Access to Highly Enantioenriched Donepezil-like 1,4-Dihydropyridines as Promising Anti-Alzheimer Prodrug Candidates via Enantioselective Tsuji Allylation and Organocatalytic Aza-Ene-Type Domino Reactions

Article abstract of DOI:10.1021/acs.joc.8b01442

This work aims at exploiting both the enantioselective Tsuji allylation of allyl carbonate 6 and an organocatalytic aza-ene-type domino reaction between enal 3a and β-enaminone 4a to develop a straightforward access to all of the four possible stereoisomers of a donepezil-like 1,4-dihydropyridine 1a (er up to 99.5:0.5; overall yield up 64%), an anti-Alzheimer's prodrug candidate. This strategy was extended to the preparation of other enantioenriched 1,4-dihydropyridines 1b-i (eight examples), highlighting its potential in the development of these chiral AChE inhibitors.

Full text of DOI:10.1021/acs.joc.8b01442

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Article
Access to highly enantioenriched donepezil-like 1,4-dihydropyridines
as promising anti-Alzheimer prodrug candidates via enantioselective
Tsuji allylation and organocatalytic aza-ene-type domino reactions
Mihaela-Liliana TINTAS, Rabah Azzouz, Ludovic Peauger, Vincent GEMBUS,
Emilie Petit, Laetitia Bailly, Cyril Papamicaël, and Vincent Levacher
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01442 • Publication Date (Web): 13 Jul 2018
Downloaded from http://pubs.acs.org on July 14, 2018
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Access
to
highly
enantioenriched
donepezil-like
1,4-
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dihydropyridines as promising anti-Alzheimer prodrug candidates
via enantioselective Tsuji allylation and organocatalytic aza-ene-
type domino reactions
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MihaelaꢀLiliana ꢁînꢂaꢃ,† Rabah Azzouz,# Ludovic Peauger, # Vincent Gembus,*,# Emilie Petit,†
Laetitia Bailly,† Cyril Papamicaël,† and Vincent Levacher*,†
†Normandie Université, UNIROUEN, INSA Rouen, CNRS, COBRA, 76000
Rouen, France.
# VFP Therapies, R&D, 1 rue Tesnière, 76130 Mont SaintꢀAignan, France.
Table of Content Graphic :
ABSTRACT
This work aims at exploiting both the enantioselective Tsuji allylation of allyl carbonate 6 and
an organocatalytic azaꢀeneꢀtype domino reaction between enal 3a and βꢀenaminone 4a to
develop a straightforward access to all of the four possible stereoisomers of a donepezilꢀlike
1,4ꢀdihydropyridine 1a (er up to 99.5:0.5; overall yield up 64%); an antiꢀAlzheimer prodrug
candidate. This strategy was extended to the preparation of other enantioenriched 1,4ꢀ
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dihydropyridines 1b-i (8 examples), highlighting its potential in the development of these
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chiral AChE inhibitors.
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INTRODUCTION
1,4ꢀdihydropyridine nucleus (DHPs) is viewed as a privileged scaffold due to its virtue for
selectively modulating diverse receptors, channels and enzymes, when conveniently
substituted.1 Particularly, these compounds are closely related to the NADH (ꢀ NAD+)
coenzyme by mimicking its oxidoꢀreductive activity. Bodor et al. took advantage of these
redox properties to develop a brain targeting chemical delivery system (CDS) based on the
1,4ꢀdihydrotrigonelline ↔ trigonelline system.2,3 For several years, our group has been
interested in this approach,4 and as part of our Alzheimer’s disease research program, we
have recently described the design and preparation of several prodrugs of donepezil
analogues based on a bioꢀoxidisable strategy and tested their inhibitory activities against
human acetyl cholinesterase (hAChE).4g,f In most of cases, the designed drugs displayed
high inhibitory activities although, as expected, the corresponding prodrugs were inactive.
However, during these research investigations, we highlighted that some of the obtained 1,4ꢀ
dihydropyridine (1,4ꢀDHP) derivatives showed nonetheless a significant inhibitory activity.
One of the most active 1,4ꢀDHP, the compound 1a, displayed a threeꢀdigit nanomolar activity
against hAChE (Scheme 1a, IC50 = 0.415 ꢀM). The tested 1,4ꢀDHPs are issued from a nonꢀ
stereocontrolled synthesis (Scheme 1a), affording a mixture of the all four possible
stereomers due to the presence of two chiral carbons at both tetralone and 1,4ꢀ
dihydropyridine rings. Obviously, it is well known that enantiomers of a chiral drug may
display marked differences in their pharmacological behavior arising from strong differences
in their interactions with enzymes, proteins, receptors and other chiral molecules in living
systems.5 Keeping this in mind, we turned our interest toward the investigation of the
structureꢀactivity relationship of each stereoisomers AꢀD of 1a with hAChE. To address this
issue, all the four stereoisomers AꢀD were isolated by super critical fluid chromatography on
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a chiral stationary phase. An in vitro evaluation of the soꢀobtained four stereoisomers AꢀD
highlighted a striking disparity of the biological activity (i.e. IC50, Scheme 1a).4f To complete
our investigation, it was necessary to attribute the absolute configuration at both stereogenic
centers of each stereoisomer AꢀD and we naturally turned our attention to enantioselective
synthesis of the target chiral 1,4ꢀDHPs 1a. Although the racemic preparation of 4ꢀsubstituted
1,4ꢀDHPs is well documented in the literature,6 only a few catalytic asymmetric approaches
are reported. These are either based on the organocatalytic asymmetric construction of 1,4ꢀ
DHPs7 or more recently on regioselective organocatalytic 1,4ꢀaddition of enolate derivatives
to Nꢀalkyl pryridinium salts.7fꢀg Taking the structure of our target 1a into account, the
organocatalytic azaꢀeneꢀtype cascade reaction described by Kanger et al. appeared to be
the most appropriate approach to provide access to highly enantioenriched donepezilꢀlike
1,4ꢀdihydropyridine prodrugs.7e It involves an iminium activation of α,βꢀunsaturated aldehyde
by means of JørgensenꢀHayashi catalyst in the presence of βꢀenaminones or βꢀenamino
esters to furnish the desired 1,4ꢀDHPs in good yields (45ꢀ86%) along with moderate to very
good enantioselectivities (62ꢀ96%). According to this approach, the enantioenriched enal 3a
precursor would be accessible by an enantioselective Tsuji allylation8 / crossꢀmetathesis
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sequence from
αꢀtetralone 2a, whereas the starting enaminone 4a would be prepared by
condensation of benzylamine with transꢀmethoxyꢀ3ꢀbutenꢀ2ꢀone (Scheme 1b). Herein, we
report a straightforward access to donepezilꢀlike 1,4ꢀdihydropyridine prodrugs 1a-i and an
asymmetric approach allowing the preparation of each of the four possible stereoisomers via
an aminocatalyzed cyclisation as the key step.
Scheme 1. (a) Previous non-stereocontrolled route to donepezil-like 1,4-dihydropyridine
prodrug 1a; (b) Asymmetric approach developed in this work
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RESULTS AND DISCUSSION
First of all, we set out to explore the scope of this new straightforward route to prepare
donepezilꢀlike 1,4ꢀdihydropyridine prodrugs 1a-i in a nonꢀstereocontrolled fashion.6 To this
end, the required enals (±)ꢀ3a-c were prepared in a twoꢀstep sequence by allylation of
arylketones 2a-c9 affording the corresponding
αꢀallylated arylketones (±)ꢀ5a-c in 46ꢀ68%
yields followed by crossꢀmetathesis in the presence of an excess of crotonaldehyde (Scheme
2). Thus, HoveydaꢀGrubbs 2nd generation catalyst (2.5 mol%) in dichloromethane at reflux
overnight were used to afford the expected racemic enals (±)ꢀ3a-c in good to excellent yields
(83ꢀ91%).
Scheme 2. Preparation of enals (±)-3a-c
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Following the reaction conditions described by Renaud et al.,6g the desired dihydropyridine
1a was obtained by reacting enal (±)ꢀ3a with enaminone 4a in the presence of scandium
triflate as a catalyst in dichloromethane (Table 1, entry 1). Besides the preparation of the
target 1a, a representative panel of 1,4ꢀDHPs 1b-g was also prepared by reacting various
enamine derivatives 4a-f with enals (±)ꢀ3a-c. Except βꢀenamino nitrile 4f which failed to react
(entries 9ꢀ10), all other 1,4ꢀDHPs 1a-g were obtained in fair to good yields (up to 68%) after
purification by flash chromatography (Entries 1ꢀ8). Compared to our previously reported
synthesis depicted in scheme 1a,4f this new route provides a more convergent and direct
access to 3,4ꢀdisubstitited 1,4ꢀDHPs with fair overall yields.
Table 1. Preparation of (±)-1,4-DHPs 1a-i a
Entry
(±)ꢀ3
R1
n
4
R2
R3
Cpd
Yield (%)
1
2
3
4
6
7
8
9
3a
3b
3b
3b
3b
3c
3c
3c
CH3O
H
2
2
2
2
2
1
1
1
4a benzyl
4a benzyl
C(O)CH3
C(O)CH3
C(O)CH3
C(O)CH3
C(O)CH3
C(O)CH3
CO2CH3
CN
1a
1b
1c
1d
1e
1f
62
35
59
65
45
55
68
0b
4b
4c
4d
H
H
H
CH3O
CH3O
CH3O
(2’ꢀmethyl)ꢀbenzyl
phenyl
nꢀpropyl
4a benzyl
4e
4f
1g
1h
(2’ꢀmethyl)ꢀbenzyl
benzyl
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0b
3b
2
4f
CN
1i
10
H
benzyl
a Reaction conditions: reactions performed at room temperature (21°C) under argon atmosphere with
3a-c (1.0 equiv), 4a-f (1.0 equiv), Sc(OTf)3 (5 mol%), Na2SO4 (3.0 equiv.) in CH2Cl2 (0.1M). b No reaction
occurred with 5 mol% or 1.1 equiv of Sc(OTf)3.
