Indole-olefin-oxazoline (IndOlefOx)-ligands: Synthesis and utilization in asymmetric Rh-catalyzed conjugate addition

Article abstract of DOI:10.1016/j.tetasy.2011.02.020

The synthesis and utility of novel indole-olefin-oxazoline (IndOlefOx)-ligands are described. The use of these ligands was demonstrated in rhodium catalyzed asymmetric conjugate additions between 2-cyclopentenone, 2-cyclohexenone, and 2-cycloheptenone with different boron reagents with good yields and enantioselectivities of up to 94%.

Full text of DOI:10.1016/j.tetasy.2011.02.020

Tetrahedron: Asymmetry 22 (2011) 468–475
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Indole-olefin-oxazoline (IndOlefOx)-ligands: synthesis and utilization
in asymmetric Rh-catalyzed conjugate addition
⇑
Noora Kuuloja, Jan Tois, Robert Franzén
Department of Chemistry and Bioengineering, Laboratory of Chemistry, Tampere University of Technology, Korkeakoulunkatu 8, 33720 Tampere, Finland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 6 December 2010
Accepted 17 February 2011
The synthesis and utility of novel indole-olefin-oxazoline (IndOlefOx)-ligands are described. The use of
these ligands was demonstrated in rhodium catalyzed asymmetric conjugate additions between 2-cyclo-
pentenone, 2-cyclohexenone, and 2-cycloheptenone with different boron reagents with good yields and
enantioselectivities of up to 94%.
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
where a challenging substrate, chromenone, was used as an enone.
In this example, the phenylboronic acid produced the 1,4-addition
The transition metal catalyzed conjugate addition of organome-
tallic reagents to electron-deficient alkenes is a widely used pro-
cess in organic chemistry. The stability and chemoselective
nature of organoboron compounds make these handy tools for this
reaction.1 Despite the many examples of this transformation, the
examples are usually restricted to the utilization of only one cer-
product in low yield (32%), whereas the use of sodium tetraphen-
ylborate as a coupling partner improved the yield to 75%. In a study
on stereogenic quaternary carbon centers, Hayashi et al.4b noticed
a similar phenomenon. The desired products were obtained only
by utilizing sodium tetraphenylborate in the addition reaction. It
was discovered later that a different Rh-source and ligand allowed
the use of phenylboroxine as well.5 Recently, Glorius et al.2a re-
ported the utilization of an oxazoline based ligand (OlefOx) in a
conjugate addition. These ligands enabled the use of phenylboronic
tain boron reagent with
a specific substrate and ligand
(Scheme 1).2–4 Liao et al.4a have reported a rhodium catalyzed
addition reaction in the presence of a chiral bis-sulfoxide ligand,
PhB(OH)2
PhB(OH)2
or
PhBpin
or
or
a Chiral ligand
[Rh]
or
R = H, Alkyl
PhBF3K
Ph4BX
PhBF3K
O
O
O
O
IndOlefOx-ligand
[Rh(eth)2Cl]2
KOH
a Chiral ligand
[Rh]
R = H
∗
∗
Ph
º
R
dioxane, 80 C
Ph4BNa
Ph
R
63-98%
81-94% ee
a Chiral ligand
[Rh]
R = H, Alkyl
Previous work2,3,4
Specific ligand and reaction conditions
for each boron reagent
This work
One ligand for different
boron reagents
Scheme 1. Asymmetric addition of boron compounds to enones.
⇑
Corresponding author.
E-mail address: robert.franzen@tut.fi (R. Franzén).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.02.020

N. Kuuloja et al. / Tetrahedron: Asymmetry 22 (2011) 468–475
469
acid in the construction of quaternary carbon centers for the first
2. Results and discussion
time. However, the use of other boron reagents was not investi-
gated. Our recent interest toward oxazolines and indoles as ligand
scaffolds6 inspired us to synthesize a series of novel indole-
olefin-oxazoline ligands in order to investigate the conjugate addi-
IndOlefOx-ligands 1–6 (Fig. 1) were synthesized according to
Scheme 2. Compounds 11 and 12 were obtained from commer-
cially available 2-indolecarboxylic acid 8 (52% and 56% yields, over
3 steps). The aldehydes were then subjected to a Wittig reaction
with phosphonium salts to provide the olefinic compounds 13–
16 in good yields (71–86%). After hydrolysis, acids 17–20 were
subjected to BOP mediated amide formation with aminoalcohols.7
Finally, amido alcohols 21–26 were treated with MsCl in the pres-
ence of DMAP to give the desired IndOlefOx ligands 1–6 (Fig. 1) in
acceptable overall yields (13–26%, over 7 steps). All purifications
were carried out by recrystallization and there was no need for col-
umn chromatography.
tion between an
a,b-unsaturated enone and different boron re-
agents (Scheme 1).
OMe
OMe
To evaluate the utility of the IndOlefOx-ligands, the conjugate
addition of phenylboronic acid to 2-cyclohexenone was chosen as
the model reaction (Table 1). With ligand 1, the reaction proceeded
smoothly and the addition product was obtained in 98% yield and
64% ee (Table 1, entry 1). Glorius et al.2a noticed that electron-
donating methoxy groups in their structurally similar ligands in-
creased the enantioselectivity. Also in our case, ligands 2–5 with
N
N
N
O
N
R
O
2 R = Me
1
3
R = MOM
a
3,4-dimethoxy motif gave the highest enantioselectivities
OMe
(Table 1, entries 2–5). Methoxy groups at the 2- and 5-positions
in ligand 6, however, reduced both the yield and enantioselectivity
(Table 1, entry 6). We believe that the proximity of the methoxy
substituent at the ortho-position affects complex formation in a
negative manner. The oxazoline-moieties of ligands 2–5 were
derived either from phenylalaninol (ligands 2 and 3) or valinol
(ligands 4 and 5). The ligands derived from phenylalaninol (Table 1,
entries 2 and 3) gave better results than those derived from valinol
(Table 1, entries 4 and 5) in terms of yield and ee%. We also com-
pared the ligands with different substituents at the indole nitro-
gen. When ligands 4 and 5 were compared, higher yields and ee%
were obtained when the ligand bore a methyl-group at the 1-
position (Table 1, entries 4 and 5). Although ligands 2 and 3 both
MeO
OMe
OMe
N
O
N
N
R
N
O
4 R = Me
5 R = MOM
6
Figure 1. Structures of the prepared IndOlefOx-ligands 1–6.
O
O
H
H
O
O
cat. H2SO4
O
POCl3
O
NaH, R1X
N
EtOH
86%
DMF
80%
DMF
OEt
N
H
OH
N
H
OEt
N
OEt
R1
75-81%
H
8
9
10
11-12
R2
R2
R2
S)-aminoalcohol,
BOP, DIPEA
(
NaOH
NaH, Phosphonium salt
MeOH/THF/water
87-99%
DMF
O
O
O
DCM
71-86%
54-94%
R3
N
N
OEt
OH
N
HN
R1
13-16
R1
17-20
R1
21-26
OH
R2
MsCl, DMAP
Et3N
R3
N
O
DCM
N
61-99%
R1
1-6
Scheme 2. Synthesis route to IndOlefOx-ligands 1–6.

470
N. Kuuloja et al. / Tetrahedron: Asymmetry 22 (2011) 468–475
Table 1
discovered that ligand 2 was found to be the most practical ligand
for this reaction, when taking into account reaction time, yield and
enantioselectivity.
