An approach to the isoschizozygane alkaloid core using a 1,4-dipolar cycloaddition of a cross-conjugated heteroaromatic betaine

Article abstract of DOI:10.1021/ol0508779

(Chemical Equation Presented) A new strategy for the synthesis of the isoschizozygane alkaloid core has been developed that is based on a 1,4-dipolar cycloaddition reaction of a cross-conjugated heteroaromatic betaine. The resulting cycloadduct undergoes

Full text of DOI:10.1021/ol0508779

ORGANIC
LETTERS
2005
Vol. 7, No. 14
2925-2928
An Approach to the Isoschizozygane
Alkaloid Core Using a 1,4-Dipolar
Cycloaddition of a Cross-Conjugated
Heteroaromatic Betaine
Albert Padwa,* Andrew C. Flick, and Hyoung Ik Lee
Department of Chemistry, Emory UniVersity, Atlanta, Georgia 30322
chemap@emory.edu
Received April 21, 2005
ABSTRACT
A new strategy for the synthesis of the isoschizozygane alkaloid core has been developed that is based on a 1,4-dipolar cycloaddition reaction
of a cross-conjugated heteroaromatic betaine. The resulting cycloadduct undergoes loss of COS, and further reduction delivers a 5a-aza-
acenaphthylene intermediate that was transformed into the isoschizozygane skeleton upon treatment with acid.
The schizozyganes represent a small group of hexacyclic
indoline alkaloids1 that were obtained from the twigs of the
East African monotypic shrub Schizozygia caffaeoides.2,3 In
addition to the major alkaloid schizozygine (1),4 a pair of
minor alkaloids were isolated,5 and their structures were
established as isoschizogaline (2) and isoschizogamine (3)
on the basis of extensive NMR studies.3 A partial biosynthetic
pathway was invoked to explain the formation of their
unusual aminal-containing ring system3 by assuming attack
of the indoline nitrogen on a transient iminium ion derived
from the schizozygane skeleton.6 The resulting aziridinium
ion intermediate could then be reductively opened to provide
the isoschizozygane core.3 The striking structural features
of the isoschizozyganes, alongside their interesting biological
properties,7 have combined to make these natural products
challenging targets for synthesis. Heathcock and Hubbs were
the first to describe a concise synthesis of (()-isoschizoga-
mine,8 and more recently Magomedov presented an alterna-
tive strategy to the cyclopenta[b]quinoline core using a
formal hetero Diels-Alder reaction.9 In this paper, we
describe a different synthetic approach to the isoschizozygane
alkaloids which uses an intramolecular 1,4-dipolar cycload-
dition reaction of a cross-conjugated heteroaromatic betaine10
to construct the novel hexacyclic skeleton. Our initial
retrosynthetic analysis was based on our earlier work dealing
with the intramolecular [3+2]-cycloaddition of thioiso-
(1) Saxton, J. E. In Indoles, Part Four, The Monoterpenoid Indole
Alkaloids; Saxton, J. E., Ed.; Wiley: New York, 1984; Chapter IX, pp 437-
486.
(2) Renner, U.; Kernweisz, P. Experientia 1963, 19, 244.
(3) Ha´jicek, J.; Taimr, J.; Budesinsky, M. Tetrahedron Lett. 1998, 39,
505.
(4) Renner, U.; Fritz, H. HelV. Chim. Acta 1965, 48, 308.
Figure 1.
(5) Renner, U. Lloydia 1964, 27, 406.
(6) Kompis, I.; Hesse, M.; Schmid, H. Lloydia 1971, 34, 269.
10.1021/ol0508779 CCC: $30.25
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mu¨nchnones across tethered π-bonds11 and is illustrated in
Scheme 1. We assumed that the hexacyclic skeleton of
Scheme 2
Scheme 1
spectroscopic properties and also by analogy to related
cycloadditions using isomu¨nchnones where X-ray data had
been obtained.15
Unfortunately, all of our attempts to induce an analogous
reaction using the closely related ortho-nitro-substituted
thioamide 8 failed to give any signs of an internal cycload-
duct. Similar experiments were carried out using the related
o-NHBoc and o-Br aryl piperidinethiones 9 and 10. In both
of these cases no product attributable to intramolecular
cycloaddition could be detected.16 Whereas the reaction of
the cis-aryl alkenyl-substituted piperidinethiones 8-10 failed
to produce an internal cycloadduct, reaction in the presence
of N-phenylmaleimide proved fruitful. Bimolecular cycload-
dition occurred in 75-80% yield, providing a 1:1 mixture
of diastereomeric cycloadducts (i.e., 12-14), thereby estab-
lishing that the expected 1,3-dipole was indeed being formed.
The interaction of two reacting groups in the same
molecule has always been of paramount concern to organic
chemists.17 The geometric requirements for interaction are
generally evaluated through systems that have the reacting
centers connected together by a few intervening atoms. This
linkage provides a cyclic transition state that imposes distinct
restrictions upon the bond angles at the reacting centers.18
The ultimate success of the intramolecular thioisomu¨nchnone
cycloaddition of 8 will be critically dependent on the relative
rate of the internal cycloaddition as compared to unproductive
decomposition pathways. Conformational factors in the
transition state play an important role in achieving the
required two-plane orientation approach necessary for the
cycloaddition. It would appear that the presence of an ortho
isoschizogamine (3) could be formed from a compound of
type 4 by a sequence of enamide protonation, acyl-iminium
ion cyclization, and lactamization. Enamide 4 may be
generated by extrusion of sulfur from cycloadduct 5 followed
by reduction of both the nitro and keto groups and a
subsequent dehydration. The key cycloadduct 5 should be
accessible from an intramolecular dipolar cycloaddition of
the 1,3-dipole present in the mesoionic betaine 6.
To test the feasibility of the retrosynthetic strategy outlined
in Scheme 1, our initial efforts were focused on model
substrates. Several cis-aryl alkenyl-substituted piperidineth-
iones were prepared by Castro-Stevens coupling12 of the
acetylenic NH-lactams followed by nickel boride-catalyzed
hydrogenation of the alkynyl group13 and subsequent conver-
sion to the thiolactams using Lawesson’s reagent.14 Treatment
of the simple phenyl-substituted thiolactam 7 with bro-
moacetyl chloride and triethylamine at 25 °C gave the desired
cycloadduct 11 in 85% yield as a single diastereomer
corresponding to endo-cycloaddition (Scheme 2). Assignment
of the stereochemistry of cycloadduct 11 is based on its
(7) Kariba, R. M.; Houghton, P. J.; Yenesew, A. J. Nat. Prod. 2002, 65,
566.
(8) Hubbs, J. L.; Heathcock, C. H. Org. Lett. 1999, 1, 1315.
(9) Magomedov, N. A. Org. Lett. 2003, 5, 2509.
(10) Padwa, A.; Coats. S. J.; Semones, M. A. Tetrahedron 1995, 51,
6651.
(11) (a) Padwa, A.; Harring, S. R.; Hertzog, D. L.; Nadler, W. R.
Synthesis 1994, 993. (b) Osterhout, M. H.; Nadler, W. R.; Padwa, A.
Synthesis 1994, 123. (c) Heidelbaugh, T. M.; Liu, B.; Padwa, A. Tetrahedron
Lett. 1998, 39, 4757.
(12) (a) Castro, C. E.; Stevens, R. D. J. Org. Chem. 1963, 28, 2163. (b)
Stevens, R. D.; Castro, C. E. J. Org. Chem. 1963, 28, 3313.
(13) Brown, C. A.; Brown, H. C. J. Am. Chem. Soc. 1963, 85, 1003.
(14) Pedersen, B. S.; Scheibye, S.; Clausen, K.; Lawesson, S.-O. Bull.
Soc. Chim. Belg. 1978, 87, 293.
(15) (a) Padwa, A.; Hertzog, D. L.; Nadler, W. R.; Osterhout, M. H.;
Price, A. T. J. Org. Chem. 1994, 59, 1418. (b) Padwa, A.; Hertzog, D. L.;
Nadler, W. R. J. Org. Chem. 1994, 59, 7072.
(16) Several unidentifiable products were formed that appear to be derived
by addition of adventitious water across the thioisomu¨nchnone dipole
followed by ring opening and subsequent coupling with unreacted dipole.
(17) Deslongchamps, P. Stereoelectronic Effects in Organic Chemistry;
Pergamon Press: Oxford, 1983.
(18) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734.
2926
Org. Lett., Vol. 7, No. 14, 2005

