Enantioselective Mannich reaction of γ-malonate-substituted α,β-unsaturated esters with N-Boc imines catalyzed by chiral bifunctional thiourea-phosphonium salts

Article abstract of DOI:10.1016/j.tet.2018.12.052

A novel enantioselective Mannich reaction of γ-malonate-substituted α β-unsaturated esters with N-protected arylaldimines was realized by using asymmetric phase-transfer catalysis (APTC). With amino acid-derived bifunctional thiourea-phosphonium salts as a catalyst, a series of enantio-enriched Mannich products could be synthesized under very mild and simple reaction conditions with high yields and enantioselectivities.

Full text of DOI:10.1016/j.tet.2018.12.052

Accepted Manuscript
Enantioselective Mannich reaction of γ-malonate-substituted α,β-unsaturated esters
with N-Boc imines catalyzed by chiral bifunctional thiourea-phosphonium salts
Jiaxing Zhang, Gang Zhao
PII:
S0040-4020(18)31542-4
https://doi.org/10.1016/j.tet.2018.12.052
TET 30038
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 17 October 2018
Revised Date: 20 December 2018
Accepted Date: 24 December 2018
Please cite this article as: Zhang J, Zhao G, Enantioselective Mannich reaction of γ-malonate-
substituted α,β-unsaturated esters with N-Boc imines catalyzed by chiral bifunctional thiourea-
phosphonium salts, Tetrahedron (2019), doi: https://doi.org/10.1016/j.tet.2018.12.052.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT
Enantioselective Mannich Reaction of γ-malonate-substituted
α,β-unsaturated esters with N-Boc Imines Catalyzed by Chiral
Bifunctional Thiourea-phosphonium Salts
Jiaxing Zhang, Gang Zhao*
Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
Fax: 0086-21-64166128; Tel: 0086-21-54925182
E-mail: zhaog@mail.sioc.ac.cn

ACCEPTED MANUSCRIPT
Enantioselective Mannich reaction of γ-malonate-substituted
α,β-unsaturated esters with N-Boc imines catalyzed by chiral
bifunctional thiourea-phosphonium salts
Jiaxing Zhang, Gang Zhao*
Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
E-mail: shyj@mail.ahnu.edu.cn, zhaog@mail.sioc.ac.cn
Abstract: A novel enantioselective Mannich reaction of γ-malonate-substituted α,
β-unsaturated esters with N-protected arylaldimines was realized by using asymmetric
phase-transfer catalysis (APTC). With amino acid-derived bifunctional
thiourea-phosphonium salts as a catalyst, a series of enantio-enriched Mannich
products could be synthesized under very mild and simple reaction conditions with
high yields and enantioselectivities.
Keywords: Bifunctional thioureas; phosphonium salts; Mannich reaction; asymmetric
catalysis; phase-transfer catalysis
1. Introduction
Chiral β-amino carbonyl compounds are very useful building blocks in the
synthesis of numerous biologically and pharmaceutically active substances.[1] Being
one of the most convenient way to these useful compounds, the enantioselective
Mannich reaction has received much research attention and impressive advances have
[2]
been achieved by using both metal catalysis and organocatalysis.[3] In this regard,
over the past decade, asymmetric organocatalytic Mannich reaction of various
[4]
malonates to imines or imine surrogates has made significant advances.
Various
chiral organocatalysts including cinchona alkaloid-derived phase-transfer catalysts [5]
[6]
and thioureas, bifunctional tertiary amine-thiourea catalysts,
and
guanidine-bisthiourea catalysts [7] have all been successfully applied in this reaction.
Particularly, Enders and co-workers have recently utilized γ-malonate-substituted α,
β-unsaturated esters to react with N-protected arylaldimines, which involes a novel
domino Mannich/aza-Michael process. [8] Such a process provided a highly useful
1

ACCEPTED MANUSCRIPT
new way to enantio-enriched polysubstituted pyrrolidines. However, with bifunctional
tertiary amine-thiourea catalysts, the practicality of this process was somewhat
impaired by the long reaction time (3-11 days), relatively high catalyst loading and
not-so-satisfactory enantioselectivities.
On the other hand, our group has developed chiral amino acid-derived
phase-transfer catalysts. [9] In the field of asymmetric PTC, quaternary ammonium
[4]
salt-based catalysts have been utilized in the Mannich-type reaction of malonates
while the compatibility of quaternary phosphonium salt-based catalysts with this
reaction remains unknown. Our group has very recently reported novel bifunctional
thiourea-phosphonium salts as highly efficient catalysts in asymmetric aza-Henry
reactions and Mannich reactions.[10] We report herein that these bifunctional
thiourea-phosphonium salts are also highly effective for the catalytic enantioselective
Mannich reaction of aldimines with γ-malonated-substituted α,β-unsaturated esters,
which is highly complementary to current methods.
2. Results and discussion
Using the reaction between N-Boc imine 2a and γ-malonate-substituted α,
β-unsaturated ester 3a as the model reaction, we first tested the catalytic efficiency of
different bifunctional phosphonium salts (Table 1, entries 1-8). In general, these
catalysts showed high efficiency in this Mannich reaction, which could proceed to
completion to give almost quantitative yields within 12 h at room temperature with a
catalyst loading of 5 mol%. Both the thiourea moiety and the amino acid skeletons
have significant influence on the reaction. The catalyst 1c derived from
L-phenylalanine with the thiourea structure gave better enantioselectivity than the
acetyl amine and the urea structure (entries 1-3). Then catalyst 1e derived from
L-isoleucine with the 3, 5-bis(trifluoromethyl)phenyl thiourea moiety was found to be
better to give 61% ee (entry 5). Further structural modification in the thiourea moiety
or the substitution types of the phosphonium center is failed to improve the
enantioselectivity (entries 6-11). Next, solvent effect was explored with catalyst 1e,
but the enantioselectivity was also not improved (entries 12-15).
2

ACCEPTED MANUSCRIPT
Table 1 Screening of catalysts and solvents.a
Entry
Catalyst
Solvent
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
CH2Cl2
THF
97
98
95
99
99
99
99
99
96
94
99
95
99
99
99
2
1a
1b
1c
1d
1e
1f
1g
1h
1i
35
50
59
61
55
55
59
33
43
59
19
9
9[d]
10[d]
11[d]
12
13
14
15
1j
1k
1e
1e
1e
1e
TBME
PhCF3
27
56
a Reaction conditions: 2a (0.15 mmol), 3a (0.1 mmol) and base (0.2 mmol) in the presence of 1 (5
mol%) in solvents (1.0 mL).
b Isolated yields.
c Determined by chiral stationary phase HPLC.
d Reaction time was 8 h and 0.5 mmol K2CO3 was used.
To further improve the enantioselectivity, we then screened different bases
(Table 2). Pleasingly, when a milder base KF was used, a significantly improved
enantioselectivity of 81% ee at 0 oC (entry 8). Moreover, the catalyst loading amount
3

ACCEPTED MANUSCRIPT
could be decreased to 3 mol% while maintain the same high chemical yield and
enantioselectivity (entry 10), while a reduction in the amount of KF to inferior results
(entry 11). Thus, the optimum reaction conditions were identified as follows: 3 mol%
of 1e and 5 equiv. of KF in toluene at 0 oC.
Table 2 Screening of bases. a
Entry
Base
Time [h]
T [oC]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
9
KOH
Na2CO3
K2CO3
K2HPO4
KF
CsF
K2HPO4
KF
8
rt
rt
rt
rt
rt
rt
0
0
-10
0
complicated
nd
68
60
75
74
70
76
81
80
82
57
15
15
15
15
15
24
24
32
24
50
99
99
99
99
98
96
97
92
97
90
KF
KF
KF
10[d]
11[e]
0
a
Reaction conditions: 2a (0.15 mmol), 3a (0.1 mmol) and base (0.5 mmol) in the presence of 1e
(5 mol%) in toluene (1.0 mL).
b Isolated yields.
c Determined by chiral stationary phase HPLC.
d 3 mol% of catalyst 1e was used.
e 0.05 mmol KF was used.
Next, a series of N-Boc-protected aryl aldimines 2a-2p and different substituted
γ-malonate-substituted α,β-unsaturated esters 3a-3f were investigated under the
optimized conditions (Table 3). In general, excellent yields and high
enantioselectivities were obtained within a relatively short reaction time (12-30 h).
For different 3, increasing the steric hindrance of the ester moieties seemed slightly
favored in terms of enantioselectivity (entries 1-5). As to different aldimines 1, when
Ar was a substituted benzene ring, good to excellent yields and high ee values were
generally obtained, irrespective of the electronic nature of the substituents on the
benzene ring. Notably, an apparent meta effect was observed: the more sterically
4

