The 4,5-methano-l-proline as a chiral organocatalysts in direct asymmetric aldol reactions

Article abstract of DOI:10.1016/j.tet.2015.04.075

The 4,5-methano-l-proline was studied for the direct asymmetric aldol reaction of acetone or cyclohexanone with various aromatic and aliphaticaldehydes at -20 °C or 0 °C. A loading of only 5mol % of derivative 1a was employed in this catalytic system, and excellent enantioselectivities (up to 99% ee) and yields (up to 98% yield) could be achieved.

Full text of DOI:10.1016/j.tet.2015.04.075

Accepted Manuscript
The 4,5-methano-L-proline as a chiral Organocatalysts in Direct Asymmetric Aldol
Reactions
Na Yu, Sheng Han, Han Yu
PII:
S0040-4020(15)00585-2
10.1016/j.tet.2015.04.075
TET 26678
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 6 February 2015
Revised Date: 20 April 2015
Accepted Date: 21 April 2015
Please cite this article as: Yu N, Han S, Yu H, The 4,5-methano-L-proline as a chiral Organocatalysts in
Direct Asymmetric Aldol Reactions, Tetrahedron (2015), doi: 10.1016/j.tet.2015.04.075.
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ACCEPTED MANUSCRIPT
Graphical Abstract
The 4,5-methano-L-proline as
Leave this area blank for abstract info.
Organocatalysts in Direct Asymmetric Aldol
Reactions
Na Yu, Sheng Han a,*, Han Yu a,*
aSchool of Chemical and Environmental Engineering, Shanghai Institute of Technology, Shanghai 201418, PR
China

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
The 4,5-methano-L-proline as a chiral Organocatalysts in Direct Asymmetric
Aldol Reactions
Na Yu, Sheng Han a, ,Han Yu a,
aSchool of Chemical and Environmental Engineering, Shanghai Institute of Technology, Shanghai 201418, PR China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The 4,5-methano-L-proline was studied for the direct asymmetric aldol reaction of acetone or
cyclohexanone with various aromatic and aliphaticaldehydes at -20 °C or 0 °C. A loading of
only 5mol% of derivative 1a was employed in this catalytic system, and excellent
enantioselectivities (up to 99% ee) and yields (up to 98% yield) could be achieved.
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved
.
asymmetric organocatalysis
asymmetric aldol reactions
4,5-Methano-L-proline
———
Corresponding author. Tel.: +86-21-60873560;e-mail:hanyu201212@gmail.com(H. Yu); hansheng654321@sina.com (S. Han).

2
Tetrahedron
ACCEPTED MANUSCRIPT
1. Introduction
organocatalyst 1a and benzoic acid is crucial for the reactivity of
this catalytic system. For further details, the loading of the
additive was also studied. The reaction afforded a good ee value
but only a moderate yield when a larger amount of additive was
used (20 mol%; Table 1, Entry 13). However, a much higher
yield was obtained when this reaction was carried out with 2-10
mol % of benzoic acid (Table 1, Entries 6, 14, and 15). Then, we
tested a lower loading of catalyst 1a in DMF. To our delight, the
decreased catalyst loading (from 30 to 10 mol%) could still
maintain the product yield and enantioselectivity (Table 1,
Entries 4, 9 and 10). When further decreasing the amount of
The asymmetric direct aldol reaction is one of the most
important carbon-carbon bond forming reactionsin organic
synthesis, in particular in the synthesis of β-hydroxycarbonyl
structural unit found in many natural products.1 Since the
publication of apioneering work by List and Barbas,2 the
asymmetric aldol reaction catalyzed by L-proline has been a
representative reaction in the field of organocatalysis, after which
extraordinary progress has been sought in order to find more
selective and efficient catalytic systems for these direct aldol
reaction.3,4 A number of catalysts have been reported with a
modified pyridine ring moiety of L-proline, making it effecting
in asymmetric reactions. For example, the groups of Alexakis,5
Wang,6 Hayashi,7 Zhao,8 Palomo,9 Jacobsen,10 Chen,11 and Loh,12
among many others,13,14 have developed a series of efficient
proline-like catalysts (moleculescontaining a proline moiety) to
improve the stereoselectivity in asymmetric reactions. However,
the catalytic systems retain several shortcomings, such as: the
low reaction activity, high catalyst loading requirements and
unsatisfactory results. Thus, the search for highly efficient
proline-like organocatalysts still remains a worthwhile endeavor.
catalyst 1a to
5 mol%, up to 85% yield and 95%
enantioselectivity were obtained by extending the reaction time.
Even with 2 mol% of catalyst 1a, similar results were still
obtained in this reaction (Table 1, Entry 12). Thus, the most
efficient catalytic system involved 5 mol% of catalyst 1a and 2
mol% of benzoic acid in DMF.
Table1. Influence of catalysts and additives for aldol reaction
between acetone and 4-nitrobenzaldehydea
The Hanessian group15 had reported the synthesis of 4,5-
methano-L-prolines and the enzymatic activity of the
corresponding N-(3-mereapto-2-(R)-methyl-propionyl) analogs
as inhibitors of angiotensin converting enzyme (Figure1). We
found that these proline-like compounds are unique for their rigid
bicyclic structure with two H atoms attached to the bridgehead C
atoms lying on the same side of the ring. The X-ray structure and
solid state conformational characteristics of its revealed
considerable flattening of the pyrrolidine ring compared to L-
proline. To the best of our knowledge, 4,5-methanoproline as a
catalysis can surpass the venerable proline in conjugate additions
of nitroalkanesto cyclic enonesin many cases.15a Recently, our
group have used it as chiral organocatalysts in asymmetric
Michael addition of aldehydes to nitroolefins, which afforded
excellent diastereo- and enantioselectivities in high yields for a
series of aldehydes and nitroolefins.16 This paper concerns the
application of 4,5-methano-L-prolines to asymmetric direct aldol
reaction of various aldehydes with acetone or cyclohexanone.
trans-4,5-methano-L-proline 1a showed excellent catalytic
behavior for these asymmetric reactions.
Additive
(mol%)
Yield
(%)b
80
Ee
Catalyst
(mol%)
Time
(h)
Entry
(%)c
1
1a (30)
1b (30)
Proline
1a (30)
1a (30)
1a (30)
1a (30)
1a (30)
1a (20)
1a (10)
1a (5)
14
14
14
6
-
89
2
-
78
73
76
98
95
90
90
92
96
95
95
92
91
92
95
92
3d
4
-
68
PhCOOH (10)
TFA (10)
90
5
6
89
6
10
9
CH3COOH (10)
TsOH (10)
TfOH (10)
PhCOOH (10)
PhCOOH (10)
PhCOOH (10)
PhCOOH (10)
PhCOOH (20)
PhCOOH (5)
PhCOOH (2)
PhCOOH (2)
85
7
86
8
11
8
75
COOH
COOH
9
91
N
H
N
H
10
11
12
13
14
15
16
7
89
1a
1b
9
85
Figure1.The structure of trans-4,5-methano-L-proline (1a) and cis-4,5-
methano-L-proline (1b).
1a (2)
12
9
83
2. Results and discussion
1a (5)
70
We first applied 1a and 1b in the direct aldol reaction between
acetone and p-nitrobenzaldehyde as the model reaction in DMF
to determine the effect of different configurations of the catalyst
used in the reaction. The results showed that high yields and
excellent enantioselectivities could be obtained in the presence of
catalyst 1a, whereas a poorer yield and a moderate ee value were
obtained with catalyst 1b (Table 1, entries 1 and 2). Next, the
effect of additive of this reaction was investigated. All of the acid
additives dramatically improved the yield and enantioselectivity
in the reaction (Table 1, entries 4-8). The best results were
obtained with benzoic acid as the additive. The addition of
trifluoroaceticacid also gave similar results with benzoic acid
(entries 4 and 5). It could be concluded that the combination of
1a (5)
9
84
1a (5)
9
82
Proline
9
85
aThe reaction was carried out with acetone(2.5 mmol) and 4-
nitrobenzaldehyde(0.5 mmol) at 0 °C in DMF (1 mL) according tothe general
procedure.bIsolated yield.cDetermined by chiralHPLC analysis by using a
Chiralpak AS-H column, and the configurationwas assigned as R by
comparison with the literaturedata.d The date come from ref. 2.
Influence of solvents on the reaction was further explored and
the aldol reaction was successful in many organic solvents. The
best enantioselectivity (95% ee) was achieved in DMF (Table 2,

