First synthesis of N-indigoglycosides - Analogues of cancerostatic akashines

Article abstract of DOI:10.1055/s-2005-918489

The first and surprisingly simple synthesis of N-indigoglycosides has been accomplished based on glycosylation of N-benzylindigo with tri-O-pivaloyl- α-L-rhamnosyl trichloroacetimidate and subsequent rearrangement of the O- into the N-glycoside. N-Indigog

Full text of DOI:10.1055/s-2005-918489

PAPER
3531
First Synthesis of N-Indigoglycosides – Analogues of Cancerostatic Akashines
F
irst Synthesis of
N
-
In
a
digoglycosi
r
des tin Hein,*a Dirk Michalik,b Peter Langer*a,b
a
b
Received 9 October 2005
Dedicated to Professor Steven V. Ley, FRS, on the occasion of his 60th birthday
NH2
OH
OH
Abstract: The first and surprisingly simple synthesis of N-indi-
H3C
goglycosides has been accomplished based on glycosylation of N-
benzylindigo with tri-O-pivaloyl-a-L-rhamnosyl trichloroacetimi-
date and subsequent rearrangement of the O- into the N-glycoside.
N-Indigoglycosides are of considerable pharmacological relevance
and occur in cancerostatic natural akashines.
O
O
Cl
N
N
Cl
H
O
Key words: indigo, N-heterocycles, rearrangements, regioselectiv-
ity
Akashine A
Figure 1 Akashine A isolated from terrestric Streptomyces
Heterocyclic N-glycosides are of considerable pharmaco-
logical relevance and occur in a number of unusual natural
products. For example, indolo[2,3-a]carbazole glyco-
sides, including the natural products staurosporine, K-
252d, rebeccamycin, and the tjipanazoles,1,2 represent
promising anticancer agents; for example, rebeccamycin
induces a topoisomerase I mediated DNA cleavage.3 Syn-
thetically available indigo and 6,6¢-dibromoindigo (pur-
pur) represent well-known dyes which have been used for
a long time; they possess many technical applications and
are of considerable theoretical interest.4 Indigo has been
isolated from many plants and fungi.5 Until recently, only
three natural derivatives of indigo – the well-known pur-
pur (isolated from purpur snail)6a and two other brominat-
ed indigos6b – were known. In 2002, Laatsch et al.
reported the isolation of akashine A, B and C from ter-
restric Streptomyces (Figure 1).7 Besides the indigo moi-
ety, the akashines contain a N-glycosidic 4-amino-4,6-
didesoxyglucose (akashine A) or a 4-acetamido-4,6-
didesoxyglucose moiety (akashine B). They exhibit a con-
siderable activity against various human tumor cell lines,
in contrast to pharmacologically inactive indigo. Herein,
we report what is, to the best of our knowledge, the first
synthetic approach to N-indigoglycosides.
lied on the glycosylation of glycine derivatives, intramo-
lecular acylation, to give a glycosylated indoxyl, and
subsequent oxidative dimerization. This approach again
failed, due to deglycosylation during the formation of the
indoxyl moiety. Our third approach took advantage from
the higher solubility of di-O-pivaloylleukoindigo (2),
readily available from indigo (1), in organic solvents
(Scheme 1). The glycosylation of 2 using a variety of con-
ditions and substrates was studied: the BF3·OEt2-mediated
reaction of 2 with tri-O-acetylglucal (3) resulted in forma-
tion of a separable mixture of the N- and C-glycosylated
indigos 4 and 5 in low yield. The anomeric configuration
in the glycosides was proved to be a (4) and b (5), respec-
tively.
O
OPiv
H
N
H
N
a
N
N
H
H
O
PivO
1
2
AcO
AcO
O
b
The synthesis of heterocyclic N-glycosides is not straight-
forward in many cases. For example, Van Vranken et al.
reported that the direct glycosylation of fully unsaturated
bis-indoles failed; eventually, the glycosylation of 2,2¢-in-
dolylindolines and subsequent oxidation led to the desired
product.8 In fact, our initial attempts to prepare N-indi-
goglycosides were unsuccessful: the direct acid-mediated
glycosylation of indigo failed, due to the low solubility of
the latter in nearly all solvents. An alternative strategy re-
AcO
3
PivO
OPiv
AcO
AcO
+
H
N
H
N
O
O
OPiv
H
N
N
PivO
AcO
AcO
5
4
Scheme 1 Glycosylation reaction of O-pivaloylleukoindigo (2).