6
7
8
9
With enals (±)ꢀ3a-c and enamines 4a-f in hands, a general screening was performed to find
the optimal reaction conditions for the enantioselective tandem azaꢀene type reaction/
cyclization cascade as oneꢀpot entry to enantiomerically enriched 1,4ꢀDHPs 1a-i (Table 2).
We first investigated the reaction between enal (±)ꢀ3a and enamine 4a in the presence of
MacMillan’s catalyst I with trifluoroacetic acid (TFA) and Na2SO4 (Table 2, entry 1).10 After
16h of reaction at room temperature, no trace of 1,4ꢀDHP 1a could be observed by
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1
conducting a H NMR analysis from the crude mixture. Similarly, the use of an admixture of
catalyst II (20 mol%) and benzoic acid (BA) (20 mol%) in toluene at room temperature was
disappointing since a very low catalytic activity was observed giving only traces of 1a (Table
2, entry 2). A great stride forward was next reached by the use of the more bulky catalyst S-
III in combination with BA. Thus, the expected 1,4ꢀDHP 1a was obtained in up to 30% yield
and a good enantiomeric ratio (er= 88:12) for both diastereomers, however with a poor
reproducibility (Table 2, entry 3). Only traces of 1a was obtained when decreasing the
catalyst loading from 30 to 10 mol% (Table 2, entries 4ꢀ5). Addition of 3Å molecular sieves
as water scavengers provided reproducible yields up to 35% and a similar enantiomeric ratio
(Table 2, entry 6). One may note that 4Å molecular sieves turned out to be even more
efficient, furnishing 1a in up to 49% yield (Table 2, entry 7). To our delight, when mixing
catalyst S-III with the more acidic saccharin in toluene at 40 ºC, 1,4ꢀDHP 1a was isolated in a
satisfactory 60% yield after only 0.5h along with similar enantiomeric ratios (er= 84:16 and
85:15) (Table 2, entry 8). Finally, by using dichloroethane (DCE) as solvent, the enantiomeric
ratio of both diastereomers could be somewhat improved (er= 92:8 and 88:12) without
erosion of the yield (Table 2, entry 9).
Table 2. Screening reaction conditions for asymmetric aminocatalyzed cascade synthesis of
1,4-DHPs 1a-ia,b
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dr j
major
/minor
Time
(h)
Yield
(%)
er k
major /minor
Entry
3
4
Cat.
Additive
Solvent
Cpd
1c
3a
3a
3a
3a
3a
3a
3a
3a
3a
4a
4a II
I
TFA, Na2SO4
BA
BA
BA
BA
DCE
16
18
18
36
36
18
18
0.5
2
2
2
4
8
4
2
2
2
4
4
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
1e
1f
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
2d
toluene
toluene
toluene
toluene
toluene
toluene
toluene
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
traces
10ꢀ30h
traces
30
35
49
60
61
45
55
47
65
56
62
54
52
51
3d
4a (S)-III
4a (S)-III
4a (S)-III
4a (S)-III
4a (S)-III
4a (S)-III
4a (S)-III
88:12 / 88:12
ꢀ
4e
5f
52/48
52/48
51/49
55/45
60/40
52/48
58/42
57/43
55/45
53/47
51/49
52/48
55/45
53/47
58/42
88:12 / 87:13
87:13 / 86:14
88:12/ 88:12
84:16 / 85:15
92:8 / 88:12
93:7 / 93:7
93:7 / 95:5
89:11 / 88:12
92:8 / 91:9
90:10 / 91:9
92:8 / 92:8
88:12 / 94:6
87:13 / 90:10
84:16 / 86:14
86:14 / 89:11
6d
BA, MS 3Åi
BA, MS 4Åi
Saccharin
Saccharin
Saccharin
Saccharin
Saccharin
Saccharin
Saccharin
Saccharin
Saccharin
Saccharin
7d
8g
9g
10g
11g
12g
13g
14g
15g
16g
17g
18g
19g
3b 4a (S)-III
3b 4b (S)-III
3b 4c (S)-III
3b 4d (S)-III
3c
3c
3c
3b 4f
3c 4f
3b 4f
4a (S)-III
4e (S)-III
4f
1g
1h
1i
(S)-III
(S)-III
(R)-III Saccharin
(R)-III Saccharin
1hl
1il
52
Configuration assigned according to the predicted model reported by Kanger7e. Reaction conditions: all reactions were
a
b
performed under argon atmosphere. 3 (1.4 equiv), 4 (1.0 equiv), I (40 mol%), TFA (40 mol%), Na2SO4 (3.0 equiv.), rt. d 3 (1.0
c
equiv), 4 (1.0 equiv), catalyst (20 mol%), benzoic acid (20 mol%), rt. e 10 mol% of catalyst was used. f 30 mol% of catalyst was
used. g 3 (1.0 equiv), 4 (1.0 equiv), III (20 mol%), Saccharin (40 mol%), 40°C. reaction performed in triplicate. Molecular
h
i
sieves (0.4 g /mmol). Diasteromeric ratio determined by HPLC. Enantiomeric ratio determined by chiral HPLC. l Opposite
configuration was obtained.
j
k
Having determined the optimal conditions, we next examined the scope of the reaction by
reacting enamines 4a-f with enals (±)ꢀ3b-c (Entries 10ꢀ19). Firstly, enamines 4a-d with either
a benzyl, phenyl or nꢀpropyl group reacted efficiently with racemic aldehyde (±)ꢀ3b to lead to
the corresponding 1,4ꢀDHPs 1b-e in 45 to 65% yields and good enantiomeric ratios ranging
from 88:12 to 95:5 (Table 2, entries 10ꢀ13). Comparable yield (56%) and enantiomeric ratios
(er= 90:10 and 91:9) were obtained by reacting enal (±)ꢀ3c possessing an indanone moiety
and enamine (±)ꢀ4a (Table 2, entry 14). Pleasingly, the method was efficiently applied to the
preparation of 1,4ꢀDHPs having an ester or a nitrile functional group at the Cꢀ3 position
(Table 2, entries 15ꢀ19). Thus, when the βꢀenamino ester 4e was reacted with enal (±)ꢀ3c,
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the 1,4ꢀDHP 1g was isolated in 62% yield and an enantiomeric ratio up to 92:8 (Table 2,
4
5
Entry 15).
6
7
8
9
Similarly, the reaction between βꢀenamino nitrile 4f and enal (±)ꢀ3b or (±)ꢀ3c afforded the
corresponding DHPs 1h,i in 45ꢀ52% yields and enantiomeric ratios ranging from 87:13 to
94:6 (Table 2, entries 16ꢀ17). Unsurprisingly, when R-III catalyst was used instead of S-III
catalyst, DHPs 1h,i were obtained with comparable yields (51ꢀ52%) and an inversion of the
enantiomeric ratios ranging from 84:16 to 89:11 (Entries 18ꢀ19).
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To achieve our initial goal, namely the asymmetric synthesis of each of the four
stereoisomers of 1,4ꢀDHP 1a, both enals (S)ꢀ3a and (R)ꢀ3a were prepared in a threeꢀstep
sequence including an enantioselective Tsuji allylation as key step (Scheme 3). Thus, the
required allyl carbonate 6 was prepared in a good yield (71%) by adding allyl chloroformate
to a mixture of αꢀtetralone 2a previously treated with KHMDS and TMEDA in THF at ꢀ78 °C.11
Scheme 3. Synthesis of the four stereoisomers of the target prodrug 1a
The soꢀobtained carbonate 6 was subjected to a palladiumꢀcatalyzed decarboxylative
asymmetric allylic alkylation (PdꢀDAAA) reaction to yield the αꢀallyl ketones 5a.12 So, a
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solution of Pd2(dba)3 and (R,R)ꢀ or (S,S)ꢀANDEN Trost ligand in 1,4ꢀdioxane was stirred for
30 minutes at room temperature prior to cannulation of the resulting mixture into a solution of
allyl carbonate 6. Following this procedure, αꢀallyl ketones (R)ꢀ5a and (S)ꢀ5a were obtained
in very good yields (81ꢀ94%) and high enantiomeric ratios (er= 98:2 and 95:5 respectively).
Both αꢀallyl ketones (R)ꢀ5a and (S)ꢀ5a were subjected to crossꢀmetathesis furnishing enals
(R)ꢀ3a and (S)ꢀ3a in good yields (96 and 83% respectively) without affecting enantiomeric
ratios (er= 98:2 and 95:5 respectively). Lastly, enals (R)ꢀ3a and (S)ꢀ3a were engaged in the
enantioselective organocatalytic azaꢀeneꢀtype domino reaction with enaminone 4a in
presence of (S)ꢀ or (R)ꢀJørgensenꢀHayashi catalyst III and saccharin as cocatalyst (Table 3).
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Table 3. Enantioselective organocatalytic aza-ene type domino reaction with enals (S)- or (R)-3a
er c
major /minor
1aa
Yield (%)b
drc
IC50d (ꢀM)
Entry
3
III
1
2
3
4
(R)ꢀ3a
(S)ꢀ3a
(S)ꢀ3a
(R)ꢀ3a
(S)
(R)
(S)
(R)
(R,R)ꢀ1a
(S,S)ꢀ1a
(S,R)ꢀ1a
(R,S)ꢀ1a
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48
59
42
93:7
92:8
90:10
91:9
98:2
99.5:0.5
99.5:0.5
99:1
nde
0.286
0.173
0.924
Configuration assigned according to the predicted model reported by Kanger7e.
isolated yield.
a
b
c
determined by chiral SFC. d In vitro inhibition test of hAChE. e nd: not determined (% inhibition of hAChE <
50% at 10 ꢄM)
Therefore, using (S)ꢀ or (R)ꢀIII catalyst, enal (R)ꢀ3a afforded, respectively diastereomers
(R,R)ꢀ1a and (R,S)ꢀ1a in good yields (64% and 42% respectively) with excellent
diastereomeric and enantiomeric ratios (dr= 93:7 and er= 98:2; and dr= 91:9 and er= 99:1
respectively). Then, in presence of (S)ꢀ or (R)ꢀIII, enal (S)ꢀ3a led respectively to the formation
of diastereomers (S,R)ꢀ1a and (S,S)ꢀ1a in good yields (59% and 48% respectively) along
with excellent diastereomeric and enantiomeric ratios (dr= 91:9 and er= 99.5:0.5; and dr=
91:9 and er= 99.5:0.5 respectively). Thus, the absolute configuration of the four
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stereoisomers AꢀD previously isolated by chiral super critical fluid chromatography was
assigned affording valuable informations on the structureꢀactivity relationship. Firstly, the
configuration of the chiral center carried by the dihydropyridine moiety appears to have a
minor impact on the inhibitory activity against hAChE (Table 3, entries 1 vs 4 / entries 2 vs 3).