Screening of ligands 1–7 in 1,4-addition of phenylboronic acid to 2-cyclohexenonea
O
[Rh(eth)2Cl]2 (5mol%)
O
After the successful reaction with phenylboronic acid, we
turned our attention to different boron reagents. All reactions were
performed with the most promising ligand 2 at 80 °C. With all the
tested organoboron compounds, moderate to excellent yields
(63–98%) and good enantioselectivities (83–94%) were achieved
(Table 2, entries 1–7). In addition to the commercially available
boron reagents, we also investigated the suitability of triethyl-
ammonium tetra-arylborates9 (TEATAB) in the reaction (Table 2,
entries 6 and 7). Tetra-arylborates are noteworthy coupling part-
ners, which can transfer all four aryl groups from the substrate
to the product efficiently.9,10 A literature survey revealed that usu-
ally 2–4 equiv of tetra-arylborate are needed for successful conju-
gate additions.4 We found that the amount of tetra-arylborate can
be decreased even to 0.5 equiv and, therefore, better atom-
economy can be achieved (Table 2, entries 5 and 7). In addition,
enones with different ring sizes were tested in the reaction (Table 2,
entries 8 and 9).
ligand (11mol%)
B(OH)2
KOH (30mol%)
dioxane
º
40-80 C
Entry
Ligand
Temp (°C)
Time (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
1
2
3
4
80
80
80
80
80
80
80
60
40
80
4
2
98
87
57
72
44
68
46
78
43
33
64
89
89
89
74
61
0
92
94
—
24
24
24
24
24
21
24
24
5
6
7d
2
2
—
10
a
General procedure: ligand (0.057 mmol) and [Rh(eth)2Cl]2 (0.026 mmol) were
stirred in dioxane (1.6 ml) 10 min. Next, PhB(OH)2 (0.78 mmol) was added to the
reaction followed by 1 M KOH (aq) (0.16 ml) and cyclohexenone (0.52 mmol). The
reaction mixture was stirred until TLC showed an absence of starting material (max
24 h).
b
3. Conclusion
Yield of isolated product.
Determined by HPLC analysis with chiral stationary phase column (Chiralpak
c
IA).
In conclusion, we have designed and synthesized six indole-
olefin-oxazoline (IndOlefOx)-ligands. These ligands were prepared
conveniently in acceptable overall yields without chromatographic
purification. We have demonstrated that these ligands enabled
the utilization of all common organoboron reagents for a Rh-
catalyzed asymmetric 1,4-addition reaction with good yield and
enantioselectivity.
d
See Ref. 8.
induced good enantioselectivities, the yield with ligand 3 was
much lower (Table 1, entries 2 and 3). When the reactions were
performed with ligand 2 (at reduced temperatures), higher enanti-
oselectivity was achieved at the expense of yield and reaction
times (Table 1, entries 8 and 9). To prove the indispensability of
the olefinic moiety in the ligand structure, the double bond in li-
gand 4 was reduced to afford ligand 7.8 Conjugate addition reac-
tions with this ligand gave a racemic mixture with low yield
(Table 1, entry 7). The reaction without any ligand produced a race-
mic product in 33% yield (Table 1, entry 10). In conclusion, we have
4. Experimental
4.1. General
All solvents and chemicals were used as received. Dioxane and
1 M KOH (aq) solutions were bubbled with argon before use. TLC
was performed on precoated (Silica Gel 60 F254) aluminum plates
and visualization was performed by UV-light or using Hanessian’s
stain (5 g CeSO4, 25 g (NH4)Mo7O24ꢀ4H2O, 450 ml water, 50 ml con-
cd H2SO4) Silica Gel 60, particle size 0.040–0.063 nm was used for
chromatography. 1H and 13C NMR spectra were measured at 300
and 75 MHz, respectively, using CDCl3 or DMSO-d6 as solvents.
Table 2
Rhodium-catalyzed 1,4-addition of phenylboron reagents to cyclic enonesa
O
[Rh(eth)2Cl]2(5mol%)
O
ligand 2 (11mol%)
KOH (30mol%)
Chemical shifts are reported in
tetramethylsilane.
d values (ppm) relative to
Ph-B
dioxane
n
º
80 C
n
4.2. Preparation of compounds 9–12
4.2.1. Ethyl-1H-indole-2-carboxylate 9
Entry
Enone
Ph-B
Equiv
Time (h)
Yieldb (%)
eec,d (%)
A solution of indole-2-carboxylic acid 8 (25 g, 0.16 mol) and
concentrated H2SO4 (2 ml) in EtOH (250 ml) was refluxed for
18 h. The reaction mixture was allowed to cool at room tempera-
ture, concentrated and filtered. The crude product was washed
with water and recrystallized from EtOH. Product 9 was obtained
1
2
3
4
5
6
7
8
9
n = 1
n = 1
n = 1
n = 1
n = 1
n = 1
n = 1
n = 0
n = 2
PhB(OH)2
PhBpin
PhBF3K
Ph4BNa
Ph4BNa
Ph4BNHEt3
Ph4BNHEt3
PhBpin
1.2
1.2
1.2
1.2
0.5
1.2
0.5
1.2
1.2
2
24
24
4
87
78
63
79
66
67
98
94
89
89
94
86
90
90
81
83
91
75
6
22
22
24
24
as
a
yellow solid (20.5 g, 80%). Mp 122–123 °C; 1H NMR
(300 MHz, DMSO-d6) d: 11.91 (br s, 1H), 7.66 (d, 1H, J = 8.3 Hz),
7.49 (d, 1H, J = 8.0 Hz), 7.16 (s, 1H) 7.26 (t, 1H, J = 7.6 Hz), 7.07 (t,
1H, J = 7.6 Hz), 4.34 (q, 2H, J = 7.1 Hz), 1.33 (t, 3H, J = 7.1 Hz); 13C
NMR (75 MHz, DMSO-d6) d: 161.4, 137.5, 127.4, 126.8, 124.7,
122.1, 120.2, 112.7, 107.7, 60.5, 14.3. HRMS-ESI (m/z) for
PhBpin
a
General procedure: ligand 2 (0.057 mmol) and [Rh(eth)2Cl]2 (0.026 mmol) were
stirred in dioxane (1.6 ml) for 10 min. Next, the phenylboron reagent (0.78 mmol)
was added to the reaction followed by 1 M KOH (aq) (0.16 ml) and the cyclic enone
(0.52 mmol). The reaction mixture was stirred until TLC showed an absence of
starting material (max 24 h).
C11H11NO2Na, (M+Na) found 212.0676, calcd 212.0687.
b
Yield of isolated product.
Determined by HPLC analysis with a chiral stationary phase column (Chiralpak
4.2.2. Ethyl-3-formyl-1H-indole-2-carboxylate11 10
c
At first, POCl3 (9.8 ml, 0.11 mol) was added dropwise to DMF
(30 ml) at 0 °C to obtain the chloroiminium ion. A solution of
IA/Chiralpak IC).
d
The specific rotation has been determined for the products obtained.

