Chiral phosphoric acid-catalyzed enantioselective three-component Mannich reaction of acyclic ketones, aldehydes and anilines

Full text of DOI:10.1016/j.tet.2018.05.055

Accepted Manuscript
Chiral phosphoric acid-catalyzed enantioselective three-component Mannich reaction
of acyclic ketones, aldehydes and anilines
Shuo Tong, Qian Wang, Mei-Xiang Wang, Jieping Zhu
PII:
S0040-4020(18)30603-3
10.1016/j.tet.2018.05.055
TET 29562
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 2 April 2018
Revised Date: 17 May 2018
Accepted Date: 18 May 2018
Please cite this article as: Tong S, Wang Q, Wang M-X, Zhu J, Chiral phosphoric acid-catalyzed
enantioselective three-component Mannich reaction of acyclic ketones, aldehydes and anilines,
Tetrahedron (2018), doi: 10.1016/j.tet.2018.05.055.
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ACCEPTED MANUSCRIPT
Graphical Abstract
Chiral Phosphoric Acid-Catalyzed
Leave this area blank for abstract info.
Enantioselective Three-Component Mannich
Reaction of Acyclic Ketones, Aldehydes and
Anilines
Shuo Tong,a Qian Wang,a Mei-Xiang Wang,b Jieping Zhua
aInstitute of Chemical Sciences and Engineering,
Ecole Polytechnique Fédérale de Lausanne,
EPFL-SB-ISIC-LSPN, CH-1015 Lausanne, Switzerland
bKey Laboratory of Bioorganic Phosphorous and
Chemical Biology (Ministry of Education),
Tsinghua University, Beijing 10084, China

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Chiral Phosphoric Acid-Catalyzed Enantioselective Three-Component Mannich
Reaction of Acyclic Ketones, Aldehydes and Anilines
Shuo Tonga, Qian Wanga, Mei-Xiang Wangb, and Jieping Zhua*
aInstitute of Chemical Sciences and Engineering, Ecole Polytechnique Fédérale de Lausanne, EPFL-SB-ISIC-LSPN, CH-1015 Lausanne, Switzerland
bKey laboratory of Bioorganic Phosphorous and Chemical Biology (Ministry of Education), Tsinghua University, Beijing 100084, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A catalytic asymmetric three-component Mannich reaction of alkyl aryl ketones 2 with anilines
3 and aldehydes 4 was developed. In the presence of a catalytic amount of chiral phosphoric acid
(TRIP, 1h), the reaction of 2, 3 and 4 afforded the syn-adduct 5 as a major product in good to
excellent enantiomeric excess. Acetone also acted as Mannich donor to afford the β-amino
ketones in good yields and enantioselectivity. The resulting β-amino ketones can be reduced
stereoselectively to either 1,3-syn or 1,3-anti amino alcohols.
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved
.
asymmetric synthesis
chiral phosphoric acid
chiral Brønsted acid
Mannich reaction
multicomponent reaction
organocatalysis
1. Introduction
The Mannich reaction is one of the most important C-C bond
forming reactions in organic chemistry.1 It affords β-amino
carbonyl compounds of significant synthetic importance. The
reaction creates up to two stereocenters, a significant amount of
work has therefore been devoted to render this reaction
enantioselective.2 Since List’s pioneering report in 2000 on the
proline-catalyzed three-component reaction of acetone, anisidine
and aldehyde,3 the chiral amine catalysis has played a key role in
the recent development of asymmetric Mannich reaction.4
Akiyama5 and Terada’s6 seminal disclosure in 2004 on the
chiral phosphoric acid (CPA)-catalyzed two-component Mannich
reaction has rapidly propelled the CPA to a statue of a privileged
organocatalyst in asymmetric synthesis.7,8 Many variations on the
CPA-catalyzed enantioselective Mannich reaction have since
been developed. In general, highly reactive 1,3-dicarbonyl
compounds,9 azlactones,10 α-diazoketones/diazophosphonates,11
pre-synthesized ketene silyl acetals,12 enol ethers,13 enamines14 or
enecarbamates15 were employed as Mannich donors and pre-
synthesized N-acylated/sulfonylated imines as electrophilic
partners. To the best of our knowledge, there were very few
reports dealing with the CPA-catalyzed direct enantioselective
three-component Mannich reaction. Gong and co-workers
reported in 2007 the first example of anti-selective three-
component enantioselective reaction of cyclohexanone, anilines
and aryl aldehydes (eq 1, Scheme 1).16 Zhang documented in
2012 that the same reaction afforded syn-Mannich adduct as a
Scheme 1. CPA-catalyzed direct enantioselective Mannich
reaction.
major product when chiral bisphosphorylimide was used as a
catalyst (eq 2, Scheme 1).17 In the same year, Enders developed a
new planar chiral CPAs and applied it to the direct Mannich
reaction of cyclohexanone.18 Rueping19 reported a CPA-catalyzed
Mannich reaction of acetophenone with preformed imines which
was followed by Dughera’s report on the direct three-component
Mannich reaction of acetophenone derivatives.20 CPA-catalyzed
direct Mannich reaction of acyclic ketone leading to the three-

2
Tetrahedron
ACCEPTED MANUSCRIPT
component adduct with generation of two vicinal stereocenters
remained nevertheless unknown at the outset of our work. As a
continuation of our interest in developing CPA-catalyzed
asymmetric transformations,21 we report herein the first examples
of CPA-catalyzed direct asymmetric three-component Mannich
reaction of alkyl aryl ketones 2 with anilines 3 and aldehydes 4
(eq 3, Scheme 1). The reaction afforded the syn-adducts 5 as a
major product with good to excellent enantiomeric excess. The
resulting β-amino ketones can be reduced stereoselectively to
either 1,3-syn or 1,3-anti amino alcohols.
Figure 1. Structures of chiral phosphoric acids
O
ArHN
O
Conditionsa
R2
+
ArNH2
R3CHO
+
2. Results and discussion
R1
R3
R1
R2
The direct three-component Mannich reaction of
propiophenone (2a), para-nitroaniline (3a) and benzaldehyde (4a)
was examined in the presence of a catalytic amount of (S)-
BINOL-derived phosphoric acids 1 (0.05 equiv). To our delight,
the reaction in the presence of 1a (R = H) gave indeed the desired
product 5a in 51% yield, albeit with very low diastereo- and
enantioselectivity (entry 1, Table 1). Varying the structure of the
CPA revealed that both the diastereo- and enantioselectivity of
the reaction depend highly on the nature of the C3 and C3’
substituents (entries 2-8). The TRIP 1h bearing 2,4,6-
triisopropylphenyl groups at the C3 and C3’ position of the
BINOL backbone turned out to be the most efficient catalyst. It
gave the two separable diastereomers in a ratio of 87:13. The ee
of the two isomers was very different. While the ee of the major
syn-adduct 5a was excellent (97.4%), that of the minor anti-
adduct was low (6.0%). It is worth noting that the anti-isomer
(92.6% ee) was isolated with much higher ee than that of the syn-
isomer (55.8%) when CPA 1c was used as a catalyst (entry 3).
Among the CPAs examined, 1h was the only one that gave the
3a Ar = 4-NO2C6H4
5
2
4
ArHN
Ph
O
ArHN
Ph
O
ArHN
Ph
O
OMe
Cl
98.2% ee,c 87:13 dr
ArHN
Me
5b 58%b
97.6% ee,c 88:12 dr
5d 31%b
5c 54%d
96.6% ee,c 84:16 dr
O
ArHN
Ph
O
ArHN
Ph
O
S
Ph
O
Cl
5e 57%b
5g 50%b
99.4% ee,c 80:20 dr
ArHN
5f 67%b
97.0% ee,c 81:19 dr
80.4% ee,c 56:44 dr
O
ArHN
O
ArHN
O
Cl
Ph
Ph
Ph
Br
5j 56%b
97.6% ee,c 82:18 dr
Br
5i 59%b
5h 50%d
92.0% ee,c 83:17 dr
93.6% ee,c 84:16 dr
ArHN
Ph
O
ArHN
Ph
O
ArHN
Ph
O
three-component
Mannich
adduct
with
appreciable
Ph
Ph
diastereoselectivity. A higher loading of catalyst 1h (0.1 equiv)
gave the same level of enantiocontrol (entry 9), whereas a lower
loading caused a decrease in the reaction efficiency (entry 10).
