A synthetic route to highly substituted 1,2,3,4-tetrahydroisoquinolines via Yb(OTf)3-catalyzed diastereoselective ring opening of bridged oxazolidines: Asymmetric synthesis of 2-azapodophyllotoxin

Article abstract of DOI:10.1002/chem.201002938

We herein report a robust and efficient synthetic route to highly functionalized enantiopure 1,2,3,4-tetrahydroisoquinolines (THIQs) from Garner aldehyde. We utilized the inherent chirality of Garner aldehyde through 1,2- and 1,3-/1,4-asymmetric inductions iteratively to obtain 1,2,3,4-tetrasubstitued THIQs using rigid and isolable bridged oxazolidines without any external chiral sources. All possible stereoisomers of bridged oxazoliodines were efficiently synthesized from L- and D-Garner aldehydes and transformed into fully functionalized THIQs via diastereoselective ring opening with various nucleophiles in the presence of Yb(OTf)₃. This methodology furnished four out of eight possible diastereomers of 1,2,3,4-tetrasubstituted THIQs despite the electronic nature of substituents on the aryl rings. Finally, the enantioselective synthesis of 2-azapodophyllotoxin was achieved with an overall yield of 35.4 % (eight steps) from D-Garner aldehyde using this synthetic route. A concise and efficient synthetic route to highly functionalized enantiopure 1,2,3,4-tetrahydroisoquinolines (THIQs) from the Garner aldehyde via Yb(OTf)₃-catalyzed diastereoselective ring opening of bridged oxazolidines is reported. This methodology was successfully applied to the synthesis of four stereoisomers of THIQ and the enantioselective total synthesis of 2-azapodophyllotoxin (1) in eight steps from D-Garner aldehyde in an overall yield of 35.4 %. Copyright

Full text of DOI:10.1002/chem.201002938

FULL PAPER
DOI: 10.1002/chem.201002938
A Synthetic Route to Highly Substituted 1,2,3,4-Tetrahydroisoquinolines via
YbACHTUNGTRENNUNG(OTf)3-Catalyzed Diastereoselective Ring Opening of Bridged
Oxazolidines: Asymmetric Synthesis of 2-Azapodophyllotoxin
Ajay Kumar Srivastava,[a] Minseob Koh,[a] and Seung Bum Park*[a, b]
Abstract: We herein report a robust
stereoisomers of bridged oxazoliodines
were efficiently synthesized from l-
and d-Garner aldehydes and trans-
formed into fully functionalized THIQs
via diastereoselective ring opening with
various nucleophiles in the presence of
Yb(OTf)3. This methodology furnished
and efficient synthetic route to highly
functionalized enantiopure 1,2,3,4-tet-
rahydroisoquinolines (THIQs) from
Garner aldehyde. We utilized the in-
herent chirality of Garner aldehyde
through 1,2- and 1,3-/1,4-asymmetric
inductions iteratively to obtain 1,2,3,4-
tetrasubstitued THIQs using rigid and
isolable bridged oxazolidines without
any external chiral sources. All possible
ACHTUNGTRENNUNG
four out of eight possible diastereo-
mers of 1,2,3,4-tetrasubstituted THIQs
despite the electronic nature of sub-
stituents on the aryl rings. Finally, the
enantioselective synthesis of 2-azapo-
dophyllotoxin was achieved with an
overall yield of 35.4% (eight steps)
from d-Garner aldehyde using this syn-
thetic route.
Keywords: 2-azapodophyllotoxin
·
Garner aldehyde · natural products ·
tetrahydroisoquinoline
synthesis
·
total
Introduction
hibit a wide range of biological activities. For example, 2-
azapodophyllotoxin (1), a nitrogen variant of podophyllo-
toxin, is a potent antitumor agent,[8] whereas 11-hydroxyery-
thratidine (2) exhibits curare-like, sedative, hypotensive, and
central nerve system (CNS) depressant activities.[9] Simple
C-4-hydroxy THIQ 3 possesses anti-inflammatory and anti-
allergic properties,[10] while 8-O-methyl-dioncophyllinol D
(4) and dioncophyllinol D (5), the naturally occurring naph-
thoisoquinolines, exhibit antimalarial and antiviral activities
(Figure 1).[11]
Since completion of the human genome project in 2003, bio-
medical communities have focused on elucidation of the
gene functions and associated control of gene products by
small-molecule modulators.[1] The systematic perturbation of
protein functions using bioactive small molecules,[2] which is
also known as chemical genetics/genomics, is one of the
major research areas in the new interdisciplinary field of
chemical biology.[3] To enable discovery of novel small mole-
cules that act as perturbing agents in biological systems, it is
essential to construct a collection of drug-like small mole-
cules with maximized molecular diversity. To accomplish
this, we adopted a diversity-oriented synthesis (DOS) ap-
proach that focused on the development of new methods for
synthesis of drug-like polyheterocycles and the efficient con-
struction of small molecule libraries containing a large
number of structurally diversified molecular frameworks.[4]
We then pursued the development of a novel route for
the efficient synthesis of highly functionalized 1,2,3,4-tetra-
hydroisoquinolines (THIQs),[5] a privileged structural motif
that is frequently found in bioactive natural products and
therapeutic agents.[6] In particular, C-4-oxidized THIQs[7] ex-
Figure 1. THIQ-containing natural products and bioactive analogues.