ACCEPTED MANUSCRIPT
demanding m-substituted aryl imines gave higher ee values (entries 6-17). Moreover,
heteroaryl imines 2n and 2o also took part in the reaction to give excellent yields,
albeit with relatively lower ees (65% and 70%) (entries 18 and 19).
Table 3 Substrate scope study. a
Entry
2 (Ar)
3 (R1/ R2)
Time (h)
4
Yield (%)[b] ee (%)[c]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
2a (Ph)
2a (Ph)
2a (Ph)
2a (Ph)
2a (Ph)
3b (Me/Me)
3c (Bn/Me)
3d (Ph/ Me)
3e (Me/Et)
3f (Et/ Et)
3a (Et/ Me)
3a (Et/ Me)
3a (Et/ Me)
3a (Et/ Me)
3a (Et/ Me)
3a (Et/ Me)
24
24
24
24
24
20
20
20
20
20
24
20
24
24
20
20
20
24
30
12
12
99
99
96
99
99
99
85
98
97
84
95
98
83
93
99
99
80
95
60
99
99
77
83
78
81
81
85
87
81
79
81
81
80
83
81
85
86
86
70
87
88
90
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
4s
2b (o-ClC6H4)
2c (m-ClC6H4)
2d (p-ClC6H4)
2e (p-FC6H4)
2f (p-BrC6H4)
2g (p-MeC6H4)
2h (p-MeOC6H4) 3a (Et/ Me)
2i (p-NO2C6H4)
2j (m-FC6H4)
3a (Et/ Me)
3a (Et/ Me)
3a (Et/ Me)
2k (m-MeC6H4)
2l (m-MeOC6H4) 3a (Et/ Me)
2m (m-BrC6H4)
2n (2-Thienyl)
2o (α-Naphthyl)
2c (m-ClC6H4)
2k (m-MeC6H4)
3a (Et/ Me)
3a (Et/ Me)
3a (Et/ Me)
3c (Bn/Me)
3c (Bn/Me)
4t
4u
4v
a Reaction conditions: 2a (0.15 mmol), 3a (0.1 mmol) and base (0.5 mmol) in the presence of 1e (3
mol%) in toluene (1.0 mL).
b Isolated yields.
c Determined by chiral stationary phase HPLC.
In order to get more insight into the role of the cooperative action between the
thiourea moiety and the phosphonium center in these bifunctional
thiourea-phosphonium salts in this reaction, control experiments were performed with
two variants of the catalyst 1c under the optimized reaction conditions as in Table 3
5

ACCEPTED MANUSCRIPT
(Figure 1a). The use of catalyst 1m with a blocked hydrogen bonding site or catalyst
1n without the quaternary phosphonium center all led to much inferior results in terms
of yield, enantioselectivity and reaction time compared to their parent catalyst 1c.
This result indicates the importance of cooperative catalysis of the two functionalities
in the catalytic process. Moreover, allyl-substituted and methyl-substituted malonates
were investigated under the optimized conditions (Figure 1b), furnishing the desired
products with good enantioselectivities. The absolute configuration of 4y was assigned to be
S by comparison of the optical rotation values with the literature data [10c] and those of others
were determined by analogy. The product 4p was treatment with TBAB
(tetrabutylammonium bromide) and Cs2CO3 gave the pyrrolidine product 5 with 96% yield
and 61% ee (Figure 1c) [13]
.
Figure 1. Control experiments and product transformatiom.
3. Conclusion
In conclusion, we have successfully applied amino acid-derived bifunctional
6

ACCEPTED MANUSCRIPT
thiourea-phosphonium salts to catalyze asymmetric Mannich reaction between
γ-malonate-substituted α, β-unsaturated esters and N-Boc aryl aldimines. These
phase-transfer catalysts demonstrated high efficiency in the reaction, providing the
desired products in excellent yields and high enantioselectivities within much
shortened reaction time compared to previously used organocatalysts. Further
applications of this kind of phase-transfer catalysts to other reactions as well as
synthetically useful conversions of the chiral β-amino carbonyl products are underway
in our laboratory.
4. Experimental
4.1 General information
1
The H NMR spectra were recorded on a Bruker (400 MHz) spectrometer. All
chemical shifts (δ) were given in ppm. Data were reported as follows: chemical shift,
integration, multiplicity (s = single, d = doublet, t = triplet, q = quartet, br = broad, m
= multiple) and coupling constants (Hz). 13C NMR spectra were recorded on a
DPX-400 (400 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 apparatus 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.).
[11, 3c]
All starting imines were synthesized according to reported methods.
All
bifunctional phosphonium salt catalysts were synthesized according to procedures
reported previously. [10a] 3a-3c, 3e-3f [12] were prepared by literature procedure.
4.2 Preparation of catalysts 3
In a flame dried, one-necked round-bottom flask NaH (60% in oil, 1.0 equiv.) was
suspended in anhydrous THF (0.15 M) and the reaction was cooled to 0 °C. Malonic
ester (1.0 equiv.) was added in small portions over a period of 30 minutes and the
reaction was stirred for 1 h at 0 °C. After the addition of alkyl 4-bromocrotonate (1.3
eq.) the reaction was stirred for further 60 minutes at 0 °C. The mixture was quenched
by the addition of aqueous HCl (1.0 N) and extracted three times with
dichloromethane. The combined organic layers were dried over sodium sulfate,
filtered and concentrated in vacuo. Column chromatography (petroleum ether: ethyl
7

ACCEPTED MANUSCRIPT
acetate = 10:1 to 5:1) afforded the pure products as colorless oils.
4.2.1 (E)-4-methyl 1, 1-diphenyl but-3-ene-1, 1, 4-tricarboxylate (3d)
3d was synthesized according to the general procedure using NaH (360 mg, 9 mmol),
THF (70 mL), diphenylmalonate (2.3 g, 9 mmol) and (E)-methyl-4-bromocrotonate
(1.97 g, 1.3 mL, 11 mmol).
o
1
1.6 g yield (50%, white solid), m.p. = 52-53 C. H-NMR (400 MHz, CDCl
3
): δ
3.03-3.06 (m, 2H), 3.75 (s, 3H), 4.00 (t, J = 8.0 Hz, 1H), 6.06 (d, J = 16.0 Hz, 1H),
7.02-7.08 (m, 1H), 7.10-7.13 (m, 4H), 7.24-7.28 (m, 2H), 7.37-7.41 (m, 4H) ppm.
13
C-NMR (100 MHz, CDCl ): δ 31.1, 50.7, 51.7, 121.2, 124.2, 126.4, 129.6, 143.2,
3
150.3, 166.3, 166.6 ppm; IR (Neat) 2951, 1753, 1724, 1591, 1492, 1273, 1190, 1162,
1134, 747, 689; HRMS(MALDI): calcd. for [M+Na]+ (C20H18O6) requires 377.1001,
found 377.0993.
4.3 Preparation of catalysts 1j and 1k
To a solution of the corresponding amino acid-derived bifunctional phosphine (1.0
equiv.) in anhydrous toluene was added the corresponding benzylic halide (1.2 equiv.),
and the resulting mixture was stirred at 110oC for 8h. Then the mixture was allowed
to cool to ambient temperature and concentrated under reduced pressure. The crude
mixture was purified by flash column chromatography to afford the desired phase
transfer catalyst (CH2Cl2/MeOH = 20:1).
4.3.1
((2S,3S)-2-(3-(3,5-bis(trifluoromethyl)phenyl)thioureido)-3-methylpentyl)(4-fluoroben
zyl)diphenylphosphonium bromide (1j)
25
Yield: 72%; White solid. m.p. = 108-110oC; [α]D = -50.1 (c = 1.2, CHCl3); H-NMR
1
(400 MHz, CDCl ): δ 9.81 (bs, 2H), 8.13 (s, 2H), 7.82 (m, 1H), 7.69-7.72 (m, 6H),
3
7.55-7.59 (m, 3H), 6.86-6.90 (m, 5H), 5.15 (m, 1H), 4.66-4.83 (m, 2H), 3.68-3.72 (m,
1H), 3.51 (d, J = 16.0 Hz, 1H), 1.81 (m, 1H), 1.26-1.28 (m, 1H), 1.18-1.20 (m, 1H),
13
1.01 (d, J = 8.0 Hz, 3H), 0.80 (t, J = 8.0 Hz, 3H); C-NMR (100 MHz, CDCl
3
): δ
180.9, 164.4 (d, JC-P = 4 Hz), 161.9 (d, JC-P = 4 Hz), 141.2, 135.7 (d, JC-P = 2.9 Hz),
135.3 (d, JC-P = 3 Hz), 133.8 (d, JC-P = 1.4 Hz), 133.7 (d, JC-P = 1.4 Hz), 132.6 (d, JC-P
= 5.6 Hz), 132.5 (d, JC-P = 5.6 Hz), 131.6 (q, JC-F = 24 Hz), 130.8 (d, JC-P = 12.2 Hz),
130.6 (d, JC-P = 12.4), 123.7 (q, JC-F = 271.4 Hz), 123.0, 122.9-123.0 (m), 117.8,
117.7, 117.0 (d, JC-P = 3.1 Hz), 116.9, 116.7 (d, JC-P = 3.1 Hz), 52.1 (d, JC-P = 4.4 Hz),
41.3 (d, JC-P = 12.0 Hz), 28.9 (d, JC-P = 45.3 Hz), 26.0, 24.9 (d, JC-P = 51.2 Hz), 15.2,
31
19
11.9; P-NMR (163 MHz, CDCl
3
): δ 25.2; F-NMR (282 MHz, CDCl ): δ -62.9,
3
-111.7; IR (Neat) 3048, 2963, 2962, 2878, 1549, 1510, 1473, 1438, 1284, 1177, 1134,
846, 739, 681; HRMS(MALDI): calcd. for [M-Br]+ (C34H33N2F7PS) requires
665.1985, found 665.1980.
4.3.2
((2S,3S)-2-(3-(3,5-bis(trifluoromethyl)phenyl)thioureido)-3-methylpentyl)-diphenyl(4-
methylbenzyl)phosphonium bromide (1k)
8

