2017
Please cite this article as: Ji X, Cao W-G, Zhao G, Dual-reagent organophosphine catalyzed asymmetric
Mannich reactions of isocyanoacetates with N-Boc-aldimines, Tetrahedron (2017), doi: 10.1016/
j.tet.2017.08.031.
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ACCEPTED MANUSCRIPT
Dual-reagent Organophosphine Catalyzed Asymmetric Mannich
Reaction of Isocyanoacetates with N-Boc-aldimines
，
b
Xiong Jia, Weiguo Cao*, a and Gang Zhao*
a Department of Chemistry, Innovative Drug Research Center, Shanghai University, Shanghai 200444,
People’s Republic of China
Fax: (+86)-21-6613-4856; e-mail: wgcao@staff.shu.edu.cn
b
Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, People’s Republic of
China
Fax: (+86)-21-6416-6128; e-mail: zhaog@sioc.ac.cn

ACCEPTED MANUSCRIPT
Dual-reagent Organophosphine Catalyzed Asymmetric Mannich Reactions of
Isocyanoacetates with N-Boc-aldimines
Xiong Jia, Wei-Guo Caoa, , Gang Zhaob,
aDepartment of Chemistry, Innovative Drug Research Center, Shanghai University, Shanghai 200444 (P. R. China)
bKey Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Science, 345 Lingling Road,
Shanghai, 200032 (P. R. China)
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A combination of an amino-acid derived chiral phosphine catalyst and methyl acrylate has been
employed to catalyze the direct Mannich reaction of α-aryl isocyanoacetate and N-Boc-aldimines
efficiently. The loading of the catalyst could be as low as 0.5 mol% without compromise on the yield
and enantioselectivity and the corresponding chiral adducts were obtained in excellent yields (up to
98%) and good enantioselectivities (up to 95%).
Available online
Keywords:
Organophosphine
Dual-reagent catalysis
Isocyanoacetates
Mannich reaction
1. Introduction
Trivalent phosphine that possessed the characteristic of powerful nucleophilicity and Lewis base, is widely used in organocatalysis.1
Over the past few decades, most of the organic phosphine-catalyzed asymmetric reactions essentially proceeded to combine phosphine
with electron-deficient alkene, giving rise to a zwitterion which subsequently reacts with an appropriate reactant such as alkene (the
Rauhut-Currier reaction),2 allene (cycloaddition),3 or aldehyde (the Mortia-Baylis-Hillman reaction).4 To overcome the limitation of
this general catalysis mode, our group has developed dual-reagent catalysis strategy, which utilized the oxygen anion of zwitterion
formed from the phosphine catalyst and methyl acrylate as a Brønsted base or a Lewis base to catalyze related Mannich reactions5 or
Strecker reactions.6 As a new catalytic strategy, exploring the applicability of this model becomes very important.
Isocyanide is a versatile reagent for heterocyclic synthesis.7 Recently, the asymmetric additions of isocyanoacetates to carbon-carbon
double bonds,8 carbon-heteroatom multiple bonds9 and other electrophiles such as azodicarboxylates10 have provided efficient ways to
prepare a wide range of optically active heterocyclic compounds. In addition, multicomponent reactions with isocyanoacetate
derivatives have also been used for synthesis of varieties of peptides and peptide mimetics11. In the majority of the asymmetric addition
reactions, chiral ligands and metals have cooperatively catalyzed the reaction of isocyanoacetates to afford excellent results. However,
in the absence of metals, the reaction of α-phenylisocyanoacetates with aldimine still remains an unexplored area.9b, 9e Herein, we wish
to report our preliminary findings on this reaction via the dual-reagent catalysis.
2. Results and discussion
In a model investigation, the reaction between α-phenylisocyanoacetate (1a) and N-Boc-benzaldimine (2a) was evaluated in the
presence of dual-reagent catalysts in toluene at room temperature (table 1). The thiourea hydrogen-bonding vs amide N-H and urea
(table 1, entries 1-3) gave better results with the catalyst 4c used, which quickly afford the corresponding addition product 3a and the
diastereomers 3aʹ in high yields and moderate enantioselectivity (97% yield, 75%, 76% ee, 79:21 dr, table 1, entry 3). Next, another
chiral phosphine catalysts derived from isoleucine were evaluated. Unfortunately, catalyst 4d afforded poor results on the
enantioselectivity (table 1, entry 4). Based on our previous studies,5, 6 the acidity of hydrogen bonding played an important role in the
enantioselectivity control. Thus we then examined the electronic effect of phenyl group on thiourea moiety (table 1, entries 5-8), but no
improved results were obtained. With catalyst 4c as the optimal, the effect of solvents was investigated. It was notable that toluene was
still the best (table 1, entries 9-14). Reactions run at lower temperature (i.e. -30 or -50 ˚C) delivered higher enantioselectivities (table 1,
entries 15-17).
———
Corresponding author.
zhaog@sioc.ac.cn (G. Zhao)
Corresponding author.
wgcao@staff.shu.edu.cn (W. Cao)
1

ACCEPTED MANUSCRIPT
Given the dual-reagent catalysis is highly effective, we tried to lower the catalyst loading of 4c from 5 mol% down to 0.5 mol% and
0.1%, and to our delight, the product could also be obtained in excellent enantioselectivity (83, 93%) although extension of reaction
time is required (table 1, entries 18 and 19). Considering 2 hours are reasonable time for this reaction, we then use 0.5 mol% of catalyst
4c in toluene at -30 as the optimal reaction condition for this Mannich reaction.
Table 1 Screening of the reaction conditions a
cat. 4 (5 mol%)
methyl acrylate (5 mol%)
NC
CO2Me
NBoc
H
NHBoc
Ph
H
NHBoc
Ph
Ph
Ph
+
+
solvent, T
CN CO2Me
MeO2C NC
3 (a+a')
1a
2a
PPh2
PPh2
S
PPh2
O
PPh2
S
HN
HN
X
HN
HN
HN
HN
HN
CF3
CF3
R
F3C
CF3
4e: R = C6H5
CF3
CF3
4f: R = 4-CH3C6H4
4g: R = 4-NO2C6H4
4h: R = 4-CF3C6H4
4a
4d
4b: X = O
4c: X = S
Entry
1
2
3
4
5
6
7
8
Catatlyst
4a
4b
4c
Solvent
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
CH2Cl2
THF
Temperature/( )
Time
3 h
Yield b (%)
dr c
ee c (%)
18, -18
48, 60
75, 76
48, 34
45, 27
32, 73
75, 70
67, 61
18, 19
Racemic
0, -14
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
95
95
97
87
97
96
92
95
89
68
84
71
82
74
92
95
92
98
98
2.8:1
3.8:1
3.8:1
3.8:1
2.7:1
2.7:1
5.2:1
4.9:1
1:1.3
1:1.8
1.4:1
1:1
1.5:1
2.8:1
2.4:1
3.3:1
3.3:1
3.3:1
3.3:1
15 min
5 min
5 min
30 min
1 h
5 min
5 min
5 min
1 h
20 min
20 min
10 min
10 min
15 min
20 min
30 min
2 h
4d
4e
4f
4g
4h
4c
4c
4c
4c
4c
4c
4c
4c
4c
4c
4c
9
10
11
12
13
14
15
16
17
18d
19e
acetonitrile
ethyl acetate
fluorobenzene
mesitylene
toluene
5, -10
56, 70
69, 72
72, 82
79, 92
77, 93
83(93)f, 93
82, 93
rt
-10
-30
-50
-30
-30
toluene
toluene
toluene
toluene
20 h
a Unless otherwise specified, all reactions were carried out with α-phenylisocyanoacetates 1a (0.1 mmol) and imines 2a
(0.20 mmol) in the presence of methyl acrylate (5 mol%) and catalyst 4 (5 mol%) in solvent (1.0 mL).
b Isolated yield.
c Determined by chiral HPLC analysis.
d 0.5 mol% of methyl acrylate and catalyst 4c were used.
e 0.1 mol% of methyl acrylate and catalyst 4c were used.
f In brackets, enantiomeric excess after recrystallization from ethanol/n-pentane
With the optimized conditions established, the scope of the reaction with respect to isocyanoacetates was investigated. As
summarized in table 2, isocyanoacetates 1b-1h with N-Boc-benzaldimine 2a could be smoothly converted into the corresponding
products in good yields, moderate diastereoselectivities and good enantioselectivities (up to 98% yield, 2.5 : 1 dr, 93% ee; Table 2
entries 1-7). We found that α-phenylisocyanoacetates with an electron-donating group on the phenyl were better than that with
electron-withdrawing groups on the enantioselectivity. Isocyanoacetates 1i-1k with different ester substituents subjected to this
reaction also gave the product 3i-3k (table 2 entries 8-10), respectively, with good yields (up to 98%) and good ee values (up to 93%).
An improved diastereoselectivity (dr 1 : 9, table 2, and entry 9) was obtained with tert-butyl 2-isocyano-2-phenylacetate (1j) probably
due to the large steric resistance reasons and the reaction time was extended to 40 hours.
