A rapid stereocontrolled synthesis of the 3a-hydroxy-pyrrolo-
[2,3-b]indole skeleton, a building block for 10b-hydroxy-
pyrazino[1Ј,2Ј:1,5]pyrrolo[2,3-b]indole-1,4-diones
Steven V. Ley,* Ed Cleator and Peter R. Hewitt
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge,
UK CB2 1EW. E-mail: svl1000@cam.ac.uk; Fax: ϩ44 (0)1223 336442;
Tel: ϩ44 (0)1223 336398
Received 21st July 2003, Accepted 8th September 2003
First published as an Advance Article on the web 15th September 2003
A
two-step selenocyclisation–oxidative deselenation
It was proposed that 3a-hydroxy-pyrroloindoles such as 2
should be available via oxidative deselenation of the corre-
sponding 3a-phenylseleno-pyrroloindoles, which were to be
obtained via selenocyclisation of a protected tryptophan deriv-
ative.6 Orthogonal N-protecting groups were desired so that
selective deprotection of the aliphatic amine could be achieved,
allowing for the desired subsequent peptide coupling without
participation of the indole nitrogen.
Accordingly, starting from commercially available N-α-Z-
tryptophan 3, esterification using thionyl chloride in methanol
and subsequent indole N-protection with di-tert-butyldicarbon-
ate (Boc2O) proceeded uneventfully to provide the diprotected
tryptophan methyl ester 4 (Scheme 3). This was subject to
selenocyclisation. The success of this selenocyclisation reaction
in terms of yield and stereocontrol (exo vs. endo products) has
been found to be dependent on the particular N-protecting
groups employed.7 Yields up to 83% have been reported as an
11 : 1 mixture of diastereomers, with the observed kinetic bias
in favour of the exo product; alternatively, the product can be
obtained diastereopure but in a modest 40% yield. We found,
however, that the present case was optimal in terms of both
yield and stereocontrol, producing exo selenide 5 in 93% yield
as a single diastereomer.
sequence was used to establish the 3a-hydroxy-pyrrolo-
[2,3-b]indole core; these tricycles were used as effective
precursors to 10b-hydroxy-pyrazino[1Ј,2Ј:1,5]pyrrolo-
[2,3-b]indole-1,4-diones.
The 10b-hydroxy-pyrazino[1Ј,2Ј:1,5]pyrrolo[2,3-b]indole-1,4-
dione core (Fig. 1) is of pharmaceutical interest. Many
biologically active natural products are also based on this
structure, such as the sporidesmins1 and certain members of
the brevianamide2 and okaramine3 families.
Fig.
1
The 10b-hydroxy-2,3,6,10b,11,11a-hexahydro-5aH-pyrazino-
[1Ј,2Ј:1,5]-pyrrolo[2,3-b]indole-1,4-dione core.
It was envisaged that compounds such as 1 could be most
efficiently prepared from tricyclic pyrroloindoles 2 (Scheme 1).
Oxidative deselenation could then be achieved. Pleasingly,
treatment of 5 with an excess of wet mCPBA afforded the
corresponding tertiary benzylic alcohol 6 in quantitative yield,
presumably via oxidation to the selenone, elimination of benz-
eneseleninic acid8 and attack of water on the carbocation thus
formed. The stereochemistry of the alcohol is constrained to be
the same as that of the parent selenide, owing to the necessarily
syn [5,5] ring junction.
Removal of the Z protecting group in 6 via catalytic
hydrogenolysis was found to proceed smoothly to afford the
monoprotected diamine 7. Attention was then turned to
effecting coupling of the amine 7 with an N-protected amino
acid. A range of coupling procedures was attempted, including
the use of acid chlorides, 1-hydroxy-7-azabenzotriazole based
reagents9 and in situ activation of the acid to the pentafluoro-
phenol ester; all such attempts, however, were unsuccessful.
Similar problems were observed by Overman and Paone in the
course of their synthesis of ditryptophenaline,10 and it is
thought that the steric environment in the neighbourhood of
the free amine is too hindered for coupling to take place.
However, it did prove possible to obtain an X-ray diffraction
crystal structure of 7, from which the absolute stereochemistry
was proven unambiguously.†
Scheme 1 Retrosynthetic approach. P = Protecting group.
Existing methods for generating compounds with the core
structures of 1 or 2 have suffered from problems with poor yield
and stereocontrol.4 One notable exception was Danishefsky’s
dimethyldioxirane (DMDO) oxidation of tryptophan deriv-
atives. Using this procedure, the 3a-hydroxy-pyrroloindole was
produced as a single diastereomer in 42% yield over four steps
from -tryptophan (Scheme 2), following extensive substrate
screening of tryptophan-derived congeners to identify the
derivative most amenable to the desired oxidative cyclisation.5
In order to reduce the steric crowding and facilitate the
necessary amide coupling, the Boc group had to be removed.
Owing to the acid-sensitivity of the aminal functionality in
the absence of electron-withdrawing groups, it was decided
to remove the Boc group before hydrogenolysis of the Z
group. Rapid protolysis with trifluoroacetic acid (TFA) gave
Scheme 2 Danishefsky’s cyclisation using DMDO.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 4 9 2 – 3 4 9 4
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 3
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