ACCEPTED MANUSCRIPT
25
Yield: 70%; White solid. m.p. = 204-206oC; [α]D = -70.7 (c = 1.6, CHCl3); H-NMR
1
(400 MHz, CDCl ): δ 9.77-9.80 (m, 2H), 8.10 (s, 2H), 7.75-7.78 (m, 3H), 7.53-7.61
3
(m, 8H), 7.01 (d, J = 7.6 Hz, 2H), 6.80 (d, J = 7.2 Hz, 2H), 5.21 (m, 1H), 4.73-4.80 (t,
J = 16.0 Hz, 1H), 4.48-4.55 (t, J = 16.0 Hz, 1H), 3.49-3.58 (m, 1H), 2.51-2.58 (t, J =
14.4 Hz, 1H), 2.28 (s, 3H), 1.82 (m, 1H), 1.02 (d, J = 6.8 Hz, 3H), 0.84 (t, J = 7.2 Hz,
13
3H); C-NMR (100 MHz, CDCl
3
): δ 180.8, 141.2, 139.5 (d, JC-P = 4 Hz), 135.5 (d,
JC-P = 3 Hz), 135.1 (d, JC-P = 3 Hz), 133.8 (d, JC-P = 9.3 Hz), 133.6 (d, JC-P = 9.1 Hz),
131.5 (q, JC-F = 34 Hz), 130.7, 130.6, 130.5, 130.5, 130.4, 123.8 (q, JC-P = 272 Hz),
123.5 (d, JC-P = 9 Hz), 122.9, 119.7, 119.4, 118.6, 117.9, 117.5, 117.1, 52.1 (d, JC-P
=
5 Hz), 41.5 (d, JC-P = 12 Hz), 29.3 (d, JC-P = 45 Hz), 25.9, 24.8 (d, JC-P = 52 Hz), 21.5,
31
19
15.4, 12.0; P-NMR (163 MHz, CDCl
3
): δ 23.5; F-NMR (282 MHz, CDCl ): δ
3
-62.8; IR (Neat) 3047, 2965, 2877, 1549, 1457, 1386, 1277, 1177, 1134, 738, 681;
HRMS(MALDI): calcd. for [M-Br]+ (C35H36N2F6PS) requires 661.2236, found
661.2240.
4.4 General procedure for the enantioselective Mannich reaction
To a suspension of the corresponding γ-malonate substituted α, β-unsaturated ester 3
(0.1 mmol) in toluene (1.0 ml) was added catalyst 1e (3 mol%) and aryl aldimine
(0.15 mmol) sequentially, and the resulting mixture was stirred at 0oC for 5 min. Then
KF (28 mg, 0.5 mmol) was added. The resulting suspension was vigorously stirred at
0 oC for 12-30 h, and then purified by column chromatography (petroleum ether/ethyl
acetate = 10/1 – 4/1) on silica get to afford the product.
4.4.1
4,4-diethyl-1-methyl-(S,E)-5-((tert-butoxycarbonyl)amino)-5-phenylpent-1-ene-1,4,4-t
ricarboxylate (4a)
25
Yield: 97%; colorless oil. Enantiomeric excess: 82%, [α]D = -20.2 (c = 2.70, CHCl3),
determined by HPLC (Chiralpak AD-H column hexane/i-PrOH 9:1, flow rate 1.0
1
ml/min, tminor = 11.4 min, tmajor = 14.4 min, λ = 254 nm); H-NMR (400 MHz,
CDCl ): δ 7.27-7.29 (m, 5H), 6.84-6.92 (m, 1H), 6.57 (d, J = 13.2 Hz, 1H), 5.81 (d, J
3
= 15.6 Hz, 1H), 5.20 (d, J = 9.6 Hz, 1H), 4,16-4.25 (m, 4H), 3.70 (s, 3H), 2.59-2.62
13
(m, 2H), 1.37 (s, 9H), 1.27 (t, J = 7.2 Hz, 3H), 1.20 (t, J = 7.2 Hz, 3H); C-NMR
(100 MHz, CDCl ): δ 169.5, 169.1, 166.2, 154.6, 143.2, 137.7, 128.4, 128.2, 128.0,
3
124.3, 79.6, 62.0, 58.9, 51.5, 37.3, 29.6, 28.2, 14.0, 13.8; IR (Neat) 3431, 2980,
1724, 1658, 1494, 1367, 1275, 1169; HRMS(MALDI): calcd. for [M+Na].+
(C24H33NO8Na) requires 486.2098, found 486.2095.
4.4.2 trimethyl-(S,
E)-5-((tert-butoxycarbonyl)amino)-5-phenylpent-1-ene-1,4,4-tricarboxylate (4b)
25
Yield: 99%; colorless oil. Enantiomeric excess: 77%, [α]D = -25.2 (c = 2.85, CHCl3),
determined by HPLC (Chiralpak AS-H column hexane/i-PrOH 95:5, flow rate 1.0
1
ml/min, tminor = 9.4 min, tmajor = 12.8 min, λ = 254 nm); H-NMR (400 MHz, CDCl
3
):
δ 7.22-7.31 (m, 5H), 6.81-6.88 (m, 1H), 6.44 (d, J = 8.8 Hz, 1H), 5.81 (d, J = 15.6
Hz, 1H), 5.21 (d, J = 9.2 Hz, 1H), 3.75 (s, 3H), 3.73 (s, 3H), 3.71 (s, 3H), 2.60-2.64
9

ACCEPTED MANUSCRIPT
13
(m, 2H), 1.38 (s, 9H); C-NMR (100 MHz, CDCl ): δ 169.7, 169.5, 166.2, 154.6,
3
142.9, 137.5, 128.5, 128.3, 127.8, 124.4, 79.7, 63.1, 58.8, 52.8, 51.5, 37.3, 29.6, 28.2;
IR (Neat) 3434, 2977, 2954, 1723, 1658, 1495, 1436, 1366, 1276, 1169;
HRMS(MALDI): calcd. for [M+Na]+ (C22H29NO8Na) requires 458.1785, found
458.1793.
4.4.3
4,4-dibenzyl-1-methyl-(S,E)-5-((tert-butoxycarbonyl)amino)-5-phenylpent-1-ene-1,4,4
-tricarboxylate (4c)
25
Yield: 99%; colorless oil. Enantiomeric excess: 83%, [α]D = -19.1 (c = 2.45, CHCl3),
determined by HPLC (Chiralpak AD-H column hexane/i-PrOH 9:1, flow rate 1.0
1
ml/min, tminor = 27.6 min, tmajor = 17.1 min, λ = 254 nm); H-NMR (400 MHz,
CDCl ): δ 7.29-7.32 (m, 15H), 6.77-6.85 (m, 1H), 6.50 (d, J = 8.0 Hz, 1H), 5.67 (d, J
3
= 15.6 Hz, 1H), 5.18-5.25 (m, 2H), 5.11 (s, 2H), 3.65 (s, 3H), 2.55-2.68 (m, 2H),
13
1.36 (s, 9H); C-NMR (100 MHz, CDCl
3
): δ 169.7, 169.5, 166.6, 155.1, 143.1,
138.0, 135.3, 134.9, 129.15, 129.13, 129.11, 129.07, 129.0, 128.7, 128.5, 125.2, 80.2,
68.4, 68.3, 63.4, 59.4, 52.0, 37.9, 30.2, 28.8; IR (Neat) 3446, 2977, 1723, 1655,
1496, 1275, 1246, 1168, 753, 699; HRMS(MALDI): calcd. for [M+Na]+
(C34H37NO8) requires 610.2417, found 610.2428.
4.4.4
1-methyl-4,4-diphenyl-(S,E)-5-((tert-butoxycarbonyl)amino)-5-phenylpent-1-ene-1,4,4
-tricarboxylate (4d)
24
Yield: 96%; colorless oil. Enantiomeric excess: 78%, [α]D = +5.1 (c = 2.60, CHCl3),
determined by HPLC (Chiralpak AD-H column hexane/i-PrOH 9:1, flow rate 1.0
1
ml/min, tminor = 48.3 min, tmajor = 24.0 min, λ = 254 nm); H-NMR (400 MHz,
CDCl ): δ 7.25-7.44 (m, 15H), 6.97-6.99 (m, 1H), 6.56 (m, 1H), 6.02 (d, J = 15.6 Hz,
3
1H), 5.52 (d, J = 8.8 Hz, 1H), 3.71 (s, 3H), 2.98-2.99 (m, 2H), 1.39 (s, 9H);
13
C-NMR (100 MHz, CDCl ): δ 167.8, 166.1, 154.7, 150.1, 149.9, 142.2, 137.3,
3
129.8, 129.7, 129.6, 128.7, 128.6, 128.4, 128.3, 126.6, 126.5, 125.3, 121.3, 121.1,
121.0, 115. 4, 80.1, 63.3, 59.3, 51.6, 37.8, 28.3, 28.2; IR (Neat) 3447, 2977, 1756,
1724, 1655, 1492, 1367, 1163, 748, 688; HRMS(MALDI): calcd. for [M+Na]+
(C34H32NO8) requires 582.2104, found 582.2103.
4.4.5
1-ethyl-4,4-dimethyl-(S,E)-5-((tert-butoxycarbonyl)amino)-5-phenylpent-1-ene-1,4,4-t
ricarboxylate (4e)
26
Yield: 99%; colorless oil. Enantiomeric excess: 81%, [α]D = -23.0 (c = 2.80, CHCl3),
determined by HPLC (Chiralpak AD-H column hexane/i-PrOH 95:5, flow rate 1.0
1
ml/min, tminor = 32.1 min, tmajor = 27.8 min, λ = 254 nm); H-NMR (400 MHz,
CDCl ): δ 7.23-7.31 (m, 5H), 6.78-6.84 (m, 1H), 6.46 (d, J = 9.2 Hz, 1H), 5.80 (d, J
3
= 15.6 Hz, 1H), 5.22 (d, J = 9.2 Hz, 1H), 4.16 (q, J = 7.2 Hz, 2H), 3.75 (s, 3H), 3.73
13
(s, 3H), 2.60-2.64 (m, 2H), 1.38 (s, 9H), 1.27 (t, J = 7.2 Hz, 3H); C-NMR (100
MHz, CDCl ): δ 169.8, 169.5, 166.8, 154.6, 142.5, 137.5, 128.4, 128.3, 127.9, 124.9,
3
79.7, 63.1, 58.7, 52.8, 37.3, 28.2, 18.3, 14.2; IR (Neat) 3448, 2979, 1719, 1654,
10