Table 2 Substrate Scope of Isocyanoacetates 1 and N-Boc-aldimines 2 in the Asymmetric Mannich Reaction a
2

ACCEPTED MANUSCRIPT
Entry
1
2
3
4
5
6
7
1 (Ar1/R)
2 (Ar2)
3/3ʹ
Time (h)
Yield b (%)
91
dr c
2.3:1
1.8:1
2:1
1.5:1
2:1
2.3:1
2.5:1
4:1
9:1
3:1
1.3:1
2:1
2:1
1.8:1
2:1
1.1:1
1.2:1
2:1
1.2:1
1.4:1
2:1
ee d (%)
79, 92
82, 93
80, 88
81, 92
82, 87
72, 82
79, 81
93, 89
91, 70
92, 85
72, 89
81, 89
75, 91
82, 93
82, 93
82, 93
80, 94
68, 95
64, 90
52, 80
50, 79
1b (3-MeC6H4/Me)
1c (4-MeC6H4/Me)
1d (3-MeOC6H4/Me) 2a (Phenyl)
1e (4-MeOC6H4/Me)
1f (4-FC6H4/Me)
1g (4-ClC6H4/Me)
1h (4-BrC6H4/Me)
1i (Phenyl/Bn)
1j (Phenyl/t-Bu)
1k (Phenyl/i-Pr)
1a (Phenyl/Me)
1a (Phenyl/Me)
1a (Phenyl/Me)
1a (Phenyl/Me)
1a (Phenyl/Me)
1a (Phenyl/Me)
1a (Phenyl/Me)
1a (Phenyl/Me)
1a (Phenyl/Me)
1a (Phenyl/Me)
1a (Phenyl/Me)
2a (Phenyl)
2a (Phenyl)
3b/3bʹ
3c/3cʹ
3d/3dʹ
3e/3eʹ
3f/3fʹ
3g/3gʹ
3h/3hʹ
3i/3iʹ
4
4
2
4
1
1
1
3
40
35
2
2
2
2
2
2
2
94
92
98
95
98
98
95
98
96
98
85
88
94
96
97
92
2a (Phenyl)
2a (Phenyl)
2a (Phenyl)
2a (Phenyl)
2a (Phenyl)
2a (Phenyl)
2a (Phenyl)
2b (3-MeC6H4)
2c (4-MeC6H4)
2d (3-MeOC6H4)
2e (4-MeOC6H4)
2f (4-FC6H4)
2g (4-ClC6H4)
2h (4-BrC6H4)
2i (4-NO2C6H4)
2j (3-BrC6H4)
2k (2-furanyl)
2l (2-thienyl)
8 d
9 d
10 d
11
12
13
14
15
16
17
18
19
20 d
21 d
3j/3jʹ
3k/3kʹ
3l/3lʹ
3m/3mʹ
3n/3nʹ
3o/3oʹ
3p/3pʹ
3q/3qʹ
3r/3rʹ
3s/3sʹ
3t/3tʹ
1.5
2
4
90
92
85
3u/3uʹ
3v/3vʹ
3
92
a All reactions were carried out with isocyanoacetates 1 (0.10 mmol), imines 2 (0.20 mmol), methyl acrylate (0.5 mol%) and
catalyst 4c (0.5 mol%) in toluene (1.0 mL) at -30
b Isolated yield.
.
c Unless otherwise noted, the diastereomeric ratio was determined by 1H NMR spectroscopic analysis of the crude product.
d The dr and ee value were determined by chiral HPLC analysis.
A variety of N-Boc-aldimines 2b-2l were also tested for the Mannich reaction with α-phenylisocyanoacetate 1a. As shown in table 2,
the desired products 3ʹ (and 3) were obtained in high yields and mostly high-to-excellent enantioselectivities (Table 2, entries 11-19).
In the cases of heterocyclic aldimine substrates, the reactions proceeded to give moderate enantioselectivities, which afforded the
product with 80% ee (3uʹ) and 79% ee (3vʹ) (Table 2, entries 20-21). The effect of para-substitution on the benzene ring is always
better than that of the meta-substitution, irrespective of the imines moiety or the isocyanoacetate moiety.
Inspired by Dixon’s work,9d we quickly obtained the adduct 5a and 5aʹ in good yield under the condition of acetoxysilver and
methyldiphenylphosphane. Unfortunately, the enantioselectivity decreased to 74% and 71% (Scheme 1). We also tried to use a single
diastereomer 3a (or 3aʹ) to turn off the ring. From the HPLC data (see supporting information), we found that each diastereomer had
partial isomerization and converted to the other diastereomer.
Scheme 1. Transformation of 3a and 3aʹ to 5a and 5aʹ
The absolute configuration of compound 3a and 3tʹ were confirmed by single-crystal X-ray structural analysis (figure 1, see
supporting information).12 The structure enabled the (2R,3S) assignment of the newly formed stereogenic centers in 3tʹ , and the (2S,3S)
in 3a , the configurations of other diastereomers were determined by analogy. Based on previous reports5c, 9e and on the known absolute
stereochemical configuration of 3a with 3tʹ, a transition-state model rationalizing the stereochemical outcome of the Mannich reaction
between 1a and 2a in the presence of dual-reagent catalyst is proposed in Scheme 2. In the transition-state II, the rotation of the enolate
ion could play an important role on the presence of diastereomers.
3

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Figure 1 X-Ray crystal structure of 3a and 3tʹ.
Scheme 2. Proposed transition-state model
3. Conclusion
In summary, we have successfully developed a dual-reagent organophosphine catalyzed asymmetric Mannich reaction of α-
phenylisocyanoacetates with N-Boc-aldimines. The corresponding products were obtained in excellent yields (up to 98%) and with
moderate to good enantioselectivities (up to 95% ee) under mild reaction conditions with the catalyst as low as 0.5 mol%. Further
studies on dual-reagent catalysis are underway in our group to broaden their applications in asymmetric reactions.
4. Experimental
4.1 General information
1
The H NMR spectra were recorded on a Bruker (400 MHz). All chemical shifts (δ) were given in ppm. Data were reported as follows:
chemical shift, multiplicity (s = single, d = doublet, t = triplet, q = quartet, br = broad, m = multiplet) and coupling constants (Hz), intergration.
13C NMR spectra were recorded on a DPX-400 (100 MHz). Flash column chromatography was performed using H silica gel. For thin-layer
chromatography (TLC), silica gel plates (HSGF 254) were used and compounds were visualized by irradiation with UV light. Analytical high
performance liquid chromatography (HPLC) was carried out on SHIMADZU equipment using chiral columns. Melting points were
determined on a SGW X-4 melting point and were uncorrected. Optical rotations were measured on a JASCO P-1010 Polarimeter at λ =589
nm. IR spectra were recorded on a Perkin-Elmer 983G instrument. Mass spectra analysis was performed on API 200 LC/MS system (Applied
Biosystems Co. Ltd.).
4.2 Preparation of catalysts 5
To a stirred solution of α-amino acid-derives phosphine (1.0 mmol) in CH2Cl2 (10 mL), isothiocyanatobenzene (2.0 mmol) was added. Then
the reaction was vigorously stirred for 4 h. After removal of the solvent, direct purification by silica gel chromatography (15% EtOAc-
petroleum ether) provided products.
4.2.1 (S)-1-(1-(diphenylphosphanyl)-3,3-dimethylbutan-2-yl)-3-phenylthiourea (4e)
Yield:82%; White solid; m.p. 51-52 oC, [α]D23.6 = +42.1 (c 0.5, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 8.71-8.56 (br, 1H), 7.51-7.43 (m, 4H),
7.35-7.20 (m, 9H), 7.09-7.07 (m, 2H), 5.98 (m, 1H), 4.81-4.74 (m, 1H), 2.51-2.47 (m, 1H), 2.00 (t, J =12.0 Hz, 1H), 0.91 (s, 9H); 13C NMR
(CDCl3, 100 MHz) ) δ 180.7, 139.2 (d, JC-P = 12.6 Hz), 138.7 (d, JC-P = 12.5 Hz), 136.2, 133.1 (d, JC-P = 18.9 Hz), 132.7 (d, JC-P = 19.2 Hz),
129.9, 128.6, 128.6 (d, JC-P = 6.7 Hz), 128.4 (d, JC-P = 6.7 Hz), 126.9, 125.3, 60.9 (d, JC-P = 14.5 Hz), 36.4 (d, JC-P = 6.7 Hz), 31.3 (d, JC-P
=
4

ACCEPTED MANUSCRIPT
14.2 Hz), 26.5; 31P NMR (400 MHz, CDCl3) δ -23.4 (s); IR (Neat): 3379, 3247, 3051, 2961, 1596, 1531, 1497, 1433, 1367, 1253, 1181, 1092,
738, 696; HRMS (ESI): calcd for [M+H]+ (C25H30N2PS)+ requires 421.1862; found 421.1862.
4.2.2 (S)-1-(1-(diphenylphosphanyl)-3,3-dimethylbutan-2-yl)-3-(p-tolyl)thiourea (4f)
o
23.5
1
Yield:81%; White solid; m.p. 52-53 C, [α]D
= +46.4 (c 0.5, CHCl3); H NMR (CDCl3, 400 MHz) δ 8.39-8.32 (br, 1H), 7.51-7.30 (m,
10H), 7.14-7.12 (m, 2H), 6.96-6.94 (m, 2H), 5.89 (d, J =6.4 Hz, 1H), 4.76-4.73 (m, 1H), 2.49-2.46 (m, 1H), 1.97 (t, J =12.0 Hz, 1H), 0.89 (s,
9H); 13C NMR (CDCl3, 100 MHz) δ 180.9, 139.3 (d, JC-P = 13.4 Hz), 138.0 (d, JC-P = 14.0 Hz), 133.1 (d, JC-P = 19.1 Hz), 132.7 (d, JC-P = 19.2
Hz), 130.5, 128.6, 128.6, 128.5, 128.3 (d, JC-P = 6.8 Hz), 125.6, 60.8 (d, JC-P = 14.0 Hz), 36.4 (d, JC-P = 6.6 Hz), 31.4 (d, JC-P = 15.0 Hz), 26.5,
21.1; 31P NMR (400 MHz, CDCl3) δ -23.3 (s); IR (Neat): 3378, 3200, 3051, 2961, 2867, 1584, 1531, 1478, 1433, 1367, 1329, 1260, 1184,
1092, 817, 740, 696; HRMS (ESI): calcd for [M+H]+ (C26H30N2PS)+ requires 433.1873; found 433.1872.
4.2.3 (S)-1-(1-(diphenylphosphanyl)-3,3-dimethylbutan-2-yl)-3-(4-(trifluoromethyl)phenyl)thiourea (4h)
Yield:85%; White solid; m.p. 64-65 oC, [α]D23.7 = +16.6 (c 2.0, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 9.26 (br, 1H), 7.55-7.47 (m, 6H), 7.33-
7.29 (m, 7H), 6.32 (m, 1H), 4.87-4.85 (m, 1H), 2.58-2.54 (m, 1H), 2.18 (t, J =12.0 Hz 1H), 0.99 (s, 9H); 13C NMR (CDCl3, 100 MHz) ) δ
180.4, 140.2, 138.8 (d, JC-P = 12.4 Hz), 138.3 (d, JC-P = 13.3 Hz), 133.1 (d, JC-P = 18.8 Hz), 128.8, 128.7 (d, JC-P = 6.6 Hz), 128.5 (d, JC-P = 6.7
Hz), 127.4 (q, JC-F = 32.7 Hz), 126.8, 123.9 (q, JC-F = 270.5 Hz), 123.7, 61.0 (d, JC-P = 13.7 Hz), 36.5 (d, JC-P = 6.5 Hz), 31.1 (d, JC-P = 13.7
Hz), 26.6; 19F NMR (CDCl3, 376 MHz) δ -62.2 (s); 31P NMR (400 MHz, CDCl3) δ -23.3 (s); IR (Neat): 3264, 3052, 2962, 1615, 1532, 1478,
1433, 1368, 1324, 1266, 1123, 1067, 1015, 840, 746, 696; HRMS (ESI): calcd for [M+H]+ (C26H29N2F3PS)+ requires 489.1736; found
489.1735.
