Total synthesis of (-)-indolactam v

Article abstract of DOI:10.1039/c0ob01115k

The total synthesis of protein kinase C activator (-)-indolactam V (IL-V) has been successfully completed with two separate approaches: From known 4-nitrotryptophan derivative 3 in 8 steps (49% overall yield) and from l-glutamic acid in 12 steps (18% overall yield), where 4-nitrotryptophanol derivative 4 served as a key intermediate. Derivatives 3 and 4, both incorporating indole 4-substitution and the C-9 stereocenter in IL-V, were synthesized via the Pd-catalyzed indole synthesis from 3-nitro-2-iodoaniline 5 with aldehydes 6 and 7, respectively. Aldehyde 7 was, meanwhile, synthesized from l-glutamic acid in 5 steps (68% yield). Lactamization of the 9-membered ring was achieved using HATU in THF in good yield.

Full text of DOI:10.1039/c0ob01115k

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PAPER
Total synthesis of (-)-indolactam V†
Zhengren Xu,a Fengying Zhang,a Lihe Zhanga and Yanxing Jia*a,b
Received 5th December 2010, Accepted 5th January 2011
DOI: 10.1039/c0ob01115k
The total synthesis of protein kinase C activator (-)-indolactam V (IL-V) has been successfully
completed with two separate approaches: From known 4-nitrotryptophan derivative 3 in 8 steps (49%
overall yield) and from L-glutamic acid in 12 steps (18% overall yield), where 4-nitrotryptophanol
derivative 4 served as a key intermediate. Derivatives 3 and 4, both incorporating indole 4-substitution
and the C-9 stereocenter in IL-V, were synthesized via the Pd-catalyzed indole synthesis from
3-nitro-2-iodoaniline 5 with aldehydes 6 and 7, respectively. Aldehyde 7 was, meanwhile, synthesized
from L-glutamic acid in 5 steps (68% yield). Lactamization of the 9-membered ring was achieved using
HATU in THF in good yield.
NA39-17. Due to the potent activity and peculiar structure
Introduction
involving a 9-membered lactam ring bridging the indole 3- and
4-positions, indolactam V has attracted much attention in the area
of organic and medicinal chemistry.5–9 Two general strategies are
available in the literature for the synthesis of these 3,4-disubstituted
indoles, one involves direct functionalization at the less reactive 4-
position of an existing indole nucleus,10 and the other resides in the
application of a pre-existing 4-substituted indole, which is usually
prepared by indole synthesis.11 Generally, the major challenge in
the synthesis of IL-V is how to construct optically pure 4-amino
tryptophanol derivatives.
Teleocidins A and B (Fig. 1)1 produced by actinomycetes are
interesting indole alkaloids primarily because of their tumor-
promoting activity, which involves binding and activating a group
of kinase receptors including protein kinase C.2 (-)-Indolactam V
(IL-V)3 (1), an active fragment of teleocidins, has long been
considered a biosynthetic precursor to the teleocidin class.4
Indolactam V was first synthesized and named by Shudo5a before
its isolation from natural source Streptoverticillium blastmyceticum
Recently, an appealing synthetic method for benzofunction-
alized indoles, especially optically pure tryptophan derivatives,
through a Pd-catalyzed reaction of o-haloanilines and aldehydes
has been developed by Zhu and Jia, and since then it has
already found applications in the synthesis of several natural
products.12–13 Taking advantage of such methodology for the
assembly of 4-halotryptophan derivatives,12i–k we have recently
reported the total synthesis of clavicipitic acid and aurantioclavine,
both of which hold a 7-membered azapino[5,4,3-cd]-indole ring
system. In order to further extend the substrate scope of the
methodology and define its utilities in the total synthesis of natural
products, as well as its potential applications in diversity-oriented
synthesis (DOS),14 we describe herein two separate approaches
to the total synthesis of (-)-indolactam V from either known 4-
nitrotryptophan derivative 3 or tryptophanol derivative 4. Both 3
and 4 are optically pure and prepared via the Pd-catalyzed indole
synthesis from 3-nitro-2-iodoaniline 5 and L-glutamic acid-derived
aldehydes 6 and 7, respectively.
