Double Cycloisomerization as a Novel and Expeditious Route to Tricyclic Heteroaromatic Compounds: Short and Highly Diastereoselective Synthesis of (±)-Tetraponerine T6

Article abstract of DOI:10.1021/ol027129t

(Matrix Presented) Cu-Assisted double cycloisomerization of bis-alkynylpyrimidines afforded the 5-6-5 tricyclic heteroaromatic skeleton. This transformation was used as a key step in the highly diastereoselective total synthesis of (±)-tetraponerine T6.

Full text of DOI:10.1021/ol027129t

ORGANIC
LETTERS
2
002
Vol. 4, No. 26
697-4699
Double Cycloisomerization as a Novel
and Expeditious Route to Tricyclic
Heteroaromatic Compounds: Short and
Highly Diastereoselective Synthesis of
4
(±)-Tetraponerine T6
Joseph T. Kim and Vladimir Gevorgyan*
Department of Chemistry, UniVersity of Illinois at Chicago, 875 West Taylor Street,
Chicago, Illinois 60607-7061
Vlad@uic.edu
Received October 17, 2002
ABSTRACT
Cu-Assisted double cycloisomerization of bis-alkynylpyrimidines afforded the 5−6−5 tricyclic heteroaromatic skeleton. This transformation
was used as a key step in the highly diastereoselective total synthesis of (±)-tetraponerine T6.
We have recently reported a novel, general, and efficient
method for the construction of 2-monosubstituted and 2,5-
disubstituted pyrroles, as well as fused aromatic heterocycles
containing a pyrrole ring, via the Cu-assisted cycloisomer-
ization of alkynyl imines. The generality and synthetic
usefulness of this novel methodology was demonstrated by
achieving the shortest synthesis of (()-monomorine in three
To examine the possibility of assembling a 5-6-5
tricyclic heteroaromatic skeleton, we synthesized bis-pro-
pynylpyrimidine derivatives 1a-c and tested them under
pyrrolization conditions. A sequential double pyrrolization
of 1 posed a certain challenge. Indeed, as shown in Scheme
2, the first pyrrolization of 1 can proceed in three possible
ways (paths A-C). Among them, paths A and B, after the
first cycloisomerization, will produce pyrrolopyrimidines 3
and 4, which after the second pyrrolization will be converted
1
steps and 47% overall yield (Scheme 1). This successful
result encouraged us to investigate a possible multiple
pyrrolization protocol. If this unprecedented cascade trans-
formation proves to be successful, combined with a further
functionalization sequence, it can provide us with a concep-
tually novel and expeditious route to various polycyclic
alkaloid skeletons.
Scheme 1. Short Synthesis of (()-Monomorine
Herein, we report the first example of double pyrrolization
of pyrimidine derivatives into the bis-pyrrolopyrimidines and
employment of this transformation in the short and highly
diastereoselective synthesis of (()-tetraponerine T6.
(
1) Kel’in, A. V.; Sromek, A. W.; Gevorgyan, V. J. Am. Chem. Soc.
2
001, 123, 2074.
1
0.1021/ol027129t CCC: $22.00 © 2002 American Chemical Society
Published on Web 12/07/2002