substituent on the aromatic ring of the above systems twists
the dipole sufficiently away from the preferred transition state
for cycloaddition so that other pathways compete.
protic amidine or thioamide with a 1,3-bielectrophile derived
from malonic acid.21,22 Although several intermolecular 1,4-
dipolar cycloadditions have been described in the literature,23
applications of the intramolecular type are still rare but have
significant synthetic potential.24
To overcome this problem, we thought it would be
advantageous to study a more highly activated dipole,
especially one that can be employed at a higher temperature
for the cycloaddition. The formation and dipolar trapping
of thioisomu¨nchnones via the interaction of rhodium car-
benoids derived from diazo thioamides have not been
investigated to the same extent as that of the corresponding
isomu¨nchnone system.19 The advantage of using this method
to generate the dipole is that the reaction can be carried out
at much higher temperatures (i.e., 180 °C). Our hope was
that we might be able to induce the internal cycloaddition
to occur using the o-phenyl-nitro-substituted diazo thioamide
system 15. We were pleased to find that the Rh(II)-catalyzed
reaction of 15 in xylene at 180 °C provided cycloadduct 16
in 83% yield (Scheme 3). In an attempt to remove the sulfur
The synthesis of 5a-aza-acenaphthylen-5-one 20 com-
menced from the easily available thiolactam 8 (Scheme 4).
Scheme 4
Scheme 3
atom, we exposed a sample of 16 to molybdenum hexacar-
bonyl in acetic acid according to a method developed by
Alper and Blias for the reduction of thiols.20 Under these
conditions, however, compound 16 was converted to lactam
17 by reduction of both the sulfur bridge and nitro group,
and the resulting anilino group then underwent a subsequent
lactamization reaction with the adjacent ester functionality.
At this point in time we reasoned that it might be possible
to avoid the difficulties associated with the presence of the
extra carboethoxy group in cycloadduct 16 by employing a
1,4-dipole for construction of the structural backbone of the
isoschizozygane class of alkaloids. In contrast to 1,3-dipoles,
much less in known about the cycloaddition behavior of 1,4-
dipoles. This class of reactive intermediates attracted little
synthetic attention until the elements of a 1,4-dipole were
incorporated into a cross-conjugated heteroaromatic betaine
by cyclo-condensation of an appropriately substituted mono-
Generation of the bright yellow isolable betaine 18 was
accomplished by the reaction of 8 with carbon suboxide25
at 25 °C for 5 h. Heating a sample of 18 at 120 °C for 3 h
in toluene afforded 20 as a single diastereoisomer in 66%
(21) Ollis, W. D.; Stanforth, S. P.; Ramsden, C. A. Tetrahedron 1985,
41, 2239.
(22) Potts, K. T.; Sorm, M. J. Org. Chem. 1972, 37, 1422.
(23) (a) Kappe, T.; Golser, W.; Hariri, M.; Stadlbauer, W. Chem. Ber.
1979, 112, 1585. (b) Friedrichsen, W.; Kappe, T.; Bo¨ttcher, A. Heterocycles
1982, 19, 1083.
(24) Potts, K. T.; Rochanapruk, T.; Padwa, A.; Coats, S. J.; Hadjiara-
poglu, L. J. Org. Chem. 1995, 60, 3795.
(25) (a) Kappe, T.; Ziegler, E. Angew. Chem., Int. Ed. Engl. 1974, 13,
491. (b) Hopff, H.; Hegar, G. HelV. Chim. Acta 1961, 44, 2016. (c)
Staudinger, H.; Bereza, S. Ber. 1908, 41, 4461.
(19) Padwa, A.; Kinder, F. R.; Zhi, L. Synlett 1991, 287.
(20) Alper, H.; Blais, C. J. Chem. Soc., Chem. Commun. 1980, 169.
Org. Lett., Vol. 7, No. 14, 2005
2927

