Synthesis of tetrahydroisoquinoline (TIQ)-oxazoline ligands and their application in enantioselective Henry reactions

Article abstract of DOI:10.1016/j.tetasy.2010.04.053

A novel family of eleven new tetrahydroisoquinoline (TIQ)-oxazoline intermediates and five corresponding copper(II) catalysts has been developed and applied to the catalytic asymmetric Henry reaction of various aldehydes with nitromethane to provide β-hydroxy nitroalkanes in high conversion (>99%). This paper describes the synthesis of the TIQ compounds from L-dihydroxyphenylalanine (L-DOPA) as the starting material. The chiral ligands were complexed in situ with various transition metals such as Cu, Sc, Co, Zn, Ni and Mn and tested as a chiral catalyst for the Henry reaction. The reaction was optimized in terms of the metal, counter ion, solvent, temperature and over a range of substrates. The corresponding catalyst with copper(II) acetate and 2-propanol as the solvent provides the best enantioselectivities (up to 77% ee) of the corresponding nitroalcohol for 4-chlorobenzaldehyde.

Full text of DOI:10.1016/j.tetasy.2010.04.053

Tetrahedron: Asymmetry 21 (2010) 846–852
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis of tetrahydroisoquinoline (TIQ)–oxazoline ligands and their
application in enantioselective Henry reactions
Rahul B. Kawthekar a, Sai Kumar Chakka a, Vivian Francis a, Pher G. Andersson c, Hendrik G. Kruger a,
,
*
Glenn E. M. Maguire a, Thavendran Govender b,
*
a School of Chemistry, University of KwaZulu-Natal, Durban, South Africa
b School of Pharmacy and Pharmacology, University of KwaZulu-Natal, Durban, South Africa
c Department of Organic Chemistry, Uppsala University, Uppsala, Sweden
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel family of eleven new tetrahydroisoquinoline (TIQ)–oxazoline intermediates and five correspond-
ing copper(II) catalysts has been developed and applied to the catalytic asymmetric Henry reaction of
various aldehydes with nitromethane to provide b-hydroxy nitroalkanes in high conversion (>99%). This
Received 5 April 2010
Accepted 19 April 2010
Available online 2 June 2010
paper describes the synthesis of the TIQ compounds from L-dihydroxyphenylalanine (L-DOPA) as the
starting material. The chiral ligands were complexed in situ with various transition metals such as Cu,
Sc, Co, Zn, Ni and Mn and tested as a chiral catalyst for the Henry reaction. The reaction was optimized
in terms of the metal, counter ion, solvent, temperature and over a range of substrates. The corresponding
catalyst with copper(II) acetate and 2-propanol as the solvent provides the best enantioselectivities (up to
77% ee) of the corresponding nitroalcohol for 4-chlorobenzaldehyde.
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
biosynthetic pathways32 contributing further to the level of inter-
est conferred upon it. Previous reports on the use of TIQ derivatives
Chiral ligands containing nitrogen donor atoms are widely used
as catalysts for asymmetric carbon–carbon bond forming reac-
tions.1 In particular, the Henry reaction is one of the classic meth-
ods for carbon-carbon bond formation in organic synthesis2 and
has received much attention after the pioneering work of the
Shibasaki et al.3–25 Moreover, compounds containing a chiral-oxaz-
oline ring are one of the most frequently used classes of ligands in
asymmetric catalysis. Specific structural features of oxazoline rings
have been used with great success in asymmetric reactions due to
their modular nature and applicability to a wide range of metal-
catalyzed transformations.26 The majority of these ligands are
synthesized from readily available chiral amino alcohols through
amidation followed by chlorination and base-induced cyclization
to obtain the oxazoline.27 Evans et al. reported a novel Cu-bis(oxaz-
oline) catalyst which could efficiently catalyze the asymmetric
nitroaldol reaction with a variety of aldehydes in excellent yield
and 96% ee.28
as ligands have yielded limited success, with poor to moderate
enantioselectivities in asymmetric catalysis such as allylic alkyl-
ation33, borane-mediated hydrogenation34,35 and the addition of
diethylzinc to benzaldehyde.36 We are investigating the use of this
class of scaffold as chiral ligands and have recently reported TIQ
amino alcohols for the asymmetric transfer hydrogenation of pro-
chiral ketones.37 Herein we report the synthesis of a new class of
oxazoline ligands built on the TIQ scaffold, and as a preliminary
investigation we evaluated its efficiency for the asymmetric Henry
reaction of aldehydes with nitromethane (Fig. 1).
2. Results and discussion
2.1. Synthesis of the TIQ–oxazoline ligands
The synthesis of each ligand was achieved from commercially
available L-3,4-dihydroxyphenylalanine (L-DOPA) 4 as the starting
material. Compound 7 was synthesized as reported previously37
and upon hydrolysis with lithium hydroxide yielded the N-Cbz-
protected amino acid 8. This molecule served as the key intermedi-
ate for the synthesis of all the ligands. The amide bond coupling to
the appropriate amino alcohols was facilitated by 1-[3-(dimethyl-
amino) propyl]-3-ethylcarbodiimide (EDC) and 1-hydroxybenzo-
triazole (HOBt) to yield the hydroxyl amides 9–11b. Attempts to
form the oxazoline ring via chlorination and base-mediated cycli-
zation27 were unsuccessful with our system and low yields of
To the best of our knowledge, only a few syntheses of oxazoline
ligands with sp2 and sp3 nitrogen systems have been reported.11,12
It has been reported that the TIQ class of molecules exhibits a wide
array of biological effects including stimulation of b3-adrenergic
receptor29, d opioid receptor antagonist30 and 5HT1A receptor
antagonism.31 It is also a common key intermediate in many
* Corresponding authors.
E-mail address: govenderthav@ukzn.ac.za (T. Govender).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.04.053

R. B. Kawthekar et al. / Tetrahedron: Asymmetry 21 (2010) 846–852
847
O
O
O
O
O
O
O
O
O
N
N
N
NH
NH
NH
2b
2a
1
O
O
O
O
O
O
N
N
NH
NH
3a
3b
Figure 1. Novel chiral TIQ–oxazoline ligands used in this study.
product were obtained. This was possibly due to harsh reaction con-
ditions such as high temperatures and the use of SOCl2 as the chlo-
rination agent. However, the use of the Mitsunobu reaction38–42
for the preparation of oxazoline derivatives, under mild and neutral
conditions was found to be successful for our ligand synthesis. The
Mitsunobu protocol was used to convert the hydroxyl amides
9–11b to the corresponding oxazolines 12–14b. Removal of the
Cbz-protecting group was facilitated with Pd/C under a hydrogen
atmosphere to yield ligands 1–3b. The sequence of reactions is pre-
sented in Scheme 1. Intermediates 8–14b are all new compounds.
