Enantioselective Diels-Alder reaction of 1,2-dihydropyridines with aldehydes using β-amino alcohol organocatalyst

Article abstract of DOI:10.1021/jo501433c

(Chemical Equation Presented) The enantioselective Diels-Alder reaction of 1,2-dihydropyridines with aldehydes using an easily prepared optically active β-amino alcohol catalyst was found to provide optically active isoquinuclidines, an efficient syntheti

Full text of DOI:10.1021/jo501433c

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Article
Enantioselective Diels-Alder Reaction of 1,2-Dihydropyridines
with Aldehydes using beta-Amino Alcohol Organocatalyst
Yoshihito Kohari, Yuko Okuyama, Eunsang Kwon, Taniyuki Furuyama, Nagao Kobayashi, Teppei
Otuki, Jun Kumagai, Chigusa Seki, Koji Uwai, Gang Dai, Tatsuo Iwasa, and Hiroto Nakano
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo501433c • Publication Date (Web): 26 Sep 2014
Downloaded from http://pubs.acs.org on September 28, 2014
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Enantioselective Diels-Alder Reaction of 1,2-Dihydropyridines with Aldehydes
9
using β-Amino Alcohol Organocatalyst
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Yoshihito Kohari,† Yuko Okuyama,‡ Eunsang Kwon,§ Taniyuki Furuyama,∥ Nagao Kobayashi,∥ Teppei
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†
†
†
†
#
†,*
⊥
Otuki, Jun Kumagai, Chigusa Seki, Koji Uwai, Gang Dai, Tatsuo Iwasa, and Hiroto Nakano
†Department of Bioengineering, Graduate School of Engineering, Muroran Institute of Technology, 27-
1 Mizumoto, Muroran 050-8585, Japan
‡Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8585, Japan
§Research and Analytical Center for Giant Molecules, Graduate School of Sciences, Tohoku University,
6-3 Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan
∥Department of Chemistry, Graduate School of Science, Tohoku University, 6-3 Aoba, Aramaki, Aoba-
ku, Sendai 980-8578, Japan
⊥College of Chemistry and Environmental Science, Inner Mongolia Normal University, Huhhot, Inner
Mongolia 010022, China
#Division of Engineering for Composite Functions, Graduate School of Engineering, Muroran Institute
of Technology, 27-1 Mizumoto, Muroran 050-8585, Japan
*E-mail: catanaka@mmm.muroran-it.ac.jp.
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R4
R2
R1O2C
tBu
Ph
Ph
OH
R7
R5
R6
R3
R3
1 (10 mmol)
N
R7
+
H2N
R4
R5
MeCN-H2O
0 oC, 24-36 h
R2
CO2R1
• CF3CO2H
N
9
O
1
R6
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CHO
R1 = Ph or Bn R7 = H, CO2Me or CN
R2-6 = H, Me, Ph or allyl
up to 96%, up to 98% ee
ABSTRACT: The enantioselective Diels-Alder reaction of 1,2-dihydropyridines with aldehydes using
an easily prepared optically active β-amino alcohol catalyst was found to provide optically active
isoquinuclidines, an efficient synthetic intermediate of pharmaceutically important compounds such as
oseltamivir phosphate, with a satisfactory chemical yield and enantioselectivity (up to 96%, up to 98%
ee). In addition, the obtained highly optically pure isoquinuclidine was easily converted to a optically
active piperidine having four successive carbon centers.
key word: β-aminoalcohol organocatalyst, Diels-Alder reaction, isoquinuclidine derivatives
■INTRODUCTION
The asymmetric Diels-Alder (DA) reaction using 1,2-dihydropyridines as a diene with acroleins is an
important reaction for the construction of optically active isoquinuclidines (2-
azabicyclo[2.2.2]octanes).1 Isoquinuclidines are found widely in natural products such as iboga-type
alkaloids, which have varied and interesting biological properties (Scheme 1).2
In particular, the anti-cancer drugs, vinblastine and vincristine, possess isoquinuclidines, with an
aspidosperma portion3 and ibogaine which reduces cravings for alcohol and other drugs by means of its
ability to boost the levels of a growth factor known as the glial cell line-derived neurotrophic factor
(GDNF).4 Furthermore, isoquinuclidines can be used as synthetic intermediates for the synthesis of
oseltamivir phosphate, an important anti-influenza drug.5 It is therefore desirable to establish an
effective catalytic asymmetric synthetic methodology for the production of optically active
isoquinuclidines. A well-established route to the optically active ring system is through the asymmetric
Diels-Alder reaction of 1,2-dihydropyridines with dienophiles. However, only a few examples using
organometallic catalysts or organocatalysts have been reported by our group and others.6
Scheme 1. Utility of Isoquinuclidines
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CO2Me
*
HO
OH
OH
*
*
CO2Et
*
O
N
CO2Bn
AcHN
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optically active
piperidines
NH2 • H3PO4
oseltamivir phosphate
(tamiflu)
THIS WORK
R
N
dienophile
R'
N
R
Diels-Alder
reaction
R'
isoquinuclidines
1,2-dihydro-
pyridines
organocatalyst
THIS WORK
MeO
new drugs
N
vinblastine or
vincristine
N
ibogaine
Despite the obvious advantages of the catalytic enantioselective version using an organocatalyst, to the
best of our knowledge, only two examples employing the MacMillan catalyst7 and our developed
oxazolidine catalyst8 have been reported for the organocatalytic asymmetric version of this reaction. The
reaction using the MacMillan catalyst affords a low chemical yield (26%), but excellent
enantioselectivity (99% ee). Moreover, our oxazolidine is relatively unstable in air, although it affords a
good chemical yield (71%) and excellent enantioselectivity (99% ee). Most recently, we proved that the
enantioselective DA reaction of 1,2-dihydropyridines with acroleins using a simple β-amino alcohol
which is the precursor of our developed oxazolidine catalyst is an efficient synthetic methodology for
obtaining optically active isquinuclidines at synthetically useful levels of chemical yield (96%) and
enatiomeric excess (98% ee), and the preliminary results have been communicated.9
β-amino alcohol salt A is stable in air, and has the two advantageous features of easy preparation and
desirable structural characteristics. Thus, it can be derived easily from the corresponding amino acid
ester and contains both an amino covalent site and hydroxyl noncovalent binding site in a single
molecule (Scheme 2). Thus, the iminium ion intermediate was first formed from the condensation of A
with acrolein. Here, the steric influences of both the α- and β-position substituent and an organic acid
fixed with both a hydroxyl group at the α-position and an amino group at the β-position by hydrogen
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bonding might be able to control the approach of a diene that was fixed by hydrogen bonding
interactions between the hydrogen on the iminium ion intermediate and the carbonyl group on 1,2-
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Scheme 2. Function of β-Amino Alcohol Organocatalyst
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steric
influence
R2
R2
R2
R2
noncovalent
site
OH
R1
R1
O
• acid
Ph
covalent
bonding
HN
NH2 • acid
!-amino alcohols
oxazolidines
A
B
+
N
O
CO2R
acrolein
1,2-dihydropyridines
catalyst B
pathway Y
pathway X
catalyst A
Ph
R2
steric
influence
R2
O
Ph
tBu
steric
influence
R1
H
O
O
N
X
N
steric
steric
H
H
O
hydrogen
bonding
R
• acid
influence
influence
Ph
O
N
R
O
O
O
N
RO2C
N
CHO
optically active
isoquinuclidines
dihydropyridines, to afford high enantioselectivity in the reaction (pathway X), although the oxazolidine
catalyst B8 controls the approach of the diene only by the steric interactions of substituents at both sides
of the amino covalent site (pathway Y).
In this paper, we describe the details of the practical enantioselective DA reaction of several 1,2-
dihydropyridines with acroleins using β-amino alcohol organocatalysts, the determination of absolute
stereochemistry of the obtained optically active isoquinuclidies using X-ray and CD spectroscopy, and
also convenient transformation of the obtained optically active isoquinuclidines to optically active
piperidines having four successive stereogenic centers.
■RESULTS AND DISCUSSION
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Primary β-amino alcohol salt catalysts 2a-p having several substituent groups at the α-position or β-
position were easily converted from the corresponding α-amino acid esters (Scheme 3).
Scheme 3. Synthesis of β-Amino Alcohol Organocatalyst
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R2
R2
R2
R2
OH
R1
"
R1
acid (HA)
Amino acid
esters
!
R3
NH2 • HA
CH2Cl2
0 oC, 5 min
quant.
NH2
2a-p
1a-j,l
a : R1 = tBu,
R2 = Ph,
R2 = Ph,
R2 = Ph,
R2 = Ph,
R2 = Ph,
R2 = p-F-Ph,
R2 = p-Me-Ph,
R2 = Et,
R3 = OH, HA = TFA
R3 = OH, HA = TFA
R3 = OH, HA = TFA
R3 = OH, HA = TFA
R3 = OH, HA = TFA
R3 = OH, HA = TFA
b : R1 = iPr,
c : R1 = Me,
d : R1 = Ph,
e : R1 = Bn,
f : R1 = tBu,
g : R1 = tBu,
h : R1 = tBu,
i : R1 = tBu,
j : R1 = tBu,
k : R1 = tBu,
R
3 = OH, HA = TFA
R3 = OH, HA = TFA
R3 = OH, HA = TFA
R3 = OH, HA = TFA
R2 = Me,
R2 = H,
R2 = Ph,
R3 = H,
HA = TFA
l : R1 = CH2OH, R2 = Ph,
R3 = OH, HA = TFA
R3 = OH, HA = TCA
R3 = OH, HA = TBA
R3 = OH, HA = AcOH
R3 = OH, HA = HCl
m: R1 = tBu,
n : R1 = tBu,
o : R1 = tBu,
p : R1 = tBu,
R2 = Ph,
R2 = Ph,
R2 = Ph,
R2 = Ph,
TTMSSCl
Et3N
Ph
Ph
OH
Ph
Ph
OH
TFA
TTMSSO
TTMSSO
CH2Cl2
0 o
CH2Cl2
0 to rt
24 h
NH2
NH2
C
5 min
quant.