Fig. 1 Structures of several naturally occurring teleocidins.
aState Key Laboratory of Natural and Biomimetic Drugs, School of
Pharmaceutical Sciences, Peking University, 38 Xueyuan Road, Beijing,
100191, China. E-mail: yxjia@bjmu.edu.cn; Fax: +86 8280 5166; Tel: +86
8280 5166
Results and discussion
bState Key Laboratory of Applied Organic Chemistry, Lanzhou University,
Lanzhou, 730000, China
Our retrosynthetic analysis of (-)-indolactam V is shown in
Scheme 1, it was envisioned that IL-V could be achieved from ei-
ther 4-nitrotryptophan derivative 3 or 4-nitrotryptophanol deriva-
tive 4 after the introduction of a valine moiety via SN 2 displacement
† Electronic supplementary information (ESI) available: Experimental
procedures and physical data for compounds 7 and 19, and copies of spec-
tra for compounds 1, 4, 7–15 and 19–21. See DOI: 10.1039/c0ob01115k
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Pd-catalyzed indole synthesis method from 3-nitro-2-iodoaniline
5 and aldehyde 6. Meanwhile, we envisioned that 4 could be
transformed to IL-V in a more concise manner than that from
3, by avoiding additional modifications after the indole synthesis,
and 4 could also be synthesized by the same method from 3-nitro-
2-iodoaniline 5 and aldehyde 7. Chiral building block aldehydes 6
and 7 would be obtained from commercially available L-glutamic
acid.
Our first-generation synthesis of (-)-indolactam V commenced
with known 4-nitrotryptophan derivative 3 (Scheme 2).12k At-
tempts to reduce the nitro group with a zinc/acetic acid system
only resulted in 4-aminotryptophan derivative 8 in low yield (30–
40%), accompanied with a substantial amount of polymerized side
products. To our delight, hydrogenation of 3 with Pd/C afforded
8 cleanly, in 91% isolated yield. However, the SN 2 displacement
reaction of 8 with the chiral triflate 2 under the same conditions
reported for a similar substrate by Kogan6f proceeded quite slowly,
and afforded the desired product 9 in only 55% yield after
refluxing for 7 days. We reasoned that the steric hindrance of
the di-Boc protection at the nitrogen and methyl ester group
might affect the rate of the reaction, and the relatively lower
yield might be attributed to the decomposition of 8 or/and 9
under the refluxing conditions for such a long period. In order
to make the SN 2 displacement reaction more efficient, we chose
to reduce the steric hindrance of compound 3. In this regard,
selective partial deprotection of di-Boc with Mg(ClO4)2 afforded
10, which upon NaBH4 reduction of the methyl ester gave 4-
nitrotryptophanol derivative 13. Hydrogenation of the nitro group
of 10 and 13 with Pd/C produced 4-aminotryptophan derivative
11 and 4-aminotryptophanol derivative 14, respectively. Both 11
and 14 were subjected to the same SN 2 displacement reaction. The
Boc group was found to have a limited effect on the reaction,
as 12 could be obtained in 60% yield from 11 after refluxing
for 6 days. On the other hand, 4-aminotryptophanol derivative
Scheme 1 Retrosynthetic analysis of (-)-indolactam V.
with chiral triflate 2 based on literature precedent,6f followed
by lactamization to form a 9-membered ring. 4-Nitrotryptophan
derivative 3 has been prepared previously by our group via a new
Scheme 2 SN 2 displacement reaction for the introduction of a valine moiety.
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Table 1 Reaction conditions for 9-membered lactam formation
14 could be transformed to 15 in 78% yield after refluxing for
24 h.
With the 4-valine substituted tryptophanol derivative 15 in
hand, initial attempts to remove both the benzyl ester and Boc
group in a one-pot manner by hydrogenation with Pd/C in
acid solution (trifluoroacetic acid15a or camphorsulfonic acid6f)
were, however, unsuccessful, and only trace amount of des-N-
methylindolactam V 17 was detected after lactam formation with
HATU in DMF. On the contrary, hydrogenation of 15 with Pd/C
in ethanol followed by TFA/CH2Cl2 (1 : 5) treatment in a step-
by-step manner smoothly afforded 16, which was subsequently
used in the next lactamization step after the solvent being
removed without further purification. It was noteworthy that
relatively dilute concentrations of both the substrate and TFA
were important in the Boc-deprotection step, and the yield would
otherwise be diminished after lactamization.