O
O
HO
O
iv
O
OH
i, ii, iii
NH2
N
HO
O
Cbz
4
7
O
O
R1 R2
O
O
O
O
OH
OH
Cbz
N
H
v
vi
N
N
Cbz
1 = H, R2 = H
8
9
R
10a R1 = H, R2 = i-Pr
1
= i-Pr, R2 = H
10b
R
11a R1 = H, R2 = Ph
1
= Ph, R2 = H
O
11b
R
R1
R2
R1
R2
O
O
O
O
N
N
N
vii
NH
Cbz
O
R1 = H, R2 = H
R
12
R
1 = H, R2 = H
13a R1 = H, R2 = i-Pr
13b
1
1 = H, R2 = i-Pr
2a
1 = i-Pr, R2 = H
14a R1 = H, R2 = Ph
14b
2b R1 = i-Pr, R2 = H
R
1 = H, R2 = Ph
3b R1 = Ph, R2 = H
3a
R
R
1 = Ph, R2 = H
Scheme 1. Reagents for the synthesis of ligands 1–3b: (i) benzaldehyde, K2CO3, EtOH/H2O, 1.5 h; (ii) CbzCl, KHCO3, dioxane/H2O, 0 °C to rt, 3 h; (iii) Me2SO4, KHCO3, acetone,
reflux, 24 h; (iv) LiOH, THF, MeOH, H2O, rt, 22 h; (v) EDC, HOBt, NMM, DMF, rt, 18 h; (vi) DEAD, PPh3, DCM, 0 °C to rt, 2 h; (vii) Pd/C, H2 (1 atm), MeOH, rt, 1.5 h.

848
R. B. Kawthekar et al. / Tetrahedron: Asymmetry 21 (2010) 846–852
Table 1
The enantioselective Henry reaction of p-nitrobenzaldehyde with nitromethane in the presence of different ligandsa
OH
TIQ-Oxazoline ligand 1-3b
CHO
1 mol%
NO2
Cu(OAc)2.H2O
S
H3C NO2
+
2-propanol, rt, 24 h
O2N
O2N
Entry
Ligand
Conv.b (%)
eec (%)
1
2
3
4
5
1
99
95
97
99
99
28
27
52
62
42
2a
2b
3a
3b
a
All the reactions were carried out with 0.33 mmol of 4-nitrobenzaldehyde, 3.3 mmol of nitromethane, 0.03 mmol ligand and 0.035 mmol Cu(OAc)2ꢀH2O in 2 mL of
2-propanol.
b
Determined by HPLC.
c
The enantiomeric excess was determined by HPLC using a Chiralcel IB-H column. Reported values are the average of two runs.
2.2. Metal screening and reaction optimization
in the reactivity. On the basis of these observations, it became clear
that 1 mol % of ligand is the optimal quantity for the reaction at
room temperature as well as at lower temperatures.
It was found that the type of solvent had a significant effect on
both the conversion and enantioselectivity of the Henry products
with the best catalyst system [3a–Cu(OAc)2ꢀH2O, see Table 3].
2-Propanol was found to be the best solvent for this catalytic sys-
tem (Table 3, entry 5). The use of different protic and aprotic sol-
vents such as THF, ethanol, methanol, n-butanol, acetonitrile and
dichloromethane led to a decrease in enantioselectivities.
The metal-catalyzed Henry reaction between p-nitrobenzalde-
hyde and nitromethane was used as a benchmark reaction to eval-
uate the enantioselectivity of the TIQ–oxazoline ligands 1–3b
(Table 1). All the reactions were complete in 24 h with just
1 mol % of the ligands 1–3b using Cu(OAc)2ꢀH2O as the metal
source in the presence of 2-propanol at room temperature. The
procedure used to execute the reaction was similar to that reported
before.25,28 Ligand 1 gave 28% ee with the model reaction (Table 1).
This is comparable to the selectivity obtained with ligand 2a (27%
ee), derived from (R)-valinol, whereas ligand 2b, derived from
(S)-valinol, gave 52% ee for the same reaction. The (S)-phenylgly-
cinol-derived TIQ–oxazoline ligand 3a was found to be the most
selective with 62% ee. From these results, it is deduced that the
presence and orientation of the substituent on the oxazoline ring
are crucial for enantioselectivity. Furthermore, ligand 3a was iden-
tified as the most effective among the chiral catalytic series, and
was selected for further optimization.
The benchmark reaction was investigated using ligand 3a and
Cu(OAc)2ꢀH2O at different substrate/catalyst molar ratios as well
as at different temperatures, and the results are summarized
(Table 2). Loading of the ligands and the reaction temperature
had a significant influence on the efficiency of the reaction with re-
gard to selectivity and reactivity. Entry one was repeated with
1 mol % of the ligand, the reaction was complete in 24 h at room
temperature and the nitroaldol adduct was obtained in 62% ee with
99% conversion (Table 2). A lower loading (0.5 mol %) resulted in a
reduction in enantioselectivity to 49% ee (Table 2, entry 2). No sig-
nificant advantage was realized with an increased amount of the
ligand (2 and 5.0 mol %). Decreased reaction temperatures led to
slightly higher enantioselectivities but with a significant decline
The effect of other transition metals as Lewis acids was investi-
gated by forming catalytic complexes with the TIQ–oxazoline
Table 3
Effect of various solvents on the enantioselective Henry reaction of p-nitrobenzalde-
hyde with nitromethane at room temperature using ligand 3a–Cu(OAc)2ꢀH2Oa
Entry
Solvent
Conv.b (%)
eec (%)
1
2
3
4
5
6
THF
Ethanol
Methanol
2-Propanol
Acetonitrile
Dichloromethane
97
89
89
99
4
33
47
36
62
16
39
75
a
All the reactions were carried out with 0.33 mmol of 4-nitrobenzaldehyde,
3.3 mmol of nitromethane, 0.03 mmol of ligand and 0.35 mmol Cu(OAc)2ꢀH2O in
2 mL of appropriate solvent.
b
Determined by HPLC.
The enantiomeric excess was determined by HPLC using a Chiralcel IB-H col-
c
umn. Reported values are the average of two runs.