On the contrary, the tetralone’s stereogenic center seems to have a greater influence on the
capacity of 1a to inhibit the enzyme activity. Whereas the diastereomers (S,S)ꢀ1a and (S,R)ꢀ
1a display low IC50 values (Table 3, entries 2 and 3), much weaker inhibitory activity is
observed for the stereomers with the (R) configuration at the carbon atom adjacent to the
carbonyl group of the tetralone (Table 3, entries 1 and 4).
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CONCLUSION
In conclusion, an asymmetric approach toward a family of chiral donepezilꢀlike 1,4ꢀ
dihydropyridines 1, highly soughtꢀafter as antiꢀAlzheimer prodrugs, was developed by
implementing two highly stereoselective key steps; i.e. a catalytic enantioselective Tsuji
allylation from enol carbonate 6 and an enantioselective organocatalytic azaꢀeneꢀtype
domino reaction between enals 3a-c and βꢀenaminones or βꢀenamino esters 4a-f. It should
be noticed that the reaction conditions initially reported by Kanger et al.7e had to be adapted
by means of saccharin as coꢀcatalyst to boost the yield (45ꢀ65%) and dichloroethane as
solvent to increase the enantiomeric ratio of 1,4ꢀDHPs 1 (er up to 95:5). This stereoselective
route toward chiral donepezilꢀlike 1,4ꢀdihydropyridine prodrugs 1 provides a useful extension
of known asymmetric transformations to the development of promising chiral prodrug
4eꢀf
prototypes.
In addition, the opportunity to have a robust access to all stereoisomers of
prodrugs 1 will enable us to accelerate the lead optimization phase while securing the
chemical development of this new class of antiꢀAlzheimer drugs.
EXPERIMENTAL SECTION
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General Information: All commercial reagents were used without further purification. The
solvents were dried with appropriate desiccants and distilled prior to use or were obtained
anhydrous from commercial suppliers. Silica gel (60, 230–400 mesh or 70–230 mesh) was
used for column chromatography. Reactions were monitored by thin layer chromatography
on silica gel precoated aluminium plates. UV light at 254 nm or KMnO4 stains were used to
visualize TLC plates. 1H, 13C{1H} NMR spectra were recorded using a spectrometer operating
at 300 and 75 MHz respectively. Abbreviations used for peak multiplicities are s: singlet, d:
doublet, t: triplet, q: quadruplet, dd: doublet of doublet, br: broad and m: multiplet. Coupling
constants J are in Hz and chemical shifts are given in ppm and calibrated with DMSOꢀd6 or
CDCl3 (residual solvent signals). 1H NMR spectra obtained in CDCl3 were referenced to 7.26
ppm and in DMSOꢀd6 were referenced to 2.50 ppm. 13C{1H} NMR spectra obtained in CDCl3
were referenced to 77.16 ppm. High resolution mass spectra were measured by ESI.
Microwave experiments were conducted in a monomode cavity with a microwave power
delivery system ranging from 0 to 850 W allowing pressurized reactions (0 to 30 bars) to be
carried out in sealed glass vials (4 to 30 mL) equipped a snap cap and a silicon septum. The
temperature (0 to 300 °C) was monitored via a contactꢀless infrared sensor and was
calibrated with a ruby Thermometer. Diasteromeric ratios were determined by reversedꢀ
phase HPLC using Accucore C18 column (150x2.1mm, 2.6 ꢀm, flow= 0.3 mL.minꢀ1) with UV
detection using a gradient (20 to 55%) of acetonitrile in ammonium acetate buffer (20 mM).
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2-allyl-6,7-dimethoxy-tetralone-1-one ((±)-5a). In a microwave vial, to a solution of 2a
(412.5 mg, 2.0 mmol) and allyl alcohol (0.68 mL, 10.0 mmol) in dry toluene (3 mL) were
added freshly distilled 2,2ꢀdimethoxypropane (0.37 mL, 3.0 mmol), pꢀtoluenesulfonic acid
(68.8 mg, 0.4 mmol) and 3 Å molecular sieves (ca. 600 mg). The vial was sealed and heated
in a microwave reactor at 200 °C for 1.5 h. The cooled reaction mixture was diluted with
CH2Cl2 (20 mL) and washed successively with saturated aqueous solution of NaHCO3 and
brine. The combined organic phase was dried over MgSO4 and concentrated to dryness. The
residue was purified by column chromatography (Petroleum ether/EtOAc = 3:1) to afford the
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title compound (±)ꢀ5a as a colorless oil (247.1 mg, 50%). H NMR (300 MHz, CDCl3) δ 7.51
4
5
(s, 1H), 6.64 (s, 1H), 5.91ꢀ5.76 (m, 1H), 5.12ꢀ5.04 (m, 2H), 3.92 (s, 3H), 3.90 (s, 3H), 2.95ꢀ
6
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2.85 (m, 2H), 2.78ꢀ2.71 (m, 1H), 2.55ꢀ2.40 (m, 1H), 2.32ꢀ2.14 (m, 2H), 1.92ꢀ1.78 (m, 1H). 13
C
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NMR (75 MHz, CDCl3) δ 198.4, 153.4, 147.9, 138.9, 136.4, 125.7, 116.8, 110.1, 108.8, 56.0,
55.9, 46.5, 34.2, 28.3, 28.2. HRMS (ESI+) calcd for [M+H]+ C15H19O3 m/z 247.1334, found
247.1323.
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2-allyl-6-methoxy-tetralone-1-one ((±)-5b). To a solution of LiHMDS (4.15 g, 24.8 mmol) in
THF (20 mL) cooled at ꢀ78°C was added slowly a solution of 2b (3.5 g, 19.86 mmol) in dry
THF (60 mL). After the addition was complete, the solution was stirred at ꢀ78°C for 30
minutes, then HMPA (7 mL, 40.2 mmol) was added slowly and stirred for other 5 minutes
followed by the addition of a solution of allyl bromide (2.6 mL, 30.08 mmol) in dry THF (10
mL) at the same temperature. The mixture was left to warm slowly to room temperature (2ꢀ
3h) and quenched at 0°C with aqueous 1N HCl (20 mL), and then extracted with diethyl ether
(3x). The combined organic phase was dried over MgSO4 and concentrated to dryness. The
residue was purified by column chromatography (Petroleum ether/EtOAc = 95:5) to afford the
title compound (±)ꢀ5b as a colorless oil (2.9 g, 68%). 1H NMR (300 MHz, CDCl3) δ 8.01 (d, J
= 8.8 Hz, 1H), 6.82 (dd, J = 8.7, 2.5 Hz, 1H), 6.68 (d, J = 2.4 Hz, 1H), 5.97ꢀ5.73 (m, 1H),
5.13ꢀ5.04 (m, 2H), 3.85 (s, 3H), 2.95ꢀ2.93 (m, 2H), 2.81ꢀ2.67 (m, 1H), 2.58ꢀ2.42 (m, 1H),
2.34ꢀ2.13 (m, 2H), 1.94ꢀ1.74 (m, 1H). 13C NMR (75 MHz, CDCl3) δ 198.4, 163.5, 146.7,
136.6, 130.0, 126.3, 116.9, 113.2, 112.6, 55.6, 46.9, 34.3, 29.1, 28.1. HRMS (ESI+) calcd for
[M+Na]+ C14H16O2Na+ m/z 239.1048, found 239.1043.
2-allyl-5,6-dimethoxy-indan-1-one ((±)-5c). From LiHMDS (0.8 g, 4.78 mmol) in THF (40
mL), 2c (1.0g, 5.2 mmol) in THF (40 mL), HMPA (1.7 mL, 9.56 mmol), allyl bromide (0.86
mL, 7.17 mmol) diluted in THF (5 mL) and following the procedure described for the
synthesis of compound (±)ꢀ5b, the title compound (±)ꢀ5c was obtained as a colorless oil (0.5
g, 46%) after purification by column chromatography on silica gel (Petroleum ether/EtOAc =
2:1). 1H NMR (300 MHz, CDCl3) δ 7.13 (s, 1H), 6.83 (s, 1H), 5.83ꢀ5.68 (m, 1H), 5.13ꢀ5.00 (m,
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2H), 3.93 (s, 3H), 3.87 (s, 3H), 3.15 (dd, J = 17.7, 8.0 Hz, 1H), 2.79ꢀ2.57 (m, 3H), 2.29ꢀ2.12
(m, 1H). 13C NMR (75 MHz, CDCl3) δ 206.9, 155.6, 149.4, 149.1, 135.6, 129.4, 116.9, 107.4,
104.3, 56.2, 56.1, 46.8, 35.8, 31.8. HRMS (ESI+) calcd for [M+H]+ C14H17O3 m/z 233.1178
found 233.1175.
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General procedure for the synthesis of enal derivatives 3a-c: Under Argon atmosphere,
crotonaldehyde (20 mmol) was added to a solution of the corresponding allyl derivative 5a-c
(5.0 mmol) in degassed CH2Cl2 (10.0 mL). HoveydaꢀGrubbs' 2nd (2.5% mol) was then added,
and the reaction mixture was heated to 40 °C overnight. After cooling at room temperature,
the reaction mixture was filtered over Celite® and the filtrate was concentrated to dryness and
purified by column chromatography on silica gel to give the expected aldehydes 3a-c.