Performing the reaction in other solvents such as
dichloromethane, acetonitrile, and toluene afforded the syn-
adduct with reduced ee (entries 11-13).
N3
5l 52%d
66.2% ee,c 70:30 dr
5m 92%d
5k 29%b
72.4% ee,c 72:28 dr
96.0% ee,c 93:7 dr
Table 1. Catalytic enantioselective direct Mannich reaction:
Condition surveya
5k
Scheme 2. CPA-catalyzed three-component Mannich reaction.
a
Reaction conditions: aryl aldehyde 4 (0.25 mmol), 4-nitro-aniline
3a (0.25 mmol), ketone 2 (1.25 mmol), 1h (0.05 equiv) in CHCl3
b
(2.5 mL, c 0.1 M), rt, 48 h. Combined yield of diastereomerically
pure syn- and anti-isomers. c Determined by SFC analysis on a chiral
stationary phase. d Yield of an unseparable mixture of syn- and anti-
isomers.
entry
Catalyst 1
(mol%)
1a (5)
1b (5)
1c (5)
1d (5)
1e (5)
1f (5)
1g (5)
1h (5)
1h (10)
1h (2.5)
1h (5)
1h (5)
1h (5)
solvent
dr
(syn/anti)b
44/56
51/49
51/49
50/50
55/45
57/43
52/48
87/13
86/14
87/13
88/12
76/24
81/19
yield
(%)c
51
57
76
45
31
37
52
52
53
43
55
49
43
ee (%)d
1
2
3
4
5
6
7
8
9
10
11
12
13
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CH2Cl2
CH3CN
Toluene
5.1 (11.2)
61.2 (78.1)
55.8 (92.6)
11.3 (41.0)
9.0 (38.8)
17.6 (60.6)
26.0 (64.2)
97.4 (6.0)
97.5 (6.4)
96.6 (7.1)
89.1 (8.9)
85.9 (8.6)
88.8 (10.5)
The scope of this CPA-catalyzed three-component Mannich
reaction was next investigated varying the aldehydes and the
acyclic ketones. 4-Nitroaniline was kept unchanged since our
preliminary experiments indicated that other anilines afforded the
three-component adducts with much lower d.r. and ee. As shown
in Scheme 2, propiophenones with both electron-withdrawing
and donating groups on the phenyl ring participated in the
reaction efficiently to give the desired Mannich-products (5b-5d)
in excellent enantioselectivities and good diastereoselectivites.
Heteroaromatic ketones such as 2-propanoylfuran and 2-
propanoylthiofuran were converted to the three-component
a
Reaction conditions: 4a (0.25 mmol), aniline 3a (0.25 mmol),
propiophenone (2a, 1.25 mmol), CPA 1, solvent (2.5 mL, c 0.1
b
1
c
M), rt, 48 h. Determined by H NMR. Combined yield of syn
adducts without event. Benzaldehydes bearing
a halogen
d
and anti isomers. Enantiomeric excess of syn-product and anti-
product (in bracket) was determined by supercritical fluid
chromatography (SFC) analysis on chiral stationary phase.
substituent at different positions of the benzene ring took part in
the reaction to afford the corresponding syn-adducts 5g-5j with
excellent ees (92.0-99.4%). The reaction of n-butyrophenone

3
with 4-nitroaniline (3a) and benzaldehyde 4a furnished 5k in low
yield but with excellent diastereoselectivity (syn/anti d.r. 93:7)
and enantioselectivity (96% ee). α-Azidophenylethanone and
cyclohexanone also participated in the reaction as Mannich
donors to afford the adduct 5l and 5m, respectively, with
moderate d.r. and ees.
5q in 81% yield with similar ee. On the other hand, 4-
ACCEPTED MANUSCRIPT
methoxyaniline (0.2 equiv) also speeded up the reaction to afford
5q in 74% yield but with much reduced ee (68%). It is reasonable
to expect that the added aniline might condense with acetone to
form enamine which is more reactive than the enol form of the
acetone. Under the reaction conditions, transamination between
imine 7 and aniline 3b may also occur to give (E)-N-4-
(methoxyphenyl)-1-phenylmethanimine (7b). However, Mannich
adduct resulting from the reaction of 6 with 7b was not observed
due probably to the reduced reactivity of 7b relative to 7a. The
results of these control experiments clearly indicated that aniline
is not simply acting as a reactant leading to imines, it might also
be involved in the key C-C bond forming process.
The syn-relative stereochemistry of 5k was determined by X-
ray crystallographic analysis of the racemic compound (cf
Supporting information).22 The absolute configuration (2S,3S)
was tentatively assigned by comparison of its optical rotation
with that of the closely related analogues.23 The stereochemistry
of all other Mannich adducts was assigned by analogy.
Acetone was also examined as a Mannich donor (Scheme 3).
The reaction of acetone with aldehyde and 4-nitroaniline afforded
the desired β-amino ketone 5n-5p in good to excellent yields.
However, the enantioselectivity was in general diminished
compared to the reactions involving propiophenones. For
example, 5n was isolated with 87% ee which was much lower
than that of 5a (97.4% ee).
It is obvious that the presence of an electron-withdrawing
(NO2) or an electron-donating group (OMe) could not only
modulate the electrophilicity of the in situ formed imines, but
also the basicity of the imine nitrogen, hence the strength of the
hydrogen bonding formed with CPA.24 We suspected that aniline
may also condense with ketones to form enamines which is in
principle more nucleophilic than enol. Indeed, CPA-catalyzed
Mannich reaction involving pre-formed enamines14 and
enamides14 are known. Assuming that the trans-enamine/trans-
enol is the most reactive species and the cis-trans isomerization
was rapid under the reaction conditions,25 then a transition state
model A involving dual activation of both the nucleophile and
the electrophile can be proposed to account for the observed
stereochemical outcome (Scheme 5).
Scheme 3. Three-component asymmetric Mannich reaction of
a
acetone. Reaction conditions: 4a (0.25 mmol), aniline 3a (0.25
mmol), ketone 6 (2.5 mmol), catalyst 1h (5 mol%) in CHCl3 (2.5 mL,
c 0.1 M), rt, 48 h. Yield of isolated product. Determined by
Scheme 5. Stereochemical model.
b
c
The so obtained β-amino ketone can be converted to 1,3-
aminoalcohols in a stereoselective manner. Reduction of 5a with
LAH and catecholborane afforded 1,3-anti 8 and 1,3-syn 9,
respectively, in excellent yield and diastereoselectivity.23
supercritical fluid chromatography (SFC) on a chiral stationary phase.
O2N
LiAlH4 (5 equiv)
THF, -78 oC, 1 h
94%
NH OH
O2N
NH
O
8
O2N
5a
NH OH
catecholborane (10 equiv)
THF, 0 oC, 12 h
89%
9
Scheme 6. Stereoselective reduction of 5a.
Scheme 4. Control experiment.