3
entry 1). Although a slight difference in enantioselectivity was
observed in THF and CHCl3 (Table 2, entries 2 and 6), the
reaction required longer reaction time. However, the
enantiomeric excess decreased further when water was used as a
solvent (Table 2, entry 4). When decreasing the reaction
temperature to -20 °C, product 3a was obtained with 99% ee. It
was found that the reaction temperature have an effect on
improving the enantioselectivity of the aldol product.
was allowed to react with benzaldehyde (1.27 mL, 12.5mmol)
ACCEPTED MANUSCRIPT
by using the catalyst 1a(32 mg, 0.25 mmol) with benzoic acid as
an additive in DMF (12.5 mL) at 0 °C. The reaction was
complete in 16 h, and the aldol product was obtained in 86%
yield and 93% ee (Table 2, entry 14).
Table 3.Scope of direct asymmetric aldol reactions of acetone
with various aldehydes catalyzed by1aa
Table 2.Influence of solvents and temperature for aldol reaction
between acetone and 4-nitrobenzaldehyde catalyzed by 1aa
Time Yield
Ee
Entry
Product
R
(h)
14
(%)b
90
87
85
86
87
92
95
88
92
81
<6
82
75
86
<17
35
(%)c
1
2
2a
2b
2c
2d
2e
2f
Ph
95
Time
(h)
9
Yield
(%)b
82
Ee
(%)c
95
Temp.
(°C)
Entry
Solvent
2-NO2C6H4
4-NO2C6H4
2-BrC6H4
4-BrC6H4
2-CF3C6H4
4-CF3C6H4
4-FC6H4
4-ClC6H4
4-CH3C6H4
iPr
12
97
99
97
98
97
99
98
97
98
-
3
12
1
2
3
4
5
6
7
8
DMF
THF
0
0
4
12.5
12.5
12
11
11
14
9.5
12
13
12
82
91
5
MeCN
Water
0
75
72
6
0
73
45
7
2g
2h
2i
12
Acetone
Chloroform
Toluene
DMF
0
47
67
8
13.5
13.5
15
0
56
90
9
0
80
58
10
11
12
13
14d
15e
16
2j
-20
85
99
2k
2l
15
aThe reaction was carried out with acetone(2.5 mmol) and 4-
nitrobenzaldehyde(0.5 mmol) in solvent at suitable temperature according to
2-Naphthyl
2-Furyl
8.5
15
95
80
93
-
b
c
the general procedure. Isolated yield. Determined by chiral HPLC analysis
by using a Chiralpak AS-H column, and the configurationwas assigned as R
by comparison with the literature data.
2m
2n
2o
2p
Ph
16
To increase the scope of the methodology, the aldol reaction
was extended to several aromatic and aliphatic aldehydes and the
results are summarized in Table 3. The reaction of acetone with
aromatic aldehydes bearing electron-withdrawing group led to
excellent enantioselectivities (97-99%) and high yields (85-92%)
due to the strong electrophilicity of the substrates (Table 2,
entries 2-9). The effect of steric hindrance on the reaction
outcome has been tested. When an electron-withdrawing group
was introduced at the ortho-position of the phenyl ring, product
remain in high enantioselectivity (97-98%)(Table 2, entries 2, 4
and 6). Weak electrophilic aldehydes, such as 4-
methylbenzaldhyde, required a longer reaction time to give the
corresponding aldol products in moderate yield (Table 2, entry
10). The benzaldehyde and 2-naphthaldehyde reacted with
acetone to generate the aldol product with extremely high
enantioselectivities (Table 2, entries 1 and 12; ee up to 95% and
98%, respectively). Nevertheless, as for less-reactive aliphatic
aldehydes such as isobutyraldehyde, only a trace amount of the
aldol adduct could be obtained in this system (Table 2, entries 11
and 15). This may be due to the fact that the formation of
imidazolidinethiones between isobutyraldehyde and the
organocatalyst occurs more quickly in this reaction system. To
expand the range of the substrates, compounds containing
heterocyclessuch as furyl rings were also employed in this
reaction, which proceeded with excellent enantioselectivities (up
to 80% ee, entry 13). To show the practicality of the method, the
reaction was testedat a large scale. Acetone (3.69 mL, 50.3 mmol)
iPr
12
4-CO2C6H4
12
<5
aThe reaction was carried out with acetone(2.5 mmol) and various aldehydes
b
(0.5 mmol) in DMF at -20 °C according tothe general procedure. Isolated
yield. cDetermined by chiral HPLC analysis by using a Chiralpak AS-H
column, and the configurationwas assigned as R by comparison with the
literaturedata. dThe reaction was conducted with acetone (3.69 mL, 50.3
mmol) and benzaldehyde (40.0 mmol)) in the presence of catalyst 1a (32 mg,
0.25 mmol) with benzoic acid as an additive in DMF (12.5 mL) at -20 °C.
eThe reaction was carried out at 25 °C.
Finally, to further examine the generality of this
catalyticsystem, cyclohexanone was used as the aldol donor with
different aromatic aldehydes. Up to 93% yield and excellent
diastereoselectivity and enantioselectivity(86-99% ee) were
obtained under the optimal reaction conditions (Table 4). For
others type of ketone, such as 2,2-dimethyl-1,3-dioxan-5-one and
3,4-dihydronaphthalen-1(2H)-onewas also reacted with p-
nitrobenzaldehyde to generate the aldol product with extremely
high enantioselectivities (Figure.2, ee up to 96% and 91%,
respectively).
Table 4. Scope of direct asymmetric aldol reactions of
cyclohexanone with various aldehydes catalyzed by1aa

