Polycyclic indole alkaloid-type compounds by MCR

Article abstract of DOI:10.1039/b917660h

Polycyclic indole moieties are often part of bioactive natural or synthetic products, however traditionally have to be synthesized over several steps involving time consuming sequential multi-step syntheses. We herein communicate an efficient and flexible

Full text of DOI:10.1039/b917660h

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Polycyclic indole alkaloid-type compounds by MCRw
a
b
a
¨
Wei Wang, Eberhardt Herdtweck and Alexander Domling*
Received (in Cambridge, UK) 26th August 2009, Accepted 25th November 2009
First published as an Advance Article on the web 11th December 2009
DOI: 10.1039/b917660h
Polycyclic indole moieties are often part of bioactive natural or
synthetic products, however traditionally have to be synthesized
over several steps involving time consuming sequential multi-step
syntheses. We herein communicate an efficient and flexible
2-step procedure to complex multicyclic indole alkaloid-type
compounds involving Ugi MCR and Pictet–Spengler reaction.
unprotected 2-isocyanoethylindole 1 with 2-formyl benzoic
acid 3 and aminoacetaldehyde dimethyl acetal 4 and the Ugi
product of this transformation can be isolated in 65% yield.
Acid-mediated PS reaction, however, yielded only very poor
yields of the expected product 7 despite extensively varying the
conditions including temperature, solvent and acid catalyst
(Scheme 1). Interestingly, protection of the indole proton by a
Boc group 2 increased the yield of the PS reaction to 80% 7
upon treatment of the Ugi product 6 with formic acid at room
temperature. Two diastereomers of 7 were separated in the
following PS reaction with a 3 : 1 ratio.
The Pictet–Spengler reaction (PS-2CR) is an intramolecular
variant of the Mannich three component reaction and is very
useful for the assembly of natural products and biopharma-
ceutical compounds.1 Several years ago we reported on the
combination of the Ugi and PS-2CR2 and in the meantime the
combination of MCRs and PS-2CR became quite popular to
rapidly assemble molecular diversity.3 For example the orexin I
antagonist almorexant (Fig. 1) currently undergoing phase III
clinical trials for sleeping disorders has been discovered by a
combination of the Ugi-3CR and a subsequent PS-2CR.4
Herein we wish to report on the first Ugi–PS combination
where electron rich indolethylamine-derived isocyanides react
in the Ugi–PS reactions with a diversity of bifunctional
ketocarboxylic acid derivatives and orthogonally protected
aminoacetaldehyde, to yield structurally intriguing polycyclic
indole alkaloid-type compounds.
We investigated the reaction and introduced different
starting materials to find out scope and limitations (Scheme 2).
Not to our surprise the Ugi reaction in most cases went very
well despite the fact that in several cases quaternary carbon
centres and sterically encumbered products are formed.
Only with the 6-oxoheptanoic acid 9, the Ugi product could
not be produced presumably due to intermolecular reactions.
The other oxo components reacted in mostly good to
very good yields (Table 1). Even hindered cyclic ketones
(10 2-(2-oxocyclopentyl)acetic acid) reacted satisfactorily.
The Ugi products were isolated and purified before subjecting
them to the PS procedure. Typically the Ugi products were
formed as mixtures of enantiomers or diastereomers in equal
or almost equal ratio, respectively.
We recently introduced tryptophane-derived isocyanides for
use in Ugi reactions with the aim to use the resulting molecules
for further transformations involving indoles.5 Specifically, we
are interested in the reaction of the intermediate Ugi products
in the PS reaction to build-up polycyclic indole alkaloid-type
compounds. We initially reported one case of the Ugi–Pictet–
Spengler transformation cascade leading to a polycyclic
product and would like to report here details on this synthesis
strategy.5a Additionally we also introduce here aliphatic and
cyclic oxocarboxylic acids leading to a much greater diversity
of products.
Ugi–PS compound 16 contains three stereocenters and gives
rise to 8 stereoisomers. The intermediate Ugi products 21 and
22 have only two stereocenters and could be separated by
chromatography in 45% and 15% yields, respectively. The
subsequent PS reactions yielded a third stereocenter. Starting
from Ugi product 21 PS products 16a and 16b could be
separately isolated in 58% and 38% yields, respectively;
whereas Ugi product 22 yielded an inseparable 1 : 1 mixture
of PS product 16c in 70% yield. The relative stereochemistry
of the separate diastereomers 16a and 16b has been assigned
by 2D NMR experiments (ESIw). Fortunately, the polar
diastereomer of 16b, a hexacyclic indole derivative also
crystallized and yielded X-ray diffraction suitable crystals.