N. Kuuloja et al. / Tetrahedron: Asymmetry 22 (2011) 468–475
471
ethyl-1H-indole-2-carboxylate 9 (19 g, 0.10 mol) in DMF (30 ml)
was added to the vessel containing the formylating agent and the
resulting mixture was stirred at room temperature for 1 h and at
70 °C for 6 h. The reaction mixture was poured into cold water
(400 ml) and neutralized with 2 M NaOH. The yellow precipitate
was collected by filtration to give product 10 as a yellow powder
(18 g, 86%). Mp 187–188 °C; 1H NMR (300 MHz, DMSO-d6) d:
12.84 (s, 1H), 10.62 (s, 1H), 8.26 (d, 1H, J = 8.07 Hz), 7.58 (dt, 1H,
J = 8.23, 0.94 Hz), 7.41 (ddd, 1H, J = 9.0, 6.0, 1.3 Hz), 7.31 (ddd,
1H, J = 8.0, 7.0, 1.1 Hz), 4.46 (q, 2H, J = 7.1 Hz), 1.41 (t, 3H,
J = 7.1 Hz); 13C NMR (75 MHz, DMSO-d6) d: 187.6, 160.2, 135.8,
132.8, 126.0, 124.8, 123.6, 122.4, 118.4, 113.2, 61.8, 14.1. HRMS-
124.9, 122.9, 122.7, 121.3, 110.7, 61.2, 32.5, 12.7 (also small peaks
from Z-isomer). HRMS-ESI (m/z) for C20H19NO2Na, (M+Na) found
328.1315, calcd 328.1313.
4.4.2. (E)-Ethyl 3-(3,4-dimethoxystyryl)-1-methyl-indole-2-
caboxylate 14
Yellow solid (3.3 g, 71%). 114–115 °C; 1H NMR (CDCl3) d: 8.12
(d, 1H, J = 8.1 Hz), 7.80 (d, 1H, J = 16.6 Hz), 7.40–7.38 (m, 2H),
7.26–7.08 (m, 4H), 6.88 (d, 1H, J = 8.2 Hz), 4.45 (q, 2H, J = 7.1 Hz),
4.01 (s, 3H), 3.97 (s, 3H), 3.91 (s, 3H), 1.49 (t, 3H, J = 7.1 Hz); 13C
NMR (CDCl3) d: 162.7, 149.2, 148.7, 139.3, 131.6, 130.4, 125.5,
124.6, 122.5, 121.4, 120.9, 120.8, 119.5, 111.3, 110.5, 108.4, 60.9,
55.9, 55.8, 32.3, 14.5. HRMS-ESI (m/z) for C22H23NO4Na, (M+Na)
found 388.1501, calcd 388.1525.
ESI (m/z) for
C12H11NO3Na, (M+Na) found 240.0636, calcd
240.0637.
4.3. General procedure for compounds 11 and 12
4.4.3. (E)-Ethyl 3-(3,4-dimethoxystyryl)-1-(methoxymethyl)-1H-
indole-2-carboxylate 15
A solution of ethyl-3-formyl-1H-indole-2-carboxylate 10 (5 g,
23 mmol) in DMF (60 ml) was added dropwise under argon to an
ice-cooled suspension of NaH (1.4 g, 35 mmol) in DMF (30 ml).
After stirring at 0 °C for 20 min, the alkyl halide (28 mmol) was
added dropwise and the reaction mixture was allowed to reach
the room temperature and stirred for 1.5 h. The reaction mixture
was poured into ice-water and slightly yellow solid was collected
by filtration to give the product.
Compound 15 was prepared according to the general procedure
above using (3,4-dimethoxybenzyl)triphenylphosphonium bro-
mide (8.0 g, 16 mmol), sodium hydride (0.86 g, 22 mmol) and in-
dole aldehyde 12 (2.82 g, 11 mol) as starting materials. The
reaction was quenched using satd NH4Cl (300 ml). Yellow solid
(2.6 g, 56%). Mp 94–96 °C; 1H NMR (CDCl3) d: 8.11 (d, 1H,
J = 8.1 Hz), 7.77 (d, 1H, J = 16.6 Hz), 7.57 (d, 1H, J = 8.4 Hz), 7.43 (t,
1H, J = 9.0 Hz), 7.30–7.10 (m, 4H), 6.89 (d, 1H, J = 8.0 Hz), 5.95 (s,
2H), 4.47 (q, 2H, J = 7.1 Hz), 3.96 (s, 3H), 3.92 (s, 3H), 3.28 (s, 3H),
1.50 (t, 3H, J = 7.1 Hz); 13C NMR (CDCl3) d: 162.6, 149.3, 149.0,
139.7, 131.7, 131.4, 126.2, 125.3, 123.4, 122.6, 121.8, 120.5, 119.8,
111.4, 111.3, 108.6, 75.2, 61.2, 56.1 (2C), 55.9, 14.6. HRMS-ESI for
4.3.1. Ethyl-3-formyl-1-methyl-indole-2-carboxylate 11
Solid (4.0 g, 75%). Mp 108 °C; 1H NMR (300 MHz, CDCl3) d: 10.64
(s, 1H), 8.50 (dt, 1H, J = 8.0, 1.0 Hz), 7.46–7.32 (m, 3H), 4.51 (q, 2H,
J = 7.1 Hz), 4.05 (s, 3H), 1.47 (t, 3H, J = 7.1); 13C NMR (75 MHz,
CDCl3) d: 188.6, 161.3, 138.4, 133.8, 126.4, 124.9, 124.3, 124.0,
120.0, 110.6, 62.4, 32.6, 14.5. HRMS-ESI (m/z) for C13H13NO3Na
(M+ Na) found 254.0781, calcd 254.0793.
C23H25NO5Na, (M+Na) found 418.1626, calcd 418.1630.
4.4.4. (E)-Ethyl 3-(2,5-dimethoxystyryl)-1-methyl-indole-2-
caboxylate 16
Compound 16 was prepared according to the reaction condi-
tions described above using (2,5-dimethoxybenzyl)triphenylphos-
phonium bromide (3.03 g, 6.15 mmol) in DMF (100 ml), sodium
hydride (0.33 g, 8.20 mmol) and indole-aldehyde 11 (0.95 g,
4.10 mmol) in DMF (20 ml) as starting materials. Yellow solid
(1.00 g, 67%). Mp 101–103 °C; 1H NMR (CDCl3) d: 8.16 (d, 1H,
J = 8.2 Hz), 7.88 (d, 2H, J = 16.8 Hz), 7.60 (d, 2H, J = 16.8 Hz), 7.40
(d, 2H, J = 3.7 Hz), 7.27–7.21 (m, 2H), 6.88–6.78 (m, 2H), 4.46 (q,
2H, J = 7.1), 4.04 (s, 3H), 3.86 (s, 3H), 3.83 (s, 3H), 1.49 (t, 3H,
J = 7.1 Hz); 13C NMR (CDCl3) d: 162.9, 154.1, 151.6, 139.6, 128.6,
126.0, 125.6, 125.4, 124.9, 123.2, 122.9, 121.9, 121.3, 113.7,
112.6, 111.2, 110.6, 61.1, 56.4, 56.0, 32.5, 14.7. HRMS-ESI (m/z)
for C22H23NO4Na, (M+Na) found 388.1550, calcd 388.1525.