[a] Dr. A. K. Srivastava, M. Koh, Prof. Dr. S. B. Park
Department of Chemistry, Seoul National University
Seoul, 151-747 (Korea)
Because of the biomedical importance of THIQs, asym-
metric strategies for the synthesis of 1-substituted or 1,3-/
3,4-disubstituted THIQs have been developed.[12] However,
a flexible and efficient synthetic route for all possible stereo-
isomers of C-1, C-3, and C-4 substituted THIQs has not yet
been developed.[7,13] Most of the known asymmetric synthet-
ic routes involve the Pictet–Spengler reaction or the Bis-
Fax : (+82)2-884-4025
E-mail: sbpark@snu.ac.kr
[b] Prof. Dr. S. B. Park
Department of Biophysics and Chemical Biology
Seoul National University, Seoul, 151-747 (Korea)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201002938.
Chem. Eur. J. 2011, 17, 4905 – 4913
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4905

chler–Napieralski cyclization/reduction sequence of b-aryle-
thylamines that undergo ring closure after condensation
with aldehydes to produce only 1,3-syn isomers as the major
product. These methods inevitably require electron-donating
groups at the phenyl ring for successful cyclization,[14] and
are therefore not applicable to electron-deficient aryl sys-
tems. Reported approaches for the synthesis of 1,3-anti
THIQs involve nucleophilic addition to 3,4-dihydroisoquino-
line (DHIQ) precursor as iminium intermediates at very low
temperatures; however, these methods achieved a high level
of diastereoselectivity via 1,3-asymmetric induction only
when a bulky C-3 substituents
alized THIQs via bridged oxazolidine intermediates, our
study commenced with the addition of l-Garner aldehyde 6
with properly functionalized Grignard reagents 7a–g at
ꢀ788C, which was followed by benzylation of the resulting
alcohols to obtain anti-8a–g as the major products. Depro-
tection reaction of 8a–g with 5n HCl in THF produced cor-
responding 3,4-dihydroisoquinolines anti-9a–g (Table 1),
which were readily converted to the desired bridged oxazoli-
dines 10a–o upon treatment with various N-modifying
agents, such as acyl halides, anhydrides, sulphonyl chlorides,
and alkyl halides via iminium formation and subsequent in-
was pre-installed on the DHIQ
Table 1. Diastereoselective Synthesis of intermediates 8 and DHIQs 9 from l-Garner aldehyde.
precursors.[15] Schreiber and co-
workers also utilized DHIQ-de-
rived iminium intermediates to
synthesize 1-alkyne-substituted
THIQs in the presence of
CuBr/QUINAP as catalysts,[16]
whereas Inomata et al. em-
ployed DHIQ-N-oxide for C-1
functionalization using a tarta-
ric-acid-derived chiral auxiliary
to obtain 1-substituted THIQs
with poor to moderate enantio-
selectivity.[17] The direct alkyla-
tion of a C-1 lithiated THIQ
offers an alternative route of
synthesis, but this provides only
modest diastereoselectivity.[18]
All these methods can access
Entry
R1
Intermediate (8a–g)
Yield [%] (d.r.[a]
)
DHIQ (9a–g)
Yield [%]
1
2
3
4
5
6
7
H
5-F
4-F
4-Cl
4-OMe
4,5-OMe
4,5-dioxole
anti-8a
anti-8b
anti-8c
anti-8d
anti-8e
anti-8 f
anti-8g
78 (9:1)
anti-9a
anti-9b
anti-9c
anti-9d
anti-9e
anti-9 f
anti-9g
83
89
85
80
73
65
79
83 (14:1)
81 (16:1)
76 (9:1)
73 (12:1)
64 (21:1)
86 (>99:1)
[a] Diastereomeric ratio was determined by isolated yields.
the enantiomerically enriched THIQs in various yields and
diastereoselectivities in the presence of specific substituents
on aryl systems, and the resulting THIQs are certain diaste-
reomers without robustness for the synthesis of other diaste-
reomers. Given the biomedical applications of THIQs and
the limitation of current synthetic methodologies, there is a
great need for the development of robust and modular syn-
thesis for highly functionalized 1,2,3,4-THIQs without the
limitation of electronic characteristics on the aromatic ring.
In addition, the synthetic method should allow for stereo-
chemical diversification of THIQ with a high degree of dia-
stereoselectivity, and yet should be efficient enough to be
applied for the total synthesis of complex bioactive THIQs.
To address this unmet need, we synthesized a series of enan-
tiopure bridged oxazolidine intermediates starting from
Garner aldehyde[19] through internal asymmetric inductions
and envisioned utilization of these bridged oxazolidines for
C-1 functionalization with various nucleophiles, which
allows an expeditious synthetic route for the stereodiversifi-
cation of fully functionalized 1,2,3,4-THIQs.
tramolecular nucleophilic addition of C-3’-OH (Table 2).
The absolute stereochemistry at the C-4 position of anti-9a
was confirmed by the observed coupling constant between
C-3 and C-4 protons, which was found to be 8.0 Hz.