The structure of 16b in the solid state is shown in Fig. 2.
Ketocarboxylic acids are known to be bifunctional
substrates in Ugi chemistry yielding lactams of varying ring
sizes. However in order to perform a PS reaction an oxo
component has to react with an indolethylamine fragment.
Thus we introduced a protected aldehyde fragment the amine
component in the Ugi reaction by employing aminoacetalde-
hyde dimethyl acetal 4.z In a first example we reacted
a University of Pittsburgh, Drug Discovery Institute, Pittsburgh,
PA 15261, USA. E-mail: asd30@pitt.edu; Fax: +1 412-383-5298;
Tel: +1 412-383-5300
b Technische Universitat Munchen, Lehrstuhl fur Anorganische
¨
Chemie, Garching bei Munchen, Germany
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¨
¨
w Electronic supplementary information (ESI) available: 1D and 2D
NMRs of novel compounds, crystallographic details. CCDC 749252.
For ESI and crystallographic data in CIF or other electronic format
see DOI: 10.1039/b917660h
Fig. 1 Almorexants as an example of a compound discovered by the
efficient sequence Ugi-3CR and PS-2CR.
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Scheme 1 Synthesis sequence involving an intramolecular U-4CR and a subsequent PS-2CR.
Scheme 2 General structure scheme of Ugi–PS sequence.
The X-ray structure is fully consistent with the relative stereo-
chemistry assigned by 2D NMR analysis (Fig. 3).
The ease of synthesis and the increase in molecular complexity
during the 2-step sequence are worthwhile mentioning, e.g. 16
could be formed in 50% yield over two steps, which is excellent
when considering that six new bonds are formed (2 C–C,
1 C–O, 3 C–N). In fact, the yield per bond formation is 89%.
16 is a highly complex molecule containing in total 6 cycles,
4 heterocycles (pyrrole, piperazinone, hydropyridine, g-lactam)
and two carbocyles (benzene, cyclopentane). Three cycles are
annulated, and three cycles, however are connected to each
other via a common quaternary carbon which is formed during
the Ugi reaction. The ring sizes comprise three 5-membered
and three 6-membered rings.
Fig. 2 ORTEP style plot of compound 16b in the solid state. Thermal
ellipsoids are drawn at the 50% probability level.
In summary we have described a very efficient two step
sequence towards highly complex polycyclic indole alkaloid-type
Fig. 3 Relative configuration of 16b as of X-ray analysis.
Table 1 Polycyclic indole product results
Oxo carboxylic
acid
Polycyclic
indole product
Diastereomer 21
45% + 22 15%b,d
16a 58% + 16c 70% 17 48%
16b 38%d (1 : 1)c (1 : 1.58)c
Ugi product
PS product
6 60%a
20 80%b
14 63% (3 : 1)c No
No
23 55%b
24 53%b
25 60%a
7a 60% +
7b 20%d
19a 45% +
19b 50%d
18 48% (1 : 1)c
b
c
All yields refer to isolated yields.a Reaction with aminoacetaldehyde dimethyl acetal. Reaction with aminoacetaldehyde diethyl acetal. The
d
products are the two diastereomer mixtures, the ratio of diastereomer is shown. The two diastereomers are separated.
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molecules involving an Ugi-4CR and a subsequent PS
reaction. Significantly, aliphatic acyclic and cyclic as well as
aromatic oxo acids are substrates for this reaction sequence.
Scope and limitation of the sequence are described. Further
work is being performed in our laboratory to investigate the
intriguing biological activities of these molecules and will be
reported in due course.
Evaporation and purification by preparative TLC or column chromato-
graphy gave the corresponding polycyclic product.
Less polar product 16a, C20H21N3O2, Mw: 335.40 g molꢁ1; HRMS
(ESI-TOF) m/z (calc.): 335.1634, (found) [M]+
: 335.1598, m/z
[M + H]+: 336.2. 1H-NMR (CDCl3, 600 MHz): d = 1.62 (dt, J =
7.98, 5.63 Hz, 1 H), 1.91 (dd, J = 8.24, 14.42 Hz, 1 H), 1.95 (dd, J =
8.24, 11.20 Hz, 1 H), 2.22 (m, 1 H), 2.35 (m, 4 H), 2.59 (dd, J = 4.22,
14.29 Hz, 1 H), 2.75 (ddd, J = 3.81, 10.21, 22.61 Hz, 1 H), 2.80
(m, 1 H), 2.86 (ddt, J = 2.58, 5.85, 6.75 Hz, 1 H), 3.27 (dd, J = 11.31,
13.11 Hz, 1 H), 4.96 (dd, J = 5.94, 13.32 Hz, 1 H), 5.11 (dd, J = 4.42,
12.76 Hz, 1 H), 5.20 (dd, J = 5.92, 11.08 Hz, 1 H), 7.14 (t, J =
7.32 Hz, 1 H), 7.22 (t, J = 7.59 Hz, 1 H), 7.37 (d, J = 8.10 Hz, 1 H),
7.53 (d, J = 7.80 Hz, 1 H), 9.03 (s, 1 H). 13C-NMR (CDCl3, 150.92 MHz):
d = 21.2, 22.9, 26.4, 32.7, 34.9, 40.2, 43.2, 50.2, 51.3, 73.7, 110.1,
111.2, 118.4, 119.9, 122.4, 126.4, 130.5, 136.6, 169.7, 183.2.
