Highly Enantioselective Synthesis of Functionalized Glutarimide Using Oxidative N-Heterocyclic Carbene Catalysis: A Formal Synthesis of (?)-Paroxetine

Article abstract of DOI:10.1021/acs.joc.9b00320

A simple yet highly effective approach toward enantioselective synthesis of trans-3,4-disubstituted glutarimides from readily available starting materials is developed using oxidative N-heterocyclic carbene catalysis. The catalytic reaction involves a formal [3 + 3] annulation between enals and substituted malonamides enabling the production of glutarimide derivatives in a single chemical operation via concomitant formation of C-C and C-N bonds. The reaction offers easy access to a broad range of functionalized glutarimides with excellent enantioselectivity and good yield. Synthetic application of the method is demonstrated via formal synthesis of (?)-paroxetine and other bioactive molecules.

Full text of DOI:10.1021/acs.joc.9b00320

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Article
Highly enantioselective synthesis of functionalized glutarimide using
oxidative N-heterocyclic carbene catalysis: a formal synthesis of (-)-paroxetine
Arka Porey, Surojit Santra, and Joyram Guin
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00320 • Publication Date (Web): 18 Mar 2019
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The Journal of Organic Chemistry
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Highly
enantioselective
synthesis
of
functionalized
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glutarimide using oxidative N-heterocyclic carbene catalysis:
a formal synthesis of (-)-paroxetine
Arka Porey, Surojit Santra and Joyram Guin*
School of Chemical Sciences, Indian Association for the Cultivation of Science, 2A & 2B Raja S. C. Mullick Road,
Jadavpur, Kolkata-700032 (India)
Supporting Information Placeholder
O
R
R
simple substrates
operational simplicity
scalability
valuable products
> 25 examples
NHPG
O
O
R
PG
*
*
PGHN
X
*
H
*
*
NHC, [O]
+
O
N
O
N
O
NHPG
PG
PG
up to 94% yield, 99% ee, 99:1 dr
ABSTRACT: A simple yet highly effective approach towards enantioselective synthesis of trans-3,4-disubstituted glutarimides
from readily available starting materials is developed using oxidative NHC-catalysis. The catalytic reaction involves a formal [3+3]
annulation between enals and substituted malonamides enabling the production of glutarimide derivatives in single chemical
operation via concomitant formation of C-C and C-N bonds. The reaction offers easy access to a board range of functionalized
glutarimides in excellent enantioselectivity and good yield. Synthetic application of the method is demonstrated via formal
synthesis of (-)-paroxetine and other bioactive molecules.
Enantioselective N-heterocyclic carbene (NHC) catalysis
emerges as a reliable synthetic tool for efficient and selective
conversion of simple substrates to complex molecules. In
particular, NHC catalyzed annulation reaction has recognized
as a powerful synthetic strategy for the construction of
different class of functionalized heterocycles.5 Accordingly,
biologically relevant six-membered heterocycles like
dihydropyranone, dihydropyridinone and dihydropyridazin-3-
one derivatives have been synthesized using stereoselective
[3+3] annulation between α,β-unsaturated acylazolium ion and
1,3-bis-nucleophiles such as 1,3-diones, β-ketoesters, β-
ketoamides.6 However, the synthesis of enantioenriched
glutarimide derivatives using NHC-catalyzed [3+3] annulation
reaction is relatively unknown and the synthesis of spiro-
INTRODUCTION
Cyclic imides particularly glutarimide derivatives are
extremely valuable nitrogen heterocycles. These structural
units occur frequently in various natural products1 and
pharmaceuticals (Fig. 1).2 Furthermore, substituted
glutarimides serve as key precursors of functionalized
piperidines of biological relevance.3 Notably, enantioenriched
piperidine rings possessing trans related substituents at C3 and
C4 position are found in different synthetic drugs like (-)-
paroxetine and (+)-femoxetine (Fig. 1).4 In view of great
significance of enantioenriched glutarimides in organic
synthesis and medicinal chemistry, the development of a
catalytic and enantioselective synthesis of these molecules
would be highly desirable.
Scheme 1. Enantioselective synthesis of trans-3,4-
disubstituted glutarimide via oxidative NHC-catalysis
Figure 1. Some selected examples of biologically active
glutarimides and piperidine derivatives
O
O
MeO
O
O
R
N
N
O
R
NHAr
O
N
O
H
Ar
O
ArHN
*
NHC, [O]
*
+
O
F
N
O
O
NHAr
Ph
O
O
Ar
N
O
Me
R
Ph
up to 94% yield, 99% ee
acylazolium ion
O
O
N
O
N
O
H
H
HN
MeN
(+)-Femoxetine
( )-Thalidomide

glutarimide has been reported very recently.7 Continuing our
current research activity towards NHC catalysis,8 herein, we
report a general strategy for highly enantioselective synthesis
( )-Glutethimide

(-)-Paroxetine
1
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of functionalized glutarimides using oxidative NHC-catalysis.
precatalyst 3e could not improve the reaction outcome and
3
4
5
6
7
8
9
The reaction proceeds through formal [3+3] annulation
between readily available enals and malonamide derivatives to
structurally different azolium salts 3f gave inferior result
(entries 5 and 6). Slight improvement on the yield of 4 was
realized using 15 mol% of the precatalyst 3d (entry 7). By
carrying out the reaction at 0 °C, the reaction afforded the
product 4 in 97% ee albeit with moderate yield (entry 8). This
reactivity issue at 0 °C was resolved by adding 3Å MS into the
reaction mixture (entry 9). Presumably, 3Å MS inhibits the
hydrolysis of the in situ formed acyl donor intermediate.
Further lowering of reaction temperature was detrimental to
the reaction (entry 10). Importantly, the reaction could be
scalable, working well with 0.85 g of malonamide 2c to afford
0.9 g of 4 in 72% yield with 91% ee and 4:1 dr (entry 11).
Having identified the optimized reaction condition, different
functionalized aromatic as well as aliphatic enals were
subjected to the catalytic annulation reaction with amide 2c
(Table 2). The enals bearing alkyl/aryl substituents at o/p
position of the aromatic ring were effectively converted to the
products 5-8. Mesityl substituted enal gave moderate yield of
the product 9 with 99% ee and dr = 13:1. The reaction also
worked well with the substrates having halides, delivering the
products 10-15 with good yield and stereoselectivity.
Enantioenriched glutarimides 16-22 having synthetically
important functional groups such as electron rich: OMe, OiPr
and OAc and electron deficient: azide, nitro and
trifluoromethyl were obtained in yields ranging 48-90%, ee =
88-99% and dr = 3:1-7:1, irrespective of their position. The
reaction furnished products 23
afford
highly
enantioselective
trans-3,4-disubstituted
glutarimides in single chemical operation (Scheme 1).
Table 1. Reaction developmenta
O
O
Ph
ArHN
O
O
O
3a-f
cat.
, DBU
ArHN
*
*
+
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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29
30
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36
37
38
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44
45
46
47
48
49
50
51
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56
57
58
59
60
oxidant, THF, temp.
N
O
ArHN
Ar
Ph
1a
2c
4
Ar = m-tolyl
N
O
O
N
Ph
N
BF4
N
N
Ar
N
N
N
TMSO
Ph
Ph
Ph
N
BF4
BF4
Mes
3f
tBu
3e
Z
tBu
3a
, Z = H, Ar = mesityl
3b
, Z = NO2, Ar = mesityl
O
O
3c
, Z = H, Ar = 2,4,6 triphenylbenzene
tBu
tBu
3d
entry
1
, Z = H, Ar = 2,4,6 triisopropylbenzene
oxidant
cat. (mol%)
3a (10%)
3b (10%)
3c (10%)
3d (10%)
3e (10%)
3f (10%)
3d (15%)
3d (15%)
3d (15%)
3d (15%)
3d (15%)
temp. (°C) ee (%) yield (%)
20
20
20
20
20
20
20
0
91
85
87
94
87
-
56
55
2
3
51
4
58
Scheme 2. Formal synthesis of (-) Paroxetine and other
important molecules
5
48
6
trace
73
O
F
O
O
7
94
97
95
-
*
*
Ref. 12
(-)-paroxetine
8
58
HN
9b
10b
11b,c
0
81
X
X
X
PMP
Boc
O
PMP
HN
O
-10
0
trace
72
HO
N
iv
iii
*
*
*
*
*
*
91
N
N
N
PMP
PMP
PMP
aReaction conditions: 1a (2.0 equiv), 2c (1.0 equiv), 3 (10-15
mol%), DBU (15-20 mol%), oxidant (1.5 equiv) in THF; isolated
yield; dr = 4:1 determined by 1H NMR analysis; ee determined by
36
37
34
35
32
33
, X = H, 64%, 95% ee
, X = F, 62%, 95% ee
, X = H, 72%, 96% ee
, X = F, 68%, 95% ee
, X = H, 53%, 96% ee
, X = F, 55%, 95% ee
X
X
partial
reduction
Ar = m-tolyl
b
ii
HPLC analysis on a chiral stationary phase. Reaction performed
O
O
using 3Å MS. cPreparative scale experiment.
i
PMPHN
ArHN
complete
v
*
*
reduction
*
*
RESULTS AND DISCUSSION
O
O
PMPN
ArN
PMP
HN
We began the catalytic reaction using cinnamaldehyde 1a
and different malonamides 2 under various reaction conditions
with 10 mol% of mesityl substituted NHC 3a (see, Supporting
Information). Initial optimization studies revealed that the
product 4 could be obtained in good stereoselectivity (91% ee,
dr = 4:1) with 56% yield using DBU, oxidant, substituted
malonamide 2c9 and THF (Table 1, entry 1). Further reaction
optimization studies were then carried out employing different
chiral NHCs. Accordingly, 1-amino-2-indanol derived
azolium salts 3a-d were first examined in this reaction (entries
1-4). Both the azolium salts 3a and 3d afforded the product 4
in nearly identical yield. However, slight improvement on ee
value of the product 4 was obtained with the salt 3d having tri-
isopropyl benzene substituent. The morpholino-based
O
O
4, X = H; 10, X = F
30, X = H, 63%, 97% ee
, X = F, 51%, 96% ee
*
*
31
vi
N
PMP
ArHNOC
Ph
CONHAr
CONHAr
CO2Et
38
, 63%, 97% ee
vii
ArHN
OH
*
*
viii
O
Ph
39
, 79%, 97% ee
40
, 82%, 97% ee
NHAr
O
CONHAr
Ph
*
=
CCDC 1878494
OMs
41
, 87%, 97% ee
Reaction conditions: i) PMP-NH2, LiCl cat., THF, 160 C, 72 h; ii) LAH, THF, 25 C, 12 h;
iii) (Boc)2O, DMAP, THF, 25 C, 6 h; iv) DIBALH, THF, 3-4 h; v) LAH, THF, reflux, 12 h;
vi) EtOH, HCl (1 M), 80 C, 12 h; vii) LAH, THF, 25 C, 6 h; viii) MsCl, pyridine, 25 C, 2 h.
2
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Table 2. Substrate scopea
O
6
7
8
9
O
O
R
3d
cat.
(15 mol%), DBU (20 mol%
N
N
N
ArHN
*
ArHN
NHAr
R
O
iPr
*
+
THF, 48 h, 4Å MS, 0 C
BF4
N
O
O
O
1b-z
2c
3d
iPr
Ar
Ar = m-tolyl
5-29
iPr
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
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
O
O
O
O
O
O
O
O
O
O
NHAr
O
O
O
ArN
NHAr
ArN
NHAr
ArN
NHAr
ArN
NHAr
ArN
NHAr
ArN
ArN
NHAr
O
O
O
O
O
O
O
8
6
9
5
7
10
11
Me
94%, 97% ee, dr = 4:1
Ph
F
Cl
Ph
Me
c72%, 97% ee, dr = 4:1
b,c58% (1 g), 87% ee
c67%, 98% ee, dr = 3:1
66%, 96% ee, dr = 6:1
78%, 95% ee, dr = 4:1
57%, 99% ee, dr = 13:1
78%, 99% ee, dr = 6:1
O
O
O
O
O
O
O
O
O
O
O
O
ArN
NHAr
ArN
NHAr
ArN
NHAr
ArN
NHAr
ArN
NHAr
ArN
NHAr
Br
O
O
O
=
O
O
O
12
14
16
17
13
15
iPrO
Br
I
MeO
Br
c63%, 96% ee, dr = 5:1
c76%, 98% ee, dr = 3:1
c57%, 96% ee, dr = 5:1
c71%, 97% ee, dr = 3:1
81%, 97% ee, dr = 5:1 81%, 88% ee, dr = 7:1
CCDC 1878492
O
O
O
O
O
O
O
O
O
O
O
O
O
O
ArN
NHAr
ArN
NHAr
ArN
NHAr
ArN
NHAr
ArN
NH2
ArN
NHAr
ArN
NHAr
O
O
O
O
O
O
O
19
18
22
23
24
20
21
O
S
OMe
OAc
CF3
O2N
N3
c48%, 91% ee, dr = 3:1
70%, 95% ee, dr = 3:1
72%, 97% ee, dr = 3:1
OMe
90%, 90% ee, dr = 3:1
61%, 99% ee, dr = 3:1
71%, 92% ee, dr = 4:1
NHAr
68%, 97% ee, dr = 3:1
O
O
O
O
O
O
O
O
O
ArN
O
ArN
NHAr
ArN
NHAr
ArN
NHAr
ArN
NHAr
O
O
O
O
O
=
27
25
26
29
28
56%, 82% ee, dr = 3:1
67%, 94% ee, dr = 5:1
56%, 98% ee, dr = 4:1
CCDC 1878493
53%, 98% ee, dr > 99:1
63%, 98% ee, dr = 6:1
aReaction conditions: aldehydes (0.2 mmol), 2c (0.1 mmol), 3d (15 mol%), DBU (20 mol%), 3Å MS (50 mg) in THF (1.0 mL); isolated
yields; diastereomeric ratio (dr) determined by 1H NMR analysis; ee determined by HPLC analysis on a chiral stationary phase. bReaction
performed with 1 g of aldehyde. cReaction performed using aldehyde (0.1 mmol) and amide 2c (0.15 mmol).
and 24 in equal efficiency, when phenyl ring of the substrate
was replaced with aromatic heterocycle. Naphthyl substituted
enals were found to be suitable substrates for the reaction
(products 25 and 26). Importantly, the reaction afforded the
product 27 in a single diastereoisomer with 98% ee with 9-
anthranyl substituted enal. Substrate scope of the reaction was
also evaluated with aliphatic enals. Notably, the aliphatic enals
are challenging substrates for the oxidative NHC-catalysis.
With this catalytic process, the aliphatic enals having
cyclohexyl and cyclopropyl structural scaffold were
transformed to the corresponding products 28 and 29 in good
stereoselectivity albeit with moderate isolated yield of 56%.
Absolute stereochemistry determined to be 3R, 4R for the
compound 15 via single-crystal X-ray analysis.10
Synthetic utility of the method was demonstrated by the
preparation of different valuable enantioenriched materials
(Scheme 2). Accordingly, enantioenriched synthesis of
medicinally potent piperidine derivatives 36 and 37 were
accomplished using the enantioenriched glutarimides 4 and 10.
The synthesis involved four simple transformations:
transamidation with p-methoxy aniline to install easily
removable PMP-group,11 LiAlH4 mediated imide reduction,
Boc-protection and finally DIBAL-H reduction, delivering the
alcohols 36 and 37 in single diastereoisomer with excellent ee
value. Absolute configuration 3S, 4R of the alcohol 37 was
confirmed by analogy with the reported sign of optical rotation
data (see, Supporting Information).12 The enantioenriched
alcohol 37 could be transformed to the marketed drug (-)-
paroxetine13 via etherification with sesamol followed by PMP
deprotection.12 Furthermore, complete reduction of the
glutarimide 30 gave access to the enantioenriched amino
piperidine derivative 38. The product 4 was also converted to
an open chain ester 39 upon treatment with ethanol. The ethyl
ester 39 was reduced with LiAlH4 to afford the
enantioenriched alcohol 40. Single crystal X-ray analysis of
the mesyl protected alcohol 41 resulted in R absolute
stereochemistry (Scheme 2).
A possible catalytic cycle is depicted in Scheme 3, in which
free carbene is formed via deprotonation of azolium salt with a
catalytic amount of DBU. The in-situ generated carbene then
undergoes nucleophilic addition to carbonyl group of enal to
form the Breslow intermediate I, which provides the α,β-
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unsaturated azolium ion II upon oxidation.14 Conjugate
= triplet, dt = doublet of triplet, m = multiplet, br. = broad),
3
4
5
6
7
8
9
addition of the enolizable diamide to the azolium ion II results
in the formation of enolether III. The intermediate IV is most
likely formed through an internal proton transfer from the
intermediate III. Finally, the intermediate IV delivers the
desired product via imide formation along with the
regeneration of carbene.
coupling constants (Hz) and integration. 13C chemical shifts
are reported in ppm (δ) from tetramethylsilane (TMS) with the
solvent resonance as the internal standard (CDCl3 δ 77.0 ppm).
High resolution mass spectra were measured on Q-Tof micro
MS system by electron spray ionization (ESI) technique. IR
spectra were recorded on PerkinElmer FT-IR spectrometer
(model: Spectrum Two) as Neat. The wave numbers (n) are
reported in cm−1. Optical rotations were measured on an Anton
Paar automatic polarimeter and are reported as follows:
concentration (c = g/dL), and solvent. The enantiomeric
excesss were determined by HPLC (Shimadzu) analysis
employing a chiral stationary phase column specified in the
individual experiment, by comparing the samples with the
appropriate racemic mixtures.
Scheme 3. Probable catalytic cycle for the reaction
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
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N
DBU
*
O
O
R
NAr1
N
*
ArHN
*
BF4
N
N
*
N
O
H
N
Ar1
R
n
O
u
c
n
a
l
e
e
Ar
o
d
d
i
o
n
d
t
i
p
a
i
t
i
o
NHC
h
m
f
i
i
l
i
c
m
r
o
H
O
N
*
Ar
NAr1
O
N
Ar
N
N
Enals 1a, 1g, 1h, 1i, 1o, 1p, 1q, 1r, 1t, 1x are commercially
available and the rest of the enals were synthesized following
the similar reported procedure15 that is briefly described in
GP-1. See also Supporting Information for synthetic scheme
of those enals.