(E)-4-(6,7-dimethoxy-1-oxo-tetralon-2-yl)but-2-enal ((±)-3a). From crotonaldehyde (182.0
mg, 2.6 mmol), (±)ꢀ5a (160.0 mg, 0.65 mmol), HoveydaꢀGrubbs' 2nd (10 mg, 5% mol) and
CH2Cl2 (5.0 mL). Purification by column chromatography on silica gel (Petroleum
ether/EtOAc = 1:1) gave (±)ꢀ3a as an offꢀwhite powder (146.0 mg, 82%). 1H NMR (300 MHz,
CDCl3) δ 9.51 (d, J = 7.9 Hz, 1H), 7.49 (s, 1H), 6.98ꢀ6.88 (m, 1H), 6.65 (s, 1H), 6.17 (dd, J =
15.7, 7.9 Hz, 1H), 3.92 (s, 3H), 3.90 (s, 3H), 3.05ꢀ2.85 (m, 3H), 2.71ꢀ2.52 (m, 2H), 2.21ꢀ2.12
(m, 1H), 1.95ꢀ1.78 (m, 1H). 13C NMR (75 MHz, CDCl3) δ 197.1, 193.8, 156.5, 153.6, 148.0,
138.8, 134.5, 125.2, 110.1, 108.6, 56.1, 56.0, 46.0, 33.4, 29.0, 28.5. HRMS (ESI+) calcd for
[M+H]+ C16H19O4 m/z 275.1283, found 275.1279.
(E)-4-(6-methoxy-1-oxo-tetralon-2-yl)but-2-enal ((±)-3b). From crotonaldehyde (1.43 g,
20.3 mmol), (±)ꢀ5b (1.1 g, 5.09 mmol), HoveydaꢀGrubbs' 2nd (80.0 mg, 2.5% mol) and CH2Cl2
(1.0 mL). Purification by column chromatography on silica gel (Petroleum ether/EtOAc = 4:1)
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gave (±)ꢀ3b as an offꢀwhite powder (1.1 g, 88%). H NMR (300 MHz, CDCl3) δ 9.52 (d, J =
7.9 Hz, 1H), 8.02 (d, J = 8.8 Hz, 1H), 7.01ꢀ6.82 (m, 2H), 6.69 (d, J = 2.4 Hz, 1H), 6.19 (dd, J
= 15.6, 7.9 Hz, 1H), 3.86 (s, 3H), 3.04ꢀ2.91 (m, 3H), 2.71ꢀ2.52 (m, 2H), 2.29ꢀ2.09 (m, 1H),
1.99ꢀ1.76 (m, 1H). 13C NMR (75 MHz, CDCl3) δ 197.1, 194.0, 163.8, 156.7, 146.5, 134.7,
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130.1, 125.9, 113.5, 112.6, 55.6, 46.6, 33.5, 29.4, 28.9. HRMS (ESI+) calcd for [M+Na]+
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C15H16O3Na m/z 267.0997 found 267.1003.
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(E)-4-(5,6-dimethoxy-1-oxo-indan-2-yl)but-2-enal ((±)-3c). From crotonaldehyde (0.63 mg,
0.75 mL, 8.99 mmol), (±)ꢀ5c (0.5 g, 2.15 mmol), HoveydaꢀGrubbs' 2nd (17.0 mg, 2.5% mol)
and dichloromethane (15 mL). Purification by column chromatography on silica gel
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(Petroleum ether/EtOAc = 1:1) gave (±)ꢀ3c as an yellow solid (0.51 g, 91%). H NMR (300
MHz, CDCl3) δ 9.51 (d, J = 7.8 Hz, 1H), 7.18 (s, 1H), 7.02ꢀ6.78 (m, 2H), 6.19 (dd, J = 15.7,
7.8 Hz, 1H), 3.97 (s, 3H), 3.92 (s, 3H), 3.27 (dd, J = 16.9, 7.4 Hz, 1H), 3.02ꢀ2.83 (m, 2H),
2.71 (dd, J = 17.0, 3.3 Hz, 1H), 2.62ꢀ2.47 (m, 1H). 13C NMR (75 MHz, CDCl3) δ 205.5, 193.9,
156.1, 155.3, 149.8, 148.7, 134.6, 129.0, 107.5, 104.5, 56.5, 56.3, 46.0, 34.7, 32.1. HRMS
(ESI+) calcd for [M+H]+ C15H17O4 m/z 261.1126, found 261.1131.
General procedure for the synthesis of enamines 4a-f: A mixture of the corresponding
commercial enol ether (5.0 mmol) and commercial amine (5.0 mmol) was heated under
vacuum. The methanol byꢀproduct was eliminated as it forms, affording only the expected
enamines 4a-f which were used without further purification.
(Z)-4-(benzylamino)but-3-en-2-one (4a). From 4ꢀmethoxyꢀ3ꢀbutenꢀ2ꢀone (500.0 mg, 5.0
mmol) and benzylamine (535.0 mg, 5.0 mmol). The mixture was heated to 60°C for 50 min to
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give enaminone 4a as an yellow oil (875.0 mg, 100%). H NMR (300 MHz, CDCl3) δ 10.07
(br s, 1H), 7.37ꢀ7.24 (m, 5H), 6.71 (dd, J = 12.7, 7.4 Hz, 1H), 5.06 (d, J = 7.4 Hz, 1H), 4.38
(d, J = 6.1 Hz, 2H), 2.08 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 197.8, 152.4, 138.0, 128.9,
128.8, 127.8, 127.5, 127.1, 94.5, 52.5, 29.1. HRMS (ESI+), calcd for C11H14NO 176.10699
found 176.10685.
(Z)-4-((2-methylbenzyl)amino)but-3-en-2-one (4b). From 4ꢀmethoxyꢀ3ꢀbutenꢀ2ꢀone (801.0
mg, 8.0 mmol) and 2ꢀmethylbenzylamine (969.0 g, 8.0 mmol). The mixture was heated to
1
60°C for 30 min to give enaminone 4b as an yellow oil (1.50 mg, 99%). H NMR (300 MHz,
CDCl3) δ 10.05 (s, 1H), 7.25ꢀ7.02 (m, 4H), 6.67 (dd, J = 12.7, 7.4 Hz, 1H), 5.04 (d, J = 7.4
Hz, 1H), 4.35 (d, J = 5.9 Hz, 2H), 2.31 (s, 3H), 2.06 (s, 3H). 13C NMR (75 MHz, CDCl3) δ
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197.8, 152.3, 136.0, 135.8, 130.7, 128.0, 127.9, 126.5, 94.5, 50.7, 29.2, 19.2. HRMS (ESI+)
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calcd for [M+H]+ C12H16NO m/z 190.1231, found 190.1232.
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(Z)-4-(phenylamino)but-3-en-2-one (4c). From 4ꢀmethoxyꢀ3ꢀbutenꢀ2ꢀone (1.0 g, 10.0 mmol)
and aniline (931.0 mg, 10.0 mmol). The mixture was heated to 60°C for 40 min to give
enaminone 4c as a red oil (1.52 g, 94%). 1H NMR (300 MHz, CDCl3) δ 11.60 (br s, 1H), 7.33ꢀ
7.18 (m, 3H), 7.06ꢀ7.00 (m, 3H), 5.29 (d, J = 7.7 Hz, 1H), 2.15 (s, 3H). 13C NMR (75 MHz,
CDCl3) δ 199.0, 143.1, 140.4, 129.8, 123.5, 116.2, 97.5, 29.7. HRMS (ESI+) calcd for [M+H]+
C10H12NO m/z 162.0919, found 162.0911.
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(Z)-4-(propylamino)but-3-en-2-one (4d). From 4ꢀmethoxyꢀ3ꢀbutenꢀ2ꢀone (1.0 g, 10.0 mmol)
and nꢀpropylamine (591.0 mg, 10.0 mmol). The mixture was heated to 60 °C for 2h to give
1
enaminone 4d as a deep orange oil (1.25 g, 98%). H NMR (300 MHz, CDCl3) δ 9.81 ( br s,
1H), 6.62 (dd, J = 12.8, 7.3 Hz, 1H), 4.94 (d, J = 7.3 Hz, 1H), 3.15ꢀ3.09 (m, 2H), 2.02 (s, 3H),
1.65ꢀ1.46 (m, 2H), 0.91 (t, J = 7.4 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 197.3, 152.8, 93.5,
50.9, 29.0, 24.4, 11.2. HRMS (ESI+) calcd for [M+H]+ C7H14NO m/z 128.1075, found
128.1075.
(E)- and (Z)-methyl 3-((2-methylbenzyl)amino)acrylate (4e). From methyl transꢀ3ꢀ
methoxyacrylate (581.0 mg, 5.0 mmol) and 2ꢀmethylbenzylamine (606.0 g, 5.0 mmol). The
mixture was heated to 60°C for 16h to give compound 4e (Z/E = 1:1) as an offꢀwhite gel
1
(875.0 mg, 85%). H NMR (300 MHz, CDCl3) δ 8.06 (s, 0.5H), 7.58 (dd, J = 13.3, 7.8 Hz,
0.5H), 7.22ꢀ7.14 (m, 4H), 6.66 (dd, J = 13.1, 8.0 Hz, 0.5H), 4.82 (d, J = 13.2 Hz, 0.5H), 4.60
(br s, 0.5H), 4.54 (d, J = 8.0 Hz, 0.5H), 4.33 (d, J = 5.8 Hz, 1H), 4.17 (d, J = 5.2 Hz, 1H), 3.66
(s, 1.5H), 3.64 (s, 1.5H), 2.31 (s, 1.5H), 2.31 (s, 1.5H). 13C NMR (75 MHz, CDCl3) δ 171.2,
170.0, 152.2, 136.6, 136.3, 136.0, 130.8, 130.6, 128.6, 128.3, 127.9, 127.8, 126.5, 126.4,
82.4, 50.7, 50.4, 50.3, 43.6, 19.2, 19.0. HRMS (ESI+) calcd for [M+H]+ C12H16NO2 m/z
206.1181, found 206.1174.
