An approach to the synthesis of enantiopure tetrahydroisoquinoline via a key asymmetric Ugi reaction

Article abstract of DOI:10.1055/s-0032-1317931

An approach to the synthesis of the multisubstituted tetrahydroisoquinoline featuring an asymmetric Ugi reaction of α-amino acid, aromatic aldehyde and an isocyanide has been developed. The promising utility of the strategy is demonstrated by a synthesis of an enantiopure functionalized 1,3-trans-tetrahydroisoquinolin-4-ol from natural l-valine. The configuration of the two stereocenters at C-1 and C-4, generated in the Ugi reaction and Pomeranz-Fritsch-type cyclization separately, was controlled very well and determined by NMR studies. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0032-1317931

LETTER
▌241
lAettner Approach to the Synthesis of Enantiopure Tetrahydroisoquinoline via a
Key Asymmetric Ugi Reaction
Synthesis of Enantiopure Tetrahydroisoquinoline
Li Pan, Ruijiao Chen, Dongshun Ni, Liang Xia, Xiaochuan Chen*
Key Laboratory of Green Chemistry & Technology of Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064,
P. R. of China
Fax +86(28)85413712; E-mail: chenxc@scu.edu.cn
Received: 31.10.2012; Accepted after revision: 28.11.2012
aldehyde and an isocyanide in a nucleophilic solvent (e.g.
Abstract: An approach to the synthesis of the multisubstituted
methanol) have been reported to produce a 1,1′-iminodi-
tetrahydroisoquinoline featuring an asymmetric Ugi reaction of
carboxylic acid derivative with a new chiral center.11 Al-
α-amino acid, aromatic aldehyde and an isocyanide has been devel-
oped. The promising utility of the strategy is demonstrated by a
though 1,1′-iminodicarboxylic acid derivatives have
synthesis of an enantiopure functionalized 1,3-trans-tetrahydroiso- showed some biological12 and synthetic12a,c,13 importance,
quinolin-4-ol from natural L-valine. The configuration of the two
stereocenters at C-1 and C-4, generated in the Ugi reaction and
the application of the compound as a key intermediate in
the construction of tetrahydroisoquinolines is seldom re-
Pomeranz–Fritsch-type cyclization separately, was controlled very
ported. Only Cuifolini group employed a related asym-
well and determined by NMR studies.
metric Ugi reaction to prepare a cyclization precursor for
Key words: Ugi reaction, α-amino acid, aromatic aldehyde, tetra-
hydroisoquinoline, asymmetric synthesis
the synthesis of quinocarcin framework very recently;
however, the subsequent formation of tetrahydroisoquin-
oline ring has not been described.14
Thus, our tetrahydroisoquinoline synthesis began with the
Tetrahydroisoquinolines are the privileged structural units
Ugi reaction of L-(S)-valine (5), vanillin methyl ether (6)
and isocyanoalkyl alkyl carbonate 7. Compound 7 is a po-
found in a number of bioactive and medical molecules in-
cluding natural products (Figure 1). Many substituted tet-
rahydroisoquinoline compounds possess a wide range of
important properties in pharmacy such as antitumor and
OMe
HO
antibiotic,1 antineoplastic,2 anti-inflammatory and anti-
allergic,3 antiviral,4 central nerve system (CNS) depres-
sant activities5 and so on. Furthermore, some of them have
been used as potent antimalarial,6 ionotropic glutamate re-
ceptor antagonist,7 and therapeutic agents for imagining
VMAT-2 in brain.8 Therefore, the development of meth-
ods for the asymmetric construction of multisubstituted
tetrahydroisoquinolines has attracted much attention.9 For
the stereoselective synthesis of polysubstituted tetrahy-
droisoquinolines, the effective control of the configura-
tion of those stereocenters on the ring, especially C-1
position, is a key issue.
