Generation of aza-ortho-xylylenes via ring opening of 2-(2-acylaminophenyl) aziridines: Application in the construction of the communesin ring system

Article abstract of DOI:10.1021/ol061461d

A new protocol for generating aza-ortho-xylylenes via acid-catalyzed or fluoride-promoted ring opening of 2-(2-acylaminophenyl)aziridines is described. This methodology has been exploited in the rapid construction of a hexacyclic substructure of communesi

Full text of DOI:10.1021/ol061461d

ORGANIC
LETTERS
2006
Vol. 8, No. 18
3995-3998
Generation of Aza-ortho-xylylenes via
Ring Opening of
2-(2-Acylaminophenyl)aziridines:
Application in the Construction of the
Communesin Ring System
Seth L. Crawley and Raymond L. Funk*
Department of Chemistry, PennsylVania State UniVersity, UniVersity Park,
PennsylVania 16802
rlf@chem.psu.edu
Received June 14, 2006
ABSTRACT
A new protocol for generating aza-ortho-xylylenes via acid-catalyzed or fluoride-promoted ring opening of 2-(2-acylaminophenyl)aziridines is
described. This methodology has been exploited in the rapid construction of a hexacyclic substructure of communesin B.
The communesins are an emerging class of structurally
intriguing and biologically active Penicillium metabolites.1
Communesin B (Scheme 1) exhibits the most interesting
biological profile and is moderately cytotoxic against P-388
(ED50 ) 0.88 µM),1b LoVo (MIC ) 3.9 µM),1b and KB
(MIC ) 8.8 µM)1a cells whose mechanism of action may
involve the disruption of microfilaments.1b Therefore, it is
surprising that communesin B has only recently elicited the
interest of synthetic groups2 despite its first isolation by
Numata in 1993.1a
We recently reported a strategy for the construction of the
hexacyclic core ring system 5 of communesin B2b that
featured an intramolecular cycloaddition of a N-acyl-aza-
ortho-xylylene 4 with a tethered indole (Scheme 1). The
intermediate 4 was generated via thermolysis of the carbonate
derivative 3, which in turn was readily prepared via ami-
nolysis of the epoxide 2 with the benzazepine 1 (Scheme
1). To elaborate the pyrrolidine ring of communesin B, we
had hoped to prepare compound 7 (Scheme 2) whose C(9)
ester substituent could be converted to several diazo com-
pounds for the planned C-H insertion reactions at C(8).
(1) (a) Communesins A and B: Numata, A.; Takahashi, C.; Ito, Y.;
Takada, T.; Kawai, K.; Usami, Y.; Matsumura, E.; Imachi, M.; Ito, T.;
Hasegawa, T. Tetrahedron Lett. 1993, 34, 2355. (b) Communesin B
(erroneously assigned to be nomofungin): Ratnayake, A. S.; Yoshida, W.
Y.; Mooberry, S. L.; Hemscheidt, T. K. J. Org. Chem. 2001, 66, 8717. (c)
Ratnayake, A. S.; Yoshida, W. Y.; Mooberry, S. L.; Hemscheidt, T. K. J.
Org. Chem. 2003, 68, 1640. (d) Communesins B, C, D, and E: Jadulco,
R.; Edrada, R. A.; Ebel, R.; Berg, A.; Schaumann, K.; Wray, V.; Steube,
K.; Proksch, P. J. Nat. Prod. 2004, 67, 78. (e) Hayashi, H.; Matsumoto,
H.; Akiyama, K. Biosci. Biotechnol. Biochem. 2004, 68, 753. (f) Commu-
nesins G and H: Dalsgaard, P. W.; Blunt, J. W.; Munro, M. H. G.; Frisvad,
J. C.; Christopherson, C. J. Nat. Prod. 2005, 68, 258.
(2) (a) May, J. A.; Zeiden, R. K.; Stoltz, B. M. Tetrahedron Lett. 2003,
44, 1203. (b) Crawley, S. L.; Funk, R. L. Org. Lett. 2003, 5, 3169. (c)
May, J. A.; Stoltz, B. Tetrahedron 2006, 62, 5262. (d) Yang, J.; Song, H.;
Xiao, S.; Wang, J.; Qin, Y. Org. Lett. 2006, 8, 2187.
10.1021/ol061461d CCC: $33.50
© 2006 American Chemical Society
Published on Web 08/11/2006