*
N
O
R
HO
R
N
IV
N
Ar1
H
o
I
x
r
l
i
e
d
f
a
n
n
a
s
o
t
t
r
n
i
e
t
o
o
a
r
r
n
t
n
i
p
H
O
H
O
N
Ar
H
*
General procedure for synthesis of enals (GP-1):
N
O
N
N
Ar1
*
Ar
N
O
Step-1: Ethyl (triphenylphosphoranylidene)acetate (1.2
equiv.) was added to a solution of aldehyde (1.0 equiv) in
anhydrous dichloromethane (10 mL/g) under an inert
atmosphere. The solution was stirred for 16 h at 25 °C.
Volatiles were removed in vacuo and the resulting solid
purified by flash chromatography to give the desired α,β-
unsaturated ester.
N
II
R
N
conjugate
addition
III
N
Ar1
H
R
ArHN
NHAr
ArHN
NHAr
O
O
O
O
H
CONCLUSIONS
Step-2: To a solution of the above obtained α,β-unsaturated
ester (1.0 equiv) in dichloromethane (0.2 M) at -78 °C was
added dropwise DIBAL-H in THF (2.1 equiv) and the reaction
mixture was stirred until complete consumption of the α,β-
unsaturated ester was realized (usually 4 h). The reaction was
quenched by slow addition of 10% aqueous NaOH. Finally,
the reaction mixture was extracted with DCM and the
combined organic layer was washed with brine, dried over
Na2SO4 and concentrated under reduced pressure. The crude
material was purified by column chromatography to give the
desired α,β-unsaturated alcohol.
In conclusion, we have demonstrated an efficient NHC-
catalytic approach to highly enantioselective and biologically
active trans-3,4-disubstituted glutarimides via annulation
between enals and 1,3-diamides under oxidative conditions.
Notable aspects of this catalytic enantioselective reaction
include: simple substrates, excellent enantioselectivity,
scalability and operational ease. Starting from the product 10,
a formal synthesis of the marketed drug (-)-paroxetine is
completed with excellent stereoselectivity (ee and dr).
EXPERIMENTAL SECTION
Step-3: To a solution of α,β-unsaturated alcohol (1.0 equiv)
in anhydrous DCM was added PDC (1.5 equiv). After stirring
for 24 hours at 25 °C, the solution was diluted with diethyl
ether and hexane (1:1) and filtered through celite pad and
washed with ether. The combined filtrate was concentrated in
vacuo and purified by column chromatography to give the
desired enal.
General Information: Unless otherwise stated, all reagents
and solvents were purchased from commercial suppliers and
used without further purification. THF was freshly dried prior
to the reaction over Na. 3Å MS was activated by heating at
elevated temperature (> 150 ºC) under vacuum for 12 h. All
reactions were performed in flame-dried schlenk tubes (inner
diameter
= 18 mm, length = 105 mm) with glass
3-(2-Methylphenyl)-2-propenal (1b): Prepared according
to GP-I from the corresponding α,β-unsaturated alcohol
(320.0 mg) to afford 1b (246.0 mg) as white solid in 78%
yield (step-3). Spectroscopic data are in good agreement with
reported values.16
stoppers/silicon septum and Teflon coated magnetic stirring
bar. Reactions were monitored by thin layer chromatography
(TLC) analysis on silica gel 60 F254 and visualization was
accomplished with short wave UV light at 254 nm or KMnO4
staining solutions followed by heating, crude product was
purified by column chromatography on Merck silica gel (100-
200 mesh). 1H and 13C NMR spectra were recorded on Bruker
AVANCE III 500, 400 and 300 MHz spectrometers in
deuterated solvents. Proton chemical shifts are reported in
ppm (δ) relative to tetramethylsilane (TMS) with the solvent
resonance employed as the internal standard (CDCl3 δ 7.26
3-(4-Methylphenyl)-2-propenal (1c): Prepared according
to GP-I from the corresponding α,β-unsaturated alcohol
(500.0 mg) to afford 1c (440.0 mg) as white solid in 88% yield
(step-3). Spectroscopic data are in good agreement with
reported values.16
3-[1,1'-Biphenyl]-4-yl-2-propenal
(1d):
Prepared
1
according to GP-I from the corresponding α,β-unsaturated
alcohol (430.0 mg) to afford 1d (304.0 mg) as white solid in
ppm). H NMR data are reported as follows: chemical shift,
multiplicity (s = singlet, d = doublet, dd = doublet of doublet, t
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71% yield (step-3). 1H NMR (400 MHz, CDCl3) δ = 9.46 (d, J
(step-3). Spectroscopic data are in good agreement with
2
= 8.0 Hz, 1H), 7.66 (d, J = 7.2 Hz, 1H), 7.47-7.24 (m, 9H),
6.61 (q, J = 8.0 Hz, 1H) ppm. 13C{1H} NMR (100 MHz,
CDCl3) δ = 193.8, 151.7, 143.3, 139.5, 131.9, 130.7, 130.6,
129.7, 129.3, 128.3, 127.8, 127.7, 126.9 ppm. HRMS (ESI-
TOF) m/z : [M+H]+ calcd for C15H12O 209.0961; found
209.0963. IR (Neat) ѵmax = 3059, 2737, 1675, 1620, 1596,
1474, 1127, 1098, 1008 cm-1.
reported values.17
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3-(1-Naphthalenyl)-2-propenal (1w): Prepared according
to GP-I from the corresponding α,β-unsaturated alcohol
(300.0 mg) to afford 1w (210.0 mg) as white solid in 71%
yield (step-3). Spectroscopic data are in good agreement with
reported values.16
3-Cyclohexyl-2-propenal (1y): Prepared according to GP-I
from the corresponding α,β-unsaturated alcohol (300.0 mg) to
afford 1y (190.0 mg) as colorless liquid in 64% yield (step-3).
Spectroscopic data are in good agreement with reported
values.21
3-(2,4,6-Trimethylphenyl)-2-propenal (1f): Prepared
according to GP-I from the corresponding α,β-unsaturated
alcohol (500.0 mg) to afford 1f (330.0 mg) as white solid in
67% yield (step-3). Spectroscopic data are in good agreement
with reported values. 17
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3-Cyclopropyl-2-propenal (1z): Prepared according to GP-
I from the corresponding α,β-unsaturated alcohol (320.0 mg)
to afford 1z (200.0 mg) as white solid in 64% yield (step-3).
Spectroscopic data are in good agreement with reported
values.22
3-(2-Bromophenyl)-2-propenal (1j): Prepared according to
GP-I from the corresponding α,β-unsaturated alcohol (300.0
mg) to afford 1j (190.0 mg) as white solid in 64% yield (step-
3). Spectroscopic data are in good agreement with reported
values. 17
Diamides 2a-f were synthesized following the similar
3-(3-Bromophenyl)-2-propenal (1k): Prepared according
to GP-I from the corresponding α,β-unsaturated alcohol
(450.0 mg) to afford 1k (336.0 mg) as white solid in 75%
yield (step-3). Spectroscopic data are in good agreement with
reported values.18
23
reported procedure
that is briefly described in GP-2. See
also Supporting Information for synthetic scheme of diamides
2a-f.
General procedure for the synthesis of diamides (GP-2):
A pressure tube (30 mL) equipped with a magnetic stirrer
was charged with diethyl malonate (1.0 equiv) and appropriate
aniline derivative (2.0 equiv.). The pressure tube was capped
and heated at 160 °C for 12 h. After completion the reaction
mixture was diluted with hexane and the precipitate formed
was filtered, washed with (1:1) DCM:Hexane and dried to
afford the desired diamides.
3-(4-Iodophenyl)-2-propenal (1l): Prepared according to
GP-I from the corresponding α,β-unsaturated alcohol (500.0
mg) to afford 1l (410.0 mg) as white solid in 83% yield (step-
3). Spectroscopic data are in good agreement with reported
values.19
3-(2-Methoxyphenyl)propenal (1m): Prepared according
to GP-I from the corresponding α,β-unsaturated alcohol
(300.0 mg) to afford 1m (210.0 mg) as pale yellow solid in
71% yield (step-3). Spectroscopic data are in good agreement
with reported values.20
Malonamide 2a: Prepared according to GP-2, combining
diethylmalonate (1.0 g) and aniline (1.16 g) to afford 2a (1.03
g) as white solid in 65% yield. Spectroscopic data are in good
agreement with reported values.24
3-[2-(1-methylethoxy)phenyl]-propenal (1n): Prepared
according to GP-I from the corresponding α,β-unsaturated
alcohol (440.0 mg) to afford 1n (270.0 mg) as white solid in
62% yield (step-3). 1H NMR (400 MHz, CDCl3) δ =9.69 (d, J
= 7.6 Hz, 1H), 7.83 (d, J = 16.0 Hz, 1H), 7.54 (d, J = 6.4 Hz,
1H), 7.37 (t, J = 6.8 Hz, 1H), 6.97-6.93 (m, 2H), 6.78 (dd, J =
16.0, 8.0 Hz, 1H), 4.69-4.62 (m, 1H), 1.40-1.38 (d, J = 6.02
Hz, 1H) ppm. 13C{1H} NMR (100 MHz, CDCl3) δ = 194.5,
156.7, 148.6, 132.5, 128.9, 128.7, 123.7, 120.5, 113.6, 70.8,
22.0 ppm. HRMS (ESI-TOF) m/z: [M+H]+ calcd for
C12H14O2 191.1067; found 191.1069. IR (Neat) ѵmax = 2978,
1673, 1597, 1482, 1247, 1129, 1093, 952, 751 cm-1.
Malonamide 2b: Prepared according to GP-2 combining
diethylmalonate (1.0 g) and 2-methylaniline (1.34 g) to afford
2b (916.0 mg) as white solid in 52% yield. Spectroscopic data
are in good agreement with reported values.24
Malonamide 2c: Prepared according to GP-2 combining
diethylmalonate (3.0 g) and 3-methylaniline (4.01 g) to afford
2c (3.17 g) as off-white solid in 60% yield. Spectroscopic data
are in good agreement with reported values.24
Malonamide 2d: Prepared according to GP-2 combining
diethylmalonate (1.0 g) and 3-phenylaniline (2.11 g) to afford
1
2d (964.0 mg) as white solid in 38% yield. H NMR (400
MHz, CDCl3) δ = 9.64 (s, 1H), 7.87 (m, 1H), 7.61-7.58 (m,
6H), 7.41-7.37 (m, 10H), 3.72(s, 2H) ppm. 13C{1H} NMR
(100 MHz, CDCl3) δ = 165.8, 142.1, 140.4, 137.7, 129.3,
128.7, 127.5, 127.1, 123.7, 119.1, 119.0, 44.8 ppm. HRMS
(ESI-TOF) m/z : [M+H]+ calcd for C27H22N2O2 407.1754;
found 407.1755. IR (Neat) ѵmax = 3282, 3060, 1649, 1608,
1544, 1478, 1235, 886, 794, 752, 696 cm-1.
3-(4-Trifluoromethylphenyl)propenal (1s): Prepared
according to GP-I from the corresponding α,β-unsaturated
alcohol (400.0 mg) to afford 1s (260.0 mg) as white solid in
66% yield (step-3). Spectroscopic data are in good agreement
with reported values. 16
3-(2-Thienyl)-2-propenal (1u): Prepared according to GP-I
from the corresponding α,β-unsaturated alcohol (200.0 mg) to
afford 1u (104.0 mg) as white solid in 53% yield (step-3).
Spectroscopic data are in good agreement with reported
values. 16
Malonamide 2e: Prepared according to GP-2 to combining
diethylmalonate (1.0 g) and aniline (1.53 g) to afford 2e (1.07
g) as white solid in 55% yield. Spectroscopic data are in good
agreement with reported values.24
3-(2-Naphthalenyl)-2-propenal (1v): Prepared according
to GP-I from the corresponding α,β-unsaturated alcohol
(450.0 mg) to afford 1v (335.0 mg) as white solid in 75% yield
Malonamide 2f: Prepared according to GP-2 combining
diethylmalonate (1.0 g) and aniline (1.33 g) to afford 2a (1.26
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g) as white solid in 71% yield. Spectroscopic data are in good
1H), 3.16 (dd, J = 17.4, 4.2 Hz, 1H), 3.03 (d, J = 17.1 Hz, 1H)
agreement with reported values.24
ppm. 13C{1H} NMR (100 MHz, CDCl3) δ =148.5, 144.8,
144.5, 140.3, 139.2, 138.7, 136.3, 134.8, 129.3, 129.3, 129.1,
129.0, 128.7, 128.5, 128.5, 127.7, 127.4, 125.1, 123.6, 77.4,
61.9, 59.7, 37.0 ppm. HRMS (ESI-TOF) m/z: [M-BF4]+
calcd for C36H29N3O 518.2234; found 518.2233. IR (Neat)
ѵmax = 3045, 2928, 1591, 1210, 1106, 1064, 973, 892 cm-1.
[α]D 25 = -4.81 (c = 0.81, CHCl3).
Azolium salts 3a-f were synthesized according to the
literature procedure.25
2,4,6 triphenylbromobenzene was synthesized according to
the reported procedure.26
Synthesis
of
1,3,5-(triphenyl)phenylhydrazine
hydrochloride (B), see also Supporting Information:
General procedure (GP-3): NHC-catalyzed 1,4-
conjugate addition reaction: To a flame dried Schlenk tube
equipped with a magnetic stir bar, carbene precursor 3d (7.6
mg, 0.015 mmol, 0.15 equiv), activated 3Å MS (50.0 mg) and
THF (1.0 mL) were placed under argon. To the resulting
mixture, DBU (3.0 µL, 0.020 mmol) was added at 25 °C and
the mixture was stirred for another 5 min. To the mixture, 1,3-
diamide 2c (0.1-0.11 mmol, 1-1.1 equiv) and oxidant (0.15
mmol, 1.5 equiv) were added successively. The reaction tube
was cooled to 0 ºC. To the cold solution, an appropriate enal
(0.1-0.2 mmol, 1.0-2.0 equiv) was added and the reaction was
continued for 48 h while maintaining the reaction temperature
at 0 ºC. The progress of the reaction was monitored by TLC
analysis. The crude reaction mixture was concentrated under
reduced pressure and purified by gradient column
chromatography from 1:1 DCM:Hexane to DCM to
DCM:EtOAc (95:5) to afford the desired compound.
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Step I: An oven dried 250 mL two necked flask fitted with
Ar-inlet, magnetic stirring bar, reflux condenser and septum
was charged with Mg (234.0 mg, 9.76 mmol, 1.5 equiv,
activated with a spatula tip of iodine). The Mg was covered
with
THF
(2
ml),
subsequently
2-bromo-1,3,5-
triphenylbenzene (2.5 g, 6.51 mmol, 1.0 equiv), the rest of the
THF (8 ml) and 0.1 ml 1,2-dibromoethane (as activator) were
added via different syringes maintaining the exothermic
Grignard-reaction active. After complete addition of all the
components, the resulting grey solution was placed in a pre-
heated oil bath and the solution was heated under refluxed for
24 h.
Step II: To a stirred solution of di-tert-butyl azodicarboxylate
(1.16 g, 5.00 mmol) in THF (4 mL) at -78 °C, was added the
pre-formed Grignard reagent. The resulting solution was
stirred at -78 °C for 5 h before the reaction was quenched with
acetic acid (0.5 mL). The mixture was allowed to warm to
room temperature and diluted with H2O (10 mL). The aqueous
layer was extracted with Et2O. The combined organic layers
were washed with brine, dried over Na2SO4, filtered and
concentrated in vacuo. The crude material was purified by
column chromatography to afford the product A (2.3 g, 86%).
Compound 4: The GP-3, combining 2c and enal 1a gave
compound 4 along with minor diastereomer (34.0 mg, 81%,
combined yield) as off-white solid. The diastereomeric ratio
(dr) determined to be 4:1 by 1H NMR analysis. 1H NMR (500
MHz, CDCl3)
δ = 8.10 (s, 1Hmajor), 7.34-7.21 (m,
14Hmajor+minor), 7.18-7.04 (m, 6Hmajor+minor), 6.93-6.77 (m,
6Hmajor+minor), 4.13 (d, J = 4.5 Hz, 1Hmajor), 4.07-4.05 (m,
1Hminor), 3.96 (d, J = 4.0 Hz, 1Hmajor), 3.86 (d, J = 4.5 Hz,
1Hminor), 3.61 (dd, J = 17.5, 9.5 Hz, 1Hminor), 3.38 (dd, J =
17.5, 5.5 Hz, 1Hmajor), 3.10 (d, J = 5.0 Hz, 1Hminor), 3.05 (dd, J
= 17.0, 5.5 Hz, 1Hmajor), 2.31 (s, 3H minor), 2.28 (s, 3Hmajor),
2.46 (s, 3H major), 2.21 (s, 3Hminor), ppm. 13C{1H} NMR (125
MHz, CDCl3) δ = 171.4, 171.0, 170.9, 170.9, 163.9, 163.1,
140.2, 139.5, 139.5, 139.1, 138.9, 137.8, 137.0, 136.6, 134.7,
134.3, 129.8, 129.3, 129.2, 128.9, 128.8, 128.7, 128.7, 128.1,
127.8, 127.1, 126.8, 125.8, 125.8, 125.1, 125.0, 121.1, 120.7,
117.5, 117.1, 55.9, 54.9, 37.2, 36.6, 36.3, 35.3, 21.4, 21.4,
21.3 ppm. HRMS (ESI-TOF) m/z: [M+H]+ calcd for
C26H25N2O3 413.1860; found 413.1861. IR (Neat) ѵmax = 3331,
3031, 2920, 1736, 1667, 1552, 1489, 1245, 1191, 765, 695 cm-
1. HPLC: The enantiomeric excess (% of ee = 96, minor
diastereoisomer and 95, major diastereoisomer) was
determined by HPLC analysis using Daicel Chiralpak IE-3
column: n-hexane:i-PrOH = 83:17, flow rate 1.0 mL/min, λ =
254 nm: τmajor = 15.27 min, τminor = 21.85 min for minor
diastereoisomer and τminor = 24.63 min, τmajor = 30.99 min for
major diastereoisomer.