4
Tetrahedron
ACCEPTED MANUSCRIPT
4.2. General Procedure for the asymmetric aldol reaction
To amixture of catalyst 1a and benzoic acid in DMF (1 mL)
was addedacetone (0.2 mL, 2.5 mmol, 5 equiv.). Then, the
aldehyde(0.5 mmol, 1 equiv.) was added at 0 °C. After TLC
analysis indicatedcomplete consumption of the starting material,
the reactionmixture was quenched with saturated NH4Cl aqueous
solution, extracted with EtOAc, and dried with anhydrous
Na2SO4. The crude product was purified by flash silica gel
chromatography (hexane/EtOAc) to afford pure aldol products.
All aldol products are knowncompounds, and their spectroscopic
data are identical to those reportedin the literature. The ee values
were determined by chiral HPLC analysis.
Time Yield
Ee
(%)d
95
Entry
Product
3a
R
Ph
(h)
18
16
21
19
17
15
16
(%)b
93
Anti/syncc
98:2
1
2
3
4
5
6
7
3b
4-CH3OC6H4
4-NO2C6H4
4-ClC6H4
4-CF3C6H4
2-Naphthyl
2-Furyl
87
97:3
96
3c
90
96:4
99
4.2.1.(R)-4-Hydroxy-4-phenyl-butan-2-one (2a).17
3d
86
97:3
97
1
3e
87
96:4
98
According to the general procedureto give pale yellow oil. H
NMR (400 MHz, CDCl3): δ 2.18 (s, 3H), 2.82 (m, 2H), 3.37 (brs,
1H), 5.15 (m, 1H), 7.28-7.35 (m,5H). Enantiomeric excess: 95%,
determined by HPLC (Daicel Chiralpak AS-H, i-PrOH/Hexane
=15/ 85), UV 220 nm, flow rate 1.0 mL/min. R-isomer, tR= 10.1
min and S-isomer, tR= 11.5 min.
3f
92
94:6
96
3g
91
93:7
86
aThe reaction was carried out with cyclohexanone(2.5 mmol) and various
aldehydes(0.5 mmol) in DMF at -20 °C according to the general procedure.
bIsolated yield. cDetermined by 1H NMR of the crudeproduct. dDetermined by
chiral-phase HPLC analysis of the anti product.
4.2.2.(R)-4-Hydroxy-4-(2’-nitrophenyl)-butan-2-one (2b).17
1
According to the general procedureto give pale yellow oil. H
NMR (400 MHz, CDCl3): δ 2.23 (s, 3H), 2.73-3.10 (m, 2H), 3.79
(brs, 1H), 5.65-5.67(m, 1H), 7.41(t, 1H), 7.66 (t, 1H), 7.87-7.96
(dd, J = 8.1, 25.5 Hz, 2H). Enantiomeric excess: 99%,
determined by HPLC (Daicel Chiralpak AS-H, i-PrOH/Hexane =
30/70), UV 220 nm, flow rate 1.0 mL/min. R-isomer, tR
=13.1min and S-isomer, tR = 9.5 min.
4.2.3.(R)-4-Hydroxy-4-(2’-nitrophenyl)-butan-2-one (2c).18
1
According to the general procedureto give pale yellow oil. H
NMR (400 MHz, CDCl3): δ 2.19 (s, 3H), 2.83-2.84 (m, 2H), 3.68
(brs, 1H), 5.24 (m, 1H), 7.50-7.52(d, J= 8.4 Hz, 2H), 8.14-8.16
(d, J = 8.4 Hz, 2H). Enantiomeric excess: 95%, determined by
HPLC (Daicel Chiralpak AS-H, i-PrOH/Hexane=30/70), UV 254
nm, flow rate 1.0 mL/min. R-isomer, tR= 17.2min and S-isomer,
tR=23.1 min.
Figure2. The 2,2-dimethyl-1,3-dioxan-5-one and 3,4-dihydronaphthalen-
1(2H)-one reacted with p-nitrobenzaldehyde.
3. Conclusion
4.2.4.(R)-4-Hydroxy-4-(2’-bromophenyl)-butan-2-one (2d).18
In summary, trans-4,5-methano-L-proline 1a is a very highly
efficient chiral organocatalyst for the asymmetric aldol reactions
of various aldehydes with acetone or cyclohexanone. Moreover,
it is worthwhile to highlight that thereactions could achieve high
enantioselectivity ranging from 84 to 99%ee and up to 98% yield
by employing only 5 mol% of organocatalyst 1a. The advantages
of this catalytic system are clear, and it is to some extent a green
and atom economical approach. Further application of 4,5-
methano-L-prolineorganocatalysts to other important asymmetric
reactions is underway.
According to the general procedureto give pale yellow oil.1H
NMR (400 MHz, CDCl3): δ 2.12(s, 3H), 2.52-2.61(m, 1H), 2.86-
2.92(m, 1H) 3.58-3.59 (d, J = 3.2 Hz,1H), 5.34-5.37(m, 1H),
7.02-7.07(t, 1H), 7.23-7.28 (t,1H), 7.40-7.53(dd, J= 7.7, 32.2 Hz,
2H) .Enantiomeric excess: 98%, determined by HPLC (Daicel
Chiralpak AS-H, i-PrOH/Hexane=15/85), UV 220 nm, flow rate
1.0 mL/min. R-isomer, tR = 13.0 min and S-isomer, tR = 9.3 min.
4.2.5.(R)-4-Hydroxy-4-(4’-bromophenyl)-butan-2-one (2e).19
According to the general procedure to give pale yellow oil. 1H
NMR (400 MHz, CDCl3): δ 2.24 (s, 3H), 2.73-2.75 (m, 1H),
3.12-3.17 (m, 1H), 3.70 (m, 1H), 5.67-5.69 (m, 1H), 7.44-7.46 (d,
J = 8.4 Hz, 2H), 7.89-7.97 (d, J= 8.4 Hz, 2H). Enantiomeric
excess: 96%, determined by HPLC (Daicel Chiralpak AS-H, i-
PrOH/Hexane=10/90), UV 220 nm, flow rate 1.0mL/min. R-
isomer, tR = 17.7 min and S-isomer, tR = 23.4 min.
4. Experimental section
4.1. General
1
All H NMR spectra were recorded on Bruker AV 300 or
Varianmercury Plus 400 using CDCl3 as solvent and TMS as
internal standard unless otherwise noted, chemicalshifts are given
in(ppm) and coupling constants (J) in Hz. HRMS was performed
on Analysis Center of Shanghai Institute of Technology
University. The Enantioselectivity was measured by high
performance liquid chromatography (HPLC) using chiral column
(Chiralcel OD, AD, AS, OJ, OZ) with hexane/2-propyl alcohol as
eluent. Column chromatography was performed using 300-400
mesh silica gel. All commercially available substrates were used
as received.
4.2.6.(R)-Hydroxy-4-(2’-(trifluoromethyl)phenyl)-butan-2-
one(2f).19
According to the general procedure to give pale yellow oil. 1H
NMR (400 MHz, CDCl3): δ 2.19(s, 3H), 2.75-2.78(m, 2H), 3.66-
3.67 (m, 1H), 5.55-5.57(m, 1H), 7.37-7.40(t, 1H), 7.59-7.62(m,
2H), 7.80-7.82 (m, 1H). Enantiomeric excess: 99%, determined