Scheme 1
Scheme 3
the anticipated facile ring closure of the piperidine ring on
the acetylene moiety of pentacycle 11 would provide alkene
10, a handle for the introduction of the C(11) epoxide
substituent. It seemed likely that the intramolecular cycload-
dition of the N-acyl-aza-ortho-xylylene would also proceed
through the endo transition state 12 with the ester substituent
occupying a position on the convex face.2b However, we were
concerned about the ramifications of the C(12a) substituent
which emerges in a highly congested environment, hence
the choice of the compact ethynyl group. Moreover, it was
anticipated that the primary amine of indole 15, vis-a`-vis
the secondary amine of benzazepine 1, would allow the
efficient assembly of various aza-ortho-xylylene precursors.
In particular, we were intrigued by the prospect of preparing
the aziridine 13 by sequential substitution reactions of
dibromide 14 with tryptamine 15 for the purpose of examin-
ing its acid- or base-induced ring opening as a means for
generating the desired N-acyl-aza-ortho-xylylene 12.5
We began this investigation by preparing an aziridine that
lacked the potentially problematic C(12a) ethynyl substituent
(Scheme 4). Thus, alkylation of 1-methyltryptamine with the
dibromide 14 provided the trans aziridine 16 in good yield.
The stereochemistry of the aziridine was assigned as trans
based upon the observed vicinal coupling constant of 2.8
Hz. This value is quite similar to the vicinal coupling
constants reported for related trans aziridines and is smaller
than the coupling constant that would be expected for the
cis diastereomer (6-7 Hz).6
Accordingly, we examined the aminolysis of epoxide 8 with
the benzazepine 1. Unfortunately, we were unable to obtain
any of the desired alcohol 9 using a variety of reaction
conditions.3
Scheme 2
We could now evaluate whether protonation of the
aziridine 16 would lead to its ring opening and afford the
In view of these difficulties, we decided to investigate a
synthesis that is more closely related to possible biosynthetic
pathways.2a,c,4 Specifically, the synthesis would begin with
a tryptamine derivative thereby necessitating elaboration of
the seven-membered ring later in the synthetic sequence
(Scheme 3). One advantage of this redesigned route is that
(4) (a) Fuchs, J. R.; Funk, R. L. J. Am. Chem. Soc. 2004, 126, 5068. For
labeling studies consistent with the tryptamine dimerization pathway
previously proposed for the calycanthaceous alkaloids, see: (b) Wigley, L.
J.; Mantle, P. G.; Perry, D. A. Phytochemistry 2006, 67, 561. For seminal
examples of proposed calycanthaceous alkaloid biosynthesis, see: (c)
Woodward, R. B.; Yang, N. C.; Katz, T. J. Proc. Chem. Soc. 1960, 76. (d)
Robinson, R.; Teuber, H. J. Chem. Ind. 1954, 783.
(3) (a) Fujiwara, M.; Imada, M.; Baba, A.; Matsuda, H. Tetrahedron
Lett. 1989, 30, 739. (b) Chini, M.; Crotti, P.; Favero, L.; Macchia, F.;
Pineschi, M. Tetrahedron Lett. 1994, 35, 433. (c) Kotsuki, H.; Shimanouchi,
T.; Teraguchi, M.; Kataoka, M.; Tatsukawa, A.; Nishizawa, H. Chem. Lett.
1994, 2159. (d) Meguro, M.; Asao, N.; Yamamoto, Y. J. Chem. Soc., Perkin
Trans. 1 1994, 2597. (e) Chakraborti, A. K.; Kondaskar, A. Tetrahedron
Lett. 2003, 44, 8315 and references therein.
(5) For a review on the synthesis and applications of aza-ortho-xylylenes,
see: Wojciechowski, K. Eur. J. Org. Chem. 2001, 3587.
(6) For similar aziridine syntheses, see: (a) Ploux, O.; Caruso, M.;
Chassaing, G.; Marquet, A. J. Org. Chem. 1988, 53, 3154. (b) Toke´s, A.;
Likei, G.; Janzso´, G. Synth. Commun. 1990, 20, 1905. (c) Davoli, P.; Forni,
A.; Moretti, I.; Prati, F.; Torre, G. Tetrahedron 2001, 57, 1801. (d)
Comstock, L. R.; Rajski, S. R. Tetrahedron 2002, 58, 6019.
3996
Org. Lett., Vol. 8, No. 18, 2006