As shown in Table 2, we successfully synthesized a series
of bridged oxazolidines with various N-substituents as single
diastereomers in good yields. The formation of enantiopure
bridged oxazolidine was confirmed by 1H/13C NMR spectros-
copy and crystallographic analysis of compound 10h
(Figure 2). Therefore, we were confident that we could gen-
erate a series of highly diversified and enantiomerically pure
key intermediates, bridged oxazolidines 10, with the flexible
modification potential at the bridged nitrogen.
Screening of catalysts for nucleophilic addition: After the
successful construction of bridged oxazolidines, we exam-
ined their reactivity toward the diastereoselective addition
of various nucleophiles at the C-1 position. The use of allyl-
trimethylsilane (allyl TMS), a silane-based carbon nucleo-
phile, was particularly interesting because of its neutral
nature and mild reactivity along with its high-yielding and ir-
reversible reactions.[20] Along with these advantages, the
steric interactions are also minimized with this small nucleo-
phile.[21] Initially, we pursued the stereoselective nucleophilic
opening of Fmoc-protected bridged oxazolidine 10b with
allyl TMS in the presence of Brønsted–Lowry acids. How-
Results and Discussion
Preparation of bridged oxazolidines: On the basis of our
proposed method for asymmetric synthesis of fully function-
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Chem. Eur. J. 2011, 17, 4905 – 4913

Highly Substituted 1,2,3,4-Tetrahydroisoquinolines
FULL PAPER
Table 3. Reaction optimization on diastereoselective nucleophilic open-
ing of bridged oxazolidine 10b through the activation with various Lewis
acids for asymmetric synthesis of 1,2,3,4-tetrasubstituted THIQ 11a.
Entry
Lewis acid
no catalyst
T [8C]
t
d.r.[a] 1b/1a
1
2
3
4
5
6
7
8
35
1 d
1 h
NR[b]
98:2
99:1
97:3
91:9
97:3
95:5
96:4
95:5
94:6
96:4
97:3
96:4
97:3
96:4
Yb
N
ꢀ20
ꢀ78
ꢀ20
ꢀ20
25
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
BF3·OEt2
TiCl4
CuACTHNGURETNNU(G OTf)2
TMSOTf
AgOTf
10 min
15 min
10 min
30 min
10 min
3 h
3 h
3 h
3 h
3 h
Er
Ho
In(OTf)3
Sm(OTf)3
Tm(OTf)3
Sn(OTf)2
Zn(OTf)2
Sc(OTf)3
ACHTUNGTRENNUNG
9
N
10
11
12
13
14
15
N
G
E
Figure 2. Chemical structure and ORTEP diagram of bridged oxazolidine
10h.
G
3 h
3 h
3 h
T
A
Table 2. Preparation of enantiopure bridged oxazolidines with various N-
modifications.
[a] Diastereomeric ratio was determined by HPLC analysis. [b] NR = no
reaction.
can be carried out in the air without the need to provide an
[22]
inert atmosphere. Thus, we selected YbACTHNUTRGENUG(N OTf)3 as the opti-
mized Lewis acid catalyst on the basis of its excellent yield
and diastereoselectivity, which is presumably a result of its
strong oxophilicity[23] and high coordination number.[24] The
acid-sensitive carbamate-based bridged oxazolidines (10a,
10c) provided deprotected DHIQ anti-9a as the major prod-
uct along with a small amount of desired THIQs under the
identical reaction condition. In the case of N-modified
bridged oxazolidines with benzoyl (10d), substituted benzo-
yl (10e–f), substituted sulfonyl (10g–h) and benzyl (10i), we
did not observe any chemical conversion under the opti-
Entry Substrate R2-X
R1
R2
Product Yield
[%]
1
2
3
4
5
anti-9a
anti-9a
anti-9a
anti-9a
anti-9a
G
H
H
H
H
H
Boc
Fmoc
Cbz
Bz
p-
MeOBz
p-
NO2Bz
Ts
Ns
Bn
10a
10b
10c
10d
10e
88
78
81
73
76
MeOBzCl
p-
6
anti-9a
H
10 f
68
NO2BzCl
TsCl
NsCl
7
8
9
10
11
12
13
14
15
anti-9a
anti-9a
anti-9a
anti-9b
anti-9c
anti-9d
anti-9e
anti-9 f
anti-9g
H
H
H
10g
10h
10i
10j
10k
10l
10m
10n
10o
89
91
92[a]
91
93
92
83
72
73
mized reaction condition with YbACHTNUTRGNEUNG(OTf)3, or even at the ele-
BnBr
vated temperature. Therefore, we selected Fmoc-protected
bridged oxazolidine 10b as a model system for further study
due to its acid-stability and synthetic versatility. The stereo-
chemistries of 11a and its deprotected 12a were verified by
1H NMR analyses.[25] We also performed NOE and gradient-
selected COSY (gCOSY) correlations to confirm the rela-
tive stereochemistry at the C-1 position of 12a (Scheme 1
FmocCl
FmocCl
FmocCl
FmocCl
FmocCl
FmocCl
6-F
7-F
7-Cl
7-OMe
6,7-OMe Fmoc
6,7-diox- Fmoc
ole
Fmoc
Fmoc
Fmoc
Fmoc
[a] The reaction was carried out overnight in refluxing diethyl ether.
ever, this condition yielded THIQs in moderate yields with
no diastereoselectivity (data not shown). Therefore, we
turned our attention to Lewis acids for the activation of
bridged oxazolidines.