4.3 Preparation of isocyanoacetates 1d and 1k8
4.3.1 Methyl 2-isocyano-2-(3-methoxyphenyl)acetate (1d)
1
Yield:42%; light yellow oil; H NMR (CDCl3, 400 MHz) δ 7.34-7.30 (m, 1H), 7.05-7.03 (m, 1H), 7.01-7.00 (m, 1H), 6.94-6.91 (m, 1H),
5.34 (s, 1H), 3.82 (s, 3H), 3.78 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 166.0, 161.4, 160.1, 133.0, 130.2, 118.9, 115.1, 112.2, 60.1, 55.4, 53.8;
IR (Neat): 3008, 2956, 2839, 2150, 1758, 1603, 1589, 1492, 1455, 1436, 1265, 1208, 1265, 1208, 1035, 781, 746, 691; HRMS (ESI): calcd
for [M-H]- (C11H10O3N)- requires 204.0666; found 204.0667.
4.3.2 Isopropyl 2-isocyano-2-phenylacetate (1k)
Yield:32%; light yellow oil; 1H NMR (CDCl3, 400 MHz) δ 7.48-7.45 (m, 2H), 7.40-7.39 (m, 3H), 5.32 (s, 1H), 5.07-4.98 (m, 1H), 1.25 (d,
J = 6.0 Hz, 3H), 1.16 (d, J = 6.4 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 165.0, 161.0, 132.0, 129.4, 129.1, 71.1, 60.5, 21.5, 21.3; IR (Neat):
2984, 2938, 2149, 1750, 1496, 1455, 1377, 1254, 1209, 1174, 1104, 1020, 960, 733, 696; HRMS (ESI): calcd for [M-H]- (C12H12O4N)-
requires 202.0874; found 202.0872.
4.4 Asymmetric dual-reagent catalyzed Mannich-type reactions
The reactions were carried out in a dry round-bottom flask reactor (5 mL). To a solution of catalyst 4c (0.005 mmol) in toluene (1.0 mL) at
room temperature were added methyl acrylate (0.005 mmol), stirring 5 minutes, then lowered temperature to -30 , added isocyanoacetates 1a
(0.1 mmol), and finally N-Boc-aldimines 2a (0.2 mmol), the resulting mixture was stirred vigorously. When the reaction was finished
(determined by TLC analysis), the crude mixture was warmed to the room temperature and purified by flash column chromatography (silica
gel: petroleum ether/AcOEt = 10 : 1) to afford the products.
4.5 Characterization data of products 3a, 3a
ʹ-3v, 3vʹ
4.5.1 Methyl (2S,3S)-3-((tert-butoxycarbonyl)amino)-2-isocyano-2,3-diphenylpropanoate (3a)
o
1
Yield:98% (3a and 3aʹ); White solid; m.p. 125-126 C, [α]D25.1 = -38.7 (c 1.0, CHCl3); H NMR (CDCl3, 400 MHz) δ 7.82-7.80 (m, 2H),
7.49-7.35 (m, 8H), 5.92 (d, J = 9.2 Hz, 1H), 5.22 (d, J = 8.8 Hz, 1H), 3.60 (s, 3H), 1.21 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ 166.4, 164.1,
154.3, 136.1, 132.4, 129.3, 128.8, 128.7, 128.5, 128.2, 126.2, 80.3, 58.7, 53.8, 28.0; IR (Neat): 3341, 2978, 2137, 1745, 1703, 1513, 1499,
1451, 1367, 1247,1168, 1009; HRMS (ESI): calcd for [M+H]+ (C22H25O4N2)+ requires 381.1809; found 381.1811; enantiomeric excess: 83%,
determined by HPLC (Chiralpak AD-H+AS-H, hexane/i-PrOH 93/7, flow rate 0.9 mL/min; tmajor = 22.3 min, tminor = 16.6 min, λ = 220 nm);
Methyl (2R,3S)-3-((tert-butoxycarbonyl)amino)-2-isocyano-2,3-diphenylpropanoate (3aʹ)
o
25.1
1
White solid; m.p. 178-180 C, [α]D = -69.4 (c 0.5, CHCl3); H NMR (CDCl3, 400 MHz) δ 7.48 (m, 2H), 7.30-7.29 (m, 3H), 7.20-7.11
(m, 3H), 7.04-7.03, 5.71 (m, 2H), 3.85 (s, 3H), 1.40(s, 9H); 13C NMR (CDCl3, 100 MHz) δ 166.8, 164.2, 154.2, 135.0, 131.8, 129.3, 128.7,
128.3, 128.0, 127.9, 125.9, 80.5, 76.6, 60.2, 54.1, 28.2; IR (Neat): 3341, 2979, 2137, 1754, 1720, 1495, 1451, 1367, 1247,1167; HRMS (ESI):
5

ACCEPTED MANUSCRIPT
calcd for [M+H]+ (C22H25O4N2)+ requires 381.1809; found 381.1812; enantiomeric excess: 93%, determined by HPLC (Chiralpak AD-H and
AS-H, hexane/i-PrOH 93/7, flow rate 0.9 mL/min; tmajor = 30.4 min, tminor = 18.6 min, λ = 220 nm).
4.5.2 Methyl (2S,3S)-3-((tert-butoxycarbonyl)amino)-2-isocyano-3-phenyl-2-(m-tolyl)propanoate (3b)
Yield:91% (3b and 3bʹ); colorless oil; [α]D28.5 = -51.3 (c 1.0, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 7.58-7.57 (m, 2H), 7.48-7.45 (m, 2H),
7.40-7.30 (m, 4H), 7.21-7.19 (m, 1H), 5.91 (d, J = 8.4 Hz, 1H), 5.17 (d, J = 7.6 Hz, 1H), 3.60 (s, 3H), 2.41 (s, 3H), 1.22 (s, 9H); 13C NMR
(CDCl3, 100 MHz) δ 166.4, 163.9, 154.3, 138.5, 136.2, 132.4, 130.0, 128.7, 128.6, 128.4, 128.2, 128.4, 128.2, 126.8, 123.3, 80.2, 58.4, 53.8,
28.0, 21.5; IR (Neat): 3328, 2958, 2925, 2135, 1754, 1720, 1493, 1367, 1248, 1166, 1085, 1022; HRMS (ESI): calcd for [M+H]+
(C23H27O4N2)+ requires 395.1965; found 395.1970; enantiomeric excess: 79%, determined by HPLC (Chiralpak AD-H, hexane/i-PrOH 95/5,
flow rate 1.0 mL/min; tmajor = 16.9 min, tminor = 7.6 min, λ = 220 nm);
Methyl (2R,3S)-3-((tert-butoxycarbonyl)amino)-2-isocyano-3-phenyl-2-(m-tolyl)propanoate (3bʹ)
White solid; m.p. 171-173 oC, [α]D28.5 = -77.1 (c 0.28, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 7.28-7.25 (m, 2H), 7.20-7.10 (m, 5H), 7.04-
7.02 (m, 2H), 5.68 (dd, J1 = 9.6 Hz, J2 = 24.0 Hz, 2H), 3.86 (s, 3H), 2.30 (s, 3H), 1.40 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ 166.8, 163.9,
154.2, 138.5, 135.1, 131.7, 130.0, 128.5, 128.3, 128.0, 127.9, 126.4, 123.0, 80.5, 60.0, 54.1, 28.2, 21.5; IR (Neat): 3329, 2956, 2925, 2134,
1747, 1704, 1498, 1391, 1367, 1248, 1167, 1034, 1009, HRMS (ESI): calcd for [M+H]+ (C23H27O4N2)+ requires 395.1965; found 395.1964;
enantiomeric excess: 92%, determined by HPLC (Chiralpak AS-H, hexane/i-PrOH 95/5, flow rate 1.0 mL/min; tmajor = 5.3 min, tminor = 7.9
min, λ = 220 nm).
4.5.3 Methyl (2S,3S)-3-((tert-butoxycarbonyl)amino)-2-isocyano-3-phenyl-2-(p-tolyl)propanoate (3c)
Yield:94% (3c and 3cʹ); colorless oil; [α]D25.7 = -35.5 (c 1.0, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 7.67-7.65 (m, 2H), 7.47-7.45 (m, 2H),
7.39-7.34 (m, 3H), 7.25-7.23 (m, 2H), 5.88 (d, J = 10.0 Hz, 1H), 5.17 (d, J = 8.4 Hz, 1H), 3.60 (s, 3H), 2.36 (s, 3H), 1.21 (s, 9H); 13C NMR
(CDCl3, 100 MHz) δ 166.1, 165.3, 154.3, 148.1, 143.4, 131.8, 129.8, 129.5, 129.1, 126.0, 123.6, 81.0, 76.1, 58.3, 54.2, 28.0; IR (Neat): 3358,
2977, 2927, 2135, 1746, 1704, 1513, 1392, 1367, 1249, 1168, 1009; HRMS (ESI): calcd for [M+H]+ (C23H27O4N2)+ requires 395.1965; found
395.1972; enantiomeric excess: 82%, determined by HPLC (Chiralpak AD-H, hexane/i-PrOH 95/5, flow rate 1.0 mL/min; tmajor = 10.6 min,
tminor = 8.6 min, λ = 220 nm);
Methyl (2R,3S)-3-((tert-butoxycarbonyl)amino)-2-isocyano-3-phenyl-2-(p-tolyl)propanoate (3cʹ)
1
White solid; m.p. 171-173 oC, [α]D25.5 = -83.2 (c 0.5, CHCl3); H NMR (CDCl3, 400 MHz) δ 7.37-7.35 (m, 2H), 7.21-7.09 (m, 5H), 7.05-
7.04 (m, 2H), 5.67 (dd, J1 = 10.0 Hz, J2 = 25.2 Hz, 2H), 3.85 (s, 3H), 2.30 (s, 3H), 1.40(s, 9H); 13C NMR (CDCl3, 100 MHz) δ 166.3, 165.3,
154.1, 147.8, 142.4, 131.1, 129.9, 129.1, 129.1, 129.7, 123.1, 81.2, 75.9, 59.8, 54.4, 28.2; IR (Neat): 3359, 2923, 2133, 1754, 1722, 1499,
1368, 1275, 1260, 1165; HRMS (ESI): calcd for [M+H]+ (C23H27O4N2)+ requires 395.1965; found 395.1970; enantiomeric excess: 92%,
determined by HPLC (Chiralpak AS-H, hexane/i-PrOH 95/5, flow rate 1.0 mL/min; tmajor = 5.5 min, tminor = 8.4 min, λ = 220 nm).