5
by HPLC (Daicel Chiralpak AS-H, i-PrOH/Hexane=10/90), UV
254 nm, flow rate 1.0 mL/min. R-isomer, tR = 11.6min and S-
isomer, tR = 7.4 min.
m), 1.72-1.50 (3H, m), 1.40-1.22 (1H, m). Enantiomeric excess:
ACCEPTED MANUSCRIPT
96%, determined by HPLC (Daicel Chiralpak OD-H, i-
PrOH/Hexane= 10/90), UV 254nm, flow rate 0.5 mL/min. tR
(major) = 22.3 min, tR (minor) = 31.9 min.
4.2.7.(R)-Hydroxy-4-(4’-(trifluoromethyl)phenyl)-butan-2-one
(2g).19
4.2.14.(2S,1’R)-2-(hydroxy(4-methoxyphenyl)methyl)
cyclohexan-1-one (3b).20
Accordingto the general procedure to give pale yellow oil.1H
NMR (400 MHz, CDCl3): δ 2.20 (s, 3H), 2.84 (d, J= 6.3 Hz, 2H),
3.48 (d, J = 3.2 Hz, 1H), 5.21 (m, 1H), 7.48(d, J= 8.1 Hz, 2H),
7.61 (d, J = 8.1 Hz, 2H). Enantiomeric excess: 98%, determined
by HPLC (Daicel Chiralpak AS-H, i-PrOH/Hexane=10/90), UV
254 nm, flow rate 1.0 mL/min. R-isomer, tR = 9.2 min and S-
isomer, tR = 7.8 min. = 7.4Hz, 3H).
According to the general procedure to give pale yellow oil. 1H
NMR (400 MHz, CDCl3): δ 7.24 (2H, d, J =8.4 Hz), 6.88 (2H, d,
J = 8.7 Hz), 4.74 (1H, dd, J = 8.7, 2.4 Hz), 3.93 (1H, d, J = 2.7
Hz), 3.80 (3H, s), 2.65-2.49 (1H, m), 2.52-2.43 (1H, m), 2.35
(1H, td, J = 12.9, 5.4 Hz), 2.15-2.04 (1H, m),1.84-1.73 (1H, m),
1.70-1.45 (3H, m), 1.36-1.24 (1H, m). Enantiomeric excess:
97%, determined by HPLC (Daicel Chiralpak AS-H, i-
PrOH/Hexane = 10/90), UV 254nm, flow rate 0.5 mL/min. tR
(major) = 60.9 min, tR (minor) = 64.2 min.
4.2.8.(R)- 4-Hydroxy-4-(4’-fluorophenyl)-butan-2-one (2h).19
According to the general procedure to give pale yellow oil.
1H NMR (400 MHz, CDCl3): δ 2.19 (s, 3H), 2.74-2.90 (m, 2H),
3.32 (brs, 1H), 5.13 (m, 1H), 7.03 (m, 2H), 7.30 (m, 2H).
Enantiomeric excess: 98%, determined by HPLC (Daicel
Chiralpak AS-H, i-PrOH/Hexane =10/90), UV 220 nm, flow rate
1.0 mL/min. R-isomer, tR =12.4 min and S-isomer, tR =13.8 min.
4.2.15.(2S,1’R)-2-(hydroxy(4-Nitrophenyl) methyl) cyclohexan-1-
one (3c).20
According to the general procedure to give pale yellow oil. 1H
NMR (400MHz, CDCl3): δ 8.21 (2H, d, J = 8.7 Hz), 7.51 (2H, d,
J = 8.7 Hz), 4.90 (1H, dd, J = 8.4, 3.0 Hz), 4.09 (1H, d, J = 3.0
Hz ), 2.65-2.45 (2H,m), 2.36 (1H, td, J = 13.2, 5.7 Hz), 2.17-2.06
(1H, m), 1.87-1.78 (1H, m), 1.67-1.51 (3H, m),1.45-1.31 (1H,
m). Enantiomeric excess: 90%, determined by HPLC (Daicel
Chiralpak AD-H, i-PrOH/Hexane= 20/80), UV 254nm, flow rate
0.5 mL/min. tR (major) = 41.3min, tR (minor) = 52.6 min.
4.2.9.(R)-4-Hydroxy-4-(4’-chlorophenyl)-butan-2-one (2i).19
1
According to thegeneral procedure to give pale yellow oil. H
NMR (400 MHz,CDCl3): δ 2.18 (s, 3H), 2.82 (m, 2H), 3.46 (brs,
1H), 5.11 (m, 1H), 7.29 (m, 4H). Enantiomeric excess: 98%,
determined by HPLC (Daicel Chiralpak AS-H, i-PrOH/Hexane
=10/90), UV220 nm, flow rate 1.0 mL/min. R-isomer, tR = 16.9
min and S-isomer, tR = 20.9 min.
4.2.16.(2S,1’R)- 2-(4-chlorophenyl)(hydroxy) methyl)
cyclohexan-1-one (3d).20
1
4.2.10.(R)-4-Hydroxy-4-(4-methylphenyl)-butan-2-one (2j).19
According to the general procedure to give pale yellow oil. H
According to the general procedure to give pale yellow oil. 1H