To our delight, the Lewis acid-catalyzed allylation provid-
ed the desired THIQ 11a in high yields with 91–99% diaste-
reoselectivity (Table 3), which confirmed that chiral enrich-
ment of nucleophilic ring opening is caused by the unique
structural elements of key bridged oxazolidine intermediates
and not the presence of Lewis acids. The remarkable effi-
ciency of lanthanide triflates is noteworthy as the reaction
Scheme 1. Spectroscopic confirmation of the stereochemical outcomes of
THIQs 12a via Fmoc deprotection of 11a.
Chem. Eur. J. 2011, 17, 4905 – 4913
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4907

S. B. Park et al.
and Figure S2). Strong signals were found to indicate cross-
talk between the C-1 proton and C-3-CH2 in 12a; however,
there was no NOE correlation between the C-1 and C-3
protons, which confirms the 1,3-anti stereochemistry.
To examine the general scope of the stereoselective ring
opening of bridged oxazolidines (10b, 10j–o), the reaction
was tested with various nucleophiles in the presence of Yb-
ACHTUNGTRENNUNG(OTf)3. As shown in Table 4, a wide variety of substituents
can be introduced at the C-1 position of THIQ via asymmet-
ric nucleophilic ring opening of 10b (entries 1–7, Table 4). It
produced through the addition of allyl TMS in excellent
yields with high diastereoselectivity, irrespective of the elec-
tronic character of the substituents on the aryl rings. It is
worth noting that our synthetic method is general enough to
access highly functionalized enantiopure THIQs with both
electron-donating and electron-withdrawing substituents, in
contrast to reported methods for asymmetric synthesis of
THIQs that are applicable only to electron-rich aryl systems.
One additional feature was that we observed the slightly ex-
tended reaction time with electron-rich bridged oxazolidine
intermediates (10m–o) com-
pared to electron-poor counter-
Table 4. Diastereoselective ring opening of enantiopure bridged oxazolidines with various nucleophiles in the
presence of Yb(OTf)3 for asymmetric synthesis of 1,2,3,4-tetrasubstituted THIQs.
part (10j–l), which provides the
evidence that the mechanism of
this synthetic route for highly
ACHTUNGTRENNUNG
functionalized
enantiopure
THIQs is clearly different from
the conventional methods.
Entry Substrate Nu
R1
R3
Product Yield [%]
(1b/1a)[a]
The subsequent Fmoc depro-
tection was carried out to
obtain a clear spectrum and
confirm the exact structure and
relative stereochemistry of the
compound. The base-promoted
Fmoc deprotection of 11c, 11d,
and 11e unexpectedly led to
the formation of C-1-unmodi-
fied DHIQ 12c via elimination
of the azide, cyanide, and mor-
pholine moieties, respectively
(Table 5). This elimination can
be prevented by modification
of the functional groups of
these newly introduced C-1
groups in 11c–e prior to Fmoc
deprotection.
AHCTUNGTRENNUNG
1
2
10b
10b
allyl-TMS
H
H
11a
11b
95 (98:2)
84 (96:4)
1-phenyl-1-trimethylsilyloxyethylene
3
4
10b
10b
TMSN3
TMSCN
H
H
N3
CN
11c[b]
11d[b]
86 (92:8)
67 (58:42)
5
10b
TMS-morpholine
indole
H
11e[b]
84 (>99:1)
6
10b
H
11 f
89 (80:20)
7
10b
2,6-dimethoxyphenol
H
11g
89 (92:8)
8
10j
allyl-TMS
allyl-TMS
allyl-TMS
allyl-TMS
allyl-TMS
allyl-TMS
4’-F
11j
86 (>99:1)
89 (>99:1)
91 (>99:1)
81 (>99:1)
72 (>96:4)
64 (>99:1)
9
10k
10l
3’-F
11k
11l
10
11
12
13
3’-Cl
10m
10n
10o
3’-OMe
3’,4’-OMe
3’,4’-dioxole
11m
11n
11o
Synthesis of other possible ste-
reoisomers of THIQs and effect
of C-4 stereochemistry: We
next attempted the asymmetric
synthesis of other possible ste-
[a] Diastereomeric ratio was determined by HPLC analysis. [b] Product contains C3’-OTMS.