Table 4
Effect of Lewis acid on the enantioselective Henry reaction of p-nitrobenzaldehyde
with nitromethane using ligand 3aa
Entry
Lewis acid
Conv.c (%)
eed (%)
Table 2
1b
2
3
4
5
6
7
8
9
—
CuCl2
Cu(OTf)2
10
3
5
99
12
2
97
99
99
rac
rac
10
62
rac
rac
12
25
rac
The effect of the loading of ligand 3a–Cu(OAc)2ꢀH2O and temperature on the
enantioselective Henry reaction of p-nitrobenzaldehyde with nitromethanea
Entry
Mol %
Temperature
Time (h)
Conv.b (%)
eec (%)
Cu(OAc)2ꢀH2O
Co(ClO)4
1
2
3
4
5
6
7
1
0.5
2
5
1
rt
rt
rt
rt
0
0
ꢁ15
24
24
24
24
90
90
90
99
95
99
99
83
89
45
62
49
59
46
70
69
68
Sc(OTf)2
Zn(II)(OAc)2ꢀH2O
Ni(II)(OAc)2ꢀ2H2O
Mn(II)(OAc)2ꢀ2H2O
2
1
a
All the reactions were carried out with 0.33 mmol of 4-nitrobenzaldehyde,
3.3 mmol of nitromethane, 0.03 mmol of ligand and 0.35 mmol metal salt in 2 mL of
2-propanol.
a
All the reactions were carried out with 0.33 mmol of 4-nitrobenzaldehyde and
b
Reaction was performed in the absence of metal.
Determined by HPLC.
The enantiomeric excess was determined by HPLC using a Chiralcel IB-H col-
3.3 mmol of nitromethane in 2 mL of 2-propanol.
c
b
Determined by HPLC.
The enantiomeric excess was determined by HPLC using a Chiralcel IB-H col-
d
c
umn. Reported values are the average of two runs.
umn. Reported values are the average of two runs.

R. B. Kawthekar et al. / Tetrahedron: Asymmetry 21 (2010) 846–852
849
Table 5
Enantioselective Henry reaction of nitromethane with different aldehydes using ligand 3a–Cu(OAc)2ꢀH2Oa
Entry
Aldehyde
Ligand 3a (mol %)
Temperature (°C)
Time (h)
Conv.b (%)
eec (%) (R/S)d
1
2
3
4
5
6
7
8
9
4-Chlorobenzaldehyde
4-Chlorobenzaldehyde
4-Chlorobenzaldehyde
4-Fluorobenzaldehyde
4-Fluorobenzaldehyde
4-Fluorobenzaldehyde
4-Methylbenzaldehyde
4-Methylbenzaldehyde
4-Methylbenzaldehyde
3,5-Dimethoxybenzaldehyde
Piperonal
1
1
2
1
1
2
1
1
2
1
1
1
rt
0
0
rt
0
0
rt
0
0
rt
rt
rt
24
90
90
24
90
90
24
90
90
24
24
24
97
22
50
25
3
10
84
16
24
76
87
96
62(S)
76(S)
77(S)
52(S)
72(S)
67(S)
60(S)
72(S)
63(S)
40(S)
53(S)
64(S)
10
11
12
Naphthaldehyde
a
All the reactions were carried out with 0.33 mmol of corresponding benzaldehyde, 3.3 mmol of nitromethane, 0.03 mmol ligand and 0.035 mmol Cu(OAc)2ꢀH2O in 2 mL of
2-propanol.
b
Determined by HPLC.
c
The enantiomeric excess was determined by HPLC using a Chiralcel IB-H column. Reported values are the average of two runs.
d
The absolute configurations were established by comparison with the literature data.25
ligand 3a (Table 4). Different counter ions were also investigated
for the best catalytic system. The acetate counter ion was found
to be crucial for the best reactivity of ligand 3a with the copper(II)
ion giving the best selectivity.
3. Conclusion
In conclusion, we have explored a new class of chiral TIQ–oxaz-
oline–Cu(OAc)2ꢀH2O catalysts for the asymmetric Henry reaction.
To the best of our knowledge, this is the first report describing
the use of the TIQ-backbone in combination with an oxazoline ring
with a sp2, sp3 nitrogen system for the asymmetric Henry reaction.
This effective TIQ ligand is readily prepared by using the Mitsun-
obu protocol to form the external oxazoline ring under mild condi-
tions. More importantly, the catalysts 3a-Cu(OAc)2. H2O gave 62%
ee at minimal catalyst loading (1 mol %) at room temperature
and afforded 77% ee at lower temperature. Efforts are underway
to elucidate the mechanistic details and other significant applica-
tions of this catalytic system.
As shown in Table 5, the scope of the catalytic enantioselective
Henry reaction was demonstrated by treatment of various aro-
matic aldehydes with nitromethane in the presence of 1 mol % of
TIQ–oxazoline 3a–Cu(OAc)2ꢀH2O complex in 2-propanol. In all
cases, the reactions proceeded with moderate to good enantiose-
lectivities. In general, the reactions performed at room tempera-
ture exhibit moderate enantioselectivity (40–64% ee, Table 5,
entries 1, 4, 7 and 10–12). Higher enantiomeric excesses (72–77%
ee, Table 5, entries 2, 3, 5 and 8) are observed at 0 °C for aromatic
aldehydes bearing either electron-withdrawing (4-fluorobenzalde-
hyde) or electron-donating (4-chlorobenzaldehyde, 4-methylbenz-
aldehyde) groups. It became clear that the electronic nature and
steric hindrance of the substituent on the aromatic rings do not
have much of an effect on the enantioselectivity of our system.
(Table 5, entries 3, 5 and 8).
4. Experimental
4.1. General
Despite high enantioselectivities obtained by other groups for
this reaction, some limitations are still encountered such as high
catalyst loading, a low temperature required and the use of addi-
tives for optimal enantioselectivity. In most instances, a high
catalyst loading is the essential parameter to obtain high enanti-
oselectivities. Christensen et al. used a 20-mol % of CuII–BOX
(BOX = bis-oxazoline) system for the addition of silyl nitronates
to aldehydes with moderate enantioselectivities.10–12 Maheswaran
et al. also used a 20-mol % of dichloro[(ꢁ)-sparteine-N,N0]copper(II)
complex for the Henry reaction with nitromethane and obtained a
97% ee.14 You and Ma have reported 10 mol % for a series of new
chiral bis-imidazoline ligands and their application to the cop-
per(II)-catalyzed Henry reaction with a best enantioselectivity of
98% ee.43
Reagents and solvents were purchased from Aldrich, Merck and
Fluka. All NMR spectra were recorded on Bruker AVANCE III 400 or
600 MHz instruments at room temperature. Chemical shifts are ex-
pressed in ppm downfield from CDCl3 as an internal standard and
coupling constants are reported in Hz. Thin layer chromatography
(TLC) was performed using Merck Kieselgel 60 F254. Crude com-
pounds were purified with column chromatography using silica
gel (60–200 mesh except if stated different). All solvents were dried
using standard procedures. All IR spectra were recorded on a
Perkin–Elmer spectrum 100 instrument with a universal ATR
attachment. Optical rotations were recorded on a Perkin-Elmer
Polarimeter (Model 341). All melting points are uncorrected. All test-
ing reactions were carried out under dry UHP Argon gas (99.999 %
purity). High resolution mass spectrometric data were obtained
using a Bruker micrOTOF-Q II instrument operating at ambient
temperatures and a sample concentration of approximately 1 ppm.