Scheme 2. Sequential Double Pyrrolizationa
Scheme 3. Retrosynthetic Analysis for 6
easily prepared from the known pyrimidine dione 9 (Scheme
a
Reagents and conditions: (a) CuBr, Et N-DMA, 150 °C, 10
3
3
).
The synthesis began with pyrimidine dione 9, which was
h.
7
routinely prepared from ethyl acetoacetate. Treatment of 9
with phosphorus oxybromide in benzene followed by So-
nogashira coupling with propyne proceeded uneventfully
to give bis-propynylpyrimidine 8 in excellent overall yield.
The next step, a sequential double pyrrolization of 8, gave
into the desired product 2. In contrast to the above cases,
path C leads to dead-end intermediate 5. Experiments have
shown that in the presence of 1 equiv of CuBr in dilute
8
3
Et N-DMA at 150 °C, bis-propynylpyrimidines 1a-c were
5
-6-5 tricyclic bis-pyrrolopyrimidine 7 in 52% yield
smoothly converted into the tricyclic bis-pyrrolopyrimidines
2
(Scheme 4).
2
a-c in 48-51% yield. Under these reaction conditions,
no other low-molecular weight compounds, besides 2, were
detected by GC-MS analyses of the crude reaction mixture.
In contrast, when the reaction was performed at both reduced
temperature (130 °C) and reduced copper loading (50 mol
Scheme 4. Synthesis of Bis-pyrrolopyrimidine 7a
%), early stage GC-MS analyses revealed the presence of
two isomeric compounds in about a 5:1 ratio, along with
starting material 1 and product 2. As the reaction progressed,
the amount of tricyclic product 2 increased and the amounts
of the starting material and its two unidentified isomers
decreased. At this stage, it is unclear which of these three
structures (3-5) corresponded to the two fleeting isomers
3
observed by GC-MS. Taking into account that the yield per
each pyrrolization in the transformation 1 f 2 is about 70%
and that the cycloisomerization yields for propyne derivatives
are normally 10-20% lower than that of their higher
a
Reagents and conditions: (a) C
reflux, 2h, 81%; (b) CuI, Pd(PPh Cl
00%; (c) CuBr, Et N-DMA, 150 °C, 10 h, 52%.
6
H
5
N(CH
3
)
2
, POBr
3
, benzene,
3
)
2
2
, propyne, Et
3
N, 50 °C, 3 h,
1
3
5
homologues, we considered 48-51% yield for the double
pyrrolization to be a rather satisfactory result.
Direct complete hydrogenation of heteroaromatic com-
pound 7 to 6 proved not to be simple. It is well-known that
Encouraged by successful synthesis of 5-6-5 tricyclic
bis-pyrrolopyrimidine core 2, we attempted a total synthesis
6
of (()-tetraponerine T6, which can be considered to be a
(6) T6 Tetraponerine T6 is the one of the major venom alkaloids isolated
reduced derivative of 2. Indeed, T6 could be made by
complete reduction of heteroaromatic compound 7, a higher
homologue of 2b, which, in turn, is the double-pyrrolization
product of bis-propynylpyrimidine 8. The latter could be
from the poison gland of the Neo Guinean ant Tetraponera sp. For isolation
of tetraponerines, see: (a) Merlin, P.; Braekman, J. C.; Daloze, D.; Pasteels,
J. M. J. Chem. Ecol. 1988, 14, 517. (b) Braekman, J. C.; Daloze, D.; Pasteels,
J. M.; Vanhecke, P.; Declercq, J. P.; Sinnwell, V.; Franke, W. Z.
Naturforsch. 1987, 42c, 627. Tetraponerines are made of the tricyclic
skeletons (6-6-5 and 5-6-5), which are unprecedented alkaloid cores
isolated from animals. Moreover, their interesting insecticidal activities (LD50
-
9
(2) Double pyrrolization of the unsubstituted bis-propynylpyrimidine
) 2 × 10 mol/ant mg) have made them attractive synthetic targets for
chemists; see refs 2b and 4. To date, four diastereo- and enatioselective
syntheses of tetraponerine T6 have been described; see: (a) Stragies, R.;
Blecher, S. J. Am. Chem. Soc. 2000, 122, 9584. (b) Yue, C.; Gauthier, I.;
Royer, J.; Husson, H. P. J. Org. Chem. 1996, 61, 4949. (c) Plehiers, M.;
Heilporn, S.; Ekelmans, D.; Leclercq, S.; Sangermano, M.; Braekman, J.
C.; Daloze, D. Can. J. Chem. 2000, 78, 1030. (d) Devijver, C.; Macours,
P.; Braekman, J. C.; Daloze, D.; Pasteels, J. M. Tetrahedron, 1995, 40,
10913.
proceeded with a somewhat lower yield, probably due to a competing
polymerization process.
(3) Possible allenic structures for the observed isomers were discounted,
since propargyl-allenyl isomerization is a rate-determining step in the entire
cycloisomerization; thus, allenyl intermediates were never detected during
the reaction course. See refs 1 and 4.
(
4) Kel’in, A.; Gevorgyan, V. J. Org. Chem. 2002, 67, 95.
(5) For lower thermal stability of the terminal allenic intermediates, see
refs 1 and 4.
(7) See Supporting Information for details.
4698
Org. Lett., Vol. 4, No. 26, 2002