should be noted that the 4-hydroxy-3,5-dimethoxyphenyl
moiety was introduced via p-C attack. The resulting fully
functionalized THIQs (11a–g, 11j–o) were isolated in good
to excellent yields and diastereoselectivity. However, the in-
troduction of a CN group at the C-1 position caused a signif-
icant decrease in diastereoselectivity, presumably because of
the increased acidity of the C-1 hydrogen owing to the intro-
duction of nitrile (entry 4, Table 4).[26] In the case of polar
silane-based nucleophiles such as TMSN3, TMSCN, and
TMS-morpholine, the addition products underwent TMS
protection on C-3-CH2OH. We then examined the scope of
this transformation with various bridged oxazolidine inter-
mediates 10j–l and 10m–o containing electron-poor and
electron-rich aryl rings, respectively. As shown in entries 8–
13 of Table 4, the corresponding THIQs were successfully
reoisomers of THIQs to investigate the effect of C-4 config-
uration on the stereochemical outcome of the nucleophilic
ring opening of bridged oxazolidines. Thus, we synthesized
all possible stereoisomeric bridged oxazolidines. First, com-
pound 10b’ was prepared as a diastereomeric counterpart of
10b, from syn-8a. We also synthesized enantiopure bridged
oxazolidines ent-10b and ent-10b’, as enantiomeric counter-
parts of 10b and 10b’, from d-serine-derived Garner alde-
hyde using a similar synthetic procedure as described for
10b (Scheme 2). The absolute stereochemistry at the C-4
position of syn-9a was confirmed by the observed coupling
constant between C-3 and C-4 protons, which was found to
be 1.5 Hz.
These newly synthesized bridged oxazolidines (10b’, ent-
10b, and ent-10b’) were further treated with allyl TMS
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Highly Substituted 1,2,3,4-Tetrahydroisoquinolines
Table 5. Fmoc deprotection of 1,2,3,4-tetrasubstituted THIQs.
FULL PAPER
which has no major control on
the facial selectivity of nucleo-
philic attacks on iminium and
generates THIQs without good
diastereoselectivity. These re-
sults indicate that C-4-OBn
plays a role in the reaction.[28]
To prove this hypothesis, we
Entry
Substrate
Product
Yield [%]
Entry
Substrate
Product
Yield [%]
1
2
3
4
5
6
11b
11c
11d
11e
11 f
11g
12b
12c
12c
12c
12 f
12g
94
83
89
80
91
86
7
8
9
10
11
12
11j
11k
11l
11m
11n
11o
12j
12k
12l
12m
12n
12o
93
96
98
92
84
89
performed
time-dependent
monitoring of this chemical
transformation using 1H NMR
analysis for both diastereomers
10b and 10b’. In the case of
10b, the reaction was complet-
ed within 35 min without any
formation of iminium inter-
mediate as we did not observe
any signal in the region of d
8.0–12.0 ppm (Figure 3), while
its diastereomeric bridged oxa-
zolidine, 10b’, required the ex-
tended time for the reaction
completion. More importantly,
we observed a small peak at d
9.24 ppm, which is a firm indi-
cation for the formation of imi-
nium intermediate during the
reaction (Figure 4). The pres-
ence of C-4-OBn on the same
face of the nucleophilic attack
in 10b probably provides assis-
Scheme 2. Synthesis of all possible stereoisomeric bridged oxazolidines. a) i) 7a, THF, ꢀ788C, ii) BnBr, NaH,
DMF; b) 5n HCl, THF, RT, 2 h; c) FmocCl, CH2Cl2, RT, 3–4 h.
under optimized reaction conditions. Surprisingly, 10b’ and
ent-10b’ required more time for completion of the reaction
and with deterioration of diastereoselectivity, while ent-10b
provided the desired THIQ with a high degree of diastereo-
selectivity similar to 10b (Scheme 3). This significant loss of
diastereoselectivity with substrates 10b’ and ent-10b’ at the
C-1 position of the resulting THIQs was strongly correlated
with the orientation of C-4-OBn.[27] This deterioration of
diastereoselectivity was presumably a result of the extended
reaction time of less reactive substrate 10b’ and ent-10b’
under mild activation by YbACHTNUTRGENNG(U OTf)3, which might lead to the
undesired reaction path through iminium intermediates.
When the reaction of 10b’ was carried out at ꢀ788C in the
presence of BF3·OEt2 as a Lewis acid with a single coordina-
tion site,[28] we observed the restoration of diastereoselectiv-
ity for the formation of enantiopure THIQs 11a’ and ent-
11a’.
Scheme 3. Effect of C-4 stereochemistry on 1,3-/1,4-asymmetric induction
at C-1 position of THIQs. a) 20 mol% Yb
b) BF3·OEt2, CH2Cl2, ꢀ788C; c) 20% piperidine, DMF.
G
Mechanistic investigations: The different stereochemical
outcomes found in the nucleophilic ring opening of two dia-
stereomeric bridged oxazolidines (10b and 10b’) led us to
study the mechanism of this transformation. As mentioned
earlier, the poor diastereoselectivity of 10b’ was presumably
caused by the bypassed formation of iminium intermediate,
tance through an electronic effect, while the opposite is true
for diastereomeric 10b’ making it less reactive and leading
to the partial conversion of 10b’ to iminium intermediate,
which causes a loss in diastereoselectivity. In order to ex-
Chem. Eur. J. 2011, 17, 4905 – 4913
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S. B. Park et al.
Figure 3. Time-dependent 1H NMR spectra of diastereoselective ring opening of bridged oxazolidine 10b with allyl TMS in the presence of Yb
The region of d 5.0–10.5 ppm in 1H NMR spectra is shown only for clarification.
ACHTUNGTRENNUNG(OTf)3.