MeO
MeO
OAc
H
N
N
Me
S
N
O
O
OH
O
OH
Dihydrotetrabenazine (2)
O
MeO
NH
4
3
HO
Ecteinascidin 743 (1)
N
2
1
OH
Up to now, stereocontrol at C-1 on tetrahydroisoquinoline
ring has been achieved from appropriate chiral substrates
mostly by stereoselective Pictet–Spengler reaction,9d,g,k,n
radical cyclization of imine9e or reduction of dihydroiso-
quinoline.9a,l,n Recently, we became interested in the de-
velopment of asymmetric Ugi reaction based on chiral
substrates and their application in synthesis.10 As part of
the research, we report here a new route to the synthesis
of enantiopure 4-hydroxy-1,3-trans-tetrahydroisoquino-
lines featuring an asymmetric Ugi reaction with chiral α-
amino acid, by which the chiral center at C-1 is formed in
high stereoselectivity (Scheme 1). Ugi five-center four-
component reactions (U-5C-4CR) of an α-amino acid, an
O
O
OH
N
O
OMe
OH
O
NH
MeO
OMe
OH
Dioncophyllinol D (3)
OMe
Azapodophyllotoxin (4)
Figure 1 Several bioactive tetrahydroisoquinoline alkaloids
OH
R1
CO2H
NH2
R1
CO2Me
R
R1
3
4
1
R
R
NH
N
+
R3NC
R2
SYNLETT 2013, 24, 0241–0245
O
NHR3
CHO
Advanced online publication: 13.12.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1317931; Art ID: ST-2012-W0933-L
© Georg Thieme Verlag Stuttgart · New York
Scheme 1 Our synthetic strategy for tetrahydroisoquinoline

242
L. Pan et al.
LETTER
tential convertible isonitrile to permit post-modification 9, in which the amide bond was easily cleaved by addition
of the C-terminal amide formed in the reaction,15 so that of a nucleophile or reduction according to literature meth-
the substituents at C-1 in the resultant tetrahydroisoquin- ods (Scheme 2).15 However, under various conditions
olines are probably not limited only to amides. In previous only complex mixtures containing none of the desired N-
studies on the U-5C-4CR, the case utilizing electron-rich acyloxazolidione 9 were obtained.
aromatic aldehydes is limited due to their reduced electro-
philicity.16 Indeed, condensation of 5, 6 and 7 in methanol
at room temperature proceeded relatively slow, and gave
OMe
OMe
OMe
MeO
MeO
OCO2R
t-BuOK
THF
MeO
the desired products 8 in 59% yield after stirring for three
days concomitant with 26% recovered aldehyde 6 (Table
1, entry 1). Longer reaction time did not seem to facilitate
further conversion of the materials. Elevating the temper-
ature accelerated the rate of the reaction, but decreased the
yield of product 8 and of recovered aldehyde 6 (entry 2).
Although TiCl4 was reported as an efficient catalyst in this
U-5C-4CR with some aromatic aldehydes,16 for our reac-
tion, addition of some Lewis acids including TiCl4 led to
a drop in yield (entries 3–5). Only molecular sieves
showed a beneficial effect on the reaction, affording 817
and 6 in slightly improved yield (entry 6). Gratifyingly,
excellent diastereoselectivity was observed in the reac-
tion, and only single product isomer was obtained. The
absolute configuration of the new chiral center in 8 was
unknown at this stage, and could be determined readily af-
ter further construction of the tetrahydroisoquinoline ring.
O
NH
N
HN
OH
HN
HN
O
O
O
CO2Me
CO2Me
CO2Me
8 R = Bn
10 R = Ph
9
Scheme 2 Attempt on the formation of oxazolidinone
Similar results were observed when 10 was employed in-
stead of 8 to produce 9. Fortunately, the amide bond in 8
could be activated via protection of the amide nitrogen as
the tert-butyl carbamate. Thus, 8 was treated with Boc2O
in the presence of DMAP to give the desired product 11 in
78% yield, along with a small amount of the recovered
material 8 (18%), which could be transformed to 11 once
again in the same yield. Under these conditions the free
secondary amino group did not react with Boc2O at all.