3. Conclusion
When aniline, 4-methoxyaniline, 4-methylaniline and 4-
chloroaniline were used as amine inputs, the reaction proceeded
smoothly to provide the adduct in high yields, but with very low
ees (<10% ee). The importance of 4-nitroaniline to the
enantioselectivity of the aforementioned direct enantioselective
Mannich reaction was intriguing. We performed following
control experiments in order to better understand the role of
anilines. Reaction of acetone with a preformed imine 7a under
standard conditions for 6 h provided 5q in 61% yield with 83%
ee. Adding a catalytic amount of 4-nitroaniline (0.2 equiv) to the
reaction mixture accelerated significantly the reaction to afford
In conclusion, we developed a chiral phosphoric acid-
catalyzed asymmetric three-component Mannich reaction. In the
presence of a catalytic amount of CPA 1h, the reaction of acyclic
ketones, 4-nitroaniline and aldehydes afforded syn-β-amino
ketones in moderate yield with excellent enatioselectivities (up to
99.4% ee) and good diastereoselectivities (up to 93/7 d.r.). The
resulting β-amino ketones can be reduced stereoselectively to
either 1,3-syn or 1,3-anti amino alcohols

4
Tetrahedron
ACCEPTED MANUSCRIPT
4. Experimental section
(d, J = 9.2 Hz, 2H, anti), 4.82 (d, J = 4.9 Hz, 1H, anti), 4.74 (d, J
= 4.6 Hz, 1H, syn), 4.03-3.97 (m, 1Hsyn + 1Hanti), 3.87 (s, 3H,
anti), 3.82 (s, 3H, syn), 1.39 (d, J = 7.1 Hz, 3H, syn), 1.20 (d, J =
7.0 Hz, 3H, anti); 13C NMR (100.6 MHz, CDCl3) (mixture of
syn- and anti-isomers) δ 202.7, 200.5, 164.1, 164.0, 152.6, 152.5,
140.5, 139.7, 138.5, 138.0, 130.7, 130.6, 129.6, 129.0, 128.9,
128.6, 127.9, 127.8, 126.6, 126.29, 126.26, 125.9, 114.2, 113.8,
112.5, 111.7, 61.0, 59.1, 55.6, 55.5, 45.7, 45.1, 17.3, 11.6;
Column Daicel Chiracel AD-H; 15% MeOH: syn-tR1 = 10.74 min
98.3%; syn-tR2 = 14.07 min 1.7%; anti-tR1 = 12.59 min 37.2%;
anti-tR2 = 28.92 min 62.8%.
4.1. Enantioselctive direct three-component Mannich
reaction: General procedure
A solution of aniline 3 (0.25 mmol), aldehyde 4 (0.25 mmol),
ketone 2 (1.25 mmol, 5 equiv) and 1h (9.4 mg, 0.0125 mmol,
0.05 equiv) in CHCl3 (2.5 mL) was stirred at rt for 48 h. The
reaction mixture was quenched with aqueous saturated NaHCO3
solution (10 mL) and extracted with CH2Cl2 (3Ɛ10 mL). The
combined organic phases were washed with brine, dried over
Na2SO4, filtered and the filtrate was concentrated in vacuo.
Purification of the crude reaction mixture by flash column
chromatography on silica gel (petroleum ether/EtOAc) afforded
the three-component adduct 5.
4.1.4. (2
amino)-3-phenylpropan-1-one (5d)
Purification: Flash chromatography
ether/EtOAc: 6/1-5/1). 5d-syn (27 mg, 27%) as a yellow oil.
S,3S)-1-(4-Chlorophenyl)-2-methyl-3-((4-nitrophenyl)
(SiO2,
petroleum
4
.
1.1. (2S,3S)-2-Methyl-3-((4-nitrophenyl)amino)-1,3-diphenylprop
an-1-one (5a)
Purification: Flash petroleum
20
1
[a]D +32.3 (c 0.3, CHCl3); H NMR (400 MHz, CDC13) δ 7.96
(d, J = 9.1 Hz, 2H), 7.85 (d, J = 8.5 Hz, 2H), 7.45 (d, J = 8.4 Hz,
2H), 7.36-7.25 (m, 5H), 6.44 (d, J = 9.1 Hz, 2H), 5.18 (br s, 1H),
4.82 (d, J = 5.3 Hz, 1H), 3.99-3.92 (m, 1H), 1.24 (d, J = 7.0 Hz,
3H); 13C NMR (100.6 MHz, CDCl3) δ 200.9, 152.2, 140.3, 139.4,
138.7, 134.1, 129.6, 129.3, 129.1, 128.0, 126.6, 126.0, 112.4,
58.9, 46.4, 11.9; Column Daicel Chiracel OD-H; 15% MeOH: tR1
= 6.19 min 99.1%; tR2 = 6.58 min 0.9%. 5d-anti (4 mg, 4%) as a
chromatography
(SiO2,
ether/EtOAc: 6/1-5/1). 5a-syn (41 mg, 45%) as a yellow solid.
[a]D20 +51.0 (c 1.0, CHCl3); 1H NMR (400 MHz, CDC13) δ 7.99-
7.95 (m, 4H), 7.63 (t, J = 7.4 Hz, 1H), 7.51 (t, J = 7.6 Hz, 2H),
7.38-7.30 (m, 5H), 6.46 (d, J = 9.2 Hz, 2H), 5.28 (br s, 1H), 4.88
(d, J = 5.0 Hz, 1H), 4.05 (qd, J = 7.0, 5.1 Hz, 1H), 1.26 (d, J =
7.0 Hz, 3H); 13C NMR (100.6 MHz, CDCl3) δ 202.2, 152.4,
139.6, 138.6, 135.8, 133.7, 129.00, 128.97, 128.3, 127.9, 126.6,
126.0, 112.5, 58.8, 46.3, 11.6; Column Daicel Chiracel AD-H; 15%
MeOH: tR1 = 7.96 min 98.7%; tR2 = 9.98 min 1.3%. 5a-anti (6
1
yellow oil. H NMR (400 MHz, CDC13) δ 8.00 (d, J = 9.1 Hz,
2H), 7.57 (d, J = 8.5 Hz, 2H), 7.31 (d, J = 8.5 Hz, 2H), 7.26-7.16
(m, 5H), 6.51 (d, J = 9.1 Hz, 2H), 6.44 (br s, 1H), 4.76 (d, J = 4.6
Hz, 1H), 4.04-3.97 (m, 1H), 1.41 (d, J = 7.0 Hz, 3H); 13C NMR
(100.6 MHz, CDCl3) δ 203.3, 152.4, 140.3, 140.2, 138.2, 134.9,
129.5, 128.99, 128.95, 128.0, 126.3, 126.2, 111.8, 60.8, 45.7,
17.1; Column Daicel Chiracel OD-H; 15% MeOH: tR1 = 5.41 min
61.3%; tR2 = 6.60 min 38.7%.
1
mg, 7%) as a yellow oil. H NMR (400 MHz, CDC13) δ 7.92 (d,
J = 9.2 Hz, 2H), 7.60 (dd, J = 8.3, 1.1 Hz, 2H), 7.44 (t, J = 7.4 Hz,
1H), 7.28 (t, J = 7.8 Hz, 2H), 7.21-7.15 (m, 4H), 7.09 (t, J = 6.8
Hz, 1H), 6.44 (d, J = 9.2 Hz, 2H), 6.33 (br s, 1H), 4.70 (d, J = 4.8
Hz, 1H), 3.99 (qd, J = 7.1, 5.1 Hz, 1H), 1.33 (d, J = 7.1 Hz, 3H);
13C NMR (100.6 MHz, CDCl3) δ 204.4, 152.6, 140.3, 138.1,
136.6, 133.6, 128.9, 128.6, 128.2, 127.8, 126.32, 126.25, 111.8,
60.8, 45.6, 17.2; Column Daicel Chiracel AD-H; 15% MeOH: tR1
= 7.77 min 52.9%; tR2 = 14.44 min 47.1%.