1
Figure 4. Time-dependent H NMR spectra of diastereoselective ring opening of epimeric bridged oxazolidine 10b’ with allyl TMS in the presence of Yb-
ACHTUNGTRENNUNG
(OTf)3. The region of d 5.0–10.5 ppm in 1H NMR spectra is shown only for clarification.
plain the deterioration in the stereochemical outcome of
substrate 10b’, we investigated probable conformations of
the transition state of 10b’ and their reactivity towards the
nucleophilic addition via iminium intermediates, unlike the
case of substrate 10b.
Considering the stereoelectronic aspects, the C4-substitu-
ent bearing electronegative oxygen prefers to occupy the
pseudoaxial position of DHIQ intermediate to maximize the
electrostatic interactions with iminium carbocation.[29] Along
with this, allylic strains also play a pivotal role in determin-
ing the facial selectivity of nucleophilic addition toward its
cyclic iminium.[30] Therefore, the extended reaction time in
temperature can preserve the bridged oxazolidine 10b’ and
allow the b-face attack to produce 1b-11a’ as the major
product (Scheme 4).
Enantioselective total synthesis of 2-azapodophyllotoxin:
Having a facile methodology for the asymmetric synthesis of
fully functionalized THIQs, we focused on the enantioselec-
tive total synthesis of 2-azapodophyllotoxin (1). This 2-aza
analogue of podophyllotoxin, which is a potential anticancer
agent, became an important target as it showed similar cyto-
toxic properties to podophyllotoxin without the possibility
of epimerization at the C-2 center, thereby facilitating the
natural transformation of podophyllotoxin to inactive picro-
podophyllin under physiological conditions.[31] The reported
syntheses of azapodophyllotoxin were accomplished by the
Pictet–Spengler reaction or via metal-assisted reduction of
DHIQ precursors.[32] However, these routes lack synthetic
the presence of YbACHTUNGTRENNUNG(OTf)3 allows the formation of cyclic imi-
nium intermediate of 10b’, whose transition state might
adopt C4-OBn at the pseudoaxial orientation and make
both a- and b-faces equally approachable by the nucleo-
phile. In contrast, the activation of BF3·OEt2 at the lower
4910
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Chem. Eur. J. 2011, 17, 4905 – 4913

Highly Substituted 1,2,3,4-Tetrahydroisoquinolines
FULL PAPER
Scheme 5. Enantioselective synthesis of 2-azapodophyllotoxin 1. a) i) 7g,
THF, ꢀ788C!RT, 2 h; ii) BnBr, NaH, DMF, 08C!RT, 4 h, 79% (after
two steps); b) 5n HCl, THF, RT, 3 h, 80%; c) FmocCl, THF, reflux,
Scheme 4. Plausible reaction mechanism for the diastereoselective ring
opening of bridged oxazolidines 10b and 10b’.
3.5 h, 91%; d) YbACTHUNTRGNE(UNG OTf)3, CH2Cl2, RT, 28 h, d.r. 93:7, 83%; e) i) 20% pi-
peridine, DMF, 10 min; ii) (Boc)2O, THF, RT, 30 min; iii) Me2SO4,
K2CO3, acetone, reflux, 1 h, 85% (after three steps); f) NaH, THF, RT,
5 h, 91%; g) H2, 10% Pd/C, THF, 1 atm, 3 h, 96%.
generality and failed to provide enantiopure 2-azapodophyl-
lotoxin (1) through direct enantioselective synthesis. There-
fore, we envisioned enantioselective synthesis of 2-azapodo-
phyllotoxin (1) using our bridged oxazolidine intermediate
ent-10o, which was obtained from d-Garner aldehyde in
four steps. The resulting ent-10o was subjected to diastereo-
selective ring opening with 2,6-dimethoxy-1-silyloxyben-
robust enough to produce a diverse collection of biologically
relevant 1,2,3,4-tetrasubstituted THIQs, despite the elec-
tronic nature of the substituents on the aryl rings, which
clearly differentiates this methodology from other reported
routes for the synthesis of THIQs, such as the Pictet–Spen-
gler reaction and the Bischler–Napieralski cyclization/reduc-
tion. We demonstrated the stereodiversification of THIQs
through the synthesis of all four possible diastereomers of
bridged oxazolidines in a highly efficient manner. In addi-
tion, we proposed a plausible mechanism on the basis of our
time-dependent 1H NMR study with two diastereomeric
bridged oxazolidines. Finally, we successfully accomplished
the first enantioselective total synthesis of 2-azapodophyllo-
toxin 1 with an overall yield of 35.4% (eight steps) from d-
Garner aldehyde for validation of our synthetic methodolo-
gy. Application of this method to the construction of various
chiral THIQ-based natural products and their analogs and
the subsequent biological evaluation of the synthesized
THIQs are currently underway and will be reported in due
course.