Lactamization of the crude known compound 166f using either
HATU (Table 1, entry 1) or HBTU/HOBt (Table 1, entry 2) in
DMF in the presence of the Hu¨nig’s base followed by reductive
methylation using formaldehyde/cyanoborohydride in acetoni-
trile in the presence of acetic acid afforded IL-V in moderate
50% and 55% yield, respectively. More satisfactory results were
obtained when the solvent was switched to THF (Table 1, entries
3 and 4), and the yield of IL-V could reach as high as 73% by using
HATU throughout this 4-step operation. This represents one key
improvement in the synthesis of IL-V.
Although the conversion of 3 to (-)-indolactam V could be
successfully achieved, several functional group transformations
from tryptophan derivative 3 were required. In order to streamline
the synthesis and improve the efficiency of the synthesis, we envi-
sioned that the 4-nitrotryptophanol derivative 4 could be directly
synthesized via the Pd-catalyzed indole synthesis from 3-nitro-2-
iodoaniline 5 and properly protected aldehyde 7 (Scheme 3).
The known aldehyde 7 prepared either from Garner’s aldehyde15
or L-glutamic acid16 has been reported; however, these approaches
have several disadvantages. In total 4 steps are required to convert
Garner’s aldehyde to 7 in less than 39% overall yield, while
environmentally unfriendly Wittig reagents as well as expensive
Pd/C and DIBAL-H are employed.15b Although the synthesis of
Entry
Conditionsa,b
Yieldc
1
2
3
4
HATU, DIPEA, DMF
HBTU, HOBt, DIPEA, DMF
HATU, DIPEA, THF
50%
55%
73%
70%
HBTU, HOBt, DIPEA, THF
a Stirred at room temperature under argon atmosphere for 48 h in
a concentration of 0.034 M (based on 15). b Other conditions are
identical. c Overall isolated yield of IL-V in 4 steps. HATU: 2-(7-aza-1H-
benzotriazole-1-yl)-1,1,3,3-tetramethyluronium
HBTU:
hexafluorophosphate.
2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate. HOBt: N-hydroxybenzotrizole. DIPEA: N,N-
diisopropylethylamine
7 from L-glutamic acid derivative has been reported,16 it includes
a few unnecessary functional group transformations, and there is
still room for improvement to streamline the synthesis in larger
quantities.
Our modified synthetic route to 7 is summarized in Scheme 3.
Treatment of L-glutamic acid with TMSCl in dry methanol,
followed by Boc protection with Boc2O/Et3N afforded N-Boc-
glutamic dimethyl ester 18. Reduction of the two methyl esters
Scheme 3 Total synthesis of (-)-indolactam V from L-glutamic acid.
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of 18 to give diol-19 was effected by NaBH4 in THF/MeOH
(5 : 1), which is easier to manipulate compared with the CaCl2-
containing system.16a Protecting the amino alcohol 19 with
2,2-dimethoxypropane in the presence of catalytic amount of
BF3·Et2O followed by the Swern oxidation afforded the desired
aldehyde 7. The new route for the synthesis of 7 consists merely
of 5 steps (68% overall yield), and requires only two column
chromatography purifications.
Reaction of 7 with 3-nitro-2-iodoaniline 5 under the same
Pd-catalyzed indole synthesis conditions provided the desired 4-
nitrotryptophanol derivative 4 in 75% yield. Hydrogenation of
the nitro group followed by SN 2 displacement with chiral triflate 2
afforded 4-valine substituted tryptophanol derivative 21 smoothly,
which could be transformed to (-)-IL-V following the same
sequence described for 15 in 55% overall yield (not optimized).
The NMR spectra and optical rotation of our synthesized (-)-IL-
V are in full accord with those reported in an isolation paper.3
60.3, 52.1, 28.0, 27.5; HRMS (ESI): m/z calcd. for C22H32N3O6:
434.2286; found: 434.2296.