(Z)-3-(benzylamino)acrylonitrile (4f). From 3ꢀmethoxyacrilonitrile (415.0 mg, 2.0 mmol) and
benzylamine (535.0 mg, 5.0 mmol). The mixture was heated to 110 °C for 4h to give a yellow
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oil (789.0 mg, 100%). 1H NMR (300 MHz, CDCl3) δ 7.40ꢀ7.28 (m, 5H), 7.11 (dd, J = 13.8, 7.5
Hz, 1H), 4.58 (br s, 1H), 4.17 (d, J = 5.4 Hz, 2H), 4.03 (d, J = 13.8 Hz, 1H). 13C NMR (75
MHz, CDCl3) δ 151.0, 136.3, 128.5, 127.5, 127.1, 122.2, 61.3, 47.2. HRMS (ESI+) calcd for
[M+H]+ C10H11N2 m/z 159.0922, found 159.0924.
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General procedure for the synthesis of 1,4-DHPs 1a-g by scandium triflate catalysis
(Method A). To a suspension of Sc(OTf)3 (49.1 mg, 10 mol%), Na2SO4 (0.42 g, 3 equiv) in
dry CH2Cl2 (3.5 mL) were added a solution of enamine freshly prepared 4a-f (1.0 mmol, 1
equiv) and enal (±)ꢀ3a-c (1.0 mmol, 1 equiv) in dry CH2Cl2 (1.5 mL). The mixture was stirred
at room temperature (21°C) until total consumption of enal (TLC). The reaction solution was
filtered on Celite® and concentrated under vacuum. The crude residue was purified by
column chromatography on silica gel to afford the 1,4ꢀDHPs 1a-g.
General procedure for the synthesis of 1,4-DHPs 1a-i by enantioselective
aminocatalysis (Method B). Under argon atmosphere, a mixture of the enal 3a-c (1.0
mmol, 1 equiv), saccharin (73.2 mg, 40 mol%), (R)ꢀ or (S)ꢀIII (65.1 mg, 20 mol%) and the
enamine 4a-f (1.0 mmol, 1 equiv) in dry dichloroethane (0.25M) was stirred at 40°C until total
consumption of enal (TLC). Upon completion of the reaction and cooling to room
temperature, the mixture was diluted with dichloromethane. The resulting solution was then
filtered over Celite® and concentrated to dryness. The crude residue was directly purified
column chromatography on silica gel to give the desired 1,4ꢀdihydropyridines 1a-i.
2-((3-acetyl-1-benzyl-1,4-dihydropyridin-4-yl)methyl)-6,7-dimethoxy-3,4-
dihydronaphthalen-1(2H)-one (1a). Method A: From enamine 4a (140. mg, 0.8 mmol), (±)ꢀ
3a (242.0 mg, 0.88 mmol). Purification by column chromatography on silica gel (EtOAc
gradient in petroleum ether) gave 1a as a yellow oil (118.1 mg, 62%). Method B: From
enamine 4a (70.1 mg, 0.4 mmol), (±)ꢀ3a (110.0 mg, 0.4 mmol) and (S)ꢀIII (20 mol%).
Purification by column chromatography on silica gel (EtOAc gradient in petroleum ether)
gave the enantioꢀenriched DHP 1a (103.5 mg, 60%). HPLC Chiralpak® IE column; 60/33/7
heptane/DCM/isopropanol; flow rate = 1 mL.minꢀ1; t1 = 26.07 min (minor), t2 = 28.4 min
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(minor), t3 = 30.4 min (major), t4 = 43.1 min (major); dr = 60:40; er major = 95:5; er minor =
85:5. 1H NMR (300 MHz, CDCl3) δ 7.51 (s, 0.5H), 7.49 (s, 0.5H), 7.47ꢀ7.11 (m, 6H), 6.65 (s,
0.5H), 6.62 (s, 0.5H), 5.98ꢀ5.93 (m, 1H), 5.09ꢀ5.04 (m, 1H), 4.45 (s, 1H), 4.44 (s, 1H), 3.91
(s, 3H), 3.88 (s, 3H), 3.73ꢀ3.68 (m, 1H), 3.21ꢀ3.08 (m, 0.5H), 2.91ꢀ2.84 (m, 1.5H), 2.73ꢀ2.64
(m, 0.5H), 2.60ꢀ2.48 (m, 0.5H), 2.40ꢀ2.05 (m, 5H), 1.95ꢀ1.81 (m, 1H), 1.65ꢀ1.51 (m, 0.5H),
1.44ꢀ1.32 (m, 0.5H). 13C NMR (75 MHz, CDCl3) δ 199.9, 199.7, 195.4, 194.2, 153.2, 153.1,
147.7, 142.9, 142.8, 138.9, 138.7, 136.8, 136.7, 128.9, 128.0, 127.9, 127.8, 126.9, 126.8,
125.6, 125.3, 113.7, 113.3, 110.2, 110.1, 108.7, 108.6, 108.2, 57.8, 57.7, 56.0, 55.9, 43.4,
42.3, 38.1, 37.7, 29.4, 28.3, 28.1, 27.2, 26.8, 24.6, 24.4. HRMS (ESI+) calcd for [M+H]+
C27H30NO4 m/z 432.2175, found 432.2182.
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2-((3-acetyl-1-benzyl-1,4-dihydropyridin-4-yl)methyl)-6-methoxy-3,4-
dihydronaphthalen-1(2H)-one (1b). Method A: From enamine 4a (140.0 mg, 0.8 mmol),
(±)ꢀ3b (200.0 mg, 0.8 mmol). Purification by column chromatography on silica gel (EtOAc
gradient in Petroleum ether) gave 1b as a yellow oil (110.0 mg, 35%). Method B: From
enamine 4a (71.8 mg, 0.41 mmol), (±)ꢀ3a (102.6 mg, 0.42 mmol) and (S)ꢀIII (20 mol%).
Purification by column chromatography on silica gel (EtOAc gradient in petroleum ether)
gave the enantioꢀenriched DHP 1b (74.1 mg, 45%). HPLC analytic separation: Chiralpak® IC
column; 80/20 heptane/ethanol; flow rate = 1 mL.minꢀ1; t1 = 28.08 min (major), t2 = 32.6 min
(minor), t3 = 34.6 min (major), t4 = 37.3 min (minor); dr = 52:48; er major = 93:7; er minor =
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93:7. H NMR (300 MHz, CDCl3) δ 7.96ꢀ7.92 (m, 1H), 7.41ꢀ7.16 (m, 6H), 6.82ꢀ6.78 (m, 1H),
6.71ꢀ6.68 (m, 1H), 5.97ꢀ5.92 (m, 1H), 5.08ꢀ5.02 (m, 1H), 4.47 (s, 2H), 3.81 (s, 3H), 3.73ꢀ3.63
(m, 1H), 3.13 (ddd, J = 16.8, 7.1, 4.3 Hz, 0.5H), 2.91ꢀ2.79 (m, 1.5H), 2.72ꢀ2.60 (m, 0.5H),
2.57ꢀ2.47 (m, 0.5H), 2.39ꢀ2.22 (m, 1H), 2.19 (s, 1.5H), 2.16 (s, 1.5H), 2.15ꢀ1.74 (m, 2H),
1.63ꢀ1.50 (m, 0.5H), 1.45ꢀ1.36 (m, 0.5H). 13C NMR (75 MHz, CDCl3) δ 199.9, 199.8, 195.6,
195.0, 163.3, 163.2, 146.7, 146.6, 143.1, 142.9, 136.8, 136.8, 129.8, 129.0, 129.0, 128.1,
128.0, 127.98, 127.0, 126.9, 126.2, 113.8, 113.3, 113.1, 113.0, 112.3, 110.2, 108.3, 57.9,
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57.8, 55.4, 43.9, 42.7, 38.1, 37.7, 29.2, 28.9, 28.3, 28.1, 27.7, 27.0, 24.7, 24.5. HRMS (ESI+)
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2-((3-acetyl-1-(2-methylbenzyl)-1,4-dihydropyridin-4-yl)methyl)-6-methoxy-3,4-
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dihydronaphthalen-1(2H)-one (1c). Method A: From enamine 4b (140. mg, 1.1 mmol), (±)ꢀ
3b (266.0 mg, 1.1 mmol). Purification by column chromatography on silica gel (EtOAc
gradient in petroleum ether) gave 1c as a yellow oil (269.6 mg, 59%). Method B: From
enamine 4b (94.6 mg, 0.50 mmol), (±)ꢀ3b (122.0 mg, 0.50 mmol) and (S)ꢀIII (20 mol%).
Purification by column chromatography on silica gel (EtOAc gradient in petroleum ether)
gave the enantioꢀenriched DHP 1c (207.6 mg, 55%). HPLC Chiralpak® IAꢀ3 column; 90/10
heptane/(isopropanol/ethanol = 1:1); flow rate = 1.5 mL.minꢀ1; t1 = 19.94 min (minor), t2 =
23.1 min (minor), t3 = 26.8 min (major), t4 = 37.6 min (major); dr = 52:48; er major = 92:8; er
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minor = 95:5. H NMR (300 MHz, CDCl3) δ 7.97ꢀ7.91 (m, 1H), 7.25ꢀ7.03 (m, 5H), 6.79ꢀ6.75
(m, 1H), 6.67ꢀ6.64 (m, 1H), 5.91ꢀ5.86 (m, 1H), 5.05ꢀ5.00 (m, 1H), 4.43 (s, 1H), 4.41 (s, 1H),
3.83 (s, 3H), 3.70ꢀ3.65 (m, 1H), 3.19ꢀ3.05 (m, 0.5H), 2.98ꢀ2.78 (m, 1.5H), 2.72ꢀ2.58 (m,
0.5H), 2.58ꢀ2.44 (m, 0.5H), 2.43ꢀ2.25 (m, 1H), 2.28 (s, 3H), 2.15 (s, 1.5H), 2.12 (s, 1.5H),
2.12ꢀ1.98 (m, 1H), 1.92ꢀ1.82 (m, 1H), 1.68ꢀ1.45 (m, 0.5), 1.43ꢀ1.37 (m, 0.5H). 13C NMR (75
MHz, CDCl3) δ 199.9, 199.7, 195.6, 195.0, 163.3, 163.2, 146.7, 146.6, 143.0, 142.8, 135.9,
134.5, 134.4, 130.8, 129.7, 128.2, 128.1, 127.9, 127.6, 126.6, 126.5, 126.4, 126.0, 113.8,
113.4, 113.1, 113.0, 112.4, 110.1, 108.2, 56.0, 55.9, 55.4, 43.9, 42.8, 38.4, 37.9, 29.1, 28.9,
28.4, 28.2, 27.7, 27.0, 24.6, 24.4, 19.2. HRMS (ESI+) calcd for [M+H]+ C27H30NO3 m/z
416.2226 found 416.2227.