zene[33] in the presence of Yb
ACTHNUTRGENUN(G OTf)3 at room temperature to
give the desired THIQ 13 in 83% yield with excellent dia-
stereoselectivity. Compound 13 was then converted to com-
pound 14 via one-pot transformation: Fmoc deprotection,
and subsequent Boc protection and methylation of the
phenol using dimethyl sulfate and K2CO3 in acetone. The
treatment of resulting methylated compound with NaH in
THF yielded 14, and the subsequent debenzylation of 14
using catalytic hydrogenation furnished 2-azapodophyllotox-
in 1 with an overall yield of 35.4% (eight steps) from d-
Garner aldehyde (Scheme 5). The spectroscopic data were
in accordance with the reported one.[32b]
Conclusion
In summary, we developed a concise and highly diastereose-
lective synthetic route for the construction of fully function-
alized THIQs. We introduced a new series of bridged oxazo-
lidines from Garner aldehydes as key intermediates with ex-
ceptional potential for the asymmetric synthesis of various
THIQs. The inherent chirality of Garner aldehyde was uti-
lized through 1,2- and 1,3-/1,4-asymmetric inductions itera-
tively to obtain 1,2,3,4-tetrasubstitued THIQs using rigid
and isolable bridged oxazolidines. The methodology is
Experimental Section
General methods: See Supporting Information.
General procedure for the preparation of 3,4-dihydroisoquinolines: 5n
HCl (1 mL) was added to a solution of 8 (1.03 mmol) in THF (5 mL) and
the reaction mixture was then stirred at room temperature for 2 h. After
complete disappearance of the starting material, the reaction mixture
was diluted with CH2Cl2 and washed with water (2ꢁ5 mL). The aqueous
layer was then basified by the addition of saturated NaHCO3 and extract-
Chem. Eur. J. 2011, 17, 4905 – 4913
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4911

S. B. Park et al.
ed by CH2Cl2 (3ꢁ10 mL), after which the combined organic extract was
dried over anhydrous Na2SO4(s). The filtrate was then condensed under
reduced pressure and the crude mixture was recrystallized using ethyl
acetate/hexane to obtain the pure DHIQs.
ArH), 6.78 (s, 1H, ArH), 6.64 (s, 2H), 5.97 (s, 1H), 5.92 (s, 1H), 5.58 (s,
1H), 5.02 (s, 1H), 4.62 (s, 1H), 4.58 (s, 2H), 3.74 (s, 3H), 3.54 (s, 6H),
3.51 (s. 1H), 3.42 (s, 1H), 2.21 (s, 1H), 1.49 (s, 9H); 13C NMR (125 MHz,
CDCl3): d = 154.1, 153.0, 148.5, 146.7, 138.0, 128.6, 128.3, 128.0, 123.3,
110.4, 104.0, 101.5, 81.0, 70.9, 68.1, 63.9, 60.9, 56.0, 48.7, 28.3; HRMS
(FAB): m/z: calcd for: C32H37NO9 579.2468: found 579.2472 [M+].
General procedure for the preparation of bridged oxazolidines: Acyl
chloride/sulphonyl chloride/alkyl halide (1.5 mmol) was added to a solu-
tion of DHIQ (1 mmol) in dry CH2Cl2 (5 mL) and the reaction mixture
was then stirred until all of the starting material was converted to the
products. The solvent was then evaporated and the crude was purified by
silica-gel flash column chromatography. Anhydrous THF and diethyl
ether were used as a solvent for the preparation of 10a with (Boc)2O and
10i with benzylbromide, respectively.
The resulting methylated compound (60 mg, 0.10 mmol) was dissolved in
anhydrous THF (1.5 mL) and cooled to 08C followed by the addition of
NaH (4.9 mg, 0.020 mmol). After the reaction completion was monitored
by TLC, the reaction mixture was quenched by the addition of saturated
NaHCO3 and extracted with CH2Cl2 twice. The combined organic layer
was dried on anhydrous Na2SO4(s) and the filtrate was condensed under
reduced pressure. The crude product was purified by silica-gel flash
column chromatography to obtain 14 (47.6 mg, 91%) as sticky solid.
[a]2D8 =ꢀ93.69 (c = 0.13, CHCl3); Rf =0.23 (40% EtOAc in hexanes);
1H NMR (500 MHz, CDCl3): d = 7.43–7.37 (m, 5H, ArH), 7.06 (s, 1H,
ArH), 6.49 (s, 2H, ArH), 6.46 (s, 1H, ArH), 5.99 (dd, J=1.5, 5.0 Hz,
2H), 5.81 (s, 1H), 4.84 (d, J=12.0 Hz, 1H), 4.75 (d, J=12.0 Hz, 1H),
4.60 (d, J=8.5 Hz, 1H), 4.39 (t, J=9.0 Hz, 1H), 4.17–4.14 (m, 1H), 3.98–
3.94 (m, 1H), 3.84 (s, 3H), 3.79 ppm (s, 6H); 13C NMR (125 MHz,
CDCl3): d = 156.4, 153.6, 148.0, 147.8, 138.2, 137.5, 136.7, 129.2, 129.1,
128.7, 128.0, 127.9, 107.9, 106.4, 106.1, 101.6, 76.9, 73.3, 67.6, 61.0, 56.6,
56.5, 52.7 ppm; HRMS (FAB): m/z: calcd for: C28H27NO8: 505.1737;
found 505.1736 [M]+.
