Asymmetric aza-Friedel-Crafts reaction of indoles induced by O-pivaloylated d-galactosylamine as the chiral auxiliary

Article abstract of DOI:10.1016/j.tet.2012.03.115

The diastereoselective formation of β-N-glycosidically linked 3-indolyl methanamine derivatives 5 has been achieved with high yield via an aza-Friedel-Crafts reaction. The reaction was performed by using O-pivaloylated galactosylamine 1 as a chiral templa

Full text of DOI:10.1016/j.tet.2012.03.115

Tetrahedron 68 (2012) 4830e4837
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Asymmetric aza-FriedeleCrafts reaction of indoles induced by O-pivaloylated
D-galactosylamine as the chiral auxiliary
,
b
,
a,
*
Haohao Yang a, Bing Cui a, Guiping Wu a, Zhiwei Miao a , Ruyu Chen
*
a State Key Laboratory and Institute of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, PR China
b Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology (Ministry of Education), Tsinghua University, Beijing 100084, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
The diastereoselective formation of b-N-glycosidically linked 3-indolyl methanamine derivatives 5 has
been achieved with high yield via an aza-FriedeleCrafts reaction. The reaction was performed by using
Received 28 December 2011
Received in revised form 20 March 2012
Accepted 30 March 2012
O-pivaloylated galactosylamine 1 as a chiral template and SnCl4 combining TBAI as catalyst in DCM at
ꢀ50 ꢁC.
Available online 5 April 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
aza-FriedeleCrafts reaction
Indole
Asymmetric synthesis
Carbohydrate auxiliaries
Lewis acid catalyzed
1. Introduction
reaction of indoles with aldimines for the synthesis of 3-indolyl
methanamine derivatives, bisindole alkylation events are very
The development of diastereo- and enantioselective synthetic
methods for the preparation of indole derivatives remains an im-
portant goal in modern organic synthesis because of their biological
activities.1 Various indole derivatives such as 3-substituted indoles,
are common components of drugs and are generally found to be of
pharmaceutical interest in a variety of therapeutic area.2 Accord-
ingly, considerable efforts have been devoted to the development of
stereoselective approaches for indole derivatives synthesis.3 The
asymmetric FriedeleCrafts reaction of indoles with imines repre-
sents the most direct and convenient approach in terms of reagent
availability.4 The products of this reaction provide easy access to the
synthesis of enantiopure 3-indolyl methanamine derivatives.5 In
view of the significance of controlling the stereochemistry in an
absolute sense, the strategies of asymmetric catalysis,6 enzymatic
resolution7 and chiral auxiliary-mediated induction8 have been
employed for the preparation of 3-substituted indoles. However,
the issues of unprotected indole substrate usage, reaction stereo-
selectivity control and amine N-substituent removal remain to be
addressed and are the subject of intense investigation. Especially,
during the reaction of direct asymmetric aza-FriedeleCrafts
difficult to be avoided (Scheme 1).9
R'
R
PHN
R'
N
H
Lewis Acid
NP
R'
*
Product
HN
R
Lewis Acid
H
decomposition
N
H
N
H
Scheme 1. Enantioselectiveaza-FriedeleCraftsreactiontowards3-indolylmethanamines.
Carbohydrates are valuable as enantiomerically pure starting
materials in chiral pool syntheses of many chiral natural products
and drugs.10 Carbohydrate derivatives are efficient auxiliaries
for stereo-differentiation in many stereoselective chiral synthe-
ses.11,12 Lewis acid induced nucleophilic addition to Schiff bases
of 2,3,4,6-tetra-O-pivaloyl-b-D-galactopyranosyl amine 1 was firstly
reported by Kunz in 1987.13 This chiral auxiliary has already
been used in diastereoselective Strecker,13 Ugi,14 Mannich15 and
tandem MannicheMichael reactions.16 Recently, we reported
a convenient and efficient synthetic protocol for preparation of
* Corresponding authors. Tel.: þ86 22 2350 4783; fax: þ86 22 2350 2351; e-mail
a
-aminophosphinic acid derivatives in high yields and high
address: miaozhiwe@nankai.edu.cn (Z. Miao).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.03.115

H. Yang et al. / Tetrahedron 68 (2012) 4830e4837
4831
enantiostereoselectivities, utilizing SnCl4 as the promoter and
(Table 1, entries 2e5). Other Lewis acids were tested (e.g., AlCl3, CuI,
CuBr, MgCl2, Cu(OAc)2 and NiCl2) were able to promote the addition
and gave moderate yields and diastereoselectivities (Table 1, entries
6e11). Particularly, when lowering the reaction temperature to
ꢀ50 ꢁC and decreasing the loading amount of catalyst, SnCl4
(20 mol %) was able to catalyze the addition and obtained the
product in 83% yield with the ratio of diastereoselectivity 10:1
(Table 1, entries 12 and 14). Higher diastereoselectivity may be
maintained at catalyst loadings as low as 10 mol % (13:1 dr, 73%
yield, Table 1, entry 15). Compared with SnCl4, both BF3$Et2O and
ZnCl2$Et2O applied in DCM at ꢀ50 ꢁC can catalyze this reaction
with lower yields and diastereoselectivities (Table 1, entries 16 and
17). The molar equivalents of indole 4 relative to that of 3a is 2:1
(Table 1, entries 1e22).
Following this evaluation of Lewis acids, a solvent screen was
undertaken. The reaction proceeded in Et2O, THF, and CHCl3 to af-
ford the desired product in good to high yields and with moderate
diastereoselectivities (Table 1, entries 18e20). Toluene gave a high
conversion rate but with a slight decrease in the diastereomeric
excess (Table 1, entry 21). Among the solvents tested, DCM was
found to be the best with respect to catalytic activity and asym-
metric induction. When decreasing the amount of catalyst, a drop-
off in both the reaction rate and dr value of the product was ob-
served (Table 1, entry 22).
O-pivaloylated D-galactosylamine as chiral auxiliary by means of
Mannich-type reactions.17 Herein we report an efficient asym-
metric synthesis of 3-indolyl methanamine derivatives in which
glycosylamine 1 was used as the stereodifferentiating auxiliary.
2. Results and discussion
The synthesis of
amine derivatives 5 started with the condensation of 2,3,4,6-tetra-
O-pivaloyl- -galactopyranosyl amine 1 and arylaldehyde 2. In
b-N-glycosidically linked (3-indolyl)methan-
b-D
order to prepare N-(2,3,4,6-tetra-O-pivaloyl-
D
-galacopyranosyl)
-galacopyranosyl)
aldimines 3, N-(2,3,4,6-tetra-O-pivaloylated-
D
amine 1 was reacted with aldehydes in the presence of acetic acid
in 2-propanol. The reactions proceeded smoothly within a short
period of time at room temperature under dehydrating condi-
tions.18 We initially investigated the reaction of O-pivaloylated N-
galactosylimine 3a (R¼p-NO2C6H4) with indole 4 in dichloro-
methane (DCM) without the aid of Lewis acid, no product 5a was
detected (Table 1, entry 1). Since the nucleophilicity of indole is low
and the electrophilicity of imines 3 is only moderate, the reaction
between these compounds requires activation by a Lewis acid to
proceed. In this sense, various Lewis acids were tested in the re-
action of the O-pivaloylated N-galactosylimine 3a with indole 4 in
DCM at room temperature.