NMR (400 MHz, CDCl3): δ 2.20 (s, 3H), 2.35 (s, 3H) 2.77-2.88
(m, 2H), 3.32 (s, 1H), 5.25 (d, J = 8.7Hz, 2H), 7.17 (d, J = 7.8
Hz, 2H), 7.26 (d, J = 7.8 Hz, 2H). Enantiomeric excess: 98%,
determined by HPLC (Daicel Chiralpak AS-H, i-PrOH/Hexane =
10/90), UV 220 nm, flow rate 1.0 mL/min. R-isomer, tR = 10.6
min and S-isomer, tR = 13.4 min.
NMR (400MHz, CDCl3): δ 7.29 (4H, dd, J = 20.4,8.4 Hz), 4.76
(1H, dd, J = 8.7, 2.7 Hz), 3.99 (1H, d, J = 3.0 Hz), 2.61-2.44 (2H,
m), 2.35 (1H, td, J = 12.9, 5.4 Hz), 2.15-2.05 (1H, m), 1.85-1.75
(1H, m), 1.70-1.50 (3H, m), 1.37-1.20 (1H, m). Enantiomeric
excess: 98%, determined by HPLC (Daicel Chiralpak AD-H, i-
PrOH/Hexane= 10/90), UV 254 nm, flow rate 0.5 mL/min. tR
(major) = 26.5 min, tR (minor) = 31.8 min.
4.2.17.(2S,1’R)-2-(hydroxyl(4-
4.2.11.(R)-4-Hydroxy-4-(naphthalene-2-yl)butan-2-one (2l).19
trifluoromethyl)phenyl)methyl)cyclohexan-1-one (3e).21
According to the general procedure to give pale yellow oil. 1H
NMR (400 MHz, CDCl3): δ 2.21 (s, 3H), 2.95 (m, 2H), 3.44 (brs,
1H), 5.34 (m,1H), 7.43 (m, 1H),7.83 (m, 4H), 7.94-8.01(m, 2H).
Enantiomeric excess: 96%, determined by HPLC (Daicel
Chiralpak AS-H, i-PrOH/Hexane=30/70), UV 254nm, flow rate
1.0 mL/min. R-isomer, tR = 15.0 min and S-isomer, tR = 16.8
min.
According to the general procedure to give pale yellow oil.
1H NMR (400MHz, CDCl3): δ 7.74-7.55 (3H, m), 7.40-7.38(1H,
t, J = 7.2 Hz), 5.30 (1H, d, J = 9.3 Hz), 4.03 (1H, t, J = 3.0 Hz),
2.81-2.69 (1H, m), 2.55-2.45(1H, m), 2.37 (1H, td, J = 12.9, 4,8
Hz), 2.15-2.03 (1H, m), 1.81-149 (3H, m), 1.48-1.23 (1H, m).
Enantiomeric excess: 97%, determined by HPLC (Daicel
Chiralpak AD-H, i-PrOH/Hexane= 10/90), UV 254nm, flow rate
0.5 mL/min. tR (major) = 32.9 min, tR (minor) = 35.2 min.
4.2.12.(R)-4-Hydroxy-4-(2’-furyl) -butan-2-one (2m).19
According to the general procedure to give pale yellow oil. 1H
NMR (400 MHz, CDCl3): δ 2.13(s, 3H), 2.75-2.78(m, 2H) 3.66-
3.67 (m, 1H), 4.98-5.05(m, 1H),6.37-6.40(m, 1H), 6.47-6.51(m,
1H) 7.67-7.72 (m,1H). Enantiomeric excess: 84%, determined by
HPLC (Daicel Chiralpak AS-H, i-PrOH/Hexane=30/70), UV
254nm, flow rate 1.0 mL/min. R-isomer, tR = 6.9min and S-
isomer, tR = 9.3 min.
4.2.18.(2S,1’R)-2-(hydroxy(naphthalene-2-yl) methyl)
cyclohexan-1-one (3f).21
1
According to the general procedure to give pale yellow oil. H
NMR (400 MHz, CDCl3): δ 7.87-7.78 (3H, m), 7.75 (1H, s), 7.47
(3H, d, J = 7.2 Hz), 4.96 (1H, d, J = 8.7 Hz), 4.08 (1H, s), 2.77-
2.65 (1H, m),2.55-2.44 (1H, br-d, J = 13.8 Hz), 2.36 (1H, td, J =
12.9, 5.7 Hz), 2.14-2.00 (1H, m), 1.80-1.36 (5H, m).
Enantiomeric excess: 93%, determined by HPLC (Daicel
Chiralpak AD-H, i-PrOH/Hexane= 10/90), UV 254nm, flow rate
0.5 mL/min. tR (major) = 47.5 min, tR (minor) = 54.7 min.
4.2.13.(2S,1’R)-2-(hydroxy(phenyl) methyl) cyclohexan-1-one
(3a).20
According to the general procedureto give pale yellow oil. 1H
NMR (400 MHz,CDCl3): δ 7.50-7.24 (5H, m), 4.80(1H, d, J =
9.0 Hz), 4.00 (1H, m), 2.70-2.56 (1H, m), 2.55-2.44 (1H, m),
2.34 (1H, td, J = 12.3, 5.4Hz), 2.16-2.03 (1H, m), 1.87-1.73 (1H,