4.1.5. (2S,3S)-1-(Furan-2-yl)-2-methyl-3-((4-nitrophenyl)
amino)-3-phenylpropan-1-one (5e)
Purification:
Flash
chromatography
(SiO2,
petroleum
20
ether/EtOAc: 5/1). 5e-syn (28 mg, 32%) as a yellow oil. [a]D
+42.4 (c 0.1, CHCl3); 1H NMR (400 MHz, CDC13) δ 7.96 (d, J =
9.2 Hz, 2H), 7.65-7.63 (m, 1H), 7.35-7.24 (m, 6H), 6.57 (dd, J =
3.6, 1.7 Hz, 1H), 6.44 (d, J = 9.2 Hz, 2H), 5.26 (br s, 1H), 4.88 (d,
J = 4.9 Hz, 1H), 3.87-3.80 (m, 1H), 1.20 (d, J = 7.1 Hz, 3H); 13C
NMR (100.6 MHz, CDCl3) δ 190.4, 152.3, 151.9, 147.1, 139.3,
138.6, 128.9, 127.9, 126.6, 126.0, 118.4, 112.8, 112.5, 58.7, 47.0,
10.7; IR: υ (cm-1) 3365 (w), 1665 (w), 1597 (s), 1463 (m), 1304
(s), 1288 (s), 1111 (s), 753 (s), 701 (m). HRMS (ESI) calcd for
C20H18N2O4 [M+H]+ 351.1339; found 351.1330. Column Daicel
Chiracel IA; 10% MeOH: tR1 = 7.21 min 90.2%; tR2 = 8.00 min
9.8%. 5e-anti (22 mg, 25%) as a yellow oil; 1H NMR (400 MHz,
CDC13) δ 7.99 (d, J = 9.2 Hz, 2H), 7.50-7.49 (m, 1H), 7.26-7.15
(m, 5H), 6.98 (d, J = 3.6 Hz, 1H), 6.49 (d, J = 9.2 Hz, 2H), 6.43
(dd, J = 3.6, 1.6 Hz, 1H), 6.18 (br s, 1H), 4.73 (d, J = 5.1 Hz, 1H),
3.84-3.77 (m, 1H), 1.38 (d, J = 7.1 Hz, 3H); 13C NMR (100.6
MHz, CDCl3) δ 191.9, 152.4, 152.3, 147.4, 140.1, 138.2, 128.8,
127.8, 126.3, 126.2, 118.8, 112.6, 111.9, 60.7, 46.6, 16.5; IR: υ
(cm-1) 3363 (w), 1663 (w), 1598 (s), 1464 (m), 1306 (s), 1112
(m), 754 (m). HRMS (ESI) calcd for C20H18N2O4 [M+H]+
351.1339; found 351.1330. Column Daicel Chiracel IA; 10%
MeOH: tR1 = 7.77 min 32.7%; tR2 = 8.32 min 67.3%.
4.1.2. (2S,3S)-2-Methyl-3-((4-nitrophenyl)amino)-3-
phenyl-1-(p-tolyl)propan-1-one (5b)
Purification:
Flash
chromatography
(SiO2,
petroleum
ether/EtOAc: 6/1-5/1). 5b-syn (48 mg, 51%) as a yellow solid.
[a]D20 +15.0 (c 0.86, CHCl3); 1H NMR (400 MHz, CDC13) δ 7.94
(d, J = 9.2 Hz, 2H), 7.86 (d, J = 8.3 Hz, 2H), 7.35-7.27 (m, 7H),
6.42 (d, J = 9.2 Hz, 2H), 5.30 (br s, 1H), 4.83 (d, J = 4.8 Hz, 1H),
4.00 (qd, J = 7.0, 4.7 Hz, 1H), 2.42 (s, 3H), 1.21 (d, J = 6.9 Hz,
3H); 13C NMR (100.6 MHz, CDCl3) δ 201.7, 152.4, 144.8, 139.6,
138.5, 133.2, 129.7, 129.0, 128.4, 127.9, 126.6, 126.0, 112.5,
58.9, 46.0, 21.7, 11.4. [α]D +15.0 (c 0.86, CHCl3); Column Daicel
Chiracel AS-H; 10% MeOH: tR1 = 5.15 min 98.8%; tR2 = 5.87
1
min 1.2%. 5b-anti (7 mg, 7%) as a yellow oil. H NMR (400
MHz, CDC13) δ 7.99 (d, J = 9.2 Hz, 2H), 7.57 (d, J = 8.2 Hz, 2H),
7.28-7.14 (m, 7H), 6.50 (d, J = 9.2 Hz, 2H), 4.75 (d, J = 4.6 Hz,
1H), 4.06-4.00 (m, 1H), 2.36 (s, 3H), 1.39 (d, J = 7.1 Hz, 3H);
13C NMR (100.6 MHz, CDCl3) δ 204.0, 152.6, 144.7, 140.4,
138.0, 134.1, 129.4, 128.9, 128.3, 127.8, 126.31, 126.26, 111.8,
60.9, 45.4, 21.6, 17.3; Column Daicel Chiracel AS-H; 10%
MeOH: tR1 = 6.35 min 47.9%; tR2 = 6.72 min 52.1%.
4.1.3. (2S,3S)-1-(4-Methoxyphenyl)-2-methyl-3-((4- nitrophen
yl)amino)-3-phenylpropan-1-one (5c)
4.1.6. (2S,3S)-2-Methyl-3-((4-nitrophenyl)amino)-3-
phenyl-1-(thiophen-2-yl)propan-1-one (5f)
Purification:
Flash
chromatography
(SiO2,
petroleum
Purification:
Flash
chromatography
(SiO2,
petroleum
ether/EtOAc: 5/1). 5c (53 mg, 54%) as a mixture of syn-/anti-
20
1
ether/EtOAc: 5/1). 5f-syn (49 mg, 54%) as a yellow oil. [a]D
+
(ratio 84/16). H NMR (400 MHz, CDC13) (mixture of syn- and
1
60.0 (c 0.3, CHCl3); H NMR (400 MHz, CDC13) δ 7.96 (d, J =
9.1 Hz, 2H), 7.79 (d, J = 3.8 Hz, 1H), 7.70 (d, J = 4.9 Hz, 1H),
7.36-7.26 (m, 5H), 7.16 (t, J = 4.4 Hz, 1H), 6.45 (d, J = 9.1 Hz,
2H), 5.30 (br s, 1H), 4.87 (d, J = 5.0 Hz, 1H), 3.83-3.77 (m, 1H),
anti-isomers) δ 7.99 (d, J = 9.3 Hz, 2H, syn), 7.95 (d, J = 8.8 Hz,
2H, anti), 7.94 (d, J = 9.2 Hz, 2H, anti), 7.65 (d, J = 9.0 Hz, 2H,
syn), 7.35-7.14 (m, 5Hsyn + 5Hanti), 6.96 (d, J = 9.0 Hz, 2H, anti),
6.81 (d, J = 9.0 Hz, 2H, syn), 6.50 (d, J = 9.2 Hz, 2H, syn), 6.42

5
1.25 (d, J = 7.0 Hz, 3H); 13C NMR (100.6 MHz, CDCl3) δ 194.6,
Purification: Flash chromatography (SiO2, petroleum
ACCEPTED MANUSCRIPT
20
152.4, 142.9, 139.4, 138.6, 135.1, 132.4, 129.0, 128.5, 128.0,
126.6, 125.9, 112.6, 59.4, 48.2, 11.6; IR: υ (cm-1) 3372 (w), 1639
(w), 1597 (m), 1479 (w), 1411 (w), 1307 (s), 1112 (s), 828 (m),
752 (m), 724 (s), 696 (m). HRMS (ESI) calcd for C20H18N2O3S
[M+H]+ 367.1111; found 367.1115. Column Daicel Chiracel AD-
H; 20% MeOH: tR1 = 5.82 min 98.2%; tR2 = 6.92 min 1.2%. 5f-
ether/EtOAc: 4/1). 5i-syn (48 mg, 49%) as a yellow oil. [a]D
+54.9 (c 0.3, CHCl3); 1H NMR (400 MHz, CDC13) δ 7.97 (d, J =
9.1 Hz, 2H), 7.93 (d, J = 7.8 Hz, 2H), 7.61 (t, J = 7.3 Hz, 1H),
7.50 (t, J = 7.7 Hz, 2H), 7.35 (s, 1H), 7.29-7.23 (m, 3H), 6.43 (d,
J = 9.1 Hz, 2H), 5.24 (br s, 1H), 4.80 (br s, 1H), 4.03-3.97 (m,
1H), 1.24 (d, J = 7.0 Hz, 3H); 13C NMR (100.6 MHz, CDCl3) δ
201.8, 152.0, 141.9, 138.9, 135.6, 135.0, 133.9, 130.3, 129.0,
128.3, 128.2, 126.7, 126.0, 124.9, 112.5, 58.5, 46.0, 11.6; IR: υ
(cm-1) 3369 (w), 1677 (w), 1597 (s), 1475 (m), 1306 (s), 1285 (s),
1185 (m), 1111 (s), 973 (m), 752 (s), 693 (s). HRMS (ESI) calcd
for C22H19ClN2O3 [M+Na]+ 417.0982; found 417.0981. Column
1
anti (isolated as a mixture of syn- and anti-isomers) H NMR
(400 MHz, CDC13) (for anti-isomer) δ 7.99 (d, J = 9.2 Hz, 2H),
7.61 (d, J = 4.1 Hz, 1H), 7.35-7.15 (m, 6H), 6.99-6.97 (m, 1H),
6.49 (d, J = 9.2 Hz, 2H), 4.73 (d, J = 4.6 Hz, 1H), 3.86-3.77 (m,
1H), 1.45 (d, J = 7.1 Hz, 3H); 13C NMR (100.6 MHz, CDCl3) (for
anti-isomer) δ 196.3, 152.5, 144.0, 140.2, 138.1, 135.3, 132.8,
128.9, 128.3, 127.9, 126.23, 126.20, 111.8, 60.9, 47.7, 17.2.