To determine the optimal conditions, the suitable amount of
indole was examined by running the reaction at ꢀ50 ꢁC. In the
presence of 10 mol % of SnCl4 in DCM, reaction of imine 3a with
equimolar indole 4 gave the desired product 5a in 59% yield with
The results revealed that Mg(ClO4)2, Cu(OTf)2, FeCl3 and SnCl4
only gave the double-alkylation product 6a when used in a stoi-
chiometric amount, and no desired product of 5a was observed
Table 1
Survey of the conditions for the formation of 5aa
NO2
OPiv
CHO
NO2
+
PivO
PivO
H
N
OPiv
PivO
OPiv
PivO
O
OPiv
N
H
NO2
2a
4
O2N
O
O
NH2
OPiv
N
PivO
PivO
Lewis acid
solvent
OPiv
HN
5a
N
H
N
H
1
3a
6a
Entry
Lewis acid (equiv)
T (ꢁC)
Solvent
Reaction time (h)
Indole (equiv)
Yieldb (5a/6a) [%]
drd [%]
1
2
3
4
5
6
7
8
d
rt
rt
rt
rt
rt
rt
rt
rt
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
Et2O
20
20
20
20
20
20
11
10
10
23
12
1
1
8
8
4
32
18
19
2
18
8
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
1
3
5
n.r.c
0:85
0:82
0:78
0:80
83:7
31:55
68:11
53:15
17:55
57:11
0:77
d
Mg(ClO4)2 (1)
Cu(OTf)2 (1)
FeCl3 (1)
SnCl4 (1)
AlCl3 (1)
CuI (1)
CuBr (1)
MgCl2 (1)
Cu(OAc)2 (1)
NiCl2 (1)
d
d
d
d
8:1
6:1
6:1
4:1
5:1
4:1
d
9
rt
rt
rt
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
SnCl4 (1)
ꢀ50
ꢀ50
ꢀ50
ꢀ50
ꢀ50
ꢀ50
ꢀ50
ꢀ50
ꢀ50
ꢀ50
ꢀ50
ꢀ50
ꢀ50
ꢀ50
SnCl4 (0.5)
SnCl4 (0.2)
SnCl4 (0.1)
BF3$Et2O (0.1)
ZnCl2$Et2O (0.1)
SnCl4 (0.1)
SnCl4 (0.1)
SnCl4 (0.1)
SnCl4 (0.1)
SnCl4 (0.05)
SnCl4 (0.1)
SnCl4 (0.1)
SnCl4 (0.1)
0:73
d
83:Trace
73:Trace
70:Trace
80:Trace
50:22
91:Trace
77:Trace
97:Trace
74:Trace
59:Trace
85:Trace
81:Trace
10:1
13:1
10:1
9:1
6:1
7:1
9:1
6:1
9:1
7:1
14:1
13:1
THF
CHCl3
Toluene
DCM
DCM
DCM
DCM
8
8
8
a
All reactions were carried out under the optimal conditions reported in the text, unless otherwise indicated.
b
c
Isolated yield.
No reaction.
d
Determined from the crude product by 1H NMR.

4832
H. Yang et al. / Tetrahedron 68 (2012) 4830e4837
7:1 diastereoselectivity (Table 1, entry 23). When we increased the
amount of indole, the reaction proceeded faster and led to the
product with a slightly higher selectivity. When 3 equiv of indole
was used, an optimal result was obtained in terms of both the yield
and diastereoselectivity of 5a (85% yield, 14:1 dr, Table 1, entry 24).
A further increase of the amount of indole had no significant effect
on the yield or the selectivity (Table 1, entry 25). Thus, the optimal
reaction conditions for this transformation were determined to be
0.5 mmol of 3, 3 equiv of indole 4, 10 mol % of SnCl4 in DCM as
solvent at ꢀ50 ꢁC.
result was obtained (83% yield, >19:1 dr) when 20 mol % of tetra-
butylammonium iodide (TBAI) was employed in this reaction (Table
2, entry 15). Thus, the optimal reaction conditions for this trans-
formation were determined to be 0.5 mmol O-pivaloylated N-gal-
actosylimine 3, 3 equiv of indole 4,10 mol % of SnCl4 combined with
20 mol % of TBAI in DCM as solvent at ꢀ50 ꢁC.
With these optimized conditions in hand, the general scope of
aldimines 3 and indole derivatives was examined in this asym-
metric FriedeleCrafts reaction. As expected, O-pivaloylated N-gal-
actosylimine
3 bearing both electron-rich and electron-poor
Under these optimum conditions, we next examined the gen-
erality of this reaction with various aldimines 3 and indoles 4.
Surprisingly, except imines 3a and 3k, other aldimines 3 only led to
bis-alkylation products 6 quantitatively (Table 2, entries 1e11). In
general, the aza-FriedeleCrafts reaction of less activated substrates,
such as imines of aromatic aldehydes, was limited mainly due to the
lower reactivity and the formation of double-alkylation product 6.19
In order to overcome this drawback, the influence of additives on
the reaction was examined. The reaction of O-pivaloylated N-gal-
actosylimine 3b (R¼p-ClC6H4) with indole 4 in the presence of
10 mol % SnCl4 in dichloromethane (DCM) at ꢀ50 ꢁC was chosen as
an initial example. It was found that the addition of Ph3P or Et3N
made almost no difference on the outcome of the reaction (Table 2,
entries 12e13). When 2 equiv of acetone was added, the reaction
proceeded smoothly to provide corresponding FriedeleCrafts ad-
ducts in good yield and high dr value (76% yield, >19:1 dr, entry 14).
However, the reaction time was taken 96 h. Interestingly, good
aromatic groups gave the corresponding asymmetric aza-Frie-
deleCrafts products 5aej in good to high yields and diaster-
eoselectivities (Table 2, entries 16e24), which contrast the results
of a chiral copper complex that showed a strong electronic effect for
this reaction.5b Furthermore, several substituted indoles have been
tested in the reaction with imine 3b, respectively. For the substrates
with electron-donating group (4b) and electron-withdrawing
group (4c), the reactions underwent smoothly, affording the
products with high yields and diastereoselectivities (Table 2, en-
tries 25 and 26).20
The diastereomeric ratio of 5 was determined by 1H NMR of the
crude reaction mixture. Consistent with our experimental results,
there exists only
by both electronic and steric effects. Therefore, with the newly
formed stereocenter in the reaction, only two diastereoisomers S-
and R-5 were generated. The absolute configuration of the major
product 5 was defined as
b-anomer in the chiral auxiliary that is controlled
b
b
bS by X-ray analysis of compound 5a
Table 2
The aza-FriedeleCrafts reaction of N-(2,3,4,6-tetra-O-pivaloylated-D-galactosyl)aldimines 5aek
R
OPiv
PivO
OPiv
H
N
OPiv
Ar
R
O
R
PivO
N
H
3eqv
Ar
PivO
O
4
N
OPiv
Ar
R
+
PivO
N
N
H
10 mol% SnCl4
additive, DCM, -50 °C
H
N
3
6
5
H
Entry
Ar
R
Additive (equiv)
Time [h]
Yielda (5/6) [%]
drb
14:1
1
2
3
4
5
6
7
8
p-NO2C6H4 (3a)
p-ClC6H4 (3b)
o-ClC6H4 (3c)
m-ClC6H4 (3d)
p-BrC6H4 (3e)
o-BrC6H4 (3f)
o-FC6H4 (3g)
p-FC6H4 (3h)
m-CH3C6H4 (3i)
p-CH3C6H4 (3j)
2-NO2e3-OCH3C6H3 (3k)
p-ClC6H4 (3b)
p-ClC6H4 (3b)
p-ClC6H4 (3b)
p-ClC6H4 (3b)
p-NO2C6H4 (3a)
o-ClC6H4 (3c)
m-ClC6H4 (3d)
p-BrC6H4 (3e)
o-BrC6H4 (3f)
o-FC6H4 (3g)
H (4a)
H (4a)
H (4a)
H (4a)
H (4a)
H (4a)
H (4a)
H (4a)
H (4a)
H (4a)
H (4a)
H (4a)
H (4a)
H (4a)
H (4a)
H (4a)
H (4a)
H (4a)
H (4a)
H (4a)
H (4a)
H (4a)
H (4a)
H (4a)
5-OCH3 (4b)
5-Br (4c)
H (4a)
d
8
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
12
48
48
96
8
8
8
8
8
8
8
8
8
85:trace
0:93
0:92
0:90
0:97
0:97
0:91
0:98
0:96
d
d
d
d
d
d
d
d
d
d
d
d
d
d
9
d
d
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
d
0:90
85:Trace
0:79
d
d
>19:1
d
Ph3P (0.2)
TEA (0.2)
Acetone (2)
TBAI (0.2)
TBAI (0.2)
TBAI (0.2)
TBAI (0.2)
TBAI (0.2)
TBAI (0.2)
TBAI (0.2)
TBAI (0.2)
TBAI (0.2)
TBAI (0.2)
TBAI (0.2)
TBAI (0.2)
TBACl (0.2)
0:89
d
76:Trace
83:Trace
89:Trace
92:Trace
77:Trace
96:Trace
75:Trace
93:Trace
71:Trace
72:Trace
70:Trace
86:Trace
83:Trace
0:80
>19:1
>19:1
14:1
13:1
>19:1
>19:1
12:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
d
p-FC6H4 (3h)
m-CH3C6H4 (3i)
p-CH3C6H4 (3j)
p-ClC6H4 (3b)
p-ClC6H4 (3b)
p-BrC6H4 (3e)
8
8
8
4
a
After purification by chromatography.