2q
• TFA
1q
41%
Ph
Ph
OH
Me
MeI
K2CO3
Ph
Ph
OH
tBu
tBu
TFA
1a
CH2Cl2
0 o
EtOH
HN
HN
80 o
24 h
48%
C
C
Me
1r
• TFA
5 min
quant.
3
Thus, catalysts 2a-j,m-p having an aliphatic or aromatic moiety at the α- and/or β-positions,respectively,
were easily prepared by well known Grignard reaction or reduction of the corresponding α-amino acid
esters, followed by the treatment of the corresponding β-amino alcohols 1a-j,l with acids (TFA:
CF3CO2H; TCA: CCl3CO2H; TBA: CBr3CO2H; AcOH or HCl) in quantitative yields. Primary amine
salt 2k with no substitution for the hydroxyl group was prepared by the well-known method10via the
oxazolidinones followed by treatment with TFA. Furthermore, the bulkier β-amino alcohol salt catalyst
2q having a super silyl [tris(trimethylsilyl)silyl: TTMSS] group11 at the β-position was also easily
prepared from the reaction of 1l with TTMSSCl followed by treatment of the corresponding TTMSS-
amino alcohol 1q with TFA. Furthermore, a secondary β-amino alcohol salt catalyst 3 which was more
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effective for the formation of the iminium salt with acrolein 5 was also easily synthesized by the N-
methylation12 of 1a using MeI in the presence of K2CO3 in EtOH, followed by treatment of 1r with TFA
in quantitative yield (Scheme 3). The optically purities (>99% ee) of the obtained β-amino alcohols
were checked by HPLC.
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We first examined the DA reaction of common 1-phenoxycarbonyl-1,2-dihydropyridine 4a with
acrolein 5 using the optically active catalysts 2a-q, 3 under the same reaction conditions as used for the
oxazolidines organocatalyst8.9 The results are summarized in Table 1.
Table 1. DA Reaction of 4 with 5 Using β-Amino Alcohol Catalyst
cat.
2a-q, 3
(10 mol%)
RO2C
RO2C
N
N
+
and/or
CHO
N
CHO
MeCN
H2O
(19:1)
0 oC, 24 h
O
CO2R
6a': R = Ph
6b': R = tBu
6a: R = Ph
6b: R = tBu
4a,b
a: R = Ph
5
b: R = tBu
rt, 1 h
quant.
NaBH4
EtOH
RO2C
RO2C
N
N
OH
OH
7a,b
7a',b'
yield endo/exob
endo-6a
ee (%)c
entry cat. diene
(%)a
(6a/6a’)
1
2
2a
2a
2b
2c
2d
2e
2f
4a
4b
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
98
endo only
96
-
trace
90
-
3
endo only
94
64
13
87
93
95
-
4
31
17:1
5
27
4:1
6
80
endo only
7
73
endo only
8
2g
2h
2i
75
endo only
9
trace
10
-
10
11
12
13
6:1
21
-
2j
trace
trace
66
-
2k
1a
-
-
endo only
95
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2l
2m
2n
2o
2p
2q
3
4a
4a
4a
4a
4a
4a
4a
50
65
19:1
83
5
6
7
8
15
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17
18
19
20
endo only
95
-
trace
trace
10
-
9
-
endo only
50:1
-
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90
86
-
64
trace
-
aIsolated yield. endo/exo ratio was determined by H NMR. Enantiomeric excess was determined by
b
1
c
HPLC using a chiral column.
The reaction of 4a with 5 barely proceeded in the absence of a catalyst. Initially, the catalytic activity of
catalysts 2a-e having an aromatic diphenyl group at the α-position was examined by the reaction of 4a
(1 equiv) with 5 (3 equiv) at 0 °C in MeCN-H2O (19:1) in the presence of 10 mol% of catalysts 2a-e,
respectively, to give the DA adducts 6a,a’, and its chemical and optical yields were determined by
conversion to the alcohols 7a,a’9 (entries 1,3-6). It has already found that MeCN-H2O (19:1) solvent is
the best solvent for the same reaction using MacMillan organocatalyst by Fukuyama and co-workers.5
The reaction catalyzed by 2-tert-butyl-2a with TFA gave the endo-DA adduct 6a in excellent chemical
yield (98%) and with excellent enantioselectivity (96% ee) (entry 1). In contrast with the result of diene
4a, the use of 1-tert-butoxycarbonyl-1,2-dihydropyridine 4b afforded only a trace of the corresponding
DA adduct 6b (entry 2). The use of 2-isopropyl-2b with TFA gave a slight decrease in both chemical
yield (90%) and enantioselectivity (94% ee) (entry 3). Furthermore, 2-methyl-2c with TFA afforded
both the endo-6a and exo-6a’ DA adducts as a mixture in only low chemical yield and enantioselectivity
(31%, 64% ee) (entry 4). In addition, bulkier 2-phenyl-2d with TFA also produced a significant
decrease in both chemical yield and enantioselectivity (27%, 13% ee), and afforded both the endo-6a
and exo-6a’DA adducts as a mixture (entry 5). On the other hand, 2-benzyl-2e with TFA showed a high
catalytic activity, to afford the endo-DA adduct 6a (80%, 87% ee) (entry 6). To observe the electronic
effect of the substituent group on the phenyl group at the α-position in β-amino alcohol, the catalytic
activities of β-amino alcohols 2f,g with TFA having p-fluoro electron-withdrawing or p-methyl
electron-donating groups on the phenyl groups at the α-position was also tested in the reaction (entries 7,
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8). Although both catalysts afforded fairly good asymmetric inductions and good chemical yields (entry
7, 2f: 73%, 93% ee; entry 8, 2g: 75%, 95% ee), they did not give better results than those of catalyst 2a.
Furthermore, the catalytic activities of amino alcohols 2h and 2i containing aliphatic diethyl and
dimethyl groups with TFA, respectively, at the α-position were also examined under the same reaction
conditions of those of entries 1-8 (entries 9, 10). However, the reaction using 2h barely proceeded (entry
9) under these reaction conditions, while the reaction using 2i also afforded the DA adduct 6a in only
poor yield (10%, 21% ee) (entry 10). Similarly, amino alcohol 2j with no substitution for a substituent at
the α-position with TFA also barely showed any catalytic activity (entry 11). We also tested the reaction
using catalyst 2k with no substitution for the hydroxyl group at the α-position, but the catalyst no longer
worked (entry 12). Furthermore, the same reaction using β-amino alcohol 1a as a catalyst and TFA as a
co-catalyst was also examined, but it did not give better results than the reaction using a catalyst with
TFA salt 2a for either chemical yield or enantioselectivity (66%, 95% ee) (entry 13). The catalytic
activity of 2-hydroxylmethyl-2l with TFA having two hydrogen bonding sites at α- and β-positions was
also examined, and the reaction afforded the endo-6a in moderate chemical yield (50%) and good
enantioselectivity (83% ee) (entry 14). The above experiment showed that, 2-tert-butyl-2a with TFA is
the best catalyst in this DA reaction of 1,2-dihydropyridine 4a with 5. These results indicated that the
influences of both the steric effect of diphenyl group and the hydrogen bonding ability by hydroxyl
groups at the α-position on the β-amino alcohol is important in order to proceed the reaction with a
satisfactory enantioselectivity and a chemical yield.
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The catalytic activity of 2-tert-butylated catalysts 2m-o with other Brønsted acids (TCA, TBA, AcOH)
was also tested (entries 15-17), respectively. Catalyst 2m with TCA afforded the DA adduct 6a in good
chemical yield (65%) and with excellent enantioselectivity (95% ee) (entry 15). However, neither
catalyst 2n with TBA nor catalyst 2o with AcOH yielded any DA adduct (entries 16, 17). It may be for
the bulky steric influence of TBA and for the weak acidity of AcOH, although the reasons are not clear.
On the other hand, the reaction using catalyst 2p with strong HCl as an acid barely proceeded at all,
although high enantioselectivity was obtained (10%, 90% ee) (entry 18). Bulkier 2-TTMSSOCH2-2q
with TFA afforded the DA adduct 6a in good chemical yield and enantioselectivity (64%, 86% ee), but
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it did not give better enantioselectivity than the reaction using a catalyst with TFA salt 2a (96% ee)
(entry 19). In addition, the catalytic activity of the more effective secondary β-amino alcohol salt
catalyst 3 with TFA for formation of the iminium salt was examined under the same reaction conditions
as used for catalyst 2a (entry 20). However, the catalyst did not show any catalytic activity.
In order to optimize the reaction conditions using the superior catalyst 2a, we next examined the
effects of both reducing the molar ratio of catalyst 2a and reducing the ratio of MeCN to H2O in the
MeCN-H2O solvent in this reaction (Table 2).
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Table 2. Optimize of 4a with 5 Using Catalyst 2a
solvent
(MeCN/H2O)
19:1
yield
(%)b
98
6a
ee (%)c
96
entrya
cat. 2a
1
2
10
5
19:1
72
94
3
4
5
6
7
8
9
10
2.5
10
10
10
10
10
10
10
19:1
MeCN only
25:1
15:1
10:1
1:1
toluene only
CH2Cl2 only
35
32
70
63
45
36
trace
trace
93
92
95
94
94
95
-
-
aThe reaction was carried out at 0 °C for 24 h. bIsolated yield. cEnantiomeric excess was determined by
HPLC using a chiral column.