Compound 9. A solution of 4-aminotryptophan derivative 8
(128 mg), (R)-2-((trifluoromethylsulfonyl)oxy)-3-methylbutanoic
acid phenyl methyl ester 2 (106 mg) and 2,6-lutidine (35 mg) in
◦
1,2-dichloroethane (2.0 mL) was stirred and heated at 70 C for
7 days until the starting material was consumed. Purification with
FCC (PE-EtOAc, 2 : 1) afforded compound 9 (101 mg, 55%) as
colorless oil. [a]D -61 (c 2.00, CHCl3); nmax(KBr)/cm-1: 3351,
23
2974, 1785, 1738, 1514, 1369, 1283, 1140, 1094, 851, 780, 731; 1H
NMR (400 MHz, CDCl3): d = 8.56 (1H, br s), 7.31–7.38 (5H, m),
6.93 (1H, t, J = 7.6 Hz), 6.76–6.78 (2H, m), 6.17 (1H, d, J = 7.6
Hz), 5.44 (1H, dd, J = 2.8, 10.8 Hz), 5.21 (1H, d, J = 12.4 Hz),
5.10 (1H, d, J = 12.4 Hz), 4.89 (1H, d, J = 8.4 Hz), 4.05 (1H, dd,
J = 6.0, 8.0 Hz), 3.93 (1H, dd, J = 2.8, 15.6 Hz), 3.76 (3H, s),
3.43 (1H, dd, J = 11.2, 15.6 Hz), 2.20–2.28 (1H, m), 1.22 (18H,
s), 1.09 (1H, d, J = 6.8 Hz), 1.02 (1H, d, J = 6.8 Hz); 13C NMR
(100 MHz, CDCl3): d = 173.6, 170.9, 151.2, 141.8, 138.1, 135.7,
128.5, 128.3, 128.2, 123.1, 122.0, 115.5, 110.5, 102.4, 100.0, 82.9,
66.4, 62.0, 59.9, 52.1, 31.6, 28.2, 27.5, 19.0, 18.7; HRMS (ESI):
m/z calcd. for C34H46N3O8: 624.3279; found: 624.3277.
Conclusions
In conclusion, we have successfully completed the total synthesis
of (-)-indolactam V either from the known 4-nitrotryptophan
derivative 3 in 8 steps (49% overall yield) or from L-glutamic acid
in 12 steps (18% overall yield). Our synthesis features not only Pd-
catalyzed 4-nitrotryptophan and 4-nitrotryptophanol synthesis to
incorporate both indole 4-substitution and a C-9 stereocenter in
IL-V, an improvement for lactamization, but also short, efficient
synthesis of aldehyde 7. The practical aspects of our synthetic
strategy enables gram-scale preparation of (-)-IL-V.
N-Boc-4-nitrotryptophan derivative 10. To a stirring solution
of 3 (156 mg) in acetonitrile was added Mg(ClO4)2 (4 mg), and
the reaction mixture was heated at 90 ◦C for 20 min. After the
solvent being removed in vacuo, the residue was purified with FCC
(CH2Cl2-MeOH, 20 : 1) to give 10 (116 mg, 95%) as a yellowish
foam. [a]D +47.8 (c 1.00, CHCl3); nmax(KBr)/cm -1: 3368, 2978,
23
1693, 1518, 1366, 1323, 1166, 1055, 788, 734; 1H NMR (300 MHz,
CDCl3) showed the presence of two rotamers in a ratio of 3.3/1,
major rotamer shown: d = 9.84 (1H, br s), 7.86 (1H, d, J = 6.0 Hz),
7.61 (1H, d, J = 6.0 Hz), 7.29 (1H, br s), 7.14 (1H, br s), 5.28 (1H,
br s), 4.55 (1H, br s), 3.67 (3H, s), 3.47–3.52 (1H, m), 3.33 (1H,
br s), 1.34 (9H, s); 13C NMR (75 MHz, CDCl3) major rotamer
shown: d = 173.2, 155.6, 142.5, 139.2, 129.1, 120.4, 119.1, 118.2
(2¥C), 109.8, 80.0, 55.1, 52.2, 30.1, 28.0; HRMS (ESI): m/z calcd.
for C17H25N4O6: 381.1769; found: 381.1761.
Experimental
Flash chromatography was performed using silica gel from
Qingdao Mar. Chem. Ind. Co. Ltd. (200–300 mesh). Thin layer
chromatography was performed with TLC plates from Merck
(60 F254) using phosphomolybdic acid solution for visualisation.
Melting points are uncorrected. Infrared spectra were recorded on
Thermo Nicolet Nexus-470 FT-IR spectrometers. Mass spectra
were recorded on a Bruker APEX IV FT-MS (ESI spectrometer.
NMR spectra were recorded on JEOL JNM-AL 300 MHz
spectrometer and Bruker Avance III 400 MHz spectrometer.
Chemical shifts d are reported in ppm with the deuterated solvent
as internal standard.