It seemed highly unlikely that the acyl transfer took place
following the cycloaddition because we had previously
learned that much more vigorous conditions were required
for the removal of the robust carbamate functionality present
in our initial cycloadduct 5 (KOH, NH2NH2, 150 °C).2b
Therefore, the more likely scenario is that acyl transfer
precedes the cycloaddition and, in fact, is responsible for
the generation of the aza-ortho-xylylene 20. A possible
mechanism is outlined in Scheme 5. Thus, acid-promoted
Scheme 4
Scheme 5
key aza-ortho-xylylene intermediate. Brønsted acids pos-
sessing nonnucleophilic counterions were first investigated
because they would be less prone to undergo intermolecular
nucleophilic ring opening of the aziridine.7 The best results
were obtained when bis[(trifluoromethyl)sulfonyl]imide
(HNTf2)8 was employed. Thus, treatment of aziridine 16 at
room temperature with HNTf2 provided the cycloadduct 17
1
whose structure was assigned upon the basis of H NMR
spectral data. In particular, both the C(8) and C(9) proton
resonances appeared as doublets with a large trans coupling
constant indicative of a diaxial relationship of these two
protons. The alternative exo cycloadduct would be expected
to have a much smaller (axial, equatorial) vicinal coupling
constant. Moreover, the C(6) aminal proton exhibited a strong
nOe with the C(8) methine proton. However, subsequent
X-ray crystallographic analysis of carbamate 17 proved to
be even more informative (Figure 1). Although the stereo-
cyclization of the aziridine with the proximate carbamate
moiety would afford the aziridinium ion 18 that could
undergo proton transfer and ring opening of the six-
membered ring to the N-acylaziridinium ion 19,9 the actual
species that triggers ring opening of the aziridine en route
to aza-ortho-xylylene and thence cycloadduct 17.
Although this result was intriguing, it was unfortunate in
the sense that it is preferable to have the piperidine nitrogen
of 17 unprotected at this stage of the synthesis to investigate
its closure with a C(12a) ethynyl substituent (vide supra). A
possible solution to this problem would be to simultaneously
remove the carbamate functionality while generating the aza-
ortho-xylylene. Some guidance could be derived from the
work of Saegusa and Ito who demonstrated that aza-ortho-
xylylenes could be generated by fluoride-promoted 1,4-
elimination of trimethylamine from ortho-[N-alkyl-N-
(trimethylsilyl)amino]benzyl trimethylammonium salts.10
Accordingly, the TEOC carbamate 21 (Scheme 6) was
prepared from 1-methyltryptamine and the TEOC analogue
of dibromide 14. We were pleased to discover that treatment
of the carbamate 21 with 4 equiv of TBAF effected a smooth
conversion to the cycloadduct 22, presumably via a pathway
involving decarboxylative ring opening of aziridine 23 to
the aza-ortho-xylylene 24.
Figure 1. X-ray structure of cycloadduct 17.
chemical assignment was confirmed, we were surprised to
discover that the ethoxycarbonyl had migrated to the aziridine
nitrogen.
(9) N-Acylaziridinium ions have been previously observed or proposed;
see: (a) Olah, G. E.; Szilagyi, P. J. J. Am. Chem. Soc. 1969, 91, 2949. (b)
Huffman, J. W.; Kamiya, T. Tetrahedron Lett. 1966, 7, 1857.
(10) (a) Ito, Y.; Nakatsuka, M.; Saegusa, T. J. Am. Chem. Soc. 1980,
102, 863. (b) Ito, