Easy access to fully functionalized chiral tetrahydro-β-carboline alkaloids

Article abstract of DOI:10.1021/jo1025833

A four-step synthetic route to fully substituted chiral tetrahydro-β-carbolines (THBCs) is described. Starting from the (R,S,S)-Friedel-Crafts/Henry adduct obtained from three-component coupling of an indole, nitroalkene, and aldehyde catalyzed by imidazoline-aminophenol-CuOTf, the (1S,3S,4R)-THBCs were readily synthesized in a three-step operation including reduction of the nitro-functionality and Pictet-Spengler cyclization.

Full text of DOI:10.1021/jo1025833

NOTE
pubs.acs.org/joc
Easy Access to Fully Functionalized Chiral Tetrahydro-β-Carboline
Alkaloids
Takayoshi Arai,* Makiko Wasai, and Naota Yokoyama
Department of Chemistry, Graduate School of Science, Chiba University, Inage, Chiba 263-8522, Japan
S Supporting Information
b
ABSTRACT: A four-step synthetic route to fully substituted
chiral tetrahydro-β-carbolines (THBCs) is described. Starting
from the (R,S,S)-FriedelꢀCrafts/Henry adduct obtained from
three-component coupling of an indole, nitroalkene, and
aldehyde catalyzed by imidazoline-aminophenolꢀCuOTf,
the (1S,3S,4R)-THBCs were readily synthesized in a three-
step operation including reduction of the nitro-functionality
and PictetꢀSpengler cyclization.
arboline skeletons are frequently encountered in
β-Cpharmacology due to their significant biological activ-
ity in binding to serotonin receptors in the CNS (central nervous
system). As demonstrated by recerpine (1), the tetrahydro-β-
carbolines (THBCs) show more complex stereochemical diver-
sity, and the complex structures of these molecules has been
strictly linked with their specific biological activities (Figure 1).1
For access to the highly substituted β-carboline framework, tryp-
tophan has been widely utilized as the key precursor. Pictetꢀ
Spengler cyclization of tryptophan-derived substrates can incor-
porate C1 and C3 functionalities into the THBCs.2 However,
obtaining 4-substituted β-carbolines, such as ZK 93423 (2),3
jadiffine (3),4 and neonaucleoside C (4),5 normally requires
elaborate multistep syntheses to introduce substituents at the
C4-position.
Busacca and co-workers reported a Pd-mediated cross-cou-
pling of arylboronic acids and Grignard reagents for the prepara-
tion of 4-aryl-, 4-alkyl-, and 4-acetylcarboline derivatives.6 Bandini
and Umani-Ronchi et al. reported an elegant intramolecular
cyclization to give a variety of 4-functionalized THBCs.7 Roussi
et al. recently reported direct functionalization at the 4-position
of THBCs.8 In Roussi’s methodology, the substituent at position
4 is introduced by nucleophilic attack to an oxidized intermediate
of the THBC. Although these studies represent outstanding
contributions toward obtaining functionalized tetrahydro-β-car-
bolines, a more flexible synthetic approach is still desirable for the
development of diverse β-carbolines.
Aiming toward the synthesis of fully functionalized THBCs,
we prepared a series of FCH adducts, as listed in Scheme 1.
A chiral imidazolineꢀaminophenolꢀCuOTf complex was
able to catalyze the asymmetric FCH reaction of an indole,
nitroalkene, and aldehyde to give the corresponding (R,S,S)-
FCH adducts as the major isomers.10
Reduction of the major isomers (having over 99% ee) of the
(R,S,S)-FCH adducts (1aꢀd) to the corresponding β-amino
alcohols (2aꢀd) was examined (Table 1). Reduction using
nickel boride, which has been widely utilized for the reduction
of nitroaldol adducts, resulted in a mixture of amines 2 with
hydroxyamines 3.11 In contrast, the conventional method using
Zn powder under acidic conditions more readily reduced the
nitro functionality to give the desired β-amino alcohols 2
predominantly while maintaining the diastereo- and enantio-
purities.12 For substrate 1c having an alkyl substituent at the R1
position, in particular, the Zn-nanopowder13 was quite powerful
for the reduction.