First, the influence of the molar ratio of the catalyst 2a was examined (entries 1-3). The use of 5 mol%
of 2a afforded the DA adduct 6a with enantioselectivity (94% ee) very similar to that of the reaction
containing 10 mol% of 2a (entry 1), but the chemical yield decreased to 72% (entry 2). At 2.5 mol%,
the reaction was sluggish and the chemical yield was poor (35%), but the enantioselectivity (93% ee)
was comparable to that obtained at higher levels of catalyst loading (entry 3). It may be for the decrease
of the rate of catalytic cycles, although the reasons is not clear. Next, the solvent effect on the catalytic
activity of the superior catalyst 2a was examined using 4a and 5 in MeCN-H2O solvent mixed in
different ratios (entries 4-8). The enantioselectivity was highly dependent on the ratio of MeCN to H2O
solvent in this reaction. The reaction performed in only MeCN gave poor results for the chemical yield
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(32%, 92% ee) (entry 4). Furthermore, the reactions using MeCN-H2O in the ratios 25:1, 15:1, 10:1 and
1:1 also produced poor to moderate chemical yields (36-70%) (entries 5-8), although the
enantioselectivity of these reactions (94-95% ee) was nearly equivalent to that of the reaction in MeCN-
H2O solvent of 19:1 ratio. The decrease of chemical yield in entry 4 might be due to poor solubilities of
the used catalyst and the iminium intermediate formed from the catalyst and acrolein. Furthermore, in
both cases of entries 6-8 the hydrolysis of the iminium intermediate formed from the catalyst and
dienophile was promoted by the increased amount of water. We also examined the reactions in toluene
and CH2Cl2, respectively, as other solvents (entries 9,10, Table 2). However, the reactions hardly
proceeded in these solvents.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
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39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
From the results shown in Table 1 and Table 2, it appeared that the reaction using 10 mol% of catalyst
2a, 2-tert-butyl-1-diphenyl amino alcohol with TFA, in MeCN-H2O (19:1) was the most effective for
producing the desired DA adduct 6a in a satisfactory chemical and optical yield.
Synthetically useful 1-benzyloxycarbonyl-1,2-dihydropyridine 8 containing an easy deprotecting
benzyloxycarbonyl group on the nitrogen atom was also examined using the superior catalyst 2a and
acrolein 5 (Scheme 4). The reaction of 8 with 5 was carried out at 0 °C for 24 h in the presence of 10
mol% of catalyst 2a, to give the corresponding endo-DA adduct 9. The chemical and optical yields of
the DA adduct 9 were determined by converting to the alcohol 10. As a result, catalyst 2a showed fairly
good catalytic activity, affording the desired DA adduct 9 in good chemical yield and excellent
enantioselectivity (75%, 96% ee), which was similar to the results of the reaction using 1-
phenoxycarbonyl-1,2-dihydropyridine 4a. The effect of reducing the molar ratio of catalyst 2a in the
reaction using diene 8 was also examined.
Scheme 4. DA Reaction of 8 with 5 Using β-Amino Alcohol Catalyst
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7
BnO2C
cat.
N
2a
8
N
9
+
MeCN/H2O
(19:1)
0 oC, 24 h
O
CO2Bn
CHO
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
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47
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49
50
51
52
53
54
55
56
57
58
59
60
9
5
8
cat. 2a DA adduct 9
10 mol% 75%, 96% ee
BnO2C
NaBH4
EtOH
5
//
60%, 95% ee
32%, 81% ee
N
2.5 //
rt, 1 h
quant.
OH
10
At a low catalytic loading of 5 mol% of 2a, the results (60%, 95% ee) were as satisfactory as those
using 10 mol % of 2a, but 2.5 mol% greatly decreased both the chemical yield and enantioselectivity
(32%, 81% ee).
To increase the effectiveness of this reaction, we examined the DA reactions of 1,2-dihydropyridines
4a or 8 with the substituted acroleins 11a,b (Scheme 5). Only few examples of the DA reactions of 4a
or 8 with a highly functionalized dienophiles employing an organometallic catalyst or an organocatalyst
have been reported by our group8 and others13. The DA adducts 12a-c are obtained by this reaction have
useful four functional groups (amino, aldehyde, ester and olefin) on the isoquinuclidine ring. Therefore,
the adducts might have a high potential utility as a synthetic intermediate of pharmacologically
important optically active compounds such as an antiviral drug.
Scheme 5. DA Reactions of 4a,8 with 11 Using Catalyst 2a
RO2C
4a or 8
cat. 2a
N
X
(10 mol%)
+
MeCN-H2O
(19:1)
0 oC, 24 h
CHO
X
O
12a: R = Ph, X = CO2Me
12b: R = Bn, X = CO2Me
12c: R = Ph, X = CN
11a: X = CO2Me
11b: X = CN
RO2C
N
X
NaBH4
EtOH
rt, 1 h
quant.
OH
13a: R = Ph, X = CO2Me, 96%, 98% ee, endo only
13b: R = Bn, X = CO2Me, 93%, 98% ee, endo only
13c: R = Ph, X = CN,
50%, 95% ee, endo only
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8
The reactions of the dienes 4a or 8 with dienophiles 11a,b, respectively, were carried out at 0 °C for 24
h in the presence of 10 mol% of the superior catalyst 2a, to give the single DA adducts 12a-c, and the
chemical and optical yields were determined by converting to the alcohols 13a-c, respectively.
As a result, the desired synthetically useful DA adducts 12a-c were obtained in the performed reactions.
The reactions of 4a or 8 with dienophile 11a, respectively, afforded the corresponding DA adducts
13a,b9 in excellent chemical yields and almost complete enantioselectivity (12a: 96%, 98% ee, 12b:
93%, 98%ee) in both reactions. On the other hands, the reaction using dienophile 11b14 with 4a also
afforded the DA adduct 12c in excellent enantioselectivity (95% ee), although the chemical yield was
moderate (50%). The absolute stereochemistries of the obtained optically active isoquinuclidies 12a was
determined by X-ray analysis of the Br-lactone derived from 12a and those of 12b was determined by
the conversion from 12a to 12b in our privious paper.9
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
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57
58
59
60
Next, we examined the DA reactions of several different substituted 1,2-dihydropyridines inserting a
methyl group in different position on pyridine ring. The enantioselective DA reaction using substituted
1,2-dihydropyridines as a diene has not been reported until now. The diene 14a15 was prepared from the
reaction of pyridine with phenyl chloroformate, followed by Grignard reaction of the obtained
pyridinium salts with MeMgBr in good yield (67%). Furthermore, the dienes 14b-d16 were obtained
from N-carboxylation of the corresponding pyridines, followed by reduction using NaBH4, respectively
(14b: 58%, 14c: 56%, 14d: 42%). The reactions of 1-phenoxycarbonyl-1,2-dihydropyridines 14a-d
having a methyl group at positions 2-4 and 6 on the ring with acrolein 5, respectively, were carried out
at 0 °C for 36 h in the presence of 10 mol% of the superior catalyst 2a, to afford the corresponding DA
adducts 15 (Table 3).
Table 3. DA Reactions of 14 with 5 Using Catalysts 2a
R1 H
R4
R1
NOE
R1O2C
R3
3
PhO2C
R3
R5
R6
R3
R2
cat. 2a
(10 mol%)
R2
R2
NaBH4
N
N
H
+
5
5
MeCN-H2O
(19:1)
0 oC, 36 h
EtOH
rt, 1 h
quant.
N
R4
R4
R5
16a,c
R5
CO2Ph
CHO
OH
14a-d
15a,c
DA
adduct
yield
(%)a
Ee
(%)b
entry
diene
R1
R2
R3
R4
R5
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1
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14a
14b
14c
14d
Me
H
H
Me
H
H
H
H
H
H
H
H
H
15a
cmc
15c
cmc
50
-
91
-
H
Me
H
80
80
-
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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H
H
H
Me
-
aIsolated yield. bEnantiomeric excess was determined by HPLC. ccm: complex mixture.
The chemical and optical yields of the obtained DA adduct 15 were determined by converting to the
alcohol 16. The results were different in the functional group of a position on the 1,2-dihydropyridines
used. The reactions using 2-methyl-1,2-dihydropyridines 14a afforded the corresponding DA adduct
15a in moderate chemical yield and with good enantioselectivity (15a: 50%, 91% ee) (entry 1).
Furthermore, 4-methyl-1,2-dihydropyridine 14c also afforded the DA adduct 15c in 80% yield and with
80% ee (entry 3). Unfortunately, the reactions using other unstable dihydropyridines 14b,d having the 3
or 6 positions at a methyl group, respectively, did not afford the corresponding DA adducts, but
complex mixtures in the reaction conditions (entries 2,4); however, the reasons for failure were not clear.
We next examined the DA reactions of 1,2-dihydropyridines 17 containing bulkier phenyl groups and
those of 20 having synthetically useful allyl groups at the 2-position on the rings with acrolein 5
(Scheme 6).
Scheme 6. DA Reactions of 17,20 with 5 Using Catalyst 2a
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8
Ph
PhO2C
cat. 2a
(10 mol%)
N
+
5
N
Ph
MeCN-H2O
(19:1)
0 oC, 48 h
9
CO2Ph
CHO
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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59
60
17
18
EtOH
Ph
PhO2C
H
NOE
NaBH4
rt, 1 h
3
quant.
N
H
5
18: 50%, 92% ee,
endo only
19
OH
cat. 2a
(10 mol%)
PhO2C
N
+
5
N
MeCN-H2O
(19:1)
0 oC, 48 h
CO2Ph
CHO
20
21
EtOH
H
NaBH4
rt, 1 h
NOE
PhO2C
quant.