23
N-Boc-4-aminotryptophan derivative 11. White foam; [a]D
+3 (c 2.00, CHCl3); nmax(KBr)/cm-1: 3384, 2978, 1740, 1699, 1508,
1366, 1166, 738; H NMR (400 MHz, CDCl3): d = 8.36 (1H, br
1
s), 6.97 (1H, t, J = 7.6 Hz), 6.81 (1H, d, J = 7.6 Hz), 6.80 (1H,
s), 6.36 (1H, d, J = 7.6 Hz), 5.90 (1H, d, J = 7.2 Hz), 4.57 (1H,
d, J = 6.4 Hz), 4.08 (2H, br s), 3.67 (3H, s), 3.33–3.35 (2H, m),
1.39 (9H, s); 13C NMR (100 MHz, CDCl3): d 173.0, 155.7, 140.1,
138.0, 123.0, 121.9, 116.6, 109.7, 106.2, 103.0, 79.8, 55.7, 52.1,
29.8, 28.2; HRMS (ESI): m/z calcd. for C17H23N3O4K: 372.1320;
found: 372.1322.
N,N-Di-Boc-4-aminotryptophan derivative 8. 10% Palladium
on carbon (10 mg) was added to a solution of 4-nitrotryptophan
derivative 3 (156 mg) in methanol (2.0 mL), and the mixture was
hydrogenolyzed at 4 atm hydrogen for 9 h, at which point TLC
indicated complete reaction (PE-EtOAc, 3 : 2). Purification with
FCC (PE-EtOAc, 2 : 1) afforded the desired 4-aminotryptophan
23
Compound 12. White foam; [a]D +8 (c 2.00, CHCl3);
n
max(KBr)/cm-1: 3392, 2969, 1736, 1513, 1367, 1163, 733; 1H NMR
(400 MHz, CDCl3) show the presence of two rotamers, major
rotamer shown: d = 8.38 (1H, br s), 7.29–7.34 (5H, m), 6.96 (1H,
t, J = 8.0 Hz), 6.82 (1H, d, J = 8.0 Hz), 6.81 (1H, s), 6.24 (1H, d,
J = 8.0 Hz), 5.87 (1H, d, J = 6.8 Hz), 5.19 (1H, d, J = 12.4 Hz),
1.14 (1H, d, J = 12.4 Hz), 4.75 (1H, d, J = 10.0 Hz), 4.53–4.58 (1H,
m), 4.06 (1H, dd, J = 5.6, 9.6 Hz), 3.70 (3H, s), 3.41–3.48 (1H, m),
3.27–3.33 (1H, m), 2.25–2.33 (1H, m), 1.34 (9H, s), 1.14 (1H, d,
J = 6.8 Hz), 1.10 (1H, d, J = 6.8 Hz); 13C NMR (100 MHz, CDCl3)
major rotamer shown: d = 173.8, 173.1, 155.7, 141.5, 137.7, 135.6,
23
derivative 8 (133 mg, 91%) as white foam. [a]D -89 (c 2.00,
CHCl3); nmax(KBr)/cm-1: 3355, 2979, 1782, 1738, 1366, 1281, 1139,
1094, 850, 736; 1H NMR (400 MHz, CDCl3): d = 8.55 (1H, br s),
6.90 (1H, t, J = 8.0 Hz), 6.80 (1H, s), 6.79 (1H, d, J = 8.0 Hz), 6.29
(1H, d, J = 8.0 Hz), 5.40 (1H, dd, J = 4.0, 10.0 Hz), 4.02 (2H, br s),
3.76 (3H, s), 3.74 (1H, dd, J = 4.0, 15.2 Hz), 3.37 (1H, dd, J = 10.0,
15.2 Hz), 1.27 (18H, s); 13C NMR (100 MHz, CDCl3): d = 171.1,
151.5, 140.6, 138.2, 122.7, 122.5, 116.5, 110.5, 105.4, 102.9, 83.0,
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128.4, 128.3, 128.2, 123.2, 121.8, 116.7, 109.8, 103.3, 101.7, 79.7,
66.5, 62.5, 55.8, 52.1, 31.5, 29.9, 28.1, 19.2, 18.9; HRMS (ESI):
m/z calcd. for C29H38N3O6: 524.2755; found: 524.2749.