Acyl carbamate 11 was easily reduced to alcohol 12 as a
single isomer with NaBH4 in a THF–H2O mixture, where-
as the methyl ester group remained intact (Scheme 3). The
introduction of the hydroxyl function could enrich varia-
tion of structure at the position by different post-transfor-
mation. The subsequent reduction of ester 12 to the
corresponding aldehyde using DIBAL-H was unsuccess-
ful probably owing to the presence of the free hydroxyl
and amino groups, and afforded a complex mixture which
could not form the tetrahydroisoquinoline ring by
Pomeranz–Fritsch-type reaction18 under acidic condi-
tions.
Table 1 Investigation of Asymmetric Ugi Reaction of 5, 6 and 7 in
Methanola
OMe
MeO
CHO
CO2H
NH2
OCO2Bn
MeOH
+
5
NH
OMe
HN
OCO2Bn
OMe
6
CN
O
CO2Me
7
8
Entry Time Additive
(h)
T
(°C)
Yield Recovered
of 8
6
Thus we tried to construct tetrahydroisoquinoline via lac-
tone 13 where interference of hydroxyl group could be
avoided in the subsequent reduction (Scheme 4). After
much experimentation, refluxing of 12 in xylene in the
presence of acetic acid gave the desired morpholin-2-one
13 in 71% yield (87% based on conversion). Treatment of
13 with DIBAL-H smoothly furnished the corresponding
hemiacetal 14 as a mixture of two diastereoisomers, a po-
tential precursor for Pomeranz–Fritsch cyclization. How-
ever, all attempts to cyclize failed to provide the desired
tetrahydroisoquinoline 15 probably owing to disfavored
configuration.
1
2
3
4
5
6
7
72
12
48
48
48
72
12
–
–
r.t.
50
r.t.
r.t.
r.t.
r.t.
50
59% 26%
52% 11%
38% 24%
50% 42%
36% 22%
64% 31%
59% 14%
TiCl4 (5 mol%)
ZnCl2 (100 mol%)
Sc(OTf)3 (10 mol%)
4 Å MS
4 Å MS
a Reaction conditions: 5, 6 and 7 were used in a ratio of 1:1:1, and the
concentration was 0.3 mol/L.
Therefore, the synthetic route was adjusted as shown in
Scheme 5. Protection of alcohol 12 as TBS ether gave 16.
Reduction of methyl ester in 16 with LiAlH4 furnished al-
cohol 17. By virtue of the new hydroxyl group, the sec-
ondary amine 17 was masked as aminonitrile 18 by a two-
step sequence involving formation and opening of oxa-
zolidine ring. Oxidation of the primary alcohol to the cor-
To obtain more tetrahydroisoquinolines with different
substituent at C-1, the selective conversion of the amide
bond generated in the Ugi reactions is desirable and nec-
essary. Therefore, our efforts focused on the transformation
of Ugi product 8 to the corresponding N-acyloxazolidione
Synlett 2013, 24, 241–245
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Enantiopure Tetrahydroisoquinoline
243
OMe
OMe
OMe
MeO
MeO
MeO
OCO2Bn
OCO2Bn
Boc2O
NaBH4
THF
NH
NBoc
OH
HN
HN
HN
DMAP
O
O
78% (95%)
90%
CO2Me
12
CO2Me
CO2Me
8
11
Scheme 3 Conversion of 8 into amino alcohol 12; the yield in parentheses is based on conversion
OMe
OMe
MeO
MeO
O
H+
MeO
AcOH, xylene
DIBAL-H
12
NH
reflux
toluene, –78 °C
92%
HN
MeO
HN
71% (87%)
15
O
O
OH
14
O
13
Scheme 4 Attempt on construction of tetrahydroisoquinoline 15 via 13
responding aldehyde with Dess–Martin periodinane and H-1 (δ = 3.99 ppm) but between H-3 and H-a (δ = 3.74
resulted in the cyclization precursor, which was stirred in and 3.86 ppm) reveals 1,3-trans-configuration (Figure 2).