4.3.2. Ethyl-3-formyl-1-(methoxymethyl)-indole2-carboxylate
12
Solid (4.9 g, 81%). Mp 66–68 °C; 1H NMR (300 MHz, CDCl3) d:
8.51 (d, 1H, J = 8.0 Hz), 7.59 (d, 1H, J = 9.0 Hz), 7.48–7.35 (m, 2H),
5.95 (s, 2H), 4.54 (q, 2H, J = 7.1 Hz), 3.31 (s, 3H), 1.48 (t, 3H,
J = 7.1 Hz); 13C NMR (75 MHz, CDCl3) d: 188.9, 163.9, 138.4,
132.6, 126.9, 124.9, 124.7, 124.1, 121.3, 111.4, 75.6, 62.6, 56.6,
14.5. HRMS-ESI (m/z) for C14H15NO4Na (M+Na) found 284.0910,
calcd 284.0899.
4.4. General procedure for the Wittig reaction 13–16
The phosphonium salts12 (20 mmol) were dissolved in DMF
(95 ml) under argon and cooled to 0 °C. Sodium hydride (1.04 g,
26.0 mmol) was added and reaction mixtures were stirred at 0 °C
for 20 min. Immediately, after the addition of NaH, a deep red solu-
tion was obtained. Indole aldehyde 11 or 12 (3.0 g, 13 mmol) in
DMF (30 ml) was added dropwise and the reaction mixtures were
allowed to stir at rt for 2.5 h. The reaction mixtures were poured in
to 0.5 M HCl (300 ml) and a yellow solid was collected by filtration.
The crude products 13–16 were recrystallized from i-PrOH.
4.5. General procedure for ester hydrolysis 17–20
The ester 13–16 (8.76 mmol) was dissolved in a MeOH/THF/
water (2:2:1) solvent mixture. Next, NaOH (1.81 g, 45.3 mmol)
was added and the reaction mixture stirred for 1 h at 80 °C. The
solvents were removed and the residue diluted with water. The
reaction mixture was acidified using conc. HCl (aq) and the yellow
solids (17–20) were collected by filtration.
4.4.1. (E)-Ethyl 3-styryl-1-methyl-indole-2-caboxylate 13
4.5.1. (E)-3-Styryl-1-methyl-1H-indole-2-carboxylic acid 17
Compound 17 was prepared according to the reaction condi-
tions described above using ester 13 (1.28 g, 4.19 mmol) as starting
material. Yellow solid (0.90 g, 97%). Mp 167–169 °C; 1H NMR
(DMSO-d6) d: 8.16, (d, 1H, J = 8.1 Hz), 7.95 (d, 1H, J = 16.8 Hz),
7.63–7.57 (m, 3H), 7.41–7.24 (m, 6H), 4.00 (s, 3H); 13C NMR
(DMSO-d6) d: 163.4, 138.8, 138.2, 128.9, 128.8, 127.3, 127.2,
126.0, 125.3, 123.8, 122.6, 122.1, 121.3, 119.2, 111.3, 32.3.
HRMS-ESI (m/z) for C18H15NO2Na, (M+Na) found 300.1018, calcd
300.1000.
Compound 13 was prepared according to the reaction condi-
tions described above using benzyltriphenylphosphonium bromide
(4.3 g, 9.7 mmol), sodium hydride (0.5 g, 13.0 mmol) and indole-
aldehyde 11 (1.5 g, 6.50 mmol) as the starting materials. Yellow so-
lid (1.28 g, 65%). Mp 88–90 °C; 1H NMR (CDCl3) d: 8.11 (d, 1H,,
J = 8.2 Hz), 7.93 (d, 1H, J = 16.7 Hz), 7.56 (d, 2H, J = 7.59 Hz), 7.41–
7.35 (m, 4H), 7.28–7.22 (m, 4H), 4.46 (q, 2H, J = 7.1 Hz), 4.04 (s,
3H), 1.48 (t, 3H, J = 7.1 Hz) (16% of Z-isomer); 13C NMR (CDCl3) d:
162.9, 139.5, 138.6, 130.7, 128.9, 127.5, 126.6, 126.4, 125.7,

472
N. Kuuloja et al. / Tetrahedron: Asymmetry 22 (2011) 468–475
4.5.2. (E)-3-(3,4-Dimethoxystyryl)-1-methyl-1H-indole-2-
carboxylic acid 18
121.5, 112.2, 111.3, 64.0, 53.5, 37.1, 31.3. HRMS-ESI (m/z) for
27H26N2O2Na, (M+Na) found 433.1879, calcd 433.1892.
C
Compound 18 was prepared according to the reaction condi-
tions described above using ester 14 (3.20 g, 8.76 mmol) as a start-
ing material. Yellow solid (2.56 g, 87%). Mp 185–187 °C; 1H NMR
(DMSO-d6) d: 8.15 (d, 1H, J = 8.2 Hz), 7.81 (d, 1H, J = 16.8 Hz),
7.61 (d, 1H, J = 8.4 Hz), 7.40 (td, 1H, J = 9.0, 1.0 Hz), 7.27–7.12 (m,
4H), 6.98 (d, 1H, J = 8.4 Hz), 3.98 (s, 3H), 3.82 (s, 3H), 3.78 (s,
3H); 13C NMR (DMSO- d6) d: 164.09, 149.6, 149.1, 139.4, 131.8,
129.7, 127.4, 125.8, 124.4, 122.8, 121.7, 121.2, 120.3, 119.1,
112.7, 111.8, 110.4, 56.2, 56.1, 32.8. HRMS-ESI for C20H19NO4Na,
(M+Na) found 360.1224, calcd 360.1212.
4.6.2. (S,E)-3-(3,4-Dimethoxystyryl)-N-(1-hydroxy-3-
phenylpropan-2-yl)-1-methyl-1H-indole-carboxamide 22
Compound 22 was prepared according the reaction conditions
described above using substituted indole-2-carboxylic acid 18
(1.2 g, 3.60 mmol), phenylalaninol (0.65 g 4.00 mmol) and BOP
(1.64 g, 3.90 mmol) as starting materials. Yellowish solid (1.4 g,
84%). Mp 176–178 °C;
½
a 2D0
ꢁ
¼ ꢂ77:6 (c 0.5, CHCl3); 1H NMR
(DMSO-d6) d: 8.55 (d, 1H, J = 8.9 Hz), 8.14 (d, 1H, J = 8.0 Hz), 7.49
(d, 1H, J = 8.2 Hz), 7.37–7.06 (m, 10H), 6.94 (d, 1H, J = 8.3 Hz),
5.02 (t, 1H, J = 6.1 Hz), 4.40 (m, 1H), 3.83 (s, 3H), 3.77 (s, 3H),
3.63–3.59 (m, 2H), 3.46 (s, 3H), 2.98 (dd, 1H, J = 12.9 Hz, 4.9 Hz),
2.73 (dd, 1H, J = 13.5 Hz, 9.7 Hz); 13C NMR (DMSO-d6) d: 161.5,
148.9, 148.0, 139.1, 137.2, 135.0, 131.4, 129.2, 128.1, 126.0,
125.7, 124.0, 123.3, 121.3, 120.6, 119.5, 118.6, 111.9 (2C), 110.5,
108.8, 63.3, 55.4 (2C), 53.0, 36.6. 30.6. HRMS-ESI (m/z) for
4.5.3. (E)-3-(3,4-Dimethoxystyryl)-1-(methoxymethyl)-1H-
indole-2-carboxylic acid 19
Compound 19 was prepared according to the reaction condi-
tions described above using ester 15 (2.57 g, 6.50 mmol) as a start-
ing material. Yellow solid (2.30 g, 97%). Mp 133–135 °C; 1H NMR
(DMSO-d6) d: 8.16 (d, 1H, J = 8.1 Hz), 7.77 (d, 1H, J = 16.9 Hz),
7.73 (d, 1H, J = 9.6 Hz), 7.42 (t, 1H, J = 7.50 Hz), 7.32–7.14 (m,
4H), 6.99 (d, 1H, J = 8.4 Hz), 5.92 (s, 2H), 3.82 (s, 3H), 3.78 (s, 3H),
3.13 (s, 3H); 13C NMR (DMSO-d6) d: 163.2, 148.9, 148.6, 139.0,
130.9, 130.2, 126.4, 125.6, 124.3, 122.3, 121.7, 121.3, 120.1,
118.7, 112.0, 111.7, 109.8, 74.4, 67.1, 55.5, 55.4. HRMS-ESI (m/z)
for C21H21NO5Na, (M+Na) found 390.1304, calcd 390.1317.