With the β-amino alcohols 2 in hand, the PictetꢀSpengler
condensation was examined in the reaction of 2a with benzalde-
hyde. However, in this case, use of the typical acidic conditions
resulted in a inseparable mixture of compounds.2,14 The mix of
products was assumed to result from oxazolidine ring formations
mediated by intramolecular cyclization of the hydroxy group to
the generated imine intermediate. This consideration led us to
perform simple protection of the hydroxy group. After examina-
tion of several protecting groups, triethylsilyl (TES) was selected
as the most appropriate group for further transformation. The
corresponding O-TES derivatives 4aꢀd were easily obtained
using TESCl and imidazole in DMF (see details in the Support-
ing Information).
In a research program aimed at exploring new asymmetric
catalysts, we have succeeded in developing chiral imidazolineꢀ
aminophenolꢀmetal catalysts.9 A chiral imidazolineꢀ
aminophenolꢀCuOTf complex was able to catalyze the asym-
metric Henry reaction, FriedelꢀCrafts reaction, and tandem
FriedelꢀCrafts/Henry (FCH) reaction. The resulting highly
functionalized indoles provide a fascinating precursor for the
synthesis of β-carbolines. Herein, we report the successful
transformation of FCH adducts to THBCs.
The PictetꢀSpengler reaction using 4a and benzaldehyde still
proved difficult to promote by the simple addition of Brønsted
Received: January 5, 2011
Published: March 04, 2011
r
2011 American Chemical Society
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|

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NOTE
Removal of the TES group under the acidic conditions of
PictetꢀSpengler cyclization would be explained by the close
proximity of the nitrogen atom of the THBC adduct to the
hydroxy group. Thus, the presence of the TFA acid group near
the nitrogen base of the THBC results in spontaneous cleavage of
the SiꢀO bond to give 5.
In conclusion, we have readily obtained fully substituted
(1S,3S,4R)-THBCs in a four-step synthesis starting from the
previously developed catalytic asymmetric FCH reaction. This
new family of diverse chiral THBCs offers a fascinating source for
pharmacological investigations. As such, biological assays on the
obtained THBCs are underway in our research group.
Figure 1. Representative examples of β-carboline alkaloids.
’ EXPERIMENTAL SECTION
Scheme 1. Tandem Catalytic Asymmetric FriedelꢀCrafts/
Henry Reaction
FriedelꢀCrafts/Henry Reaction. Imidazolineꢀaminophenol li-
gand (14.9 mg, 19 μmol) in toluene (0.43 mL) was added to
(CuOTf)2 C6H6 (4.4 mg, 8.7 μmol) under Ar, and the mixture was
3
stirred for 2 h at room temperature. To the resulting clear green solution
were sequentially added 1,1,1,3,3,3-hexafluoroisopropyl alcohol (35 μL,
0.34 mmol), benzaldehyde (34.6 μL, 0.34 mmol), nitrostyrene (25.4 mg,
0.17 mmol), and indole (39.8 mg, 0.34 mmol). After being stirred at the
indicated temperature,8b the reaction mixture was purified by silica gel
column chromatography (hexane/AcOEt = 3:1) to afford the adduct 1a
(47.5 mg, 75%): 1H NMR (400 MHz, CDCl3) δ 8.16 (br, 1H, NH), 7.82
(d, 1H, J = 7.7 Hz), 7.12ꢀ7.45 (m, 14H), 5.67 (dd, 1H, J = 11.2 Hz, 3.4
Hz), 5.25 (d, 1H, J = 11.2 Hz), 5.03 (br, 1H), 3.25 (br, 1H); 13C NMR
(100 MHz, CDCl3) δ 43.8, 72.1, 96.0, 111.5, 114.0, 119.3, 120.3, 122.4,
122.7, 125.2, 126.3, 127.4, 128.4, 128.7, 128.8, 136.2, 138.9, 139.3;
HRMS calcd for C23H20N2O3 (M) 372.1474, found m/z 372.1477;
[R]20 = þ50.2 (c = 0.2, CHCl3); IR (neat) 3419, 3029, 1548,
D
1369 cmꢀ1. Enantiomeric excess was determined by HPLC with a
Chiralcel OD-H column (90:10 hexane/2-propanol, 0.8 mL/min,
254 nm); minor enantiomer tR = 38.6 min, major enantiomer
tR = 43.8 min.
acid and/or Lewis acids. However, the problem was soon
resolved by preformation of the imines before the PictetꢀSpengler
cyclization. Thus, after formation of the imine in CHCl3, sub-
sequent treatment with TFA gave the desired PictetꢀSpengler
adduct 5a in 47% yield (Table 2, entry 5). The use of MgSO4 and
3 equiv of aldehyde for effective formation of the imine improved
the yield of 5a to 67% (entry 6).