TFE containing 2% TFA at –10 °C to give the desired tet- Consequently, the absolute configuration of C-1 and C-4
rahydroisoquinolin-4-ol 1919 in 72% yield over two steps, in 19 was determined to R and S, respectively. Hence Ugi
along with recovered aldehyde (20%). The key cycliza- product 8 from (S)-valine should have the S,R configura-
tion proceeded with excellent diastereoselectivity, and the tion. This result supported the stereochemistry of the sim-
single isomer 19 was obtained exclusively.
ilar Ugi reactions employing primary α-amino acids in the
most reports earlier.11c–f Namely, the newly formed ste-
reogenic center of the major isomer has the reverse con-
figuration to the amino acids employed. Ciufolini group
reported the converse stereoinduction in favor of (S,S)-
product on the Ugi reaction with various (S)-amino acids
including valine and aromatic aldehydes, but this general
stereochemical conclusion was deduced just by a particu-
lar example, the cyclic amide derived from an Ugi product
using (S)-glutamic acid 5-methyl ester.15 Nevertheless,
the new route opens an efficient access to enantiopure 1,3-
trans-tetrahydroisoquinolin-4-ols using α-amino acids as
starting material. On the other hand, 1,3-cis-tetra-
hydroisoquinolin-4-ols such as 20 could also be possibly
prepared by this approach from optically active serine, in
which the inherent hydroxyl group could be converted
into aldehyde to serve for Pomeranz–Fritsch-type cycliza-
tion at appropriate stage (Scheme 6). Some important al-
kaloids including ecteinascidins and naphthridinomycins
contain the 4-oxidized 1,3-cis-tetrahydroisoquinoline
structure similar to 20.
OMe
OMe
MeO
MeO
LiAlH4
TBSCl
97%
i) (CHO)n
12
OTBS
OTBS
THF
77%
ii) TMSCN,
BF3•OEt2
HN
HN
OH
CO2Me
16
82%
17
OMe
MeO
OH
MeO
MeO
i) DMP
N
CN
OTBS
OH
ii) TFA–TFE (2%)
72%
NC
N
OTBS
19
18
Scheme 5 Stereoselective synthesis of tetrahydroisoquinolin-4-ol 19
from 12; DMP = Dess–Martin periodinane, TFA = trifluoroacetic
acid, TFE = trifluoroethanol
OMe
NOE
MeO
NOE
The configuration of the cyclic compound 19 was ana-
lyzed by detailed NMR studies. In its NOESY HNMR
spectra, H-3 (δ = 2.73 ppm) has obvious correlation with
H-4 (δ = 4.57 ppm), that show cis configuration relation-
ship between the substituent at C-3 and C-4 (Figure 2).
Whereas the observation of correlation not between H-3
H
H
Ha
H
4
TBSO
3
OH
1
N
H
NC
Figure 2 Determination of the configuration of 19
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 241–245

244
L. Pan et al.
LETTER
OH
OH
CO2H
NH2
HO
CO2Me
R2
R
R
MeOH
NH
NP
+
R
R'NC
R1
CHO
O
NHR'
20
Scheme 6 Devised strategy to 1,3-cis-tetrahydroisoquinoline from L-serine
(7) Chimirri, A.; De Luca, L.; Ferro, S.; De Sarro, G.; Ciranna,
L.; Gitto, R. ChemMedChem 2009, 4, 917.