C29H30N2O4Na, (M+ Na) found 493.2089, calcd 493.2103.
4.6.3. (S,E)-3-(3,4-Dimethoxystyryl)-N-(1-hydroxy-3-
phenylpropan-2-yl)-1-(methoxymethyl)-1H-indole-
carboxamide 23
Compound 23 was prepared according the reaction conditions
described above using substituted indole-2-carboxylic acid 19
(1.2 g, 3.27 mmol), phenylalaninol (0.524 g, 3.46 mmol) and BOP
(1.40 g, 3.31 mmol) as starting materials. Pure product was ob-
tained after recrystallization from i-PrOH. Yellowish solid (0.88 g,
4.5.4. (E)-3-(2,5-Dimethoxystyryl)-1-methyl-1H-indole-2-
carboxylic acid 20
Compound 20 was prepared according to the reaction condi-
tions described above using ester 16 (0.66 g, 1.81 mmol) as a start-
ing material. Yellow solid (0.50 g, 82%). Mp 172–174 °C; 1H NMR
(DMSO-d6) d: 8.03 (d, 1H, J = 8.2 Hz), 7.92 (d, 1H, J = 16.9 Hz),
7.62 (d, 1H, J = 8.4 Hz), 7.46–7.38 (m, 2H), 7.24 (t, 1H, J = 7.9 Hz),
7.14 (d, 1H, J = 3.0 Hz), 6.07 (d, 1H, J = 9.0 Hz), 6.97 (d, 1H,
J = 9.0 Hz) 6.84 (dd, 1H, J = 8.9 Hz, 3.0 Hz), 3.99 (s, 3H), 3.81 (s,
3H), 3.75 (s, 3H); 13C NMR (DMSO-d6) d: 164.0, 155.5, 154.1,
151.4, 139.4, 128.1, 125.8, 124.4, 124.2, 124.1, 122.3, 121.9,
120.3, 113.8, 113.3, 111.9, 111.7, 56.8, 56.1, 32.8. HRMS-ESI (m/z)
for C20H19NO4Na, (M+Na) found 360.1197, calcd 360.1212.
54%). Mp 169–171 °C;
½
a 2D0
ꢁ
¼ ꢂ45:1 (c 1.0, CHCl3); 1H NMR
(DMSO-d6) d: 8.62 (d, 1H, J = 8.8 Hz), 8.16 (d, 1H, J = 8.0 Hz), 7.59
(d, 1H, J = 8.2 Hz), 7.38–7.19 (m, 9H), 7.09 (dd, 1H, J = 8.4 Hz,
1.4 Hz) 6.94 (d, 1H, J = 8.4 Hz), 5.45 (A, 1H, JAB = 11.1 Hz), 5.37 (B,
1H, JAB = 11.1 Hz), 5.00 (t, 1H, J = 5.8 Hz), 4.45–4.33 (m, 1H), 3.82
(s, 3H), 3.78 (s, 3H), 3.60–3.55 (m, 2H), 2.98–2.88 (m, 1H), 2.92
(s, 3H), 2.81–2.73 (m, 1H); 13C NMR (DMSO-d6) d: 162.02, 149.6,
148.8, 139.7, 137.7, 135.0, 131.8, 129.7, 128.8, 127.8, 126.7,
125.3, 124.4, 122.2, 122.0, 120.0, 119.6, 114.3, 112.5, 112.0,
109.6, 75.0, 63.8, 56.2, 56.1, 56.0, 54.0, 37.1. HRMS-ESI (m/z) for
C30H32N2O5Na, (M+Na) found 523.2212, calcd 523.2209.
4.6. General procedure for amido alcohols 21–267
4.6.4. (S,E)-3-(3,4-Dimethoxystyryl)-N-(1-hydroxy-3-
methylbutan-2-yl)-1-methyl-1H-indole-carboxamide 24
Compound 24 was prepared according to the reaction condi-
tions described above using substituted indole-2-carboxylic acid
18 (1.2 g, 3.6 mmol), valinol (0.419 g, 4.0 mmol) and BOP (1.64 g,
3.9 mmol). The product was recrystallized from i-PrOH. Yellowish
The substituted indole-2-carboxylic acid 17–20 (3.60 mmol)
was dissolved in a mixture of DCM (10 ml) and DMF (1.5 ml).
Amino alcohol (4.00 mmol) was added, followed by BOP (benzotri-
azole-1-yl-oxy-tris(dimethylamino)-phosphonium
hexafluoro-
phosphate) (1.64 g, 3.90 mmol). The pH of the reaction mixtures
was adjusted to between 9 and 10 with DIPEA. The product precip-
itated out during the reaction. When the reaction reached comple-
tion, according to TLC, the solvents were removed in vacuo and the
reaction mixture was diluted with water. Pure product 21–26 was
collected by filtration (1.4 g, 84%).
solid (1.2 g, 81%). Mp 181–183 °C; ½a D20
ꢁ
¼ ꢂ14:4 (c 1.0, CHCl3); 1H
NMR (CDCl3) d: 7.93 (d, 1H, J = 8.0 Hz), 7.35–7.00 (m, 6H), 6.84
(d, 1H, J = 8.3 Hz), 6.33 (d, 1H, J = 8.9 Hz), 4.04 (m, 1H), 3.93 (s,
3H), 3.90 (s, 3H), 3.87 (s, 3H), 3.86–3.82 (m, 1H), 3.72–3.67 (m,
1H), 1.93 (sep, 1H, J = 6.8 Hz), 1.00 (d, 3H, J = 6.8 Hz), 0.97 (d, 3H,
J = 6.8 Hz); 13C NMR (CDCl3) d: 163.7, 149.4, 148.9, 138.5, 131.6,
131.2, 130.6, 125.1, 124.6, 121.7, 121.1, 119.8, 118.5, 115.3,
111.4, 110.4, 108.3, 64.1, 57.8, 56.2, 56.1, 31.6, 29.5, 19.9, 19.1.
HRMS-ESI (m/z) for C25H30N2O4Na, (M+Na) found 445.2104, calcd
445.2103.