4.5.4 Methyl (2S,3S)-3-((tert-butoxycarbonyl)amino)-2-isocyano-2-(3-methoxyphenyl)-3-phenylpropanoate (3d)
Yield:92% (3d and 3dʹ); colorless oil; [α]D24.1 = -40.8 (c 1.0, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 7.47-7.44 (m, 2H), 7.40-7.33 (m, 6H),
6.95-6.92 (m, 1H), 5.92 (d, J = 9.2 Hz, 1H), 5.20 (d, J = 8.4 Hz, 1H), 3.86 (s, 3H), 3.61 (s, 3H), 1.23 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ
166.3, 164.1, 159.8, 154.3, 136.1, 134.0, 129.7, 128.8, 128.4, 128.2, 118.5, 115.2, 111.8, 80.3, 58.5, 55.4, 53.8, 28.0; IR (Neat): 3361, 3193,
2955, 2923, 2852, 2135, 1747, 1720, 1659, 1632, 1495, 1468, 1257, 1166, 1015; HRMS (ESI): calcd for [M+H]+ (C23H27O5N2)+ requires
411.1914; found 411.1917; enantiomeric excess: 80%, determined by HPLC (Chiralpak AD-H, hexane/i-PrOH 95/5, flow rate 1.0 mL/min;
tmajor = 26.5 min, tminor = 11.5 min, λ = 220 nm);
Methyl (2R,3S)-3-((tert-butoxycarbonyl)amino)-2-isocyano-2-(3-methoxyphenyl)-3-phenylpropanoate (3dʹ)
colorless oil; [α]D24.3 = -87.2 (c 0.5, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 7.23-7.15 (m, 4H), 7.07-7.05 (m, 3H), 6.99 (m, 1H), 6.85-6.82 (m,
1H), 5.68 (dd, J1 = 8.0 Hz, J2 = 20.0 Hz, 2H), 3.86 (s, 3H), 3.73 (s, 3H), 1.40(s, 9H); 13C NMR (CDCl3, 100 MHz) δ 166.7, 164.1, 159.7,
154.2, 135.1, 133.3, 129.7, 128.3, 128.0, 127.9, 118.2, 114.9, 111.7, 80.5, 76.5, 60.1, 55.3, 54.1, 28.2; IR (Neat): 3340, 2956, 2927, 2854,
2136, 1755, 1720, 1603, 1586, 1494, 1454, 1368, 1250, 1165, 1045; HRMS (ESI): calcd for [M+H]+ (C23H27O5N2)+ requires 411.1914; found
411.1921; enantiomeric excess: 88%, determined by HPLC (Chiralpak IC, hexane/i-PrOH 95/5, flow rate 1.0 mL/min; tmajor = 10.5 min, tminor
= 11.5 min, λ = 220 nm).
4.5.5 Methyl (2S,3S)-3-((tert-butoxycarbonyl)amino)-2-isocyano-2-(4-methoxyphenyl)-3-phenylpropanoate (3e)
Yield:98% (3e and 3eʹ); White solid; m.p. 70-71 oC, [α]D27.7 = -37.8 (c 1.0, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 7.70-7.68 (m, 2H), 7.46-
7.44 (m, 2H), 7.38-7.36 (m, 3H), 6.96-6.93 (m, 2H), 5.85 (d, J = 10.0 Hz, 1H), 5.18 (d, J = 9.2 Hz, 1H), 3.82 (s, 3H), 3.60 (s, 3H), 1.23 (s,
9H); 13C NMR (CDCl3, 100 MHz) δ 166.6, 163.8, 160.3, 154.3, 136.1, 128.7, 128.4, 128.1, 127.6, 124.4, 114.0, 80.3, 58.6, 55.4, 53.7, 28.0;
IR (Neat): 3358, 2977, 2929, 2136, 1745, 1717, 1609, 1456, 1295, 1186, 1033, 1009; HRMS (ESI): calcd for [M+H]+ (C23H27O5N2)+ requires
411.1914; found 411.1917; enantiomeric excess: 81%, determined by HPLC (Chiralpak AD-H, hexane/i-PrOH 95/5, flow rate 1.0 mL/min;
tmajor = 14.5 min, tminor = 12.1 min, λ = 220 nm);
6

ACCEPTED MANUSCRIPT
Methyl (2R,3S)-3-((tert-butoxycarbonyl)amino)-2-isocyano-2-(4-methoxyphenyl)-3-phenylpropanoate (3eʹ)
o
26.5
1
White solid; m.p. 78-80 C, [α]D = -64.0 (c 1.5, CHCl3); H NMR (CDCl3, 400 MHz) δ 7.40-7.38 (m, 2H), 7.19-7.15 (m, 3H), 7.05-7.03
(m, 2H), 6.82-6.80 (m 2H), 5.67-5.66(m, 2H), 3.85 (s, 3H), 3.77 (s, 3H), 1.40(s, 9H); 13C NMR (CDCl3, 100 MHz) δ 167.0, 163.8, 160.1,
154.2, 135.1, 128.3, 128.0, 127.9, 127.3, 123.8, 113.9, 80.5, 76.2, 60.1, 54.0, 28.2; IR (Neat): 3356, 2977, 2932, 2137, 1754, 1718, 1610,
1513, 1456, 1255, 1184, 1166, 1033; HRMS (ESI): calcd for [M+H]+ (C23H27O5N2)+ requires 411.1914; found 411.1919; enantiomeric excess:
92%, determined by HPLC (Chiralpak AS-H, hexane/i-PrOH 95/5, flow rate 1.0 mL/min; tmajor = 8.4 min, tminor = 14.5 min, λ = 220 nm).
4.5.6 Methyl (2S,3S)-3-((tert-butoxycarbonyl)amino)-2-(4-fluorophenyl)-2-isocyano-3-phenylpropanoate (3f)
Yield:95% (3f and 3fʹ); colorless oil; [α]D25.4 = -39.2 (c 1.0, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 7.81-7.78 (m, 2H), 7.46-7.43 (m, 2H),
7.39-7.37 (m, 3H), 7.15-7.10 (m, 2H), 5.87 (d, J = 10.4 Hz, 1H), 5.19 (d, J = 9.6 Hz, 1H), 3.61 (s, 3H), 1.23 (s, 9H); 13C NMR (CDCl3, 100
MHz) δ 166.3, 164.6, 163.3 (d, JC-F = 251.6 Hz), 154.3, 135.8, 128.9, 128.6, 128.4, 128.3, 128.3, 128.1, 115.6 (d, JC-F = 21.8 Hz), 80.5, 76.4,
58.9, 53.9, 28.0; 19F NMR (CDCl3, 376 MHz) δ -112.6 (s); IR (Neat): 3355, 2979, 2136, 1746, 1704, 1510, 1242, 1168, 1010;.HRMS (ESI):
calcd for [M+H]+ (C22H24O4N2F)+ requires 399.1715; found 399.1717; enantiomeric excess: 82%, determined by HPLC (Chiralpak AD-H,
hexane/i-PrOH 97/3, flow rate 0.9 mL/min; tmajor = 14.9 min, tminor = 11.8 min, λ = 220 nm);
Methyl (2R,3S)-3-((tert-butoxycarbonyl)amino)-2-(4-fluorophenyl)-2-isocyano-3-phenylpropanoate (3fʹ)
White solid; m.p. 169-170 oC, [α]D25.4 = -48.7 (c 0.5, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 7.49-7.46 (m, 2H), 7.22-7.17 (m, 3H), 7.04-6.97
(m, 5H), 5.65 (dd, J1 = 10.8 Hz, J2 = 13.2 Hz, 2H), 3.87 (s, 3H), 1.40(s, 9H); 13C NMR (CDCl3, 100 MHz) δ 166.7, 164.7, 163.1 (d, JC-F
=
248.3 Hz), 154.2, 134.9, 128.5, 128.1, 128.0, 128.0, 127.8, 127.8, 115.7 (d, JC-F = 21.8 Hz), 80.7, 76.0, 60.4, 54.2, 28.2; 19F NMR (CDCl3, 376
MHz) δ -112.1 (s); IR (Neat): 3357, 2920, 2850, 2136, 1753, 1718, 1509, 1275, 1259, 1166, 1048; HRMS (ESI): calcd for [M+H]+
(C22H24O4N2F)+ requires 399.1715; found 399.1720; enantiomeric excess: 87%, determined by HPLC (Chiralpak AS-H, hexane/i-PrOH 97/3,
flow rate 0.9 mL/min; tmajor = 14.5 min, tminor = 12.1 min, λ = 220 nm).
4.5.7 Methyl (2S,3S)-3-((tert-butoxycarbonyl)amino)-2-(4-chlorophenyl)-2-isocyano-3-phenylpropanoate (3g)
Yield:98% (3g and 3gʹ); colorless oil; [α]D27.3 = -29.0 (c 1.0, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 7.76-7.74 (m, 2H), 7.46-7.42 (m, 3H),
7.40-7.36 (m, 4H), 5.87 (d, J = 10.0 Hz, 1H), 5.20 (d, J = 10.0 Hz, 1H), 3.61 (s, 3H), 1.23 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ 166.2,
164.5, 154.2, 135.2, 132.1, 131.6, 130.0, 129.5, 128.8, 126.1, 123.0, 80.5, 76.4, 58.2, 54.0, 28.0; IR (Neat): 3358, 2922, 2851, 2135, 1746,
1704, 1494, 1275, 1260, 1167, 1014; HRMS (ESI): calcd for [M+H]+ (C22H24O4N2Cl)+ requires 415.1419; found 415.1423; enantiomeric
excess: 72%, determined by HPLC (Chiralpak AD-H, hexane/i-PrOH 97/3, flow rate 0.9 mL/min; tmajor = 14.4 min, tminor = 12.5 min, λ = 220
nm);
Methyl (2R,3S)-3-((tert-butoxycarbonyl)amino)-2-(4-chlorophenyl)-2-isocyano-3-phenylpropanoate (3gʹ)
1
White solid; m.p. 120-122 oC, [α]D25.5 = -34.5 (c 1.0, CHCl3); H NMR (CDCl3, 400 MHz) δ 7.45-7.43 (m, 2H), 7.30-7.27 (m, 2H), 7.21-
7.15 (m, 3H), 7.06-7.04 (m, 2H), 5.68 (m, 2H), 3.86 (s, 3H), 1.40(s, 9H); 13C NMR (CDCl3, 100 MHz) δ 166.5, 164.5, 154.1, 134.2, 131.5,
131.1, 129.6, 129.5, 128.9, 125.8, 122.6, 80.8, 76.3, 59.7, 54.2, 28.2; IR (Neat): 3358, 2924, 2136, 1755, 1721, 1493, 1275, 1260, 1166, 1097;
HRMS (ESI): calcd for [M+H]+ (C22H24O4N2Cl)+ requires 415.1419; found 415.1422; enantiomeric excess: 82%, determined by HPLC
(Chiralpak AS-H, hexane/i-PrOH 95/5, flow rate 1.0 mL/min; tmajor = 5.4 min, tminor = 7.8 min, λ = 220 nm).