catalytic hydrogenation of pyrimidine derivatives in acidic
media is cis diastereoselective and stops at the stage of
9
formation of stable amidinium derivatives. Accordingly, as
expected, catalytic hydrogenation of 7 over PtO
conditions gave amidinium salt 11 as a single cis isomer.
2
under acidic
1
0
The total synthesis of (()-tetraponerine T6 was completed
by highly diastereoselective reduction of crude 11 with
4
LiAlH to give 6 as the sole stereoisomer in 64% yield for
two steps (Scheme 5).
Scheme 5. Reductive Transformations of 7a
Figure 1. Transition states for the nucleophilic attack of hydride
at the amidinium ion 11.
favorable “chairlike” transition state i instead of an R-face
delivery of a hydride through the disfavored “boatlike”
transition state ii to form an epi (()-T6 (Figure 1). The
relative configuration of (()-tetraponerine T6 was confirmed
a
Reagents and conditions: (a) H
2
(50 psi), PtO
2
, HBr, MeOH,
rt, 40 h; (b) LiAlH
for two steps.
4
, THF, 4 Å MS, from 0 °C to rt, 2 h, 64% yield
1
12
by NOESY and H NOE experiments.
In conclusion, the first Cu-assisted double pyrrolization
of bis-alkynylpyrimidine to the 5-6-5 heteroaromatic core
was demonstrated. Highly selective hydrogenation/reduction
of the resulting bis-pyrrolopyrimidine allowed for the short,
efficient, and highly diastereoselective total synthesis of (()-
tetraponerine T6 in five steps and 27% overall yield. The
multiple pyrrolization-reductive functionalization protocol
can serve as a new, short, and efficient approach toward
various polycyclic alkaloid structures.
The highly stereoselective reduction of 9, which we believe
is stereoelectronically controlled, deserves a special note.
Two possible transition states can account for the delivery
of hydride to the newly formed stereogenic center at the C-4
position. Obviously, the nucleophilic attack of a hydride
proceeds from the â-face to give (()-T6 through the most
1
1
(
8) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
467. (b) Sonogashira, K. In ComprehensiVe Organic Synthesis; Trost, B.
M., Fleming, I., Eds.; Pergamon Press: New York, 1991, Vol. 3, p 521.
9) For hydrogenation of pyrimidines, see: (a) Brown, D. J. The
4
(
Acknowledgment. We gratefully acknowledge the fi-
nancial support of the National Institutes of Health (GM-
64444). We also thank Dr. Michael Rubin for fruitful
discussions and Dr. John Harwood for the NOE experiment.
Pyrimidines. In The Chemistry of Heterocyclic Compounds; Wiley &
Sons: New York, 1994; Vol. 52, pp 790-793. (b) Brown, D. J. T. The
Pyrimidines Supplement I. In The Chemistry of Heterocyclic Compounds;
Wiley & Sons: New York, 1970; pp 337-341.
13
(
10) C NMR analysis of crude 9 revealed that it is a single diastereomer.
The relative configuration of its stereogenic centers was proved by a NOE
experiment after the subsequent reduction step.
Supporting Information Available: Experimental de-
tails. This material is available free of charge via the Internet
at http://pubs.acs.org.
(
11) For stereoelectronic control in addition of nucleophiles to an
amidinium ion, see: (a) Perrin, C. L.; Young, D. B. J. Am. Chem. Soc.
001, 123, 4451. (b) F u¨ l o¨ p, F.; Simon, K.; T o´ th, G.; Hermecz, I.; M e´ sz a´ ros,
2
Z.; Bern a´ th, G. J. Chem. Soc., Perkin Trans. 1982, 12, 2801. (c) Kirby, A.
J. Stereoelectronic Effects, Oxford Chemistry Primer no. 36; Oxford
University Press: Oxford, 1996; pp 54-55. (d) Barluenga, J.; Tom a´ s, M.;
Kouznetsov, V.; Rubio, E. J. Org. Chem. 1994, 59, 3699.
OL027129T
(12) For the NOESY and 1H NOE experiments of 6, see Supporting
Information.
Org. Lett., Vol. 4, No. 26, 2002
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