Recently the groups of Sasai3–5 and Bandini16,17 described highly
enantioselective Henry reactions (99% ee) catalyzed by copper(II)
complexes with diamino ligands using 5 mol % and 12 mol % of
ligand, respectively. Feng et al. have described the use of 10 mol %
of copper(I) complexes with N,N0-dioxide16 and tetrahydrosalen
ligands with 96% ee.18 Finally, Evans et al. reported the 1 mol %
copper acetate/bisoxazoline-catalyzed addition of nitromethane to
aldehydes on large-scale reactions with an excellent 94% enantio-
meric excess after 56 h.28 The low catalyst loading of our TIQ-based
compounds could therefore be a promising new class of catalyst. A
computational chemistry investigation of chiral steric hinderance
induced by the ligand may be required to improve the enantiose-
lectivity of the reaction.
4.2. General procedure for the enantioselective Henry reaction
After a study of the methods used in the literature for this pro-
cedure, it was decided to use the method by Ginotra et al.25, and
the method was slightly modified.
A solution of ligand 3a (1.3 mg, 0.031 mmol) and Cu(OAc)ꢀH2O
(0.7 mg, 0.035 mmol) in anhydrous 2-propanol (2 mL) was stirred
for 4 h at room temperature under Ar. To the resulting green solu-
tion, nitromethane (0.18 mL, 3.3 mmol) and p-nitrobenzaldehyde

850
R. B. Kawthekar et al. / Tetrahedron: Asymmetry 21 (2010) 846–852
(50 mg, 0.33 mmol) were added at room temperature. The reaction
mixture was stirred for the appropriate time and the progress of
the reaction was monitored by TLC (EtOAc/hexane, 15:85,
Rf = 0.12). After completion of the reaction, the volatile compo-
nents were removed under reduced pressure and the residue was
purified by column chromatography on silica gel (EtOAc/hexane,
15:85 and increased to 20:80) to afford the nitro aldol product. It
was obtained in a maximum of 62% ee. Enantiomeric excess was
determined by HPLC with a Chiralcel IB-H column (hexane/2-pro-
panol 85:15, k = 254 nm); flow rate 0.8 mL/min; tR = 16.5 min (R),
dry dichloromethane (80 mL) and triphenylphosphine (2.0 equiv)
were added at room temperature and under N2 atmosphere. The
reaction mixture was cooled to 0 °C and to this was added a solu-
tion of diethylazodicarboxylate (2.2 equiv) in dry dichloromethane
(20 mL) in a dropwise manner over a period of 20 min. The result-
ing reaction mixture was stirred at the same temperature for 4 h
under N2 atmosphere. After completion of the reaction, the reac-
tion mixture was diluted with dichloromethane (10 mL), washed
with water (2 ꢃ 10 mL), dried over anhydrous MgSO4 and concen-
trated under reduced pressure to yield crude product, which was
purified by column chromatography using EtOAc/hexane, 35:65,
as the eluent to yield pure compounds 12–14b.
18.8 min (S); ½a 2D5
¼ þ21 (c 1, CH2Cl2). The reaction was repeated
ꢂ
for three times and the average value is reported.
4.3. Synthesis of the precursors
4.6. General procedure for nitrogen deprotection 1–3b
4.3.1. (1R,3S)-2-Benzyl 3-methyl 6,7-dimethoxy-1-phenyl-3,4-
dihydroisoquinoline-2,3(1H)-dicarboxylate 7
See Ref. 37.
This method was adapted from the literature.45 A solution of
Cbz-protected TIQ–oxazoline (0.8 g) in methanol (30 mL) was
added to
a suspension of 10 wt % Pd/C (0.4 g) in methanol
(10 mL). The reaction mixture was connected to a hydrogen source
at atmospheric pressure and stirred at room temperature for 6 h.
The Pd/C was filtered off on a Celite pad and the filtrate was con-
centrated under reduced pressure to afford the crude TIQ–oxazo-
line ligand. The crude compounds were purified on a deactivated
silica gel column. The deactivation was performed as follows: the
column was packed with a suspension of silica gel in 20% Et3N/
CH2Cl2 and the silica was washed with 1% Et3N/CH2Cl2. The chro-
matography was performed using 0–2%MeOH/1%Et3N/CH2Cl2 as
the eluent to afford pure oxazoline compounds 1–3b.
4.3.2. (1R,3S)-2-(benzyloxycarbonyl)-6,7-dimethoxy-1-phenyl-
1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid 8
The experimental procedure used for this reaction was taken
from the literature.44 To a round-bottomed flask were added 7
(6.0 g, 0.013 mmol), LiOHꢀH2O (4.6 g, 0.19 mmol), THF (142 mL),
MeOH (9.5 mL) and H2O (4.7 mL). The reaction mixture was al-
lowed to stir for three days until TLC indicated that all starting
material had been consumed (Rf = 0.4, EtOAc/hexane, 30:70). The
organic solvents were removed under reduced pressure; the aque-
ous layer was acidified to pH 12 using 10% HCl and a white solid
filtered off, washed with 10 mL of water and dried under vacuum
4.6.1. (1R,3S)-Benzyl 3-(2-hydroxyethylcarbamoyl)-6,7-dime-
thoxy-1-phenyl-3,4-dihydroisoquino-line-2(1H)-carboxylate 9
Rf = 0.3 (EtOAc/hexane, 6:4). Pale yellow solid (1.8 g, yield 82%);
to yield
8 as a white solid (5.6 g, 96%); mp: 86–88 °C;
½
a 2D0
ꢂ
¼ þ23:1 (c 0.13, CH2Cl2); (NMR spectra are reported for a mix-
ture of two rotamers).45 1H NMR (400 MHz, DMSO): d 7.45–7.11
(m, 10H), 6.91 (d, J = 6.96 Hz, 1H), 6.75 (d, J = 6.84 Hz, 1H), 6.09
(d, J = 10.68 Hz, 1H), 5.14–4.94 (m, 3H), 3.79–3.64 (m, 6H), 3.18–
3.01 (m, 2H); 13C NMR (100 MHz, DMSO): d 172.9, 172.6, 155.4,
147.6, 145.0, 143.9, 136.5, 129.4, 128.2, 128.1, 128.0, 127.7,
127.6, 127.4, 127.0, 126.8, 126.3, 125.8, 125.6, 123.3, 123.0,
mp: 154–156 °C (CH2Cl2); ½a D20
¼ þ44:0 (c 0.5, CH2Cl2); (NMR spec-
ꢂ
tra are reported for a mixture of two rotamers). 1H NMR (400 MHz,
CDCl3): d 7.96 (s, 1H), 7.40–6.98 (m, 10H), 6.88 (m, 1H), 6.62 (s,
1H), 6.22 (m, 1H), 5.37–5.00 (m, 2H), 4.83 (m, 1H), 3.86 (s, 3H),
3.79 (s, 3H), 3.51–2.98 (m, 6H); 13C NMR (100 MHz, CDCl3): d
173.1, 162.5, 148.8, 148.0, 128.5, 128.2, 127.4, 127.4, 125.8,
125.6, 125.3, 111.7, 110.9, 110.7, 67.9, 61.9, 61.4, 57.6, 56.2, 56.0,
111.5, 111.2, 66.4, 66.2, 59.0, 58.7, 55.6, 55.4, 55.0, 54.9; IR mmax
/
cmꢁ1 (neat): 3603, 3498, 2938, 1686, 1606, 1515, 1404, 1224,
1090, 990, 696. HR ESI MS: m/z = 470.1574 [M+Na]+ (calcd for
C26H25NNaO6 470.1556).