Reagents and conditions: a) 1) Na2S2O4, NaOH, H2O, 50 °C, 20 min;
2) PivCl, –10 → 0 °C, 45%; b) BF3·OEt2, 4Å MS, CH2Cl2, –10 →
20 °C, 8 h.
SYNTHESIS 2005, No. 20, pp 3531–3534
Advanced online publication: 24.11.2005
DOI: 10.1055/s-2005-918489; Art ID: C19205SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
5

3532
M. Hein et al.
PAPER
Our final and successful strategy is depicted in Scheme 2. 100 °C) resulted in complete debenzylation and formation
N-Benzylindigo (6), which shows a good solubility in of N-indigoglycoside 10 in high yield. The cleavage of the
many organic solvents, was prepared by reaction of 1 with pivaloyl groups is under current investigation.
sodium hydride and benzyl bromide in DMF.9 The
The structures of the indigoglycosides were investigated
by NMR spectroscopy. For example, it has been con-
TMSOTf-mediated reaction of 6 with tri-O-pivaloyl-a-L-
rhamnosyl trichloroacetimidate (7)10 afforded the O-indi-
firmed that 9 again exists as an N-glycoside containing an
goglycoside 8 (4Å MS, CH2Cl2, –20 °C, 1.5 h). Interest-
a-rhamnose moiety. The NMR signals of 4, 5, and 9 were
ingly, extension of the reaction time (20 °C, 8–12 h)
1
assigned by DEPT and two-dimensional H,1H-COSY,
resulted in the rearrangement of 8 into the desired N-indi-
goglycoside 9. Further extension of the reaction time or
elevated temperature resulted in a dramatic decrease in
yield, due to side reactions. Besides using 6 as starting
material, the O → N rearrangement – which is, to the best
of our knowledge, unprecedented so far – represents the
key step of our synthesis. Hydrogenation of 9 resulted in
1
1H,1H-NOESY and H,13C correlation spectra (HSQC,
HMBC) recorded with a Bruker Avance 500 spectrome-
ter. For example, in the HMBC spectrum of 9 cross peaks
were found for C-14a with H-11,13,CH2; C-7a with H-
4,6,15; C-10a with H-12; C-3a with H-5. In the NOESY
spectrum cross peaks were found for H-20 with H-
15,18,19; H-14 with H-13,CH2(b); and H-7 with H-16.
discharge of the colour indicating reduction of the indigo
The NMR results confirm the suggested structure given in
moiety rather than debenzylation. However, we observed
Figure 2. Interestingly, the rhamnose possesses a 4C1 con-
that an NMR solution of 9 slowly underwent oxidative de-
benzylation in the presence of air.11 In fact, by stirring an
AcOH solution of 9 in an oxygen atmosphere (2 h,
formation which is supported by 3J15,16 = 9.8 Hz, 3J18,19
=
<1.0 Hz, and by an NOE between H-15 and H-20.
m
p
o
O
O
i
H
N
H
N
a
O
3
4
7
14
3a
14a
10a
OPiv
5
6
8 N
9
13
12
N
N
2
H
Bn
O
O
19
18
O
1
10
N
7a
16
N
1
11
6
O
15
17
20
15
O
Me
O 16
19 Me20
OPiv
H3C
PivO
PivO
HN
O
OPiv
α-L-Rhamnose 4C1
18
O
CCl3
17
O
O
O
O
b
O
OPiv
7
Figure 2 Structure elucidation of N-indigoglycoside 9
OPiv
OPiv
PivO
PivO
H3C
OPiv
OPiv
In conclusion, we have reported the first and surprisingly
simple synthesis of N-indigoglycosides. Our approach re-
lies on, firstly, the glycosylation of N-benzylindigo with
tri-O-pivaloyl-a-L-rhamnosyl trichloroacetimidate and,
secondly, on the unprecedented rearrangement of the O-
into the desired N-glycoside; this rearrangement possess-
es considerable synthetic value. We believe that the strat-
egy outlined herein will be applicable to the synthesis of a
wide range of pharmacologically relevant N-indigoglyco-
sides including akashine A, B and C. These studies are
currently in progress in our laboratory.