N
H
21: 60%, 92% ee,
endo only
22
OH
Dienes 17 and 2014 were prepared from the reaction of pyridine with phenyl chloroformate, followed by
Grignard reaction of the obtained pyridinium salts with PhMgBr or AllylMgBr, respectively, in good
yields (17: 60%, 20: 70%).
In consideration of the bulky structures 17 and 20, the reactions were carried out at 0 °C for a longer
reaction time of 48 h in the presence of 10 mol% of the superior catalyst 2a, to give the corresponding
endo-DA adducts 18 and 21, respectively (Scheme 6). The chemical and optical yields of the obtained
DA adducts 18 and 21 were determined by converting to the alcohols 19 and 22, respectively. As a
result, the reaction of 17 containing a phenyl group afforded the corresponding DA adduct 18 with
moderate chemical yield and satisfactory enantioselectivity (50%, 92% ee). Furthermore, 1,2-
dihydropyridines 20 also had fairly good enantioselectivity (92% ee) and moderate yield (60%),
respectively. The relative configurations of the stereogenetic centers in 3 and 5-positions of the obtained
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isoquinuclidines 15a, 18 and 21 were determined from the NOE difference spectra (NOEDS) of the
corresponding alcohols 16a, 19 and 22. Thus, NOE enhancement was observed between the hydrogen at
the 3-position and the hydrogen at the 5-position when the 3- and 5-positions were irradiated,
respectively.8,17
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
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59
60
The absolute configuration of the centers of the DA adducts 3-methyl-15a, 3-phenyl-18, and 3-allyl-21
were determined as follows (Scheme 7).
Scheme 7. Br-Lactonizations of 6a, 18
R
NaClO4
plausible
PhO2C
NaH2PO4•2H2O
Me2C=CHMe
reaction course
from 23' to 24
6a
or
N
tBuOH-H2O
0 oC to rt
1.5 h
18
CO2H
23 : R = H
Ph
CO2Ph
Br2
23': R = Ph
aq. NaHCO3
CH2Cl2, rt
N
O
Br2
Br
Br
aq. NaHCO3
CH2Cl2, rt
PhO2C
Br
C
O
N
Ph
PhO2C
O
N
O
255
H
O
H
X-ray analysis
Br
O
24: 56%, 99% ee
X-ray analysis
The assignment of the DA adduct 18 was carried out by X-ray analysis of Br-lactone 24, which was
easily converted from the DA adduct 18 (Scheme 7). Interestingly, the 2-azabicyclo[2.2.2]octane ring
system forming isoquinuclidine 18 containing a phenyl group at the 3-position was transformed to a 2-
azabicyclo[3.2.1]octane ring system forming the Br-lactone 24 by Br-lactonization of the carboxylic
acid 23’ in moderate yield, which might be through the plausible reaction path of Scheme 7.
Considering that the isoquinuclidine 6a with no substitution for a substituent at the 3-position gave the
corresponding the γ-Br-lactone 255 retaining the 2-azabicyclo[2.2.2]octane ring system, this
transformation from 18 to 24 might result from the steric influence of the bulky phenyl group at the 3-
position on the DA adduct 18. Br-lactone 24, having a fused azabicyclo[3.2.1]octaneandthe β-lactone
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ring system, might also be a useful synthetic intermediate for creating new biologically active
compounds.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 1. UV-vis absorption and CD spectra of 7a (a), 16a (b), 19(c), and 22 (d) in methanol
CD spectroscopy can also be used to determine the absolute stereochemistry of the DA adducts 15a, 18,
and 21. The absorption and CD spectra of alcohols 7a, 16a, 19, and 22 are shown in Figure 1. The
difference between these compounds is only one substituent at the 3-position. All of the compounds
have intense absorption bands at around 260 nm, which originate from the benzoate group at the
nitrogen. Only the CD spectra of 19 shows intense negative first and positive second Cotton effects due
to coupling of the two excitons originating from the N-benzoate group and the phenyl group at the 3-
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position. On the basis of exciton coupling theory,18 the negative-to-positive CD signal in ascending
6
7
8
energy is consistent with an anticlockwise screw arrangement of two chromophores (Figure 2).
9
Ph
Ph
S
H
H
S
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
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CO2Ph
CO2Ph
N
N
S
S
OH
OH
19
Ph
S
H
CO2Ph
N
S
OH
19
Figure 2. Optimized structure of (3S, 7S)-19. The molecular geometry was optimized at the DFT
level using the B3LYP/6-311++G(d,p).
Furthermore, the absolute stereochemistry of 19 was already determined to be the same as that of 24,
whose structure was analyzed by X-ray diffraction. Thus, from this standpoint also, the arrangement of
the two chromophores in 19 is anticlockwise. In the case of 7a (H), 16a (Me), and 22 (allyl), there is no
chromophore that can interact effectively with the benzoate group, so that the CD intensities are
relatively weak, which in turn suggests that we can neglect the difference of the substituent group at the
3rd position. Although it is not always entirely safe to determine the absolute stereochemistry of these
compounds from only the CD spectra, we can use the CD spectra of 7a as a standard, since the absolute
stereochemistry of 7a (S configuration) was determined by X-ray diffraction of 255 (Scheme 7). As seen
in this figure, 7a, 16a, and 22 show commonly negative CD peaks at around 270 nm, while the shape of
the overall CD envelope is similar to that of 7a, suggesting strongly that the configuration of these
compounds is the same. Thus, the stereochemistry of 16a and 22 also appears to be in an S configuration
at the 7-position.
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Based on both the high enantiopurity (96% ee) of the optically active DA adduct (7S)-6a which was
obtained from the reaction of diene 4a with dienophile 5 and Isihara’s, Seebach’s and Melchiorre’s
detailed studies19 for an amino organocatalized DA reaction mechanism, a model of the enantioselective
reaction is proposed as follows (Scheme 8). Thus, the reaction might be through the intermediate I-1
that has a less steric interaction between the tert-butyl substituent in β-position in the catalyst and the
olefin part of the dienophile.9 Then, the iminium ion intermediate generated by 2a with 4a and 5 was
fixed by hydrogen bonding interactions between the hydrogen on the iminium ion intermediate and the
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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46
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53
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58
59
60
-
carbonyl group on the diene 4a and CF3CO2 counter anion. Subsequently, 4a was prevented from
approaching the sterically hindered Si-face of the iminium ion intermediate by the steric influences of
bulky tert-butyl, diphenyl group and the hydrogen bonding of hydroxyl group with a TFA moiety. Thus,
4a attacks from the sterically less hindered Re-face. The conformational predominancy of the iminium
ion intermadiate I-1 was indicated by our calculation study.9
Scheme 8. Plausible Reaction Mechanism for DA Reaction of 4a with 5 Using 2a
Ph
Ph
Ph
Ph
OH
H
OH
H
4a
+
catalyst A
N
N
pathway X
H
5
I-1
I-2
Ph
steric
influence
Ph
H
O
O
N
CF3
O
H
steric
influence
hydrogen
bonding
O
Ph
O
N
Re face
attack
96% ee
(7S)-6a
Many medicines and biologically active compounds include a piperidine skeleton20 in their structure.
Therefore, it is important to develop an effective and convenient synthetic methodology for optically
active piperidines containing two or more stereogenic centers in the structure. In order to develop this
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kind of methodology, we attempted to obtain a optically active piperidine derivative containing four
continuous carbon centers by means of the ozonolysis of DA adduct 28 converted from 13b (Scheme 9).
Scheme 9. Conversion from Isoquinuclidines 13b to Piperidines 28
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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60
BnO2C
BnO2C
1)
O3
TBSOTf
(i-Pr)2NEt
CH2Cl2-MeOH
N
N
CO2Me
CO2Me
-78°C, 1 min
CH2Cl2
0°C, 1 h
93%
NaBH4
0°C, 20 min
97%
2)
HO
13b
TBSO
26
CO2Me
CO2Me
*
*
*
*
HO
OH
OH
HO
OTBS
OH
TBAF
*
*
*
*
THF
0 °C, 2 h
92%
N
N
CO2Bn
CO2Bn
27
28
Ozonolysis of the TBSO-compound 26, followed by reduction using NaBH4 afforded the desired
optically active [2R,3S,4R,5R]-piperidine derivative 27 having four successive stereogenic centers at the
2,3,4,5-positions in excellent yield (97%). Furthermore, the TBS group on 27 was easily deprotected by
TBAF, to afford a piperidine alcohol 28 in 92% yield. The obtained polyfunctional piperidine alcohol
28 is expected to function as a useful synthetic intermediate for several pharmacologically-important
compounds, such as azasugars.21
■CONCLUTION
In conclusion, new optically active β-amino alcohol salt organocatalysts 2a-p were prepared easily in
two steps, and showed dramatic reactivity for affording optically active isoquinuclidines with
satisfactory chemical yields and enantioselectivities (up to 98% yield, up to 96% ee) in the DA reactions
of 1,2-dihydropyridines 4a,b, 8, 14, 17 and 20 with acroleins 5 or 11a,b. In particular, the reactions
catalyzed by 2a containing a 2-tert-butyl moiety with TFA afforded the corresponding endo-DA adducts
6a,b, 9, 12a,b,c, 15a,c, 18, and 21 in good to excellent chemical yields and with excellent
enantioselectivities, when 10 mol% of catalyst was used. The developed β-amino alcohol catalyst might
be superior for practical use. One advantage is that the catalyst is very stable in air, and is prepared
easily in two steps. In addition, the highly optically pure isoquinuclidine 13b obtained here was easily
converted to the optically active piperidine 28 having four successive carbon centers, which may be
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useful as a synthetic intermediate for the creation of new drugs. Studies aimed at examining the scope
and limitations of this β-amino alcohol organocatalyst for the catalytic asymmetric version of the DA
reactions of other 1,2-dihydropyridines with other acroleins are now in progress.