4.6.1. (S,E)-3-Styryl-N-(1-hydroxy-3-phenylpropan-2-yl)-1-
methyl-1H-indole-carboxamide 21
Compound 21 was prepared according the reaction conditions
described above using substituted indole-2-caboxylic acid 17
(1.0 g, 3.61 mmol), phenylalaninol (0.6 g, 3.97 mmol) and BOP
(1.60 g, 3.79 mmol) as starting materials. Yellowish solid (1.41 g,
4.6.5. (S,E)-3-(3,4-Dimethoxystyryl)-N-(1-hydroxy-3-
methylbutan-2-yl)-1-(methoxymethyl)-1H-indole-carboxamide
25
94%). Mp 198–200 °C;
½
a 2D0
ꢁ
¼ ꢂ65:7 (c 1.0, CHCl3); 1H NMR
(DMSO-d6) d: 8.59 (d, 1H, J = 8.9 Hz), 8.12 (d, 1H, J = 8.07 Hz),
7.53–7.49 (m, 3H), 7.40–7.51 (m, 12H), 5.04 (br s, 1H), 4.43–4.67
(m, 1H), 3.59 (d, 2H, J = 5.9 Hz), 3.49 (s, 3H), 3.00 (dd, 1H,
J = 13.9 Hz, 4.7 Hz), 2.72 (dd, 1H, J = 13.3 Hz, 10.5 Hz); 13C NMR
(DMSO-d6) d: 162.1, 139.7, 139.0, 137.8, 126.3, 129.8, 128.3,
128.8, 127.3, 126.7, 126.4, 126.2, 124.7, 124.0, 122.2, 121.9,
Compound 25 was prepared according to the reaction condi-
tions described above using substituted indole-2-carboxylic acid
19 (1.2 g, 3.26 mmol), valinol (0.357 g, 3.46 mmol) and BOP
(1.40 g, 3.31 mmol) as starting materials. Crude product was
washed with i-PrOH (50 ml). Yellowish solid (1.1 g, 73%). Mp
181–183 °C; ½a 2D0
ꢁ
¼ ꢂ10:5 (c 1.0, CHCl3); 1H NMR (DMSO-d6) d:

N. Kuuloja et al. / Tetrahedron: Asymmetry 22 (2011) 468–475
473
8.48 (d, 1H, J = 9.1 Hz), 8.18 (d, 1H, 7.9 Hz), 7.65 (d, 1H, J = 8.2 Hz),
7.46 (d, 1H, J = 16.7 Hz), 7.37–7.22 (m, 4H), 7.14 (dd, 1H, J = 8.3 Hz,
1.6 Hz) 6.94 (d, 1H, J = 8.3 Hz), 5.64 (s, 2H, J = 5.63 Hz), 4.73 (t, 1H,
J = 5.5 Hz), 3.97–3.95 (m, 1H), 3.82 (s, 3H), 3.77 (s, 3H), 3.67–3.50
(m, 2H), 3.16 (s, 3H), 1.92 (sep, 1H, J = 6.6 Hz), 0.99 (d, 3H,
J = 6.75 Hz), 0.95 (d, 3H, J = 6.75 Hz); 13C NMR (DMSO-d6) d:
167.4, 148.9, 148.2, 137.1, 134.8, 131.2, 127.0, 124.6, 123.7,
121.5, 121.3, 119.4, 119.2, 113.5, 111.8, 111.2, 108.6, 61.5, 56.9,
55.5 (2C), 55.4, 28.7, 18.8, 18.5. HRMS-ESI (m/z) for C26H32N2O5Na,
(M+Na) found 475.2187, calcd 475.2209.
1H, J = 8.1 Hz), 7.72 (d, 1H, J = 16.6 Hz), 7.38–7.16 (m, 9H), 7.09–
7.07 (m, 2H), 6.87 (d, 1H, J = 8.8 Hz), 4.70–4.63 (m, 1H), 4.40 (dd,
1H, J = 9.2, 8.5 Hz), 4.18 (dd, 1H, J = 7.3 Hz, 8.4 Hz), 4.01 (s, 3H),
3.93 (s, 3H), 3.91 (s, 3H), 3.24 (dd, 1H, J = 13.8, 5.6 Hz), 2.14 (dd,
2H, J = 13.8 Hz, 8.1 Hz); 13C NMR (CDCl3) d: 159.0, 149.3, 148.7,
139.4, 138.1, 132.1, 129.5, 129.5, 129.1, 128.7, 126.8, 125.2,
124.7, 124.6, 122.0, 121.2, 120.8, 119.3, 119.1, 111.6, 110.3,
109.3, 71.2, 68.1, 56.2, 56.0, 42.0, 32.3. HRMS-ESI (m/z) for
C29H29N2O3, (M+H) found 453.2173, calcd 453.2178.
4.7.3. (S,E)-4-Benzyl-2-(3-(3,4-dimethoxystyryl)-1-
(methoxymethyl)-1H-indol-2-yl)-4,5-dihyrdoxazole 3
4.6.6. (S,E)-3-(2,5-Dimethoxystyryl)-N-(1-hydroxy-3-
phenylpropan-2-yl)-1-methyl-1H-indole-carboxamide 26
Compound 26 was prepared according to the reaction condi-
tions described above using substituted indole-2-carboxylic acid
20 (0.45 g, 1.33 mmol), phenylalaninol (0.22 g, 1.47 mmol) and
BOP (0.590 g, 1.40 mmol) as starting materials. Yellowish product
Compound 3 was prepared according to the general procedure
using amido alcohol 23 (0.87 g, 1.74 mmol), DCM (20 ml), Et3N
(1.82 ml, 13 mmol), DMAP (39 mg, 20 mol %) and MsCl (0.30 ml,
4.10 mmol) as starting material. The reaction mixture was heated
to 50 °C. The reaction was monitored by TLC using an eluent sys-
tem of Hex/EtOAc 2:1. The crude product was filtered through a
short pad of silica using Hex/EtOAc (1:1) as an eluent. Yellow oil
(0.48 g, 78%). Mp 221–223 °C; ½a D20
ꢁ
¼ ꢂ124:6 (c 0.5, DMF); 1H
NMR (DMSO-d6) d: 8.57 (d, 1H, J = 9.0 Hz), 7.97 (d, 1H, J = 7.9 Hz),
7.50 (d, 1H, 8.2 Hz), 7.38–7.17 (m, 10H), 6.95 (d, 1H, J = 9.0 Hz)
6.79 (dd, 1H, J = 8.9, 3.0 Hz), 5.00 (t, 1H, J = 5.7 Hz), 4.40–4.32 (m,
1H), 3.81 (s, 3H), 3.77 (s, 3H), 3.58–3.55 (m, 2H), 3.46 (s, 3H),
2.98 (dd, 1H, J = 13.7 Hz, 4.9 Hz), 2.70 (dd, 1H, J = 13.6 Hz,
9.7 Hz); 13C NMR (DMSO-d6) d: 162.0, 154.1, 151.1, 139.8, 137.8,
136.1, 129.8, 128.7, 128.2, 126.7, 124.7, 124.0, 122.7, 121.5,
121.5, 121.4, 120.5, 113.9, 113.2, 112.7, 111.4, 110.4, 63.8, 56.9,
56.1, 53.8, 37.2, 31.3. HRMS-ESI (m/z) for C29H30N2O4Na, (M+ Na)
found 493.2095, calcd 493.2103.