Step II: The obtained product A (2.3 g, 4.28 mmol) was
dissolved in i-PrOH (5.4 mL). To the solution, HCl (4 M in
dioxane, 5.4 mL) was added. The resulting mixture was stirred
at room temperature for 24 h. Upon dilution with cooled Et2O,
the desired hydrazine hydrochloride was precipitated. The
precipitate was collected by cannula filtration, washed with
Et2O and dried under vacuum to give the 1,3,5-
(triphenyl)phenylhydrazine hydrochloride (B) as white solid
(1.59 g, 75%).
Synthesis of the azolium salt 3c:
To a solution of (1R,2S) morpholinone (265 mg, 1.40 mmol)
in CH2Cl2 (7.0 mL) was added trimethyloxonium
tetrafluoroborate (155.0 mg, 1.47 mmol). The mixture was
stirred for 12 h at 25 °C before a solution of 1,3,5-
(triphenyl)phenylhydrazine (518 mg, 1.54 mmol (synthesized
from the hydrazine hydrochloride B) was added. The mixture
was stirred for another 12 h. The solvent was evaporated under
vacuum and chlorobenzene (7 mL) was added, followed by
triethyl orthoformate (2.32 mL, 14 mmol). The flask was fitted
with a reflux condenser and heated at 110 °C (oil bath
temperature) for 12 h. All the low boiling materials were
removed under reduced pressure and the crude mass was
purified by FC using EtOAc:Hexane (1:1) to afford the
Compound 5: The GP-3, combining 2c and enal 1b gave 5
along with minor diastereomer (28.0 mg, 66%, combined
yield) as off-white solid. The diastereomeric ratio (dr)
1
1
determined to be 6:1 by H NMR analysis. H NMR (500
MHz, CDCl3) δ = 8.15 (s, 1Hmajor), 7.72 (s, 1Hminor), 7.33-7.23
(m, 4Hmajor+minor), 7.21-7.03 (m, 14Hmajor+minor), 7.03-7.01 (m,
1Hminor), 6.96-6.90 (m, 2Hminor), 6.89-6.80 (m, 3Hmajor), 4.33
(dd, J = 10.0, 5.5 Hz, 1Hmajor), 4.19-4.14 (m, 1Hminor), 3.91 (d,
1
azolium salt 3c (513 mg, 60%) as white solid. H NMR (300
MHz, CDCl3) δ = 10.05 (s, 1H), 7.69-7.64 (m, 4H), 7.53-7.45
(m, 3H), 7.39-7.31 (m, 5H), 7.28-7.23 (m, 6H), 7.19-7.17 (m,
1H), 7.05 (t, J = 7.5 Hz, 1H), 6.08 (d, J = 7.8 Hz, 1H), 5.98
(d, J = 3.6 Hz, 1H), 4.88-4.79 (m, 2H), 4.59 (d, J = 15.9 Hz,
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J = 3.0 Hz, 1Hmajor), 3.81 (d, J = 5.0 Hz, 1Hminor), 3.63 (dd, J =
55.5, 53.7, 36.3, 35.5, 33.5, 32.9, 21.4, 21.2 ppm. HRMS
(ESI-TOF) m/z : [M+H]+ calcd for C32H29N2O3 489.2173;
found 489.2175. IR (Neat) ѵmax = 3313, 3023, 2919, 1735,
1681, 1489, 1364, 1188, 751, 695 cm-1. HPLC: The
enantiomeric excess (% of ee = 91, minor diastereoisomer and
99, major diastereoisomer) and diastereomeric ratio (dr =
88:12) were determined by HPLC analysis using Daicel
Chiralpak IA-3 column: n-hexane:i-PrOH = 80:20, flow rate
1.0 mL/min, λ = 254 nm: τmajor = 5.05 min, τminor = 5.86 min
for minor diastereoisomer and τminor = 15.27 min, τmajor = 8.31
min for major diastereoisomer.
17.5, 6.0 Hz, 1Hminor), 3.33 (dd, J = 17.5, 6.0 Hz, 1Hmajor),
2.99-2.90 (m, 2Hmajor+minor), 2.38 (s, 3H minor), 2.35 (s, 3Hmajor),
2.32 (s, 3H minor), 2.30 (s, 3Hmajor), 2.24 (s, 3Hmajor), 2.20 (s, 3H
minor) ppm. 13C{1H} NMR (125 MHz, CDCl3) δ = 171.4, 171.3,
171.1, 170.9, 164.0, 163.1, 139.5, 139.1, 138.8, 137.1, 136.6,
136.3, 135.9, 135.7, 134.9, 134.5, 131.6, 131.5, 129.8, 129.7,
129.2, 128.9, 128.8, 128.7, 127.9, 127.7, 126.8, 126.7, 125.9,
125.8, 125.3, 125.1, 124.8, 121.3, 120.8, 117.7, 117.2, 55.1,
53.9, 36.2, 35.7, 33.8, 33.1, 31.8, 21.3, 21.2, 19.4 ppm.
HRMS (ESI-TOF) m/z: [M+H]+ calcd for C27H27N2O3
427.2016; found 427.2015. IR (Neat) ѵmax = 3322, 3022, 2922,
1736, 1682, 1554, 1490, 1372, 1241, 1197, 763, 694 cm-1.
HPLC: The enantiomeric excess (% of ee = 98, minor
diastereoisomer and 96, major diastereoisomer) was
determined by HPLC analysis using Daicel Chiralpak IE-3
column: n-hexane:i-PrOH = 80:20, flow rate 1.0 mL/min, λ =
254 nm: τmajor = 12.53min, τminor = 16.76 min for minor
diastereoisomer and τminor = 13.32 min, τmajor = 15.23 min for
major diastereoisomer.
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Compound 8: The GP-3, combining 2c and enal 1e gave
compound 8 along with minor diastereomer (38.0 mg, 78%,
combined yield) as white solid. The diastereomeric ratio (dr)
1
1
determined to be 4:1 by H NMR analysis. H NMR (500
MHz, CDCl3) δ = 8.13 (s, 1Hmajor), 7.54-7.47 (m, 8Hmajor+minor),
7.39-7.35 (m, 4Hmajor+minor), 7.30-7.25 (m, 8H5H-major+3H-minor),
7.19-7.10 (m, 6Hmajor+minor), 7.06-7.03 (m, 2Hminor), 6.97-6.95
(m, 1Hminor), 6.90-6.77 (m, 5H3H-major+2H-minor), 4.16 (d, J = 4.5
Hz, 1Hmajor), 4.11-4.07 (m, 1Hminor), 4.00 (d, J = 4.0 Hz,
1Hmajor), 3.89 (d, J = 5.0 Hz, 1H minor), 3.63 (dd, J = 17.5, 9.5
Hz, 1Hminor), 3.41 (dd, J = 17.5, 5.0 Hz, 1Hmajor), 3.13-3.06 (m,
2Hmajor+minor), 2.31 (s, 3H minor), 2.85 (s, 3Hmajor), 2.24 (s, 3H
major), 2.18 (s, 3Hminor) ppm. 13C{1H} NMR (125 MHz, CDCl3)
δ = 171.3, 170.9, 170.9, 163.9, 163.1, 141.1, 140.8, 140.8,
140.3, 140.2, 139.4, 139.3, 139.1, 138.9, 137.1, 136.9, 136.8,
134.8, 134.5, 129.8, 129.2, 128.9, 128.9, 128.8, 127.9, 127.9,
127.6, 127.6, 127.6, 127.3, 127.1, 127.0, 125.8, 125.2, 125.1,
121.1, 120.8, 117.6, 117.3, 55.9, 54.9, 37.1, 36.7, 36.6, 35.1,
21.4, 21.3, 21.2 ppm. HRMS (ESI-TOF) m/z : [M+Na]+
calcd for C32H28N2O3Na 511.1998; found 511.1996. IR (Neat)
ѵmax = 3332, 3029, 2921, 1735, 1666, 1488, 1372, 1190, 764,
695 cm-1. HPLC: The enantiomeric excess (% of ee = 97,
minor diastereoisomer and 95, major diastereoisomer) was
determined by HPLC analysis using Daicel Chiralpak IE-3
column: n-hexane:i-PrOH = 80:20, flow rate 1.0 mL/min, λ =
254 nm: τmajor = 16.32 min, τminor = 23.12 min for minor
diastereoisomer and τminor = 25.41 min, τmajor = 33.65 min for
major diastereoisomer.
Compound 6: The GP-3, combining 2c and enal 1c gave
compound 6 along with minor diastereomer (40.0 mg, 94%,
combined yield) as white solid. The diastereomeric ratio (dr)
1
1
determined to be 4:1 by H NMR analysis. H NMR (300
MHz, CDCl3) δ = 8.11 (s, 1Hmajor), 7.32-7.23 (m, 4Hmajor+minor),
7.18-7.04 (m, 14Hmajor+minor), 6.96-6.93 (m, 1Hminor), 6.88-6.82
(m, 3H1H-major+2H-minor), 6.79-6.76 (m, 2Hmajor), 4.09-3.98 (m,
1Hmajor+minor), 3.93 (d, J = 3.9 Hz, 1Hmajor), 3.84 (d, J = 4.5 Hz,
1Hminor), 3.57 (dd, J = 17.4, 9.6 Hz, 1Hminor), 3.35 (dd, J =
11.7, 5.4 Hz, 1Hmajor), 3.03 (m, 2Hmajor+minor), 2.26 (m,
18Hmajor+minor) ppm. 13C{1H} NMR (75 MHz, CDCl3) δ =
171.6, 171.2, 171.1, 171.0, 164.0, 163.2, 139.5, 139.4, 139.0,
138.8, 137.8, 137.5, 137.1, 137.0, 136.6, 134.7, 134.3, 129.9,
129.8, 129.2, 129.2, 128.8, 128.7, 128.7, 126.9, 126.7, 125.7,
125.7, 125.1, 125.0, 121.1, 120.6, 117.5, 117.1, 55.9, 54.9,
36.9, 36.7, 36.4, 34.9, 21.4, 21.3, 20.9 ppm. HRMS (ESI-
TOF) m/z : [M+Na]+ calcd for C27H26N2O3 Na 449.1841;
found 449.1842. IR (Neat) ѵmax = 3332, 3023, 2921, 1736,
1667, 1489, 1243, 1191, 754, 695 cm-1. HPLC: The
enantiomeric excess (% of ee = 96, minor diastereoisomer and
97, major diastereoisomer) was determined by HPLC analysis
using Daicel Chiralpak IE-3 column: n-hexane:i-PrOH =
83:17, flow rate 1.0 mL/min, λ = 254 nm: τmajor = 16.48 min,
τminor = 23.69 min for minor diastereoisomer and τminor = 26.36
min, τmajor = 33.35 min for major diastereoisomer.
Compound 9: The GP-3, combining 2c and enal 1f gave
compound 9 along with minor diastereomer (26.0 mg, 57%,
combined yield) as white solid with excellent diastereomeric
1
ratio. H NMR (300 MHz, CDCl3) δ = 7.67 (s, 1H), 7.29 (t, J
= 7.8 Hz, 1H), 7.18-7.15 (m, 1H), 6.98-6.90 (m, 5H), 6.80-
6.75 (m, 3H), 4.53-4.43 (m, 1H), 4.18 (d, J = 12.0 Hz, 1H),
3.23-3.12 (m, 1H), 2.91 (dd, J = 17.1, 4.8 Hz, 1H), 2.36 (s,
6H), 2.31 (s, 3H), 2.14-2.13 (m, 6H), ppm. 13C{1H} NMR (75
MHz, CDCl3) δ = 171.3, 164.7, 139.5, 138.6, 137.0, 134.7,
131.8, 130.9, 130.9, 129.8, 129.2, 128.8, 128.5, 125.4, 125.2,
120.9, 117.3, 54.8, 35.9, 32.0, 21.6, 21.3, 20.6 ppm. HRMS
(ESI-TOF) m/z : [M+H]+ calcd for C29H31N2O3 455.2329;
found 455.2327. IR (Neat) ѵmax = 3329, 3029, 2921, 1735,
1667, 1613, 1489, 1355, 1189, 1046, 756, 694 cm-1. HPLC:
The enantiomeric excess (% of ee = 99 of both the
diastereomer) was determined by HPLC analysis using Daicel
Chiralpak IE-3 column: n-hexane:i-PrOH = 80:20, flow rate
1.0 mL/min, λ = 254 nm: τmajor = 10.36 min, τminor = 20.34 min
for minor diastereoisomer and τminor = 13.15 min, τmajor = 16.98
min for major diastereoisomer.
Compound 7: The GP-3, combining 2c and enal 1d gave
compound 7 along with minor diastereomer (38.0 mg, 78%,
combined yield) as white solid. The diastereomeric ratio (dr)
1
1
determined to be 6:1 by H NMR analysis. H NMR (500
MHz, CDCl3) δ = 7.45-7.20 (m, 18Hmajor+minor), 7.13-7.05 (m,
8Hmajor+minor), 6.99-6.97 (m, 2Hmajor+minor), 6.86-6.78(m,
6Hmajor+minor), 4.29-4.24 (m, 2Hmajor+minor), 3.72 (d, J = 3.0 Hz,
1Hmajor), 3.55 (d, J = 5.0 Hz, 1H minor), 3.47 (dd, J = 17.0, 9.5
Hz, 1Hminor), 3.22 (dd, J = 18.0, 6.0 Hz, 1Hmajor), 2.94 (dd, J =
18.0, 4.0 Hz, 1Hmajor), 2.79 (dd, J = 17.5, 5.0 Hz, 1H minor),
2.28 (s, 3H minor), 2.27 (s, 3Hmajor), 2.23 (s, 3H minor), 2.22 (s,
3Hmajor) ppm. 13C{1H} NMR (125 MHz, CDCl3) δ = 171.3,
169.9, 164.1, 163.9, 142.5, 142.3, 140.8, 140.7, 139.3, 138.9,
137.7, 136.9, 136.7, 135.4, 134.8, 134.6, 131.4, 131.3, 129.7,
129.3, 129.1, 128.9, 128.9, 128.8, 128.3, 128.0, 127.8, 127.7,
125.9, 125.7, 125.2, 125.1, 125.0, 121.3, 120.7, 117.7, 117.2,
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Compound 10: The GP-3, combining 2c and enal 1g
= 8.47 (s, 1Hminor), 8.18 (s, 1Hmajor), 7.52 (d, J = 8.0 Hz,
3
4
5
6
7
8
9
compound 10 along with minor diastereomer (31.0 mg, 72%,
2Hmajor), 7.49 (d, J = 8.0 Hz, 2Hminor), 7.40-7.28 (m,
4Hmajor+minor), 7.25-7.06 (m, 10Hmajor+minor), 6.98-6.80 (m,
6Hmajor+minor), 4.19-4.13 (m, 1Hmajor), 4.12-4.07 (m, 1Hminor),
3.97 (d, J = 4.5 Hz, 1Hmajor), 3.92 (d, J = 4.5 Hz, 1Hminor), 3.68
(dd, J = 17.5, 9.0 Hz, 1Hminor), 3.42 (dd, J = 17.5, 5.0 Hz,
1Hmajor), 3.15 (dd, J = 17.5, 5.0 Hz, 1Hminor), 3.07 (dd, J =
17.5, 6.0 Hz, 1Hmajor), 2.39 (s, 3Hminor), 2.37 (s, 3Hmajor), 2.32
(s, 3Hmajor), 2.30 (s, 3Hminor) ppm. 13C{1H} NMR (75 MHz,
CDCl3) δ = 171.0, 170.7, 170.6, 163.5, 162.7, 139.6, 139.5,
139.1, 139.0, 138.9, 136.8, 136.5, 134.4, 134.1, 132.3, 132.3,
129.9, 129.2, 129.2, 128.8, 128.8, 128.6, 128.5, 125.9, 125.8,
125.0, 124.9, 122.0, 121.7, 121.0, 120.6, 117.4, 117.1, 55.6,
54.1, 36.6, 36.5, 36.4, 34.9, 21.4, 21.2 ppm. HRMS (ESI-
TOF) m/z: [M+H]+ calcd for C26H24BrN2O3 491.0965 and
combined yield) as white solid. The diastereomeric ratio (dr)
1
1
determined to be 4:1 by H NMR analysis. H NMR (500
MHz, CDCl3) δ = 8.33 (s, 1Hminor), 8.08 (s, 1Hmajor), 7.33-7.25
(m, 2Hmajor+minor), 7.24-7.06 (m, 12Hmajor+minor), 7.04-6.95 (m,
4Hmajor+minor), 6.91-6.73 (m, 6Hmajor+minor), 4.15-4.09 (m,
1Hmajor), 4.08-4.02 (m, 1Hminor), 3.91 (d, J = 4.5 Hz, 1Hmajor),
3.84 (d, J = 4.5 Hz, 1Hminor), 3.62 (dd, J = 17.5, 9.0 Hz,
1Hminor), 3.36 (dd, J = 17.5, 5.5 Hz, 1Hmajor), 3.08 (dd, J =
17.5, 5.5 Hz, 1Hminor), 3.01 (dd, J = 17.5, 5.5 Hz, 1Hmajor), 2.32
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
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(s, 3Hminor), 2.29 (s, 3Hmajor), 2.25 (s, 3Hmajor), 2.22 (s, 3Hminor
)
ppm. 13C{1H} NMR (75 MHz, CDCl3) δ = 171.2, 170.8,
170.7, 163.7 (d, J = 245.2 Hz), 163.6, 162.9, 160.4, 139.5,
139.5, 139.0, 138.9, 136.8, 136.5, 135.8, 135.8, 134.5, 134.1,
133.5, 133.5, 129.9, 129.2, 129.2, 128.8, 128.8, 128.7, 128.7,
128.6, 128.5 (d, J = 7.5 Hz), 128.5, 128.4, 125.9, 125.8, 125.0,
124.9, 121.0, 120.6, 117.4, 117.1, 116.3 (d, J = 21.0 Hz,
major), 116.2 (d, J = 21.0 Hz), 116.0, 115.9, 56.0, 54.5, 36.8,
36.5, 34.7, 21.4, 21.3, 21.2 ppm. HRMS (ESI-TOF) m/z :
[M+H]+ calcd for C26H24FN2O3 431.1772; found 431.1771. IR
(Neat) ѵmax = 3334, 2925, 1736, 1670, 1512, 1240, 1206, 836,
781, 695 cm-1. HPLC: The enantiomeric excess (% of ee = 98,
minor diastereoisomer and 97, major diastereoisomer) was
determined by HPLC analysis using Daicel Chiralpak IE-3
column: n-hexane:i-PrOH = 83:17, flow rate 1.0 mL/min, λ =
254 nm: τmajor = 11.74 min, τminor = 14.31 min for minor
diastereoisomer and τminor = 18.78 min, τmajor = 24.36 min for
major diastereoisomer.