Diastereomeric ratio determined from the crude product by HPLC.
b

H. Yang et al. / Tetrahedron 68 (2012) 4830e4837
4833
(Fig. 1).21 To demonstrate the efficient removal of the auxiliary,
compound 5h was treated with a solution of sodium methoxide in
methanol to give 8h in quantitative yield, which was reacted with
benzyloxycarbonyl chloride (CbzCl) to provide less polar compound
9h in order to facilitate the determination of its enantiomeric ex-
cess by chiral HPLC (Scheme 2).
Based on Kunz’s findings22 and our experimental results,
a plausible mechanism was proposed in Fig. 2. The preferred for-
mation of the S-configured diastereomer of 5 can be rationalized by
an attack of indole from Re side of (E)-imines 3. In the transition
state, the tin should have octahedral coordination. Two co-
ordination sites of the tin(IV) chloride are occupied by the imine
nitrogen and the carbonyl oxygen atoms of the (C-2) pivaloyloxy
group (TS I). The imine$SnCl4 complex maintains the H-eclipsed
conformation, because chelation by the auxiliary’s pivaloyl group
inhibits rotation along the NeC bond. According to this ration-
*
alization, the SN20-type attack of indole 4 from the front side of the
imine is initiated and form TS II. The mechanism indicates that the
pivaloyl group in the aldimines 3 plays a significant role in con-
trolling the diastereoselective addition of indoles 4 to N-gal-
actosylaldimines 3. We envisaged that the coordination of the SnIV
catalyst to the N-glycoside nitrogen of the initial FriedeleCrafts
reaction product (TS III) resulting from N-galactosylaldimine 3
would enhance the ability of the N-glycoside moiety as a leaving
group, facilitating the formation of the highly stabilized carboca-
tion intermediate (TS IV), required for the final FriedeleCrafts
alkylation.
In contrast, in the presence of TBAI, it is reasonable to assume
a preferential coordination of the SnIV atom to the iodine atom of
TBAI, instead of the N-glycoside nitrogen, resulting in a lower
leaving group capacity of the N-glycoside moiety, which would
make more difficult the cleavage of the CeN bond and formation of
the carbocation intermediate (TS III). To support this hypothesis,
and to have an insight of the coordination mode around the tin
atom, tetrabutylammonium chloride (TBACl) was employed in this
reaction. Compared with TBAI, there was only double-alkylation
product 6 obtained in quantitative yield when TBACl combining
SnCl4 as catalyst in the reaction (Table 2, entry 27).
Fig. 1. The ORTEP drawing of 5a.
OPiv
F
PivO
F
H
N
OPiv
O
O
PivO
PivO
H2N
PivO
(1) MeOH/Na
+
OPiv
OH
(2) HOAc, H2O
RT
OPiv
HN
HN
5h
3. Conclusion
7
8h
F
CbzNH
In conclusion, we have developed the asymmetric aza-Frie-
deleCrafts reaction of indole in high yields and high diaster-
eoselectivities, utilizing SnCl4 combining TBAI as catalyst and
CbzCl/Na2CO3
8h
THF/H2O 2:1 (v/v)
0 °C
HN
O-pivaloylated -galactosylamine 3 as chiral auxiliary. The O-piv-
D
9h
aloylated galactosylamine 3 is an effective chiral template in
the synthesis of chiral N-galactosyl 3-indolyl methanamine 5.
Scheme 2. Synthesis of (S)-(4-fluorophenyl)(1H-indol-3-yl)methanamine 8h.
O
Cl
O
Ph
N
Cl
Cl
TS I
Sn
N
O
Cl
Ph
H
N
H
O
O
tBu
+
O
SnCl4
H
Cl
Sn
O
tBu
H
N
N
Cl
Cl
Cl
H
TS I
O
H
Cl
TBAI
N
H
N
Cl
Cl
Cl
Ph
O
Sn
H
tBu
TS II
O
O
O
O
N
H
N
Ph
Ph
O
O
+
H
tBu
TS III
H
tBu
Bu4N I SnCl4
TBAI
H
N
Bu4N I
O
N
H
Ph
H
N
N
Ph
H
Ph
OPiv
N
H
N
N
H
H
6
H
5
TS IV
Fig. 2. Plausible reaction mechanism.

4834
H. Yang et al. / Tetrahedron 68 (2012) 4830e4837
(S)-3-Indolyl (phenyl) methanamine 8 can be detached easily from
the carbohydrate template, which can be recycled. Further studies
are being conducted with regard to scope of this reaction and re-
lated FriedeleCrafts-type additions induced by carbohydrate as
chiral auxiliary.
(ESI): m/z calcd for C41H55N3O11þNaþ: 788.3734 [MþNaþ]; found:
788.3736.
4.3.2. N-[Indol-3-yl-(4-chlorophenyl)methyl]-(2,3,4,6-tetra-O-piv-
aloyl-
NMR (400 MHz, CDCl3):
b-D
-galactosyl)amine (5b). White solid, mp 180e182 ꢁC; 1H
d¼1.11 (s, 9H, C(CH3)3), 1.24 (s, 9H,
4. Experimental section
C(CH3)3), 1.24 (s, 9H, C(CH3)3), 1.26 (s, 9H, C(CH3)3), 2.57 (d,
3J1,NH¼13.0 Hz, 1H, NeH), 3.83 (t, J5,6¼6.8 Hz, 1H, 6a-H), 3.97 (dd,
3
3
2
4.1. General experimental section
3J1,NH¼13.0, J1,2¼8.1 Hz, 1H, 1-H), 4.04 (dd, J6a,6b¼11.1 Hz,
3J5,6a¼6.8 Hz, 1H), 4.23 (dd, 2J6a,6b¼11.1 Hz, 3J5,6b¼6.8 Hz, 1H, 6b-H),
All reactions were carried out under an inert atmosphere and in
heat-dried glassware. Anhydrous DCM was obtained by distillation
from calcium hydride. Flash column chromatography was per-
5.06e5.15 (m, 2H, 2-H, 3-H), 5.40 (d, 3J3,4¼2.0 Hz, 1H, 4-H), 5.67 (s,
3
1H, CeH), 6.95 (d, J2 ,indoleeNH¼2.2 Hz, 1H, 20-H), 7.07 (t, J¼7.4 Hz,
0
1H, Ph), 7.18 (t, J¼7.3 Hz, 1H, Ph), 7.26 (s, 1H, Ph), 7.28 (s, 1H, Ph),
7.33 (d, J¼8.2 Hz, 1H, Ph), 7.41 (d, J¼8.4 Hz, 2H, Ph), 7.62 (d,
J¼7.9 Hz, 1H, Ph), 8.01 (s, 1H, indole NeH); 13C NMR (101 MHz,
formed on silica gel (particle size 10e40 mm, Ocean Chemical Fac-
tory of Qingdao, China). Nitrogen gas (99.999%) was purchased
from Boc Gas Inc. 1H, and 13C spectra were recorded on Brucker-400
(400 MHz for 1H, 101 MHz for 13C) spectrometers. Chemical shifts
were reported in parts per million downfield from internal
Si(CH3)4. The crystal structure was determined on a Bruker SMART
1000 CCD diffractometer. Mass spectra were recorded on a LCQ
advantage spectrometer with ESI resource. HRMS were recorded on
APEXII and ZAB-HS spectrometer. Melting points were determined
on a T-4 melting point apparatus (uncorrected).
CDCl3):
d
¼27.11, 27.19, 27.21, 27.37, 38.73, 38.78, 38.89, 39.08, 53.41,
61.87, 67.41, 69.01, 71.48, 71.67, 86.28, 111.21, 119.10, 119.55, 119.55,
121.42, 122.46, 125.64, 128.47, 129.48, 132.90, 136.41, 140.70, 176.94,
177.17, 177.56, 177.99; MS (ESI): m/z: 777.3 [MþNaþ]; HRMS (ESI):
m/z calcd for C41H55ClN2O9þNaþ: 777.3488 [MþNaþ]; found:
777.3491.
