Studies towards the total synthesis of Batzelladine A: Synthesis of a model pyrrolo[1,2-c]pyrimidine

Article abstract of DOI:10.1016/S0040-4039(02)02261-X

A new approach to the synthesis of fragments related to the batzelladine alkaloids has been developed using a formal asymmetric aza-Diels-Alder reaction.

Full text of DOI:10.1016/S0040-4039(02)02261-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 9191–9194
Studies towards the total synthesis of Batzelladine A:
synthesis of a model pyrrolo[1,2-c]pyrimidine
Mark C. Elliott* and Matthew S. Long
Department of Chemistry, Cardiff University, PO Box 912, Cardiff, CF10 3TB, UK
Received 6 August 2002; revised 18 September 2002; accepted 4 October 2002
Abstract—A new approach to the synthesis of fragments related to the batzelladine alkaloids has been developed using a formal
asymmetric aza-Diels–Alder reaction. © 2002 Elsevier Science Ltd. All rights reserved.
1
1
Over the last five years we have investigated the reac-
tions of alkenylazolines with heterocumulenes, leading
to a stereoselective preparation of fused pyrimidines
generated in situ (Scheme 1). While the precise order
of steps in the formation of 4 from 3 is unknown, we
reasoned that use of a substrate such as 5 would lead to
key intermediates suitable for the synthesis of batzel-
ladine A. Herein we report the successful realization of
this approach.
1
and piperidines. It occurred to us that the placement of
functionality within our products is very similar to that
found in the bi- and tricyclic portions of the batzel-
2
ladine alkaloids, e.g. Batzelladine A (1). These natural
There are a number of approaches to compounds such
products inhibit the binding of HIV envelope glyco-
protein gp120 to CD4 receptors, and so are of potential
interest for the treatment of HIV. The limited availabil-
ity of the natural products renders them attractive
2
as 5 (R =CH OP), mostly featuring elaboration of
2
pyroglutamic acid derivatives. Initial studies showed
that O-methylation and subsequent nucleophilic attack
12
3–10
as a method of amide elaboration suffered from
reproducibility and protecting group issues. As a result
of this we used the route shown in Scheme 2, in which
all of the steps are reliable. Our approach begins with
the synthesis of ethyl (S)-pyroglutamate 7 from glu-
tamic acid 6. Thionation with Lawesson’s reagent was
followed by Eschenmoser sulfide contraction with 9 to
give 10 in good overall yield. Compound 10 was formed
as a single double bond isomer, assumed to be that
targets for total synthesis,
and so we sought to apply
our methodology in this area.
13
shown, although we were unable to observe any diag-
nostic NOE enhancements which would confirm this
assignment. Chemoselective reduction of the aliphatic
The desired approach would require a 2-alkenylpyrro-
line as substrate. Since these compounds are expected
to be tautomerically unstable with respect to the corre-
sponding enamines, we initially investigated the use of
blocked alkenylpyrrolines such as 2. This has the clear
disadvantage that additional steps are required to intro-
duce and remove the blocking group, and various prob-
lems with the preparation of such compounds led us to
abandon this route. A more efficient approach is high-
lighted by the total synthesis of saxitoxin from the
Kishi group, in which the putative alkenylpyrroline is
*
Corresponding author. Tel.: +44 (0)29 20874686; fax: +44 (0)29
0874030; e-mail: elliottmc@cardiff.ac.uk
2
Scheme 1.
0
040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02261-X