In summary, a new approach to the construction of the
chiral 1,3-substituted tetrahydroisoquinolin-4-ol was de-
veloped. 1,1′-Iminodicarboxylic acid derivative such as 8,
swiftly assembled via asymmetric Ugi reaction of α-ami-
no acid, aromatic aldehyde and isocyanide in alcohol, was
employed as a key intermediate to synthesize tetrahy-
droisoquinoline compound for the first time. By this ap-
proach, (1R,3S,4S)-tetrahydroisoquinolin-4-ol 19 was
synthesized conveniently from L-valine in nine steps with
high stereoselectivity. On the basis of excellent stereoin-
duction of the chiral substrates in the Ugi condensation
and Pomeranz–Fritsch-type cyclization, stereochemistry
of the two new chiral centers was controlled well. Further
efforts to utilize this approach for asymmetric synthesis of
more tetrahydroisoquinoline members from various α-
amino acids and aromatic aldehydes are currently under
way in our lab.
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Acknowledgment
We thank the Sichuan University Analytical and Testing Center as
well as the Prof. Xiaoming Feng group for NMR determination.
This work was supported by grants from the National Natural Sci-
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Synlett 2013, 24, 241–245
© Georg Thieme Verlag Stuttgart · New York

LETTER
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Synthesis of Enantiopure Tetrahydroisoquinoline
245
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HRMS (ESI+): m/z [M + H]+ calcd for C26H35N2O8:
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(19) 19: [α]D20 +3 (c = 0.7, in CH2Cl2). IR (neat): 3498, 2954,
2928, 2859, 2710, 2610, 2252, 1608, 1510, 1462, 1343, 1311,
1251, 1221, 1152, 1108, 1046, 934, 838, 775, 666, 637 cm–1.
1H NMR (400 MHz, CDCl3): δ = 6.80 (s, 1 H), 6.77 (s, 1 H),
4.57 (br t, J = 6.2 Hz, 1 H), 3.99 (t, J = 5.8 Hz, 1 H), 3.89 (s,
3 H), 3.88 (s, 3 H), 3.86–3.88 (m, 2 H), 3.74 (dd, J = 5.8, 9.9
Hz, 1 H), 3.59 (d, J = 17.5 Hz, 1 H), 2.73 (dd, J = 2.4, 10.5
Hz, 1 H), 2.08–2.12 (m, 1 H), 1.59 (d, J = 2.9 Hz, 1 H), 1.10
(d, J = 4.5 Hz, 3 H), 1.09 (d, J = 4.6 Hz, 3 H), 0.85 (s, 9 H),
0.01 (s, 3 H), –0.04 (s, 3 H). 13C NMR (100 MHz, CDCl3):
δ = 149.0, 148.6, 129.1, 125.9, 118.8, 111.6, 111.1, 66.8,
64.8, 63.7, 62.2, 55.9, 38.7, 25.8, 20.3, 20.0, 18.1, –5.4, –5.6.
HRMS (ESI+): m/z [M + H]+ calcd for C23H39N2O4Si:
435.2679; found: 435.2675.
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Ciufolini, M. A. Org. Lett. 2004, 6, 3281.
(17) 8: [α]D20 –74 (c = 0.6, in CH2Cl2). IR (neat): 3372, 2960,
2838, 1739, 1678, 1514, 1461, 1395, 1262, 1147, 1026, 903,
789, 739 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.32–7.37
(m, 5 H), 6.78–6.91 (m, 3 H), 5.13 (s, 2 H), 4.15–4.28 (m, 2
H), 4.13 (s, 1 H), 3.84 (s, 3 H), 3.82 (s, 3 H), 3.69 (s, 3 H),
3.43–3.65 (m, 2 H), 2.85 (d, J = 6.0 Hz, 1 H), 1.91–2.01 (m,
1 H), 0.93 (d, J = 6.8 Hz, 3 H), 0.90 (d, J = 6.8 Hz, 3 H). 13
NMR (100 MHz, CDCl3): δ = 174.8, 172.2, 154.9, 149.3,
C
149.1, 143.0, 130.3, 128.6, 128.3, 120.9, 111.1, 110.3, 69.8,
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 241–245