9
10
11
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13
14
15
16
17
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19
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22
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■EXPERIMENTAL SECTION
General Methods. All commercial reagents were purchased and used without further purification.
All reactions were carried out under argon atmosphere in flame-dried glassware with magnetic stirring.
Thin layer chromatography (TLC) was performed on silica gel 60 F254 and analytes were detected using
UV light (254 nm) and iodine vapor. Column chromatography was carried out on silica gel 60N (40–
100 µm) and preparative TLC was carried out on silica gel 60 F254. Melting points were measured using
a micro-melting point apparatus. Infrared (IR) spectra were measured with a FT/IR spectrophotometer.
1H-NMR (500 MHz) and 13C-NMR (125 MHz) spectra were measured in CDCl3 or DMSO-d6. 1H-NMR
data were reported as follows: chemical shifts in ppm from tetramethylsilane or the residual solvent as
an internal standard, integration, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, dd =
double-doublet, m = multiplet and br = broad), coupling constants (Hz), and assignment. 13C-NMR
spectra were measured with complete proton decoupling. Chemical shifts were reported in ppm from the
residual solvent as an internal standard. High performance liquid chromatography (HPLC) was
performed using the chiral columns AD-H, AS-H and OD-H 4.6 mm x 25 cm column. Optical rotations
were measured with a digital polarimeter. HRMS spectra were performed by EI or FAB using sector
instruments. Circular dichroism (CD) spectra were measured using a spectropolarimeter.
General Procedure for the Synthesis of 1f, 1h and 1i. To a dry Et2O (20.0 mL) solution of
corresponding aryl or alkylmagnesium bromide (10.0 mmol), L-tert-butyl-leucine methyl ester
hydrochloride (0.36 g, 2.0 mmol) in dry Et2O (5.0 mL) solution was added at 0 °C for 30 min under
Argon. The resulting mixture was stirred at room temperature for 24 h and then quenched with saturated
o
NH4Cl at 0 C. The organic layer was washed with brine, dried over Na2SO4. Solvent was evapolated
under a reduced pressure. The residue was purified by silicagel column chromatography (n-hexane :
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EtOAc = 5 : 1) to give the corresponding β-amino alcohols 1f (0.24 g, 40%), 1h (79.7 mg, 23%) and 1i
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(61.0 mg, 21%).
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(S)-2-Amino-1,1-bis(4-fluorophenyl)-3,3-dimethylbutan-1-ol (1f). Colorless crystal. Mp 196-198 °C;
[α]D22= -146.34 (c 0.41, CHCl3); IR (neat) cm-1: 3244, 2971, 1686, 1507; 1H-NMR (500 MHz, CDCl3) δ
7.60 (2H, dd, J = 8.7, 5.2 Hz), 7.48 (2H, dd, J = 8.6, 5.5 Hz), 7.00 (2H, t, J = 8.6 Hz), 6.91 (2H, t, J =
8.6 Hz), 4.54 (0.7H, br), 3.75 (1H, s), 1.45 (2H, br), 0.78 (9H, s); 13C-NMR (125 MHz, CDCl3) δ 162.5,
162.5, 160.6, 160.5, 145.6, 145.5, 141.0, 141.0, 127.8, 127.7, 127.3, 127.2, 115.5, 115.3, 114.7, 114.6,
79.4, 63.8, 35.6, 29.1; FAB-MS m/z: 306 (M+H)+; HRMS (FAB): calcd for C18H22F2NO (M+H)+
306.1669, found: 306.1656.
(S)-4-Amino-3-ethyl-5,5-dimethylhexan-3-ol (1h). Colorless oil. [α]D25= -24.46 (c 0.49, CHCl3); IR
(neat) cm-1: 2961, 2881, 1229; 1H-NMR (500 MHz, CDCl3) δ 2.57 (1H, s), 1.82-1.75 (1H, m), 1.54-1.38
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(3H, m), 1.04 (9H, s), 0.96-0.90 (6H, m); C-NMR (125 MHz, CDCl3) δ 75.4, 62.7, 35.3, 29.6, 29.4,
28.9, 8.3, 8.0; FAB-MS m/z: 174 (M+H)+; HRMS (FAB) calcd for C10H24NO (M+H)+: 174.1858, found:
174.1866.
(S)-3-Amino-2,4,4-trimethylpentan-2-ol (1i). Colorless oil. [α]D25= -18.15 (c 0.21, CHCl3); IR (neat)
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cm-1: 2980, 2856, 1220; H-NMR (500 MHz, CDCl3) δ 2.36 (1H, s), 1.32 (3H, m), 1.15 (3H, m), 1.04
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(9H, s); C-NMR (125 MHz, CDCl3) δ 72.3, 68.4, 35.1, 30.0, 28.9, 25.8; FAB-MS m/z: 146 (M+H)+;
HRMS (FAB) calcd for C8H20NO (M+H)+: 146.1545, found: 146.1542.
Supersilylation of 1l. To a solution of 2l (0.46 g, 1.9 mmol) in dry CH2Cl2 (20 mL) and
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chrolotris(trimethylsilyl)silane (0.80 mg, 2.8 mmol), Et3N (0.32 mL, 2.3 mmol) was added at 0 C for
o
10 min under Argon. The solution was stirred at 45 C for 24 h and then quenched with H2O. The
resulting mixture was extracted with CH2Cl2. The combined organic layer was washed with brine, dried
over Na2SO4. Solvent was removed under a reduced pressure. The residue was purified by preparative
thin-layer chromatography (SiO2, n-hexane : EtOAc = 5 : 1) to give the 1q (0.38 mg, 41 %).
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(S)-2-Amino-1,1-diphenyl-3-(tris(trimethylsilyl)silyloxypropan-1-ol (1q). Light yellow oil. [α]D25= -
41.33 (c 0.75, EtOH); IR (neat) cm-1: 2948, 2892, 1448, 1244; 1H-NMR (500 MHz, CDCl3) δ 7.58-7.13
(10H, m), 3.83 (1H, dd, J = 6.0, 2.9 Hz), 3.52 (1H, dd, J = 9.7, 6.0 Hz), 3.32 (1H, dd, J = 9.5, 2.9 Hz),
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0.11 (27H, s); C-NMR (125 MHz, CDCl3) δ 146.0, 145.4, 128.6, 128.3, 126.8, 126.6, 125.8, 125.2,
79.5, 69.5, 57.2, 0.26; EI-MS m/z: 489 (M)+; HRMS (EI) calcd for C24H43NO2Si4: 489.2371 (M)+,
found: 489.2367.
Methylation of 1a. To a solution of 1a (0.27 g, 1.0 mmol) in EtOH (10.0 mL), K2CO3 (0.41 g, 3.0
mmol) and MeI (0.12 mL, 2.0 mmol) was added at 0 °C. The resulting mixture was refluxed for 24 h.
The reaction mixture was quenched with water and extracted with EtOAc. The combined organic layer
was washed with brine, dried over Na2SO4. Solvent was removed under a reduced pressure. The residue
was purified by preparative thin-layer chromatography (SiO2, n-hexane : EtOAc = 5 : 1) to give the
corresponding secondary β-amino alcohol 1r (0.14 g, 48%).
(S)-3,3-Dimethyl-2-methylamino-1,1-diphenylbutan-1-ol (1r). Colorless crystal. Mp 104-107 °C;
[α]D24= -149.99 (c 0.28, CHCl3); IR (neat) cm-1: 3282, 2951; H-NMR (500 MHz, CDCl3) δ 7.76 (2H,
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dd, J = 8.6, 1.1 Hz), 7.63 (2H, dd, J = 8.6, 1.1 Hz), 7.32-7.29 (2H, m), 7.22-7.15 (3H, m), 7.17-7.09 (1H,
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m), 3.29 (1H, s), 2.16 (3H, s), 0.77 (9H, s); C-NMR (125 MHz, CDCl3) δ 150.3, 145.1, 127.8, 127.6,
127.0, 126.5, 126.2, 79.7, 74.4, 38.6, 37.6, 29.2; FAB-MS m/z: 284 (M+H)+; HRMS (FAB) calcd for
C19H26NO (M+H)+: 284.2014, found: 284.2012.
General Procedure for the Synthesis of Catalyst 2a-q and 3. To a solution of corresponding β-
amino alcohol 1a-l and 1q,r (0.03 mmol) in CH2Cl2 (0.7 mL), acids (CF3CO2H, CBr3CO2H, CCl3CO2H,
CH3CO2H, HCl) (0.036 mmol) was added at 0 °C. The resulting mixture was stirred at that temperature
for 5 min. Solvent was removed under a reduced pressure to afford the corresponding catalysts 2a-q, 3.
(S)-1-Hydroxy-3,3-dimethyl-1,1-diphenylbutan-2-amininium trifluoroacetate (2a)8. Colorless crystal
(EtOAc). Mp 160-164 °C; [α]D24= -63.49 (c 0.38, EtOH); IR (neat) cm-1: 3301, 1686, 1134; H-NMR
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(500 MHz, DMSO-d6) δ 7.64 (2H, d, J = 7.4 Hz), 7.54 (2H, d, J = 7.4 Hz), 7.40 (br, 2H), 7.32 (t, 2H, J
= 7.4 Hz), 7.24-7.19 (3H, m), 7.11 (1H, t, J = 7.2 Hz), 6.28 (1H, s), 4.34 (1H, s), 0.79 (9H, s); 13C-NMR
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(125 MHz, DMSO-d6) δ 146.8, 145.9, 129.1, 128.3, 127.6, 127.2, 126.3, 126.2, 80.6, 63.3, 35.7, 29.1;
FAB-MS m/z: 270 (M+H-CF3CO2H)+; HRMS (FAB) (M+H-CF3CO2H)+ calcd for C18H24NO: 270.1858,
found: 270.1859.