2-((3-acetyl-1-phenyl-1,4-dihydropyridin-4-yl)methyl)-6-methoxy-3,4-
dihydronaphthalen-1(2H)-one (1d). Method A: From enamine 4c (161.4. mg, 1.1 mmol),
(±)ꢀ3b (268.2 mg, 1.1 mmol). Purification by column chromatography on silica gel (EtOAc
gradient in petroleum ether) gave 1d as a yellow oil (277.0 mg, 65%). Method B: From
enamine 4c (80.6 mg, 0.50 mmol), (±)ꢀ3b (122.0 mg, 0.50 mmol) and (S)ꢀIII (20 mol%).
Purification by column chromatography on silica gel (EtOAc gradient in petroleum ether)
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gave the enantioꢀenriched DHP 1d (91.4 mg, 47%). HPLC Chiralpak® IAꢀ3 column; 80/20
heptane/(isopropanol/ethanol = 1:1); flow rate = 1.0 mL.minꢀ1; t1 = 15.8 min (major), t2 = 18.0
min (minor), t3 = 22.6 min (major), t4 = 24.6 min (minor); dr = 57:43; er major = 89:11; er
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minor = 88:12. H NMR (300 MHz, CDCl3) δ 7.96 (d, J = 8.7 Hz, 0.5H), 7.95 (d, J = 8.7 Hz,
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0.5H), 7.51 (s, 0.5H), 7.46 (s, 0.5H), 7.40ꢀ7.35 (m, 2H), 7.21ꢀ7.15 (m, 3H), 6.79ꢀ6.75 (m, 1H),
6.68 (d, J = 2.4 Hz, 0.5H), 6.65 (d, J = 2.4 Hz, 0.5H), 6.47ꢀ6.41 (m, 1H), 5.21ꢀ5.16 (m, 1H),
3.82 (s, 1.5H), 3.81 (s, 1.5H), 3.76ꢀ3.66 (m, 1H), 3.21ꢀ3.08 (m, 0.5H), 2.97ꢀ2.84 (m, 1.5H),
2.75ꢀ2.64 (m, 0.5H), 2.62ꢀ2.51 (m, 0.5H), 2.45ꢀ2.18 (m, 3H), 2.26 (s, 1.5H), 2.23 (s, 1.5H),
1.69ꢀ1.57 (m, 0.5H), 1.54ꢀ1.40 (m, 0.5H). 13C NMR (75 MHz, CDCl3) δ 199.8, 199.6, 196.2,
195.6, 163.4, 163.3, 146.6, 146.5, 143.8, 140.0 139.9, 129.9, 129.8, 126.6, 126.3, 126.2,
126.0, 125.4, 125.3, 120.1, 120.0, 116.7, 116.5, 113.2, 113.0, 112.4, 111.4, 109.6, 55.4,
44.0, 43.0, 38.3, 37.9, 29.2, 28.9, 28.5, 28.3, 27.8, 27.1, 24.9, 24.7. HRMS (ESI+) calcd for
[M+H]+ C25H26NO3 m/z 388.1913, found 388.1907.
2-((3-acetyl-1-propyl-1,4-dihydropyridin-4-yl)methyl)-6-methoxy-3,4-
dihydronaphthalen-1(2H)-one (1e). Method A: From enamine 4d (63.6 mg, 0.5 mmol), (±)ꢀ
3b (122.0 mg, 0.5 mmol). Purification by column chromatography on silica gel (EtOAc
gradient in petroleum ether) gave 1e as a yellow oil (79.6 mg, 45%). Method B: From
enamine 4d (104.3 mg, 0.82 mmol), (±)ꢀ3b (200.0 mg, 0.82 mmol) and (S)ꢀIII (20 mol%).
Purification by column chromatography on silica gel (EtOAc gradient in petroleum ether)
gave the enantioꢀenriched DHP 1e (188.3 mg, 65%). HPLC Chiralpak® IB column; 80/20
heptane/isopropanol; flow rate = 1.0 mL.minꢀ1; t1 = 8.8 min (major), t2 = 10.8 min (minor), t3 =
11.4 min (major), t4 = 12.3 min (minor); dr = 55:45, er major = 92:8; er minor = 91:9. 1H NMR
(300 MHz, CDCl3) δ 7.96 (d, J = 8.7 Hz, 0.5H), 7.93 (d, J = 8.7 Hz, 0.5H), 7.07 (s, 0.5H), 7.01
(s, 0.5H), 6.78ꢀ6.75 (m, 1H), 6.67ꢀ6.64 (m, 1H), 5.91ꢀ5.86 (m, 1H), 5.07ꢀ4.90 (m, 1H), 3.81
(s, 3H), 3.70ꢀ3.48 (m, 1H), 3.31ꢀ3.01 (m, 2.5H), 2.89 (m, 1.5H), 2.70ꢀ2.58 (m, 0.5H), 2.52ꢀ
2.38 (m, 1H), 2.28ꢀ2.23 (m, 0.5H), 2.18 (s, 1.5H), 2.15 (s, 1.5H), 2.09ꢀ1.94 (m, 1H), 1.81ꢀ1.73
(m, 1H), 1.68ꢀ1.48 (m, 2.5H), 1.34ꢀ1.28 (m, 0.5H), 0.92 (t, J = 7.3 Hz, 3H). 13C NMR (75
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MHz, CDCl3) δ 200.1, 199.9, 195.4, 194.8, 163.4, 163.3, 146.8, 146.7, 143.0, 142.9, 129.8,
127.9, 127.7, 126.3, 126.1, 113.2, 113.0, 112.5, 112.4, 109.9, 108.0, 56.4, 55.5, 43.9, 42.8,
38.3, 37.8, 29.1, 29.0, 28.2, 28.1, 27.6, 26.9, 24.7, 24.5, 23.6, 23.5, 11.0. HRMS (ESI+) calcd
for [M+H]+ C22H28NO3 m/z 354.2069, found 354.2069.
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2-((3-acetyl-1-benzyl-4H-pyridin-4-yl)methyl)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one
(1f). Method A: From enamine 4a (84.1 mg, 0.48 mmol), (±)ꢀ3c (122.3 mg, 0.47 mmol).
Purification by column chromatography on silica gel (EtOAc gradient in petroleum ether)
gave 1f as a yellow oil (107.9 mg, 55%). Method B: From enamine 4a (175.2 mg, 1.0 mmol),
(±)ꢀ3c (260.1 mg, 1.0 mmol) and (S)ꢀIII (20 mol%). Purification by column chromatography on
silica gel (EtOAc gradient in petroleum ether) gave the enantioꢀenriched DHP 1f (233.7 mg,
56%). HPLC Chiralpak® IC column; 40/50/10 heptane/DCM/isopropanol; flow rate = 1.0
mL.minꢀ1; t1 = 9.4 min (major), t2 = 15.2 min (minor), t3 = 16.9 min (major), t4 = 19.2 min
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(minor); dr = 53:47; er major = 89:11; er minor = 90:10. H NMR (300 MHz, CDCl3) δ 7.44ꢀ
7.11 (m, 7H), 6.88 (s, 0.5H), 6.84 (s, 0.5H), 6.01ꢀ5.91 (m, 1H), 5.12 (dd, J = 7.6, 5.2 Hz,
0.5H), 4.95 (dd, J = 7.6, 5.5 Hz, 0.5H), 4.47 (s, 2H), 3.96 (s, 3H), 3.90 (s, 3H), 3.78ꢀ3.71 (m,
0.5H), 3.68ꢀ3.64 (m, 0.5H), 3.33ꢀ3.02 (m, 1.5H), 2.85ꢀ2.61 (m, 1.5H), 2.22 (s, 1.5H), 2.17 (s,
1.5H), 2.00ꢀ1.88 (m, 1H), 1.58ꢀ1.36 (m, 1H).13C NMR (75 MHz, CDCl3) δ 208.5, 208.3, 195.5,
194.95, 155.5, 155.4, 149.7, 149.4, 143.3, 142.8, 136.8, 129.5, 129.2, 129.1, 128.3, 128.2,
127.1, 127.0, 114.0, 113.3, 110.1, 108.5, 107.7, 107.5, 104.4, 104.3, 58.0, 57.9, 56.3, 56.2,
45.2, 44.2, 41.2, 40.4, 34.0, 32.7, 29.8, 29.4, 24.7, 24.6. HRMS (ESI+) calcd for [M+H]+
C26H28NO4 m/z 418.2018, found 418.2021.
Methyl 4-((5,6-dimethoxy-1-oxo-2,3-dihydro-1H-inden-2-yl)methyl)-1-(2-methylbenzyl)-
1,4-dihydropyridine-3-carboxylate (1g). Method A: From enamine 4f (133.4 mg, 0.65
mmol), (±)ꢀ3c (161.0 mg, 0.62 mmol). Purification by column chromatography on silica gel
(EtOAc gradient in petroleum ether) gave 1g as a yellow oil (304.3 mg, 68%). Method B:
From enamine 4f (98.5 mg, 0.48 mmol), (±)ꢀ3c (125.1 mg, 0.48 mmol) and (S)ꢀIII (20 mol%).