493.0948; found 491.0967 and 493.0767. IR (Neat) ѵmax
=
3333, 3029, 2921, 1668, 1552, 1489, 1373, 1244, 823, 756,
694 cm-1. HPLC: The enantiomeric excess (% of ee = 92,
minor diastereoisomer and 98, major diastereoisomer) was
determined by HPLC analysis using Daicel Chiralpak IE-3
column: n-hexane:i-PrOH = 80:20, flow rate 1.0 mL/min, λ =
254 nm: τmajor = 11.10 min, τminor = 13.28 min for minor
diastereoisomer and τminor = 16.15 min, τmajor = 20.28 min for
major diastereoisomer.
Compound 13: The GP-3, combining 2c and enal 1j gave
compound 13 (31.0 mg, 63%, combined yield) as white solid,
along with the non separable minor diastereoisomer. The
1
diastereomeric ratio (dr) determined to be 5:1 by H NMR
1
analysis. H NMR (500 MHz, CDCl3) δ = 8.16 (s, 1Hmajor),
Compound 11: The GP-3, combining 2c and enal 1h gave
compound 11 along with minor diastereomer (30.0 mg, 67%,
combined yield) as white solid The diastereomeric ratio (dr)
7.61-7.58 (m, 2Hmajor+minor), 7.33-7.10 (m, 15H8H-major+7H-minor),
7.06-7.01 (m, 2Hminor), 6.93-6.86 (m, 3H1H-major+2H-minor), 6.84-
6.78 (m, 2Hmajor), 4.45 (m, 1Hmajor), 4.32-4.27 (m, 1Hminor),
4.09-4.08 (m, 2Hmajor+minor), 3.90 (dd, J = 16.5, 12.0 Hz,
1Hminor), 3.51 (dd, J = 17.5, 6.0 Hz, 1Hmajor), 3.13-3.08 (m,
1Hmajor), 2.97-2.93 (m, 1Hminor), 2.32 (s, 3H minor), 2.29 (s,
3Hmajor), 2.27 (s, 3H major), 2.20 (s, 3H minor) ppm. 13C{1H}
NMR (75 MHz, CDCl3) δ = 171.3, 171.3, 170.6, 170.1, 163.7,
162.6, 139.6, 139.5, 139.3, 139.1, 138.9, 136.9, 136.5, 136.4,
134.6, 134.2, 133.7, 129.9, 129.8, 129.6, 129.5, 129.2, 129.2,
128.9, 128.8, 128.7, 128.6, 128.2, 128.2, 127.9, 126.9, 125.9,
125.8, 125.2, 124.9, 124.7, 124.3, 121.1, 120.5, 117.5, 116.9,
53.9, 53.0, 36.7, 35.0, 34.5, 21.4, 21.4, 21.3 ppm. HRMS
(ESI-TOF) m/z : [M+H]+ calcd for C26H24BrN2O3 491.0965
1
1
determined to be 3:1 by H NMR analysis. H NMR (500
MHz, CDCl3) δ = 8.40 (s, 1Hminor), 8.09 (s, 1Hmajor), 7.32-7.23
(m, 7H4H-major+3H-minor), 7.18-7.07 (m, 9H6H-major+3H-minor), 7.02-
7.00 (m, 1Hminor), 6.89-6.84 (m, 4H1H-major+3H-minor), 6.78-6.76
(m, 3H1H-major+2H-minor), 4.13-4.09 (m, 1Hmajor), 4.07-4.04 (m,
1Hminor), 3.91 (d, J = 4.0 Hz, 1H major), 3.84 (d, J = 5.0 Hz, 1H
minor), 3.60 (dd, J = 17.5, 9.0 Hz, 1Hminor), 3.35 (dd, J = 17.5,
5.5 Hz, 1Hmajor), 3.08 (dd, J = 17.5, 5.0 Hz, 1Hminor), 3.01 (dd,
J = 17.5, 5.5 Hz, 1Hmajor), 2.32 (s, 3H minor), 2.29 (s, 3Hmajor),
2.25 (s, 3H major), 2.23 (s, 3H minor) ppm. 13C{1H} NMR (125
MHz, CDCl3) δ = 170.9, 170.8, 170.7, 170.6, 163.6, 162.8,
139.5, 139.5, 139.1, 138.9, 138.8, 136.9, 136.7, 136.5, 134.6,
134.3, 134.1, 133.8, 129.9, 129.5, 129.4, 129.2, 128.9, 128.8,
128.7, 128.7, 128.6, 128.3, 125.9, 125.9, 125.1, 125.1, 121.1,
120.8, 117.6, 117.2, 55.9, 54.4, 54.3, 36.7, 36.7, 34.9, 21.4,
21.2 ppm. HRMS (ESI-TOF) m/z : [M+H]+ calcd for
and 493.0948; found 491.0962 and 493.0763. IR (Neat) ѵmax
=
3317, 3032, 2919, 1737, 1683, 1615, 1489, 1370, 1209, 1192,
755, 693 cm-1. HPLC: The enantiomeric excess (% of ee = 96
of both the diastereoisomer) was determined by HPLC
analysis using Daicel Chiralpak IE-3 column: n-hexane:i-
C26H24ClN2O3 447.1470; found 447.1472. IR (Neat) ѵmax
=
PrOH = 80:20, flow rate 1.0 mL/min, λ = 254 nm: τmajor
13.17 min, τminor = 17.41 min for minor diastereoisomer and
τminor 20.36 min, τmajor 22.15 min for major
diastereoisomer.
=
3333, 3025, 2922, 1735, 1665, 1490, 1373, 1207, 1190, 1093,
755, 694 cm-1. HPLC: The enantiomeric excess (% of ee = 92,
minor diastereoisomer and 98, major diastereoisomer) was
determined by HPLC analysis using Daicel Chiralpak IE-3
column: n-hexane:i-PrOH = 80:20, flow rate 1.0 mL/min, λ =
254 nm: τmajor = 11.10 min, τminor = 13.28 min for minor
diastereoisomer and τminor = 16.15 min, τmajor = 20.28 min for
major diastereoisomer.
=
=
Compound 14: The GP-3, combining 2c and enal 1k gave 14
along with minor diastereomer (28.0 mg, 57%, combined
yield) as white solid. The diastereomeric ratio (dr) determined
to be 5:1 by 1H NMR analysis. 1H NMR (500 MHz, CDCl3) δ
= 8.19 (s, 1Hmajor), 7.50-7.44 (m, 4Hmajor+minor), 7.41-7.35 (m,
2Hmajor+minor), 7.35-7.27 (m, 4Hmajor+minor), 7.26-7.06 (m,
8Hmajor+minor), 6.98-6.83 (m, 6Hmajor+minor), 4.22-4.16 (m,
1Hmajor), 4.15-4.11 (m, 1Hminor), 4.00 (d, J = 3.5 Hz, 1Hmajor),
3.92 (d, J = 5.0 Hz, 1Hminor), 3.67 (dd, J = 17.5, 8.5 Hz,
Compound 12: The GP-3, combining 2c and enal 1i gave 12
along with minor diastereomer (39.0 mg, 76%, combined
yield) as white solid. The diastereomeric ratio (dr) determined
to be 3:1 by 1H NMR analysis. 1H NMR (500 MHz, CDCl3) δ
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8
9
1Hminor), 3.43 (dd, J = 17.5, 5.5 Hz, 1Hmajor), 3.17 (dd, J =
17.5, 5.5 Hz, 1Hminor), 3.09 (dd, J = 17.5, 5.0 Hz, 1Hmajor), 2.39
(s, 3Hminor), 2.37 (s, 3Hmajor), 2.33 (s, 3Hmajor), 2.30 (s, 3Hminor
17.04, 3.30 Hz, 1Hmajor), 2.92 (dd, J = 17.08, 4.26 Hz, 1Hminor),
2.31 (s, 3Hminor), 2.28 (s, 3Hmajor), 2.26 (s, 3Hmajor), 2.19 (s,
3Hminor) ppm. 13C{1H} NMR (125 MHz, CDCl3) δ = 171.8,
171.3, 171.0, 164.4, 163.7, 157.0, 156.7, 139.3, 139.0, 138.8,
137.2, 136.6, 135.0, 134.6, 129.6, 129.6, 129.0, 129.0, 128.9,
128.8, 128.8, 128.6, 128.3, 127.2, 127.0, 125.6, 125.5, 125.3,
125.1, 121.1, 121.0, 120.6, 117.5, 117.0, 111.1, 110.8, 55.4,
54.0, 53.3, 34.8, 31.6, 31.0, 21.3, 21.2, 21.2 ppm. HRMS
(ESI-TOF) m/z : [M+H]+ calcd for C27H27N2O4 443.1965;
found 443.1967. IR (Neat) ѵmax = 3322, 3018, 2922, 2841,
1734, 1666, 1491, 1357, 1243, 1204, 753, 695 cm-1. HPLC:
The enantiomeric excess (% of ee = 97 of both the
diastereoisomer) was determined by HPLC analysis using
Daicel Chiralpak IE-3 column: n-hexane:i-PrOH = 80:20, flow
rate 1.0 mL/min, λ = 254 nm: τmajor = 20.20 min, τminor = 28.36
)
ppm. 13C{1H} NMR (75 MHz, CDCl3) δ = 170.9, 170.6,
170.6, 170.5, 163.4, 162.5, 142.5, 140.1, 139.6, 139.5, 139.0,
138.9, 136.8, 136.4, 134.4, 134.1, 131.2, 131.0, 130.8, 130.7,
130.4, 130.0, 129.9, 129.2, 129.2, 128.9, 128.7, 128.6, 128.5,
126.0, 125.8, 125.7, 125.6, 125.0, 124.9, 123.3, 123.2, 121.3,
120.6, 117.7, 117.1, 55.4, 54.0, 36.8, 36.5, 35.0, 21.4, 21.3,
21.2 ppm. HRMS (ESI-TOF) m/z : [M+H]+ calcd for
C26H24BrN2O3 491.0965 and 493.0948; found 491.0963 and
493.0768. IR (Neat) ѵmax = 3320, 2922, 1736, 1681, 1614,
1489, 1553, 780, 692 cm-1. HPLC: The enantiomeric excess
(% of ee = 85, minor diastereoisomer and 96, major
diastereoisomer) was determined by HPLC analysis using
Daicel Chiralpak IE-3 column: n-hexane:i-PrOH = 83:17, flow
rate 1.0 mL/min, λ = 254 nm: τmajor = 13.35 min, τminor = 23.64
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
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
min for minor diastereoisomer and τminor = 25.53 min, τmajor
=
35.52 min for major diastereoisomer.
min for minor diastereoisomer and τminor = 18.47 min, τmajor
=
Compound 17: The GP-3, combining 2c and enal 1n gave
desired compound 17 along with minor diastereomer (38.2
mg, 81%, combined yield) as white solid. The diastereomeric
26.67 min for major diastereoisomer.
Compound 15: The GP-3, combining 2c and enal 1l gave
compound 15 along with minor diastereomer (38.0 mg, 71%,
combined yield) as white solid. The diastereomeric ratio (dr)
determined to be 3:1 by 1H NMR analysis. Compound 15 was
1
ratio (dr) determined to be 7:1 by H NMR analysis.1H NMR
(500 MHz, CDCl3) δ = 8.06 (s, 1Hmajor), 7.50 (s, 1Hminor), 7.32-
7.28 (m, 2Hmajor+minor), 7.28-7.23 (m, 2Hmajor+minor), 7.22-7.15
(m, 4Hmajor+minor), 7.15-6.99 (m, 6Hmajor+minor), 6.98-6.83 (m,
6Hmajor+minor), 6.83-6.73 (m, 4Hmajor+minor), 4.63-4.54 (m,
2Hmajor+minor), 4.30-4.21 (m, 2Hmajor+minor), 4.15-4.09 (m,
1Hmajor), 4.06 (d, J = 4.5 Hz, 1Hminor), 3.69 (dd, J = 17.5, 12.0
Hz, 1Hminor), 3.39 (dd, J = 17.5, 5.5 Hz, 1Hmajor), 3.13 (dd, J =
17.5, 2.5 Hz, 1Hmajor), 2.90 (dd, J = 17.5, 4.5 Hz, 1Hminor), 2.31
(s, 3Hminor), 2.28 (s, 3Hmajor), 2.26 (s, 3Hmajor), 2.19 (s, 3Hminor),
1.38 (d, J = 6.0 Hz, 3Hminor), 1.33 (d, J = 6.0 Hz, 3Hmajor),
1.32-1.26 (m, 6Hmajor+minor) ppm. 13C{1H} NMR (75 MHz,
CDCl3) δ = 172.0, 172.0, 171.2, 170.9, 164.4, 163.8, 155.0,
154.9, 139.3, 139.0, 138.7, 137.1, 136.4, 134.8, 134.4, 129.7,
129.6, 129.1, 128.8, 128.7, 128.7, 128.5, 126.9, 126.7, 126.3,
125.6, 125.5, 125.2, 125.0, 121.1, 120.6, 120.5, 120.4, 117.5,
116.9, 112.7, 112.6, 70.2, 69.8, 53.9, 53.2, 34.5, 34.3, 31.3,
30.8, 22.3, 22.3, 22.0, 21.9, 21.4, 21.3, 21.2 ppm. HRMS
(ESI-TOF) m/z : [M+H]+ calcd for C29H31N2O4 471.2278;
found 471.2276. IR (Neat) ѵmax = 3314, 2976, 2920, 1735,
1673, 1596, 1371, 1239, 956, 752, 692 cm-1. HPLC: The
enantiomeric excess (% of ee = 78, minor diastereoisomer and
88, major diastereoisomer) was determined by HPLC analysis
using Daicel Chiralpak ID-3 column: n-hexane:i-PrOH =
83:17, flow rate 0.6 mL/min, λ = 254 nm: τmajor = 23.33 min,
τminor = 20.72 min for minor diastereoisomer and τminor = 21.72
min, τmajor = 26.29 min for major diastereoisomer.
crystallized by slow evaporation from
a mixture of
EtOAc:iPrOH (1:6). Absolute configuration of the compound
15 was unambiguously determined by the single-crystal X-ray
1
analysis. H NMR (500 MHz, CDCl3) δ = 8.35 (s, 1Hminor),
8.10 (s, 1Hmajor), 7.64-7.59 (m, 4Hmajor+minor), 7.31-7.05 (m,
10Hmajor+minor), 7.01-6.95 (m, 4Hmajor+minor), 6.88-6.75 (m,
6Hmajor+minor), 4.06 (d, J = 5.5 Hz, 1Hmajor), 3.99-3.98 (m,
1Hminor), 3.88 (d, J = 4.5 Hz, 1Hmajor), 3.83 (d, J = 4.5 Hz, 1H
minor), 3.58 (dd, J = 17.5, 9.0 Hz, 1Hminor), 3.32 (dd, J = 17.0,
5.0 Hz, 1Hmajor), 3.05 (dd, J = 17.0, 4.5 Hz, 1Hminor), 2.98 (dd,
J = 17.5, 6.0 Hz, 1Hmajor), 2.31 (s, 3H minor), 2.29 (s, 3Hmajor),
2.24 (s, 3H major), 2.22 (s, 3H minor) ppm. 13C{1H} NMR (75
MHz, CDCl3) δ = 171.1, 170.8, 170.6, 163.6, 162.8, 139.9,
139.5, 139.06, 138.9, 138.5, 138.4, 138.2, 138.1, 137.6, 136.9,
136.6, 134.5, 134.2, 129.9, 129.3, 129.2, 129.1, 129.1, 128.9,
128.9, 128.8, 128.8, 128.5, 125.9, 125.8, 125.1, 124.9, 124.8,
121.0, 120.8, 120.7, 117.5, 117.2, 93.6, 93.2, 55.9, 55.5, 36.7,
36.6, 36.4, 35.3, 34.9, 21.5, 21.3, 21.2 ppm. HRMS (ESI-
TOF) m/z : [M+H]+ calcd for C26H24IN2O3 539.0826; found
539.0825. IR (Neat) ѵmax = 3332, 3022, 2920, 1734, 1664,
1487, 1371, 1206, 1005, 753, 694 cm-1. HPLC: The
enantiomeric excess (% of ee = 98, minor diastereoisomer and
97, major diastereoisomer) was determined by HPLC analysis
using Daicel Chiralpak IE-3 column: n-hexane:i-PrOH =
80:20, flow rate 1.0 mL/min, λ = 254 nm: τmajor = 12.78 min,
τminor = 15.16 min for minor diastereoisomer and τminor = 18.30
min, τmajor = 22.78 min for major diastereoisomer.