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192
M. C. Elliott, M. S. Long / Tetrahedron Letters 43 (2002) 9191–9194
Scheme 3.
Figure 1.
tions, since any isomerisation of 15 into 16 would require
elevated temperatures. However, this presumes a reac-
tion proceeding via an intermediate such as 17 (Fig. 2).
If the intermediate resembles 18, as originally proposed
by Kishi, the same major isomer would be expected,
although clearly the extent of selectivity would be
difficult to predict. However, in this case we have another
distinct possibility for the lower diastereoselectivity.
While a Z double bond, as in 17 would be expected to
lead to isomer 15, the E double bond isomer 19 would
give, via a similar transition state, the isomer 16. We
believe that this is a far more likely explanation for the
erosion of stereochemical control, and are currently
investigating these possibilities.
Scheme 2.
ester was followed by protection and de-acylation giving
the annulation precursor 13. All of these steps are
amenable to scale-up, so that multigram quantities of 13
are easily accessible. The double bond geometry in 13 was
confirmed by NOE studies.
The key annulation was initially attempted with benzoyl
isothiocyanate and acetaldehyde. However, instead of
the desired compound, 14 was formed as a single double
bond isomer (Scheme 3). The same compound can be
formed in higher yield if the acetaldehyde is omitted. This
contrasts with an earlier report in which N-acylation is
1
4,15
observed with similar substrates.
The conditions of Kishi were used next, leading to the
high-yielding formation of a mixture of diastereoisomers
1
6
1
5 and 16 in a 2:1 ratio. These isomers were readily
separated by flash column chromatography and sub-
Scheme 4.
jected to extensive NOE NMR studies. The minor isomer
1
6 shows a 1% NOE as shown in Fig. 1. While this is
small, there are no diagnostic enhancements shown by
the major isomer 15, so that on the basis of this, and
precedent from our previous work on alkenyloxazolines
1
and alkenylthiazolines, we tentatively assign the stereo-
chemistry of the two isomers as shown (Scheme 4).
Based on our previous work we might expect the
formation of isomer 15 exclusively under these condi-
Figure 2.

M. C. Elliott, M. S. Long / Tetrahedron Letters 43 (2002) 9191–9194
9193
H. L.; Hursthouse, M. B.; Malik, K. M. A. Tetrahedron
996, 52, 8315; (d) Black, G. P.; Murphy, P. J.; Walshe,
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6. Nagasawa, K.; Koshino, H.; Nakata, T. Tetrahedron
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Soc., Chem. Commun. 1995, 1369.
9. (a) Louwrier, S.; Ostendorf, M.; Tuynman, A.; Hiemstra,
H. Tetrahedron Lett. 1996, 37, 905; (b) Louwrier, S.;
Ostendorf, M.; Boom, A; Hiemstra, H.; Speckamp, W.
N. Tetrahedron 1996, 52, 2603; (c) Louwrier, S.; Tuyn-
man, A.; Hiemstra, H. Tetrahedron 1996, 52, 2629.
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L. E.; Shaka, A. J. J. Org. Chem. 1999, 64, 1512; (b)
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Scheme 5.
Finally, conversion of the thiourea into the required
guanidine was accomplished as shown in Scheme 5.
Serendipitously the silyl protecting group was removed
under these conditions, presumably as a result of
anchimeric assistance by the neighbouring guanidine.
The product 20 was isolated as the formate salt after
chromatography on silica gel, eluting with CH Cl /
2
2
7
MeOH/H O/formic acid (85:14:0.5:0.5).
2
Completion of the left hand side of Batzelladine A will
require removal of the hydroxymethyl group, which we
envisage will be accomplished by oxidation and either
deformylation or decarboxylation. Homologation of
this group and ring-closure will allow entry into the
tricyclic portion of the title natural products. These
studies are underway and will be reported in due
course.
11. (a) Tanino, H.; Nakata, T.; Kaneko, T.; Kishi, Y. J. Am.
Chem. Soc. 1977, 99, 2818; (b) Kishi, Y. Heterocycles
Acknowledgements
1980, 14, 1477; (c) Hong, C. Y.; Kishi, Y. J. Am. Chem.
Soc. 1992, 114, 7001.
1
2. For example, see: Thanh, G. V.; C e´ l e´ rier, J.-P.; Lhomet,
G. Tetrahedron: Asymmetry 1996, 7, 2211. This report
used an acetate protecting group which would be incom-
patible with subsequent steps in our synthesis.
We would like to thank the EPSRC for a studentship
(
to M.S.L.) and Cardiff University and The Royal
Society for additional support. We gratefully acknowl-
edge the EPSRC Mass Spectrometry Service, University
of Wales Swansea, for the provision of high-resolution
mass spectrometric data.
13. Bachi, M. D.; Breiman, R.; Meshulam, H. J. Org. Chem.
1983, 48, 1439.
1
4. Bahaji, H.; Bastide, P.; Bastide, J.; Rubat, C.; Tronche,
P. Eur. J. Med. Chem. 1988, 23, 193.
1
5. We have some concerns about the structural assignments
as given in Ref. 14. For instance, for compound 21 the
chemical shift of the alkene hydrogen was reported as 7.6
ppm, while that in compound 22 is reported as 6.5 ppm.
Additionally these compounds give peaks assigned to
N–H hydrogens at 7.3 and 5.4 ppm respectively. In
comparison, the alkene hydrogen in compound 13 res-
onates at 4.5 ppm.
References
1
. (a) Elliott, M. C.; Kruiswijk, E. Chem. Commun. 1997,
311; (b) Elliott, M. C.; Kruiswijk, E.; Willock, D. J.
Tetrahedron Lett. 1998, 39, 8911; (c) Elliott, M. C.;
Monk, A. E.; Kruiswijk, E.; Hibbs, D. E.; Jenkins, R. L.;
Jones, D. V. Synlett 1999, 1379; (d) Elliott, M. C.;
Kruiswijk, E. J. Chem. Soc., Perkin Trans. 1 1999, 3157;
2
(e) Elliott, M. C.; Kruiswijk, E; Willock, D. J. Tetra-
hedron 2001, 57, 10139.
2
. (a) Patil, A. D.; Kumar, N. V.; Kokke, W. C.; Bean, M.
F.; Freyer, A. J.; De Brosse, C.; Mai, S.; Truneh, A.;
Faulkner, D. J.; Cart e´ , B.; Breen, A. L.; Hertzberg, R. P.;
Johnson, R. K.; Westley, J. W.; Potts, B. C. M. J. Org.
Chem. 1995, 60, 1182; (b) Patil, A. D.; Freyer, A. J.;
Taylor, P. B.; Cart e´ , B.; Zuber, G.; Johnson, R. K.;
Faulkner, D. J. J. Org. Chem. 1997, 62, 1814.
Comparison with other examples in the literature show
3
. For a review, see: Heys, L.; Moore, C. G.; Murphy, P. J.
Chem. Soc. Rev. 2000, 29, 57.
that for compound 22 the reported shift is typical, while
17
that in 21 seems to us to be too high. The differing
reaction conditions for the formation of the two com-
pounds should also be considered. Compound 21 was
formed under reflux (benzene) while 22 was formed at
room temperature. It is reasonable to expect C-acylation
4. (a) Murphy, P. J.; Williams, H. L.; Hursthouse, M. B.;
Malik, K. M. A. J. Chem. Soc., Chem. Commun. 1994,
1
19; (b) Murphy, P. J.; Williams, H. L. J. Chem. Soc.,
Chem. Commun. 1994, 819; (c) Murphy, P. J.; Williams,