4.5.8 Methyl (2S,3S)-2-(4-bromophenyl)-3-((tert-butoxycarbonyl)amino)-2-isocyano-3-phenylpropanoate (3h)
Yield:98% (3h and 3hʹ); colorless oil; [α]D28.7 = -26.7 (c 1.0, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 7.69-7.67 (m, 2H), 7.58-7.56 (m, 2H),
7.45-7.37 (m, 5H), 5.86 (d, J = 10.4 Hz, 1H), 5.19 (d, J = 10.4 Hz, 1H), 3.61 (s, 3H), 1.23 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ 166.1,
164.8, 154.3, 135.7, 131.8, 131.6, 129.0, 128.6, 128.1, 123.9, 80.6, 76.6, 58.8, 54.0, 28.0; IR (Neat): 3358, 2922, 2851, 2135, 1747, 1491,
1457, 1275, 1260, 1168, 1010; HRMS (ESI): calcd for [M+H]+ (C22H24O4N2Br)+ requires 459.0914; found 459.0915; enantiomeric excess:
79%, determined by HPLC (Chiralpak AD-H, hexane/i-PrOH 97/3, flow rate 0.9 mL/min; tmajor = 15.4 min, tminor = 13.9 min, λ = 220 nm);
Methyl (2R,3S)-2-(4-bromophenyl)-3-((tert-butoxycarbonyl)amino)-2-isocyano-3-phenylpropanoate (3hʹ)
1
White solid; m.p. 145-146 oC, [α]D23.4 = -79.0 (c 1.0, CHCl3); H NMR (CDCl3, 400 MHz) δ 7.45-7.43 (m, 2H), 7.38-7.36 (m, 2H), 7.22-
7.15 (m, 3H), 7.06-7.04 (m 2H), 5.65 (dd, J1 = 9.2 Hz, J2 = 16.0 Hz, 2H), 2.86 (s, 3H), 1.40(s, 9H); 13C NMR (CDCl3, 100 MHz) δ 166.5,
165.0, 154.1, 134.8, 131.8, 131.1, 128.6,128.2, 128.0, 127.8, 123.8, 80.7, 76.2, 60.2, 54.3, 28.2; IR (Neat): 3356, 2978, 2135, 1747, 1703,
1491, 1249, 1166, 1079; 1010; HRMS (ESI): calcd for [M+H]+ (C22H24O4N2Br)+ requires 459.0914; found 459.0919; enantiomeric excess:
81%, determined by HPLC (Chiralpak AS-H, hexane/i-PrOH 95/5, flow rate 1.0 mL/min; tmajor = 5.6 min, tminor = 7.8 min, λ = 220 nm).
4.5.9 Benzyl (2S,3S)-3-((tert-butoxycarbonyl)amino)-2-isocyano-2,3-diphenylpropanoate
(3i) and
Benzyl (2R,3S)-3-((tert-
butoxycarbonyl)amino)-2-isocyano-2,3-diphenylpropanoate (3iʹ)
o
27.6
1
Yield:95%; white solid; m.p. 74-75 C, [α]D
= -56.5 (c 1.0, CHCl3); H NMR (CDCl3, 400 MHz δ 7.80-7.79 (m, 2H), 7.42-7.24 (m,
major 11H, minor 3H, dr = 4:1), 7.04-7.03 (m, 2H), 5.90 (d, J = 8.8 Hz, 1H), 5.21-5.17 (m, 1H), 5.00 (dd, J = 12.4 Hz, 2H, AB), 1.37 (s, 2.4H
minor), 1.19 (s, 9H major); 13C NMR (CDCl3, 100 MHz) δ 165.6 (166.1 minor), 164.3, 154.3, 136.0, 134.1, 132.4 (131.8 minor), 131.8, 129.3
7

ACCEPTED MANUSCRIPT
(129.2 minor), 128.7, 128.6, 128.6, 128.4 (128.5 minor), 128.2, 128.0, 127.9, 126.3, 80.3, 68.6 (69.0 minor), 58.5 (60.2 minor), 28.0 (28.2
minor); IR (Neat): 3356, 2978, 2136, 1749, 1717, 1498, 1451, 1367, 1234, 1167; HRMS (ESI): calcd for [M+H]+ (C28H29O4N2)+ requires
457.2122; found 457.2126; major diastereoisomer enantiomeric excess: 89%, tmajor = 25.2 min, tminor = 12.4 min; minor diastereoisomer
enantiomeric excess: 93%, tmajor = 59.4 min, tminor = 10.9 min, determined by HPLC (Chiralpak AD-H, hexane/i-PrOH 93/7, flow rate 0.85
mL/min, λ = 220 nm).
Tert-butyl
(2S,3S)-3-((tert-butoxycarbonyl)amino)-2-isocyano-2,3-diphenylpropanoate
(3j)
and
Tert-butyl
(2R,3S)-3-((tert-
butoxycarbonyl)amino)-2-isocyano-2,3-diphenylpropanoate (3jʹ)
Yield:98%; white solid; m.p. 123-125 oC, [α]D27.1 = -46.3 (c 1.0, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 7.80-7.78 (m, 2H), 7.56-7.54 (m,
2H), 7.43-7.36 (m, 6H), 5.83 (d, J = 9.2 Hz, 1H), 5.18 (d, J = 9.2 Hz, 1H), 1.24 (s, 9H), 1.21 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ 164.3,
163.4, 154.3, 136.5, 133.1, 129.1, 128.7, 128.5, 128.5, 128.3, 128.0, 126.1, 84.8, 80.2, 58.3, 28.0 (28.4 minor), 27.4 (27.6 minor); IR (Neat):
3357, 2979, 2932, 2136, 1718, 1498, 1450, 1394, 1370, 1258, 1049; HRMS (ESI): calcd for [M+H]+ (C25H31O4N2)+ requires 423.2278; found
423.2283; major diastereoisomer enantiomeric excess: 91%, tmajor = 30.5 min, tminor = 17.4 min; minor diastereoisomer enantiomeric excess:
70%, tmajor = 28.3 min, tminor = 24.3 min, determined by HPLC (Chiralpak IC+AD-H, hexane/i-PrOH 97/3, flow rate 0.85 mL/min, λ = 220
nm).
4.5.10 Isopropyl (2R,3S)-3-((tert-butoxycarbonyl)amino)-2-isocyano-2,3-diphenylpropanoate (3k) and Isopropyl (2R,3S)-3-((tert-
butoxycarbonyl)amino)-2-isocyano-2,3-diphenylpropanoate (3kʹ)
o
24.2
1
Yield:91%; White solid; m.p. 119-120 C, [α]D = -39.9 (c 1.0, CHCl3); H NMR (CDCl3, 400 MHz) ) dr = 1.2:1 δ 7.82-7.80 (m, 2H),
7.52-751 (m, 4H), 7.45-7.35 (m, 6H), 7.31-7.29 (m, 3.6H major), 7.17-7.11 (m, 3.8H major), 7.04-7.02 (m, 2.6H major), 5.93(d, J = 10.4 Hz,
1H), 5.70 (dd, J1 = 15.2 Hz, J2 = 10.4 Hz, 2H major), 5.19 (d, J = 11.6 Hz, 1H), 5.16-5.01 (m, 1H), 4.87-4.81 (m, 1H), 1.39 (s, 10H major),
1.32-1.30 (m, 6H major), 1.20 (s, 9H minor), 1.10 (d, J = 6 Hz, 3H minor), 0.94 (d, J = 6 Hz, 3H minor); 13C NMR (CDCl3, 100 MHz) δ
165.6 (165.2 minor), 163.9, 154.1, 135.3 (136.2 minor), 132.7 (132.0 minor), 128.7 (129.1 minor), 128.6 (128.4 minor), 128.2, 127.8 (128.0
minor), 126.2 (126.0 minor), 80.4 (80.2 minor), 72.0 (71.6 minor), 60.0 (58.5 minor), 28.0 (28.2 minor), 21.3 (21.4 minor), 21.1 (21.1 minor);
IR (Neat): 3355, 2981, 2134, 2136, 1721, 1498, 1451, 1391, 1367, 1248, 116, 1103; HRMS (ESI): calcd for [M+H]+ (C24H29O4N2)+ requires
409.2122; found 409.2126; major diastereoisomer enantiomeric excess: 92%, tmajor = 21.1 min, tminor = 23.1 min; minor diastereoisomer
enantiomeric excess: 85%, tmajor = 19.9 min, tminor = 37.7 min, determined by HPLC (Chiralpak OD-H+AS-H, hexane/i-PrOH 98/2, flow rate
0.5 mL/min, λ = 220 nm).