Compound 18: The GP-3, combining 2c and enal 1o gave 18
along with minor diastereomer (40.0 mg, 90%, combined
yield) as white solid. The diastereomeric ratio (dr) determined
to be 3:1 by 1H NMR analysis. 1H NMR (500 MHz, CDCl3) δ
= 8.06 (s, 1Hmajor), 7.31-7.24 (m, 3H2Hmajor+1Hminor), 7.18-7.05
(m, 10Hmajor+minor), 6.97 (d, J = 7.5 Hz, 1Hminor), 6.87-6.77 (m,
10Hmajor+minor), 4.06-4.00 (m, 2Hmajor+minor), 3.91 (d, J = 4.0 Hz,
1Hmajor), 3.81 (d, J = 4.5 Hz, 1Hminor), 3.73 (s, 3Hmajor), 3.71 (s,
3H minor), 3.56 (dd, J = 17.0, 9.0Hz, 1Hminor), 3.35 (dd, J =
17.5, 5.5 Hz, 1Hmajor), 3.07 (d, J = 5.0 Hz, 1H minor), 3.01 (dd, J
= 17.0, 5.0 Hz, 1Hmajor), 2.31 (s, 3H minor), 2.29 (s, 3Hmajor),
2.24 (s, 3H major), 2.21 (s, 3H minor) ppm. 13C{1H} NMR (125
MHz, CDCl3) δ = 171.5, 171.1, 171.0, 164.1, 163.3, 159.4,
159.1, 139.4, 139.4, 139.0, 138.9, 137.1, 136.8, 134.8, 134.5,
Compound 16: The GP-3, combining 2c and enal 1m gave
desired compound 16 along with minor diastereomer (36.1
mg, 81%, combined yield) as white solid. The diastereomeric
ratio (dr) determined to be 5:1 by 1H NMR analysis. 1H NMR
(500 MHz, CDCl3) δ = 8.10 (s, 1Hmajor), 7.32-7.28 (m, 1Hmajor),
7.28-7.21 (m, 4Hmajor+minor), 7.21-7.18 (m, 2Hmajor+minor), 7.16-
7.08 (m, 6Hmajor+minor), 7.03-7.00 (m, 1Hminor), 6.94-6.84 (m,
6Hmajor+minor), 6.84-6.75 (m, 4Hmajor+minor), 4.32-4.23 (m,
2Hmajor+minor), 4.14-4.10 (m, 1Hmajor), 4.07 (d, J = 4.64 Hz,
1Hminor), 3.81 (s, 3Hminor), 3.80 (s, 3Hmajor), 3.74-3.68 (m,
1Hminor), 3.39 (dd, J = 17.67, 5.94 Hz, 1Hmajor), 3.12 (dd, J =
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132.2, 129.8, 129.2, 129.1, 128.9, 128.8, 128.7, 128.2, 127.9,
rate 1.0 mL/min, λ = 254 nm: τmajor = 14.07min, τminor = 19.22
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125.8, 125.8, 125.2, 125.1, 121.2, 120.8, 117.6, 117.2, 114.7,
114.7, 56.3, 55.3, 55.2, 46.2, 36.9, 36.7, 34.7, 21.4, 21.3, 21.2
ppm. HRMS (ESI-TOF) m/z : [M+Na]+ calcd for C27H26N2O4
Na 465.1790; found 465.1792. IR (Neat) ѵmax = 3332, 2920,
2834, 1735, 1667, 1613, 1514, 1374, 1249, 1188, 1033, 753,
695 cm-1. HPLC: The enantiomeric excess (% of ee = 90 of
both the diastereoisomer) was determined by HPLC analysis
using Daicel Chiralpak IE-3 column: n-hexane:i-PrOH =
75:25, flow rate 1.0 mL/min, λ = 254 nm: τmajor = 13.99 min,
τminor = 19.95 min for minor diastereoisomer and τminor = 21.65
min, τmajor = 27.23 min for major diastereoisomer.
min for minor diastereoisomer and τminor = 23.25 min, τmajor =
29.78 min for major diastereoisomer.
Compound 21: The GP-3, combining 2c and enal 1r gave
compound 21 along with minor diastereomer (28.0 mg, 61%,
combined yield) as green solid. The diastereomeric ratio (dr)
1
1
determined to be 3:1 by H NMR analysis. H NMR (500
MHz, CDCl3) δ = 8.12 (s, 1Hmajor), 7.97 (d, J = 7.0 Hz,
2Hmajor+minor), 7.86 (d, J = 8.0 Hz, 1Hminor), 7.61 (t, J = 7.5 Hz,
1Hmajor), 7.55-7.49 (m, 2Hminor), 7.45 (t, J = 7.5 Hz, 1Hmajor),
7.41-7.36 (m, 2Hmajor+minor), 7.31-7.27 (m, 2Hmajor+minor), 7.22-
7.10 (m, 6H4Hmajor+2Hminor), 7.05-7.00 (m, 2Hminor), 6.92-6.80
(m, 6Hmajor+minor), 4.64-4.58 (m, 1Hmajor), 4.44-4.38 (m, 1Hminor),
4.24 (d, J = 5.0 Hz, 1H minor), 4.09-4.02 (m, 2Hmajor+minor), 3.54
(dd, J = 18.0, 6.5 Hz, 1Hmajor), 3.04 (dd, J = 18.0, 4.0 Hz,
1Hmajor), 2.92 (dd, J = 17.0, 4.0 Hz, 1H minor), 2.30 (s,
6Hmajor+minor), 2.25 (s, 3Hmajor), 2.19 (s, 3H minor) ppm. 13C{1H}
NMR (75 MHz, CDCl3) δ = 170.9, 170.8, 169.8, 169.8, 163.8,
162.9, 149.6, 149.3, 139.6, 139.4, 139.0, 138.8, 136.9, 136.4,
135.6, 134.4, 134.1, 133.9, 133.4, 132.1, 129.9, 129.8, 129.2,
129.1, 129.0, 128.9, 128.8, 128.7, 128.6, 128.6, 127.4, 126.1,
125.9, 125.7, 125.2, 125.1, 124.9, 120.9, 120.6, 117.3, 117.0,
55.2, 54.3, 35.5, 34.9, 32.8, 32.1, 21.4, 21.3, 21.2, 21.2 ppm.
IR (Neat) ѵmax = 3317, 2925, 1738. 1615, 1686, 1526, 1492,
1356, 1244, 1190, 782,694 cm-1. HRMS (ESI-TOF) m/z :
[M+H]+ calcd for C26H24N3O5 458.1716; found 458.1717. IR
(Neat) ѵmax = 3317, 2925, 1738, 1685, 1615, 1526, 1429, 1356,
1244, 782, 694 cm-1. HPLC: The enantiomeric excess (% of
ee = 96, minor diastereoisomer and 99, major diastereoisomer)
was determined by HPLC analysis using Daicel Chiralpak IE-
3 column: n-MTBE :i-PrOH = 95:5, flow rate 1.0 mL/min, λ =
254 nm: τmajor = 5.95 min, τminor = 7.14 min for minor
diastereoisomer and τminor = 10.69 min, τmajor = 9.14 min for
major diastereoisomer.
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16
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Compound 19: The GP-3, combining 2c and enal 1p gave 19
(34.0 mg, 68%, combined yield) as white solid along with the
non separable minor diastereoisomer. The diastereomeric ratio
(dr) determined to be 3:1 by 1H NMR analysis. 1H NMR (500
MHz, CDCl3) δ = 8.81 (s, 1Hminor), 8.15 (s, 1Hmajor), 7.32-7.24
(m, 2Hmajor+minor), 7.19-7.04 (m, 8Hmajor+minor), 6.98-6.93 (m,
2Hmajor+minor), 6.91-6.74 (m, 10Hmajor+minor), 4.11-4.04 (m,
1Hmajor), 3.99-3.93 (m, 1Hminor), 3.91 (d, J = 4.5 Hz, 1Hmajor),
3.82 (d, J = 4.5 Hz, 1Hminor), 3.72 (s, 3Hmajor), 3.60 (dd, J =
17.5, 10.5 Hz, 1Hminor), 3.55 (s, 3Hminor), 3.34 (dd, J = 17.5, 5.5
Hz, 1Hmajor), 3.08-2.97 (m, 2Hmajor+minor), 2.31 (s, 3Hminor), 2.28
(s, 3Hmajor), 2.24 (s, 6Hmajor), 2.23 (s, 3Hminor), 2.21 (s, 3Hminor
)
ppm. 13C{1H} NMR (125 MHz, CDCl3) δ = 171.3, 170.8,
170.6, 170.4, 168.7, 168.6, 164.2, 163.4, 151.7, 139.7, 139.4,
139.2, 139.0, 138.8, 137.0, 136.6, 136.5, 134.7, 134.3, 129.7,
129.7, 129.1, 128.8, 128.8, 128.7, 128.6, 125.8, 125.8, 125.6,
125.1, 125.0, 123.4, 123.3, 121.1, 120.9, 120.8, 119.1, 118.3,
117.6, 117.4, 117.2, 111.8, 111.6, 56.3, 56.0, 55.7, 55.5, 37.5,
36.6, 35.9, 35.6, 21.3, 21.1, 20.5 ppm. HRMS (ESI-TOF)
m/z : [M+Na]+ calcd for C29H28N2O6Na 523.1845; found
523.1844. IR (Neat) ѵmax = 3332, 3029, 2928, 1764, 1737,
1678, 1553, 1370, 1200, 1032, 781, 696 cm-1. HPLC: The
enantiomeric excess (% of ee = 98, minor diastereoisomer and
97, major diastereoisomer) was determined by HPLC analysis
using Daicel Chiralpak IE-3 column: n-hexane:i-PrOH =
75:25, flow rate 1.0 mL/min, λ = 254 nm: τmajor = 14.19 min,
τminor = 19.04 min for minor diastereoisomer and τminor = 21.18
min, τmajor = 27.94 min for major diastereoisomer.
Compound 22: The GP-3, combining 2c and enal 1s gave
compound 22 (23.0 mg, 48%, combined yield) as white solid
along with the non separable minor diastereoisomer. The
1
diastereomeric ratio (dr) determined to be 3:1 by H NMR
1
analysis. H NMR (500 MHz, CDCl3) δ = 8.21 (s, 1Hmajor),
7.68-7.63 (m, 4Hmajor+minor), 7.46-7.40 (m, 4Hmajor+minor), 7.39-
7.34 (m, 2Hmajor+minor), 7.30-7.13 (m, 8Hmajor+minor), 7.09-7.08
(m, 1Hminor), 6.97-6.84 (m, 5H3H-major+ 2H-minor), 4.31-4.27 (m,
1Hmajor), 4.24-4.20 (m, 1Hminor), 4.04 (d, J = 4.0 Hz, 1Hmajor),
3.98 (d, J = 4.5 Hz, 1H minor), 3.78-3.72 (m, 1Hminor), 3.45 (dd,
J = 17.0, 5.0 Hz, 1Hmajor), 3.21 (dd, J = 17.5, 5.00 Hz, 1H
minor), 3.12 (dd, J = 17.5, 5.5 Hz, 1Hmajor), 2.39 (s, 3H minor),
2.37 (s, 3Hmajor), 2.33 (s, 3H major), 2.29 (s, 3H minor) ppm.
13C{1H} NMR (75 MHz, CDCl3) δ = 170.9, 170.7, 170.6,
170.5, 163.2, 162.5, 144.3, 142.0, 139.6, 139.1, 139.0, 136.8,
136.5, 134.4, 134.0, 130.4, 130.0, 129.3, 128.9, 128.8, 128.6,
127.6, 127.4, 126.3, 126.2, 126.2, 126.1, 126.0, 125.9, 125.6,
124.9, 124.9, 122.0, 120.9, 120.7, 117.4, 117.1, 55.4, 53.9,
36.9, 36.5, 36.4, 35.2, 29.7, 21.4, 21.3 ppm. HRMS (ESI-
TOF) m/z : [M+Na]+ calcd for C27H23F3N2O3Na 503.1559;
found 503.1556. IR (Neat) ѵmax = 3332, 2925, 1737, 1673,
1617, 1490, 1553, 1325, 1167, 1070, 780 cm-1. HPLC: The
enantiomeric excess (% of ee = 90, minor diastereoisomer and
91, major diastereoisomer) was determined by HPLC analysis
using Daicel Chiralpak IE-3 column: n-hexane:i-PrOH =
80:20, flow rate 1.0 mL/min, λ = 254 nm: τmajor = 7.86 min,
Compound 20: The GP-3, combining 2c and enal 1q gave 20
along with minor diastereomer (32.3 mg, 71%, combined
yield) as yellow solid. The diastereomeric ratio (dr)
1
1
determined to be 4:1 by H NMR analysis. H NMR (300
MHz, CDCl3) δ = 8.44 (s, 1H), 8.12 (s, 1H), 7.36-7.04 (m,
14H), 7.03-6.91 (m, 4H), 6.91-6.73 (m, 6H), 4.15-4.01 (m,
2H), 3.91 (d, J = 4.5 Hz, 1H), 3.85 (d, J = 4.5 Hz, 1H), 3.62
(dd, J = 17.4, 8.7 Hz, 1H), 3.35 (dd, J = 17.4, 5.1 Hz, 1H),
3.14-2.93 (m, 2H), 2.32 (s, 3H), 2.29 (s, 3H), 2.24 (s, 3H),
2.22 (s, 3H) ppm. 13C{1H} NMR (125 MHz, CDCl3) δ =
171.1, 170.9, 170.7, 163.6, 162.9, 139.9, 139.7, 139.5, 139.5,
139.2, 139.0, 138.9, 136.9, 136.7, 136.6, 134.5, 134.4, 134.2,
129.8, 129.2, 129.2, 128.8, 128.7, 128.6, 128.6, 128.5, 128.3,
125.9, 125.8, 125.0, 125.0, 121.0, 120.7, 119.8, 119.7, 117.4,
117.1, 55.9, 54.3, 36.8, 36.6, 34.9, 21.3, 21.2 ppm. HRMS
(ESI-TOF) m/z : [M+Na]+ calcd for C26H23N5O3Na 476.1699;
found 476.1698. IR (Neat) ѵmax = 3331, 3032, 2921, 2416,
2257, 2120, 1736, 1670, 1503, 1191, 756, 694 cm-1. HPLC:
The enantiomeric excess (% of ee = 92 of both the
diastereoisomer) was determined by HPLC analysis using
Daicel Chiralpak IE-3 column: n-hexane:i-PrOH = 80:20, flow
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τminor = 8.70 min for minor diastereoisomer and τminor = 11.82
min, τmajor = 15.23 min for major diastereoisomer.
minor), 7.33-7.22 (m, 6Hmajor+minor), 7.17-7.07 (m, 6Hmajor+minor),
6.99-6.96 (m, 1Hminor), 6.90-6.76 (m, 5H3H-major+2H-minor), 4.27-
4.24 (m, 1Hmajor), 4.19-4.16 (m, 1Hminor), 4.08 (d, J = 3.5 Hz,
1Hmajor), 3.93 (d, J = 4.5 Hz, 1H minor), 3.71 (dd, J = 17.5, 10.0
Hz, 1Hminor), 3.44 (dd, J = 17.5, 5.5 Hz, 1Hmajor), 3.17-3.13 (m,
2Hmajor+minor), 2.29 (s, 3Hminor), 2.26 (s, 3Hmajor), 2.22 (s,
3Hmajor), 2.11 (s, 3Hminor) ppm. 13C{1H} NMR (125 MHz,
CDCl3) δ = 171.4, 170.9, 170.9, 164.0, 163.2, 139.4, 139.1,
138.8, 137.7, 137.1, 136.5, 135.3, 134.8, 134.5, 133.5, 133.5,
132.9, 132.7, 129.8, 129.3, 129.2, 128.9, 128.8, 128.8, 128.7,
127.9, 127.8, 127.7, 127.7, 126.7, 126.5, 126.4, 125.9, 125.8,
125.3, 125.2, 125.1, 121.3, 120.8, 117.8, 117.2, 55.9, 54.9,
37.5, 36.6, 36.5, 35.6, 21.3, 21.2 ppm. HRMS (ESI-TOF)
m/z : [M+Na]+ calcd for C30H26N2O3Na 485.1841; found
485.1842. IR (Neat) ѵmax = 3331, 3021, 2920, 1735, 1666,
1363, 1242, 1195, 749, 695, 476 cm-1. HPLC: The
enantiomeric excess (% of ee = 97, minor diastereoisomer and
94, major diastereoisomer) was determined by HPLC analysis
using Daicel Chiralpak IE-3 column: n-hexane:i-PrOH =
80:20, flow rate 1.0 mL/min, λ = 254 nm: τmajor = 17.21 min,
τminor = 23.02 min for minor diastereoisomer and τminor = 24.72
min, τmajor = 32.24 min for major diastereoisomer.
Compound 23: The GP-3, combining 2c and enal 1t gave
compound 23 along with minor diastereomer (28.1 mg, 70%,
combined yield) as white solid. The diastereomeric ratio (dr)
1
1
determined to be 3:1 by H NMR analysis. H NMR (500
MHz, CDCl3) δ = 8.26 (s, 1Hmajor), 7.34 (d, J = 1.5 Hz,
1Hmajor), 7.32-7.22 (m, 7H3Hmajor+4Hminor), 7.19-7.08 (m,
6H3Hmajor+3Hminor), 6.92-6.84 (m, 2Hmajor+minor), 6.83-6.73 (m,
2Hmajor+minor), 6.32-6.26 (m, 2Hmajor+minor), 6.24-6.17 (m,
2Hmajor+minor), 4.35-4.30 (m, 1Hminor), 4.20-4.16 (m, 1Hmajor),
4.12-4.10 (m, 1Hmajor), 3.86 (d, J = 4.5 Hz, 1Hminor), 3.43-3.36
(m, 1Hmajor+minor), 3.15-3.05 (m, 1Hmajor+minor), 2.32 (s, 3Hminor),
2.29 (s, 3Hmajor), 2.28 (s, 3Hmajor), 2.24 (s, 3Hminor) ppm.
13C{1H} NMR (100 MHz, CDCl3) δ = 170.8, 170.5, 163.3,
162.1, 153.4, 151.7, 142.6, 142.4, 139.5, 139.4, 139.1, 138.9,
137.0, 136.9, 134.6, 134.3, 129.9, 129.8, 129.2, 129.1, 128.9,
128.7, 128.6, 125.8, 125.6, 125.0, 121.1, 120.5, 117.5, 117.0,
110.8, 110.6, 107.6, 106.5, 53.0, 51.1, 36.8, 34.2, 32.0, 29.9,
21.4, 21.3, 21.3, 21.2 ppm. HRMS (ESI-TOF) m/z : [M+Na]+
calcd for C24H22N2O4Na 425.1477; found 425.1443. IR (Neat)
ѵmax = 3332, 2925, 1736, 1673, 1554, 1489, 1369, 1248, 780,
696 cm-1. HPLC: The enantiomeric excess (% of ee = 95 of
both the diastereoisomer) was determined by HPLC analysis
using Daicel Chiralpak IE-3 column: n-hexane:i-PrOH =
83:17, flow rate 1.0 mL/min, λ = 254 nm: τmajor = 16.83 min,
τminor = 24.28 min for minor diastereoisomer and τminor = 20.75
min, τmajor = 35.64 min for major diastereoisomer.