Interestingly, the TES group was removed under the cycliza-
tion conditions, and the THBCs 5 could be isolated as a single
isomer.
Reduction of FCH Adducts (Entry 3, Table 1). To a stirred
solution of FCH adduct 1a (103.5 mg, 0.278 mmol) in MeOH (2.5 mL)
were added AcOH (0.83 mL), 1 N aq. HCl (1.7 mL), and Zn powder
(363.5 mg, 5.56 mmol) at rt. After the mixture was stirred at rt for 15 h,
the insoluble residue was filtered, and then MeOH was removed by
evaporation under reduced pressure. The remaining aqueous phase was
neutralized by addition of aq. NaHCO3 solution and extracted with
CH2Cl2 (10 mL ꢁ 3). The combined organic layers were dried over
anhydrous Na2SO4. After removal of Na2SO4 by filtration, the solution
was concentrated under reduced pressure. The residual crude product
was purified by silica gel column chromatography (CHCl3/MeOH =
30:1) to afford the β-amino alcohol 2a (94.2 mg, 99%): 1H NMR (400
MHz, CDCl3) δ 8.10 (br, 1H), 7.74 (d, J = 8.2 Hz, 1H), 7.45 (m, 2H),
7.15ꢀ7.36 (m, 11H), 7.11 (m, 1H), 4.69 (d, J = 1.4 Hz, 1H), 4.43 (d, J =
9.9 Hz, 1H), 3.90 (dd, J = 2.3, 10.0 Hz, 1H), 1.28 (br, 2H); 13C NMR
(125 MHz, CDCl3) δ 144.0, 142.4, 136.3, 128.7, 128.6, 128.3, 127.0,
126.6, 125.6, 122.2, 121.5, 119.6, 119.5, 117.8, 111.1, 71.8, 60.1, 46.0;
HRMS calcd for C23H23N2O (M þ H) 343.1805, found m/z 343.1800;
[R]25.0D = þ2.0 (c = 0.71, CHCl3); IR (neat) 3416, 3059, 3028, 1453,
Under the optimized conditions, the generality of the stereo-
selective construction of THBCs was examined (Table 3).
Various aromatic aldehydes can be incorporated in the
PictetꢀSpengler reaction to give the product in quite high
diastereoselectivities. Among the reactions examined, that with
an alkyl R1 group gave a mixture of diastereomers in a ratio of
21:1. When the aliphatic aldehydes were examined, unfortu-
nately, the PictetꢀSpengler products were obtained in low yields
(ca. 10ꢀ20%).
X-ray crystallographic analysis of the PictetꢀSpengler adduct
obtained in entry 2 of Table 3 revealed a (1S,3S,4R)-configura-
tion for the THBC ring (Figure 2).
908, 737, 701 cmꢀ1
.
Reduction of FCH Adducts (Entry 5, Table 1). To a stirred
solution of FCH adduct 1c (40.7 mg, 0.121 mmol) in MeOH (1.1 mL)
were added AcOH (0.36 mL), 1 N aq. HCl (0.73 mL), and Zn-
nanopowder (158.2 mg, 2.42 mmol) at rt. After the mixture was stirred
at rt for 3 h, the insoluble residue was filtered, and then MeOH was
removed by evaporation under reduced pressure. The remaining aqu-
eous phase was neutralized by addition of aq. NaHCO3 solution and
extracted with CH2Cl2 (5 mL ꢁ 3). The combined organic layers were
The (1S,3S,4R)-configuration differs in stereochemistry from
Roussi’s adduct,8 and thus, our method can provide a new series
of fully substituted chiral THBCs. DFT calculation at the
B3LYP/6-311G level suggests that the (1S,3S,4R)-PictetꢀSpen-
gler cycloadduct obtained in Figure 2 is more stable than the
(1R,3S,4R)-epimer by 8.034 kJ/mol, which explains the diaster-
eomeric ratio of 25/1 at 300 K.
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NOTE
Table 1. Reduction to β-Amino Alcohols
yield (%)
entry
substrate
conditions
temp (°C)
time (h)
2
3
1
2
3
4
5
6
1a
1a
1a
1b
1c
1d
NiCl2 (1 equiv)ꢀNaBH4 (12 equiv)
Zn (10 equiv), 1 N HCl/AcOH (2:1)
Zn (20 equiv), 1 N HCl/AcOH (2:1)
Zn (20 equiv), 1 N HCl/AcOH (2:1)
Zna (20 equiv), 1 N HCl/AcOH (2:1)
Zna (20 equiv), 1 N HCl/AcOH (2:1)
0
0.5
24
15
18
3
20
59
99
99
98
99
57
26
0
b
rt
rt
rt
rt
ꢀ
ꢀ
ꢀ
ꢀ
3
a Zn-nanopowder13 was utilized. b Not obtained.