6
Tetrahedron
ACCEPTED MANUSCRIPT
Org. Biomol. Chem. 2010, 8, 980-983; e) Samanta, S.;Perera, S.;
Zhao, C.-G. J. Org. Chem. 2010, 75, 1101-1106; (f) Jha, V.;
Kondekar, N. B.; Kumar, P. Org. Lett. 2010, 12, 2762-2765; (g)
Blackmond,D. G.; Moran,A.; Hughes, M.; Armstrong, A.J.
Am.Chem. Soc. 2010, 132, 7598-7599.
4.2.19.(2S,1’R)-2-furan-2-yl(hydroxy)methyl) cyclohexan-1-one
(3g).21
According to the general procedure to give pale yellow oil.
1H NMR (400 MHz, CDCl3): δ 7.39 (1H, d, J = 0.6 Hz), 6.33 (1H,
dd, J = 3.0, 1.8 Hz), 6.28 (1H, d, J = 3.0 Hz), 4.83 (1H, dd, J =
8.4, 3.9 Hz), 3.88 (1H, d,J = 3.9 Hz), 2.97-2.86 (1H, m), 2.52-
2.30 (2H, m), 2.17-2.04 (1H, m), 1.89-1.78 (1H, m), 1.75-1.56
(3H, m), 1.44-1.30 (1H, m). Enantiomeric excess: 94%,
determined by HPLC (Daicel Chiralpak AD-H, i-PrOH/Hexane=
10/90), UV 254nm, flow rate 0.5 mL/min. tR (major) = 41.0 min,
tR (minor) = 43.8 min.
4. (a) Orsini, F.;Pelizzoni, F.; Forte, M.;Destro, R.; Gariboldi, P.
Tetrahedron 1988, 44, 519-541;(b) Kano, T.;Takai, J.;Tokuda,
O.;Maruoka, K. Angew. Chem. Int. Ed. 2005, 44, 3055-3057; (c)
Kano, T.; Tokuda, O.;Takai,J.;Maruoka, K. Chem. Asian J. 2006,
12, 210-215.
5. (a) Alexakis, A.; Andrey, O. Org. Lett. 2002, 4, 3611-3614; (b)
Quintard, A.; Bournaud, C.; Alexakis, A. Chem. Eur. J.2008, 14,
7504-7507; (c) Quintard, A.; Langlois, J. B.; Emery, D.; Mareda,
J.; Guénée, L.; Alexakis, A. Chem. Eur. J.2011, 17, 13433-13437.
6. (a) Wang, W.; Wang, J.; Li, H. Angew. Chem. Int. Ed.2005, 44,
1369-1371; (b) Wang, J.; Li, H.; Zu, L. S.; Gao, H.; Wang, W.
Chem. Eur. J. 2006, 12, 4321-4332.
7. Hayashi, Y.; Gotoh, H.; Hayashi T.; Shoji, M. Angew. Chem., Int.
Ed. 2005, 44, 4212-4215.
8. Gu, L. Q.; Zhao, G. Adv. Synth. Catal. 2007, 349, 1629-1632.
9. Palomo, C.; Vera, S.; A. Mielgo, A.; Gmez-Bengoa, E. Angew.
Chem. Int. Ed. 2006, 45, 5984-5987.
4.2.20. (S)-4-((S)-Hydroxy(4-nitrophenyl)methyl)-2,2-dimethyl-
1,3-dioxan-5-one (4b). 22
According to the general procedureto give pale yellow oil. 1H
NMR (CDCl3, 500 MHz), δ 8.19 (d, J =8.8 Hz, 2H), 7.60 (d,J =
8.6 Hz, 2H), 4.98 (d, J = 7.9 Hz, 1H), 4.28 (dd, J= 1.4,17.7 Hz,
1H), 4.09 (d, J = 17.7 Hz, 1H),3.82 (bs, 1H), 1.38 (s,3H), 1.21
(s,3H). Enantiomeric excess: 96%, determined by HPLC(Daicel
Chiralpak AD-H, i-PrOH/Hexane= 10/90), UV 254nm, flow rate
0.5 mL/min. tR (major) = 27.8 min, tR (minor) = 32.3 min.
10. Lalonde, M. P.; Chen, Y.; Jacobsen, E. N. Angew. Chem. Int. Ed.
2006, 45, 6366-6370.
11. (a) Reddy, R. J.; Kuan, H. H.; Chou, T. Y.; Chen, K. Chem. Eur. J.
2009, 15, 9294-9298; (b) Ting, Y. F.; Chang, C.; Reddy, R. J.;
Magar, D. R.; Chen, K. Chem. Eur. J. 2010, 16, 7030-7038.
12. Xiao, J.; Xu, F. X.; Lu, Y. P.; Loh, T. P. Org. Lett. 2010, 12,
1220-1223.
4.2.21(S)-2-((R)-hydroxy(4-nitrophenyl)methyl)-
3,4dihydronaphthalen-1(2H)-on(4a).23
13. (a) Krattiger, P.; Kovasy, R.; Revell, J. D.; Ivan, S.; Wennemers,
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Humphreys, L.; Rouden, J.; Blanchet, J. Org. Lett. 2010, 12, 3582-
3585; (c) Kano, T.; Yamaguchi, Y.; Tokuda, O.; Maruoka, K. J.
Am. Chem. Soc. 2005, 127, 16408-16409; d) Wiesner, M.; Revell,
J. D.; Tonazzi, S.; Wennemers, H. J. Am. Chem. Soc. 2008, 130,
5061-5062; (e) Zhu, S. L.; Yu, S. Y.; Ma, D. W. Angew. Chem. Int.
Ed. 2008, 47, 545–548; (f) Kano, T.; Yamaguchi, Y.; Maruoka, K.
Angew. Chem. Int. Ed. 2009, 48, 1838-1840; (g) Wiesner, M.;
Neuburger, M.; Wennemers, H. Angew. Chem. Int. Ed. 2008, 47,
1871-1874; (h) Wiesner, M.; Revell, J. D.; Wennemers, H. Chem.
Eur. J. 2009, 15, 10103-10109; (i) Scheffler, U.; Mahrwald, R. J.
Org. Chem.2012, 77, 2310-2330.(j) Giacalone, F.; Gruttadauria,
M.; Agrigento,P.; Noto, R. Chem. Soc. Rev., 2012, 41, 2406-2447.
14. (a) Cordova, A.; Notz, W.; Barbas III, C. F. Chem. Commun. 2002,
3024–3025; (b) Benaglia, M.; Cinquini, M.; Cozzi, F.; Celentano,
G. Org. Biomol. Chem. 2004, 2, 3401-3407; (c) Mestres, R.;
Green Chem. 2004, 6, 583-603. (d) Hayashi, Y.; Sumiya, T.;
Takahashi, J.; Gotoh, H.; Urushima, T.; Shoji, M. Angew. Chem.
Int. Ed. 2006, 45, 958-961; (e) Aratake, S.; Itoh, T.; Okano, T.;
Usui, T.; Shoji, M.; Hayashi, Y. Chem. Commun. 2007, 2524-
2526; (f) Aratake, S.; Itoh, T.; Okano, T.; Nagae, N.; Sumiya, T.;
Shoji, M.; Hayashi, Y.Chem. Eur. J. 2007, 13, 10246-10256. (g)
Mase, N.; Nakai, Y.; Ohara, N.; Yoda, H.; Takabe, K.; Tanaka, F.;