n
max(KBr)/cm-1: 3270, 2986, 1670, 1518, 1404, 1365, 1323, 788,
1
740; H NMR (300 MHz, CDCl3) showed the presence of two
rotamers in a ratio of 1/1: d = 10.04 (1H, br s), 9.69 (1H, br s),
7.86 (1H, d, J = 7.8 Hz), 7.65 (2H, br s), 7.52 (1H, d, J = 7.8
Hz), 7.19 (2H, br s), 7.07 (1H, t, J = 7.8 Hz), 6.90 (1H, br s), 4.26
(2H, br s), 3.95 (2H, m), 3.80 (2H, d, J = 8.7 Hz), 3.08–3.24 (4H,
m), 1.69 (3H, s), 1.61 (3H, s), 1.51 (15H, br s), 1.01 (9H, s); 13C
NMR (75 MHz, CDCl3) all rotamers shown: d = 152.8, 143.0,
142.4, 139.2, 138.9, 128.5, 126.3, 120.4, 119.7, 119.0, 117.7, 117.4,
112.2, 111.6, 94.0, 93.6, 80.7, 79.3, 67.8, 66.7, 58.0, 32.0, 30.2, 28.3,
27.8, 27.4, 24.4, 23.2; HRMS (ESI): m/z calcd. for C19H25N3O5Na:
398.1686; found: 398.1679.
N-Boc-4-nitrotryptophanol derivative 13. To a stirring solution
of 4-nitrotryptophan derivative 10 (1.66 g) in dry ethanol (20
mL) was added NaBH4 (345 mg), and the reaction mixture was
stirred at room temperature overnight until the starting material
consumed. The solvent was removed under reduced pressure, and
the residue was suspended in water. After being extracted with
EtOAc, the combined organic layers were washed with brine and
dried over Na2SO4. Purification by FCC (CH2Cl2-MeOH, 30 : 1)
afforded the desired 4-nitrotryptophanol derivative 13 (1.46 g,
23
23
95%) as an amorphous yellowish powder. [a]D -278.5 (c 1.00,
4-Aminotryptophanol derivative 20. Yellowish foam; [a]D
MeOH); nmax(KBr)/cm-1: 3560, 3368, 2983, 1682, 1515, 1318,
-42.1 (c 1.00, CHCl3); nmax(KBr)/cm-1: 3380, 2980, 1678, 1399,
1171, 1106, 757; 1H NMR (300 MHz, CDCl3) showed the presence
of two rotamers in a ratio of 7.5/1, major rotamer shown: d = 8.12
(1H, br s), 6.97 (1H, t, J = 7.8 Hz), 6.78 (1H, s), 6.70 (1H, d, J =
7.8 Hz), 6.31 (1H, d, J = 7.8 Hz), 4.93 (2H, br s), 4.19–4.24 (1H,
m), 3.91 (1H, d, J = 9.0 Hz), 3.75 (1H, dd, J = 5.7, 8.1 Hz), 3.52
(1H, d, J = 13.8 Hz), 2.73 (1H, dd, J = 11.7, 13.8 Hz), 1.68 (3H,
s), 1.56 (9H, s), 1.50 (3H, s); 13C NMR (75 MHz, CDCl3) major
rotamer shown: d = 152.6, 141.5, 138.5, 123.4, 121.4, 115.2, 111.9,
104.2, 101.1, 93.7, 80.4, 65.3, 59.0, 29.6, 28.3, 27.7, 24.2; HRMS
(ESI): m/z calcd. for C19H28N3O3: 346.2125; found: 346.2118.
1
1294, 738; H NMR (400 MHz, CD3OD) showed the presence
of two rotamers in a ratio of 2.2/1: d = 7.78 (1H, d, J = 8.0 Hz,
both), 7.66 (1H, d, J = 8.0 Hz, both), 7.37 (1H, s, major), 7.34
(1H, s, minor), 7.16 (1H, t, J = 8.0 Hz, both), 3.67–3.75 (1H, m,
both), 3.57–3.60 (1H, m, both), 3.50–3.54 (1H, m, both), 3.18–
3.27 (1H, m, both), 2.81 (1H, dd, J = 10.0, 14.4 Hz, major), 2.64
(1H, br t, J = 12.0 Hz, minor), 1.25 (9H, s, major), 0.90 (9H, s,
minor); 13C NMR (100 MHz, CD3OD) major rotamer shown: d
158.1, 144.0, 141.1, 130.3, 120.7, 120.4, 118.7, 118.1, 112.5, 79.7,
65.4, 55.2, 30.4, 28.6; HRMS (ESI): m/z calcd. for C16H22N3O5:
336.1554; found: 336.1559.