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(S)-1-Hydroxy-3-methyl-1,1-diphenylbutan-2-aminium trifluoroacetate (2b). Colorless crystal (EtOAc).
Mp 196-198 °C; [α]D23= +16.32 (c 0.49, EtOH); IR (neat) cm-1: 1688, 1665, 1523, 1134; 1H-NMR (500
MHz, DMSO-d6) δ 7.60 (2H, d, J = 7.3 Hz), 7.53 (2H, d, J = 7.3 Hz), 7.48 (2H, br), 7.33-7.28 (4H, m),
7.23-7.16 (2H, m), 6.37 (1H, s), 4.19 (1H, s), 1.83 (1H, q, J = 7.1 Hz), 0.97 (3H, d, J = 7.1 Hz), 0.91
(3H, d, J = 7.1 Hz); 13C-NMR (125 MHz, DMSO-d6) δ 145.3, 144.9, 129.0, 128.7, 127.7, 127.4, 126.3,
126.0, 80.2, 61.0, 27.5, 22.3, 17.2; FAB-MS m/z: 256 (M+H-CF3CO2H)+; HRMS (FAB) calcd for
C17H22NO: 256.1701 (M+H-CF3CO2H)+, found: 256.1704.
(S)-1-Hydroxy-1,1-diphenylpropan-2-aminium trifluoroacetate (2c). Colorless crystal (EtOAc). Mp
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197-200 °C; [α]D23= +23.34 (c 0.51, EtOH); IR (neat) cm-1: 3060, 1694, 1572, 1182, 1150; H-NMR
(500 MHz, DMSO-d6) δ 7.56-7.50 (6H, m), 7.33-7.28 (4H, m), 7.22-7.18 (2H, m), 6.41 (1H, s), 4.52
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(1H, d, J = 6.5 Hz), 1.10 (3H, d, J = 6.5 Hz); C-NMR (125 MHz, DMSO-d6) δ 144.9, 144.4, 129.0,
128.7, 127.7, 127.5, 126.2, 78.3, 52.9, 14.7; FAB-MS m/z: 228 (M+H-CF3CO2H)+; HRMS (FAB) calcd
for C15H18NO: 228.1388 (M+H-CF3CO2H)+, found: 228.1388.
(S)-2-Hydroxy-1,2,2-triphenylethanaminium trifluoroacetate (2d). Colorless crystal (EtOAc). Mp 178-
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180 °C; [α]D23= -115.19 (c 0.41, EtOH); IR (neat) cm-1: 3459, 1687, 1537, 1139; H-NMR (500 MHz,
DMSO-d6) δ 8.14 (3H, br), 7.81 (2H, d, J = 8.0 Hz), 7.42-7.39 (4H, m), 7.30-7.27 (3H, m), 7.18-7.16
(3H, m), 7.07-7.04 (2H, m), 7.00-6.97 (1H, m), 6.73 (1H, s), 5.51 (1H, s); 13C-NMR (125 MHz, DMSO-
d6) δ 144.4, 144.2, 135.4, 130.3, 129.1, 128.7, 128.0, 127.9, 127.1, 126.8, 126.5, 79.6, 60.3; FAB-MS
m/z: 290 (M+H-CF3CO2H)+; HRMS (FAB) calcd for C20H20NO: 290.1545 (M+H-CF3CO2H)+, found:
290.1543.
(S)-1-Hydroxy-1,1,3-triphenylpropan-2-aminium trifluoroacetate (2e). Colorless crystal (EtOAc). Mp
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161-163 °C; [α]D22= -36.47 (c 0.85, EtOH); IR (neat) cm-1: 1669, 1525, 1206, 1179, 1141; H-NMR
(500 MHz, DMSO-d6) δ 7.68-7.60 (7H, m), 7.35-7.18 (12H, m), 6.58 (1H, s), 4.63 (1H, s), 2.81-2.73
(2H, m); 13C-NMR (125 MHz, DMSO-d6) δ 144.8, 144.2, 137.2, 129.8, 129.1, 129.0, 128.8, 127.9,
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127.6, 127.3, 126.5, 126.2, 79.1, 58.6, 35.2; FAB-MS m/z: 304 (M+H-CF3CO2H)+; HRMS (FAB) calcd
for C21H22NO: 304.1701 (M+H-CF3CO2H)+, found: 304.1701.
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(S)-1,1-Bis(4-fluorophenyl)-1-hydroxy-3,3-dimethylbutan-2-aminium trifluoroacetate (2f). Colorless
crystal (EtOAc). Mp 179-182 °C; [α]D22= -53.43 (c 0.52, EtOH); IR (neat) cm-1: 1686, 1507, 1211, 1182,
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1136; H-NMR (500 MHz, DMSO-d6) δ 7.66 (2H, dd, J = 8.9, 5.4 Hz), 7.57 (2H, dd, J = 8.9, 5.4 Hz),
7.48 (2H, br), 7.14 (2H, t, J = 8.9 Hz), 7.07 (2H, t, J = 8.9 Hz), 6.50 (1H, s), 4.34 (1H, s), 0.80 (9H, s);
13C-NMR (125 MHz, DMSO-d6) δ 162.7, 162.4, 160.8, 160.5, 158.7, 158.4, 142.7, 142.1, 128.5, 128.4,
115.9, 115.7, 115.2, 115.0, 80.1, 63.3, 35.7, 29.1; FAB-MS m/z: 306 (M+H-CF3CO2H)+; HRMS (FAB)
calcd for C18H22F2NO: 306.1669 (M+H-CF3CO2H)+, found: 306.1667.
(S)-1-Hydroxy-3,3-dimethyl-1,1-di-p-tolylbutan-2-aminium trifluoroacetate (2g). Colorless crystal
(EtOAc). Mp 186-188 °C; [α]D22= -137.14 (c 0.35, EtOH); IR (neat) cm-1: 3436, 1676, 1519, 1183,
1132; 1H-NMR (500 MHz, DMSO-d6) δ 7.49 (2H, d, J = 8.1 Hz), 7.38 (2H, d, J = 8.1 Hz), 7.35 (2H, br),
7.11 (2H, d, J = 8.1 Hz), 7.01 (2H, d, J = 8.1 Hz), 6.13 (1H, s), 4.26 (1H, s), 2.22 (3H, s), 2.17 (3H, s),
0.79 (9H, s); 13C-NMR (125 MHz, DMSO-d6) δ; 144.1, 143.2, 136.6, 136.2, 129.6, 128.8, 126.2, 126.1,
80.4, 63.3, 35.6, 29.1, 21.0; FAB-MS m/z: 298 (M+H-CF3CO2H)+; HRMS (FAB) calcd for C20H28NO:
298.2171 (M+H-CF3CO2H)+, found: 298.2176.
(S)-4-Ethyl-4-hydroxy-2,2-dimethylhexan-3-aminium trifluoroacetate (2h). Colorless crystal (EtOAc).
Mp 173-176 °C; [α]D23= +21.73 (c 0.14, EtOH); IR (neat) cm-1: 3430, 3144, 2977, 1672, 1173, 1137;
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1H-NMR (500 MHz, DMSO-d6) δ 2,47 (brs), 1.64-1.45 (m, 4H), 1.02 (s, 9H), 0.85-0.81 (m, 6H); C-
NMR (125 MHz, DMSO-d6) δ 75.5, 63.6, 34.1, 29.4, 28.7, 28.4, 8.3, 8.1; FAB-MS m/z: 174 (M+H-
CF3CO2H)+; HRMS (FAB) calcd for C10H24NO: 174.1858 (M+H-CF3CO2H)+, found: 174.1858.
(S)-2-Hydroxy-2,4,4-trimethylpentan-3-aminium trifluoroacetate (2i). Colorless crystal (EtOAc). Mp
160-164 °C; [α]D24= -76.40 (c 1.00, EtOH); IR (neat) cm-1: 696, 799, 1604, 1689, 3393 ; 1H-NMR (500
MHz, DMSO-d6) δ 2.74 (m, 1H), 1.29 (s, 3H), 1.17 (s, 3H), 1.00 (s, 9H); 13C-NMR (125 MHz, DMSO-
d6) δ 71.7, 68.1, 33.7, 30.3, 28.7, 26.0; FAB-MS m/z: 146 (M+H-CF3CO2H)+; HRMS (FAB) calcd for
C8H20NO: 146.1545 (M+H-CF3CO2H)+, found: 146.1544.
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(S)-1-Hydroxy-3,3-dimethylbutan-2-aminium trifluoroacetate (2j). Colorless crystal (EtOAc). Mp 110-
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MHz, DMSO-d6) δ 7.67 (3H, br), 5.31 (1H, br), 3.68 (1H, td, J = 11.4, 3.6 Hz), 2.79 (1H, dd, J = 8.9,
3.6 Hz), 0.91 (9H, s); 13C-NMR (125 MHz, DMSO-d6) δ 61.7, 59.1, 32.3, 26.7; FAB-MS m/z: 118
(M+H-CF3CO2H)+; HRMS (FAB) calcd for C6H16NO: 118.1232 (M+H-CF3CO2H)+, found: 118.1233.