41.9; IR m
max/cmꢁ1 (neat): 3312, 2933, 1705, 1665, 1514, 1398,
1239, 1219, 1126, 700.48; HR ESI MS: m/z = 513.1996 [M+Na]+
(calcd for C28H30N2NaO6 513.1984).
4.4. General procedure for the formation of amino alcohols 9–
11b
4.6.2. (1R,3S)-Benzyl 3-((R)-1-hydroxy-3-methylbutan-2-ylcarba-
moyl)-6,7-dimethoxy-1-phenyl-3,4-dihydroisoquinoline-2(1H)-
carboxylate 10a
This method was adapted from the literature.45 To a round-bot-
tomed flask was added acid 8 (2.0 g, 0.044 mol) together with the
amino alcohol (1.1 equiv), HOBt (1.3 equiv) and DMF (40 mL). The
mixture was allowed to stir in an ice bath until its temperature
reached 0 °C. To the stirred mixture were added EDC (1.2 equiv)
and N-methyl morpholine (3.0 equiv) and allowed to react for
16 h at ambient temperature. The mixture was acidified with 10%
HCl until a milky precipitate formed. Ethyl acetate (20 mL) was
added to the reaction flask and allowed to stir for 15 min. The or-
ganic layer was separated and washed with H2O (2 ꢃ 20 mL) and a
saturated solution of NaHCO3 (2 ꢃ 20 mL). The organic layer was
dried over anhydrous MgSO4 and concentrated under reduced
pressure affording the crude amino alcohol, which was purified
by column chromatography using MeOH/DCM (2.5:97.5) as the
eluent to yield pure compounds 9–11b.
Rf = 0.4 (CH2Cl2/MeOH, 9.8:0.2). Off white solid (2.0 g, yield
84%); mp: 185–187 °C (CH2Cl2); ½a D20
¼ þ36:4 (c 0.11, CH2Cl2);
ꢂ
(NMR spectra are reported for a mixture of two rotamers). 1H
NMR (400 MHz, CDCl3): d 7.42–7.01 (m, 10H), 6.90–6.60 (m, 3H),
6.61–6.31 (m, 4H), 6.30–6.07 (m, 1H), 5.51–5.14 (m, 2H), 5.13–
4.81 (m, 2H), 4.62–4.26 (m, 1H), 3.98–3.76 (m, 7H), 3.46–3.03
(m, 2H), 1.78–1.68 (m, 2H); 13C NMR (100 MHz, CDCl3): d 171.5,
156.3, 148.1, 140.5, 135.9, 128.6, 128.5, 128.4, 128.3, 127.1,
125.7, 125.5, 112.0, 111.0, 68.1, 63.3, 59.5, 58.9, 58.2, 57.9, 56.5,
56.4, 55.9, 31.3, 28.4, 19.2, 17.5; IR m
max/cmꢁ1 (neat): 3549, 2958,
1697, 1662, 1515, 1405, 1238, 1220, 1127, 1090, 697; HR ESI MS:
m/z = 533.2646 [M+H]+ (calcd for C31H37N2O6 533.2642).
4.6.3. (1R,3S)-Benzyl 3-((S)-1-hydroxy-3-methylbutan-2-ylcar-
bamoyl)-6,7-dimethox-y-1-phenyl-3,4-dihydroisoquinoline-
2(1H)-carboxylate 10b
4.5. General procedure for oxazoline formation 12–14b
Rf = 0.4 (CH2Cl2/MeOH, 9.8:0.2). Pale yellow solid (2.1 g, yield
88%); mp: 136–138 °C (CH2Cl2); ½a D20
¼ þ31:8 (c 0.11, CH2Cl2);
ꢂ
This method was adapted from the literature.42 To a stirred
solution of Cbz-protected TIQ–oxazoline amino alcohol (1.0 g) in
(NMR spectra are reported for a mixture of two rotamers). 1H
NMR (400 MHz, CDCl3): d 7.47–7.05 (m, 10H), 6.98–6.86 (m, 1H),

R. B. Kawthekar et al. / Tetrahedron: Asymmetry 21 (2010) 846–852
851
6.37–6.12 (m, 1H), 5.57–5.35 (m, 1H), 5.31–5.06 (m, 2H), 4.92–4.81
(m, 1H), 3.95–3.74 (m, 6H), 3.62–2.88 (m, 5H), 1.52–1.37 (m, 1H),
0.67–0.48 (m, 3H), 0.41–0.23 (m, 3H); 13C NMR (100 MHz, CDCl3):
d 171.5, 156.3, 148.1, 140.5, 135.9, 128.6, 128.5, 128.4, 128.3,
127.1, 125.7, 125.5, 112.0, 111.0, 68.1, 63.3, 59.5, 58.9, 58.2, 57.9,
737, 698. HR ESI MS: m/z = 537.2360 [M+Na]+ (calcd for
C31H34N2NaO5 537.2365).
4.6.8. (1R,3S)-Benzyl 3-((S)-4-isopropyl-4,5-dihydrooxazol-2-yl)-
6,7-dimethoxy-1-phenyl-3,4-dihy-droisoquinoline-2(1H)-
carboxylate 13b
56.5, 56.4, 55.9, 31.3, 28.4, 19.2, 17.5; IR m
max/cmꢁ1 (neat): 3549,
2958, 1697, 1662, 1515, 1405, 1238, 1220, 1127, 1090, 697. HR
ESI MS: m/z = 533.2646 [M+H]+ (calcd for C31H37N2O6 533.2627).