4.3.3. N-[Indol-3-yl-(2-chlorophenyl)methyl]-(2,3,4,6-tetra-O-piv-
aloyl-
NMR (400 MHz, CDCl3):
b-D
-galactosyl)amine (5c). White solid, mp 123e124 ꢁC; 1H
4.2. General procedure for the preparation of O-pivaloylated
N-galactosylimines 3
d
¼1.11 (s, 9H, C(CH3)3), 1.19 (s, 9H, C(CH3)3),
1.24 (s, 9H, C(CH3)3),1.26 (s, 9H, C(CH3)3), 2.54 (d, 3J1,NH¼12.9 Hz,1H,
1-H), 3.91 (t, 3J5,6¼6.8 Hz,1H, 5-H), 3.97e4.03 (m,1H,1-H), 4.06 (dd,
3
2
To a solution of 2,3,4,6-tetra-O-pivaloyl-
b
-D
-galactopyranosyl
2J6a,6b¼11.1 Hz, J5,6a¼6.8 Hz, 1H, 6a-H), 4.26 (dd, J6a,6b¼11.1 Hz,
amine 1 (0.515 g, 1 mmol) and aldehyde 2 (1.3 mmol) in 2-propanol
(2.5 mL), 2e3 drops of acetic acid were added and the mixture was
stirred at room temperature for about 0.5 h. The appearance of
a precipitate from the solution indicated the formation of 3, after
the precipitate was filtered off, then washed with ice cold 2-
propanol and dried in vacuum, N-galactosylaldimines 3 were iso-
lated as a white solid.
3J5,6b¼6.8 Hz, 1H, 6b-H), 5.03e5.15 (m, 2H, 2-H, 3-H), 5.41 (s, 1H, 4-
H), 6.19 (s, 1H, CeH), 6.86 (d, 3J2 ,indoleeNH¼2.1 Hz, 1H, 20-H), 7.08 (t,
0
J¼7.3 Hz, 1H, Ph), 7.16e7.21(m, 3H, Ph), 7.29e7.35 (m, 2H, Ph),
7.75e7.83 (m, 2H, Ph), 8.06 (s, 1H, indole NeH); 13C NMR (101 MHz,
CDCl3):
d
¼27.14, 27.18, 27.23, 27.41, 38.77, 38.91, 39.11, 50.07, 61.77,
67.46, 69.12, 71.70, 71.72, 86.78, 111.16, 118.45, 119.58, 119.69, 122.17,
122.36,125.92,126.63,128.26,129.49,129.76,134.04,136.40,139.87,
176.98, 177.28, 177.48, 178.12; MS (ESI): m/z: 777.4 [MþNaþ]; HRMS
(ESI): m/z calcd for C41H55ClN2O9þNaþ: 777.3488 [MþNaþ]; found:
777.3481.
4.3. General procedure for the synthesis of
b-N-glycosidic
linkages (3-indolyl)methanamine derivatives 5
A
solution of N-galactosylaldimines
3
(0.156 mmol), TBAI
4.3.4. N-[Indol-3-yl-(3-chlorophenyl)methyl]-(2,3,4,6-tetra-O-piv-
(1.2 mg, 0.003 mmol) and indole (0.468 mmol) in DCM (3 mL) was
cooled to ꢀ50 ꢁC, and SnCl4 (0.0018 mL, 0.0156 mmol) was added.
The mixture was stirred for 8 h at this temperature. The mixture
was hydrolyzed with aqueous saturated solution of NaHCO3 (5 mL)
and the mixture was stirred at room temperature for 5 min. The
aqueous phase was extracted with CH2Cl2 (3ꢂ5 mL), and the or-
ganic layers were dried with anhydrous Na2SO4, filtered and con-
centrated in vacuo to yield the crude products 5, which were
purified by flash column chromatography on silica gel [petroleum
ether/ethyl acetate, 6:1(v/v)] to provide pure products 5.
aloyl-
NMR (400 MHz, CDCl3):
b-D
-galactosyl)amine (5d). White solid, mp 87e89 ꢁC; 1H
d
¼1.11 (s, 9H, C(CH3)3), 1.24 (s, 9H,
C(CH3)3), 1.26 (s, 18H, 2C(CH3)3), 2.53 (br., 1H, NeH), 3.85 (t,
3J5,6¼6.6 Hz, 1H, 5-H), 3.94e4.02 (m, 1H, 1-H), 4.05 (dd,
3
2
2J6a,6b¼11.2 Hz, J5,6a¼6.6 Hz, 1H, 6a-H), 4.23 (dd, J6a,6b¼11.2 Hz,
3J5,6b¼6.6 Hz, 1H, 6b-H), 5.06e5.19 (m, 2H, 2-H, 3-H), 5.40 (d,
3J3,4¼1.4 Hz, 1H, 4-H), 5.67 (s, 1H, CeH), 6.95 (s, 1H, 20-H), 7.08 (t,
J¼7.1 Hz,1H, Ph), 7.17 (d, J¼7.7 Hz,1H, Ph), 7.22 (d, J¼4.9 Hz, 2H, Ph),
7.34 (d, J¼7.8 Hz, 2H, Ph), 7.50 (s, 1H, Ph), 7.66 (d, J¼7.9 Hz, 1H, Ph),
8.02 (s, 1H, indole NeH); 13C NMR (101 MHz, CDCl3):
d
¼27.11, 27.19,
27.41, 38.74, 38.78, 38.91, 39.08, 53.53, 61.89, 67.44, 68.96, 71.53,
71.72, 86.33, 111.23, 119.08, 119.33, 119.75, 121.61, 122.46, 125.64,
126.38, 127.49, 127.93, 129.51, 134.37, 136.38, 144.52, 176.96, 177.21,
177.65, 178.01; MS (ESI): m/z: 777.3 [MþNaþ]; HRMS (ESI): m/z
calcd for C41H55ClN2O9þNaþ: 777.3488 [MþNaþ]; found: 777.3486.
4.3.1. N-[Indol-3-yl-(4-nitrophenyl)methyl]-(2,3,4,6-tetra-O-piv-
aloyl-
NMR (400 MHz, CDCl3):
b-D
-galactosyl)amine (5a). White solid, mp 197e198 ꢁC; 1H
d¼1.11 (s, 9H, C(CH3)3), 1.23 (s, 9H,
C(CH3)3), 1.26 (s, 9H, C(CH3)3), 1.27 (s, 9H, C(CH3)3), 2.65 (d,
3J1,NH¼13.2 Hz, 1H, NeH), 3.85 (t, J5,6¼6.8 Hz, 1H, 5-H), 3.94e4.01
3
(m, 1H, 1-H), 4.05 (dd, 2J6a,6b¼11.1 Hz, 3J5,6a¼6.8 Hz, 1H, 6a-H), 4.25
(dd, 2J6a,6b¼11.1 Hz, 3J5,6b¼6.8 Hz, 1H, 6b-H), 5.07e5.17 (m, 2H, 2-H,
4.3.5. N-[Indol-3-yl-(4-bromophenyl)methyl]-(2,3,4,6-tetra-O-piv-
aloyl-
NMR (400 MHz, CDCl3):
b-D
-galactosyl)amine (5e). White solid, mp 187e188 ꢁC; 1H
3
3-H), 5.41 (d, J3,4¼2.5 Hz, 1H, 4-H), 5.80 (s, 1H, CeH), 6.92 (d,
d
¼1.11 (s, 9H, C(CH3)3), 1.23 (s, 9H,
3
¼2.3 Hz, 1H, 20-H), 7.09 (t, J¼7.5 Hz, 1H, Ph), 7.20 (t,
C(CH3)3), 1.24 (s, 9H, C(CH3)3), 1.26 (s, 9H, C(CH3)3), 2.56 (br, 1H,
0
J2 ,
indoleeNH
3
J¼7.6 Hz, 1H, Ph), 7.35 (d, J¼8.2 Hz, 1H, Ph), 7.66 (t, J¼8.9 Hz, 3H,
NeH), 3.83 (t, J5,6¼6.6 Hz, 1H, 5-H), 3.93e4.00 (br, 1H, 1-H), 4.04
Ph), 8.13 (s, 1H, indole NeH), 8.17 (d, J¼8.6 Hz, 2H, Ph). 13C NMR
(dd, 2J6a,6b¼11.2 Hz, 3J5,6a¼6.6 Hz, 1H, 6a-H), 4.23 (dd,
3
(101 MHz, CDCl3):
d
¼26.08, 26.14, 26.17, 26.37, 37.78, 37.92, 38.08,
2J6a,6b¼11.2 Hz, J5,6b¼6.6 Hz, 1H, 6b-H), 5.03e5.17 (m, 2H, 2-H, 3-
3
52.53, 60.73, 66.28, 68.03, 70.45, 70.78, 85.43, 110.41, 117.30, 117.86,
118.90, 120.83, 121.65, 122.65, 124.38, 127.68, 135.42, 146.17, 149.18,
175.94, 176.23, 176.55, 177.01; MS (ESI): m/z: 788.4 [MþNaþ]; HRMS
H), 5.40 (d, J3,4¼1.9 Hz, 1H, 4-H), 5.65 (s, 1H, CeH), 6.94 (d,
3J2,indoleeNH¼2.1 Hz, 1H, 20-H), 7.06 (t, J¼7.5 Hz, 1H, Ph), 7.17 (t,
J¼7.6 Hz, 1H, Ph), 7.32 (s, 1H, Ph), 7.34 (d, J¼2.1 Hz, 1H, Ph), 7.37 (s,

H. Yang et al. / Tetrahedron 68 (2012) 4830e4837
4835
1H, Ph), 7.42 (d, J¼8.3 Hz, 2H, Ph), 7.62 (d, J¼7.8 Hz, 1H, Ph), 8.01(s,
1H, indole NeH); 13C NMR (101 MHz, CDCl3):
NMR (400 MHz, CDCl3):
d
¼1.03 (s, 9H, C(CH3)3), 1.16 (s, 9H,
d¼27.13, 27.20, 27.22,
C(CH3)3), 1.18 (s, 18H, 2ꢂC(CH3)3), 2.21 (s, 3H, CH3), 2.45 (d,
27.39, 38.75, 38.80, 38.91, 39.10, 53.50, 61.89, 67.45, 69.06, 71.53,
71.70, 86.32, 111.25, 119.09, 119.40, 119.71, 121.03, 121.50, 122.45,
125.64, 129.88, 131.43, 136.46, 141.31, 176.97, 177.20, 177.59, 178.01;
MS (ESI): m/z: 821.2 [MþNaþ]; HRMS (ESI): m/z calcd for
C41H55BrN2O9þNaþ 821.2983 [MþNaþ]; found: 821.2990.