Barbas III, C. F. J. Am. Chem. Soc. 2006, 128, 734-735; (h)
Ramasastry, S. S. V.; Zhang, H.; Tanaka, F.; Barbas III, C. F. J.
Am. Chem. Soc. 2007, 129, 288–289. (i) Guizzetti, S.; Benaglia,
M.; Raimondi, L.; Celentano, G. Org. Lett. 2007, 9, 1247-1250; (j)
Lei, M.; Shi, L. X.; Li, G.; Chen, S.; Fang, W. H.; Ge, Z. M.;
Cheng, T. M.; Li, R. T. Tetrahedron 2007, 63, 7892-7898; (k)
Zhao, J. F.; He, L.; Jiang, J.; Tang, Z.; Cun, L. F.; Gong, L. Z.
Tetrahedron Lett. 2008, 49, 3372-3375; l) Chimni, S. S.; Singh, S.;
Mahajan, D. Tetrahedron: Asymmetry 2008, 19, 2276-2284; (m)
Ramasastry, S. S. V.; Albertshofer, K.; Utsumi, N.; Barbas III, C.
F. Org. Lett. 2008, 10, 1621-1624; (n) Gruttadauria, M. Eur. J.
Org. Chem. 2009, 5437-5444; (o) Wiesner, M.; Upert, G.;
Angelici, G.; Wennemers, H. J. Am. Chem. Soc. 2010, 132, 6–7.
(p) Jiang, Z.; Yang, H.; Han, X.; Luo, J.; Wong, M. W.; Lu, Y.
Org. Biomol. Chem. 2010, 8, 1368-1377; (q) Watanabe, Y.;
Sawada, K.; Hayashi, M. Green Chem. 2010, 12, 384-386. (r)
Giacalone, F.; Gruttadauria, M.; Agrigento, P.; Meo, P. L.; Noto R.
Eur. J. Org. Chem., 2010, 5696-5704.
According to the general procedure to give pale yellow oil.
1H NMR (300 MHz, CDCl3) δ 8.20 (d, J = 8.8 Hz, 2H), 8.06 (d,
J = 8.0 Hz, 2H), 7.59 (d, J = 8.8 Hz, 2H), 7.53-7.23 (m, 3H), 5.12
(d, J = 8.0 Hz, 1H), 5.03 (s, 1H), 2.90 (m, 2H),2.76 (m, 1H), 1.69
(m, 2H). Enantiomeric excess: 91%, determined by HPLC
(Daicel Chiralpak AD-H, i-PrOH/Hexane= 10/90), UV 254nm,
flow rate 0.5 mL/min. tR (major) = 35.7 min, tR (minor) = 43.8
min.
Acknowledgments
Financial support by the NSFC (21402065) and the start-up
fundof Shanghai Institute of Technology is gratefully
acknowledged.
References and notes
1. (a) Perlmutter, A. Conjugative Additions in Organic Synthesis;
Pergamon Press: Oxford, 1992; (b) Casiraghi, G.; Zanardi, F.;
Appendino, G.; Rassu, G. Chem. Rev. 2000, 100, 1929-1972; (c)
Machajewski, T. D.; Wong, C. H. Angew. Chem. Int. Ed. 2000,
39, 1352-1374; (d) Northrup, A. B.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2002, 124, 6798-6799; (e) Berkessel, A.; Groger, H.
AsymmetrivOrganocatalysis; Wiley-VCH: Weinheim, 2005; (f)
Dalko, P. I. Enantioselective Organocatalysis: Reactions and
Experimental Procedure; Wiley-VCH, 2007; (g) Almasi, D.;
Alonso, D. A.; Najera, C. Tetrahedron: Asymmetry 2007, 18, 299-
365; (h) Tsogoeva, S. B. Eur. J. Org. Chem. 2007, 1701-1716; (i)
Vicario, J. L.; Badia, D.; Carrillo, L. Synthesis 2007, 2065-2092.
(j) Nakamura, S.; Hara, N.; Nakashima, H.; Kubo, K.; Shibata, N.;
Toru, T. Chem. Eur. J. 2008, 14, 8079-8081; (k) Fotaras, S.;
Kokotos, C. G.; Tsandi, E.; Kokotos, G. Eur. J. Org. Chem. 2011,
1310-1317; (l) Banon-Caballero, A.; Guillena, G.; Najera, C.
Green Chem. 2010, 12, 1599-1606; (m) Chen, W. B.; Wu, Z. J.;
Hu, J.; Cun, L. F.; Zhang, X. M.; Yuan, W. C. Org. Lett. 2011, 13,
2472-2475; (n) Malkov, A. V.; Kabeshov, M. A.; Bella, M.;
Kysilka, O.; Malyshev, D. A.; Pluháčková, K.; Kočovský, P. Org.
Lett. 2007, 9, 5473-5476.
15. (a)Hanessian, S.; Reinhold, U.; Gentile, Gabriella. Angen. Chem.
Int. Ed. 1997, 36, 1881-1884; (b) Hanessian, S.; Shao, Z. H.;
Warrier, J.S. Org. Lett. 2006, 8, 4787-4790.(c) Cheong, P.H.Y.;
Houk, K.N.; Warrier, J.K.; Hanessian, S. Adv. Synth. Catal. 2004,
346, 1111-1115.
16. Han, Y.; Mou, L; Sheng, H.Tetrahedron 2014, 70,8380-8384.
17. Kano, T.; Yamaguchi, Y.;Maruoka, K. Angew. Chem. Int. Ed.
2009, 48, 1838-1840.
2. List, B.; Lerner, R. A.;Barbas III, C. F. J. Am. Chem. Soc. 2000,
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3. For recent examples of proline-catalyzed reactions, see: (a)
Chandler,C.;Galzerano, P.;Michrowska, A.; List, B.Angew.
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7
18. Wiesner, M.;Neuburger, M.;Wennemers, H. Angew. Chem. Int.
Supplementary Material
ACCEPTED MANUSCRIPT
Ed. 2008, 47, 1871-1874.
19. Ramasastry, S. S. V.; Zhang, H.; Tanaka, F.;Barbas III, C. F. J.
Am. Chem. Soc. 2007, 129, 288-289.
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8, 4417-4420.
Supplementary data related to this article can be found
onlineat http://dx.doi.org/XXX
22. Córdova, A.; Zou, W.;Ibrahem, I.; Reyes, E.;Engqvist. M.; Liao,
W. W. Chem. Commun. 2005, 3586-3593.
Click here to remove instruction text...
23. Li, H. J.; Tian, H.Y.; Wu,Y. C.;Chen,Y. J.; Liu, L.Wang, D.;Li, C.
J. Adv. Synth. Catal. 2005, 347, 1247-1256