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19
20
21
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23
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28
29
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Compound 26: The GP-3, combining 2c and enal 1w gave
compound 26 along with minor diastereomer (29.0 mg, 63%,
combined yield) as white solid. The diastereomeric ratio (dr)
1
1
determined to be 6:1 by H NMR analysis. H NMR (500
MHz, CDCl3) δ = 8.19 (s, 1H), 8.11 (d, J = 8.5 Hz, 1H minor),
8.02 (d, J = 8.5Hz, 1Hmajor), 7.97-7.93 (m, 2Hmajor+minor), 7.87-
7.84 (m, 2Hmajor+minor), 7.66-7.55 (m, 4H2H-major+2H-minor), 7.51-
7.48 (m, 1Hmajor), 7.45-7.39 (m, 8H4H-major+4H-minor), 7.27-7.23
(m, 4H2H-major+2H-minor), 7.09-7.03 (m, 3Hminor), 6.99 (d, J = 7.5
Hz, 1H major), 6.88-6.86 (m, 2Hmajor), 6.78 (d, J = 8.0 Hz, 1H
minor), 5.08-5.07 (m, 1Hmajor), 4.87 (m, 1Hminor), 4.24 (t, J = 2.0
Hz, 1H), 4.19-4.18 (m, 1Hminor), 3.96 (dd, J = 17.0, 10.5 Hz,
1Hminor), 3.67 (dd, J = 17.5, 6.0 Hz, 1H major), 3.31 (td, J =
17.5, 2.5 Hz, 1H major), 3.18 (dd, J = 17.0, 4.0 Hz, 1Hminor),
2.41 (s, 3Hminor), 2.38 (s, 3H major), 2.37 (s, 3H major), 2.25 (s,
3Hminor) ppm. 13C{1H} NMR (125 MHz, CDCl3) δ = 171.4,
171.3, 163.9, 162.6, 139.4, 139.1, 138.8, 137.1, 136.4, 134.9,
134.4, 134.3, 133.2, 130.7, 130.6, 129.8, 129.7, 129.6, 129.5,
129.1, 128.9, 128.8, 128.7, 128.6, 127.2, 126.2, 125.8, 125.4,
125.3, 125.1, 125.0, 123.7, 122.8, 122.4, 122.0, 121.2, 120.6,
54.9, 54.3, 35.6, 35.3, 33.0, 30.7, 21.4, 21.2 ppm. HRMS
(ESI-TOF) m/z : [M+H]+ calcd for C30H27N2O3 463.2016;
found 463.2014. IR (Neat) ѵmax = 3340, 3059, 2922, 2846,
1735, 1670, 1614, 1363, 1046, 776, 695 cm-1. HPLC: The
enantiomeric excess (% of ee = 97, minor diastereoisomer and
98, major diastereoisomer) was determined by HPLC analysis
using Daicel Chiralpak IE-3 column: n-hexane:i-PrOH =
80:20, flow rate 1.0 mL/min, λ = 254 nm: τmajor = 17.56 min,
τminor = 22.55 min for minor diastereoisomer and τminor = 16.16
min, τmajor = 26.21 min for major diastereoisomer.
Compound 24: The GP-3, combining 2c and enal 1u gave
compound 24 along with minor diastereomer (30.0 mg, 72%,
combined yield) as white solid. The diastereomeric ratio (dr)
1
1
determined to be 3:1 by H NMR analysis. H NMR (500
MHz, CDCl3) δ = 9.18 (s, 1Hminor), 8.19 (s, 1Hmajor), 7.31-7.08
(m, 11H7Hmajor+4Hminor), 6.94-6.89 (m, 4H3Hmajor+1Hminor), 6.87-
6.83 (m, 3Hminor), 6.79-6.77 (m, 4H1H-major+3H-minor), 4.51-4.48
(m, 1Hminor), 4.41-4.38 (m, 1Hmajor), 4.05-4.04 (m, 1Hmajor),
3.87 (d, J = 4.5 Hz, 1H minor), 3.53-3.46 (m, 2Hmajor+minor), 3.21
(dd, J = 18.0, 5.5 Hz, 1H minor), 3.14-3.09 (m, 1Hminor), 2.32 (s,
3H minor), 2.29 (s, 3Hmajor), 2.27 (s, 3H major), 2.34 (s, 3H minor
)
ppm. 13C{1H} NMR (75 MHz, CDCl3) δ = 171.1, 170.7,
170.6, 170.5, 163.4, 162.3, 143.6, 140.6, 139.6, 139.5, 139.1,
138.9, 136.9, 134.4, 134.1, 129.9, 129.9, 129.3, 129.2, 128.9,
128.8, 128.6, 127.3, 127.2, 125.8, 125.8, 125.6, 125.3, 124.9,
124.9, 124.8, 121.1, 120.6, 117.5, 117.0, 56.3, 53.7, 38.9,
37.2, 33.5, 31.5, 29.7, 21.4, 21.3 ppm. HRMS (ESI-TOF)
m/z : [M+H]+ calcd for C24H23N2O3S 419.1424; found
419.1422. IR (Neat) ѵmax = 3332, 3027, 2922, 1736, 1667,
1614, 1553, 1361, 1196, 754, 695 cm-1. HPLC: The
enantiomeric excess (% of ee = 99, minor diastereoisomer and
97, major diastereoisomer) was determined by HPLC analysis
using Daicel Chiralpak IE-3 column: n-hexane:i-PrOH =
80:20, flow rate 1.0 mL/min, λ = 254 nm: τmajor = 13.69 min,
τminor = 22.12 min for minor diastereoisomer and τminor = 19.54
min, τmajor = 24.49 min for major diastereoisomer.
Compound 27: The GP-3, combining 2c and enal 1x gave
compound 27 (27.0 mg, 53%) as white solid with excellent
1
diastereoselectivity. H NMR (300 MHz, CDCl3) δ = 8.39 (s,
Compound 25: The GP-3, combining 2c and enal 1v gave
compound 25 along with minor diastereomer (31.0 mg, 67%,
combined yield) as white solid. The diastereomeric ratio (dr)
2H), 7.98 (d, J = 8.1 Hz, 2H), 7.59-7.46 (m, 2H), 7.45-7.29
(m, 4H), 7.22-7.14 (m, 2H), 7.07-6.98 (m, 2H), 6.86 (t, J = 7.8
Hz, 1H), 6.79-6.61 (m, 3H), 5.80-5.59 (m, 1H), 4.82 (d, J =
11.1 Hz, 1H), 3.82 (dd, J = 17.1, 14.4 Hz, 1H), 3.17 (dd, J =
17.1, 5.4 Hz, 1H), 2.34 (s, 3H), 2.03 (s, 3H) ppm. 13C{1H}
NMR (125 MHz, CDCl3) δ = 171.0, 170.9, 164.6, 139.5,
1
1
determined to be 5:1 by H NMR analysis. H NMR (500
MHz, CDCl3) δ = 8.16 (s, 1Hmajor), 7.79-7.72 (m, 5H3H-major+2H-
minor), 7.68-7.62 (m, 3H1H-major+2H-minor), 7.45-7.40 (m, 4Hmajor+-
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2
3
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5
6
7
8
9
138.5, 136.6, 134.9, 131.9, 129.8, 129.7, 129.2, 129.2, 128.9,
diastereoisomer) was determined by HPLC analysis using
Daicel Chiralpak IA-3 column: n-hexane:i-PrOH = 90:10,
flow rate 0.6 mL/min, λ = 254 nm: τmajor = 18.22 min, τminor
17.19 min for minor diastereoisomer and τminor = 25.41 min,
τmajor = 22.16 min for major diastereoisomer.
128.4, 125.5, 125.3, 123.6, 120.9, 117.4, 55.8, 37.1, 30.4,
21.3, 21.1 ppm. HRMS (ESI-TOF) m/z : [M+Na]+ calcd for
=
C34H28N2O3Na 535.1998; found 535.1996. IR (Neat) ѵmax
=
3346, 3048, 2925, 1734, 1678, 1357, 1236, 1193, 1045, 730,
695 cm-1. HPLC: The enantiomeric excess (% of ee = 98) was
determined by HPLC analysis using Daicel Chiralpak IA-3
column: n-hexane:i-PrOH = 80:20, flow rate 1.0 mL/min, λ =
254 nm: τmajor = 27.61 min, τminor = 15.01min. [α]D 25 = -3.43 (c
= 0.60, CHCl3).
Synthetic application-I: General procedure (GP-4) for the
synthesis of piperidine rings (36 and 37):
Step 1: Gram scale experiment: To a flame dried Schlenk
round bottom flask equipped with a magnetic stir bar, carbene
precursor 3d (0.15 equiv), activated 3Å MS (50.0 mg / mmol)
and THF (0.1 M) were placed under argon atmosphere. To the
resulting heterogeneous mixture, DBU (0.2 equiv) was added.
The mixture was stirred at 25 °C for 5 minutes before 1,3-
diamide 2c (1.1 equiv) and oxidant (1.5 equiv) were added
successively to the reaction mixture. The resulting mixture
was cooled to 0 ºC. To the cold reaction mixture, enal (1.5
equiv or 1.0 equiv) was added. The reaction was continued for
48 h, while maintaining the reaction temperature -2 ºC. The
progress of the reaction was monitored by TLC analysis. The
crude reaction mixture was concentrated under reduced
pressure and purified by gradient column chromatography
from 1:1 DCM:Hexane to DCM to DCM:EtOAc (95:5) to
afford the desired compound.
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
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Compound 28: The GP-3, combining 2c and enal 1y
compound 28 along with minor diastereomer (24.0 mg, 56%,
combined yield) as white solid. Compound 28 was crystallized
i
by slow evaporation from PrOH. Absolute configuration of
the compound 28 was unambiguously determined by the
single-crystal X-ray analysis. The diastereomeric ratio (dr)
1
1
determined to be 4:1 by H NMR analysis. H NMR (500
MHz, CDCl3) δ = 8.19 (s, 1Hmajor), 7.30-7.26 (m, 4Hmajor+minor),
7.22-7.20 (m, 2Hmajor+minor), 7.16-7.12 (m, 4Hmajor+minor), 6.89-
6.87 (m, 2Hmajor+minor), 6.83-6.79 (m, 4Hmajor+minor), 3.78-3.74
(m, 2Hmajor+minor), 3.30 (dd, J = 18.0, 11.0 Hz, 1H minor), 3.09
(dd, J = 17.5, 5.5 Hz, 1Hmajor), 2.89 (dd, J = 17.5, 4.5 Hz, 1H
minor), 2.80-2.76 (m, 1Hmajor), 2.63-2.62 (m, 2Hmajor+minor), 2.30
(s, 6H major+minor), 2.26 (s, 6H major+minor), 1.76-1.62 (m,
10Hmajor+minor), 1.47-1.41 (m, 2Hmajor+minor), 1.22-0.91 (m,
10Hmajor+minor) ppm. 13C{1H} NMR (75 MHz, CDCl3) δ =
172.5, 171.9, 171.5, 164.1, 163.6, 139.4, 139.0, 137.1, 137.0,
134.7, 134.4, 129.8, 129.7, 129.2, 128.9, 128.7, 128.6, 125.7,
125.6, 125.0, 124.9, 120.8, 120.5, 117.2, 116.9, 52.6, 51.7,
40.3, 38.2, 37.8, 35.3, 33.0, 31.0, 30.9, 30.5, 29.8, 26.2,
26.201, 26.1, 25.9, 25.9, 21.4, 21.3 ppm. HRMS (ESI-TOF)
m/z : [M+H]+ calcd for C26H31N2O3 419.2329; found
419.2328. IR (Neat) ѵmax = 3329, 2925, 2853, 1734, 1666,
1552, 1489, 1372, 1254, 1197, 756, 693 cm-1.HPLC: The
enantiomeric excess (% of ee = 97, minor diastereoisomer and
98, major diastereoisomer) was determined by HPLC analysis
using Daicel Chiralpak IE-3 column: n-hexane:i-PrOH =
80:20, flow rate 1.0 mL/min, λ = 254 nm: τmajor = 10.70 min,
τminor = 14.59 min for minor diastereoisomer and τminor = 16.48
min, τmajor = 20.02 min for major diastereoisomer.
Step-2: Trans amidation: To a 100 ml screw cap pressure
tube equipped with a magnetic stirr bar, was added glutarimide
(1.0 equiv), p-anisidine (8.0 eq.) and LiCl (10 mol%). The
pressure tube was evacuated and refilled with argon before
anhydrous THF (0.1 M) was added into it. The reaction
mixture was heated at 160 °C and the progress of the reaction
was monitored by TLC. The reaction was quenched by the
addition of 2(M) HCl. Aqueous layer was extracted with
EtOAc. The combined organic layer was washed with a brine
solution, dried over anhydrous Na2SO4 and concentrated under
reduced pressure. The crude product was purified by column
chromatography.
Step-3: LAH reduction: To an oven-dried schlenk tube
equipped with a magnetic stirring bar, amide (4 or 10) (1.0
equiv) and anhydrous THF (0.1 M) were added under argon
atmosphere. The solution was cooled to 0 °C and LAH (8.0
equiv) was added portion wise to the reaction mixture
maintaining the continuous flow of argon. The mixture was
stirred at 25 °C for 12 h. The reaction was quenched with
water and the aqueous layer was extracted with ethyl acetate.
The combined organic layer was washed with a brine solution,
dried over anhydrous Na2SO4 and concentrated under reduced
pressure. The crude product was purified by column
chromatography
Compound 29: The GP-3, combining 2c and enal 1z gave
compound 29 along with minor diastereomer (21.0 mg, 56%,
combined yield) as white solid. The diastereomeric ratio (dr)
1
1
determined to be 3:1 by H NMR analysis. H NMR (400
MHz, CDCl3) δ = 8.93 (s, 1Hminor), 8.22 (s, 1Hmajor), 7.31-7.27
(m, 4Hmajor+minor), 7.21-7.11 (m, 6Hmajor+minor), 6.89-6.82 (m,
6Hmajor+minor), 3.78 (d, J = 0.8 Hz, 1Hmajor), 3.68 (d, J = 4.4 Hz,
1H minor), 3.27-3.23 (m, 1Hminor), 3.18 (dd, J = 17.2, 5.2 Hz,
1Hmajor), 2.91 (dd, J = 18.0, 5.2 Hz, 1H minor), 2.80 (dd, J =
17.2, 2.4 Hz, 1Hmajor), 2.30 (s, 6Hmajor+minor), 2.26 (s,
6Hmajor+minor), 1.99-1.88 (m, 2Hmajor+minor), 0.87-0.78 (m,
2Hmajor+minor), 0.63-0.47 (m, 4Hmajor+minor), 0.34-0.14 (m,
4Hmajor+minor) ppm. 13C{1H} NMR (100 MHz, CDCl3) δ =
171.7, 171.6, 171.4, 171.4, 164.3, 163.3, 139.4, 139.0, 137.1,
134.7, 134.4, 129.7, 129.1, 128.8, 128.7, 125.6, 125.1, 120.9,
120.5, 117.3, 116.9, 55.2, 53.4, 38.1, 37.2, 35.9, 35.8, 29.6,
21.4, 21.2, 14.8, 12.1, 4.7, 4.7, 4.0, 3.8 ppm. HRMS (ESI-
TOF) m/z : [M+H]+ calcd for C23H25N2O3 377.1860; found
377.1862. IR (Neat) ѵmax = 3629, 3382, 2955, 1688, 1583,
1511, 1439, 1178, 756, 701 cm-1. HPLC: The enantiomeric
excess (% of ee = 84, minor diastereoisomer and 82, major
Step-4: Boc-protection: To a solution of amide 32 or 33 (1.0
equiv) in dry THF (0.1M) was added DMAP (0.5 equiv) and
Boc2O (2.0 equiv). The resultant mixture was allowed to stir at
room temperature until the complete consumption of amide
(generally 6 h) was realized by TLC analysis. After removal of
the volatile materials under vacuum, the crude mixture was
purified directly by flash column chromatography to deliver
the corresponding product as off-white solid.
Step-5: DIBALH reduction: To a stirred solution of imide 34
or 35 (1.0 equiv) in anhydrous THF (0.1 M) at -78 °C, was
added DIBAL-H (5.0 equiv) slowly. The reaction mixture was
allowed to warm to 0 °C and stirred until no starting material
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remained (monitored by TLC analysis, generally 4 h). The
diastereoisomer and τminor = 26.75 min, τmajor = 22.40 min for
3
4
5
6
7
8
9
reaction was quenched by sequential addition of MeOH,
saturated Rochelle Salt solution and ethyl acetate at -78 °C
The reaction was allowed to warm to room temperature and
the resulting slurry was vigorously stirred for additional 4 h
until both layers became homogeneous. The aqueous phase
was extracted with ethyl acetate and the combined organic
layer was dried over Na2SO4, filtered, and concentrated in
vacuo. The residual oil was purified by flash column
chromatography on silica gel to provide the desired product as
white solid.
major diastereoisomer.