Notes and references
z General procedure for Ugi reaction: 1 mmol of aldehyde or ketone
acid was dissolved in 1 mL MeOH, 1 mmol of isocyanide and 1mmol
amino acetal were added into the solution. The solution was stirred for
24 hours at rt. The solution was evaporated and purified by SiO2
column chromatography to give the Ugi product.Ugi product 21,
3-(2-{[1-(2,2-diethoxy-ethyl)-2-oxo-hexahydro-cyclopenta[b]pyrrole-6a-
carbonyl]-amino-ethyl)-indole-1-carboxylic acid tert-butyl ester,
C29H41N3O6, Mw: 527.65 g molꢁ1; HRMS (ESI-TOF) m/z (calc.):
527.2995, (found) [M]+
: 527.3001; HPLC-MS rt: 12.06, m/z
[M ꢁ Boc]+: 426.0. 1H-NMR (CDCl3, 600 MHz): d = 1.17 (t, J =
7.02 Hz, 3 H), 1.19 (t, J = 7.02 Hz, 3 H), 1.68 (s, 9 H), 1.80 (m, 1 H),
2.10 (m, 2 H), 2.22 (m, 2 H), 2.29 (dd, J = 6.17, 14.83 Hz, 1 H), 2.39
(t, J = 14.57 Hz, 1 H), 2.91 (dt, J = 1.56, 3.62 Hz, 1 H), 3.36 (q, J =
7.02 Hz, 1 H), 3.45 (dd, J = 7.10, 9.24 Hz, 1 H), 3.54 (m, J = 6.80 Hz,
1 H), 3.61 (m, 3 H), 3.72 (q, J = 5.47 Hz, 1 H), 4.61 (t, J = 4.72 Hz,
1 H), 6.69 (t, J = 5.48 Hz, 1 H), 7.26 (t, J = 7.74 Hz, 1 H), 7.33 (t, J =
7.50 Hz, 1 H), 7.41 (s, 1 H), 7.55 (d, J = 7.55 Hz, 2 H), 8.16 (s, 1 H).
13C-NMR (CDCl3, 150.92 MHz): d = 15.2, 15.3, 22.4, 25.0, 26.5, 28.2,
30.5, 33.8, 39.6, 44.8, 52.4, 62.8, 62.9, 100.1, 115.3, 117.5, 118.8, 122.6,
123.0, 124.5, 130.5, 172.0, 180.2.
More polar product 16b, C20H21N3O2, Mw: 335.40 g molꢁ1; HRMS
(ESI-TOF) m/z (calc.): 335.1634, (found) [M]+: 335.1598; HPLC-MS
rt: 10.05, m/z [M + H]+: 336.2. 1H-NMR (CDCl3, 600 MHz): d =
1.83–1.91 (m, 2 H), 2.01 (dd, J = 13.22, 7.93, 1 H), 2.03–2.16 (m, 3 H),
2.35 (t, J = 14.52 Hz, 1 H), 2.44 (dd, J = 6.00, 15.12 Hz, 1 H),
2.48–2.55 (m, 1 H), 2.78 (ddd, J = 1.67, 4.87, 15.63 Hz, 1 H),
2.84–2.86 (m, 1 H), 3.05 (ddd, J = 4.33, 12.84, 11.16 Hz, 1 H), 3.79
(dd, J = 6.06, 12.30 Hz, 1 H), 3.94 (dd, J = 10.06, 12.20 Hz, 1 H), 4.67
(ddd, J = 2.48, 5.09, 12.86 Hz, 1 H), 5.03 (dd, J = 6.18, 9.96 Hz, 1 H),
7.15 (t, J = 7.46 Hz, 1 H), 7.20 (t, J = 7.07 Hz, 1 H), 7.33 (d, J =
8.10 Hz, 1 H), 7.52 (d, J = 7.93 Hz, 1 H), 8.16 (s, 1 H). 13C-NMR
(CDCl3, 150.92 MHz): d = 20.2, 22.0, 25.2, 31.8, 33.9, 39.3, 46.6, 48.8,
49.5, 72.0, 110.2, 111.2, 118.5, 120.0, 122.6, 126.5, 129.4, 136.7, 171.4,
182.3.