yield as a pale yellow solid whose formation is easily
accounted for by extrusion of COS26 from the originally
formed cycloadduct 19 followed by a hydrogen shift.
Catalytic reduction of the nitro functionality (H2, Pd/C) in
20 to the corresponding amino group was followed by
enamide reduction using LAH. The transient enamine 21 was
treated with acid to furnish a 3:2-mixture of diastereomeric
aminals 22 and 23. The formation of the two observed
diastereomers can be explained by protonation of the two
diastereotopic faces of the double bond in the initially formed
enamine 21.8 Treatment of either isolated isomer with acetic
acid resulted in an equilibrated 1:6 mixture of 22 and 23
with the major diastereomer possessing the correct core
skeleton of the isoschizozygane family of alkaloids.
In summary, an efficient approach to the core skeleton of
the isoschizozyganes was accomplished by an intramolecular
1,4-dipolar cycloaddition reaction of a cross-conjugated
heteroaromatic betaine intermediate. Application of this
strategy to the synthesis of isoschizogamine is currently
underway and will be reported at a later date.
Acknowledgment. We appreciate the financial support
provided by the National Institutes of Health (GM 059384)
and the National Science Foundation (CHE-0450779).
Supporting Information Available: Spectroscopic data
and experimental details for the preparation of all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(26) Carbonyl sulfide was identified when it was trapped in an alcoholic
solution of piperidine where it formed the corresponding salt. See: Seibert,
W. Angew. Chem. 1959, 71, 194.
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