23
Compound 21. Yellowish foam; [a]D -54.4 (c 1.00, CHCl3);
23
N-Boc-4-aminotryptophanol derivative 14. Colorless oil; [a]D
n
max(KBr)/cm-1: 3398, 2975, 1735, 1683, 1398, 1369, 1247, 1174,
-2.3 (c 1.00, CHCl3); nmax(KBr)/cm-1: 3381, 2976, 2932, 1692,
1506, 1365, 1168, 1057, 733; H NMR (400 MHz, CDCl3): d =
1104, 756; 1H NMR (300 MHz, CDCl3) show the presence to two
rotamers with a ratio of 3.4/1, major rotamer shown: d = 8.23
(1H, br s), 7.26–7.32 (5H, m), 6.99 (1H, t, J = 7.8 Hz), 6.75–6.81
(2H, m), 6.31 (1H, d, J = 7.8 Hz), 5.46 (1H, br s), 5.19 (1H, d, J =
12.3 Hz), 5.08 (1H, d, J = 12.3 Hz), 4.20–4.24 (1H, m), 3.94–4.05
(2H, m), 3.62–3.74 (2H, m), 2.79 (1H, t, J = 12.3 Hz), 2.54–2.61
(1H, m), 1.67 (3H, s), 1.55 (9H, s), 1.51 (3H, s), 1.19 (1H, d, J =
6.3 Hz), 1.06 (1H, d, J = 6.6 Hz); 13C NMR (75 MHz, CDCl3)
major rotamer shown: d = 174.6, 152.1, 142.4, 138.1, 136.0, 128.3,
128.1, 127.9, 123.3, 121.7, 115.6, 111.7, 101.9, 100.7, 93.5, 80.0,
66.1, 65.3, 64.3, 59.2, 30.3, 29.3, 28.3, 27.7, 24.3, 20.7, 19.5; HRMS
(ESI): m/z calcd. for C31H41N3O5Na: 558.2938; found: 558.2930.
1
8.49 (1H, br s), 6.95 (1H, t, J = 7.6 Hz), 6.83–6.86 (2H, m), 6.36
(1H, d, J = 7.6 Hz), 5.49 (1H, d, J = 6.4 Hz), 4.25 (2H, br s), 3.72
(1H, br s), 3.52 (1H, d, J = 10.4 Hz), 3.43 (1H, d, J = 10.4 Hz), 3.17
(1H, d, J = 12.0 Hz), 2.94–3.00 (1H, m), 1.46 (9H, s); 13C NMR
(100 MHz, CDCl3): d = 156.2, 139.4, 137.9, 122.6, 122.5, 117.4,
111.0, 107.1, 103.9, 79.4, 62.1, 54.7, 28.4, 28.2; HRMS (ESI): m/z
calcd. for C16H24N3O3: 306.1812; found: 306.1807.
23
Compound 15. White foam; [a]D -47.8 (c 1.00, CHCl3);
n
max(KBr)/cm-1: 3400, 2965, 1694, 1513, 1366, 1164, 731; 1H NMR
(400 MHz, CDCl3): d = 8.43 (1H, br s), 7.33–7.34 (5H, m), 6.96
(1H, t, J = 8.0 Hz), 6.88 (1H, s), 6.80 (1H, d, J = 8.0 Hz), 6.23 (1H,
d, J = 8.0 Hz), 5.47 (1H, br s), 5.40 (1H, d, J = 7.6 Hz), 5.16 (2H,
s), 4.00 (1H, d, J = 7.2 Hz), 3.76–3.77 (1H, m), 3.63 (1H, d, J =
12.4 Hz), 3.53 (1H, d, J = 12.4 Hz), 3.12–3.23 (2H, m), 2.15–2.23
(1H, m), 1.47 (9H, s), 1.13 (1H, d, J = 6.8 Hz), 1.03 (1H, d, J = 6.8
Hz); 13C NMR (100 MHz, CDCl3): d = 175.9, 155.9, 141.8, 137.6,
135.3, 128.6, 128.5, 128.4, 123.0, 122.2, 116.2, 111.6, 102.8, 100.6,
79.3, 66.9, 62.5, 62.0, 55.3, 31.7, 28.6, 28.4, 19.6, 19.3; HRMS
(ESI): m/z calcd. for C28H38N3O5: 496.2806; found: 496.2802.