ACCEPTED MANUSCRIPT
1492, 1367, 1247, 1169, 1044; HRMS(MALDI): calcd. for [M+Na]+ (C23H31NO8Na)
requires 472.1942, found 472.1940.
4.4.6
triethyl-(S,E)-5-((tert-butoxycarbonyl)amino)-5-phenylpent-1-ene-1,4,4-tricarboxylat
e (4f)
25
Yield: 99%; colorless oil. Enantiomeric excess: 81%, [α]D = -20.2 (c = 2.70, CHCl3),
determined by HPLC (Chiralpak AD-H column hexane/i-PrOH 9:1, flow rate 1.0
1
ml/min, tminor = 11.3 min, tmajor = 13.9 min, λ = 254 nm); H-NMR (400 MHz,
CDCl ): δ 7.27-7.29 (m, 5H), 6.82-6.86 (m, 1H), 6.57 (d, J = 9.2 Hz, 1H), 5.80 (d, J
3
= 15.6 Hz, 1H), 5.20 (d, J = 9.6 Hz, 1H), 4.13-4.25 (m, 6H), 2.59-2.62 (m, 2H), 1.37
13
(s, 9H), 1.18-1.29 (m, 9H); C-NMR (100 MHz, CDCl
3
): δ 168.7, 168.3, 165.9,
143.7, 143.5, 123.9, 123.8, 110.0, 61.7, 60.4, 52.7, 50.6, 50.3, 31.1, 14.2, 14.0; IR
(Neat) 3446, 2980, 1719, 1540, 1490, 1367, 1244, 1173, 756, 703; HRMS(MALDI):
calcd. for [M+Na]+ (C25H35NO8) requires 500.2260, found 500.2248.
4.4.7
4,4-diethyl-1-methyl-(S,E)-5-((tert-butoxycarbonyl)amino)-5-(2-chloro-phenyl)pent-1-
ene-1,4,4-tricarboxylate (4g)
Yield: 99%; colorless oil. Enantiomeric excess: 85%, [α]D = -36.6 (c = 2.80, CHCl3),
26
determined by HPLC (Chiralpak AD-H column hexane/i-PrOH 95:5, flow rate 1.0
1
ml/min, tminor = 16.3 min, tmajor = 37.0 min, λ = 254 nm); H-NMR (400 MHz,
CDCl ): δ 7.28-7.30 (m, 2H), 7.13-7.20 (m, 2H), 6.71-6.75 (m, 1H), 6.59 (d, J = 8.8
3
Hz, 1H), 5.87 (d, J = 9.2 Hz, 1H), 5.73 (d, J = 15.6 Hz, 1H), 4.15-4.20 (m, 4H), 3.61
(s, 3H), 2.80-2.86 (m, 1H), 2.48-2.53 (m, 1H), 1.30 (s, 9H), 1.21 (t, J = 7.2 Hz, 3H),
13
1.15 (t, J = 7.2 Hz, 3H); C-NMR (100 MHz, CDCl
3
): δ 169.4, 169.0, 166.2, 154.4,
143.3, 136.3, 129.8, 129.2, 128.7, 127.1, 124.0, 79.6, 63.3, 62.2, 62.1, 54.2, 51.4,
35.8, 30.9, 28.2, 14.0, 13.7; IR (Neat) 3428, 2979, 2926, 1724, 1491, 1391, 1260,
1170, 1097, 801, 758; HRMS(MALDI): calcd. for [M+Na]+ (C24H32NO8Cl)
requires 520.1714, found 520.1715.
4.4.8
4,4-diethyl-1-methyl-(S,E)-5-((tert-butoxycarbonyl)amino)-5-(3-chloro-phenyl)pent-1-
ene-1,4,4-tricarboxylate (4h)
Yield: 85%; colorless oil. Enantiomeric excess: 87%, [α]D = -34.5 (c = 2.25, CHCl3),
25
determined by HPLC (Chiralpak AD-H column hexane/i-PrOH 9:1, flow rate 1.0
1
ml/min, tminor = 10.2 min, tmajor = 13.3 min, λ = 254 nm); H-NMR (400 MHz,
CDCl ): δ 7.17-7.27 (m, 5H), 6.83-6.90 (m, 1H), 6.52 (d, J = 8.8 Hz, 1H), 5.82 (d, J
3
= 15.6 Hz, 1H), 5.16 (d, J = 9,2 Hz, 1H), 4.18-4.25 (m, 4H), 3.71 (s, 3H), 2.49-2.65
13
(m, 2H), 1.38 (s, 9H), 1.20-1.29 (m, 9H); C-NMR (100 MHz, CDCl
3
): δ 169.3,
168.9, 166.1, 154.5, 142.8, 139.8, 134.3, 129.6, 128.4, 128.1, 126.5, 124.5, 79.9,
63.3, 62.5, 62.2, 62.1, 58.4, 58.3, 51.5, 37.2, 28.2, 18.4, 14.0, 13.8; IR (Neat) 3433,
2980, 1724, 1493, 1367, 1244, 1167, 1097, 870, 783, 699; HRMS(MALDI): calcd.
for [M+Na]+ (C24H32NO8Cl) requires 520.1714, found 520.1709.
4.4.9
11

ACCEPTED MANUSCRIPT
4,4-diethyl-1-methyl-(S,E)-5-((tert-butoxycarbonyl)amino)-5-(4-chloro-phenyl)pent-1-
ene-1,4,4-tricarboxylate (4i)
Yield: 98%; colorless oil. Enantiomeric excess: 81%, [α]D = -19.0 (c = 3.20, CHCl3),
24
determined by HPLC (Chiralpak AD-H column hexane/i-PrOH 9:1, flow rate 1.0
1
ml/min, tminor = 17.1 min, tmajor = 22.1 min, λ = 254 nm); H-NMR (400 MHz,
CDCl ): δ 7.27-7.29 (m, 2H), 7.21-7.23 (m, 2H), 6.82-6.90 (m, 1H), 6.53 (d, J = 9.2
3
Hz, 1H), 5.80 (d, J = 15.6 Hz, 1H), 5.16 (d, J = 9.2 Hz, 1H), 4.17-4.25 (m, 4H), 3.71
(s, 3H), 2.58-2.62 (m, 2H), 1.37 (s, 9H), 1.27 (t, J = 7.2 Hz, 3H), 1.21 (t, J = 7.2 Hz,
13
3H); C-NMR (100 MHz, CDCl
3
): δ 169.4, 168.9, 166.1, 154.5, 142.8, 136.4, 134.1,
129.5, 128.5, 124.4, 79.8, 62.4, 62.2, 58.3, 51.5, 37.2, 28.2, 14.0, 13.8; IR (Neat)
3433, 2980, 1724, 1493, 1368, 1273, 1245, 1169, 1093, 1015, 848, 756;
HRMS(MALDI): calcd. for [M+Na]+ (C24H32NO8Cl) requires 520.1714, found
520.1710.
4.4.10
4,4-diethyl-1-methyl-(S,E)-5-((tert-butoxycarbonyl)amino)-5-(4-fluoro-phenyl)pent-1-
ene-1,4,4-tricarboxylate (4j)
Yield: 97%; colorless oil. Enantiomeric excess: 79%, [α]D = -17.9 (c = 2.50, CHCl3),
26
determined by HPLC (Chiralpak AD-H column hexane/i-PrOH 9:1, flow rate 1.0
1
ml/min, tminor = 14.0 min, tmajor = 18.5 min, λ = 254 nm); H-NMR (400 MHz,
CDCl ): δ 7.26-7.27 (m, 2H), 6.97-7.01 (m, 2H), 6.82-6.90 (m, 1H), 6.53 (d, J = 8.0
3
Hz, 1H), 5.81 (d, J = 15.2 Hz, 1H), 5.17 (d, J = 8.8 Hz, 1H), 4.16-4.26 (m, 4H), 3.70
(s, 3H), 2.59-2.62 (m, 2H), 1.37 (s, 9H), 1.27 (t, J = 7.2 Hz, 3H), 1.21 (t, J = 7.2 Hz,
13
3H); C-NMR (100 MHz, CDCl
3
): δ 169.4, 169.0, 166.2, 163.7, 161.2, 154.5, 142.9,
133.7, 127.5, 124.4, 115.4, 115.2, 79.7, 62.6, 62.1, 58.3, 51.5, 37.3, 28.3, 28.2, 28.1,
18.4, 14.0, 13.8; IR (Neat) 2980, 1733, 1508, 1489, 1226, 1165, 1097, 838, 802;
HRMS(MALDI): calcd. for [M+Na]+ (C24H32NO8F) requires 504.2010, found
504.2005.
4.4.11
4,4-diethyl-1-methyl-(S,E)-5-(4-bromophenyl)-5-((tert-butoxy-carbonyl)-amino)pent-1
-ene-1,4,4-tricarboxylate (4k)
Yield: 84%; colorless oil. Enantiomeric excess: 81%, [α]D = -21.7 (c = 2.0, CHCl3),
25
determined by HPLC (Chiralpak AD-H column hexane/i-PrOH 9:1, flow rate 1.0
1
ml/min, tminor = 16.3 min, tmajor = 20.0 min, λ = 254 nm); H-NMR (400 MHz,
CDCl ): δ 7.43 (d, J = 8 Hz, 2H), 7.16 (d, J = 7.6 Hz, 2H), 6.81-6.87 (m, 1H), 6.53
3
(d, J = 8.4 Hz, 1H), 5.80 (d, J = 15.6 Hz, 1H), 5.14 (d, J = 9,2 Hz, 1H), 4.18-4.25 (m,
4H), 3.71 (s, 3H), 2.58-2.62 (m, 2H), 1.37 (s, 9H), 1.27 (t, J = 7.2 Hz, 3H), 1.22 (t, J
13
= 7.2 Hz, 3H); C-NMR (100 MHz, CDCl
3
): δ 169.3, 168.9, 166.1, 154.5, 142.8,
136.9, 132.4,131.5, 130.9, 129.8, 127.7, 127.6, 124.4, 122.3, 79.8, 62.4, 62.2, 58.4,
51.5, 37.2, 28.2, 28.1, 18.4, 15.1, 14.0, 13.8; IR (Neat) 3431, 2980, 1723, 1489,
1367, 1245, 1168, 1011, 847, 804; HRMS(MALDI): calcd. for [M+Na]+
(C24H32NO8Br) requires 564.1209, found 564.1212.
4.4.12
4,4-diethyl-1-methyl-(S,E)-5-((tert-butoxycarbonyl)amino)-5-(p-tolyl)pent-1-ene-1,4,4
12