Table 2. Optimization of PictetꢀSpengler Cyclization Using
Table 3. Stereoselective Synthesis of THBCs
4a
entry
R1
R2
R3
time (h)
yield (%)
entry
imine formation
PictetꢀSpengler cyclization yield (%)
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
19
20
19
25
19
19
19
21
24
67a
58a
72a
38a
63a
68a
70a
64b
52a
b
1
AcOH
ꢀ
∼30
ꢀ
4-BrC6H4
4-NO2C6H4
4-CH3C6H4
3-ClC6H4
Ph
2
TFA
3
MgSO4
4
Yb(OTf)3
ꢀ
5
6a
rt, 5 h, CHCl3
TFA (1.1 equiv), rt, 19 h
47
4-BrC6H4
4-BrC6H4
Ph
MgSO4, rt, 5 h, CHCl3 TFA (1.1 equiv), rt, 19 h
67
4-ClC6H4
Ph
a 3 equiv of aldehyde was utilized. b Not obtained.
n-C5H11
Ph
Cy
4-NO2C6H4
dried over anhydrous Na2SO4. After removal of Na2SO4 by filtration, the
solution was concentrated under reduced pressure. The residual crude
product was purified by silica gel column chromatography (CHCl3/
MeOH = 10:1) to afford the β-amino alcohol 2c (39.9 mg, 98%): 1H
NMR (500 MHz, CDCl3) δ 8.06 (br, 1H), 7.26ꢀ7.39 (m, 7H), 7.18 (m,
1H), 7.01ꢀ7.08 (m, 2H), 4.51 (d, J = 5.2 Hz, 1H), 3.19 (t, J = 5.7 Hz,
1H), 2.95 (m, 1H), 1.05ꢀ2.10 (m, 13H); 13C NMR (125 MHz, CDCl3)
δ 143.2, 136.6, 128.3, 127.4, 126.9, 126.3, 122.0, 121.6, 119.2, 119.2,
117.4, 111.2, 73.7, 61.8, 38.9, 32.0, 29.2, 27.5, 22.5, 14.0; HRMS calcd for
C22H29N2O (M þ H) 337.2274, found m/z 337.2263; [R]22.7D = ꢀ6.3
(c = 0.65, CHCl3); IR (neat) 3414, 3292, 3059, 2952, 2927, 2857, 1455,
a Isolatable compounds were only a single diastereoisomer of the
PictetꢀSpengler reaction and the recovered 4. b Diastereomixture in a
ratio of 21/1.
(m, 1H), 4.84 (d, J = 3.6 Hz, 1H), 4.22 (d, J = 8.4 Hz, 1H), 3.65 (dd, J =
3.8, 8.6 Hz, 1H), 0.76 (t, J = 7.9 Hz, 9H), 0.30ꢀ0.42 (m, 6H); 13C NMR
(100 MHz, CDCl3) δ 143.9, 142.8, 136.3, 129.1, 128.3, 128.0, 127.2,
126.9, 126.6, 126.2, 122.0, 121.3, 119.4, 119.2, 118.3, 111.0, 75.3, 61.0,
46.6, 6.7, 4.8; HRMS calcd for C29H37N2OSi (M þ H) 457.2670, found
m/z 457.2661; [R]24.6D = ꢀ2.0 (c = 0.33, CHCl3); IR (neat) 3421, 3166,
741, 703 cmꢀ1
.
3060, 3027, 2953, 2911, 2875, 1454, 1060, 738, 700 cmꢀ1
.
TES Protection (for 2a). To a stirred solution of 2a (94.9 mg,
0.277 mmol) in dry DMF (1.4 mL) were added TESCl (93.0 μL, 0.554
mmol) and imidazole (94.3 mg, 1.39 mmol) at 0 °C. After being stirred
for 1 h, the reaction mixture was quenched by addition of H2O. The
mixture was extracted with Et2O (5 mL ꢁ 3), and the combined organic
layers were dried over anhydrous Na2SO4. After removal of Na2SO4 by
filtration, the solution was concentrated under reduced pressure. The
residual crude product was purified by silica gel column chromatography
(hexane/AcOEt = 2:1) to afford the O-TES derivative 4a (103.7 mg,
82%): 1H NMR (400 MHz, CDCl3) δ 8.10 (br, 1H), 7.52 (d, J = 8.0 Hz,
1H), 7.41 (m, 2H), 7.19ꢀ7.35 (m, 9H), 7.11ꢀ7.18 (m, 2H), 7.05
TES Protection (for 2d). To a stirred solution of 2d (47.7 mg,
0.137 mmol) in dry DMF (0.69 mL) were added TESCl (46.0 μL,
0.274 mmol) and imidazole (46.6 mg, 0.685 mmol) at rt. After being
stirred for 1 h, the reaction mixture was quenched by an addition of H2O.