Ugi product 22, 3-(2-{[1-(2,2-diethoxy-ethyl)-2-oxo-hexahydro-
cyclopenta[b]pyrrole-6a-carbonyl]-amino}-ethyl)-indole-1-carboxylic
acid tert-butyl ester, C29H41N3O6, Mw: 527.65 g molꢁ1; HRMS (ESI-TOF)
m/z (calc.): 527.2995, (found) [M]+: 527.3001; HPLC-MS rt: 12.04,
m/z [M + H]+: 426.2. 1H-NMR (CDCl3, 600 MHz): d = 1.05 (t, J =
7.08 Hz, 3 H), 1.17 (t, J = 7.02 Hz, 3 H), 1.43 (m, 1 H), 1.59 (m, 1 H),
1.65 (m, 1 H), 1.77 (m, 1 H), 1.87 (m, 1 H), 2.02 (dd, J = 1.77,
17.43 Hz, 1 H), 2.08 (m, 1 H), 2.34–2.38 (m, 2 H), 2.60 (dd, J = 17.4,
9.78 Hz, 1 H), 2.72 (w, 1 H), 2.79 (dd, J = 7.41, 14.01 Hz, 1 H), 2.93
(t, J = 7.29 Hz, 2 H), 3.39 (dd, J = 4.21, 13.92 Hz, 1 H), 3.47 (m, 2 H),
3.52 (m, 1 H), 3.57 (dt, J = 7.02, 6.57 Hz, 1 H), 3.66 (dt, J = 7.16,
7.96 Hz, 1 H), 3.68 (dd, J = 5.48, 16.05 Hz, 1 H), 5.33 (dd, J = 4.32,
7.32 Hz, 1 H), 7.22 (t, J = 7.44 Hz, 1 H), 7.29 (dd, J = 6.69, 14.25 Hz,
1 H), 7.37 (s, 1 H), 7.55 (d, J = 7.93 Hz, 2 H), 7.98 (t, J = 5.67 Hz,
1 H), 8.12 (s, 1 H). 13C-NMR (CDCl3, 150.92 MHz): d = 15.2, 15.5,
24.8, 25.5, 28.2, 34.1, 35.0, 37.0, 39.7, 43.7, 46.2, 63.8, 64.9, 78.6, 83.4
(rotamer), 99.4, 115.3, 117.8, 118.8, 122.4, 123.0, 124.4, 130.5, 135.5
(rotamer), 149.6 (rotamer), 174.0, 177.1.
X-Ray single crystal structure analysis of compound 16b:
C20H21N3O2, Mr = 335.40, colorless fragment, monoclinic, P21/c
(no.: 14), a = 11.3899(5), b = 8.9061(4), c = 16.9450(7) A, b =
94.3181(18)1, V = 1714.02(13) A3, Z = 4, dcalc = 1.300 g cmꢁ3
,
F000 = 712, m = 0.686 mmꢁ1, 11 088 reflections, Rint = 0.023, 2862
independent data [2665: Io 4 2s(Io)], R1 = 0.0329 [Io 4 2s(Io)],
wR2 = 0.0817 [all data]. For more detailed information see the ESI.w
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(b) W. M. Whaley and T. R. Govindachari, in Organic Reactions,
ed. R. Adams, John Wiley & Sons, New York, 1951, pp. 151–190.
2 A. Domling and I. Ugi, Angew. Chem., Int. Ed., 2000, 39,
¨
3169–3210.
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15460–15461; (b) L. El Kaim, M. Gageat, L. Gaultier and
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¨
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J.-Y. Laronze, ARKIVOC, 2004, 208–222.
4 (a) C. Boss, C. Brisbare-Roch and F. Jenck, J. Med. Chem., 2009,
52, 891–903; (b) H. Aissaoui, M. Cappi, M. Clozel, W. Fischli and
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¨
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product was dissolved in 0.5 ml of HCOOH and stirred for 4 h at rt.
N. E. Shevchenko, E. S. Balenkova, G.-V. Roschenthaler and
¨
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This journal is The Royal Society of Chemistry 2010
772 | Chem. Commun., 2010, 46, 770–772