4.5.11 Methyl (2S,3S)-3-((tert-butoxycarbonyl)amino)-2-isocyano-2-phenyl-3-(m-tolyl)propanoate (3l)
Yield:98% (3l and 3lʹ); White solid; m.p. 97-98 oC, [α]D25.7 = -34.0 (c 1.0, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 7.81-7.79 (m, 2H), 7.46-
7.40 (m, 3H), 7.27 (m, 3H), 7.18-7.15 (m, 1H), 5.88 (d, J = 10.0 Hz, 1H), 5.18 (d, J = 9.6 Hz, 1H), 3.62 (s, 3H), 2.38 (s, 3H), 1.21 (s, 9H); 13
C
NMR (CDCl3, 100 MHz) δ 166.4, 164.0, 154.3, 138.1, 136.0, 132.5, 129.5, 129.2, 128.8, 128.6, 128.3, 126.3, 125.2, 80.2, 58.6, 53.7, 28.0,
21.5; IR (Neat): 3355, 2954, 2926, 2854, 2136, 1747, 1703, 1499, 1367, 1248, 1164, 1010; HRMS (ESI): calcd for [M+H]+ (C23H27O4N2)+
requires 395.1965; found 395.1968; enantiomeric excess: 72%, determined by HPLC (Chiralpak AD-H, hexane/i-PrOH 95/5, flow rate 1.0
mL/min, tmajor = 11.0 min, tminor = 7.8 min, λ = 220 nm);
Methyl (2R,3S)-3-((tert-butoxycarbonyl)amino)-2-isocyano-2-phenyl-3-(m-tolyl)propanoate (3lʹ)
o
25.8
1
White solid; m.p. 135-136 C, [α]D = -66.2 (c 1.0, CHCl3); H NMR (CDCl3, 400 MHz) δ 7.48 (m, 2H), 7.31-7.29 (m, 3H), 7.04-6.97
(m, 2H), 6.84-6.80 (m, 2H), 5.67 (m, 2H), 3.85 (s, 3H), 2.18 (s, 3H), 1.40(s, 9H); 13C NMR (CDCl3, 100 MHz) δ 166.8, 164.0, 154.2, 137.5,
134.8, 131.9, 129.2, 129.0, 128.8, 128.6, 128.6, 127.7, 126.0, 125.0, 80.4, 60.2, 54.1, 28.2, 21.2; IR (Neat): 3356, 2977, 2927, 2136, 1754,
1720, 1497, 1450, 1367, 1247, 1163, 1048; HRMS (ESI): calcd for [M+H]+ (C23H27O4N2)+ requires 395.1965; found 395.1971; enantiomeric
excess: 89%, determined by HPLC (Chiralpak AS-H, hexane/i-PrOH 95/5, flow rate 1.0 mL/min, tmajor = 5.0 min, tminor = 7.4 min, λ = 220
nm).
4.5.12 Methyl (2S,3S)-3-((tert-butoxycarbonyl)amino)-2-isocyano-2-phenyl-3-(p-tolyl)propanoate (3m)
20.9
1
Yield:85% (3m and 3mʹ); colorless oil; [α]D
= -23.9 (c 1.0, CHCl3); H NMR (CDCl3, 400 MHz) δ 7.80-7.78 (m, 2H), 7.45-7.36 (m,
5H), 7.19-7.17 (m, 2H), 5.88 (d, J = 10.0 Hz, 1H), 5.16 (d, J = 9.2 Hz, 1H), 3.61 (s, 3H), 2.35 (s, 3H), 1.20 (s, 9H); 13C NMR (CDCl3, 100
MHz) δ 166.4, 164.2, 154.3, 138.6, 133.2, 132.6, 129.3, 129.2, 128.7, 128.0, 126.3, 80.2, 58.5, 53.8, 28.0, 21.2; IR (Neat): 3353, 2978, 2928,
2136, 1747, 1717, 1498, 1450, 1367, 1250, 1167, 1010; HRMS (ESI): calcd for [M+H]+ (C23H27O4N2)+ requires 395.1965; found 395.1969;
enantiomeric excess: 81%, determined by HPLC (Chiralpak AD-H, hexane/i-PrOH 95/5, flow rate 1.0 mL/min, tmajor = 19.9 min, tminor = 10.2
min, λ = 220 nm);
Methyl (2R,3S)-3-((tert-butoxycarbonyl)amino)-2-isocyano-2-phenyl-3-(p-tolyl)propanoate (3mʹ)
o
23.8
1
White solid; m.p. 120-122 C, [α]D = -69.4 (c 0.5, CHCl3); H NMR (CDCl3, 400 MHz) δ 7.50 (m, 2H), 7.31-7.30 (m, 3H), 6.95-6.91
(m, 4H), 5.67 (dd, J1 = 9.6 Hz, J2 = 19.2 Hz, 2H), 3.85 (s, 3H), 2.23 (s, 3H), 1.39 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ 166.8, 164.0, 154.2,
138.1, 132.1, 131.9, 129.2, 128.6, 127.8, 126.0, 80.4, 60.0, 54.0, 28.2, 21.0; IR (Neat): 3356, 2926, 2136, 1755, 1721, 1497, 1450, 1367, 1247,
8

ACCEPTED MANUSCRIPT
1166; HRMS (ESI): calcd for [M+H]+ (C23H27O4N2)+ requires 395.1965; found 395.1970; enantiomeric excess: 89%, determined by HPLC
(Chiralpak AD-H, hexane/i-PrOH 95/5, flow rate 1.0 mL/min, tmajor = 34.4 min, tminor = 9.2 min, λ = 220 nm);
4.5.13 Methyl (2S,3S)-3-((tert-butoxycarbonyl)amino)-2-isocyano-3-(3-methoxyphenyl)-2-phenylpropanoate (3n)
o
25.1
1
Yield:88% (3n and 3nʹ); White solid; m.p. 94-96 C, [α]D
= -31.4 (c 1.0, CHCl3); H NMR (CDCl3, 400 MHz) δ 7.75-7.74 (m, 2H),
7.41-7.35 (m, 3H), 7.24-7.22 (m, 1H), 7.01-6.97 (m, 2H),6.86-6.84 (m, 1H), 5.84 (d, J = 9.6 Hz, 1H), 5.12 (d, J = 9.6 Hz, 1H), 3.78 (s, 3H),
3.58 (s, 3H), 1.17 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ 166.3, 164.2, 159.5, 154.3, 137.5, 132.4, 129.5, 129.3, 128.7, 126.2, 120.4, 114.4,
113.8, 80.3, 58.6, 55.3, 53.8, 28.0; IR (Neat): 3357, 2137, 1746, 1710, 1602, 1493, 1450, 1368, 1258, 1164, 1044, 1010; HRMS (ESI): calcd
for [M+H]+ (C23H27O5N2)+ requires 411.1914; found 411.1918; enantiomeric excess: 75%, determined by HPLC (Chiralpak AD-H, hexane/i-
PrOH 95/5, flow rate 1.0 mL/min, tmajor = 18.1 min, tminor = 10.9 min, λ = 220 nm);
Methyl (2R,3S)-3-((tert-butoxycarbonyl)amino)-2-isocyano-3-(3-methoxyphenyl)-2-phenylpropanoate (3nʹ)
o
25.2
1
White solid; m.p. 143-144 C, [α]D = -69.7 (c 0.5, CHCl3); H NMR (CDCl3, 400 MHz) δ 7.50 (m, 2H), 7.33-7.31 (m, 3H), 7.09-7.05
(m, 1H), 6.73-6.71 (m, 1H), 6.68-6.66 (m, 1H), 6.49-6.48 (m, 1H), 5.66 (dd, J1 = 9.6 Hz, J2 = 25.2 Hz, 2H), 3.87 (s, 3H), 3.60 (s, 3H), 1.41 (s,
9H); 13C NMR (CDCl3, 100 MHz) δ 166.7, 164.2, 158.9, 154.2, 136.4, 131.9, 129.3, 128.9, 128.7, 126.0, 120.2, 114.4, 113.5, 80.5, 60.2, 55.1,
54.1, 28.2; IR (Neat): 3356, 2137, 1754, 1722, 1602, 1494, 1451, 1368, 1246, 1163, 1047; HRMS (ESI): calcd for [M+H]+ (C23H27O5N2)+
requires 411.1914; found 411.1917; enantiomeric excess: 91%, determined by HPLC (Chiralpak AD-H, hexane/i-PrOH 95/5, flow rate 1.0
mL/min, tmajor = 21.4 min, tminor = 11.4 min, λ = 220 nm).
4.5.14 Methyl (2S,3S)-3-((tert-butoxycarbonyl)amino)-2-isocyano-3-(4-methoxyphenyl)-2-phenylpropanoate (3o)
o
25.4
1
Yield:94% (3o and 3oʹ); White solid; m.p. 50-52 C, [α]D
= -25.5 (c 1.0, CHCl3); H NMR (CDCl3, 400 MHz) δ 7.79-7.78 (m, 2H),
7.45-7.38 (m, 5H), 6.91-6.89 (m, 2H), 5.86 (d, J = 8.4 Hz, 1H), 5.15 (d, J = 8.4 Hz, 1H), 3.81 (s, 3H), 3.61 (s, 3H), 1.20 (s, 9H); 13C NMR
(CDCl3, 100 MHz) δ 166.5, 164.1, 159.8, 154.3, 132.5, 129.4, 129.3, 128.7, 128.3, 126.3, 113.8, 80.2, 58.3, 55.3, 53.8, 28.0; IR (Neat): 3356,
2977, 2933, 2137, 1746, 1715, 1612, 1513, 1450, 1367, 1251, 1167, 1033, 1009; HRMS (ESI): calcd for [M+H]+ (C23H27O5N2)+ requires
411.1914; found 411.1917; enantiomeric excess: 82%, determined by HPLC (Chiralpak AD-H, hexane/i-PrOH 95/5, flow rate 1.0 mL/min,
tmajor = 23.7 min, tminor = 13.5 min, λ = 220 nm);
Methyl (2R,3S)-3-((tert-butoxycarbonyl)amino)-2-isocyano-3-(4-methoxyphenyl)-2-phenylpropanoate (3oʹ)
White solid; m.p. 56-58 oC, [α]D25.5 = -62.5 (c 0.5, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 7.49 (m, 2H), 7.32-7.30 (m, 3H), 6.97-6.95 (m,
2H), 6.67-6.65 (m, 2H), 5.66-5.63(m, 2H), 3.85 (s, 3H), 3.71 (s, 3H), 1.40(s, 9H); 13C NMR (CDCl3, 100 MHz) δ 166.9, 164.1, 159.4, 154.2,
132.0, 129.2, 129.1, 128.7, 127.3, 126.0, 113.3, 80.5, 59.8, 55.1, 54.1, 28.2; IR (Neat): 3357, 2922, 2137, 1721, 1714, 1367, 1248, 1166, 1035;
HRMS (ESI): calcd for [M+H]+ (C23H27O5N2)+ requires 411.1914; found 411.1917; enantiomeric excess: 93%, determined by HPLC
(Chiralpak AS-H, hexane/i-PrOH 95/5, flow rate 1.0 mL/min, tmajor = 16.6 min, tminor = 8.9 min, λ = 220 nm).