H3C
c
O
O
O
O
N
N
N
N
Bn
O
Bn
O
9
8
d
HO
O
PivO
H3C
OH
OH
OPiv
OPiv
1
The H NMR (500.13 MHz) and 13C NMR (125.8 MHz) spectra
H3C
were recorded on a Bruker A 500 spectrometer in C6D6 as solvent.
Calibration of spectra was carried out on the solvent signals (C6D6:
1H NMR, d = 7.15; 13C NMR, d = 128.0).
O
O
O
e
N
N
N
N
H
H
O
Di-O-pivaloylleukoindigo (2)
O
Under an inert gas, indigo (1; 1 g, 3.81 mmol) was suspended in aq
NaOH solution (10 mL) containing NaOH (1.52 g, 38.1 mmol). To
the solution was added Na2S2O4 (1.00 g, 5.74 mmol) and the mix-
ture was stirred at 40–50 °C until all indigo had been dissolved (15–
20 min). Subsequently, the mixture was cooled to –10 °C and piv-
aloyl chloride (1.5 mL, 12.2 mmol) was added in small portions. Af-
ter the addition of each portion, the mixture was allowed to warm to
0 °C; and before adding the next portion the solution was cooled to
11
10
Scheme 2 Synthesis of N-indigoglycosides. Reagents and conditi-
ons: a) 1) NaH (1.0 equiv), DMF, 20 °C, 1 h; 2) BnBr (1.2 equiv),
20 °C, 1 h, 30%; b) TMSOTf, 4Å MS, CH2Cl2, –20 °C, 1.5 h; c) TM-
SOTf, 4Å MS, CH2Cl2, 20 °C, 8–12 h, 35% (based on 7); d) O2,
AcOH, 100 °C, 2 h, 90%; e) under investigation.
Synthesis 2005, No. 20, 3531–3534 © Thieme Stuttgart · New York

PAPER
First Synthesis of N-Indigoglycosides
3533
–10 °C. The addition was stopped when a sample of the mixture did
not change its colour to blue on exposure to air. H2O was added to
the solution to give a precipitate; the latter was collected by filtra-
tion, washed with H2O and MeOH and crystallized from a mixture
of THF and MeOH to give 2 as a colorless solid; yield: 740 mg
(45%).
7.24 (ddd, 1 H, 3J13,14 = 8.2 Hz, 3J12,13 = 7.0 Hz, 4J11,13 = 1.2 Hz, H-
13), 7.14 (d‘t’, 1 H, 3J5,6 = 3J6,7 = 7.5 Hz, 4J4,6 = 1.2 Hz, H-6), 7.07
3
4
(ddd, 1 H, 3J11,12 = 8.2 Hz, J12,13 = 7.0 Hz, J12,14 = 1.0 Hz, H-12),
6.95 (d‘t’, 1 H, 3J4,5 = 3J5,6 = 7.5 Hz, 4J5,7 = 1.2 Hz, H-5), 5.33 (dt, 1
H, 3J16,17 = 10.5 Hz, 4J15,17 = 3J17,18 = 2.2 Hz, H-17), 5.04 (‘q’, 1 H,
4
5
3J15,16 = 2.8 Hz, J15,17 = 2.2 Hz, J15,18 = 1.8 Hz, H-15), 4.81–4.37
(m, 2 H, H-16,18), 4.71 (dd, 1 H, 2J = 12.5 Hz, 3J19,20b = 8.2 Hz, H-
2
3
Reaction of Di-O-pivaloylleukoindigo (2) with Tri-O-acetyl-D-
glucal (3)
20b), 3.73 (dd, 1 H, J = 12.5 Hz, J19,20a = 2.0 Hz, H-20a), 3.63
(ddd, 1 H, 3J18,19 = 9.0 Hz, 3J19,20b = 8.2 Hz, 3J19,20a = 2.0 Hz, H-19),
1.79 (s, 3 H, OCOCH3), 1.54 [s, 9 H, OCOC(CH3)3] 1.39 (s, 3 H,
OCOCH3), 1.01 [s, 9 H, OCOC(CH3)3].