3J1,NH¼12.7 Hz, 1H, NeH), 3.75 (t, 3J5,6¼6.5 Hz, 1H, 5-H), 3.90e4.01
2
3
(m, 2H, 1-H, 6a-H), 4.16 (dd, J6a,6b¼10.9 Hz, J5,6b¼6.5 Hz, 1H, 6b-
H), 4.97e5.09 (m, 2H, 2-H, 3-H), 5.31 (s, 1H, 4-H), 5.58 (s, 1H, CeH),
6.86 (s,1H, 20-H), 6.97 (t, J¼7.2 Hz, 2H, Ph), 7.05 (d, J¼7.6 Hz,1H, Ph),
7.10 (t, J¼7.7 Hz, 1H, Ph), 7.17e7.25 (m, 3H, Ph), 7.59 (d, J¼7.8 Hz, 1H,
Ph), 8.06 (s, 1H, indole NeH); 13C NMR (101 MHz, CDCl3):
d
¼20.41,
4.3.6. N-[Indol-3-yl-(2-bromophenyl)methyl]-(2,3,4,6-tetra-O-piv-
26.03, 26.09, 26.17, 26.36, 37.71, 37.75, 37.86, 38.06, 52.99, 60.96,
66.54, 68.04, 70.58, 85.34, 110.12, 118.20, 118.44, 118.93, 120.44,
121.13, 124.33, 124.81, 127.02, 127.67, 135.39, 136.74, 141.10, 175.99,
176.21, 176.59, 177.01; MS (ESI): m/z: 757.4 [MþNaþ]; HRMS (ESI):
m/z calcd for C42H58N2O9þNaþ: 757.4035 [MþNaþ]; found:
757.4028.
aloyl-
NMR (400 MHz, CDCl3):
b-D
-galactosyl)amine (5f). White solid, mp 126e128 ꢁC; 1H
d
¼1.11 (s, 9H, C(CH3)3), 1.19 (s, 9H, C(CH3)3),
3
1.23 (s, 9H, C(CH3)3), 1.26 (s, 9H, C(CH3)3), 2.56 (d, J1,NH¼12.4 Hz,
3
1H, NeH), 3.94 (t, J5,6¼6.8 Hz, 1H, 5-H), 3.97e4.03 (m, 1H, 1-H),
2
3
4.07 (dd, J6a,6b¼10.9 Hz, J5,6b¼6.8 Hz, 1H, 6b-H), 4.28 (dd,
3
2J6a,6b¼10.9 Hz, J5,6a¼6.8 Hz, 1H, 6a-H), 5.00e5.18 (m, 2H, 2-H, 3-
3
H), 5.42 (s, 1H, 4-H), 6.14 (s, 1H, CeH), 6.87 (d, J2,indo-
4.3.10. N-[Indol-3-yl-(4-methylphenyl)methyl]-(2,3,4,6-tetra-O-piv-
¼1.9 Hz, 1H, 20-H), 7.09 (dd, J¼14.2 Hz, 6.8 Hz, 2H, Ph), 7.17 (t,
aloyl-
NMR (400 MHz, CDCl3):
b-D
-galactosyl)amine (5j). White solid, mp 115e117 ꢁC; 1H
leeNH
J¼7.5 Hz, 1H, Ph), 7.23 (d, J¼7.5 Hz, 1H), 7.32 (d, J¼8.1 Hz, 1H, Ph),
7.53 (d, J¼7.8 Hz,1H, Ph), 7.75 (d, J¼6.6 Hz,1H, Ph), 7.83 (d, J¼7.9 Hz,
1H, Ph), 8.07 (s, 1H, indole NeH); 13C NMR (101 MHz, CDCl3):
d
¼1.14 (s, 9H, C(CH3)3), 1.28 (s, 9H,
C(CH3)3), 1.29 (2s, 18H, 2ꢂC(CH3)3), 2.36 (s, 3H, CH3), 2.57 (d,
3J1,NH¼12.9 Hz, 1H, NeH), 3.85 (t, 3J5,6¼6.7 Hz, 1H, 5-H), 3.98e4.05
(m, 1H, 1-H), 4.08 (dd, 2J6a,6b¼11.2 Hz, 3J5,6a¼6.7 Hz, 1H, 6a-H), 4.26
(dd, 2J6a,6b¼11.2 Hz, 3J5,6b¼6.7 Hz, 1H, 6b-H), 5.08e5.20 (m, 2H, 2-H,
3-H), 5.42 (d, 3J3,4¼2.3 Hz,1H, 4-H), 5.69 (s, 1H, CeH), 7.00 (s, 1H, 20-
H), 7.07 (t, J¼7.5 Hz, 1H, Ph), 7.13 (d, J¼7.8 Hz, 2H, Ph), 7.17 (t,
J¼7.4 Hz, 1H, Ph), 7.33 (d, J¼8.1 Hz, 1H, Ph), 7.39 (d, J¼7.8 Hz, 2H,
Ph), 7.67 (d, J¼7.9 Hz, 1H, Ph), 8.11 (s, 1H, indole NeH); 13C NMR
d
¼26.11, 26.17, 26.19, 26.37, 37.74, 37.86, 38.07, 51.82, 60.59, 66.36,
68.08, 70.63, 70.65, 85.72, 110.09, 117.65, 118.68, 118.72, 121.11,
121.37, 123.45, 124.93, 126.23, 127.62, 129.12, 131.75, 135.37, 140.45,
175.89, 176.21, 176.43, 177.04; MS (ESI): m/z: 821.3 [MþNaþ]; HRMS
(ESI): m/z calcd for C41H55BrN2O9þNaþ: 821.2983 [MþNaþ]; found:
821.2986.