Compound 32: Prepared according to GP-4 (step-3),
combining glutarimide 30 (220 mg, 0.49 mmol, 1.0 equiv),
LiAlH4 (150 mg, 3.95 mmol, 8.0 equiv) in THF (0.01 M, 4.9
mL) for 12 h. The reaction was quenched with water and
extracted with ethyl acetate and the crude product was purified
by column chromatography from EtOAc:Hexane (25:75) to
afford the desired compound 32 (110 mg, 53%) as brown solid
with excellent diastereomeric ratio. 1H NMR (500 MHz,
CDCl3) δ = 7.32-7.29 (m, 3H), 7.25-7.22 (m, 2H), 7.00-6.95
(m, 3H), 6.88-6.85 (m, 2H), 6.75-6.72 (m, 2H), 6.61-6.57 (m,
1H), 3.83-3.80 (m, 1H), 3.79 (s, 3H), 3.73 (s, 3H), 3.66-3.63
(m, 1H), 3.18-3.12 (m, 1H), 3.00 (dt, J = 12.0, 4.4 Hz, 1H),
2.88 (dt, J = 12.00, 2.8 Hz, 1H), 2.72 (dt, J = 10.8, 3.6 Hz,
1H), 2.18-2.08 (m, 1H), 2.04-1.98 (m, 1H) ppm. 13C{1H}
NMR (100 MHz, CDCl3) δ = 170.7, 156.5, 154.1, 145.6,
143.4, 130.1, 129.0, 128.9, 128.1, 127.3, 127.0, 122.2, 121.4,
119.2, 114.6, 114.5, 113.9, 55.5, 55.4, 53.8, 52.0, 51.8, 45.4,
32.3 ppm. HRMS (ESI-TOF) m/z: [M+H]+ calcd for
C26H29N2O3 417.2173; found 417.2171. IR (Neat) ѵmax = 3294,
2926, 2841, 1650, 1509, 1243, 827 cm-1. HPLC: The
enantiomeric excess (% of ee = 96, major diastereoisomer) and
diastereomeric ratio (dr = 99:1) were determined by HPLC
analysis using Daicel Chiralpak IE-3 column: n-hexane:i-
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14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
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41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Compound 4: Prepared according to GP-4 (Step-1),
combining 1,3-diamide 2c (846.4 mg, 3.0 mmol, 1.0 equiv),
enal 1a (0.56 mL, 4.5 mmol, 1.5 equiv), 3d (226.5 mg, 0.45
mmol, 15.0 mol%), DBU (90 µL, 0.6 mmol, 20.0 mol%),
oxidant (1.84 g, 4.5 mmol, 1.5 equiv) and 3Å MS (1 g) in THF
(0.1 M, 30 mL) at -2 °C for 48 h. 3Å MS was filtered through
a
pad of celite and the crude reaction mixture was
concentrated and purified by gradient column chromatography
from 1:1 DCM:Hexane to DCM to DCM:EtOAc (95:5) to
afford the desired compound 4 (900 mg, 72%) as white solid
along with the non separable minor diastereoisomer with
diastereomeric ratio 4:1, determined by 1HNMR analysis.
HPLC: The enantiomeric excess (% of ee = 91 of both the
diastereoisomer) was determined by HPLC analysis. The
enantioselectivity of the product was further improved by
crystallization from EtOAc and hexane to afford (458 mg,
crystallization yield 51%) of 4 with enantiomeric excess (% of
ee = 97 of both the diastereoisomer).
PrOH = 80:20, flow rate 1.0 mL/min, λ = 254 nm: τmajor
15.77 min, τminor = 15.59 min for minor diastereoisomer and
τminor 45.15 min, τmajor 32.34 min for major
diastereoisomer.
=
=
=
Compound 30: Prepared according to GP-4 (step-2),
combining glutarimide 4 (400 mg, 0.97 mmol, 1.0 equiv), p-
anisidine (716 mg, 5.81 mmol, 6.0 equiv), and LiCl (4.1 mg,
0.097 mmol, 0.1 eq.) in THF (0.1 M, 9.7 mL) at 160 °C for 72
h. 2(M) HCl was added to it and the reaction mixture was
extracted with EtOAc. The crude reaction mixture was
purified by column chromatography from EtOAc:Hexane
(35:65) to afford the desired compound 30 (270 mg, 63%,
combined yield) as off-white solid along with the non
separable minor diastereoisomer. The diastereomeric ratio (dr)
Compound 34: Prepared according to GP-4 (step-4),
combining 32 (90.0 mg, 0.22 mmol, 1.0 equiv), di-tert-
butyldicarbonate (94.32 mg, 0.43 mmol, 2.0 equiv) and
DMAP (13.2 mg, 0.015 mmol, 0.5 eq.). The crude reaction
mixture was purified by column chromatography from
EtOAc:Hexane (10:90) to afford the desired compound 35 (80
mg, 72%) as white solid with excellent diastereomeric ratio.
1H NMR (500 MHz, CDCl3) δ = 7.35-7.32 (m, 2H), 7.30-7.25
(m, 3H), 6.99 (d, J = 8.5 Hz, 2H), 6.86-6.85 (m, 2H), 6.72 (d,
J = 9.0 Hz, 2H), 6.28 (d, J = 8.5 Hz, 2H), 4.04-4.00 (m, 1H),
3.96-3.93 (m, 1H), 3.79 (s, 3H), 3.76 (s, 3H), 3.67-3.64 (m,
1H), 3.05 (dt, J = 12.0, 4.0 Hz, 1H), 2.98 (t, J = 11.0 Hz, 1H),
2.90-2.86 (m, 1H), 1.99 (dt, J = 12.0, 3.5 Hz, 1H), 1.94-1.91
(m, 1H), 1.36 (s, 9H) ppm. 13C{1H} NMR (100 MHz, CDCl3)
δ = 176.3, 158.8, 153.8, 152.8, 145.7, 143.5, 131.3, 128.9,
128.51, 127.9, 126.7, 119.1, 114.4, 114.0, 82.9, 55.5, 55.3,
53.8, 51.9, 49.7, 46.7, 32.9, 27.79 ppm. HRMS (ESI-TOF)
m/z: [M+H]+ calcd for C31H37N2O5 517.2697; found 517.2695.
IR (Neat) ѵmax = 2934, 2834, 1727, 1508, 1243, 1149, 1035,
758 cm-1. HPLC: The enantiomeric excess (% of ee = 96,
major diastereoisomer) and diastereomeric ratio (dr = >99:1)
were determined by HPLC analysis using Daicel Chiralpak IE-
3 column: n-hexane:i-PrOH = 83:17, flow rate 1.0 mL/min, λ
= 254 nm: τmajor = 14.37 min, τminor = 17.01 min for minor
diastereoisomer and τminor = 23.17 min, τmajor = 12.83 min for
major diastereoisomer.
1
1
determined to be 4:1 by H NMR analysis. H NMR (500
MHz, CDCl3) δ = 8.13 (s, 1H), 7.40-7.29 (m, 14H7H-major+7H-
minor), 7.13 (d, J = 9.0 Hz, 2H minor), 7.06 (d, J = 9.0 Hz, 1H
minor), 7.00-6.95 (m, 5H4H-major+1H-minor), 6.84-6.77 (m, 4H2H-
major+2H-minor), 4.17 (dd, J = 11.0, 5.5 Hz, 1H major), 4.11 (dd, J =
10.0, 5.0 Hz, 1H minor), 4.02 (dd, J = 5.0, 1.0 Hz, 1H major), 3.91
(d, J = 4.5 Hz, 1H), 3.83 (s, 3H minor), 3.81 (s, 3H major), 3.78 (s,
3H major), 3.76 (s, 3H minor), 3.71-3.66 (m,1H minor), 3.43 (dd, J =
17.5, 5.5 Hz, 1H major), 3.16-3.08 (m, 2H1H-major+1H-minor) ppm.
13C{1H} NMR (100 MHz, CDCl3) δ = 171.7, 171.2, 171.2,
171.0, 163.9, 163.1, 159.7, 157.0, 156.9, 140.2, 137.9, 130.2,
129.7, 129.3, 129.2, 129.1, 129.1, 128.1, 127.8, 127.2, 127.1,
126.8, 122.36, 121.9, 114.8, 114.7, 114.2, 114.1, 55.9, 55.5,
55.4, 55.0, 37.3, 36.7, 36.2, 35.5 ppm. HRMS (ESI-TOF)
m/z : [M+H]+ calcd for C26H25N2O5 445.1758; found
445.1757. IR (Neat) ѵmax = 2834, 1735, 1677, 1510, 1247,
828, 773 cm-1. HPLC: The enantiomeric excess (% of ee = 92,
minor diastereoisomer and 97, major diastereoisomer) was
determined by HPLC analysis using Daicel Chiralpak IA-3
column: n-hexane:i-PrOH = 70:30, flow rate 1.0 mL/min, λ =
254 nm: τmajor = 18.73 min, τminor = 12.88 min for minor
Compound 36: Prepared according to GP-4 (step-5),
combining 34 (60.0 mg, 0.12 mmol, 1.0 equiv) and DIBALH
(0.58 mL, 1(M) in THF) in THF (0.1 M, 1.2 mL) at -78°C to rt
for 3h. The reaction mixture was quenched and extracted with
EtOAc. The crude reaction mixture was purified by column
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chromatography from EtOAc:Hexane (20:80) to afford the
3.06 (dd, J = 17.5, 6.5 Hz, 1H major) ppm. 13C{1H} NMR (125
3
4
5
6
7
8
9
desired compound 36 (22 mg, 64%) as off-white solid with
excellent diastereomeric ratio. H NMR (500 MHz, CDCl3) δ
MHz, CDCl3) δ = 171.4, 170.9, 170.9, 163.7, 163.3, 163.1(d, J
= 246.5 Hz), 163.0, 161.1, 159.8, 157.0, 157.0, 135.9, 130.2,
129.7, 129.2, 129.1, 128.9 (d, J = 7.5 Hz, minor), 128.8, 128.5
(d, J = 7.5 Hz, major), 128.4, 127.1, 126.8, 122.2, 122.0,
116.3 (d, J = 21.3 Hz, major), 116.2, 116.1 (d, J = 20.5 Hz,
minor), 116.0, 114.8, 114.7, 114.2, 114.2, 56.1, 55.4, 55.4,
37.0, 36.6, 36.5, 34.9 ppm. HRMS (ESI-TOF) m/z : [M+H]+
calcd for C26H24FN2O5 463.1664; found 463.1663. IR (Neat)
ѵmax = 3302, 2941, 2841, 1668, 1510, 1247, 829 cm-1. HPLC:
The enantiomeric excess (% of ee = 90, minor diastereoisomer
and 96, major diastereoisomer) and diastereomeric ratio (dr =
92:8) were determined by HPLC analysis using Daicel
Chiralpak IA-3 column: n-hexane:i-PrOH = 70:30, flow rate
1.0 mL/min, λ = 254 nm: τmajor = 20.86 min, τminor = 12.27 min
for minor diastereoisomer and τminor = 29.7 min, τmajor = 24.14
min for major diastereoisomer.
1
= 7.34-7.31 (m, 2H), 7.25-7.22 (m, 3H), 7.01 (d, J = 9.0 Hz,
2H), 6.86 (d, J = 9.5 Hz, 2H), 3.85-3.81 (m, 1H), 3.78 (s, 3H),
3.63-3.60 (m, 1H), 3.48 (dd, J = 11.0, 3.5 Hz, 1H), 3.34-3.30
(m, 1H), 2.74 (dt, J = 12.0, 3.0Hz, 1H), 2.62 (t, J = 11.5 Hz,
1H), 2.44 (dt, J = 11.5, 4.0 Hz, 1H), 2.24-2.17 (m, 1H), 2.03
(ddd, J = 25.0, 12.5, 4.0 Hz, 1H), 1.94-1.90 (m, 1H) ppm.
13C{1H} NMR (100 MHz, CDCl3) δ = 154.0, 145.9, 144.1,
128.7, 127.4, 126.6, 119.0, 114.4, 64.0, 55.5, 55.3, 52.2, 45.0,
44.0, 34.3 ppm. HRMS (ESI-TOF) m/z : [M+H]+ calcd for
C19H24NO2 298.1801; found 298.1800. IR (Neat) ѵmax = 3319,
2930, 2832, 1659, 1508, 1241, 1034, 700 cm-1. HPLC: The
enantiomeric excess (% of ee = 95, major diastereoisomer) and
diastereomeric ratio (dr = >99:1) was determined by HPLC
analysis using Daicel Chiralpak IE-3 column: n-hexane:i-
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
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
PrOH = 80:20, flow rate 1.0 mL/min, λ = 254 nm: τmajor
=
Compound 33: Prepared according to GP-4 (step-3),
combining 31 (173 mg, 0.38 mmol, 1.0 equiv), LiAlH4 (116
mg, 3.1 mmol, 8.0 equiv) in THF (0. 1 M, 3.8 mL) for 12 h.
The reaction was quenched with water and extracted with
ethyl acetate and the crude product was purified by column
chromatography from EtOAc:Hexane (25:75) to afford the
desired compound 33 (91 mg, 55%) as brown solid with
17.47 min, τminor = 7.67 min for minor diastereoisomer and
τminor = 9.27 min, τmajor = 10.37 min for major diastereoisomer.
[α]D 25 = -1.95 (c = 0.1, CHCl3).
Compound 10: Prepared according to GP-4 (step-1),
combining 1,3-diamide 2c (1.13 g, 4.0 mmol, 1.0 equiv), enal
1g (600 mg, 4.0 mmol, 1.0 equiv), 3d (302 mg, 0.6 mmol,
15.0 mol%), DBU (116 µL, 0.8 mmol, 20.0 mol%), oxidant
(2.45 g, 6.0 mmol, 1.5 equiv) and 3Å MS (1.5 g ) in THF (0.1
M, 40 mL) at -2 °C for 48 h. 3Å MS was filtered through a
pad of celite and the crude reaction mixture was concentrated
and purified by gradient column chromatography from 1:1
DCM:Hexane to DCM to DCM:EtOAc (95:5) to afford the
desired compound 10 (1.0 g, 58%) as white solid , along with
the non separable minor diastereoisomer. The diastereomeric
1
excellent diastereomeric ratio. H NMR (400 MHz, CDCl3) δ
=
7.26-7.23 (m, 4H2Hmajor+2Hminor), 7.06-7.03 (m, 4H
2Hmajor+2Hminor), 7.00-6.96 (m, 6H3H-major+3H-minor), 6.88-6.84 (m,
6H 3H-major+3H-minor), 6.76-6.74 (m, 4H 2H-major+2H-minor), 3.82-3.79
(m, 2H major+minor), 3.78 (s, 6H3H-major+3H-minor), 3.74 (s, 6H3H-
major+3H-minor), 3.64-3.61 (m, 2H major+minor), 3.11 (t, J = 11.2 Hz,
2H major+minor), 3.03 (dt, J = 12.0, 4.0 Hz, 2H major+minor), 2.89-
2.82 (m, 2H major+minor), 2.68 (dt, J = 10.8, 3.6 Hz, 2H major+minor),
2.11-1.95 (m, 4H2H-major+2H-minor) ppm. 13C{1H} NMR (100
MHz, CDCl3) δ = 170.6, 166.0, 162.9(d, J = 244.5 Hz), 160.4,
156.6, 155.9, 154.2, 145.5, 140.9, 139.5, 139.1, 139.1, 130.1,
129.6, 129.5, 128.8 (d, J = 8.0 Hz), 128.7, 127.3, 127.0, 122.2,
121.6, 119.3, 119.2, 115.7, 115.6 (d, J = 21.0 Hz), 115.4,
114.8, 114.6, 114.5, 114.2, 114.0, 113.9, 55.5, 55.4, 54.0,
52.2, 52.1, 45.3, 44.4, 42.0, 36.2, 32.3, 30.5, 29.6 ppm.
HRMS (ESI-TOF) m/z : [M+H]+ calcd for C26H28 FN2O3
435.2079; found 435.2077. IR (Neat) ѵmax = 3290, 2925, 2835,
1650, 1508, 1241, 827 cm-1. HPLC: The enantiomeric excess
(% of ee = 95, major diastereoisomer) and diastereomeric ratio
(dr = 97:3) were determined by HPLC analysis using Daicel
Chiralpak IE-3 column: n-hexane:i-PrOH = 80:20, flow rate
1.0 mL/min, λ = 254 nm: τmajor = 31.49 min, τminor = 43.70 min
for minor diastereoisomer and τminor = 27.37min, τmajor = 23.01
min for major diastereoisomer.
1
ratio (dr) determined to be 4:1 by H NMR analysis. HPLC:
The enantiomeric excess (% of ee = 87 of both the
diastereoisomer) was determined by HPLC analysis. The
enantioselectivity of the product was further improved by
crystallization from EtOAc and hexane to afford (550 mg,
crystallization yield 55%) of 10 with enantiomeric excess (%
of ee = 96 of both the diastereoisomer).
Compound 31: Prepared according to GP-4 (step-2),
combining glutarimide 10 (545 mg, 1.27 mmol, 1.0 equiv), p-
anisidine (935 mg, 7.60 mmol, 6.0 equiv), and LiCl (5.3 mg,
0.13 mmol, 0.1 eq.) in THF (0.1 M, 12.6 mL) at 160 °C for 72
h. 2(M) HCl was added to it and the reaction mixture was
extracted with EtOAc. The crude reaction mixture was
purified by column chromatography from EtOAc:Hexane
(35:65) to afford the desired compound 31 (300 mg, 51%,
combined yield ) as off-white solid along with the non
separable minor diastereoisomer. The diastereomeric ratio (dr)
Compound 35: Prepared according to GP-4 (step-4),
combining 33 (50.0 mg, 0.12 mmol, 1.0 equiv), di-tert-butyl
dicarbonate (51.1 mg, 0.23 mmol, 2.0 equiv) and DMAP
(7.1mg, 0.06 mmol, 0.5 eq.). The crude reaction mixture was
purified by column chromatography from EtOAc:Hexane
(10:90) to afford the desired compound 35 (42 mg, 68%) as
white solid with excellent diastereomeric ratio.