Daicel Chiracel AS-H; 15% MeOH: tR1 = 3.51 min 96.0%; tR2
=
4.07 min 4.0%. 5i-anti (isolated as a mixture of syn- and anti-
isomers) 1H NMR (400 MHz, CDC13) (for anti-isomer) δ 7.94 (d,
J = 9.1 Hz, 2H), 7.65 (d, J = 7.5 Hz, 2H), 7.47 (t, J = 7.2 Hz, 1H),
7.42 (t, J = 7.6 Hz, 2H), 7.34-7.09 (m, 4H), 6.43 (d, J = 9.2 Hz,
2H), 4.67 (d, J = 4.8 Hz, 1H), 4.00-3.90 (m, 1H), 1.33 (d, J = 7.1
Hz, 3H); 13C NMR (100.6 MHz, CDCl3) (for anti-isomer) δ
203.9, 152.2, 142.6, 138.4, 136.3, 134.9, 133.8, 130.2, 128.8,
128.15, 128.1, 126.6, 126.3, 124.6, 111.8, 60.3, 45.4, 17.1.
4.1.7. (2S,3S)-3-(4-Chlorophenyl)-2-methyl-3-((4-
nitrophenyl) amino)-1-phenylpropan-1-one (5g)
Purification:
Flash
chromatography
(SiO2,
petroleum
ether/EtOAc: 6/1-5/1). 5g-syn (39 mg, 40%) as a yellow oil.
20
1
[a]D +26.8 (c 0.3, CHCl3); H NMR (400 MHz, CDC13) δ 7.96
(d, J = 9.2 Hz, 2H), 7.92 (d, J = 7.4 Hz, 2H), 7.61 (t, J = 7.4 Hz,
1H), 7.49 (t, J = 7.7 Hz, 2H), 7.33-7.28 (m, 4H), 6.42 (d, J = 9.2
Hz, 2H), 5.26 (br s, 1H), 4.82 (d, J = 5.1 Hz, 1H), 4.02-3.95 (m,
1H), 1.23 (d, J = 7.0 Hz, 3H); 13C NMR (100.6 MHz, CDCl3) δ
201.9, 152.1, 138.8, 138.2, 135.6, 133.9, 133.7, 129.2, 129.0,
128.2, 128.0, 126.0, 112.5, 58.3, 46.1, 11.8; IR: υ (cm-1) 3364
(w), 3064 (w), 2932 (w), 1679 (w), 1596 (s), 1504 (m), 1467 (w),
1304 (s), 1112 (s), 1093 (m), 973 (m), 835 (m), 702 (m). HRMS
(ESI) calcd for C22ClH19N2O3 [M+H]+ 395.1157; found
4.1.10. (2S,3S)-
3 - (2 - Br o m o p h e n y l ) -2 -m e t h y l -3 - ( (4 -nitrophenyl)
amino)-1-phenylpropan-1-one (5j)
Purification:
Flash
chromatography
(SiO2,
petroleum
ether/EtOAc: 4/1). 5j-syn (50 mg, 46%) as a yellow oil. [α]D
+31.1 (c 0.3, CHCl3); 1H NMR (400 MHz, CDC13) δ 8.11 (d, J =
7.7 Hz, 2H), 7.94 (d, J = 9.1 Hz, 2H), 7.67-7.60 (m, 2H), 7.50 (t,
J = 7.7 Hz, 2H), 7.35 (t, J = 7.4 Hz, 1H), 7.30-7.26 (m, 1H), 7.20
(t, J = 7.6 Hz, 1H), 6.34 (d, J = 9.1 Hz, 2H), 5.56 (br s, 1H), 5.11
(d, J = 4.0 Hz, 1H), 4.31-4.24 (m, 1H), 1.15 (d, J = 7.1 Hz, 3H);
13C NMR (100.6 MHz, CDCl3) δ 202.9, 151.9, 138.8, 137.4,
135.7, 133.9, 133.7, 129.6, 129.5, 128.9, 128.6, 127.8, 125.9,
122.3, 112.5, 57.7, 41.8, 11.1; IR υ (cm-1) 3377 (w), 1677 (w),
1598 (s), 1505 (m), 1312 (s), 1290 (s), 1112 (s), 753 (m). HRMS
(ESI) calcd for C22BrH19N2O3 [M+H]+ 439.0652; found
395.1156. Column Daicel Chiracel OD-H; 10% MeOH: tR1
=
11.02 min 99.7%; tR2 = 11.62 min 0.3%. 5g-anti (10 mg, 10%) as
1
a yellow oil. H NMR (400 MHz, CDC13) δ 8.01 (d, J = 9.2 Hz,
2H), 7.70 (dd, J = 8.3, 1.1 Hz, 2H), 7.55 (t, J = 7.4 Hz, 1H), 7.39
(t, J = 7.8 Hz, 2H), 7.24-7.20 (m, 4H), 6.49 (d, J = 9.2 Hz, 2H),
6.41 (br s, 1H), 4.75 (d, J = 4.6 Hz, 1H), 4.08-4.01 (m, 1H), 1.42
(d, J = 7.1 Hz, 3H); 13C NMR (100.6 MHz, CDCl3) δ 204.1,
152.3, 138.9, 138.3, 136.3, 133.9, 133.6, 129.1, 128.8, 128.2,
127.8, 126.3, 111.8, 60.2, 45.4, 17.2; IR: υ (cm-1) 3364 (w), 3064
(w), 2932 (w), 1679 (w), 1596 (s), 1504 (m), 1467 (w), 1304 (s),
1112 (s), 1093 (m), 973 (m), 835 (m), 702 (m). HRMS (ESI)
calcd for C22ClH19N2O3 [M+H]+ 395.1157; found 395.1156.