(S)-1-Hydroxy-3,3-dimethyl-1,1-diphenylbutan-2-amininium trichloroacetate (2k). Colorless crystal
(EtOAc). Mp 160-164 °C; [α]D24= -76.40 (c 0.13, EtOH); IR (neat) cm-1: 696, 799, 1604, 1689, 3393 ;
1H-NMR (500 MHz, DMSO-d6) δ 7.49-7.46 (m, 4H), 7.40 (br, 2H), 7.31-7.28 (m, 2H), 7.23-7.18 (m,
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3H), 7.13-7.10 (m, 1H), 4.21 (d, J = 10.5 Hz, 1H), 4.14 (d, J = 10.5 Hz, 1H), 0.82 (s, 9H); C-NMR
(125 MHz, DMSO-d6) δ143.9, 141.7, 129.6, 129.2, 129.1, 128.7, 127.7, 127.1, 61.1, 52.8, 35.2, 27.8 ;
FAB-MS m/z: 254 (M+H-CF3CO2H)+; HRMS (FAB) calcd for C18H24N: 254.1909 (M+H-CF3CO2H)+,
found: 254.1908.
(S)-1,3-Dihydroxy-1,1-diphenylpropan-2-aminium trifluoroacetate (2l). Colorless crystal (EtOAc). Mp
62-64 °C; [α]D22= -14.28 (c 0.56, EtOH); IR (neat) cm-1: 3087, 1669, 1182, 1133; 1H-NMR (500 MHz,
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CDCl3) δ 7.58-7.15 (m, 10H), 6.04 (br), 4.22 (2H, t, J = 4.5 Hz), 3.66 (1H, d, J = 4.5 Hz); C-NMR
(125 MHz, CDCl3) δ 142.8, 142.7, 129.2, 128.8, 128.1, 127.7, 125.2, 125.0, 79.7, 60.0, 57.7; EI-MS
m/z: 244 (M+H-CF3CO2H)+; HRMS (FAB) [M+H-CF3CO2H]+ calcd for C15H18NO2: 244.1338, found:
244.1339.
(S)-1-Hydroxy-3,3-dimethyl-1,1-diphenylbutan-2-amininium trichloroacetate (2m). Colorless crystal
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(EtOAc). Mp 170-173 °C; [α]D25= -63.18 (c 0.36, EtOH); IR (neat) cm-1: 3394, 3284, 1660, 1341; H-
NMR (500 MHz, DMSO-d6) δ 8.32 (br), 7.64 (2H, d, J = 7.1 Hz), 7.58 (2H, d, J = 7.2 Hz), 7.28 (2H, m),
7.19 (2H, m), 7.13 (1H, m), 7.06 (1H, m), 5.32 (br), 3.79 (br), 0.76 (s, 9H); 13C-NMR (125 MHz,
DMSO-d6) δ 146.3, 145.4, 128.6, 127.8, 127.1, 126.7, 125.8, 125.7, 80.1, 62.7, 32.2, 28.6; FAB-MS
m/z: 270 (M+H-CF3CO2H)+; HRMS (FAB) calcd for C18H24NO: 270.1858 (M+H-CCl3CO2H)+, found:
270.1859.
(S)-1-Hydroxy-3,3-dimethyl-1,1-diphenylbutan-2-amininium tribromoacetate (2n). Colorless crystal
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(EtOAc). Mp 132-136 °C; [α]D24= -46.51 (c 0.34, EtOH); IR (neat) cm-1: 3379, 3283, 1650, 1334; H-
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NMR (500 MHz, DMSO-d6) δ 7.70-6.45 (m, 11H), 6.35 (s, 1H), 4.30 (s, 1H), 0.82 (s, 9H); C-NMR
(125 MHz, DMSO-d6) δ 146.0, 145.2, 128.4, 127.9, 127.9, 126.2, 126.0, 125.8, 80.0, 62.3, 32.5, 28.6;
FAB-MS m/z: 270 (M+H-CF3CO2H)+; HRMS (FAB) calcd for C18H24NO: 270.1858 (M+H-
CBr3CO2H)+, found: 270.1857.
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(S)-1-Hydroxy-3,3-dimethyl-1,1-diphenylbutan-2-amininium acetate (2o). Colorless crystal (EtOAc).
Mp 139-142 °C; [α]D25= -90.47 (c 0.42, EtOH); IR (neat) cm-1: 3321, 2962, 1530; 1H-NMR (500 MHz,
DMSO-d6) δ 7.60 (2H, dd, J = 8.6, 1.2 Hz), 7.54 (2H, dd, J = 8.6, 1.2 Hz), 7.23 (2H, t, J = 7.8 Hz), 7.14
(2H, t, J = 7.8 Hz), 7.08 (1H, t, J = 7.4 Hz), 7.01 (1H, t, J = 7.4 Hz), 3.71 (1H, s), 3.53 (br), 1.86 (3H, s),
0.71 (s, 9H); 13C-NMR (125 MHz, DMSO-d6) δ 172.7, 150.7, 148.1, 128.6, 127.9, 126.3, 126.2, 126.1,
126.1, 81.8, 63.2, 36.4, 30.1, 21.7; FAB-MS m/z: 270 (M+H-CH3CO2H)+; HRMS (FAB) calcd for
C18H24NO: 270.1858 (M+H-CH3CO2H)+, found: 270.1856.
(S)-1-Hydroxy-3,3-dimethyl-1,1-diphenylbutan-2-amininium chloride (2p). Colorless crystal (EtOAc).
Mp 230-240 °C; [α]D24= -34.40 (c 0.12, EtOH); IR (neat) cm-1: 3263, 2948; H-NMR (500 MHz,
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DMSO-d6) δ 7.66 (2H, d, J = 7.5 Hz), 7.62 (1H, br), 7.56 (2H, d, J = 7.5 Hz), 7.29 (2H, t, J = 7.7 Hz),
7.22-7.16 (3H, m), 7.09 (2H, t, J = 7.4 Hz), 6.38 (1H, s), 4.40 (1H, s), 0.82 (9H, s); 13C-NMR (125 MHz,
DMSO-d6) δ 146.8, 146.4, 129.1, 128.3, 127.5, 127.0, 126.3, 126.1, 80.5, 63.5, 35.8, 29.3; FAB-MS
m/z: 270 (M+H-HCl)+; HRMS (FAB) calcd for C18H24NO: 270.1858 (M+H-HCl)+, found: 270.1859.
(S)-1-Hydroxy-1,1-diphenyl-3-(tris(trimethylsilyl)silyloxypropan-2-aminium trifluoroacetate (2q). Light
yellow oil. [α]D25= -19.99 (c 0.45, EtOH); IR (neat) cm-1: 3387, 2950, 2893, 1675, 1246; 1H-NMR (500
MHz, CDCl3) δ 7.56 (2H, dd, J = 7.2, 1.2 Hz), 7.47 (2H, dd, J = 7.2, 1.2 Hz), 7.32-7.29 (4H, m), 7.22-
7.19 (1H, m), 7.15-7.12 (1H, m), 4.21 (1H, dd, J = 5.7, 3.2 Hz), 3.79 ((1/2)2H, dd, J = 10.6, 5.4 Hz),
3.52 ((1/2)2H, dd, J = 10.6, 2.9 Hz), 0.09 (27H, s); 13C-NMR (125 MHz, CDCl3) δ 143.1, 143.0, 129.1,
128.8, 127.9, 127.6, 125.5, 124.9, 77.8, 65.6, 58.2, 0.06; EI-MS m/z: 489 (M)+; HRMS (EI) (M-
CF3CO2H)+ calcd for C24H43NO2Si4: 489.2371, found: 489.2359.
(S)-1-Hydroxy-N,3,3-trimethyl-1,1-diphenylbutan-2-aminium trifluoroacetate (3). Colorless crystal
(EtOAc). Mp 160-164 °C; [α]D24= -76.40 (c 1.00, EtOH); IR (neat) cm-1: 696, 799, 1604, 1689, 3393 ;
1H-NMR (500 MHz, DMSO-d6) δ 7.84-6.15 (m, 10H), 5.72 (s, 1H), 2.47 (s, 3H), 0.80 (s, 9H); C-
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NMR (125 MHz, DMSO- d6) δ 159.1, 145.9, 145.0, 137.5, 133.2, 130.2, 129.1, 128.7, 128.2, 128.0,
127.5, 126.9, 81.2, 73.5, 29.0; FAB-MS m/z: 284 (M+H-CF3CO2H)+; HRMS (FAB) calcd for
C19H26NO: 284.2014 (M+H-CF3CO2H)+, found: 284.2012.
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Synthesis of 2-methyl-, phenyl- or allyl-1-phenoxycarbonyl-1,2-dihydropyridines (14a, 17 or 20).
To a solution of methylmagnesium bromide 3.0 M, phenylmagnesium bromide 3.0 M or
allylmagnesium bromide 0.7 M in ether (10 mmol) was added a solution of pyridine (0.97 mL, 12
mmol) in dry Et2O (30 mL) at -78oC over 30 min under Argon, and a solution of phenyl chloroformate
(1.26 mL, 10 mmol) in dry Et2O (25 mL) was added to the solution over 30 min. The reaction mixture
was stirred for 2 h at the same temperature. The mixture was a quenched with water and extracted with
ether, washed with brine, dried over Na2SO4. Solvent was evapolated under a reduced pressure. The
residue was purified by silicagel column chromatography (n-hexane : EtOAc = 30 : 1) to give 14a (1.44
g, 67%), 17 (1.66 g, 60%), 20 (1.68 g, 70%).
2-Methyl-1-phenoxycarbonyl-1,2-dihydropyridine (14a). Colorless crystal. Mp 49-52 °C; IR (neat) cm-
1: 1736; 1H-NMR (500 MHz, CDCl3): δ 7.40-7.14 (m, 5H), 6.82 (d, J = 7.7 Hz, (3/5)1H), 6.76 (d, J =
7.7 Hz, (2/5)1H), 5.95-5.89 (m, 1H), 5.65-5.59 (m, 1H), 5.40-5.36 (m, (2/5)1H), 5.34-5.31 (m, (3/5)1H),
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5.01-4.90 (m, 1H), 1.30 (d, J = 6.5 Hz, (2/5)3H), 1.23 (d, J = 6.5 Hz, (3/5)3H); C-NMR (125 Mz,
CDCl3): δ 151.7, 151.1, 129.5, 129.5, 125.9, 125.7, 124.8, 124.7, 124.3, 124.0, 121.7, 121.7, 121.0,
120.4, 106.5, 106.2, 49.3, 48.9, 19.8, 18.8; EI-MS m/z: 215 (M)+; HRMS (EI) (M)+ calcd for
C13H13NO2: 215.0946, found: 215.0941.