Purification by column chromatography on silica gel (EtOAc gradient in petroleum ether)
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gave the enantioꢀenriched DHP 1g (124.6 mg, 58%). HPLC Chiralpak® IAꢀ3 column; 80/20
heptane/(isopropanol/ethanol = 1:1); flow rate = 1.0 mL.minꢀ1; t1 = 16.6 min (major), t2 = 19.2
min (minor), t3 = 24.1 min (major), t4 = 26.0 min (minor); dr = 51:49; er major = 92:8; er minor
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= 92:8. H NMR (300 MHz, CDCl3) δ 7.28ꢀ7.16 (m, 6H), 6.87 (s, 0.55H), 6.85 (s, 0.45H),
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5.96ꢀ5.86 (m, 1H), 5.01 (dd, J = 7.8, 5.1 Hz, 0.55H), 4.84 (dd, J = 7.5, 5.1 Hz, 0.45H), 4.40
(s, 1.1H), 4.39 (s, 0.9H), 3.98 (s, 3H), 3.90 (s, 3H), 3.70 (s, 1.35H), 3.67 (s, 1.65H), 3.55ꢀ3.49
(m, 0.45H), 3.33ꢀ3.18 (m, 1.55H), 3.01ꢀ2.72 (m, 2H), 2.31 (s, 1.65H), 2.30 (s, 1.35H), 2.13ꢀ
1.98 (m, 1H), 1.64ꢀ1.45 (m, 1H). 13C NMR (75 MHz, CDCl3) δ 208.4, 208.2, 168.9, 168.5,
155.5, 155.4, 149.6, 149.5, 149.4, 149.3, 142.0, 141.5, 136.2, 136.1, 134.8, 134.7, 130.8,
129.5, 128.8, 128.5, 128.1, 127.8, 126.5, 108.2, 107.6, 107.5, 106.7, 104.4, 101.6, 101.3,
56.3, 56.2, 51.1, 51.0, 45.1, 44.1, 41.8, 40.5, 34.3, 32.8, 30.8, 30.6, 29.8, 19.3, 19.2. HRMS
(ESI+) calcd for [M+H]+ C27H30NO5 m/z 448.2124, found 448.2111.
1-benzyl-4-((5,6-dimethoxy-1-oxo-2,3-dihydro-1H-inden-2-yl)methyl)-1,4-
dihydropyridine-3-carbonitrile (1h). Method B: From enamine 4f (77.5 mg, 0.49 mmol),
(±)ꢀ3c (128.0 mg, 0.49 mmol) and (S)ꢀIII (20 mol%) (or (R)ꢀIII). Purification by column
chromatography on silica gel (EtOAc gradient in petroleum ether) gave the enantioꢀenriched
DHP 1h as a yellow oil (105.9 mg, 54%). HPLC Chiralpak® IE column; 60/33/7
heptane/DCM/isopropanol; flow rate = 1 mL.minꢀ1; t1 = 15.4 min (major), t2 = 17.5 min
(minor), t3 = 20.1 min (major), t4 = 21.8 min (minor); With (S)ꢀIII : dr = 50:40; er major = 88:12;
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er minor = 94:6; With (R)ꢀIII : dr = 55:45; er major = 85:15; er minor = 85:15. H NMR (300
MHz, CDCl3) δ 7.53ꢀ7.24 (m, 6H), 6.96 (s, 1H), 6.78 (m, 1H), 5.98 (m, 1H), 4.94 (dd, J = 8.1,
4.4 Hz, 0.5H), 4.84 (dd, J = 8.0, 4.4 Hz, 0.5H), 4.43 (s, 1H), 4.42 (s, 1H), 4.06 (s, 3H), 4.00
(s, 3H), 3.64ꢀ3.57 (m, 0.5H), 3.47ꢀ3.30 (m, 1.5H), 3.13ꢀ2.82 (m, 2H), 2.40ꢀ2.21 (m, 1H), 1.80ꢀ
1.65 (m, 1H). 13C NMR (75 MHz, CDCl3) δ 207.6, 207.2, 155.6, 155.5, 149.6, 149.5, 149.3,
148.9, 143.4, 143.0, 136.3, 136.2, 129.2, 129.1, 128.9, 128.4, 128.3, 128.3, 127.2, 127.1,
121.6, 121.2, 107.5, 107.4, 106.2, 105.0, 104.4, 104.3, 82.9, 82.5, 57.6, 57.5, 56.4, 56.2,
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m/z 401.1865, found 401.1852.
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1-benzyl-4-((6-methoxy-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)methyl)-1,4-
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dihydropyridine-3-carbonitrile (1i). Method B: From enamine 4f (79.1 mg, 0.5 mmol), (±)ꢀ
3b (122.1 mg, 0.5 mmol) and (S)ꢀIII (20 mol%) (or (R)ꢀIII (20 mol%)). Purification by column
chromatography on silica gel (EtOAc gradient in petroleum ether) gave the enantioꢀenriched
DHP 1i as a yellow oil (101.0 mg, 52%). HPLC Chiralpak® IE column; 60/33/7
heptane/DCM/isopropanol; flow rate = 1 mL.minꢀ1; t1 = 12.7 min (major), t2 = 13.9 min
(major), t3 = 16.4 min (minor), t4 = 17.5 min (minor); With (S)ꢀIII : dr = 55:45; er major = 87:13;
er minor = 90:10; With (R)ꢀIII : dr = 58:42; er major = 86:14; er minor = 89:11. 1H NMR (300
MHz, CDCl3) δ 7.99 (d, J = 2.9 Hz, 0.5H), 7.96 (d, J = 3.0 Hz, 0.5H), 7.39ꢀ7.29 (m, 3H), 7.21ꢀ
7.15 (m, 2H), 6.83ꢀ6.79 (m, 1H), 6.70ꢀ6.62 (m, 2H), 5.88ꢀ5.79 (m, 1H), 4.81ꢀ4.77 (m, 1H),
4.31 (s, 1H), 4.30 (s, 1H), 3.85 (s, 1.5H), 3.84 (s, 1.5H), 3.47ꢀ3.30 (m, 1H), 3.00ꢀ2.89 (m,
2H), 2.88ꢀ2.76 (m, 0.5H), 2.72ꢀ2.62 (m, 0.5H), 2.40ꢀ2.15 (m, 2H), 1.96ꢀ1.80 (1H), 1.69ꢀ1.47
(m, 1H). 13C NMR (75 MHz, CDCl3) δ 198.9, 198.8, 163.5, 163.4, 146.4, 146.3, 143.3, 142.9,
136.4, 129.9, 129.1, 129.0, 128.3, 128.2, 127.1, 113.3, 113.2, 112.4, 106.4, 105.3, 82.9,
82.2, 57.5, 57.4, 55.5, 43.1, 43.0, 39.3, 38.2, 31.2, 31.1, 31.0, 29.4, 29.0, 28.6, 28.4. HRMS
(ESI+) calcd for [M+H]+ C25H25N2O2 m/z 385.1916, found 385.1917.
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Allyl (6,7-dimethoxy-3,4-dihydronaphthalen-1-yl) carbonate (6). To a solution of KHMDS
(1.0 M solution in THF, 1.5 g, 5.82 mmol) and TMEDA (0.88 mL, 5.82 mmol) cooled at ꢀ78 °C
was added dropwise a solution of 6,7ꢀdimethoxyꢀ1ꢀtetralone 2a (1.0 g, 4.85 mmol) in 10 mL
of dry THF over a period of 30 minutes. The mixture was stirred at this temperature for 1
hour, and then was diluted with 10 mL of dry THF. When the temperature was settled at ꢀ78
°C, allyl chloroformate (0.62 mL, 6.64 mmol) was added slowly over the slurry and left to stir
for 30 minutes. The reaction was quenched with saturated aqueous NH4Cl, then extracted 3
times with diethyl ether. The combined extracts were dried over MgSO4 and concentrated in
vacuum. The crude residue was purified by column chromatography on silica gel (Petroleum
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ether/EtOAc = 3:1) to give the title enol carbonate 6 as a colorless oil (1.0 g, 71%). 1H NMR
(300 MHz, CDCl3) δ 6.74 (s, 1H), 6.69 (s, 1H), 6.03ꢀ5.95 (m, 1H), 5.69 (t, J = 4.7 Hz, 1H),
5.40 (ddd, J = 17.2, 2.8, 1.4 Hz, 1H), 5.30 (dd, J = 10.4, 1.2 Hz, 1H), 4.70 (dt, J = 5.8, 1.2 Hz,
2H), 3.86 (s, 3H), 3.83 (s, 3H), 2.78 (t, J = 8.2 Hz, 2H), 2.47ꢀ2.37 (m, 2H). 13C NMR (75 MHz,
CDCl3) δ 153.4, 148.8, 147.5, 146.0, 131.4, 129.4, 123.0, 119.4, 112.7, 111.5, 104.9, 69.0,
56.2, 56.1, 27.2, 22.2. HRMS (ESI+) calcd for [M+H]+ C16H19O5 m/z 291.1232, found
291.1223.
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General procedure for Pd-DAAA: Two ovenꢀdried 5 mL vials were individually charged with
a magnetic stirring bar. One vial was loaded with Pd2(dba)3CHCl3 (2.5 mol%) and the
corresponding chiral Anden Trost ligand (5.5 mol%); the other one was loaded with the
corresponding enol carbonate 6 (0.35 mmol). The vials were sealed and connected with a
transfer cannula. The system flushed with argon, then 1.0 mL of degassed dry 1,4ꢀdioxane
was added to both vials. After stirring for 20 min, the deep red solution containing the catalyst
was transferred via cannula into the vial containing the enol carbonate 6, and stirring was
continued for other 2 hours. The reaction mixture was concentrated in vacuo and the residue
was purified by column chromatography on silica gel to afford the title compound. The
attribution of the configuration of the novel stereocenter was done in accordance with the
literature data.
(R)-2-allyl-6,7-dimethoxy-tetralone-1-one ((R)-5a). From 6 (100.0 mg, 0.35 mmol),
Pd2(dba)3CHCl3 (15 mg, 2.5 mol %), (R,R)-Anden Trost ligand (26.0 mg, 5.5 mol %) and
2x1.0 mL of degassed dry 1,4ꢀdioxane. Purification by column chromatography on silica gel
(Petroleum ether/EtOAc = 49:1) afforded the title compound (77.0 mg, 94%) as yellowish oil.
Spectral data (1H and 13C NMR) were identical to the racemic compound. HPLC (Chiralpak®
IC column; 95:5 Heptane / Isopropanol; flow rate = 1 mL.minꢀ1; t1 = 16.44 min (minor), t2 =
19.49 min (major), 96% ee).