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M. C. Elliott, M. S. Long / Tetrahedron Letters 43 (2002) 9191–9194
in the former case and possibly N-acylation in the lat-
while we are confident that improvements will be made,
18
ter. Closer examination of the data lead us to suggest
that the compound assigned structure 21 is most proba-
bly 23, with the peaks at 7.3 and 7.6 ppm both being due
the 2:1 ratio reported herein is presently the reproducible
stereoselectivity.
17. For representative examples, see: Moyer, M. P.; Feld-
man, P. L.; Rapoport, H. J. Org. Chem. 1985, 50, 5223;
(b) Brunerie, P.; C e´ l e´ rier, J.-P.; Petit, H.; Lhommet, G. J.
Heterocyclic Chem. 1986, 23, 1183; (c) Lee, H. K.; Kim,
J.; Pak, C. S. Tetrahedron Lett. 1999, 40, 2173.
18. For a detailed review of such reactions, see: Elliott, M.
C.; Kruiswijk, E.; Long, M. S. Tetrahedron 2001, 57,
6651.
13
to NꢀH resonances. Unfortunately the C NMR data,
1
and also deuterium exchange H NMR data, which
would have allowed unambiguous assignment of struc-
tures was not presented in the original report. In the case
of compound 22 the assigned structure should be
assumed to be correct.
16. In one instance a ratio of 4:1 was obtained. However,