(-)-Indolactam V (1). 10% Palladium on carbon (44 mg) was
added to a solution of 21 (370 mg) in methanol (12 mL), and the
mixture was hydrogenolyzed with hydrogen (4 atm) for 30 min,
at which point TLC indicated the complete consumption of the
starting material. The reaction mixture was filtered through celite
and the solvent removed by evaporation. The residue was dissolved
◦
in CH2Cl2 (15 mL) and cooled to 0 C, TFA (3 ◦mL) was added
dropwise. The reaction mixture was stirred at 0 C for 3 h, and
then the solvent was removed in vacuo to give the residue, which
was dissolved in dry THF (20 mL, 0.035 M). To this solution was
added HATU (394 mg) and DIPEA (3.0 mL), and then stirred at
room temperature under argon atmosphere for 48 h. Evaporation
of the solvent gave a residue that was dissolved in EtOAc, washed
with brine and dried over Na2SO4. The solvent was removed under
reduced pressure to give crude des-N-methylindolactam V. To a
solution of this crude product in acetonitrile (10 mL) at 0 ◦C
was added formalin (37%, 514 mL), sodium cyanoborohydride
(217 mg) and acetic acid (68 mL), and the solution was stirred
at 0 ◦C for 1 h. The reaction mixture was diluted with water
4-Nitrotryptophanol derivative 4. To a degassed solution of 3-
nitro-2-iodoaniline 5 (646 mg), aldehyde 7 (630 mg) and DABCO
(1.62 g) in DMF (8.5 mL) was added Pd(OAc)2 (55 mg), and
the resultant reaction mixture was stirred at 80 ◦C under argon
atmosphere for 12 h. Water was added to the reaction mixture
after cooling, and then extracted with EtOAc. The combined
organic layers were washed with brine and dried over Na2SO4.
Purification by FCC (PE-EtOAc, 3 : 1 to 2 : 1) afforded 4 (689 mg,
75%) as yellowish foam. Recry◦stallization from CH2Cl2 gave 4
23
as yellowish cube, mp 176–177 C; [a]D -71.5 (c 1.00, CHCl3);
2516 | Org. Biomol. Chem., 2011, 9, 2512–2517
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and extracted with EtOAc. The combined organic phases were
washed with brine and dried over Na2SO4. Purification by FCC
(CH2Cl2-MeOH, 25 : 1) afforded (-)-Indolactam V (115 mg, 55%)
1994, 35, 8549–8552; (i) B. Meseguer, D. Alonso-D´ıaz, N. Griebenow,
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H. Waldmann, Chem.–Eur. J., 2000, 6, 3943–2957.
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Natsume, Tetrahedron, 1990, 46, 5113–5120; (f) H. Muratake and M.
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as yellowish foam. [a]D -196 (c 1.00, EtOH), [lit.3 [a] -170 (c
23
1
0.499, EtOH)]; H NMR (400 MHz, CDCl3), show the presence
of two rotamers in a ration of 5.9/1, major rotamer shown: d =
8.13 (1H, br s), 7.72 (1H, br s), 7.05 (1H, t, J = 8.0 Hz), 6.90 (1H,
d, J = 8.0 Hz), 6.89 (1H, br s), 6.49 (1H, d, J = 8.0 Hz), 4.40 (1H,
d, J = 10.0 Hz), 4.31–4.33 (1H, m), 3.73 (1H, dd, J = 3.6, 11.6 Hz),
3.58 (1H, dd, J = 8.4, 11.6 Hz), 3.17 (1H, d, J = 17.6 Hz), 3.05
(1H, dd, J = 3.6, 17.6 Hz), 2.91 (3H, s), 2.54–2.63 (1H, m), 0.93
(1H, d, J = 6.4 Hz), 0.63 (1H, d, J = 6.8 Hz); 13C NMR (75 MHz,
CDCl3), major rotamer shown: d = 174.9, 147.8, 139.5, 122.7,
121.5, 118.0, 114.4, 106.3, 104.1, 71.0, 64.8, 55.9, 33.8, 32.9, 28.4,
21.5, 19.3; HRMS (ESI): m/z calcd. for C17H24N3O2: 302.1863;
found: 302.1858.
Acknowledgements
Financial support from the National Natural Science Foundation
of China (NO. 20802005, 20972007), the National Basic Research
Program of China (973 Program, NO. 2010CB833200), NCET,
and Peking University are greatly appreciated.
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Org. Biomol. Chem., 2011, 9, 2512–2517 | 2517
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