4.5.15 Methyl (2S,3S) -3-((tert-butoxycarbonyl)amino)-3-(4-fluorophenyl)-2-isocyano-2-phenylpropanoate (3p)
Yield:96% (3p and 3pʹ); white solid; m.p. 58-59 oC, [α]D23.3 = -27.7 (c 1.0, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 7.78-7.76 (m, 2H), 7.48-
7.40 (m, 5H), 7.09-7.04 (m, 2H), 5.90 (d, J = 8.0 Hz, 1H), 5.15 (d, J = 8.8 Hz, 1H), 3.62 (s, 3H), 1.21 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ
166.3, 164.6, 162.9 (d, JC-F = 246.5 Hz), 154.2, 132.3, 132.1, 130.1(d, JC-F =82.0 Hz), 129.4, 128.8, 126.2, 115.5 (d, JC-F = 21.4 Hz), 80.5,
58.1, 53.9, 28.0; 19F NMR (CDCl3, 376 MHz) δ -112.9 (s); IR (Neat): 3355, 2979, 2931, 2136, 1747, 1704, 1606, 1510, 1450, 1368, 1249,
1165, 1009; HRMS (ESI): calcd for [M+H]+ (C22H24O4N2F)+ requires 399.1715; found 399.1710; enantiomeric excess: 82%, determined by
HPLC (Chiralpak AD-H, hexane/i-PrOH 95/5, flow rate 0.9 mL/min, tmajor = 20.0 min, tminor = 11.3 min, λ = 220 nm);
Methyl (2R,3S)-3-((tert-butoxycarbonyl)amino)-3-(4-fluorophenyl)-2-isocyano-2-phenylpropanoate (3pʹ)
o
23.4
1
White solid; m.p. 144-146 C, [α]D = -79.0 (c 1.0, CHCl3); H NMR (CDCl3, 400 MHz) δ 7.46 (m, 2H), 7.32-7.30 (m, 3H), 7.02-6.99
(m, 2H), 6.83-6.79 (m 2H), 5.69 (m, 2H), 1.39 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ 166.6, 164.4, 162.5 (d, JC-F = 246.3 Hz), 154.2, 131.7,
131.0, 129.7 (d, JC-F = 82.0 Hz), 129.4, 128.8, 125.8, 114. (d, JC-F = 21.5 Hz), 80.6, 76.5 59.6, 54.2, 28.2; 19F NMR (CDCl3, 376 MHz) δ -
113.4 (s); IR (Neat): 3357, 2979, 2931, 2137, 1755, 1720, 1606, 1511, 1451, 1368, 1247, 1164, 1049; HRMS (ESI): calcd for [M+H]+
(C22H24O4N2F)+ requires 399.1715; found 399.1705; enantiomeric excess: 93%, determined by HPLC (Chiralpak AS-H, hexane/i-PrOH 95/5,
flow rate 0.9 mL/min, tmajor = 14.4 min, tminor = 7.6 min, λ = 220 nm).
4.5.16 Methyl (2S,3S) -3-((tert-butoxycarbonyl)amino)-3-(4-chlorophenyl)-2-isocyano-2-phenylpropanoate (3q)
Yield:97% (3q and 3qʹ); colorless oil; [α]D24.6 = -31.2 (c 1.0, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 7.77-7.75 (m, 2H), 7.46-7.40 (m, 5H),
7.36-7.34 (m, 2H), 5.89 (d, J = 8.0Hz, 1H), 5.13 (d, J = 8.8 Hz, 1H), 3.63 (s, 3H), 1.21 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ 166.3, 164.6,
154.2, 134.8, 134.8, 132.2, 129.6, 129.5, 128.8, 128.7, 126.4, 80.6, 58.2, 54.0, 28.0; IR (Neat): 3358, 2955, 2926, 2854, 2135, 1717, 1494,
1450, 1368, 1250, 1167, 1093, 1014; HRMS (ESI): calcd for [M+H]+ (C22H24O4N2Cl)+ requires 415.1419; found 415.1422; enantiomeric
excess: 82%, determined by HPLC (Chiralpak AD-H, hexane/i-PrOH 97/3, flow rate 0.8 mL/min, tmajor = 32.2 min, tminor = 17.7 min, λ = 220
nm);
9

ACCEPTED MANUSCRIPT
Methyl (2R,3S)-3-((tert-butoxycarbonyl)amino)-3-(4-chlorophenyl)-2-isocyano-2-phenylpropanoate (3qʹ)
White solid; m.p. 54-56 oC, [α]D24.8 = -67.2 (c 1.0, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 7.48-7.46 (m, 2H), 7.34-7.32 (m, 3H), 7.12-7.10
(m, 2H), 6.96-6.74 (m, 2H), 5.65(dd, J1 = 8.8 Hz, J2 = 30 Hz, 2H), 3.86 (s, 3H), 1.40 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ 166.6, 164.5,
154.1, 134.3, 133.7, 131.5, 129.5, 129.3, 128.8, 128.1, 125.8, 80.8, 76.3, 59.7, 54.2, 28.2; IR (Neat): 3357, 2955, 2926, 2854, 2136, 1755,
1718, 1493, 1451, 1368, 1248, 1165, 1092, 1015; HRMS (ESI): calcd for [M+H]+ (C22H24O4N2Cl)+ requires 415.1419; found 415.1422;
enantiomeric excess: 93%, determined by HPLC (Chiralpak AS-H, hexane/i-PrOH 95/5, flow rate 0.8 mL/min, tmajor = 7.1 min, tminor = 12.1
min, λ = 220 nm).
4.5.17 Methyl (2R,3S)-3-(4-bromophenyl)-3-((tert-butoxycarbonyl)amino)-2-isocyano-2-phenylpropanoate (3r)
Yield:92% (3r and 3rʹ); colorless oil; [α]D26.0 = -23.2 (c 2.0, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 7.77-7.75 (m, 2H), 7.52-7.50 (m, 3H),
7.45-7.53 (m, 3H), 7.36-7.34 (m, 2H), 5.87 (d, J = 8.4 Hz, 1H), 5.13 (d, J = 8.8 Hz, 1H), 3.63 (s, 3H), 1.21 (s, 9H); 13C NMR (CDCl3, 100
MHz) δ 166.2, 164.5, 154.2, 135.2, 132.1, 131.6, 130.0, 129.5, 128.8, 126.1, 123.0, 80.5, 76.4, 58.2, 54.0, 28.0; IR (Neat): 3358, 2923, 2135,
1747, 1704, 1491, 1450, 1367, 1259, 1167, 1011; HRMS (ESI): calcd for [M+H]+ (C22H24O4N2Br)+ requires 459.0914; found 459.0917;
enantiomeric excess: 80%, determined by HPLC (Chiralpak AD-H, hexane/i-PrOH 95/5, flow rate 1.0 mL/min, tmajor = 19.3 min, tminor = 10.7
min, λ = 220 nm);
Methyl (2R,3S)-3-(4-bromophenyl)-3-((tert-butoxycarbonyl)amino)-2-isocyano-2-phenylpropanoate (3rʹ)
White solid; m.p. 51-53 oC, [α]D25.8 = -57.5 (c 0.25, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 7.47 (m, 2H), 7.34-7.32 (m, 3H), 7.28-7.26 (m,
2H), 6.90-6.88 (m, 2H), 5.67-5.64 (m, 2H), 3.86 (s, 3H), 1.40 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ 166.5, 164.5, 154.1, 134.2, 131.5, 131.1,
129.6, 129.5, 128.9, 125.8, 122.6, 80.8, 76.3, 59.7, 54.2, 28.2; IR (Neat): 3356, 2979, 2136, 1755, 1721, 1490, 1451, 1367, 1250, 1165, 1010;
HRMS (ESI): calcd for [M+H]+ (C22H24O4N2Br)+ requires 459.0914; found 459.0915; enantiomeric excess: 84%, determined by HPLC
(Chiralpak AS-H, hexane/i-PrOH 95/5, flow rate 1.0 mL/min, tmajor = 6.9 min, tminor = 13.4 min, λ = 220 nm).
4.5.18 Methyl (2S,3S)-3-((tert-butoxycarbonyl)amino)-2-isocyano-3-(4-nitrophenyl)-2-phenylpropanoate (3s)
Yield:90% (3s and 3sʹ); White solid; m.p. 70-71 oC, [α]D26.2 = -28.8 (c 1.0, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 8.24-8.22 (m, 2H), 7.76-
7.66 (m, 4H), 7.47-7.45 (m, 3H), 6.01 (d, J = 8.8 Hz, 1H), 5.23 (d, J = 9.6 Hz, 1H), 3.64 (s, 3H), 1.20 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ
166.1, 165.3, 154.3, 148.1, 143.4, 131.8, 129.8, 129.5, 129.1, 126.0, 123.6, 81.0, 76.1, 58.3, 54.2, 28.0; IR (Neat): 3357, 2979, 2918, 2135,
1747, 1720, 1608, 1526, 1450, 1368, 1349, 1275, 1259, 1165, 1111, 1069, 1010; HRMS (ESI): calcd for [M+H]+ (C22H24O6N3)+ requires
426.1660; found 426.1662; enantiomeric excess: 68%, determined by HPLC (Chiralpak AD-H, hexane/i-PrOH 90/10, flow rate 1.0 mL/min,
tmajor = 13.4 min, tminor = 8.7 min, λ = 220 nm);
Methyl (2R,3S)-3-((tert-butoxycarbonyl)amino)-2-isocyano-3-(4-nitrophenyl)-2-phenylpropanoate (3sʹ)
White solid; m.p. 61-62 oC, [α]D26.3 = -57.5 (c 2.6, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 8.00-7.98 (m, 2H), 7.45 (m, 2H), 7.35-7.33 (m,
3H), 7.20-7.18 (m, 2H), 5.76 (dd, J1 = 9.6 Hz, J2 = 40.4 Hz, 2H), 3.89 (s, 3H), 1.40(s, 9H); 13C NMR (CDCl3, 100 MHz) δ 166.3, 165.3,
154.1, 147.8, 142.4, 131.1, 129.9, 129.1, 129.1, 129.7, 123.1, 81.2, 75.9, 59.8, 54.4, 28.2; IR (Neat): 3357, 2978, 2929, 2854, 2135, 1757,
1720, 1608, 1525, 1497, 1367, 1349, 1248, 1164; HRMS (ESI): calcd for [M+H]+ (C22H24O6N3)+ requires 426.1660; found 426.1662;
enantiomeric excess: 95%, determined by HPLC (Chiralpak AS-H, hexane/i-PrOH 90/10, flow rate 1.0 mL/min, tmajor = 9.6 min, tminor = 15.7
min, λ = 220 nm).