ACCEPTED MANUSCRIPT
Supporting Information for
The 4,5-methano-L-proline as a chiral
Organocatalysts in Direct Asymmetric Aldol
Reactions
Na Yu,a Sheng Han a,*, Han Yu a,*
a School of Chemical and Environmental Engineering, Shanghai Institute of
Technology, Shanghai 201418, China
Table of Contents
1. Copies of NMR spectra of the product…………………………………………...S2
2. HPLC Data of Michael Addition Products……………………............................S11
1

ACCEPTED MANUSCRIPT
1. Copies of NMR spectra of the product
1H NMR of 2a
OH
O
1H NMR of 2b
OH
O
NO2
2

ACCEPTED MANUSCRIPT
1H NMR of 2c
OH
O
O2N
1H NMR of 2d
Br OH
O
3

ACCEPTED MANUSCRIPT
1H NMR of 2e
OH
O
Br
1H NMR of 2f
OH
O
CF3
4

ACCEPTED MANUSCRIPT
1H NMR of 2g
OH
O
F3C
1H NMR of 2h
OH
O
F
5

ACCEPTED MANUSCRIPT
1H NMR of 2i
OH
O
Cl
1H NMR of 2j
OH
O
6

ACCEPTED MANUSCRIPT
1H NMR of 2l
OH
O
1H NMR of 2m
OH
O
O
7

ACCEPTED MANUSCRIPT
1H NMR of 3a
O
OH
Ph
1H NMR of 3 b
O
OH
OCH3
8

ACCEPTED MANUSCRIPT
1H NMR of 3 c
O
OH
NO2
1H NMR of 3 d
O
OH
Cl
9

ACCEPTED MANUSCRIPT
1H NMR of 3 e
O
OH
CF3
1H NMR of 3 f
O
OH
10

ACCEPTED MANUSCRIPT
1H NMR of 3g
O
OH
O
1H NMR of 4a
O
OH
O
O
NO2
11

ACCEPTED MANUSCRIPT
1H NMR of 4b
O
OH
NO2
12

ACCEPTED MANUSCRIPT
HPLC Data of Products
HPLC data of 2a
Racemic Sample
Catalytical Sample
Peak#
Ret.Time
11.128 44564846 1526475
12.484 667042 671688
45231888 1562414
Area
Height
Area %
98.268
2.732
Height %
96.700
1
2
3.300
Total
100.000
100.000
13

ACCEPTED MANUSCRIPT
HPLC data of 2b
Racemic Sample
NO2 OH
O
*
Catalytical Sample
NO2 OH
O
Peak#
Ret.Time
17.884 54574655 1676788
19.202 766242 777665
Area
Height
Area % Height %
1
2
98.868
1.132
97.700
2.300
Total
55340897 2454454 100.000
100.000
14

ACCEPTED MANUSCRIPT
HPLC data of 2c
Racemic Sample
OH
*
O
O2N
Catalytical Sample
OH
O
O2N
Peak#
Ret.Time
Area
Height
33650
767
Area % Height %
1
2
17.175 2385801
22.200
99.591
0.409
97.772
2.228
61398
Total
2447199
34417 100.000
100.000
15

ACCEPTED MANUSCRIPT
HPLC data of 2d
Racemic Sample
Br OH
O
*
Catalytical Sample
Br OH
O
Peak# Ret.Time
Area
9.050 117895300 2934839
13.338 2361753 73542
Height Area % Height %
1
2
98.763
1.237
97.532
2.468
Total
120157053 3008381 100.000
100.000
16

ACCEPTED MANUSCRIPT
HPLC data of 2e
Racemic Sample
OH
*
O
Br
Catalytical Sample
OH
O
Br
Peak#
Ret.Time
Area
Height
Area % Height %
1
2
17.697 157384334 3231354
23.234 3123687 71012
99.347
1.653
98.578
1.422
Total
160508021 3302366 100.000
100.000
17

ACCEPTED MANUSCRIPT
HPLC data of 2f
Racemic Sample
CF3 OH
O
*
Catalytical Sample
CF3 OH
O
Peak#
Ret.Time
7.634
Area
6457164 171126
31534 2932
Height
Area % Height %
1
2
98.567
1.433
98.243
1.757
11.650
Total
6488698 174058 100.000
100.000
18

ACCEPTED MANUSCRIPT
HPLC data of 2g
Racemic Sample
OH
O
*
F3C
Catalytical Sample
OH
O
F3C
Peak#
Ret.Time
7.862
Area
5985463 384963
74651 3916
Height
Area % Height %
1
2
99.561
0.439
98.973
1.027
9.284
Total
6060114 398879 100.000
100.000
19

ACCEPTED MANUSCRIPT
HPLC data of 2h
Racemic Sample
OH
*
O
F
Catalytical Sample
OH
O
F
Peak# Ret.Time
Area
4245177 189166
46582 2312
Height
Area % Height %
1
2
12.460
13.838
98.914
1.086
98.773
1.227
Total
4291759 191478 100.000
100.000
20

ACCEPTED MANUSCRIPT
HPLC data of 2i
Racemic Sample
OH
*
O
Cl
Catalytical Sample
OH
O
Cl
Peak# Ret.Time
Area
16.639 30611732 1018748
20.269 295786 8265
Height
Area % Height %
1
2
98.874
1.126
99.364
0.636
Total
30817518 1027013 100.000
100.000
21