Under argon, compound 2 (200 mg, 0.462 mmol) was suspended in
anhyd CH2Cl2 (2 mL), containing 4Å molecular sieves (100 mg).
Subsequently, glucal 3 (123 mg, 0.452 mmol) was added and the
mixture was cooled to –10 °C. After addition of BF3·OEt2 (30 mL,
0.239 mmol), the mixture was allowed to warm to 20 °C and was
stirred for 8 h. To the solution was added a sat. aq solution of
NaHCO3 (5 mL). The aqueous and the organic layer were separated
and the latter was washed with H2O (5 mL) and brine (5 mL). The
organic layer was dried (Na2SO4), filtered and the filtrate was con-
centrated in vacuo. The products 4 and 5 were isolated by repeated
column chromatography (silica gel, n-heptane–EtOAc, 4:1) as col-
orless and yellow oils, respectively.
13C NMR (125.8 MHz, C6D6): d = 175.4 (C=O, Piv), 175.3 (C=O,
Piv), 170.7 (C=O, Ac), 168.9 (C=O, Ac), 167.9 (C-2), 156.8 (C-7a),
135.7 (C-14a), 134.2 and 134.0 (C-3a and C-10), 131.1 (C-6), 129.5
(C-17), 126.1 (C-5), 125.5 (C-16), 125.0 (C-13), 122.8 (C-4), 122.3
(C-10a), 121.5 (C-7), 120.9 (C-12), 120.7 (C-9), 119.2 (C-11),
112.9 (C-14), 92.1 (C-3), 76.6 (C-15, C-19), 64.7 (C-18), 63.1 (C-
20), 39.4 [OCOC(CH3)3], 39.1 [OCOC(CH3)3], 27.8
[OCOC(CH3)3], 27.0 [OCOC(CH3)3], 20.7 (OCOCH3), 20.1
(OCOCH3).
Indigo-N-glycoside 9
Leukoindigo-N-glycoside (4)
N-Benzylindigo (6; 100 mg, 0.284 mmol) and 2,3,4-tri-O-pivaloyl-
L-rhamnopyranosyl trichloroacetimidate (7; 155 mg, 0.276 mmol)
were dissolved in anhyd CH2Cl2 (2 mL), containing molecular
sieves (4 Å, 200 mg), under argon. The mixture was cooled to
–20 °C and TMSOTf (20 mL, 0.111 mmol) was added. After stirring
for a short time, a red-violet spot was detected by TLC indicating
the formation of 8. After stirring for 1.5 h, the mixture was warmed
to 20 °C and stirred for 8–12 h. During this time the red-violet spot
vanished while the intensity of a blue spot due to 6 increased and a
new, more polar green spot of 9 appeared. To the solution was add-
ed a sat. aq solution of NaHCO3 (5 mL). The aqueous and the organ-
ic layer were separated and the latter was washed with H2O (5 mL)
and brine (5 mL). The organic layer was dried (Na2SO4), filtered
and the filtrate was concentrated in vacuo. The residue was purified
by column chromatography (silica gel, n-heptane–EtOAc, 4:1) to
give 9 as a deep green solid; yield: 73 mg (35%).
For the numbering of atoms in 4, see Figure 3.