4.5.19 Methyl (2S,3S)-3-(3-bromophenyl)-3-((tert-butoxycarbonyl)amino)-2-isocyano-2-phenylpropanoate (3t)
Yield:92% (3t and 3tʹ); White solid; m.p. 55-56 oC [α]D23.0 = -34.2 (c 2.0, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 7.75-7.73 (m, 2H), 7.58
(m, 1H), 7.48-7.39 (m, 5H), 7.24-7.22 (m, 2H), 5.86 (d, J = 8.8 Hz, 1H), 5.12 (d, J = 8.8 Hz, 1H), 3.63 (s, 3H), 1.19 (s, 9H); 13C NMR
(CDCl3, 100 MHz) δ 166.2, 164.6, 154.2, 138.3, 132.1, 131.9, 131.4, 130.0, 129.5, 128.8, 126.8, 126.1, 122.5, 80.6, 58.1, 54.0, 28.0; IR
(Neat): 3350, 2978, 2136, 1721, 1572, 1498, 1450, 1368, 1248, 1165, 1050; HRMS (ESI): calcd for [M+H]+ (C22H24O6N3)+ requires
459.0914; found 459.0912; enantiomeric excess: 64%, determined by HPLC (Chiralpak AD-H, hexane/i-PrOH 95/15, flow rate 0.8 mL/min,
tmajor = 17.2 min, tminor = 11.9 min, λ = 220 nm);
Methyl (2R,3S)-3-(3-bromophenyl)-3-((tert-butoxycarbonyl)amino)-2-isocyano-2-phenylpropanoate (3tʹ)
White solid; m.p. 57-58 oC, [α]D23.1 = -74.4 (c 2.0, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 7.46 (m, 2H), 7.35-7.30 (m, 4H), 7.12 (m, 1H),
7.03-6.95 (m, 2H), 5.65 (m, 2H), 3.87 (s, 3H), 1.40(s, 9H); 13C NMR (CDCl3, 100 MHz) δ 166.5, 164.6, 154.1, 137.3, 131.5, 131.1, 129.6,
129.4, 128.9, 126.6, 125.8, 122.0, 80.8, 76.2, 59.7, 54.2, 28.2; IR (Neat): 3350, 2956, 2925, 2852, 2136, 1755, 1703, 1572, 1497, 1477, 1450,
1367, 1248, 1164, 1048, 855, 745; HRMS (ESI): calcd for [M+H]+ (C22H24O4N2Br)+ requires 459.0914; found 429.0915; enantiomeric excess:
90%, determined by HPLC (Chiralpak AD-H, hexane/i-PrOH 96/4, flow rate 0.9 mL/min, tmajor = 7.4 min, tminor = 12.7 min, λ = 220 nm).
4.5.20 Methyl (2S,3R)-3-((tert-butoxycarbonyl)amino)-3-(furan-2-yl)-2-isocyano-2-phenylpropanoate (3u) and Methyl (2R,3R)-3-((tert-
butoxycarbonyl)amino)-3-(furan-2-yl)-2-isocyano-2-phenylpropanoate (3uʹ)
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Yield:85%; White solid; m.p. 106-107 oC, [α]D23.1 = +3.2 (c 2.0, CHCl3); 1H NMR (CDCl3, 400 MHz) dr = 1:1, δ 7.74-7.72 (m, 2H), 7.56-
7.55 (m, 2H), 7.42-7.36 (m, 7H), 7.24 (m, 1H), 6.41-6.40 (m, 1H), 6.38-6.37 (m, 1H), 6.14 (m, 1H), 6.05 (d, J = 10.4 Hz, 1H), 5.94 (m, 1H),
5.87 (d, J = 10.4 Hz, 1H), 5.60 (d, J = 9.6 Hz, 1H), 5.13 (d, J = 10.4 Hz, 1H), 3.83 (s, 3.1H major), 3.77 (s, 3H minor), 1.42 (s, 9.5H major),
1.21 (s, 9H minor); 13C NMR (CDCl3, 100 MHz) δ 166.3, 164.0 (163.6 minor), 154.2, 149.5 (148.3 minor), 142.5 (143.0 minor), 131.7 (131.5
minor), 129.3, 128.7, 128.6, 126.2, 125.8, 80.4 (80.7 minor), 75.6 (75.3 minor), 54.6 (55.2 minor), 54.1 (54.0 minor), 27.9 (28.2 minor); IR
(Neat): 3356, 2979, 2137, 1750, 1720, 1499, 1450, 1435, 1392, 1368, 1248, 1160, 1010; HRMS (ESI): calcd for [M+H]+ (C20H23O5N2)+
requires 371.1601; found 371.1599; major diastereoisomer enantiomeric excess: 52%, tmajor = 14.5 min, tminor = 8.9 min; minor diastereoisomer
enantiomeric excess: 80%, tmajor = 33.4 min, tminor = 10.3 min, determined by HPLC (Chiralpak AD-H, hexane/i-PrOH 93/7, flow rate 1.0
mL/min, λ = 220 nm).
4.5.21 Methyl (2S,3R)-3-((tert-butoxycarbonyl)amino)-2-isocyano-2-phenyl-3-(thiophen-2-yl)propanoate (3v) and Methyl (2R,3R)-3-((tert-
butoxycarbonyl)amino)-2-isocyano-2-phenyl-3-(thiophen-2-yl)propanoate (3vʹ)
Yield:92%; White solid; m.p. 75-76 oC, [α]D23.3 = -18.4 (c 1.0, CHCl3); 1H NMR (CDCl3, 400 MHz) dr = 1.3:1, δ 7.76-7.74 (m, 2H), 7.59-
7.58 (m, 1.7H minor), 7.45-7.37 (m, 5H), 7.30 (dd, J1 = 1.2 Hz, J2 = 5.2 Hz, 1H), 7.17 (d, J = 3.2 Hz, 1H), 7.11 (dd, J1 = 1.2 Hz, J2 = 5.2 Hz,
0.8H minor), 7.01 (dd, J1 = 4.8 Hz, J2 = 3.6 Hz, 1H), 6.81-6.79 (m, 1H), 6.75-6.74 (m, 1H), 6.20 (d, J = 10.4Hz, 1H), 6.05 (d, J = 10.4 Hz,
1H), 5.53 (d, J = 10.4 Hz, 1H), 5.08 (d, J = 10.0 Hz, 1H), 3.85 (s, 2.4H minor), 3.72 (s, 3H), 1.42 (s, 7.2H minor), 1.21 (s, 9H); 13C NMR
(CDCl3, 100 MHz) δ 166.5 (166.3 minor), 164.8 (164.7 minor), 154.1, 139.2 (138.2 minor), 131.8 (132.1 minor), 129.5 (129.4 minor), 128.9,
128.8, 126.9, 126.9, 126.8, 126.4, 126.1, 125.8, 125.6, 80.7 (80.4 minor), 76.6, 55.8 (57.0 minor), 54.0 (54.1 minor), 28.0 (28.2 minor); IR
(Neat): 3354, 2978, 2136, 1754, 1718, 1498, 1450, 1434, 1367, 1248, 1161, 1009; HRMS (ESI): calcd for [M+H]+ (C20H23O4N2S)+ requires
387.1373; found 387.1369; major diastereoisomer enantiomeric excess: 50%, tmajor = 13.5 min, tminor = 16.3 min; minor diastereoisomer
enantiomeric excess: 79%, tmajor = 11.8 min, tminor = 21.3 min, determined by HPLC (Chiralpak AS-H, hexane/i-PrOH 97/3, flow rate 0.8
mL/min, λ = 220 nm).
4.6 Characterization data of products 5a+5a
ʹ
1-(Tert-butyl) 4-methyl (4S,5S)-4,5-diphenyl-4,5-dihydro-1H-imidazole-1,4-dicarboxylate (5a) and 1-(Tert-butyl) 4-methyl (4R,5S)-4,5-
diphenyl-4,5-dihydro-1H-imidazole-1,4-dicarboxylate (5aʹ)
Yield:94%; White solid; m.p. 175-176 oC, [α]D27.1 = -109.9 (c 1.0, CHCl3); 1H NMR (CDCl3, 400 MHz) dr = 1.2:1, δ 8.09 (s, 1H), 8.04 (s,
1H), 7.76-7.74 (m, 2H), 7.44-7.40 (m, 2H), 7.36-7.29 (m, 6H), 7.04-6.98 (m, 6H), 6.85 (m, 2H), 6.01 (s, 1H), 5.38 (s, 1H), 3.77 (s, 2.4H
minor), 3.16 (s, 3H major), 1.22 (s, major 9H, minor 7H); 13C NMR (CDCl3, 100 MHz) δ 169.6 (173.0 minor), 150.4 (149.6 minor), 141.9
(136.7 minor), 128.4, 128.4, 128.2, 127.7, 127.3 (127.3 minor), 126.8, 126.7, 132.1 (131.8 minor), 129.5 (129.4 minor), 82.8, 66.4, 52.1 (53.4
minor), 27.7; IR (Neat): 2980, 2923, 2852, 1732, 1707, 1612, 1446, 1382, 1278, 1257, 1222, 1129, 1081, 742, 699; HRMS (ESI): calcd for
[M+H]+ (C22H5O4N2)+ requires 381.1809; found 381.1811; major diastereoisomer enantiomeric excess: 74%, tmajor = 24.3 min, tminor = 18.3
min; minor diastereoisomer enantiomeric excess: 71%, tmajor = 20.0 min, tminor = 16.4 min, determined by HPLC (Chiralpak PC-II, hexane/i-
PrOH 90/10, flow rate 0.8 mL/min, λ = 220 nm).
Acknowledgment
Research support from the National Natural Science Foundation of China (Nos. 21272247, 21572247, 21290184) and the Chinese
Academy of Sciences (XDB 20020100) is gratefully acknowledged.
Supplementary data
Supplementary data (details of condition optimization, NMR spectra, HPLC datas and X-ray crystal data of compounds 3a and 3tʹ) associated
with this article can be found in the online version, at http://
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12