(0.57 g, 67%). ½a D20
ꢁ
¼ ꢂ26:0 (c 1.3, CHCl3); 1H NMR (CDCl3) d: 8.10
(d, 1H, J = 8.1 Hz), 7.71 (d, 1H, J = 16.6 Hz), 7.55 (d, 1H, J = 8.3 Hz),
7.37–7.08 (m, 10H), 6.88 (d, 1H, J = 8.8 Hz), 5.98 (s, 2H), 4.68 (m,
1H, J = 7.6 Hz), 4.41 (t, 1H, J = 8.9 Hz), 4.17 (t, 1H, J = 7.9 Hz), 3.93
(s, 3H), 3.91 (s, 3H), 3.25–3.19 (m, 1H), 3.26 (s, 3H), 2.82 (dd, 1H,
J = 13.7 Hz, 8.0 Hz); 13C NMR (CDCl3) d: 158.6, 149.2, 148.8,
139.4, 138.0, 131.7, 130.3, 129.4, 129.2, 128.7, 128.3, 126.7,
125.7, 125.2, 124.1, 122.0, 121.6, 120.8, 120.7, 119.4, 111.4,
111.2, 109.2, 75.2, 71.2, 68.0, 56.1, 56.0, 41.9. HRMS-ESI for
C30H30N2O4Na, (M+Na) found 505.2119, calcd 505.2103.
4.7. General procedure for ligands 1–67
4.7.4. (S,E)-2-(3-(3,4-Dimethoxystyryl)-1-methyl-1H-indol-2-yl)-
4-isopropyl-4,5-dihyrdoxazole 4
Mesylchloride (0.6 ml, 7.63 mmol) was carefully added to a stir-
red mixture of amino alcohol, Et3N (3.40 ml, 24 mmol) and DMAP
(75 mg, 20 mol %) in DCM (30 ml). The reactions were monitored
by TLC (Hex/EtOAc 1:1), to observe the formation and disappear-
ance of the mesylate intermediate. After 5 h, the oxazoline formed.
The reaction was quenched with water and diluted with DCM. The
product was extracted with DCM (2 ꢃ 50 ml). The combined DCM
fractions were washed with water (50 ml) and brine (50 ml) and
dried over Na2SO4. After filtration the solvents were removed in va-
cuo and product 1–6 was precipitated from methanol. Yellow sol-
ids 1–2 and 4–6 were filtered and 3 was obtained as a yellow oil.
Compound 4 was prepared according to the general procedure
using amido alcohol 24 (1.13 g, 2.67 mmol), DCM (30 ml), Et3N
(3.04 ml, 22 mmol), DMAP (67 mg, 20 mol %). and MsCl (0.53 ml,
6.86 mmol) as starting materials. Yellow solid (0.96 g, 89%). Mp
96–97 °C; ½a 2D0
ꢁ
¼ ꢂ46:5 (c 1.0, DMF); 1H NMR (CDCl3) d: 8.11 (d,
1H, J = 8.1 Hz), 7.79 (d, 1H, J = 16.6 Hz), 7.38–7.36 (m, 2H), 7.26–
7.18 (m, 2H), 7.12–7.07 (m, 2H), 6.88 (d, 1H, J = 8.2 Hz), 4.50–
4.41 (m, 1H), 4.23–4.13 (m, 2H), 4.03 (s, 3H), 3.96 (s, 3H), 3.91 (s,
3H), 1.89 (sep, 1H, J = 6.6 Hz), 1.10 (d, 3H, J = 6.7 Hz), 1.01 (d, 3H,
J = 6.7 Hz). 13C NMR (CDCl3) d: 158.2, 149.2, 148.5, 139.3, 132.1,
128.8, 125.1, 125.0, 124.5, 122.0, 121.1, 120.8, 119.4, 118.8,
111.4, 110.3, 108.7, 72.9, 69.8, 56.1, 55.9, 33.2, 32.3 19.1, 18.7.
HRMS-ESI (m/z) for C25H29N2O3, (M+H) found 405.2169, calcd
405.2178.
4.7.1. (S,E)-4-Benzyl-2,3-styryl-1-methyl-1H-indol-2-yl)-4,5-
dihyrdoxazole 1
Compound 1 was prepared according to the general procedure
using amido alcohol 21 (0.60 g, 1.46 mmol), DCM (14 ml), Et3N
(1.6 ml, 11.7 mmol), DMAP (36 mg, 20 mol %) and MsCl (0.28 ml,
3.65 mmol) as starting materials. Yellow solid (0.380 g, 67%). Mp
4.7.5. (S,E)-2-(3-(3,4-Dimethoxystyryl)-1-(methoxymethyl)-1H-
indol-2-yl)-4-isopropyl-4,5-dihyrdoxazole 5
109–111 °C; ½a 2D0
ꢁ
¼ ꢂ47:3 (c 1.0, CHCl3); 1H NMR (CDCl3) d: 8.11
Compound 5 was prepared according to the general procedure
using amido alcohol 25 (0.98 g, 2.15 mmol), DCM (20 ml), Et3N
(2.30 ml, 17 mmol), DMAP (51 mg, 20 mol %) and MsCl (0.40 ml,
5.25 mmol). The pure product was obtained after recrystallization
from i-PrOH. Yellow solid (0.92 g, 99%). Mp 55– 57 °C;
(d, 1H, J = 8.1 Hz), 7.84 (d, 1H, J = 16.6 Hz), 7.54–7.51 (m, 2H),
7.40–7.20 (m, 12 H), 4.73–4.63 (m, 1H), 4.41 (dd, 1H, J = 9.3 Hz,
8.5 Hz)), 4.19 (dd, 1H, J = 8.4 Hz, 7.3 Hz), 4.01 (s, 3H), 3.23 (dd,
1H, J = 13.7 Hz, 5.7 Hz), 2.84 (dd, 1H, J = 13.7 Hz, 8.0 Hz); 13C
NMR (CDCl3) d: 158.9, 139.3, 138.8, 138.0, 129.5, 129.2, 128.7,
127.0 126.7, 126.3, 125.1, 124.6, 122.8, 122.0, 120.9, 118.9, 110.4,
71.2, 68.0, 42.0, 32.4. HRMS-ESI (m/z) for C27H25N2O, (M+H) found
393.1947, calcd 393.1967.
½
a 2D0
ꢁ
¼ ꢂ43:1 (c 1.0, CHCl3); 1H NMR (CDCl3) d: 8.10 (d, 1H,
J = 8.0 Hz), 7.77 (d, 1H, J = 16.6 Hz), 7.55 (d, 1H, J = 8.3 Hz), 7.37
(td, 1H, J = 7.7, 1.2 Hz), 7.28–7.21 (m, 2H), 7.13–7.08 (m, 2H),
6.88 (d, 1H, J = 8.2 Hz), 6.03 (A, 1H, JAB = 10.7 Hz), 5.94 (B, 1H,
JAB = 10.7 Hz), 4.50–4.42 (m, 1H), 4.22–4.12 (m, 2H), 3.95 (s, 3H),
3.91 (s, 3H), 3.24 (s, 2H), 1.87 (sep, 1H, J = 6.6 Hz), 1.10 (d, 3H,
J = 6.7 Hz), 1.01 (d, 3H, J = 6.7 Hz); 13C NMR (CDCl3) d: 157.9,
149.2, 148.7, 139.2, 131.8, 130.0, 125.7, 125.0, 124.4, 122.0,
121.5, 120.7, 120.5, 119.6, 111.4, 111.2, 108.8, 75.2, 72.9, 69.9,
56.1, 55.9, 33.2, 31.6, 19.1, 18.8. HRMS-ESI (m/z) for C26H30N2O4Na,
(M+Na) found 457.2091, calcd 457.2103.