1H NMR (500.13 MHz, C6D6): d = 9.47 (br s, 1 H, NH), 7.87 (m, 1
3
H, H-7), 7.79 (d, 1 H, J13,14 = 8.2 Hz, H-14), 7.70 (d, 1 H,
3J11,12 = 8.0 Hz, H-11), 7.61 (m, 1 H, H-4), 7.26 (ddd, 1 H,
3J13,14 = 8.2 Hz, 3J12,13 = 7.2 Hz, 4J11,13 = 1.2 Hz, H-13), 7.18 (ddd, 1
3
3
4
H, J11,12 = 8.0 Hz, J12,13 = 7.2 Hz, J12,14 = 1.0 Hz, H-12), 7.13–
3
7.08 (m,
2 H, H-5,6), 5.97 (‘q’, 1 H, J15,16 = 2.5 Hz,
4J15,17 = 5J15,18 = 2.0 Hz, H-15), 5.70 (dt, 1 H, J16,17 = 10.2 Hz,
3
4J15,17 = 3J17,18 = 2.0 Hz, H-17), 5.60 (ddd, 1 H, J16,17 = 10.2 Hz,
3
3J15,16 = 2.5 Hz, 4J16,18 = 2.0 Hz, H-16), 5.35 (d‘q’, 1 H, 3J18,19 = 8.8
Hz, 3J17,18 = 4J16,18 = 5J15,18 = 2.0 Hz, H-18), 4.21 (dd, 1 H, 2J = 12.5
3
3
Hz, J19,20b = 2.5 Hz, H-20b), 3.88 (ddd, 1 H, J18,19 = 8.8 Hz,
3J19,20a = 3.8 Hz, J19,20b = 2.5 Hz, H-19), 3.61 (dd, 1 H, J = 12.5
Hz, 3J19,20a = 3.8 Hz, H-20a), 1.59 (s, 3 H, OCOCH3), 1.64 (s, 3 H,
OCOCH3), 1.39 [s, 9 H, OCOC(CH3)3], 1.24 [s, 9 H, OCOC(CH3)3].
3
2
13C NMR (125.8 MHz, C6D6): d = 176.6 (C=O, Piv), 176.1 (C=O,
Piv), 171.3 (C=O, Ac), 169.4 (C=O, Ac), 136.3 (C-7a), 135.6 (C-
14a), 131.7 (C-10), 131.0 (C-3), 130.2 (C-17), 127.8 (C-16), 123.9
(C-13), 123.7 (C-6), 122.9 (C-2), 121.35 and 121.28 (C-3a and C-
10a), 121.0 (C-5), 120.5 (C-12), 118.5 (C-4), 117.9 (C-11), 115.7
(C-9), 113.0 (C-7), 112.9 (C-14), 78.5 (C-15), 71.1 (C-19), 64.8 (C-
18), 61.2 (C-20), 39.3 [OCOC(CH3)3], 39.2 [OCOC(CH3)3], 27.4
[OCOC(CH3)3], 27.2 [OCOC(CH3)3] 20.4 (OCOCH3), 20.3
(OCOCH3).
1H NMR (500.13 MHz, C6D6): d = 8.05 (d, 1 H, 3J6,7 = 8.2 Hz, H-
7), 7.72 (d, 1 H, 3J4,5 = 7.5 Hz, H-4), 7.70 (d, 1 H, 3J11,12 = 7.5 Hz,
H-11), 7.22 (‘t’, 1 H, 3J6,7 = 8.2 Hz, 3J5,6 = 7.5 Hz, H-6), 7.05–6.94
(m, 5 H, C6H5), 6.77 (‘t’, 1 H, 3J13,14 = 8.2 Hz, 3J12,13 = 7.5 Hz, H-
3
13), 6.70 (‘t’, 1 H, J4,5 = 3J5,6 = 7.5 Hz, H-5), 6.51 (‘t’, 1 H,
3J11,12 = 3J12,13 = 7.5 Hz, H-12), 6.38 (d, 1 H, 3J13,14 = 8.2 Hz, H-14),
6.41 (d, 1 H, 3J15,16 = 9.8 Hz, H-15), 6.15 (dd, 1 H, 3J15,16 = 9.8 Hz,
3
3
3J16,17 = 3.2 Hz, H-16), 5.90 (‘t’, 1 H, J17,18 = 3.8 Hz, J16,17 = 3.2
Hz, H-17), 5.57 [d, 1 H, 2J = 7.5 Hz, CH2(a)], 5.47 [d, 1 H, 2J = 7.5
3
Hz, CH2(b)], 5.02 (d, 1 H, J17,18 = 3.8 Hz, H-18), 4.50 (q, 1 H,
3J19,20 = 7.5 Hz, H-19), 1.90 (d, 3 H, 3J19,20 = 7.5 Hz, H-20), 1.25 [s,
9 H, OCOC(CH3)3], 0.98 [s, 9 H, OCOC(CH3)3], 0.73 [s, 9 H,
OCOC(CH3)3].