ACCEPTED MANUSCRIPT
-tricarboxylate (4l)
25
Yield: 95%; colorless oil. Enantiomeric excess: 81%, [α]D = -20.6 (c = 2.40, CHCl3),
determined by HPLC (Chiralpak AD-H column hexane/i-PrOH 9:1, flow rate 1.0
ml/min, tminor = 11.1 min, tmajor = 14.4 min, λ = 254 nm); H-NMR (400 MHz,
1
CDCl ): δ 7.01-7.15 (m, 4H), 6.84-6.88 (m, 1H), 6.54 (d, J = 9.2 Hz, 1H), 5.80 (d, J
3
= 15.6 Hz, 1H), 5.16 (d, J = 9,2 Hz, 1H), 4.18-4.24 (m, 4H), 3.70 (s, 3H), 2.53-2.65
(m, 2H), 2.31 (s, 3H), 1.37 (s, 9H), 1.27 (t, J = 7.2 Hz, 3H), 1.22 (t, J = 7.2 Hz, 3H);
13
C-NMR (100 MHz, CDCl ): δ 169.5, 169.2, 166.2, 154.5, 143.3, 137.9, 134.7,
3
129.1, 127.9, 124.3, 79.5, 62.7, 62.0, 58.7, 51.5, 37.3, 30.9, 28.3, 21.1, 14.0, 13.8; IR
(Neat) 3433, 2980, 1724, 1492, 1366, 1244, 1168, 1098, 1044; HRMS(MALDI):
calcd. for [M+Na]+ (C25H35NO8) requires 500.2260, found 500.2261.
4.4.13
4,4-diethyl-1-methyl-(S,E)-5-((tert-butoxycarbonyl)amino)-5-(4-methoxy-phenyl)pent-
1-ene-1,4,4-tricarboxylate (4m)
Yield: 98%; colorless oil. Enantiomeric excess: 80%, [α]D = -36.3 (c = 1.50, CHCl3),
25
determined by HPLC (Chiralpak AD-H column hexane/i-PrOH 9:1, flow rate 1.0
1
ml/min, tminor = 19.3 min, tmajor = 25.3 min, λ = 254 nm); H-NMR (400 MHz,
CDCl ): δ 7.18 (d, J = 8.0 Hz, 2H), 6.85-6.91 (m, 1H), 6.82 (d, J = 8.0 Hz, 2H), 6.52
3
(d, J = 8.8 Hz, 1H), 5.80 (d, J = 15.6 Hz, 1H), 5.14 (d, J = 8.8 Hz, 1H), 4.18-4.24 (m,
4H), 3.78 (s, 3H), 3,70 (s, 3H), 2.53-2.65 (m, 2H), 1.37 (s, 9H), 1.21-1.29 (m, 6H);
13
C-NMR (100 MHz, CDCl ): δ 169.6, 169.2, 166.2, 159.5, 154.5, 143.3, 132.0,
3
129.8, 129.2, 124.2, 114.3, 113.7, 79.5, 62.8, 62.0, 58.4, 55.6, 55.2, 51.5, 37.3, 28.3,
28.2, 14.0, 13.8; IR (Neat) 3436, 2980, 1724, 1515, 1495, 1368, 1250, 1169, 1098,
1034, 838, 766; HRMS(MALDI): calcd. for [M+Na]+ (C25H35NO9) requires
516.2210, found 516.2215.
4.4.14
4,4-diethyl-1-methyl-(S,E)-5-((tert-butoxycarbonyl)amino)-5-(4-nitro-phenyl)-pent-1-
ene-1,4,4-tricarboxylate (4n)
Yield: 83%; pale yellow oil. Enantiomeric excess: 83%, [α]D = -30.8 (c = 1.90,
25
CHCl3), determined by HPLC (Chiralpak AD-H column hexane/i-PrOH 7:3, flow
1
rate 1.0 ml/min, tminor = 15.2 min, tmajor = 11.1 min, λ = 254 nm); H-NMR (400 MHz,
CDCl ): δ 8.17 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 8.4 Hz, 2H), 6.81-6.87 (m, 1H), 6.56
3
(d, J = 9.2 Hz, 1H), 5.83 (d, J = 15.6 Hz, 1H), 5.29 (d, J = 11.6 Hz, 1H), 4.16-4.27
(m, 4H), 3.71 (s, 3H), 3,70 (s, 3H), 2.66 (d, J = 7.2 Hz, 2H), 1.38 (s, 9H), 1.27 (t, J =
13
7.2 Hz, 3H), 1.20 (t, J = 7.2 Hz, 3H); C-NMR (100 MHz, CDCl
3
): δ 169.1, 168.7,
166.0, 154.5, 147.7, 145.3, 142.1, 129.3, 124.7, 123.5, 80.3, 62.4, 62.1, 58.4, 51.6,
37.2, 30.9, 28.2, 14.0, 13.8; IR (Neat) 3429, 2981, 1724, 1525, 1491, 1316, 1247,
1169, 1108, 1014, 859, 752, 701; HRMS(MALDI): calcd. for [M+Na]+ (C25H35NO9)
requires 531.1955, found 531.1966.
4.4.15
4,4-diethyl-1-methyl-(S,E)-5-((tert-butoxycarbonyl)amino)-5-(3-fluoro-phenyl)pent-1-
ene-1,4,4-tricarboxylate (4o)
Yield: 93%; colorless oil. Enantiomeric excess: 81%, [α]D = -26.8 (c = 2.10, CHCl3),
23
13