The mixture was extracted with Et2O (5 mL ꢁ 3), and the combined
organic layers were dried over anhydrous Na2SO4. After removal of
Na2SO4 by filtration, the solution was concentrated under reduced
pressure. The residual crude product was purified by silica gel column
chromatography (hexane/AcOEt = 2:1) to afford the O-TES derivative
4d (50.7 mg, 80%): 1H NMR (500 MHz, CDCl3) δ 8.03 (br, 1H), 7.53
(d, J = 7.7 Hz, 1H), 7.29ꢀ7.35 (m, 3H), 7.22ꢀ7.27 (m, 2H), 7.10ꢀ7.15
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NOTE
’ REFERENCES
(1) (a) Dewick, P. M. Medicinal Natural Products: A Biosynthetic
Approach, John Wiley & Sons, Inc.: Chichester, 2009. (b) Comprehensive
Natural Products Chemistry, Eds.; Cane, D. E., Barton, D. H. R., Nakanishi,
K., MethCohn, O., Kelly, J. W., Eds.; Pergamon: New York, 1999.
(2) (a) Cox, E. D.; Cook, J. M. Chem. Rev. 1995, 95, 1797–1842.
(b) Bandini, M.; Eichholzer, A. Angew. Chem., Int. Ed. 2009, 48, 9608–9644.
(3) Hollinshead, S. P.; Trudell, M. L.; Skolnick, P.; Cook, J. M.
J. Med. Chem. 1990, 33, 1062–1069.
(4) Garnier, J.; Mahuteau, J.; Plat, M.; Merienne, C. Phytochemistry
1989, 28, 308–309.
(5) Itoh, A.; Tanahashi, T.; Nagakura, N.; Nishi, T. Phytochemistry
2003, 62, 359–369.
Figure 2. X-ray structure of PictetꢀSpengler cycloadduct (entry 2,
Table 3).
(6) Busacca, C. A.; Eriksson, M. C.; Dong, Y.; Prokopowicz, A. S.;
Salvagno, A. M.; Tschantz, M. A. J. Org. Chem. 1999, 64, 4564–4568.
(7) (a) Agnusdei, M.; Bandini, M.; Melloni, A.; Umani-Ronchi, A.
J. Org. Chem. 2003, 68, 7126–7129. (b) Bandini, M.; Melloni, A.;
Piccinelli, F.; Sinisi, R.; Tommasi, S.; Umani-Ronchi, A. J. Am. Chem.
Soc. 2006, 128, 1424–1425.
(m, 3H), 7.02 (m, 1H), 4.19 (d, J = 10.0 Hz, 1H), 3.70 (dd, J = 1.4, 7.2
Hz, 1H), 3.58 (dd, J = 1.5, 10.0 Hz, 1H), 1.88 (br, 1H), 1.62ꢀ1.84 (m,
5H), 0.90ꢀ1.33 (m, 5H), 0.86 (t, J = 8.0 Hz, 9H), 0.51 (q, J = 8.0 Hz,
6H) ; 13C NMR (125 MHz, CDCl3) δ 143.4, 136.1, 128.9, 128.4, 127.3,
126.2, 122.0, 120.4, 119.4, 119.2, 118.3, 110.9, 76.7, 54.9, 48.0, 42.3, 30.1,
30.0, 26.6, 26.5, 26.4, 7.0, 5.6; HRMS calcd for C29H43N2OSi (MþH):
463.3139, found: m/z 463.3127; [R]23.0D = ꢀ63.1(c = 1.0, CHCl3); IR
(8) Rannoux, C.; Roussi, F.; Retailleau, P.; Guꢀeritte, F. Org. Lett.
2010, 12, 1240–1243.
(9) (a) Arai, T.; Yokoyama, N.; Yanagisawa, A. Chem.—Eur. J. 2008,
14, 2052–2059. (b) Arai, T.; Yokoyama, N. Angew. Chem., Int. Ed. 2008,
47, 4989–4992. (c) Yokoyama, N.; Arai, T. Chem. Commun.