PivO
OAc
14
4
H
N
14a
10a
3a
3
20
8
OAc
5
6
13
12
18
19
1
2
9
17
N
7a
10
O
H
15
13C NMR (125.8 MHz, C6D6): d = 185.5 and 185.1 (C-3 and C-10),
176.5, 176.3, 176.0 (3 C=O, Piv), 152.7 (C-14a), 150.8 (C-7a),
137.6 (Ci, Ph), 135.0 (C-13), 134.7 (C-6), 128.8 (CHm, Ph), 128.4
and 125.2 (C-2 and C-9), 127.2 (CHp, Ph), 126.7 (CHo, Ph), 124.24
and 124.17 (C-4 and C-11), 123.9 (C-3a), 122.7 (C-5), 122.1 (C-
10a), 121.4 (C-12), 116.5 (C-7), 112.8 (C-14), 82.4 (C-15), 74.6 (C-
19), 72.3 (C-18), 69.1 (C-17), 66.6 (C-16), 54.0 (CH2), 38.9, 38.7,
38.5 [3 OCOC(CH3)3] 27.1, 27.0, 26.9 [3 OCOC(CH3)3], 16.4 (C-
20).
11
7
OPiv
19
20
4 PivO
14
11
O
16
9
H
15
14a
16
3a
N
13
12
5
6
3
8
18
17
2
OAc
N
7a
7
10a
10
OAc
1
PivO
5
4
Figure 3
MS (CI, isobutene): m/z = 750 (M–, 100).
HRMS (ESI): m/z calcd for C44H51N2O9 ([M + H]+): 751.35946;
Leukoindigo-C-glycoside (5)
For the numbering of atoms in 5, see Figure 3.
1H NMR (500.13 MHz, C6D6): d = 10.11 (br s, 1 H, NH), 7.80 (d, 1
found: 751.35893.
H, 3J13,14 = 8.2 Hz, H-14), 7.68 (d, 1 H, 3J11,12 = 8.2 Hz, H-11), 7.55
3
3
(d, 1 H, J6,7 = 7.5 Hz, H-7), 7.31 (br d, 1 H, J4,5 = 7.5 Hz, H-4),
Synthesis 2005, No. 20, 3531–3534 © Thieme Stuttgart · New York

3534
M. Hein et al.
PAPER
(5) (a) Miles, P. G.; Lund, H.; Raper, J. R. Arch. Biochem.
Acknowledgment
Biophys. 1956, 62, 1. (b) Hosoe, T.; Nozawa, K.; Kawahara,
N.; Fukushima, K.; Nishimura, K.; Miyaji, M.; Kawai, K.
Mycopathologia 1999, 146, 9. (c) Falanghe, H.; Bobbio, P.
A. Arch. Biochem. Biophys. 1962, 96, 430. (d) Laatsch, H.;
Ludwig-Köhn, H. Liebigs Ann. Chem. 1986, 1847.
(6) (a) Friedländer, P. Justus Liebigs Ann. Chem. 1906, 351,
390. (b) Higa, T.; Scheuer, P. J. Heterocycles 1976, 4, 227.
(7) Maskey, R. P.; Grün-Wollny, I.; Fiebig, H. H.; Laatsch, H.
Angew. Chem. Int. Ed. 2002, 41, 597; Angew. Chem. 2002,
114, 623.
(8) (a) Chisholm, J. D.; Van Vranken, D. L. J. Org. Chem. 1995,
60, 6672. (b) Gilbert, E. J.; Van Vranken, D. L. J. Am. Chem.
Soc. 1996, 118, 5500.
(9) Meng, J.-B.; Li, P.; He, Y.-Z.; Xu, L.-L.; Wang, Y.-M.
Gaodeng Xuexiao Huaxue Xuebao 2001, 22, 63; Chem.
Abstr. 2002, 137, 179362.
This work was supported by the state of Mecklenburg-Vorpommern
(Landesforschungsschwerpunkt ‘Neue Wirkstoffe und Screening-
verfahren’).
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Synthesis 2005, No. 20, 3531–3534 © Thieme Stuttgart · New York