(101 MHz, CDCl3):
d
¼21.15, 27.14, 27.23, 27.41, 38.76, 38.81, 38.92,
4.3.7. N-[Indol-3-yl-(2-fluorophenyl)methyl]-(2,3,4,6-tetra-O-piv-
39.11, 53.81, 62.01, 67.57, 69.06, 71.59, 86.33, 111.13, 119.26, 119.50,
120.14, 121.31, 122.20, 125.85, 128.14, 128.98, 136.45, 136.83, 139.05,
177.04, 177.25, 177.68, 178.07; MS (ESI): m/z: 757.4 [MþNaþ]; HRMS
(ESI): m/z calcd for C42H58N2O9þNaþ: 757.4035 [MþNaþ]; found:
757.4028.
aloyl-
NMR (400 MHz, CDCl3):
b-D
-galactosyl)amine (5g). White solid, mp 112e114 ꢁC; 1H
d
¼1.14 (s, 9H, C(CH3)3), 1.24 (s, 9H,
C(CH3)3), 1.27 (s, 9H, C(CH3)3), 1.29 (s, 9H, C(CH3)3), 2.55 (d,
3J1,NH¼12.8 Hz, 1H, NeH), 3.91 (t, J5,6¼6.6 Hz, 1H, 5-H), 4.01e4.15
3
2
3
(m, 2H, 1-H, 6a-H), 4.25 (dd, J6a,6b¼11.1 Hz, J5,6b¼6.6 Hz, 1H, 6b-
H), 4.99e5.09 (m, 2H, 2-H, 3-H), 5.43 (s, 1H, 4-H), 6.11 (s, 1H, CeH),
7.01 (s, 1H, 20-H), 7.04 (d, J¼9.7 Hz, 1H, Ph), 7.10 (t, J¼7.4 Hz, 2H, Ph),
7.16e7.27 (m, 2H, Ph), 7.35 (d, J¼8.1 Hz,1H, Ph), 7.69 (t, J¼6.9 Hz,1H,
Ph), 7.77 (d, J¼7.9 Hz, 1H, Ph), 8.06 (s, 1H, indole NeH); 13C NMR
4.3.11. N-[Indol-3-yl-(2-methoxy-3-nitrophenyl)methyl]-(2,3,4,6-
tetra-O-pivaloyl-
b-D-galactosyl)amine (5k). White solid, mp
113e115 ꢁC; 1H NMR (400 MHz, CDCl3):
d¼1.10 (s, 9H, C(CH3)3), 1.20
(s, 9H, C(CH3)3), 1.22 (s, 9H, C(CH3)3), 1.24 (s, 9H, C(CH3)3), 2.64 (d,
3J1,NH¼13.0 Hz, 1H, NeH), 3.89 (s, 3H, OCH3), 3.98 (dd,
3J1,NH¼13.0 Hz, 3J1,2¼8.6 Hz, 1H, 1-H), 4.01e4.08 (m, 2H, 5-H, 6a-H),
4.25 (dd, 2J6a,6b¼14.2 Hz, 3J5,6b¼9.6 Hz,1H, 6b-H), 5.04e5.16 (m, 2H,
(101 MHz, CDCl3):
d
¼26.08, 26.18, 26.34, 28.67, 37.72, 37.87, 38.06,
45.40, 60.86, 66.49, 68.05, 70.62, 70.77, 85.62, 110.09, 114.33 (d,
2JC,F¼22.0 Hz), 117.62, 118.62, 120.81, 121.30, 122.86 (d, 4JC,F¼3.1 Hz),
124.74,127.52 (d, 3JC,F¼8.0 Hz),128.35,128.22,128.39,135.33,160.07
3
2-H, 3-H), 5.42 (d, J3,4¼2.9 Hz, 1H, 4-H), 5.69 (s, 1H, CeH),
1
(d, JC,F¼247.2 Hz), 175.97, 176.22, 176.49, 177.10; MS (ESI): m/z:
6.86e6.92 (m, 1H, 20-H), 7.08 (t, J¼7.4 Hz, 2H, Ph), 7.17 (t, J¼7.5 Hz,
1H, Ph), 7.28e7.34 (m, 3H, Ph), 7.77 (d, J¼8.0 Hz, 1H, Ph), 8.15 (s, 1H,
761.4 [MþNaþ]; HRMS (ESI): m/z calcd for C41H55FN2O9þNaþ:
761.3784 [MþNaþ]; found: 761.3778.
indole NeH); 13C NMR (101 MHz, CDCl3):
d
¼27.14, 27.20, 27.38,
38.74, 38.86, 39.06, 48.97, 56.36, 61.05, 67.15, 68.97, 71.49, 71.53,
86.26, 110.90, 111.13, 117.53, 119.94, 121.34, 121.86, 122.54, 125.42,
130.42, 135.49, 136.36, 142.15, 150.00, 176.86, 177.19, 177.52, 177.95;
MS (ESI): m/z: 818.4 [MþNaþ]; HRMS (ESI): calcd for
C42H57N3O12þNaþ: 818.3834 [MþNaþ]; found: 818.3839.
4.3.8. N-[Indol-3-yl-(4-fluorophenyl)methyl]-(2,3,4,6-tetra-O-piv-
aloyl-b-D
-galactosyl)amine (5h). White solid, mp 114e116 ꢁC; 1H
NMR (400 MHz, CDCl3):
d
¼1.10 (s, 9H, C(CH3)3), 1.24 (s, 18H,
2ꢂC(CH3)3), 1.26 (s, 9H, C(CH3)3), 2.58 (d, 3J1,NH¼13.1 Hz, 1H, NeH),
3
3.83 (t, J5,6¼6.8 Hz, 1H, 5-H), 3.93e4.00 (m, 1H, 1-H), 4.04 (dd,
3
2
2J6a,6b¼11.2 Hz, J5,6a¼6.8 Hz, 1H, 6a-H), 4.23 (dd, J6a,6b¼11.2 Hz,
3J5,6b¼6.8 Hz, 1H, 6b-H), 5.01e5.13 (m, 2H, 2-H, 3-H), 5.40 (d,
3J3,4¼2.1 Hz, 1H, 4-H), 5.67 (s, 1H, CeH), 6.96 (s, 1H, 20-H), 6.99 (d,
J¼8.6 Hz, 2H, Ph), 7.06 (t, J¼7.5 Hz, 1H, Ph), 7.17 (t, J¼7.2 Hz, 1H, Ph),
7.34 (d, J¼8.2 Hz, 1H, Ph), 7.42 (d, J¼5.5 Hz, 1H, Ph), 7.44 (d,
J¼5.5 Hz, 1H, Ph), 7.61 (d, J¼7.9 Hz, 1H, Ph), 8.00 (s, 1H, indole
4.3.12. N-[5-Methoxy-indol-3-yl-(4-chlorophenyl)methyl]-(2,3,4,6-
tetra-O-pivaloyl-
b
-
D
-galactosyl)amine
(5l). White
solid,
mp
123e124 ꢁC; 1H NMR (400 MHz, CDCl3):
d
¼1.03 (s, 9H, C(CH3)3),
1.16 (s,18H, 2ꢂC(CH3)3),1.18 (s, 9H, C(CH3)3), 2.47 (d, 3J1,NH¼13.0 Hz,
1H, NeH), 3.74 (s, 3H, OCH3), 3.79 (t, 3J5,6¼6.7 Hz,1H, 5-H), 3.91 (dd,
3
2
3J1,NH¼13.0 Hz, J1,2¼7.6 Hz, 1H, 1-H), 3.98 (dd, J6a,6b¼11.0 Hz,
NeH); 13C NMR (101 MHz, CDCl3):
d
¼27.13, 27.20, 27.22, 27.37,
3J5,6a¼6.7 Hz, 1H, 6a-H), 4.16 (dd, J6a,6b¼11.0 Hz, J5,6b¼6.7 Hz, 1H,
6b-H), 4.98e5.08 (m, 2H, 2-H, 3-H), 5.33 (s, 1H, 4-H), 5.54 (s, 1H,
CeH), 6.52e6.78 (m, 2H, Ph, 20-H), 7.00 (d, J¼1.8 Hz, 1H, Ph), 7.14 (d,
J¼8.8 Hz, 1H, Ph), 7.16e7.24 (m, 2H, Ph), 7.34 (d, J¼8.3 Hz, 2H, Ph),
2
3
38.75, 38.80, 38.89, 39.10, 53.39, 61.90, 67.45, 69.03, 71.53, 71.67,
2
86.28, 111.21, 115.12 (d, JC,F¼21.4 Hz), 119.14, 119.67, 119.83, 121.37,
3
122.41, 125.70, 129.66 (d, JC,F¼8.0 Hz), 136.46, 137.81 (d,
4JC,F¼2.9 Hz), 162.04 (d, JC,F¼245.4 Hz), 176.96, 177.20, 177.59,
7.91 (s, 1H, indole NeH); 13C NMR (101 MHz, CDCl3):
d¼26.10, 26.17,
1
178.01; MS (ESI): m/z: 761.3 [MþNaþ]; HRMS (ESI): m/z calcd for
C41H55FN2O9þNaþ: 761.3784 [MþNaþ]; found: 761.3790.
26.35, 37.72, 37.76, 37.86, 38.05, 52.31, 54.74, 60.84, 66.42, 67.94,
70.54, 70.72, 85.56, 99.67, 110.95, 111.66, 118.11, 121.44, 125.11,
127.43, 128.47, 130.51, 131.91, 139.69, 153.13, 175.90, 176.15, 176.51,
176.94; MS (ESI): m/z: 807.4 [MþNaþ]; HRMS (ESI): calcd for
C42H57ClN2O10þNaþ: 807.3594 [MþNaþ]; found: 807.3587.