4.7.2. (S,E)-4-Benzyl-2-(3-(3,4-dimethoxystyryl)-1-methyl-1H-
indol-2-yl)-4,5-dihyrdoxazole 2
Compound 2 was prepared according to the general procedure
using amido alcohol 22 (1.40 g, 2.98 mmol), DCM (30 ml), Et3N
(3.40 ml, 24 mmol), DMAP (75 mg, 20 mol %) and MsCl (0.60 ml,
7.63 mmol) as starting materials. Yellow solid (1.07 g, 80%). Mp
96–97 °C; ½a 2D0
ꢁ
¼ ꢂ35:5 (c 1.0, CHCl3); 1H NMR (CDCl3) d: 8.10 (d,

474
N. Kuuloja et al. / Tetrahedron: Asymmetry 22 (2011) 468–475
4.7.6. (S,E)-4-Benzyl-2-(3-(2,5-dimethoxystyryl)-1-methyl-1H-
indol-2-yl)-4,5-dihyrdoxazole 6
d: 211.1, 144.4, 128.7, 126.7, 126.6, 49.0, 44.7, 41.2, 32.8, 25.6.
The enantiomeric excess was determined by HPLC using a Chir-
alpak IA column; Hex/i-PrOH 95:5; flow rate: 0.5 ml/min; UV at
220 nm; t1 = 15.3 min (S) and t2 = 16.8 (R).
Compound 6 was prepared according the general procedure
using amido alcohol 26 (0.30 g, 0.64 mmol), DCM (6 ml), Et3N
(0.7 ml, 5.1 mmol), DMAP (16 mg, 20 mol %) and MsCl (0.12 ml,
1.60 mmol). Yellow solid (0.175 g, 61%). Mp 116–118 °C;
4.9.2. 3-Phenyl-cyclopentanone
½
a 2D0
ꢁ
¼ ꢂ36:6 (c 1.0, CHCl3); 1H NMR (CDCl3) d: 8.15 (d, 1H,
TLC (Hex/DCM/acetone 10:10:1, Hanessian’s stain): Rf = 0.51;
J = 8.1 Hz), 7.80 (d, 1H, J = 16.7 Hz), 7.57 (d, 1H, J = 16.8 Hz), 7.38–
7.21 (m, 9H), 6.85–6.75 (m, 2H), 4.71–4.62 (m, 1H), 4.40 (dd, 1H,
J = 9.3 Hz, 8.5 Hz), 4.19 (dd, 1H, J = 8.4 Hz, 7.3 Hz), 4.02 (s, 3H),
3.85 (s, 3 H), 3.82 (s, 3H), 3.24 (dd, 1H, J = 13.7 Hz, 5.5 Hz), 2.83
(dd, 1H, J = 13.7 Hz, 8.2 Hz); 13C NMR (CDCl3) d: 159.0, 153.9,
151.4, 139.4, 138.0, 129.5, 128.9, 128.7, 126.7, 125.1, 124.6,
123.8, 123.2, 122.2, 120.9, 119.5, 112.8, 112.3, 111.7, 110.3, 71.2,
68.0, 56.6, 55.9, 42.0, 32.3. HRMS-ESI (m/z) for C29H29N2O3,
(M+H) found 453.2153, calcd 453.2178.8
½
a 2D0
ꢁ
¼ ꢂ79:2 (c 1.0, CHCl3); 1H NMR (CDCl3) d: 7.36–7.22 (m,
5H), 3.46–3.35 (m, 1H), 2.65 (dd, 1H, J = 18.2 Hz, 7.7 Hz), 2.50–
2.22 (m, 4H), 2.05–1.86 (m, 1H); 13C NMR (CDCl3) d: 218.4,
143.0, 128.7, 126.8 (2C), 45.8, 42.2, 38.9, 31.2. The enantiomeric
excess was also determined by comparing the specific rotation to
the literature {½a D20
ꢁ
¼ þ87:3 (c 1.0, CHCl3), ee 99%}.13
4.9.3. 3-Phenyl-cycloheptanone
TLC (Hex/DCM/acetone 10:10:1, Hanessian’s stain): Rf = 0.62;
½
a 2D0
ꢁ
¼ ꢂ43:0 (c 0.5, CHCl3) (ee 75%); 1H NMR (CDCl3) d: 7.32–
7.27 (m, 2H), 7.22–7.16 (m, 2H), 2.91–2.89 (m, 2H), 2.66–2.57
(m, 3H), 2.08–1.97 (m, 3H), 2.10–1.43 (m, 3H). 13C NMR (CDCl3)
d: 213.6, 146.9, 128.6, 126.4, 126.3, 51.3, 43.9, 42.7, 39.2, 29.2,
24.2. The enantiomeric excess was determined by HPLC using a
Chiralpak IC column; Hex/i-PrOH 95:5; flow rate: 1.0 ml/min; UV
at 220 nm; t1 = 16.4 min (S) and t2 = 22.2 (R).
4.8. Reduction of ligand 4
4.8.1. (S)-2-(3-(3,4-Dimethoxyphenethyl)-1-methyl-1H-indol-2-
yl)-4-isopropyl-4,5-dihydrooxazole
Ligand 4 (0.1 g, 0.25 mmol) was dissolved in an MeOH/THF
(2:1) (4,5 ml) solvent mixture and NiCl2ꢀ6H2O (45 mg, 0.19 mmol)
was added. Next, NaBH4 (93 mg, 2.5 mmol) was added slowly to
the ice-cooled solution. After 30 min, the reaction was quenched
with water and extracted to the EtOAc. The combined EtOAc frac-
tions were washed with brine and dried over Na2SO4. Crude prod-
uct 7 was filtered through a short pad of silica using EtOAc as an
Acknowledgments
We thank Mrs. Päivi Joensuu (University of Oulu) for analyzing
the HMRS data. Financial support from Graduate School of Organic
Chemistry and Chemical Biology (GSOCCB) is gratefully
acknowledged.
eluent. Yellow oil (44 mg, 44%). ½a D20
ꢁ
¼ ꢂ37:7 (c 0.6, CHCl3); 1H
NMR (CDCl3) d: 7.61 (dt, 1H, J = 8.0, 0.8 Hz), 7.36–7.30 (m, 2H),
7.12 (ddd, 1H, J = 8.0, 6.3, 1.7 Hz), 6.83–6.76 (m, 2H), 6.71–6.70
(m, 1H), 4.39–4.30 (m, 1H), 4.15–4.05 (2H), 4.03 (s, 3H), 3.87 (s,
3H), 3.83 (s, 3H), 3.34–3.28 (m, 2H), 2.89–2.84 (m, 2H), 1.84 (sep,
J = 6.6 Hz), 1.06 (d, 3H, J = 6.7 Hz), 0.97 (d, 3H, J = 6.7 Hz). 13C
NMR (CDCl3) d: 158.6, 148.8, 147.3, 138.7, 135.6, 127.0, 124.1,
123.8, 121.3, 120.4, 120.1, 119.6, 112.0, 111.3, 110.0, 72.3, 69.4,
56.1, 55.9, 37.5, 33.2, 32.1, 27.7, 19.1, 18.6. HRMS-ESI (m/z) for
References
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ꢁ
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OMe
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OMe
OMe
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N
N
N
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4
7
.