Rf = 0.6 (EtOAc/hexane, 5:5). Off white solid (0.71 g, yield 73%);
mp: 80–82 °C (CH2Cl2); ½a D20
¼ þ17:65 (c 0.17, CH2Cl2); (NMR spec-
ꢂ
tra are reported for a mixture of two rotamers). 1H NMR (400 MHz,
CDCl3): d 7.48–6.85 (m, 11H), 6.41–6.12 (m, 1H), 5.68–5.08 (m,
3H), 4.84 (d, J = 8.36 Hz), 3.96–3.75 (m, 7H), 3.48–2.89 (m, 6H),
1.89–1.44 (m, 6H), 0.87–0.51 (m, 6H); 13C NMR (100 MHz, CDCl3):
d 156.4, 148.4, 130.0, 128.3, 128.0, 127.8, 126.8, 126.7, 126.1,
4.6.4. (1R,3S)-Benzyl 3-((R)-2-hydroxy-1-phenylethylcarba-
moyl)-6,7-dimethoxy-1-phenyl-3,4-dihydroisoquinoline-2(1H)-
carboxylate 11a
Rf = 0.4 (CH2Cl2/MeOH, 9.8:0.2). Off white solid (2.1 g, yield
83%); mp: 86–88 °C; ½a D20
ꢂ
¼ þ23:1 (c 0.13, CH2Cl2); (NMR spectra
111.9, 111.1, 71.8, 70.1, 60.1, 56.2, 51.2, 18.4, 17.1; IR m
max/cmꢁ1
are reported for a mixture of two rotamers). 1H NMR (400 MHz,
DMSO): d 7.42–6.61 (m, 15H), 6.39–5.76 (m, 2H), 5.31–5.04 (m,
2H), 5.0–4.52 (m, 2H), 3.98–3.77 (m, 6H), 3.70–3.25 (m, 2H),
3.16–2.96 (m, 2H); 13C NMR (100 MHz, CDCl3): d 172.7, 156.1,
149.1, 148.2, 140.5, 138.3, 135.8, 128.7, 128.5, 128.2, 127.9,
127.6, 127.2, 126.3, 125.8, 125.5, 125.1, 111.8, 111.2, 110.8, 68.1,
(neat): 3337, 2961, 1695, 1684, 1513, 1399, 1222, 1126, 1093,
1028, 737, 698. HR ESI MS: m/z = 537.2360 [M+Na]+ (calcd for
C31H34N2NaO5 537.2365).
4.6.9. (1R,3S)-Benzyl 6,7-dimethoxy-1-phenyl-3-((R)-4-phenyl-
4,5-dihydrooxazol-2-yl)-3,4-dihydroisoquinoline-2(1H)-
carboxylate 14a
66.4, 66.0, 58.8, 58.0, 57.5, 56.4, 56.4, 56.2, 56.1, 55.8; IR mmax
/
cmꢁ1 (neat): 3313, 2936, 1662, 1513, 1401, 1339, 1238, 1221,
1092, 697. HR ESI MS: m/z = 567.2474 [M+H]+ (calcd for
C34H35N2O6 567.2474).
Rf = 0.6 (EtOAc/hexane, 5:5). Colourless oil (0.85 g, yield 88%);
½
a 2D0
ꢂ
¼ ꢁ14:3 (c 0.28, CH2Cl2); (NMR spectra are reported for a mix-
ture of two rotamers). 1H NMR (400 MHz, CDCl3): d 7.24–7.02 (m,
10H), 6.95–6.64 (m, 3H), 6.58–6.33 (m, 3H), 6.31–6.06 (m, 1H),
5.53–5.15 (m, 2H), 5.14–4.81 (m, 2H), 4.63–4.26 (m, 1H), 3.98–
3.76 (m, 7H), 3.45–3.05 (m, 2H), 1.78–1.62 (m, 2H); 13C NMR
(100 MHz, CDCl3): d 167.1, 156.7, 156.3, 156.1, 148.3, 144.6,
143.2, 142.2, 136.0, 130.1, 128.4, 127.9, 127.3, 126.9, 126.7,
126.5, 126.2, 125.9, 123.1, 111.7, 111.4, 111.0, 110.6, 76.0, 75.7,
69.2, 67.5, 67.4, 62.2, 60.1, 59.6, 56.0, 55.0, 51.2; IR (neat): 3028,
2935, 1697, 1514, 1397, 1224, 1093, 993, 698; HR ESI MS: m/z =
549.2384 [M+H]+ (calcd for C34H33N2O5 549.2379).
4.6.5. (1R,3S)-Benzyl 3-((S)-2-hydroxy-1-phenylethylcarba-
moyl)-6,7-dimethoxy-1-phenyl-3,4-dihydroisoquinoline-2(1H)-
carboxylate 11b
Rf = 0.4 (CH2Cl2/MeOH, 9.8:0.2). Yellow oil (2.05, yield 81%);
½
a 2D0
ꢂ
¼ þ39:1 (c 0.23, CH2Cl2); (NMR spectra are reported for a mix-
ture of two rotamers). 1H NMR (400 MHz, CDCl3): d 7.50–7.04 (m,
12H), 6.94 (s, 1H), 6.63–6.16 (m, 4H), 5.40–5.12 (m, 2H), 5.03–4.72
(m, 2H), 3.98–3.66 (m, 7H), 3.63–3.27 (m, 2H), 3.11–2.80 (m, 4H);
13C NMR (100 MHz, CDCl3): d 172.0, 162.5, 156.2, 149.0, 141.2,
128.6, 128.3, 128.1, 127.4, 127.1, 126.0, 125.4, 111.9, 110.7, 68.0,
65.64, 59.6, 58.9, 58.1, 57.9, 56.1, 55.8, 54.3, 54.1, 36.4, 31.4,
4.6.10. (1R,3S)-Benzyl 6,7-dimethoxy-1-phenyl-3-((S)-4-phenyl-
4,5-dihydrooxazol-2-yl)-3,4-dihydr-oisoquinoline-2(1H)-
carboxylate 14b
30.9; IR m
max/cmꢁ1 (neat): 3323, 2933, 1696, 1661, 1514, 1402,
1222, 1128, 1092, 696. HR ESI MS: m/z = 567.2490 [M+H]+ (calcd
for C34H35N2O6 567.2479).