4.3.9. N-[Indol-3-yl-(3-methylphenyl)methyl]-(2,3,4,6-tetra-O-piv-
aloyl-b-D
-galactosyl)amine (5i). White solid, mp 114e116 ꢁC; 1H

4836
H. Yang et al. / Tetrahedron 68 (2012) 4830e4837
4.3.13. N-[5-Bromo-indol-3-yl-(4-chlorophenyl)methyl]-(2,3,4,6-
tetra-O-pivaloyl- -galactosyl)amine (5m). White solid, mp
122.50, 123.41, 125.87, 126.93, 127.34, 128.10, 128.50, 136.55, 136.76,
141.69, 155.81.
b-D
112e114 ꢁC; 1H NMR (400 MHz, CDCl3):
d
¼1.11 (s, 9H, C(CH3)3), 1.24
(s, 18H, 2ꢂC(CH3)3), 1.27 (s, 9H, C(CH3)3), 2.50 (d, 3J1,NH¼13.0 Hz, 1H,
Acknowledgements
3
NeH), 3.86 (t, J5,6¼6.7 Hz, 1H, 5-H), 3.94e4.03 (m, 1H, 1-H), 4.10
(dd, 2J6a,6b¼11.1 Hz, 3J5,6a¼6.7 Hz, 1H, 6a-H), 4.25 (dd,
We thank the National Natural Science Foundation of China
(21072102), the Committee of Science and Technology of Tianjin
(11JCYBJC04200) and State Key Laboratory of Elemento-Organic
Chemistry in Nankai University for financial support. We also
thank the anonymous reviewers’ helpful suggestions improving
our manuscript.
2J6a,6b¼11.1 Hz, J5,6b¼6.7 Hz, 1H, 6b-H), 5.00e5.18 (m, 2H, 2-H,
3
3-H), 5.41 (s, 1H, 4-H), 5.59 (s, 1H, CeH), 6.88 (s, 1H, 20-H), 7.21 (t,
J¼7.8 Hz, 1H, Ph), 7.24e7.29 (m, 3H, Ph), 7.40 (d, J¼8.3 Hz, 2H, Ph),
7.83 (s,1H, Ph), 8.13 (s,1H, indole NeH); 13C NMR (101 MHz, CDCl3):
d
¼27.12, 27.20, 27.26, 27.39, 38.75, 38.80, 38.91, 39.11, 53.29, 61.88,
67.37, 69.01, 71.50, 71.78, 86.44, 112.66, 113.09, 119.13, 121.85,
122.90, 125.39, 127.41, 128.57, 129.36, 133.09, 135.08, 140.41, 176.98,
177.17, 177.60, 177.97; MS (ESI): m/z: 855.3 [MþNaþ]; HRMS (ESI):
calcd for C41H54BrClN2O9þNaþ: 855.2593 [MþNaþ]; found:
855.2591.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2012.03.115.
4.4. General procedure for the synthesis of (S)-(4-
fluorophenyl)(1H-indol-3-yl)methanamine 8h
References and notes
1. (a) Joule, J. A. Indole and its Derivatives In. Science of Synthesis (Houben-Weyl
Methods of Molecular Transformations); Thomas, E. J., Ed.; Thieme: Stuttgart,
2000; Vol. 10, Chapter 10.13; (b) Bandini, M.; Melloni, A.; Piccinelli, F. In
Handbooks of CeH Bonds Transformations; Dyker, G., Ed.; Wiley-VCH: Wein-
heim, 2005; Vol. 1, pp 150e157; (c) Jorgensen, K. A. Synthesis 2003, 1117e1125;
(d) Poulsen, T. B.; Jorgensen, K. A. Chem. Rev. 2008, 108, 2903e2915; (e) Sheng,
Y.-F.; Zhang, A.-J.; Zheng, X.-J.; You, S.-L. Chin. J. Org. Chem. 2008, 28, 605e616.
2. (a) Sundberg, R. J. The Chemistry of Indoles; Academic: New York, NY, 1996; p
113; (b) Aygun, A.; Pindur, U. Curr. Med. Chem. 2003, 10, 1113e1127; (c) Somei,
M.; Yamada, F. Nat. Prod. Rep. 2005, 22, 73e103; (d) Galliford, C. V.; Scheidt, K. A.
Angew. Chem., Int. Ed. 2007, 46, 8748e8758; (e) Marti, C.; Carreira, E. M. Eur. J.
Org. Chem. 2003, 2209e2219; (f) Lin, H.; Danishefsky, S. J. Angew. Chem., Int. Ed.
2003, 42, 36e51; (g) Jensen, B. S. CNS Drug Rev. 2002, 8, 353e360; (h) da Silva,
J. F. M.; Garden, S. J.; Pinto, A. C. J. Braz. Chem. Soc. 2001, 12, 273e324; (i) Bovens,
S.; Elfringhoff, A. S.; Kaptur, M.; Reinhardt, D.; Schafers, M.; Lehr, M. J. Med.
Chem. 2010, 53, 8298e8308.
3. For recent reviews of asymmetric functionalization of indoles, see: (a) Bartoli,
G.; Bencivenni, G.; Dalpozzo, R. Chem. Soc. Rev. 2010, 39, 4449e4465; (b)
Bandini, M.; Eichholzer, A. Angew. Chem., Int. Ed. 2009, 48, 9608e9644; (c)
Barluenga, J.; Rodriguez, F.; Fananas, F. J. Chem.-Asian J. 2009, 4, 1036e1048; (d)
Kruger, K.; Tillack, A.; Beller, M. Adv. Synth. Catal. 2008, 350, 2153e2167; (e)
Metwally, M. A.; Shaaban, S.; Abdel-Wahab, B. F.; El-Hiti, G. A. Curr. Org. Chem.
2009, 13, 1475e1496.
A solution of compound 5h (295 mg, 0.4 mmol) in dry methanol
(2 mL) was treated with freshly prepared (0.5 M) solution of so-
dium methoxide (2 mL). The reaction mixture was stirred for 4 h
(TLC control). Then a few drops of water were added to the mixture,
and the mixture was neutralized with acetic acid. The mixture was
stirred at room temperature for another 4 h. The mixture was
extracted with EtOAc (3ꢂ5 mL) and the organic phase was washed
with saturated aqueous NaHCO3 (3ꢂ5 mL), dried over MgSO4, fil-
tered, and concentrated in vacuo to yield the crude product 8h. The
residue was purified by column chromatography on silica gel
[CH2Cl2/MeOH¼30:1, with 0.1% Et3N], yielding the corresponding
compound 8h (93 mg, 97% yield) as a white solid.
4.4.1. Compound 8h. White solid, yield 97%; mp 108e110 ꢁC; 1H
NMR (400 MHz, CDCl3)
d
¼5.92 (s, 1H, CeH), 6.94 (m, 3H, Ph),
6.99e7.05 (m, 1H, Ph), 7.13 (t, J¼7.1 Hz, 1H, Ph), 7.27 (d, J¼7.8 Hz, 1H,
Ph), 7.31e7.46 (m, 3H, Ph), 8.45 (s, 1H, indole NeH); 13C NMR
4. For recent reviews of catalytic asymmetric FriedeleCrafts reactions, see: (a)
Bandini, M.; Melloni, A.; Umani-Ronchi, A. Angew. Chem., Int. Ed. 2004, 43,
550e556; (b) Jørgensen, K. A. Synthesis 2003, 1117e1125; (c) Bandini, M.;
Umani-Ronchi, A. Catalytic Asymmetric FriedeleCrafts Alkylations; Wiley-WCH
Verlag GmbH & Co.: KGaA, Weinheim, 2009.
(101 MHz, CDCl3)
d
¼53.15, 111.18, 119.48, 119.59, 121.66, 122.15,
126.06, 126.97, 128.45, 136.69, 145.68. HRMS (ESI): calcd for
C15H13FN2ꢀHþ: 239.0990 [MꢀH]; found: 239.0995.
5. (a) Kang, Q.; Zhao, Z.-A.; You, S.-L. J. Am. Chem. Soc. 2007, 129, 1484e1485; (b)
Jia, Y.-X.; Xie, J.-H.; Duan, H.-F.; Wang, L.-X.; Zhou, Q.-L. Org. Lett. 2006, 8,
1621e1624.