2009, 3285–3287. (d) Arai, T.; Yokoyama, N.; Mishiro, A.; Sato, H.
Angew. Chem., Int. Ed. 2010, 49, 7895–7898.
(10) Although the structure of major FCH adduct is reported as the
(R,R,R)-form in ref 9b, the correct structure is the (R,S,S)-form. We
apologize for causing confusion. Corrigendum: Angew. Chem., Int. Ed.
2010, 49, 9555.
(neat) 3418, 3166, 3060, 2925, 2875, 2852, 1455, 1011, 738, 702 cmꢀ1
.
PictetꢀSpengler Reaction (Entry 1, Table 3). A suspension of
4a (38.8 mg, 0.0805 mmol), benzaldehyde (24.5 μL, 0.242 mmol), and
MgSO4 (80.5 mg) in dry CHCl3 (0.81 mL) was stirred for 5 h at rt under
Ar. After addition of TFA (6.6 μL, 0.089 mmol), the mixture was further
stirred for 19 h at rt. The reaction was quenched by an addition of
NaHCO3 solution. The remaining insoluble residue was filtered and
then extracted with CHCl3 (5 mL ꢁ 3). The combined organic layers
were dried over anhydrous Na2SO4. After removed of Na2SO4 by
filtration, the solution was concentrated under reduced pressure. The
residual crude product was purified by silica gel column chromatography
(hexane/AcOEt = 6:1) to afford the tetrahydro-β-carboline 5 (23.2 mg,
67%): 1H NMR (400 MHz, CDCl3) δ 7.53ꢀ7.62 (m, 3H), 7.35ꢀ7.50
(m, 6H), 7.18ꢀ7.30 (m, 7H), 7.06ꢀ7.16 (m, 2H), 7.02 (m, 1H), 6.87
(m, 1H), 5.35 (d, J = 1.6 Hz, 1H), 4.02 (d, J = 9.7 Hz, 1H), 3.95 (dd, J =
1.8, 4.1 Hz, 1H), 3.83 (dd, J = 4.1, 9.7 Hz, 1H), 3.40 (br, 1H), 2.37 (br,
1H); 13C NMR (100 MHz, CDCl3) δ 140.9, 140.4, 140.0, 136.2, 135.2,
129.9, 129.2, 128.7, 128.6, 128.5, 128.5, 127.9, 126.7, 126.5, 121.9, 119.5,
118.5, 114.4, 110.8, 74.5, 64.0, 59.5, 39.9; HRMS calcd for C30H26N2O-
Na (M þ Na) 453.1937, found m/z 453.1920; [R]25.7D = ꢀ6.4 (c = 1.0,
CHCl3); IR (neat) 3412, 3332, 3060, 3030, 2919, 1493, 1454, 909, 737,
(11) Reduction using Ni-boride:(a) Osby, J. O.; Ganem, B. Tetrahedron
Lett. 1985, 26, 6413–6416. (b) Handa, S.; Gnanadesikan, V.; Matsunaga, S.;
Shibasaki, M. J. Am. Chem. Soc. 2007, 129, 4900–4901.
(12) Reduction using ZnꢀAcOH: Oppolzer, W.; Tamura, O.;
Sundarababu, G.; Signer, M. J. Am. Chem. Soc. 1992, 114, 5900–5902.
(13) Purchased from sigma-aldrich.com (product no. 578002-5G).
(14) Examples of PictetꢀSpengler condansation: (a) Jiang, W.;
Zhang, X.; Sui, Z. Org. Lett. 2003, 5, 43–46. (b) Zhuang, W.; Hazell,
R. G.; Jørgensen, K. A. Org. Biomol. Chem. 2005, 3, 2566–2571. (c) Herrera,
R. P.; Sgarzani, V.; Bernardi, L.; Ricci, A. Angew. Chem., Int. Ed. 2005, 44,
6576–6579.
701 cmꢀ1
.
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures, ana-
b
lytical and spectral characterization data for all compounds, and
crystallographic information files (CIF) of PictetꢀSpengler
cycloadduct (entry 2, Table 3). This material is available free
of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: tarai@faculty.chiba-u.jp.
’ ACKNOWLEDGMENT
This work was supported by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Culture, Sports,
Science and Technology, Japan.
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dx.doi.org/10.1021/jo1025833 |J. Org. Chem. 2011, 76, 2909–2912