Rf = 0.6 (EtOAc/hexane, 5:5). Yellow oil (0.81 g, yield 84%);
½
a 2D0
ꢂ
¼ ꢁ39:3 (c 0.28, CH2Cl2); (NMR spectra are reported for a mix-
ture of two rotamers). 1H NMR (400 MHz, CDCl3): d 7.43–7.09 (m,
11H), 6.98–6.58 (m, 5H), 6.19–5.97 (m, 1H), 5.56–5.31 (m, 1H),
5.30–4.83 (m, 3H), 4.45–4.05 (m, 2H), 3.96–3.69 (m, 8H), 3.41–
3.10 (m, 2H); 13C NMR (100 MHz, CDCl3): d 167.1, 156.7, 156.3,
156.1, 148.3, 144.6, 143.2, 142.2, 136.0, 130.1, 128.4, 128.3,
128.1, 127.9, 127.6, 126.9, 126.5, 126.2, 125.9, 123.1, 111.7,
111.4, 110.6, 76.0, 75.7, 69.2, 67.5, 67.4, 62.2, 60.1, 59.6, 56.0,
4.6.6. (1R,3S)-Benzyl 3-(4,5-dihydrooxazol-2-yl)-6,7-dimethoxy-
1-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxylate 12
Rf = 0.3 (EtOAc/hexane, 7:3). Off white solid (0.72 g, yield 73%);
mp: 68–70 °C (hexane/EtOAc); ½a D20
¼ ꢁ3:2 (c 0.62, CH2Cl2); (NMR
ꢂ
spectra are reported for a mixture of two rotamers). 1H NMR
(400 MHz, CDCl3): d 7.43–6.40 (m, 12H), 6.11 (m, 1H), 5.39–4.77
(m, 2H), 4.24–3.44 (m, 9H), 3.34–2.89 (m, 2H), 1.25 (m, 2H); 13C
NMR (100 MHz, CDCl3): d 156.4, 148.1, 132.2, 129.5, 128.7, 128.6,
128.2, 127.9, 127.1, 126.9, 126.1, 111.7, 110.9, 68.3, 68.2, 67.6,
55.0, 51.2; IR
m
max/cmꢁ1 (neat): 3028, 2935, 1697, 1514, 1397,
1224, 1093, 993, 698. HR ESI MS: m/z = 549.2384 [M+H]+ (calcd
for C34H33N2O5 549.2385).
60.2, 59.6, 56.4, 56.2, 54.5, 51.2, 31.3; IR m
max/cmꢁ1 (neat): 2934,
1698, 1513, 1398, 1338, 1266, 1223, 1093, 993, 740, 698; HR ESI
MS: m/z = 473.2071 [M+H]+ (calcd for C28H29N2O5 473.2049).
4.6.11. 2-((1R,3S)-6,7-Dimethoxy-1-phenyl-1,2,3,4-tetrahydro-
isoquinolin-3-yl)-4,5-dihydrooxazole 1
Rf = 0.3 (CH2Cl2/MeOH, 8:2). Pale yellow oil (0.21 g, yield 40%);
4.6.7. (1R,3S)-Benzyl 3-((R)-4-isopropyl-4,5-dihydrooxazol-2-
yl)-6,7-dimethoxy-1-phenyl-3,4-dihydroisoquinoline-2(1H)-
carboxylate 13a
½
a 2D0
ꢂ
¼ ꢁ39:5 (c 0.19, CH2Cl2); 1H NMR (400 MHz, CDCl3): d 7.35–
7.15 (m, 5H), 6.68 (s, 1H), 6.34 (s, 1H), 5.34 (s, 1H), 3.95–3.75 (m,
6H), 3.65 (m, 3H), 3.02–2.75 (m, 2H), 1.50 (m, 2H); 13C NMR
(100 MHz, CDCl3): d 162.9, 148.9, 148.0, 140.6, 136.2, 130.0,
Rf = 0.6 (EtOAc/hexane, 5:5). Pale yellow solid (0.81 g, yield
83%); mp: 128–130 °C (hexane/ethylacetate);
½
a 2D0
ꢂ
¼ þ3:22 (c
128.7, 126.2, 125.9, 117.1, 114.9, 111.0, 55.7, 36.6, 31.6; IR mmax/
0.31, CH2Cl2); (NMR spectra are reported for a mixture of two rota-
mers). 1H NMR (400 MHz, CDCl3): d 7.41–6.84 (m, 10H), 6.76 (m,
1H), 6.55 (m, 1H), 6.11 (m, 1H), 5.35–4.92 (m, 3H), 4.18–3.57 (m,
9H), 3.34–2.90 (m, 2H), 1.67 (m, 2H), 1.42 (m, 1H), 0.66–0.35 (m,
6H); 13C NMR (100 MHz, CDCl3): d 156.2, 148.0, 129.8, 128.4,
128.1, 127.8, 127.6, 126.7, 126.9, 123.7, 123.3, 111.8, 111.0, 71.4,
cmꢁ1 (neat): 2946, 1685, 1610, 1542, 1232, 1112, 1058, 672; HR
ESI MS: m/z = 339.1703 [M+H]+ (calcd for C20H23N2O3 339.1708).
4.6.12. (R)-2-((1R,3S)-6,7-Dimethoxy-1-phenyl-1,2,3,4-tetra-
hydroisoquinolin-3-yl)-4-isopropyl-4,5-dihydrooxazole 2a
Rf = 0.3 (EtOAc/hexane, 5:5). Off white solid (0.35 g, yield 59%);
69.9, 67.3, 60.1, 59.6, 56.0, 51.0, 18.2, 17.8; IR
m
max/cmꢁ1 (neat):
mp: 126–128 °C (CH2Cl2); ½a D20
ꢂ
¼ ꢁ63:6 (c 0.22, CH2Cl2); 1H NMR
3337, 2961, 1695, 1684, 1513, 1399, 1222, 1126, 1093, 1028,
(400 MHz, CDCl3): d 7.31–7.18 (m, 3H), 7.19–7.18 (m, 2H), 6.62

852
R. B. Kawthekar et al. / Tetrahedron: Asymmetry 21 (2010) 846–852
(s, 1H), 6.32 (s, 1H), 5.26 (s, 1H), 3.96–3.76 (m, 6H), 3.65 (s, 3H),
3.06 (dd, J = 4.88 Hz, 1H), 2.95 (dd, J = 9.08 Hz, 1H), 2.50 (q,
J = 7.48, 14.29 Hz, 1H), 1.70 (m, 1H), 0.87 (d, J = 6.68 Hz, 3H), 0.79
(d, J = 6.80 Hz, 3H); 13C NMR (100 MHz, CDCl3): d 167.7, 147.8,
147.3, 144.7, 128.7, 128.3, 128.0, 127.2, 126.0, 111.1, 110.8, 71.7,
69.9, 62.2, 58.9, 55.88, 55.82, 46.4, 46.1, 32.3, 31.9, 18.6, 17.7,
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¼ ꢁ42:1 (c 0.38, CH2Cl2); 1H NMR
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(s, 1H), 6.31 (s, 1H), 5.19 (s, 1H), 3.96–3.82 (m, 6H), 3.65 (s, 3H),
3.06–3.0 (m, 2H), 1.73–1.63 (m, 1H), 0.87 (d, J = 6.80 Hz, 3H),
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147.8, 147.2, 144.6, 132.1, 132.0, 131.96, 131.94, 128.7, 128.5,
128.4, 128.3, 127.9, 127.2, 126.1, 111.1, 110.8, 71.9, 70.1, 62.2,
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29. Parmee, E. R.; Brockunier, L. L.; He, J. F.; Singh, S. B.; Candelore, M. R.; Cascieri,
M. A.; Deng, L. P.; Liu, Y.; Tota, L.; Wyvratt, M. J.; Fisher, M. H.; Weber, A. E.
Bioorg. Med. Chem. Lett. 2000, 10, 2283–2286.