General procedure for the nucleophilic addition
Using Yb
bridged oxazolidine (1 equiv) in dry CH2Cl2 at ꢀ208C followed by Yb-
(OTf)3 (20 mol%). The reaction mixture was then stirred until all of the
ACHTUNGTRENNUNG(OTf)3: Nucleophile (2 equiv) was added to a solution of
ACHTUNGTRENNUNG
starting material were consumed which was monitored by TLC. The reac-
tion was quenched with saturated NaHCO3 and diluted with CH2Cl2,
after which the organic phase was separated and the aqueous phase was
extracted twice with CH2Cl2. The combined organic extract was then
washed with brine and dried over anhydrous Na2SO4(s), after which the
solvent was evaporated and the crude product was purified by silica-gel
flash column chromatography.
Using BF3·OEt2: Nucleophile (2 equiv) was added to a cooled solution of
bridged oxazolidine (1 equiv) in dry CH2Cl2 at ꢀ788C followed by a 1m
solution (1.3 equiv) of BF3·OEt2 in CH2Cl2. The reaction was monitored
by TLC. After completion of the reaction, saturated NaHCO3 was added
and the reaction mixture warmed to room temperature. The organic
phase was then separated and the aqueous phase was extracted with
CH2Cl2 twice. The combined organic extract was washed with brine and
dried over anhydrous Na2SO4(s), after which the solvent was evaporated
and the crude product was purified by silica-gel flash column chromatog-
raphy.
2-Azapodophylotoxin (1): 10% Pd/C (10 mg) was added to a solution of
compound 14 (25 mg, 0.001 mmol) in methanol (0.1 mL) and the reaction
mixture was stirred for 3 h under the atmospheric pressure of hydrogen
gas. Pd/C was removed by the filtration through celite and the filtrate
was concentrated under reduced pressure to obtain 2-azapodophylotoxin
1 as a sticky solid (19.8 mg, 96%). [a]2D8 =ꢀ89.68 (c = 0.94, CHCl3); Rf =
1
0.26 (60% EtOAc in hexanes); H NMR (500 MHz, CDCl3): d = 7.12 (s,
1H, ArH), 6.50 (s, 2H, ArH), 6.42 (s, 1H), 5.98 (s, 1H, ArH), 5.96 (s,
1H, ArH), 5.80 (s, 1H), 4.60 (t, J=8.5 Hz, 1H), 4.51–4.45 (m, 2H), 3.84
(s, 3H), 3.79 (s, 6H), 3.80–3.75 (m, 1H), 3.03 ppm (d, J=8.0 Hz, 1H,
OH); 13C NMR (125 MHz, CDCl3): d = 156.9, 153.6, 148.0, 147.7, 138.2,
137.2, 131.1, 127.1, 107.9, 106.07, 105.7, 101.6, 69.6, 67.2, 61.1, 61.0, 56.9,
56.6, 56.5 ppm; HRMS (FAB): m/z: calcd for C21H21NO8: 415.1267;
found: 415.1270 [M+].
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
quinoline-6(5H)-carboxylate (13): 2,6-Dimethoxy-1-trimethylsilyloxyben-
zene (210 mg, 0.9 mmol) was added to a solution of ent-10o (25 mg,
0.045 mmol) in dry CH2Cl2 (0.5 mL), followed by YbACHTUNTGRNENG(U OTf)3 (5 mg,
9 mmol). The reaction mixture was then stirred for 28 h at room tempera-
ture until all of the starting materials were consumed. The solvent was
evaporated and the crude product was purified by silica-gel flash column
chromatography to provide the desired product 13 (d.r. 93:7). Brown
sticky solid (83%, 270 mg); [a]2D8 =ꢀ17.36 (c =0.24, CHCl3); Rf =0.25
(50% EtOAc in hexanes); 1H NMR (500 MHz, CDCl3): d = 7.81–7.55
(m, 4H, ArH), 7.39–7.19 (m, 9H, ArH), 6.79–6.58 (m, 4H, ArH), 5.98–
5.87 (m, 2H), 5.54–5.44 (m, 1H), 5.33–5.25 (m, 1H), 4.80–4.71 (m, 1H),
4.67–4.21 (m, 5H), 3.47 (s, 6H), 3.53–3.50 (m, 1H), 2.89–2.86 ppm (m,
1H); 13C NMR (125 MHz, CDCl3): d = 156.0, 148.5, 146.9, 144.3, 143.7,
141.4, 138.0, 136.0, 133.7, 133.5, 131.3, 128.7, 128.6, 128.2, 128.1, 128.0,
127.9, 127.4, 127.3, 125.4, 125.1, 124.9, 123.7, 122.4, 120.2, 110.4, 108.0,
104.1, 101.5, 74.7, 71.1, 68.1, 63.2, 58.7, 57.5, 56.5, 56.2, 47.5ppm; HRMS
(FAB): m/z: calcd for C41H37NO9: 687.2468; found: 687.2474 [M]+.
Acknowledgements
This study was supported by the National Research Foundation of Korea
(NRF) and the WCU program of the NRF funded by the Korean Minis-
try of Education, Science, and Technology (MEST). A.K.S. and M.K. are
grateful for the postdoctoral and predoctoral fellowships, respectively,
which were awarded by the BK21 Program.
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4912
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Highly Substituted 1,2,3,4-Tetrahydroisoquinolines
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Received: October 12, 2010
Revised: December 24, 2010
Published online: March 14, 2011
Chem. Eur. J. 2011, 17, 4905 – 4913
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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