Column Daicel Chiracel AD-H; 15% MeOH: tR1 = 12.06 min
48.7%; tR2 = 17.86 min 51.3%.
439.0655. Column Daicel Chiracel OD-H; 15% MeOH: tR1
=
6.79 min 98.8%; tR2 = 8.78 min 1.2%. 5j-anti (10 mg, 10%) as a
yellow oil. H NMR (400 MHz, CDC13) δ 8.02 (d, J = 9.2 Hz,
1
2H), 7.63 (d, J = 7.9 Hz, 2H), 7.58-7.56 (m, 1H), 7.49 (t, J = 7.4
Hz, 1H), 7.33 (t, J = 7.7 Hz, 2H), 7.09-7.07 (m, 1H), 7.01-6.99
(m, 2H), 6.76 (br s, 1H), 6.47 (d, J = 9.1 Hz, 2H), 5.08 (br s, 1H),
4.33-4.27 (m, 1H), 1.49 (d, J = 7.1 Hz, 3H); 13C NMR (100.6
MHz, CDCl3) δ 204.7, 152.1, 138.6, 138.3, 136.5, 133.8, 133.2,
129.4, 128.7, 128.1, 128.0, 127.9, 126.3, 122.8, 111.7, 59.8, 41.8,
17.0; IR: υ (cm-1) 3361 (w), 1681 (w), 1600 (s), 1326 (s), 1310
(s), 1113 (m), 1027 (w), 794 (w). Column Daicel Chiracel OD-H;
15% MeOH: tR1 = 4.67 min 31.6%; tR2 = 6.65 min 68.4%.
4.1.8. (2S,3S)-3-(4-Bromophenyl)-2-methyl-3-((4-
nitrophenyl) amino)-1-phenylpropan-1-one (5h)
Purification:
Flash
chromatography
(SiO2,
petroleum
ether/EtOAc: 5/1). 5h (55 mg, 50%) as a mixture of syn-/anti-
1
(ratio 84/16). H NMR (400 MHz, CDC13) (mixture of syn- and
anti-isomers) δ 8.00 (d, J = 9.2 Hz, 2H, syn), 7.96 (d, J = 9.2 Hz,
2H, anti), 7.93-7.90 (m, 2H, anti), 7.72-7.70 (m, 2H, syn), 7.60 (t,
J = 8.0 Hz, 1H, anti), 7.54 (t, J = 7.2 Hz, 1H, syn), 7.50-7.36 (m,
4Hsyn + 4Hanti), 7.24 (d, J = 8.4 Hz, 2H, anti), 7.16 (d, J = 8.4 Hz,
2H, syn), 6.49 (d, J = 9.2 Hz, 2H, syn), 6.43 (d, J = 9.2 Hz, 2H,
anti), 4.81 (d, J = 5.3 Hz, 1H, anti), 4.74 (d, J = 4.8 Hz, 1H, syn),
4.07-3.96 (m, 1Hsyn + 1Hanti), 1.40 (d, J = 7.1 Hz, 3H, syn), 1.24
(d, J = 7.0 Hz, 3H, anti); 13C NMR (100.6 MHz, CDCl3) (mixture
of syn- and anti-isomers) δ 204.0, 201.8, 152.3, 152.1, 139.4,
138.8, 138.3, 136.3, 135.6, 133.85, 133.84, 132.1, 132.0, 129.0,
128.8, 128.4, 128.22, 128.15, 128.1, 126.3, 126.0, 121.8, 121.7,
112.5, 111.8, 60.3, 58.4, 46.1, 45.4, 17.1, 12.0; Column Daicel
4.1.11. (S)-2-((S)-((4-Nitrophenyl) amino) (phenyl)
methyl)-1-phenylbutan-1-one (5k)
Purification:
Flash
chromatography
(SiO2,
petroleum
ether/EtOAc: 6/1-5/1). 5k-syn (27 mg, 29%) as a yellow oil. [α]D
1
+34.9 (c 0.52, CHCl3); H NMR (400 MHz, CDC13) δ 7.96-7.92
(m, 4H), 7.59 (t, J = 7.3 Hz, 1H), 7.48 (t, J = 7.6 Hz, 2H), 7.34-
7.24 (m, 5H), 6.42 (d, J = 9.1 Hz, 2H), 5.34 (br s, 1H), 4.76 (d, J
= 4.9 Hz, 1H), 3.91-3.86 (m, 1H), 2.10-2.00 (m, 1H), 1.64-1.55
(m, 1H), 0.80 (t, J = 7.3 Hz, 3H); 13C NMR (100.6 MHz, CDCl3)
δ 202.2, 152.4, 139.6, 138.6, 137.0, 133.7, 129.0, 128.9, 128.2,
127.9, 126.7, 126.0, 112.4, 58.8, 53.5, 19.8, 12.2; IR υ (cm-1)
3391 (w), 2930 (w), 1669 (w), 1597 (s), 1503 (m), 1482 (m),
1313 (s), 1113 (m), 698 (m). HRMS (ESI) calcd for C23H22N2O3
[M+H]+ 375.1703; found 375.1700. Column Daicel Chiracel AD-
H; 15% MeOH: tR1 = 4.91 min 98.0%; tR2 = 7.32 min 2.0%. 5k-
Chiracel AD-H; 20% MeOH: syn-tR1 = 8.57 min 96.8%; syn-tR2
=
11.12 min 3.2%; anti-tR1 = 10.08 min 42.5%; anti-tR2 = 16.27 min
57.5%.
4.1.9. (2S,3S)-3-(3-Chlorophenyl)-2-methyl-3-((4-
nitrophenyl) amino)-1-phenylpropan-1-one (5i)
1
anti (2 mg, 2%) as a yellow oil. H NMR (400 MHz, CDC13) δ
8.00 (d, J = 9.2 Hz, 2H), 7.56 (dd, J = 8.4, 1.2 Hz, 2H), 7.47 (t, J

6
Tetrahedron
ACCEPTED MANUSCRIPT
= 7.4 Hz, 1H), 7.30 (t, J = 7.8 Hz, 2H), 7.23-7.10 (m, 5H), 6.62
Purification:
Flash
chromatography
(SiO2,
petroleum
(br s, 1H), 6.50 (d, J = 9.2 Hz, 2H), 4.82 (br s, 1H), 3.92-3.87 (m,
1H), 2.07-1.96 (m, 1H), 1.90-1.80 (m, 1H), 0.97 (t, J = 7.4 Hz,
3H); 13C NMR (100.6 MHz, CDCl3) δ 205.4, 152.4, 140.3, 138.0,
137.7, 133.5, 128.9, 128.5, 128.0, 127.8, 126.3, 126.2, 111.7,
58.9, 52.7, 25.1, 12.2; IR: υ (cm-1) 3369 (w), 3061 (w), 2965 (w),
2931 (w), 1667 (w), 1596 (s), 1503 (m), 1473 (m), 1304 (s), 1217
(m), 1110 (s), 832 (m), 700 (s). HRMS (ESI) calcd for
C23H22N2O3 [M+H]+ 375.1703; found 375.1706. Column Daicel
Chiracel AD-H; 15% MeOH: tR1 = 5.84 min 28.8%; tR2 = 6.35
min 71.2%.
ether/EtOAc: 4/1). 5o (55 mg, 66%) as a yellow oil. [α]D +71.3 (c
0.36, CHCl3); 1H NMR (400 MHz, CDC13) δ 7.98 (d, J = 9.2 Hz,
2H), 7.23 (d, J = 8.6 Hz, 2H), 6.85 (d, J = 8.7 Hz, 2H), 6.48 (d, J
= 9.2 Hz, 2H), 5.55 (br s, 1H), 4.87 (t, J = 6.1 Hz, 1H), 3.77 (s,
3H), 3.01 (dd, J = 16.2, 6.7 Hz, 1H), 2.95 (dd, J = 16.2, 5.6 Hz,
1H), 2.09 (s, 3H); 13C NMR (100.6 MHz, CDCl3) δ 207.0, 159.1,
152.1, 138.2, 132.5, 127.2, 126.1, 114.4, 112.0, 55.2, 53.3, 50.1,
31.2. IR: υ (cm-1) 3368 (w), 2933 (w), 1711 (w), 1597 (s), 1504
(m), 1301 (s), 1283 (s), 1247 (s), 1110 (s), 832 (m), 735 (m). ).
HRMS (ESI) calcd for C17H18N2O4 [M+Na]+ 337.1159; found
337.1156. [α]D +71.3 (c 0.36, CHCl3). Column Daicel Chiracel
AD-H; 20% MeOH: tR1 = 5.23 min 80.9%; tR2 = 10.72 min
19.1%.
4.1.12. (2S,3R)-2-Azido-3-((4-nitrophenyl) amino)-
1,3-diphenylpropan-1-one (5l)
Purification:
Flash
chromatography
(SiO2,
petroleum
4.1.16. (S)-4-(3-Chlorophenyl)-4-((4-nitrophenyl)
amino) butan-2-one (5p)
ether/EtOAc: 4/1). 5l (50 mg, 52%) as a mixture of syn-/anti-
1
(ratio 70/30). H NMR (400 MHz, CDC13) (mixture of syn- and
anti-isomers) δ 8.03 (d, J = 9.1 Hz, 2H, anti), 7.94 (d, J = 9.1 Hz,
2H, syn), 7.86 (d, J = 7.7 Hz, 2H, syn), 7.71 (d, J = 7.7 Hz, 2H,
anti), 7.64 (t, J = 7.4 Hz, 2H, anti), 7.58 (t, J = 7.4 Hz, 1H, anti),
7.50 (t, J = 7.7 Hz, 2H, syn), 7.59-7.24 (m, 6Hsyn + 5Hanti), 6.56
(d, J = 9.1 Hz, 2H, anti), 6.42 (d, J = 9.1 Hz, 2H, syn), 6.03 (br s,
1H, anti), 5.35 (br s, 1H, syn), 5.25 (d, J = 4.5 Hz, 1H, syn), 5.15
(d, J = 4.3 Hz, 1H, anti), 5.08 (d, J = 4.6 Hz, 1H, anti), 5.04 (d, J
= 4.3 Hz, 1H, syn); 13C NMR (100.6 MHz, CDCl3) (mixture of
syn- and anti-isomers) δ 195.8, 193.9, 151.32, 151.29, 139.04,
138.98, 137.4, 136.3, 135.2, 134.5, 134.43, 134.41, 129.3, 129.2,
129.1, 129.0,128.8, 128.6, 128.4, 126.8, 126.2, 126.0, 112.4, 68.3,
64.3, 59.9, 58.0; IR: υ (cm-1) 3372 (w), 3062 (w), 2107 (m), 1684
(w), 1596 (s), 1504 (m), 1305 (s), 1287 (s), 1111 (s). HRMS
(ESI) calcd for C21H17N5O3 [M+Na]+ 410.1229; found 410.1242.
Column Daicel Chiracel AD-H; 20% MeOH: tR1 = 5.74 min
83.1%; tR2 = 12.59 min 16.9%.
Purification:
Flash
chromatography
(SiO2,
petroleum
ether/EtOAc: 3/1). 5p (45 mg, 56%) as a yellow oil. [α]D +47.6 (c
1.0, CHCl3); H NMR (400 MHz, CDC13) δ 8.01 (d, J = 9.2 Hz,
1
2H), 7.32-7.20 (m, 4H), 6.48 (d, J = 9.2 Hz, 2H), 5.49 (br s, 1H),
4.88 (t, J = 5.9 Hz, 1H), 3.03 (dd, J = 16.8, 6.4 Hz, 1H), 2.98 (dd,
J = 16.8, 5.5 Hz, 1H), 2.13 (s, 3H); 13C NMR (100.6 MHz,
CDCl3) δ 206.3, 151.7, 143.0, 138.8, 135.0, 130.4, 128.2, 126.3,
126.2, 124.3, 112.2, 53.4, 49.8, 31.1. IR: υ (cm-1) 3369 (w), 3059
(w), 2923 (w), 1712 (m), 1597 (s), 1503 (m), 1475 (m), 1303 (s),
1280 (s), 1109 (s), 836 (m), 736 (m), 693 (s). HRMS (ESI) calcd
for C16ClH15N2O3 [M+H]+ 319.0844; found 319.0844. Column
Daicel Chiracel AD-H; 15% MeOH: tR1 = 5.19 min 86.7%; tR2
6.81 min 13.3%.
=
4.2. Diastereoselective reduction of 5a
4.2.1. (1S,2S,3S)-2-Methyl-3-((4-nitrophenyl)
amino)-1,3-diphenylpropan-1-ol (8)
To a solution of 5a (18 mg, 0.05 mmol) in THF (1 mL) was
4.1.13. (S)-2-((S)-((4-
nitrophenyl)amino)(phenyl)methyl)cyclohexan-1-
one (5m)
added a solution of LiAlH4 (1 M in THF, 0.25 mL, 0.25 mmol, 5
o
equiv) at -78 C and the reaction mixture was stirred at the same
Purification:
Flash
chromatography
(SiO2,
petroleum
temperature for 1 h. After addition of a saturated solution of
potassium sodium tartrate, the reaction mixture was extracted
with Et2O (3 times) and the combined organic phases were
washed with brine, dried over Na2SO4, and filtered. After
removal of the volatiles under reduced pressure, the residue was
purified by flash chromatography (SiO2, petroleum ether/EtOAc:
5/1) to afford 9 (17 mg, 94%) as a yellow oil. [α]D +182.3 (c 0.44,
CHCl3); 1H NMR (400 MHz, CDC13) δ 7.97 (d, J = 9.2 Hz, 2H),
7.37-7.28 (m, 10H), 6.55 (br s, 1H), 6.44 (d, J = 9.2 Hz, 2H),
4.71 (d, J = 2.5 Hz, 1H), 4.52 (d, J = 8.6 Hz, 1H), 2.48-2.30 (m,
1H), 2.30 (br s, 1H), 0.73 (d, J = 7.2 Hz, 3H); 13C NMR (100.6
MHz, CDCl3) δ 152.7, 142.8, 139.4, 137.7, 128.7, 128.5, 128.2,
127.40, 127.36, 126.5, 126.3, 111.7, 77.4, 60.1, 44.9, 13.5. IR: υ
(cm-1) 3329 (w), 1598 (m), 1468 (m), 1308 (s), 1114 (m), 697
(m). HRMS (ESI) calcd for C22H22N2O3 [M+Na]+ 385.1523;
found 385.1520. Column Daicel Chiracel OD-H; 20% MeOH: tR1
= 4.77 min 2.0%; tR2 = 6.17 min 98.0%.
ether/EtOAc: 5/1). 5m (74 mg, 92%) as a mixture of syn-/anti-
(ratio 72/28). H NMR (400 MHz, CDC13) (mixture of syn- and
1
anti-isomers) δ 8.08 (d, J = 9.0 Hz, 2H, anti), 8.00 (d, J = 9.2 Hz,
2H, syn), 7.36-7.25 (m, 5Hsyn + 5Hanti), 6.64 (d, J = 9.0 Hz, 2H,
anti), 6.52 (d, J = 9.2 Hz, 2H, syn), 5.51 (br s, 1Hsyn + 1Hanti),
4.88 (d, J = 4.3 Hz, 1H, syn), 4.67 (d, J = 6.0 Hz, 1H, anti), 2.91-
2.86 (m, 1Hsyn + 1Hanti), 2.47-1.53 (m, 8Hsyn + 8Hanti); 13C NMR
(100.6 MHz, CDCl3) (mixture of syn- and anti-isomers) δ 212.6,
211.1, 152.52, 152.48, 140.0, 139.6, 138.33, 138.26, 128.74,
128.65, 127.7, 127.6, 127.4, 127.0, 126.2, 126.1, 112.2, 112.1,
58.3, 57.2, 56.8, 55.5, 42.4, 42.3, 32.3, 28.7, 28.0, 26.5, 24.7,
24.3. Column Daicel Chiracel OD-H; 7% MeOH: syn-tR1 = 14.26
min 13.8%; syn-tR2 = 16.13 min 86.2%; anti-tR1 = 12.53 min
13.8%; anti-tR2 = 13.03 min 86.2%.
4.1.14. (S)-4-((4-Nitrophenyl) amino)-4-phenylbutan-
2-one (5n)
Purification:
Flash
chromatography
(SiO2,
petroleum
4.2.2. (1R,2S,3S)-2-Methyl-3-((4-nitrophenyl)
amino)-1,3-diphenylpropan-1-ol (9)
ether/EtOAc: 5.5/1). 5n (62 mg, 87%) as a yellow solid. [α]D
+84.3 (c 0.3, CHCl3); 1H NMR (400 MHz, CDC13) δ 8.03 (d, J =
9.2 Hz, 2H), 7.39-7.30 (m, 5H), 6.52 (d, J = 9.2 Hz, 2H), 5.51 (br
s, 1H), 4.94 (t, J = 6.0 Hz, 1H), 3.05 (dd, J = 16.4, 6.8 Hz, 1H),
3.01 (dd, J = 16.4, 5.6 Hz, 1H), 2.12 (s, 3H); 13C NMR (100.6
MHz, CDCl3) δ 206.9, 152.0, 140.6, 138.5, 129.1, 127.9, 126.2,
126.0, 112.1, 53.9, 50.0, 31.2; Column Daicel Chiracel AD-H; 15%
MeOH: tR1 = 5.74 min 93.7%; tR2 = 8.02 min 6.3%.
To a solution of 5a (18 mg, 0.05 mmol) in THF (0.5 mL) was
o
added catecholborane (52 ꢀL, 0.5 mmol, 10 equiv) at 0 C and
the reaction mixture was stirred at the same temperature for 12 h.
After addition of MeOH and a saturated solution of potassium
sodium tartrate, the reaction mixture was extracted with EtOAc
three times and the combined organic phases were washed with
brine (5 times), dried over Na2SO4 and filtered. After removal of
the volatiles under reduced pressure, the residue was purified by
flash chromatography (SiO2, petroleum ether/EtOAc: 3/1) to
4.1.15. (S)-4-(4-Methoxyphenyl)-4-((4-nitrophenyl)
amino) butan-2-one (5o)

7
10
a) Zhang, W, Cheng LF, Yu J, Gong, LZ. Angew. Chem. Int. Ed.
afford 10 (16 mg, 89%) as a yellow oil. [α]D +32.4 (c 1.0,
A
CCEPTED MANUSCRIPT
CHCl3); 1H NMR (400 MHz, CDC13) δ 8.00 (d, J = 9.2 Hz, 2H),
7.41-7.22 (m, 8H), 7.10 (d, J = 7.1 Hz, 2H), 6.45 (d, J = 9.1 Hz,
2H), 4.86 (s, 1H), 4.59 (d, J = 4.7 Hz, 1H), 2.25 (m, 1H), 1.04 (d,
J = 7.1 Hz, 3H).; 13C NMR (100.6 MHz, CDCl3) δ 153.2, 143.0,
141.1, 137.6, 128.9, 128.3, 127.54, 127.46, 126.5, 126.4, 125.3,
111.4, 73.4, 62.3, 45.8, 11.2. IR: υ (cm-1) 3329 (w), 1598 (m),
1468 (m), 1308 (s), 1114 (m), 697 (m). HRMS (ESI) calcd for
C22H22N2O3 [M+Na]+ 385.1523; found 385.1520. [α]D +32.4 (c
2012; 51:4085-4088; b) Ávila EP, Justo RMS, Goncalve VP, Pereira
SAA, Diniz R, Amarante GW. J. Org. Chem. 2015; 80:590-594.
a) Zhang H. Wen XJ, Gan LH, Peng YG. Org. Lett. 2012; 14:2126-
2129; b) Jing C, Xing D, Qian Y. Hu W. Synthesis 2014; 46:1348-1354.
a) Akiyama T, Saitoh Y, Moriat H, Fuchibe K. Adv. Synth. Catal.
2005; 347:1523-1526; b) Sickert M, Schneider C. Angew. Chem. Int.
Ed. 2008; 47:3631-3634; c) Sickert M, Abels F, Lang M, Sieler J,
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135:15334-15337.
11
12
1.0, CHCl3). Column Daicel Chiracel OD-H; 20% MeOH: tR1
5.02 min >99.5%.
=
13
14
15
Li G, Kaplan MJ, Wojtas L, Antilla JC. Org. Lett. 2010; 12:1960-1963.
Tillman AL, Dixon DJ. Org. Biomol. Chem. 2007; 5:606-609.
Dagousset G, Drouet F, Masson G, Zhu J. Org. Lett. 2009; 11:5546-
5549.
Guo QX, Liu H, Guo C, Luo SW, Gu, Y, Gong, LZ. J. Am. Chem. Soc.
2007; 129:3790-3791.
Chen YY, Jiang YJ, Fan YS, Sha D, Wang Q, Zhang G, Zheng L,
Zhang S. Tetrahedron: Asymmetry 2012; 23:904-909.
Enders D, Ludwig M, Raabe G. Chirality 2012; 24:215-222.
Rueping M, Sugiono E, Schoepke, FR. Synlett 2007; 9:1441-1445.
Barbero M, Cadamuro S, Dughera S. Tetrahedron: Asymmetry 2015;
26:1180-1188.
a) Buyck T, Wang Q, Zhu, J. Angew. Chem. Int. Ed. 2013; 52:12714-
12718; b) Gualtierotti JB, Pasche D, Wang Q, Zhu J. Angew. Chem. Int.
Ed. 2014; 53:9926-9930; c) Wang Y, Wang Q, Zhu, J. Chem. Eur. J.
2016; 22:8084; d) Wu H, Wang Q, Zhu, J. Angew. Chem. Int. Ed.
2016; 55:15411; e) Zhang Y, Ao YF, Huang, ZT, Wang DX, Wang
MX, Zhu J. Angew. Chem. Int. Ed. 2016; 55:5282-5285; f) Wang Y,
Wang Q, Zhu J. Angew. Chem. Int. Ed. 2017; 56:5612-5615; g) Wu H,
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Wang Q, Zhu J. Angew. Chem. Int. Ed. 2018; 57:1995-1999.
CCDC 1059089 (5k) contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from
Acknowledgments
Financial supports from Swiss State Secretariat for Education,
Research and Innovation (N° IZCNZ0-174705), EPFL
(Switzerland) and National Natural Science Foundation of China
(21320102002, 21502202) are gratefully acknowledged. We
thank Dr. F.-T. Farzaneh and Dr. R. Scopelliti for X-ray
crystallographic analysis of 5k.
16
17
18
19
20
Dedicated with affection and great respect to the memory of
Professor Sir Derek H. R. Barton and in sincere gratitude for the
immense degree of inspiration and encouragement he provided to
one of us (J. Zhu).
21
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