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2-Phenyl-1-phenoxycarbonyl-1,2-dihydropyridine (17). Colorless solid. Mp: 49-50 C; IR (neat) cm-1:
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1730; H-NMR (500 MHz, CDCl3): δ 7.51-7.27 (m, 7H), 7.21-7.10 (m, 2H), 6.97-6.92 (m, 2H), 6.14-
6.02 (m, 1H), 5.95 (d, J = 5.7 Hz, 1H), 5.77-5.71 (m, 1H), 5.41-5.39 (m, 1H); 13C-NMR (125 MHz,
CDCl3): δ 153.1, 152.3, 151.0, 150.8, 142.0, 140.4, 129.5, 128.8, 128.7, 128.3, 127.7, 126.7, 125.9,
125.8, 125.0, 123.2, 123.0, 121.7, 121.0, 120.6, 106.2, 105.8, 57.4, 56.0; EI-MS m/z: 277 (M)+; HRMS
(EI) (M)+ calcd for C18H15NO2 277.1103, found 277.1111.
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2-Allyl-1-phenoxycarbonyl-1,2-dihydropyridine (20). Light yellow oil; IR (neat) cm-1: 1742; H-NMR
(500 MHz, CDCl3): δ 7.44-7.36 (m, 2H), 7.29-7.21 (m, 1H), 7.15-7.12 (m, 2H), 6.86 (d, J = 7.7 Hz,
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(3/5)1H), 6.82 (d, J = 7.7 Hz, (2/5)1H), 6.03-5.97 (m, 1H), 5.92-5.83 (m, 1H), 5.67 (dd, J = 9.4, 5.8 Hz,
1H), 5.44 (m, (2/5)1H), 5.36-5.34 (m, (3/5)1H), 5.14-5.08 (m, 2H), 4.99 (dd, J = 12.2, 6.1 Hz, (2/5)1H),
4.93 (dd, J = 12.2, 6.1 Hz, (3/5)1H), 2.45-2.30 (m, 2H); 13C-NMR (125 MHz, CDCl3): δ 152.9, 152.0,
151.1, 150.9, 133.6, 133.3, 129.7, 129.5, 129.5, 126.4, 125.9, 125.8, 125.3, 124.6, 123.1, 122.7, 122.1,
121.7, 121.6, 121.5, 121.0, 118.5, 118.0, 107.3, 106.8, 52.6, 52.2, 39.0, 38.4; EI-MS m/z: 241 (M)+;
HRMS (EI) (M)+ calcd for C15H15NO2 241.1103, found 241.1099.
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Synthesis of methylated 1,2-dihydropyridines 14b-d. To a solution of NaBH4 (0.38 g, 10 mmol) and
methyl pyridine (10.0 mmol) in dry methanol (7.5 mL) was added slowly phenyl or benzyl
chloroformate (10.0 mmol) at -78 oC for 30 min under Argon. The reaction mixture was stirred at that
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temperature for 2 h. After 2 h, the reaction temperature was allowed to rise slowly to 0 C was poured
into a flask with ice, and extracted with Et2O. The combined organic layer was washed with brine, dried
over Na2SO4. Solvent was evapolated under a reduced pressure. The residue was purified by silicagel
column chromatography (SiO2, n-hexane : EtOAc = 30 : 1) to give 14b (1.25 g, 58%), 14c (1.21 g,
56%), 14d (0.90 g, 42%).
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3-Methyl-1-phenoxycarbonyl-1,2-dihydropyridine (14b). Light yellow oil. IR (neat) cm-1: 1730; H-
NMR (500 MHz, CDCl3): δ 7.40-7.14 (m, 5H), 6.80 (d, J = 7.7 Hz, (3/5)1H), 6.73 (d, J = 7.7 Hz,
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(2/5)1H), 5.64 (br, 1H), 5.26-5.21 (m, 1H), 4.45 (s, (7/20)2H), 4.30 (s, (13/20)2H), 1.76 (s, 3H); C-
NMR (125 MHz, CDCl3): δ 152.7,151.8,151.1,151.0 ,130.0, 129.3, 128.6,125.8, 125.8, 123.1, 122.5,
121.7, 117.0, 116.6, 106.1, 48.6, 48.1, 20.9; EI-MS m/z: 215 (M)+; HRMS (EI) (M)+ calcd for
C13H13NO2: 215.0946, found: 215.0942.
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4-Methyl-1-phenoxycarbonyl-1,2-dihydropyridine (14c). Light yellow oil. IR (neat) cm-1: 1738; H-
NMR (500 MHz, CDCl3): δ 7.40-7.14 (m, 5H), 6.88 (d, (3/5)1H, J = 7.8 Hz), 6.82 (d, J = 7.8 Hz,
(2/5)1H), 5.30 (br, (3/5)1H), 5.26 (br, (2/5)1H), 5.17 (d, J = 8.1 Hz, (2/5)1H), 5.13 (d, J = 8.1 Hz,
(3/5)1H), 4.53 (s, (2/5)2H), 4.40 (s, (3/5)2H), 1.76 (s, 3H); 13C-NMR (125 MHz, CDCl3): δ 152.7, 151.6,
151.1, 151.0, 130.3, 130.0, 129.5, 125.8, 125.8, 125.7, 125.0, 121.7, 114.3, 113.7, 109.7, 109.6, 109.5,
44.6, 44.1, 20.7; EI-MS m/z: 215 (M)+; HRMS (EI) (M)+ calcd for C13H13NO2: 215.0946, found:
215.0939.
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6-Methyl-1-phenoxycarbonyl-1,2-dihydropyridine (14d). Light yellow oil. IR (neat) cm-1: 1739; H-
NMR (500 MHz, CDCl3): δ 7.39-7.11 (m, 5H), 5.98-5.95 (m, 1H), 5.72-5.69 (m, 1H), 5.54-5.53 (m,
1H), 4.34 (d, J = 3.2 Hz, 2H), 2.26 (s, 3H); 13C-NMR (125 MHz, CDCl3): δ 154.4, 151.2, 151.0, 129.6,
129.5, 126.2, 125.7, 124.2, 121.7, 121.1, 119.8, 113.7, 55.5, 44.1, 21.2; EI-MS m/z: 215 (M)+; HRMS
(EI) (M)+ calcd for C13H13NO2: 215.0946, found: 215.0933.
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Genaral procedure for the DA reaction of 1,2-dihydropyridines 4, 8, 14, 17, 20 with acroleins 5,
11 using catalyst 3a. To a solution of catalyst 2a (3.8 mg, 10 mol%) and 1,2-dihydropyridines 4, 8, 14,
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17, 20 (0.1 mmol) in MeCN-H2O (19:1), distilled acroleins 5 or 11 (0.3 mmol) were added at –25 C
and the solution was stirred at 0 °C for 24-36 h. The reaction was quenched by water, extracted with
Et2O. The combined organic layer was washed with brine, dried over Na2SO4. Solvent was evapolated
under a reduced pressure to give a crude DA adduct, which was used to the next reaction without
purification. To a solution of the crude DA adduct in EtOH (2.0 mL), NaBH4 (4.0 mg, 0.10 mmol) was
added at 0 °C and the mixture was stirred at room temperature for 1 h. Solvent was removed under a
reduced pressure. The reaction mixture was extracted with EtOAc. The combined organic layer was
washed with brine, dried over Na2SO4. Solvent was evapolated under a reduced pressure. The residue
was purified by preparative thin-layer chromatography (SiO2, n-hexane : EtOAc = 1 : 1) to give the
corresponding alcohols 7a (25.4 mg, 98%), 10 (20.5 mg, 75%), 13a (30.5 mg, 96%), 13b (30.8 mg,
93%), 13c (14.2 mg, 50%), 16a (13.7 mg, 50%), 16b (21.9 mg, 80%), 19 (16.8 mg, 50%) and 22(18.0
mg, 60%).
8-Cyano-7-(hydroxymethyl)-2-phenoxycarbonyl-2-azabicyclo[2.2.2]oct-5-ene (13c). Light yellow oil.
[α]D24= -17.64 (c 0.34, CHCl3); IR (neat) cm-1: 3461, 2927, 2884, 2238, 1697, 1400, 1201; H-NMR
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(500 MHz, CDCl3) δ 7.39-7.35 (m, 2H), 7.23-7.20 (m, 1H), 7.14-7.12 (m, 2H), 6.53-6.49 (m, 2H), 5.03
(brs, (3/10)1H), 4.96 (brs, (7/10)1H), 3.98 (m, (7/10)1H), 3.80 (m, (3/10)1H), 3.45-3.36 (m, 2H), 3.29
(m, (7/10)1H), 3.20 (m, (3/10)1H), 3.13 (brs, 1H), 2.74 (brs, 1H), 2.32 (brs, (7/10)1H), 2.23 (brs,
(3/10)1H) ; 13C-NMR (125 MHz, CDCl3) δ 132.74, 132.52, 129.42, 125.58, 121.80, 64.22, 47.52, 46.28,
43.20, 34.01, 28.44; EI-MS m/z: 284 (M)+; HRMS (EI) [M]+ calcd for C16H16N2O3: 284.1161, found:
284.1166. The enantiomeric excess (ee) was determined by HPLC [DAICEL Optically activecel AS-H,
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