ACCEPTED MANUSCRIPT
determined by HPLC (Chiralpak AD-H column hexane/i-PrOH 95:5, flow rate 1.0
1
ml/min, tminor = 17.7 min, tmajor = 23.7 min, λ = 254 nm); H-NMR (400 MHz,
CDCl ): δ 7.25-7.30 (m, 1H), 6.99-7.07 (m, 3H), 6.83-6.91 (m, 1H), 6.54 (d, J = 8.8
3
Hz, 1H), 5.82 (d, J = 15.6 Hz, 1H), 5.19 (d, J = 9.2 Hz, 1H), 4.18-4.28 (m, 4H), 3.71
(s, 3H), 2.56-2.68 (m, 2H), 1.38 (s, 9H), 1.27 (t, J = 7.2 Hz, 3H), 1.21 (t, J = 7.2 Hz,
13
3H); C-NMR (100 MHz, CDCl
3
): δ 169.3, 168.9, 166.1, 163.9, 161.4, 154.5, 142.8,
140.3, 129.9, 129.8, 124.5, 124.0, 115.3, 115.1, 114.8, 79.8, 62.4, 62.2, 62.1, 58.5,
51.5, 37.2, 28.2, 14.0, 13.8; IR (Neat) 3431, 2981, 1727, 1489, 1367, 1252, 1169,
868, 785, 700; HRMS(MALDI): calcd. for [M+Na]+ (C24H32NO8F) requires
504.2010, found 504.2005.
4.4.16
4,4-diethyl-1-methyl-(S,E)-5-((tert-butoxycarbonyl)amino)-5-(m-tolyl)pent-1-ene-1,4,
4-tricarboxylate (4p)
23
Yield: 99%; colorless oil. Enantiomeric excess: 85%, [α]D = -32.1 (c = 2.70, CHCl3),
determined by HPLC (Chiralpak AD-H column hexane/iPro 9:1, flow rate 1.0
1
ml/min, minor = 8.2 min, major = 10.3 min, λ = 254 nm); H-NMR (400 MHz, CDCl
3
):
δ 7.16-7.20 (m, 1H), 7.05-7.09 (m, 3H), 6.84-6.92 (m, 1H), 6.56 (d, J = 9.6 Hz, 1H),
5.80 (d, J = 15.6 Hz, 1H), 5.16 (d, J = 9.2 Hz, 1H), 4.20-4.24 (m, 4H), 3.70 (s, 3H),
2.56-2.61 (m, 2H), 2.32 (s, 3H), 1.38 (s, 9H), 1.27 (t, J = 7.2 Hz, 3H), 1.22 (t, J = 7.2
13
Hz, 3H); C-NMR (100 MHz, CDCl
3
): δ 169.5, 169.1, 166.2, 154.6, 143.3, 137.9,
137.6, 129.0, 128.8, 128.3, 125.0, 124.3, 79.5, 62.7, 62.0, 61.9, 58.9, 51.5, 37.3, 29.7,
28.3, 28.2, 21.4, 14.0, 13.8; IR (Neat) 3434, 2980, 1725, 1492, 1367, 1242, 1167,
1098, 1045, 874, 781, 707; HRMS(MALDI): clad. for [M+Na]+ (C25H35NO8)
requires 500.2260, found 500.2255.
4.4.17
4,4-diethyl-1-methyl-(S,E)-5-((tert-butoxycarbonyl)amino)-5-(3-methoxy-phenyl)pent-
1-ene-1,4,4-tricarboxylate (4q)
Yield: 99%; colorless oil. Enantiomeric excess: 86%, [α]D = -28.8 (c = 2.50, CHCl3),
26
determined by HPLC (Chiralpak AD-H column hexane/i-PrOH 9:1, flow rate 1.0
1
ml/min, tminor = 11.7 min, tmajor = 17.9 min, λ = 254 nm); H-NMR (400 MHz,
CDCl ): δ 7.19-7.24 (m, 1H), 6.86-6.92 (m, 1H), 6.81-6.85 (m, 3H), 6.55 (d, J = 9.2
3
Hz, 1H), 5.81 (d, J = 15.2 Hz, 1H), 5.17 (d, J = 9.2 Hz, 1H), 4.19-4.24 (m, 4H), 3.78
(s, 3H), 3.70 (s, 3H), 2.54-2.67 (m, 2H), 1.38 (s, 9H), 1.27 (t, J = 7.2 Hz, 3H), 1.23 (t,
13
J = 7.2 Hz, 3H); C-NMR (100 MHz, CDCl
3
): δ 169.5, 169.1, 166.2, 159.5, 154.6,
143.2, 139.2, 129.4, 124.3, 120.3, 114.0, 113.4, 79.6, 62.6, 62.0, 58.8, 55.2, 51.5,
37.3, 28.3, 28.2, 14.0, 13.8; IR (Neat) 3430, 2980, 1724, 1491, 1368, 1263, 1168,
1098, 1044, 866, 783, 703; HRMS(MALDI): calcd. for [M+Na]+ (C25H35NO9)
requires 516.2210, found 516.2203.
4.4.18
4,4-diethyl-1-methyl-(S,E)-5-(3-bromophenyl)-5-((tert-butoxycarbonyl)-amino)pent-1-
ene-1,4,4-tricarboxylate (4r)
Yield: 99%; colorless oil. Enantiomeric excess: 86%, [α]D = -16.8 (c = 0.20, CHCl3),
22
14

ACCEPTED MANUSCRIPT
determined by HPLC (Chiralpak AD-H column hexane/i-PrOH 9:1, flow rate 1.0
1
ml/min, tminor = 9.7 min, tmajor = 11.9 min, λ = 254 nm); H-NMR (400 MHz, CDCl
3
):
δ 7.34-7.35 (m, 2H), 7.09-7.16 (m, 1H), 6.75-6.83 (m, 1H), 6.45 (d, J = 9.6 Hz, 1H),
5.75 (d, J = 15.6 Hz, 1H), 5.08 (d, J = 9.6Hz, 1H), 4.11-4.18 (m, 4H), 3.63 (s, 3H),
2.48-2.60 (m, 2H), 1.31 (s, 9H), 1.20 (t, J = 7.2 Hz, 3H), 1.15 (t, J = 7.2 Hz, 3H);;
13
C-NMR (100 MHz, CDCl ): δ 169.3, 168.8, 166.1, 154.5, 142.7, 140.1, 131.3,
3
130.9, 129.9, 127.0, 124.5, 122.5, 79.9, 62.5, 62.3, 62.2, 58.4, 51.5, 37.2, 28.2, 14.0,
13.8; IR (Neat) 3433, 2959, 2924, 2853, 1725, 1493, 1367, 1260, 1167, 1097, 1018,
869, 800, 699; HRMS(MALDI): calcd. for [M+Na]+ (C24H32NO8Br) requires
564.1209, found 564.1208.
4.4.19
4,4-diethyl-1-methyl--(S,E)-5-((tert-butoxycarbonyl)amino)-5-(thiophen-2-yl)pent-1-e
ne-1,4,4-tricarboxylate (4s)
Yield: 95%; colorless oil. Enantiomeric excess: 70%, [α]D = +1.5 (c = 2.80, CHCl3),
25
determined by HPLC (Chiralpak AD-H column hexane/i-PrOH 9:1, flow rate 1.0
1
ml/min, tminor = 12.5 min, tmajor = 14.1 min, λ = 254 nm); H-NMR (400 MHz,
CDCl ): δ 7.22 (d, J = 5.2 Hz, 1H), 6.95-7.00 (m, 1H), 6.87-6.93 (m, 2H), 6.35 (d, J
3
= 9.6 Hz, 1H), 5.80 (d, J = 15.2 Hz, 1H), 5.51 (d, J = 10.0 Hz, 1H), 4.19-4.29 (m,
4H), 3.70 (s, 3H), 2.72-2.78 (m, 1H), 2.58-2.62 (m, 1H), 1.39 (s, 9H), 1.26-1.30 (m,
13
6H); C-NMR (100 MHz, CDCl
3
): δ 169.6, 169.0, 166.2, 154.4, 143.0, 140.7, 127.4,
126.5, 125.6, 124.3, 79.8, 62.8, 62.3, 62.2, 55.0, 51.5, 37.2, 28.3, 14.0, 13.8; IR
(Neat) 3448, 2981, 1724, 1490, 1368, 1247, 1168, 1097, 1043, 855, 706;
HRMS(MALDI): calcd. for [M+Na]+ (C25H35NSO8) requires 492.1668, found
492.1658.
4.4.20
4,4-diethyl-1-methyl-(S,E)-5-((tert-butoxycarbonyl)amino)-5-(naphthalen-1-yl)pent-1-
ene-1,4,4-tricarboxylate (4t)
Yield: 60%; colorless oil. Enantiomeric excess: 70%, [α]D = +1.5 (c = 2.80, CHCl3),
25
determined by HPLC (Chiralpak AD column hexane/i-PrOH 95:5, flow rate 0.5
1
ml/min, tminor = 28.3 min, tmajor = 37.8 min, λ = 254 nm); H-NMR (400 MHz,
CDCl ): δ 8.38 (d, J = 8.4 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H),
3
7.40-7.60 (m, 4H), 6.72-6.78 (m, 2H), 6.28 (d, J = 9.2 Hz, 1H), 5.61 (d, J = 15.6 Hz,
1H), 4.12-4.30 (m, 4H), 3.65 (s, 3H), 2.64-2.70 (m, 1H), 2.34-2.43 (m, 1H), 1.36 (s,
13
9H), 1.11-1.34 (m, 6H); C-NMR (100 MHz, CDCl
3
): δ 169.7, 169.4, 166.2, 154.7,
143.2, 135.0, 133.6, 132.0, 128.8, 128.7, 126.7, 125.7, 125.1, 124.9, 123.9, 123.2,
79.6, 62.1, 62.0, 52.6, 51.4, 37.1, 28.3, 14.1, 13.7; IR (Neat) 3428, 2980, 1724, 1490,
1367, 1243, 1167, 1097, 1045, 884, 860, 779; HRMS(MALDI): calcd. for [M+Na]+
(C28H35NO8) requires 536.2260, found 536.2245.
4.4.21
4,4-dibenzyl-1-methyl-(S,E)-5-((tert-butoxycarbonyl)amino)-5-(3-chloro-phenyl)pent-
1-ene-1,4,4-tricarboxylate (4u)
Yield: 99%; colorless oil. Enantiomeric excess: 90%, [α]D = -24.3 (c = 3.10, CHCl3),
24
15

ACCEPTED MANUSCRIPT
determined by HPLC (Chiralpak AD-H column hexane/i-PrOH 9:1, flow rate 1.0
1
ml/min, tminor = 18.5 min, tmajor = 14.5 min, λ = 254 nm); H-NMR (400 MHz,
CDCl ): δ 7.30-7.32 (m, 8H), 7.05-7.24 (m, 6H), 6.76-6.84 (m, 1H), 6.46 (d, J = 8.8
3
Hz, 1H), 5.69 (d, J = 15.6 Hz, 1H), 5.17-5.20 (m, 2H), 5.11 (s, 2H), 5.02-5.08 (m,
13
1H), 3.66 (s, 3H), 2.56-2.69 (m, 2H), 1.36 (s, 9H); C-NMR (100 MHz, CDCl
3
): δ
169.0, 168.7, 166.0, 154.5, 142.2, 139.7, 134.6, 134.4, 134.2, 129.7, 128.7, 128.63,
128.60, 128.52, 128.5, 128.45, 128.41, 128.1, 126.3, 124.8, 80.0, 68.03, 67.95, 62.6,
58.5, 51.5, 37.3, 28.2; IR (Neat) 3446, 2977, 1724, 1496, 1272, 1168, 1102, 1044,
783, 750, 698; HRMS(MALDI): calcd. for [M+Na]+ (C34H36NClO8) requires
644.2027, found 644.2019.
4.4.22
4,4-dibenzyl-1-methyl-(S,E)-5-((tert-butoxycarbonyl)amino)-5-(m-tolyl)pent-1-ene-1,4
,4-tricarboxylate (4v)
24
Yield: 99%; colorless oil. Enantiomeric excess: 88%, [α]D = -21.1 (c = 3.90, CHCl3),
determined by HPLC (Chiralpak AD-H column hexane/i-PrOH 9:1, flow rate 1.0
1
ml/min, tminor = 17.2 min, tmajor = 12.9 min, λ = 254 nm); H-NMR (400 MHz,
CDCl ): δ 7.31-7.32 (m, 8H), 7.17-7.22 (m, 2H), 6.94-7.12 (m, 4H), 6.77-6.85 (m,
3
1H), 6.50 (d, J = 8.8 Hz, 1H), 5.66 (d, J = 15.6 Hz, 1H), 5.16-5.22 (m, 2H), 5.12 (s,
2H), 5.07-5.10 (m, 1H), 3.65 (s, 3H), 3,70 (s, 3H), 2.58-2.67 (m, 2H), 1.36 (s, 9H);
13
C-NMR (100 MHz, CDCl ): δ 169.2, 169.0, 166.0, 142.7, 138.0, 137.4, 134.8,
3
134.4, 128.9, 128.8, 128.6, 128.56, 128.51, 128.49, 128.42, 128.37, 128.31, 124.8,
124.6, 79.6, 67.8, 62.9, 58.9, 51.4, 37.3, 28.3, 21.4; IR (Neat) 3446, 2976, 1724,
1490, 1274, 1167, 1044, 750, 689; HRMS(MALDI): calcd. for [M+Na]+
(C35H39NO8) requires 624.2573, found 624.2566.
4.4.23 dimethyl (S)-2-allyl-2-(((tert-butoxycarbonyl)amino)(phenyl)methyl)malonate
(4w)
25
Yield: 99%; colorless oil. Enantiomeric excess: 68%, [α]D = -8.83 (c = 2.63, CHCl3),
determined by HPLC (Chiral Pak AD-H column hexane/iPro 9:1, flow rate 1.0
1
ml/min, minor = 6.6 min, major = 5.9 min, λ = 220 nm); H-NMR (400 MHz, CDCl
3
):
δ 7.22-7.31 (m, 5H), 6.46 (d, J = 9.6 Hz, 1H), 5.75-5.85 (m, 1H), 5.24 (d, J = 9.6 Hz,
1H), 5.05-5.10 (m, 2H), 3.73 (s, 3H), 3,72 (s, 3H), 2.53-2.58 (m, 1H), 2.41-2.46 (m,
13
1H), 1.39 (s, 9H); C-NMR (100 MHz, CDCl
3
): δ 165.5, 165.2, 149.9, 133.1, 128.1,
123.6, 123.3, 123.0, 114.3, 74.8, 59.0, 53.6, 47.7, 47.6, 34.3, 23.5; IR (Neat) 3431,
2978, 1720, 1494, 1366, 1225, 1169; HRMS(ESI): clad. for [M+H]+ (C20H28NO6)
requires 378.1911, found 378.1915.
4.4.24 diethyl (S)-2-allyl-2-(((tert-butoxycarbonyl)amino)(phenyl)methyl)malonate
(4x)
25
Yield: 99%; colorless oil. Enantiomeric excess: 74%, [α]D = -11.3 (c = 1.88, CHCl3),
determined by HPLC (Chiralpak AD-H column hexane/i-PrOH 95:5, flow rate 0.7
1
ml/min, tminor = 11.4 min, tmajor = 10.3 min, λ = 254 nm); H-NMR (400 MHz,
CDCl ): δ 7.27-7.28 (m, 5H), 6.59 (d, J = 9.6 Hz, 1H), 5.77-5.87 (m, 1H), 5.22 (d, J
3
= 9.6 Hz, 1H), 5.04-5.10 (m, 2H), 4.15-4.24 (m, 4H), 2.52-2.58 (m, 1H), 2.39-2.45
16

ACCEPTED MANUSCRIPT
13
(m, 1H), 1.37 (s, 9H), 1.27 (t, J = 7.6 Hz, 3H), 1.21 (t, J = 7.6 Hz, 3H); C-NMR
(100 MHz, CDCl ): δ 165.3, 164.8, 149.8, 133.3, 128.3, 124.9, 124.2, 123.5, 123.3,
3
123.2, 123.1, 114.1, 74.5, 58.4, 56.9, 56.8, 53.8, 34.3, 23.5, 9.3, 9.1; IR (Neat) 3431,
2980, 1720, 1494, 1367, 1275, 1170; HRMS(ESI): calcd. for [M+H]+ (C23H32NO6)
requires 406.2224, found 406.2225.
4.4.25 dimethyl
(S)-2-(((tert-butoxycarbonyl)amino)(phenyl)methyl)-2-methyl-malonate (4y)
Yield: 99%; white solid. Enantiomeric excess: 63% (91% after recrystallization), [α]D
24
= +3.37 (c = 0.60, CHCl3), determined by HPLC (Chiralpak AD-H column
hexane/i-PrOH 9:1, flow rate 1.0 ml/min, tminor = 8.3 min, tmajor = 7.5 min, λ = 220
1
nm); H-NMR (400 MHz, CDCl
3
): δ 7.29-7.33 (m, 5H), 6.52 (d, J = 10.0 Hz, 1H),
13
5.18 (d, J = 10.0 Hz, 1H), 3.80 (s, 3H), 3.74 (s, 3H), 1.42 (s, 12H); C-NMR (100
MHz, CDCl ): δ 171.9, 171.3, 154.9, 137.9, 128.4, 128.3, 128.0, 79.6, 59.1, 53.0,
3
52.7, 28.4; IR (Neat) 3438, 2956, 1724, 1495, 1456, 1369, 1321, 1017; HRMS(ESI):
calcd. for [M+Na]+ (C18H25NO6Na) requires 374.1583, found 374.1574.
4.4.26 diethyl (S)-2-(((tert-butoxycarbonyl)amino)(phenyl)methyl)-2-methylmalonate
(4z)
25
Yield: 99%; white solid. Enantiomeric excess: 75%, [α]D = +2.86 (c = 1.37, CHCl3),
determined by HPLC (Chiralpak OD-H column hexane/i-PrOH 99:1, flow rate 1.0
1
ml/min, tminor = 7.0 min, tmajor = 7.9 min, λ = 220 nm); H-NMR (400 MHz, CDCl
3
):
δ 7.27-7.30 (m, 5H), 6.58 (d, J = 10.0 Hz, 1H), 5.14 (d, J = 10.0 Hz, 1H), 4.14-4.26
13
(m, 4H), 1.37 (s, 9H), 1.29 (t, J = 7.6 Hz, 3H), 1.20 (t, J = 7.6 Hz, 3H); C-NMR
(100 MHz, CDCl ): δ 171.3, 170.8, 154.8, 138.1, 134.4, 129.7, 129.0, 128.4, 128.1,
3
127.8, 79.3, 61.8, 61.6, 59.1, 58.9, 28.3, 20.3, 14.0, 13.8; IR (Neat) 3437, 2979,
1721, 1494, 1366, 1249, 1170, 1105; HRMS(ESI): calcd. for [M+H]+ (C20H30NO6)
requires 380.2068, found 380.2068.
4.4.27 1-(tert-butyl) 3,3-diethyl
(2S,5R)-5-(2-methoxy-2-oxoethyl)-2-(m-tolyl)-pyrrolidine-1,3,3-tricarboxylate (5)
25
Yield: 99%; colorless oil. Enantiomeric excess: 61%, [α]D = -7.66 (c = 1.37, CHCl3),
determined by HPLC (Chiralpak IC column hexane/i-PrOH 95:5, flow rate 1.0
1
ml/min, tminor = 21.5 min, tmajor = 46.0 min, λ = 220 nm); H-NMR (400 MHz,
CDCl ): δ 7.07-7.11 (m, 1H), 6.90-6.98 (m, 3H), 5.52 (s, 1H), 4.42-4.27 (m, 1H),
3
4.10-4.18 (m, 1H), 4.00-4.08 (m, 1H), 3.74-3.78 (m, 1H), 3.64 (s, 3H), 3.58-3.67 (m,
2H), 253-2.63 (m, 3H), 2.24 (s, 3H), 1.19-1.26 (m, 12H), 0.89 (t, J = 7.2 Hz, 3H);
13
C-NMR (100 MHz, CDCl ): δ 171.7, 170.1, 167.2, 154.7, 137.4, 128.4, 128.3,
3
127.9, 124.4, 110.0, 80.0, 66.5, 65.5, 65.4, 62.1, 61.5, 53.4, 51.7, 28.2, 27.9, 21.4,
14.0, 13.5; IR (Neat) 2979, 1736, 1699, 1439, 1367, 1263, 1174, 1138; HRMS(ESI):
calcd. for [M+H]+ (C25H36NO8) requires 478.2435, found 478.2434.
Acknowledgements
17