1H NMR (500 MHz, CDCl3) δ = 7.24-7.21 (m, 2H), 7.04-6.98
(m, 4H), 6.85 (d, J = 9.0 Hz, 2H), 6.75 (d, J = 8.5 Hz, 2H),
6.37 (d, J = 9.0 Hz, 2H), 3.99-3.93 (m, 2H), 3.79 (s, 3H), 3.77
(s, 3H), 3.65-3.63 (m, 1H), 3.06 (dt, J = 12.0, 4.5 Hz, 1H),
2.96 (t, J = 10.5 Hz, 1H), 2.87 (t, J = 12.0 Hz, 1H), 2.01-1.88
1
determined to be 4:1 by H NMR analysis.1H NMR (500
MHz, CDCl3) δ = 8.29 (s, 1H minor), 8.13 (s, 1H major), 7.32 (d, J
= 9.0 Hz,
1H major), 7.27-7.25 (m, 3H2H-major+1H-minor), 7.17 (d, J = 8.5 Hz,
1H minor), 7.08-7.05 (m, 4H2H-major+2H-minor), 7.08-7.03 (m, 6H2H-
major+4H-minor), 7.00-6.94 (m, 6H4H-major+2H-minor), 6.83-6.79 (m,
3H2H-major+1H-minor), 4.15 (dd, J = 11.5, 6.0 Hz, 1H major), 4.09-
4.06 (m, 1Hminor), 3.94 (d, J = 5.0 Hz, 1H major), 3.89 (d, J = 5.0
Hz, 1H minor), 3.83 (s, 3H minor), 3.81 (s, 3H major), 3.77 (s, 3H
major), 3.76 (s, 3H minor), 3.72-3.66 (m, 1H minor), 3.39 (dd, J =
17.5, 5.5 Hz, 1H major), 3.12 (dd, J = 17.5, 5.5 Hz, 1H minor),
14
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The Journal of Organic Chemistry
(m, 2H), 1.35 (s, 9H) ppm. 13C{1H} NMR (125 MHz, CDCl3)
11.5 Hz, 1H), 2.29 (dt, J = 11.5, 4.0 Hz, 1H), 2.23-2.16 (m,
1H), 1.93 (ddd, J = 16.5, 11.5, 3.0 Hz, 1H), 1.86-1.83 (m, 1H)
ppm. 13C{1H} NMR (125 MHz, CDCl3) δ = 154.0, 152.1,
146.2, 144.3, 142.4, 128.7, 127.5, 126.7, 119.0, 114.9, 114.5,
114.1, 56.5, 55.8, 55.6, 52.2, 47.4, 47.3, 41.6, 34.6 ppm.
HRMS (ESI-TOF) m/z : [M+H]+ calcd for C26H31N2O2
403.2386; found 403.2385. IR (Neat) ѵmax = 3400, 3027, 2928,
2831, 1508, 1463, 1236, 1036, 702, 530 cm-1. HPLC: The
enantiomeric excess (% of ee = 97) was determined by HPLC
analysis using Daicel Chiralpak IA-3 column: n-hexane:i-
2
3
4
5
6
7
8
9
δ = 175.9, 162.7, 160.8 (d, J = 243.5 Hz) , 158.9, 153.9, 152.7,
145.6, 139.3, 131.3, 129.4, 129.3 (d, J = 7.3 Hz), 128.8, 128.5,
127.9, 119.1, 115.2, 115.1 (d, J = 21.3 Hz), 114.5, 114.1, 83.1,
55.6, 55.3, 54.0, 51.8, 49.8, 45.7, 32.9, 27.8 ppm. HRMS
(ESI-TOF) m/z : [M+H]+ calcd for C31H36 FN2O5 535.2603;
found 535.2604. IR (Neat) ѵmax = 2935, 2844, 1729, 1699,
1509, 1289, 1247, 1151, 777 cm-1. HPLC: The enantiomeric
excess (% of ee
= 95, major diastereoisomer) and
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
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
diastereomeric ratio (dr = 97:3) were determined by HPLC
analysis using Daicel Chiralpak IE-3 column: n-hexane:i-
PrOH = 90:10, flow rate 1.0 mL/min, λ = 254 nm: τmajor
19.55 min, τminor = 17.72 min.
=
PrOH = 83:17, flow rate 1.0 mL/min, λ = 254 nm: τmajor
12.93 min, τminor = 23.26 min for minor diastereoisomer and
τminor 17.14 min, τmajor 10.66 min for major
diastereoisomer.
=
Synthetic application-ll:
=
=
Compound 39: To a 30 ml pressure tube equipped with a
magnetic stir bar, was added glutarimide 4 (400 mg, 0.48
mmol, 1.0 equiv), ethanol (2.4 mL, 0.2 M) and 1(M) HCl (2.4
mL). The reaction mixture was allowed to heat at 80 °C for 12
Compound 37: Prepared according to GP-4 (step-5),
combining 35 (35.0 mg, 0.066 mmol, 1.0 equiv) and DIBALH
(0.33 mL, 1(M) in THF) in THF (0.1 M, 0.7 mL) at 0 °C to rt
for 3h. The reaction mixture was quenched and extracted with
EtOAc. The crude reaction mixture was purified by column
chromatography from EtOAc:Hexane (20:80) to afford the
desired compound 37 (13 mg, 62%) as off-white solid with
h. After complete consumption of the glutarimide
4
(determined by TLC analysis), excess ethanol was removed
under reduced pressure and the reaction mixture was extracted
with EtOAc. The combined organic layer was washed with a
brine solution, dried over anhydrous Na2SO4 and concentrated
under reduced pressure. The crude product was purified by
column chromatography (SiO2, Hexane/EtOAc = 4:1) to
afford the title compound 39 (350 mg, 79%) as white solid. 1H
NMR (500 MHz, CDCl3) δ = 9.39 (s, 1H), 8.84 (s, 1H), 7.41-
7.39 (m, 2H), 7.26-7.17 (m, 5H), 7.14-7.09 (m, 2H), 7.04-7.03
(m, 2H), 6.97 (d, J = 7.5 Hz, 1H), 6.90 (d, J = 7.5 Hz, 1H),
3.98-3.90 (m, 3H), 3.74 (d, J = 9.5 Hz, 1H), 2.99 (dd, J =
16.0, 6.0 Hz, 1H), 2.84 (dd, J = 15.5, 9.0 Hz, 1H), 2.34 (s,
3H), 2.56 (s, 3H), 1.04 (t, J = 7.5 Hz, 3H) ppm. 13C{1H} NMR
(100 MHz, CDCl3) δ = 171.4, 167.8, 167.5, 139.1, 138.9,
138.6, 137.2, 136.8, 128.8, 128.5, 127.9, 127.5, 125.6, 121.2,
120.9, 117.7, 117.4, 61.2, 60.6, 45.5, 38.2, 21.4, 21.3, 13.9
ppm. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C28H31N2O4
459.2284; found 459.2285. IR (Neat) ѵmax = 3283, 2990, 2918,
1673, 1736, 1550, 1259, 1169, 780 cm-1. HPLC: The
enantiomeric excess (% of ee = 97) were determined by HPLC
analysis using Daicel Chiralpak IE-3 column: n-hexane:i-
PrOH = 80:20, flow rate 1.0 mL/min, λ = 254 nm: τmajor = 9.21
min, τminor = 8.15 min.
1
excellent diastereomeric ratio. H NMR (500 MHz, CDCl3) δ
= 7.21-7.18 (m, 2H), 7.02-6.98 (m, 4H), 6.87-6.85 (m, 2H),
3.84-3.80 (m, 1H), 3.78 (s, 3H), 3.62-3.58 (m, 1H), 3.47 (dd, J
= 11.0, 3.5 Hz, 1H), 3.31 (dd, J = 10.5, 7.0 Hz, 1H), 2.72 (dt,
J = 11.5, 2.5 Hz, 1H), 2.61 (t, J = 11.0 Hz, 1H), 2.44 (dt, J =
11.5, 4.0 Hz, 1H), 2.16-2.09 (m, 1H), 2.01-1.87 (m, 2H) ppm.
13C{1H} NMR (125 MHz, CDCl3) δ = 162.6, 160.6 (d, J =
243.6 Hz), 154.0, 146.2, 139.9, 128.8, 128.7 (d, J = 7.5 Hz),
118.9, 115.5, 115.3 (d, J = 20.2 Hz), 114.5, 63.8, 55.6, 55.2,
52.1, 44.3, 34.5 ppm. HRMS (ESI-TOF) m/z : [M+H]+ calcd
for C19H23FNO2 316.1707; found 316.1706. IR (Neat) ѵmax
=
2925, 2834, 1667, 1609, 1509, 1243, 826 cm-1. HPLC: The
enantiomeric excess (% of ee = 95, major diastereoisomer) and
diastereomeric ratio (dr = 97:3) were determined by HPLC
analysis using Daicel Chiralpak IE-3 column: n-hexane:i-
PrOH = 83:17, flow rate 1.0 mL/min, λ = 254 nm: τmajor
=
11.92 min, τminor = 11.52 min for minor diastereoisomer and
τminor = 8.40 min, τmajor = 10.04 min for major diastereoisomer.
[α]D 25 = -2.84 (c = 0.5, CHCl3).
Synthesis of amino piperidine 38: To an oven-dried 25.0 mL
schlenk tube equipped with a magnetic stirring bar, 30 (100
mg, 0.22 mmol, 1.0 equiv) and super dry THF (2.2 mL, 0.1 M)
were added under argon .The solution was cooled to 0 °C and
LAH (85 mg, 2.24 mmol, 1.0 equiv) was added to the reaction
mixture maintaining the continuous flow of argon. The
mixture was stirred at room temperature for 12 h. The reaction
was quenched with water and extracted with ethyl acetate. The
combined organic layer was washed with a brine solution,
dried over anhydrous Na2SO4, and concentrated under reduced
pressure. The crude product was purified by column
chromatography (SiO2, Hexane/EtOAc = 3:2, Rf = 0.8) to
Compound 40: To an oven-dried 25.0 mL schlenk tube
equipped with a magnetic stirring bar, 39 (200 mg, 0.22 mmol,
1.0 equiv) and anhydrous THF (2.1 mL, 0.1 M) were added
under argon atmosphere. The solution was allowed to cool to 0
°C. To the cold solution, LAH (16.6 mg, 0.44 mmol, 2.0
equiv) was added maintaining a continuous flow of argon. The
mixture was stirred at 25 oC for 6 h. The reaction was
quenched with water and aqueous layer was extracted with
ethyl acetate. The combined organic layer was washed with a
brine solution, dried over anhydrous Na2SO4 and concentrated
under reduced pressure. The crude product was purified by
column chromatography (SiO2, Hexane/EtOAc = 3:2, Rf = 0.8)
to afford the title compound 40 (150 mg, 82%) as white solid.
1H NMR (500 MHz, CDCl3) δ = 9.60 (s, 1H), 8.86 (s, 1H),
7.42-7.40 (m, 2H), 7.26-7.17 (m, 5H), 7.14-7.08 (m, 3H),
7.03-7.02 (m, 1H), 6.96 (d, J = 7.5 Hz, 1H), 6.88 (d, J = 7.5
Hz, 1H), 3.86 (d, J = 10.5 Hz, 1H), 3.65-3.58 (m, 2H), 3.51-
3.46 (m, 1H), 2.33 (s, 3H), 2.23 (s, 3H), 2.10-2.03 (m, 2H)
ppm. 13C{1H} NMR (100 MHz, CDCl3) δ = 168.4, 168.2,
1
afford the title compound 39 (52mg , 62%) as white solid. H
NMR (500 MHz, CDCl3) δ = 7.28-7.25 (m, 2H), 7.18 (d, J =
8.0 Hz, 3H), 6.88 (d, J = 9.0 Hz, 2H), 6.77 (d, J = 9.0 Hz,
2H), 6.61 (d, J = 9.0 Hz, 2H), 6.25 (d, J = 9.0 Hz, 2H), 3.76-
3.73 (m, 1H), 3.70 (s, 3H), 3.63 (s, 3H), 3.54-3.52 (m, 1H),
3.04 (brs, 1H), 2.86 (dd, J = 13.0, 3.5 Hz, 1H), 2.73 (dd, J =
12.0, 8.0 Hz, 1H), 2.65 (dt, J = 12.0, 2.5 Hz, 1H), 2.42 (t, J =
15
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8
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with the formal synthesis of (±)-paroxetine. We are grateful for
the help of all analytical departments of IACS.
139.7, 138.9, 138.6, 137.3, 136.9, 128.8, 128.6, 128.5, 128.1,
127.4, 125.6, 125.5, 121.2, 120.9, 117.7, 117.4, 62.0, 60.4,
46.7, 35.8, 21.4, 21.3 ppm. HRMS (ESI-TOF) m/z : [M+Na]+
calcd for C26H28N2O3Na 439.1998; found 439.1996. IR (Neat)
ѵmax = 3285, 2935, 1675, 1614, 1546, 1490, 1453, 1194, 779,
700 cm-1. HPLC: The enantiomeric excess (% of ee = 97)
were determined by HPLC analysis using Daicel Chiralpak IE-
3 column: n-hexane:i-PrOH = 90:10, flow rate 1.0 mL/min, λ
= 254 nm: τmajor = 15.33 min, τminor = 14.40min.
REFERENCES
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lactimidomycin. Chem. Commun. 2015, 51, 8634; (b) Sun, D.; Sun,
W.; Yu, Y.; Li, Z.; Deng, Z.; Lin, S. A new glutarimide derivative
from marine sponge-derived Streptomyces anulatus S71. Nat. Prod.
Res. 2014, 28, 1602; (c) Rajski, S. R.; Shen, B. Multifaceted modes of
action for the glutarimide-containing polyketides revealed.
ChemBioChem 2010, 11, 1951.
10
11
12
13
14
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16
17
18
19
20
21
22
23
24
25
26
27
28
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31
32
33
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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
Compound 41: Methanesulfonyl chloride (MsCl) (48.0 μL,
0.62 mmol, 2.0 equiv) was added to a stirred solution of
compound 40 (130.0 mg, 0.31 mmol, 1.0 equiv) in pyridine
(0.7 M, 0.44 mL) under argon atmosphere at 0 °C. The
resulting heterogeneous mixture was stirred for 2 h and slowly
warmed up to room temperature. After complete consumption
of the starting material, pyridine was removed under reduced
pressure. To the mixture, 5.0 mL water and 25.0 mL EtOAc
were added successively. The organic layer was separated and
aqueous layer was extracted with EtOAc. The combined
organic layer was washed with brine, dried over anhydrous
Na2SO4 and concentrated under vacuum. The solid residue
was purified by column chromatography (SiO2, 30% EtOAc-
Hexane, Rf = 0.52 for the product) to afford the title compound
41 (134.0 mg, 87%) as white solid. Compound 41 was
crystallized from the slow evaporation of its EtOAc solution.
Absolute configuration of compound 41 was unambiguously
determined by the single crystal X-ray analysis. 1H NMR (300
MHz, CDCl3) δ = 9.52 (s, 1H), 8.83 (s, 1H), 7.52-7.39 (m,
2H), 7.31-7.08 (m, 7H), 7.03-6.97 (m, 3H), 6.91-6.89 (m, 1H),
4.12-4.05 (m, 1H), 3.92-3.84 (m, 1H), 3.73 (d, J = 10.5 Hz,
1H), 3.57 (dt, J = 10.8, 3.9 Hz, 1H), 2.79 (s, 3H), 2.49-2.39
(m, 1H), 2.36 (s, 3H), 2.25 (s, 3H), 2.18-2.12 (m, 1H) ppm.
13C{1H} NMR (100 MHz, CDCl3) δ = 167.8, 167.5, 139.0,
138.6, 138.3, 137.2, 136.7, 128.9, 128.9, 128.6, 127.9, 127.8,
125.8, 125.7, 121.2, 120.9, 117.6, 117.4, 67.3, 62.3, 45.8,
37.1, 32.5, 21.4, 21.3, ppm. HRMS (ESI-TOF) m/z : [M+H]+
calcd for C27H31N2O5S 495.1954; found 495.1951. IR (Neat)
ѵmax = 3289, 3035, 2918, 1596, 1456, 1680, 1555, 1490, 1354,
1175, 961, 780 cm-1. HPLC: The enantiomeric excess (% of
ee = 97) were determined by HPLC analysis using Daicel
Chiralpak IE-3 column: n-hexane:i-PrOH = 80:20, flow rate
1.0 mL/min, λ = 254 nm: τmajor = 13.63 min, τminor = 14.44 min.
(2) (a) Guo, H.-f.; Li, Y.-h.; Yi, H.; Zhang, T.; Wang, S.-q.; Tao,
P.-z.; Li, Z.-r. Synthesis, structures and anti-HBV activities of
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evolution of thalidomide and its IMiD derivatives as anticancer
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Kiyota, H.; Shimizu, Y.; Oritani, T. Synthesis of actiketal, a
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Zanfally, S.; Khalifa, M.; Abou-Zeid, Y. M. Derivatives of
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Feng, X. Catalytic Michael/Ring-Closure Reaction of α,β-
Unsaturated Pyrazoleamides with Amidomalonates: Asymmetric
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M.; Sakaguchi, A.; Kobayashi, C.; Ikariya, T. Chemoselective
Hydrogenation of Imides Catalyzed by Cp*Ru(PN) Complexes and Its
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Bayod, M.; Gotor, V. Enzymatic Resolution of trans-4-(4‘-
Fluorophenyl)-3-hydroxymethylpiperidines, Key Intermediates in the
Synthesis of (−)-Paroxetine. J. Org. Chem. 2001, 66, 8947.
(4) (a) Bursavich, M. G.; Rich, D. H. Designing Non-Peptide
Peptidomimetics in the 21st Century:ꢀ Inhibitors Targeting
Conformational Ensembles. J. Med. Chem. 2002, 45, 541; (b) Bourin,
M.; Chue, P.; Guillon, Y. Paroxetine: A Review. CNS Drug Rev.
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(5) Some selected reviews on NHC-catalysis: (a) Murauski, K. J.
R.; Jaworski, A. A.; Scheidt, K. A. A continuing challenge: N-
heterocyclic carbene-catalyzed syntheses of γ-butyrolactones. Chem.
Soc. Rev. 2018, 47, 1773; (b) Zhang, C.; Hooper, J. F.; Lupton, D. W.
N-Heterocyclic Carbene Catalysis via the α,β-Unsaturated Acyl
Azolium. ACS Catal. 2017, 7, 2583; (c) Yetra, S. R.; Patra, A.; Biju,
A. T. Recent Advances in the N-Heterocyclic Carbene (NHC)-
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ASSOCIATED CONTENT
Supporting Information
1
Supporting Information: H and 13C spectra and HPLC traces of
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Corresponding Author
* E-mail: ocjg@iacs.res.in.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We acknowledge the generous financial support from Science and
Engineering Research Board, India (EMR/2016/006344) and
CSIR for fellowship to AP and SS. We thank Mr. Partha Mitra
and Mr. Manish Jana for helping with single crystal X-ray
analysis. Mr. Bhaskar Deb Mondal is acknowledged for helping
(6) Some selected examples of NHC-catalyzed enantioselective
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Zhao, C.; Guo, D.; Munkerup, K.; Huang, K.-W.; Li, F.; Wang, J.
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the reaction medium than the other amides tested in this reaction.
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