4.6.14. (R)-2-((1R,3S)-6,7-Dimethoxy-1-phenyl-1,2,3,4-
tetrahydroisoquinolin-3-yl)-4-phenyl-4,5-dihydrooxazole 3a
Rf = 0.3 (EtOAc/hexane, 5:5). White solid (0.38 g, yield 63%);
mp: 70–72 °C (CH2Cl2); ½a D20
¼ ꢁ46:4 (c 0.14, CH2Cl2); (NMR spec-
ꢂ
tra are reported for a mixture of two rotamers). 1H NMR (400 MHz,
CDCl3): d 7.33–7.18 (m, 8H), 7.13–7.08 (m, 2H), 6.68 (s, 1H), 6.37 (s,
1H), 5.33 (s, 1H), 5.16 (t, J = 17.9 Hz, 1H), 4.59 (q, J = 10.08, 8.48 Hz,
1H), 4.08 (t, J = 16.08, 1H), 4.01–3.95 (m, 1H), 3.88 (s, 3H), 3.70 (s,
3H), 3.21 (dd, J = 5.00, 5.00 Hz, 1H), 3.11 (dd, J = 8.28 Hz, 1H); 13C
NMR (100 MHz, CDCl3): d 169.2, 147.9, 147.4, 144.8, 142.1, 129.2,
128.7, 128.6, 128.3, 128.2, 127.5, 127.2, 126.5, 125.8, 111.2,
110.9, 74.9, 69.4, 58.9, 55.8, 46.9, 46.2, 32.0; IR m
max/cmꢁ1 (neat):
2931, 1652, 1511, 1450, 1246, 1220, 1113, 1027, 838, 756, 698.
HR ESI MS: m/z = 415.2016 [M+H]+ (calcd for C26H27N2O3
415.1979).
30. Labarre, M.; Butterworth, J.; St-Onge, S.; Payza, K.; Schmidhammer, H.;
Salvadori, S.; Balboni, G.; Guerrini, R.; Bryant, S. D.; Lazarus, L. H. Eur. J.
Pharmacol. 2000, 406, R1–R3.
31. Mokrosz, M. J.; Duszynska, B.; Wesolowska, A.; Borycz, J.; Chojnacka-Wojcik,
E.; Karolak-Wojciechowska, J. Med. Chem. Res. 2000, 10, 58–68.
32. Cheng, S. L.; Zhang, X. Y.; Wang, W.; Zhao, M.; Zheng, M. Q.; Chang, H. W.; Wu,
J. H.; Peng, S. Q. Eur. J. Med. Chem. 2009, 44, 4904–4919.
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6469–6473.
34. Stingl, K.; Martens, J.; Wallbaum, S. Tetrahedron: Asymmetry 1992, 3, 223–226.
35. Jones, G. B.; Heaton, S. B.; Chapman, B. J.; Guzel, M. Tetrahedron: Asymmetry
1997, 8, 3625–3636.
36. Hari, Y.; Sakuma, M.; Miyakawa, A.; Hatano, K.; Aoyama, T. Heterocycles 2008,
76, 305–311.
37. Chakka, S. K.; Andersson, P. G.; Maguire, G. E. M.; Kruger, H. G.; Govender, T.
Eur. Journal. Org. Chem. 2010, 972–980.
38. Roush, D. M.; Patel, M. M. Synth. Commun. 1985, 15, 675–679.
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40. Galeotti, N.; Montagne, C.; Poncet, J.; Jouin, P. Tetrahedron Lett. 1992, 33, 2807–
2810.
4.6.15. (S)-2-((1R,3S)-6,7-Dimethoxy-1-phenyl-1,2,3,4-tetra-
hydroisoquinolin-3-yl)-4-phenyl-4,5-dihydrooxazole 3b
Rf = 0.3 (EtOAc/hexane, 5:5). Off white solid (0.32 g, yield 53%);
mp: 70–72 °C (CH2Cl2); ½a D20
ꢂ
¼ ꢁ57:1 (c 0.28, CH2Cl2); 1H NMR
(400 MHz, CDCl3): d 7.32–7.16 (m, 8H), 7.11–7.06 (m, 2H), 6.67
(s, 1H), 6.34 (s, 1H), 5.24 (s, 1H), 5.17 (t, 1H), 4.59 (q, J = 10.08,
8.48 Hz, 1H), 4.07 (t, J = 8.12 Hz, 1H), 4.04–3.98 (t, J = 6.46 Hz,
1H), 3.85 (s, 3H), 3.68 (s, 3H), 3.16 (d, J = 6.48 Hz, 2H); 13C NMR
(100 MHz, CDCl3): d 168.9, 147.9, 147.3, 144.6, 142.1, 128.7,
128.6, 128.4, 128.1, 127.5, 127.3, 126.5, 126.0, 111.2, 110.8, 74.9,
69.4, 59.0, 55.89, 55.82, 47.1, 31.8; IR
m
max/cmꢁ1 (neat): 2907,
1738, 1658, 1511, 1451, 1351, 1244, 1220, 1115, 1027, 757, 699.
HR ESI MS: m/z = 415.2016 [M+H]+ (calcd for C26H27N2O3
415.1996).
41. Wang, F. J.; Hauske, J. R. Tetrahedron Lett. 1997, 38, 6529–6532.
42. Jiao, P.; Xu, J. X.; Zhang, Q. H.; Choi, M. C. K.; Chan, A. S. C. Tetrahedron:
Asymmetry 2001, 12, 3081–3088.
Acknowledgements
43. Ma, K. Y.; You, J. S. Chem. Eur. J. 2007, 13, 1863–1871.
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3403.
This work was supported by the UKZN productivity research
grant, a SA/Swedish Research Links Programme Grant (GUN no.
65387) and Aspen Pharmacare, SA. The NRF (South Africa) is
thanked for the support.