ACCEPTED MANUSCRIPT
Financial support from Chinese Academy of Sciences (XDB 20020100) and the
National Natural Science Foundation of China (Nos. 21572247, 21871282) is
gratefully acknowledged.
Supplementary data
Supplementary data associated with this article can be found in the online version at
doi:
References and notes
[1] For reviews in direct Mannich-type reactions, see: (a) Cόrdova A. Acc. Chem. Res.
2004, 37, 102-112; (b) Friestad G. K., Mathies A. K. Tetrahedron 2007, 63, 2541;
(c) Ting A., Schaus S. E. Eur. J. Org. Chem. 2007, 5797-5815.
[2] selected examples of metal-catalyzed asymmetric Mannich reactions: (a) Marigo
M., Kjærsgaard A., Juhl K., Gathergood N., Jørgensen K. A. Chem. Eur. J. 2003,
9, 2359-2367; (b) Hamashima Y., Sasamoto N., Hotta D., Somei H., Umebayashi
N., Sodeoka M. Angew. Chem., Int. Ed. 2005, 44, 1525-1529; (c) Sasamoto N.,
Dubs C., Hamashima Y., Sodeoka M. J. Am. Chem. Soc. 2006, 128, 14010-14011;
(d) Chen Z., Morimoto H., Matsunaga S., Shibasaki M. J. Am. Chem. Soc. 2008,
130, 2170-2171; (e) Poisson T., Tsubogo T., Yamashita Y., Kobayashi S. J. Org.
Chem. 2010, 75, 963-965; (f) Hatano M., Moriyama K., Maki T., Ishihara K.
Angew. Chem., Int. Ed. 2010, 49, 3819-3822; (g) Hatano M., Horibe T., Ishihara
K., Org. Lett. 2010, 12, 3502-3505; (h) Karimi B., Jafari E., Enders D., Chem. Eur.
J. 2013, 19, 10142-10145.
[3] (a) Lou S., Taoka B. M., Ting A., Schaus S. E. J. Am. Chem. Soc. 2005, 127,
11256-11257; (b) Kobayashi S., Arai K., Shimizu H., Ihori Y., Ishitani H.,
Yamashita Y. Angew. Chem., Int. Ed. 2005, 44, 761-764; (c) Tillman A. L., Ye J.,
Dixon D. J. Chem. Commun. 2006, 1191-1193; (d) Ting A., Lou S., Schaus S. E.
Org. Lett. 2006, 8, 2003-2006; (e) Kang Y. K., Kim D. Y. J. Org. Chem. 2009, 74,
5734-5737; (f) Hatano M., Horibe T., Ishihara K. J. Am. Chem. Soc. 2010, 132,
56-57; (g) Wang Q., Leutzsch M., van Gemmeren M., List B. J. Am. Chem. Soc.
2013, 135, 15334-15337; (h) Neuvonen A. J., Pihko P. M. Org. Lett. 2014, 16,
5152−5155; (i) Vesely J., Rios R. Chem. Soc. Rev. 2014, 43, 611-630.
(4) Selected enantioselective Mannich reactions with malonate esters: (a) Song J.,
Wang Y., Deng L. J. Am. Chem. Soc. 2006, 128, 6048-6049; (b) Song J., Shih
H.-W., Deng L. Org. Lett. 2007, 9, 603-606; (c) Hatano M., Horibe T., Ishihara K.
Org. Lett. 2010, 12, 3502-3505; (d) Verkade J. M. M., van Hemert L. J. C.,
Quaedflieg P. J. L. M., Rutjes F. P. J. T. Chem. Soc. Rev. 2008, 37, 29-41.
[5] For examples of asymmetric Mannich reactions promoted by phase-transfer
catalysts, see: (a) Fini F., Bernardi L., Herrera R. P., Pettersen D., Ricci A.,
Sgarzani V. Adv. Synth. Catal. 2006, 348, 2043-2046; (b) Marianacci O.,
Micheletti G., Bernardi L., Fini F., Fochi M., Pettersen D., Sgarzani V., Ricci A.
Chem. Eur. J. 2007, 13, 8338-8351.
[6] For examples of asymmetric Mannich reactions promoted by hydrogen-bonding
catalysts, see: (a) Lou S., Taoka B. M., Ting A., Schaus S. E. J. Am. Chem. Soc.
2005, 127, 11256-11257; (b) Song J., Wang Y., Deng L. J. Am. Chem. Soc. 2006,
128, 6048-6049; (c) Tillman A. L., Ye J., Dixon D. J. Chem. Commun. 2006,
1191-1193; (d) Song J., Shih H. W., Deng L. Org. Lett. 2007, 9, 603-606; (e)
18

ACCEPTED MANUSCRIPT
Yamaoka Y., Miyabe H., Yasui Y., Takemoto Y. Synthesis 2007, 2571-2575; (f)
Lou S., Dai P., Schaus S. E. J. Org. Chem. 2007, 72, 9998-10008; (g) Hatano M.,
Maki T., Moriyama K., Arinobe M., Ishihara K. J. Am. Chem. Soc. 2008, 130,
16858-16860; (h) Han X., Kwiatkowski J., Xue F., Huang K.-W., Lu Y. Angew.
Chem., Int. Ed. 2009, 48, 7604-7607; (i) Lee J. H., Kim D. Y. Synthesis 2010,
1860-1864; (j) Probst N., Madarász Á., Valkonen A., Pápai I., Rissanen K.,
Neuvonen A., Pihko P. M. Angew. Chem. Int. Ed. 2012, 51, 8495-8499; (k) Bae H.
Y., Kim M. J., Sim J. M., Song C. E. Angew. Chem. Int. Ed. 2016, 55,
10825-10829; (l) Cosimi E., Engl O. D., Saadi J., Ebert M. O., Wennemers H.
Angew. Chem. Int. Ed. 2016, 55, 13127-13131.
[7] (a) Takada K., Tanaka S., Nagasawa K. Synlett 2009, 1643-1646; (b) Sohtome Y.,
Tanaka S., Takada K., Yamaguchi T., Nagasawa K. Angew. Chem. Int. Ed. 2010,
49, 9254-9257; (c) Pan Y., Zhao Y., Ma T., Yang Y., Liu H., Jiang Z., Tan C. H.
Chem. Eur. J. 2010, 16, 779-782; (d) Sohtome Y., Yamaguchi T., Tanaka S.,
Nagasawa K. Org. Biomol. Chem. 2013, 11, 2780–2786.
[8] Enders D., Göddertz D. P., Beceño C., Raabe G. Adv. Synth. Catal. 2010, 352,
2863-2868.
[9] For selected reviews, see: (a) O'Donnell L. Acc. Chem. Res. 2004, 37, 506-517; (b)
Lygo B., Andrews B. I. Acc. Chem. Res. 2004, 37, 518-525; (c) Ooi T., Maruoka,
K. Acc. Chem. Res. 2004, 37, 526-533; (d) Ooi T., Maruoka K. Angew. Chem., Int.
Ed. 2007, 46, 4222-4266; (e) Hashimoto T., Maruoka K. Chem. Rev. 2007, 107,
5656-5682; (f) Shirakawa S., Maruoka K. Angew. Chem., Int. Ed. 2013, 52,
4312-4348; (g) Shirakawa S., Maruoka K. Tetrahedron Lett. 2014, 55, 3833-3839;
(h) Herchl R., Waser M. Tetrahedron 2014, 70, 1935-1960.
[10] (a) Cao D. D., Chai Z., Zhang J. X., Ye Z. Q., Xiao H., Wang H. Y., Zhao G.,
Chen J., Wu X. Chem. Commun. 2013, 49, 5972-5974; (b) Wang H. Y., Chai Z.,
Zhao G. Tetrahedron 2013, 69, 5104-5111; (c) Wang H. Y., Zhang K., Zheng C.
W., Chai Z., Cao D. D., Zhang J. X., Zhao G. Angew. Chem., Int. Ed. 2015, 54,
1775-1779; (d) Lou Y. P., Zheng C. W., Pan R. M., Jin, Q. W., Zhao G., Li Z.
Org. Lett. 2015, 17, 688-691; (e) Pan R. M., Zhang J. X, Zheng C. W., Wang H.
Y., Cao D. D., Cao W. G., Zhao, G. Tetrahedron 2017, 73, 2349-2358; (f) Jin Q.
W., Zheng C. W., Zhao G., Zou G. Tetrahedron 2018, 74, 4134-4144.
[11] WenzeA. l, Jacobsen E. N. J. Am. Chem. Soc. 2002, 124, 12964-12965.
[12] (a) Zu L. S., Li H., Xie H. X., Wang J., Jiang W., Tang Y., Wang W., Angew.
Chem. Int. Ed. 2007, 46, 3732 –3734; (b) Skouta R., Varmab R. S., Li C. J., Green
Chem., 2005, 7, 571–575.
[13] The relative stereochemistry of 5 was determined by NOE experiments and its
absolute configuration was assigned to be (2S, 5R) (for detail, see the
Supplementary data).
19