(S)-2-allyl-6,7-dimethoxy-tetralone-1-one ((S)-5a). From 6 (300.0 mg, 1.03 mmol),
Pd2(dba)3CHCl3 (45.0 mg, 2.5 mol %) (S,S)-Anden Trost ligand (78.0 mg, 5.5 mol %) and 2 x
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3 mL of degassed dry 1,4ꢀdioxane. Purification by column chromatography on silica gel
(petroleum ether/EtOAc = 49:1) afforded the title compound (200.0 mg, 81%) as yellowish oil.
Spectral data (1H and 13C NMR) was identical to the racemic compound. HPLC (Chiralpak®
IC column; 95:5 Heptane / Isopropanol; flow rate = 1 mL.minꢀ1; t1 = 16.33 min (major), t2 =
19.6 min (minor), 90% ee).
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(R,E)-4-(6,7-dimethoxy-1-oxo-tetralon-2-yl)but-2-enal ((R)-3a). Following the general
procedure for the metathesis reaction, from crotonaldehyde (91.0 mg, 1.29 mmol), (R)-5a
(70.0 mg, 0.32 mmol), HoveydaꢀGrubbs' 2nd (5 mg, 2.5% mol) and CH2Cl2 (3.0 mL).
Purification by column chromatography on silica gel (Petroleum ether/EtOAc = 1:1) gave an
offꢀwhite powder (76.0 mg, 96%). Spectral data (1H and 13C NMR) were identical to the
racemic compound. HPLC (Chiralpak® IC column, 9:1 MTBE/ isopropanol, flow rate = 1
mL.minꢀ1, t1 = 13.06 min (minor), t2 = 16.81 min (major), 95% ee).
(S,E)-4-(6,7-dimethoxy-1-oxo-tetralon-2-yl)but-2-enal (S)-3a. Following the general
procedure for the metathesis reaction, from crotonaldehyde (207.0 mg, 2.95 mmol), (S)-5a
(140.0 mg, 0.74 mmol), HoveydaꢀGrubbs' 2nd (10 mg, 2.5% mol) and CH2Cl2 (8.0 mL).
Purification by column chromatography on silica gel (Petroleum ether/EtOAc = 1:1) gave an
offꢀwhite powder (150.0 mg, 83%). Spectral data (1H and 13C NMR) were identical to the
racemic compound. HPLC: Chiralpak® IC column, 9:1 MTBE/ isopropanol, flow rate = 1
mL.minꢀ1, t1 = 12.93 min (major), t2 = 16.91 min (minor), 90% ee).
(R)-2-(((R)-1-benzyl-3-(prop-1-en-2-yl)-1,4-dihydropyridin-4-yl)methyl)-6,7-dimethoxy-
3,4-dihydronaphthalen-1(2H)-one ((R,R)-1a)
Following the general procedure for the synthesis of 1,4ꢀDHPs by enantioselective
aminocatalysis (Method B). From enal (R)ꢀ3a (50 mg, 0.18 mmol), saccharin (14 mg, 0.073
mmol, 40%), (S)ꢀJørgensen catalyst III (22 mg, 0.036 mmol) and enamine 4a (32 mg, 0.18
mmol) and dichloroethane (0.8 mL). Purification by chromatography on silica gel (Petroleum
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ether/ EtOAc = 1:1) gave 1,4ꢀDHP (R,R)ꢀ1a (50 mg, 64%) as a lightꢀyellow oil. [α]D ꢀ207.4
(c 0.43 CHCl3). 1H NMR (300 MHz, CDCl3) δ 7.47 (d, J = 4.7 Hz, 1H), 7.38ꢀ7.18 (m, 6H),
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6.62 (s, 1H), 5.93 (d, J = 5.5 Hz, 1H), 5.03 (dd, J = 7.6, 5.5 Hz, 1H), 4.46 (s, 2H), 3.92 (s,
3H), 3.89 (s, 3H), 3.72ꢀ3.69 (dd, J = 12.0, 5.6 Hz, 1H), 2.87 (t, J = 6.0 Hz, 2H), 2.60ꢀ2.42 (m,
1H), 2.42ꢀ2.29 (m, 1H), 2.18 (s, 3H), 2.14ꢀ2.05 (m, 1H), 1.89ꢀ1.78 (m, 1H), 1.45ꢀ1.19 (m,
1H). 13C NMR (75 MHz, CDCl3) δ 199.9, 195.7, 153.2, 147.8, 143.1, 138.9, 136.9, 129.1,
128.1, 128.0, 127.1, 125.8, 113.5, 110.3, 110.2, 108.8, 58.0, 56.2, 56.1, 43.55, 38.3, 29.6,
28.5, 28.4, 24.8. SFC analytic separation: Chiralpak® IA column; 30% Ethanol/Isopropanol
(70:30), flow rate = 4 mL.minꢀ1; tR,R = 4.92 min; dr = 93:7; er = 98:2.
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(S)-2-(((S)-1-benzyl-3-(prop-1-en-2-yl)-1,4-dihydropyridin-4-yl)methyl)-6,7-dimethoxy-
3,4-dihydronaphthalen-1(2H)-one ((S,S)-1a)
From enal (S)ꢀ3a (50 mg, 0.18 mmol, ee 94%), saccharin (14 mg, 0.073 mmol, 40%), (R)ꢀ
Jørgensen catalyst III (22 mg, 0.036 mmol) and enamine 4a (32 mg, 0.18 mmol) and
dichloroethane (0.8 mL). Purification by chromatography on silica gel (Petroleum ether/
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EtOAc = 1:1) gave 1,4ꢀdihydropyridine (S,S)ꢀ1a (38 mg, 48%) as a lightꢀbrown oil. [α]D
+214.4 (c 0.43 CHCl3). Spectral data (1H and 13C NMR) were identical to the compound
(R,R)ꢀ1a. SFC analytic separation: Chiralpak® IA column; 30% Ethanol/Isopropanol (70:30),
flow rate = 4 mL.minꢀ1; tS,S = 5.22 min; dr = 92:8; er = 99.5:0.5.
(S)-2-(((R)-1-benzyl-3-(prop-1-en-2-yl)-1,4-dihydropyridin-4-yl)methyl)-6,7-dimethoxy-
3,4-dihydronaphthalen-1(2H)-one ((S,R)-1a)
From enal (S)ꢀ3a (50 mg, 0.18 mmol, ee 98%), saccharin (14 mg, 0.073 mmol, 40%), (S)ꢀ
Jørgensen catalyst III (22 mg, 0.036 mmol) and enamine 4a (32 mg, 0.18 mmol) and
dichloroethane (0.8 mL). Purification by chromatography on silica gel (Petroleum
ether/EtOAc = 1:1) gave 1,4ꢀDHP (S,R)ꢀ1a (46 mg, 59%) as a yellow oil. [α]D25 ꢀ203.7 (c 0.43
CHCl3). 1H NMR (300 MHz, CDCl3) δ 7.47 (s, 1H), 7.39ꢀ7.08 (m, 6H), 6.65 (s, 1H), 5.91 (d, J
= 6.9 Hz, 1H), 5.03 (dd, J = 7.7, 5.2 Hz, 1H), 4.44 (s, 2H), 3.91 (s, 3H), 3.87 (s, 3H), 3.70ꢀ
3.58 (m, 1H), 3.1ꢀ3.07 (m, 1H), 2.85ꢀ2.79 (m, 1H), 2.69ꢀ2.61 (m, 1H), 2.32ꢀ2.23 (m, 1H), 2.15
(s, 3H), 2.12ꢀ1.98 (m, 1H), 1.89ꢀ1.80 (m, 1H), 1.53ꢀ1.63 (m, 1H). 13C NMR (75 MHz, CDCl3) δ
200.2, 195.1, 153.3, 147.8, 142.9, 139.1, 136.8, 129.1, 128.2, 128.1, 127.0, 125.5, 114.0,
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110.3, 108.8, 108.4, 57.9, 56.1, 56.0, 42.5, 37.8, 28.3, 27.3, 27.0, 24.6. SFC analytic
separation: Chiralpak® IA column; 30% Ethanol/Isopropanol (70:30), flow rate = 4 mL.minꢀ1;
tS,R = 6.08 min; dr = 90:10; er = 99.5:0.5.
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(R)-2-(((S)-1-benzyl-3-(prop-1-en-2-yl)-1,4-dihydropyridin-4-yl)methyl)-6,7-dimethoxy-
3,4-dihydronaphthalen-1(2H)-one ((R,S)-1a)
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From enal (R)ꢀ3a (5 mg, 0.18 mmol), saccharin (14 mg, 0.073 mmol, 40%), (R)ꢀJørgensen
catalyst III (22 mg, 0.036 mmol) and enamine 4a (32 mg, 0.18 mmol) and dichloroethane (0.8
mL). Purification by chromatography on silica gel (petroleum ether/EtOAc = 1:1) gave 1,4ꢀ
DHP (R,S)ꢀ1a (33 mg, 42%) as a yellow oil. [α]D25 +198.3 (c 0.43 CHCl3). Spectral data (1H
and 13C NMR) were identical to the compound (S,R)ꢀ1a. SFC analytic separation: Chiralpak®
IA column; 30% Ethanol/Isopropanol (70:30), flow rate = 4 mL.minꢀ1; tR,S = 10.0 min; dr =
91:9; er = 99:1.
AUTHOR INFORMATION
Corresponding Authors:
*Eꢀmail: vgembus@vfpꢀtherapies.com.
*Eꢀmail: vincent.levacher@insaꢀrouen.fr.
ORCID:
Vincent Gembus: 0000ꢀ0001ꢀ6510ꢀ7608
Vincent Levacher: 0000ꢀ0002ꢀ6429ꢀ1965
Notes
The authors declare no competing financial interest.
ASSOCIATED CONTENT
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Supporting Information: Copies of 1H and 13C{1H} NMR spectra, HPLC and SFC
chromatograms. This material is available free of charge via the Internet at
http://pubs.acs.org.
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ACKNOWLEDGMENT
This work was partly supported by INSAꢀRouen, Rouen University, CNRS, Labex SynOrg
(ANRꢀ11ꢀLABXꢀ0029), Région Normandie.
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