6. (a) Johannsen, M. Chem. Commun. 1999, 2233e2234; (b) Shirakawa, S.; Berger,
R.; Leighton, J. L. J. Am. Chem. Soc. 2005, 127, 2858e2859; (c) Kang, Q.; Zhao, Z.-
A.; You, S.-L. Tetrahedron 2009, 65, 1603e1607; (d) Wanner, M. J.; Hauwert, P.;
Schoemaker, H. E.; De Gelder, R.; Van Maarseveen, J. H.; Hiemstra, H. Eur. J. Org.
Chem. 2008, 180e185.
4.5. General procedure for the synthesis of (S)-benzyl(4-
fluorophenyl)(1H-indol-3-yl)methylcarbamate 9h for % ee
determination by chiral HPLC
Compound 8h (30 mg, 0.125 mmol) was dissolved in THF (3 mL),
after which water (1.5 mL) was added. The resulting mixture was
vigorously stirred at 0 ꢁC to which was added Na2CO3 (52 mg,
0.5 mmol, 4.0 equiv). The resulting mixture was stirred at 0 ꢁC for
5 min, then benzyl chloroformate (42 mg, 0.25 mmol, 2.0 equiv)
was introduced to this mixture via a syringe. The reaction mixture
was stirred at room temperature for an additional 10 min, and then
diluted with EtOAc (10 mL). The organic layer was collected,
washed with brine and dried over Na2SO4. After removal of the
solvent, the residue was subjected to flash chromatography on
silica gel [petroleum ether/ethyl acetate, 5:1 to 3:1 (v/v)] to give
compound 9h (46 mg, 99% yield) as a pale pink oil.
7. Janczuk, A.; Zhang, W.; Xie, W. H.; Lou, S. Z.; Cheng, J.-P.; Wang, P. G. Tetrahedron
Lett. 2002, 43, 4271e4274.
8. (a) Jiang, B.; Yang, C.-G.; Gu, X.-H. Tetrahedron Lett. 2001, 42, 2545e2547; (b)
Lei, F.; Chen, Y.-J.; Sui, Y.; Liu, L.; Wang, D. Synlett 2003, 1160e1164; (c) Jiang, B.;
€ €
Huang, Z.-G. Synthesis 2005, 2198e2204; (d) Abid, M.; Teixeira, L.; Torok, B. Org.
Lett. 2008, 10, 933e935; (e) Andreassen, T.; Hansen, L.-K.; Gautun, O. R. Eur. J.
Org. Chem. 2008, 4871e4876; (f) Li, B.-Y.; Li, Z.-J.; Meng, X.-B. Carbohydr. Res.
2010, 345, 1708e1712.
9. Zhang, G.-W.; Wang, L.; Nie, J.; Ma, J.-A. Adv. Synth. Catal. 2008, 350, 1457e1463.
€
10. Levy, D. E.; Fugedi, P. The Organic Chemistry of Sugars; Taylor and Francis: Boca
Raton, FL, 2006, Chapter 11e16, pp 490e845.
11. (a) Katritzky, R.; Narindoshvili, T.; Draghici, B.; Angrish, P. J. Org. Chem. 2008, 73,
511e516; (b) Knauer, S.; Kranke, B.; Krause, L.; Kunz, H. Curr. Org. Chem. 2004, 8,
1739e1761.
12. (a) Weymann, M.; Scultz-Kukula, M.; Kunz, H. Tetrahedron Lett. 1998, 39,
7835e7838; (b) Zhou, G.; Zheng, W.; Wang, D.; Zhang, P.; Pan, Y. Helv. Chim.
Acta 2006, 89, 520e526; (c) Kunz, H.; Burgard, A.; Schanzenbach, D. Angew.
Chem., Int. Ed. 1997, 36, 386e387.
13. Kunz, H.; Sager, W. Angew. Chem., Int. Ed. Engl. 1987, 26, 557e559.
14. (a) Kunz, H.; Pfrengle, W. J. Am. Chem. Soc. 1988, 110, 651e652; (b) Kunz, H.;
Pfrengle, W. Tetrahedron 1988, 44, 5487e5494.
15. Kunz, H.; Schanzenbach, D. Angew. Chem., Int. Ed. Engl. 1989, 28, 1068e1069.
16. Pfrengle, W.; Kunz, H. Angew. Chem., Int. Ed. Engl. 1989, 28, 1067e1068; (a)
Pfrengle, W.; Kunz, H. J. Org. Chem. 1989, 54, 4261e4263.
4.5.1. Compound 9h. Pink oil, yield 99%; 1H NMR (400 MHz, CDCl3)
d
¼5.03 (d, 2JH,H¼12.3 Hz, 2H, CH2), 5.41 (d, 3JNH,H¼6.9 Hz, 1H, CeH),
3
6.17 (d, JNH,H¼6.9 Hz, 1H, NeH), 6.56 (s, 1H, indole-2-H), 6.96 (t,
J¼7.4 Hz, 1H, Ph), 7.08 (t, J¼7.5 Hz, 1H, Ph), 7. 15e7.31 (m, 10H, Ph),
7.36 (d, J¼7.9 Hz, 1H, Ph), 8.11 (s, 1H, indole NeH); 13C NMR
(101 MHz, CDCl3)
d¼52.42, 66.91, 111.43, 117.32, 119.39, 119.91,

H. Yang et al. / Tetrahedron 68 (2012) 4830e4837
4837
17. Wang, Y.-D.; Wang, Y.-Y.; Yu, J.-P.; Miao, Z.-W.; Chen, R.-Y. Chem.dEur. J. 2009,
2H, 2-H, 3-H), 5.32 (s, 1H, 4-H), 5.59 (s, 1H, CeH), 6.66 (s, 1H, 20-H), 6.99 (t, J¼7.
3 Hz, 1H, Ph), 7.13 (t, J¼7.4 Hz, 1H, Ph), 7.19 (dd, J¼8.1, 3.8 Hz, 3H, Ph), 7.35 (d,
15, 9290e9293.
18. Kunz, H.; Sager, W.; Schanzenbach, D.; Decker, M. Liebigs Ann. Chem. 1991,
649e654.
J¼8.2 Hz, 2H, Ph), 7.57 (d, J¼7.9 Hz, 1H, Ph); 13C NMR (101 MHz, CDCl3):
¼26.
d
09, 26.16, 26.35, 31.73, 37.71, 37.75, 37.86, 38.06, 52.27, 60.85, 66.40, 68.01, 70.
54, 70.64, 85.33, 108.33, 116.85, 118.15, 118.18, 120.95, 125.04, 125.34, 127.41,
128.37, 136.13, 131.76, 140.00, 175.90, 176.14, 176.45, 176.94; MS (ESI): m/z: 791.5
[MþNaþ]; HRMS (ESI): calcd for C42H57ClN2O9þNaþ: 791.3645 [MþNaþ];
found: 791.3631
ꢀ
ꢀ
19. Alonso, I.; Esquivias, J.; Gomez-Arrayas, R.; Carretero, J. C. J. Org. Chem. 2008, 73,
6401e6404.
20. When 1-methyl-1H-indole was employed, a drop in the yield (75%) and dia-
stereoselectivity
chlorophenyl)methyl]-(2,3,4,6-tetra-O-pivaloyl-
White solid, mp 172e173 ꢁC; 1H NMR (400 MHz, CDCl3):
(10:1)
was
observed.
N-[1-Methyl-indol-3-yl-(4-
b
-D
-galactosyl)amine
(5n).
21. Crystallographic data for the structural analysis of compound 5a has been
deposited at the Cambridge Crystallographic Data Centre as No. CCDC 787519.
These data can be obtained free of charge by contacting The Cambridge Crys-
tallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax: þ44
1223 336033; e-mail: deposit@ccdc.cam.ac.uk.
d
¼1.03 (s, 9H,
C(CH3)3), 1.16 (s, 9H, C(CH3)3), 1.18 (s, 9H, C(CH3)3), 1.19 (s, 9H, C(CH3)3), 2.46 (d,
3J1,NH¼12.6 Hz, 1H, NeH), 3.62 (s, 3H, NeCH3), 3.77 (t, 3J5,6¼6.7 Hz, 1H, 5-H), 3.
3
3
2
3
92 (dd, J1,NH¼12.6 Hz, J12¼7.9 Hz, 1H, 1-H), 3.97 (dd, J6a,6b¼11.1 Hz, J5,6a¼6.
7 Hz, 1H, 6a-H), 4.16 (dd, 2J6a,6b¼11.1 Hz, 3J5,6b¼6.7 Hz, 1H, 6b-H), 4.94e5.10 (m,
€
22. Kunz, H.; Ruck, K. Angew. Chem., Int. Ed. Engl. 1993, 32, 336e358.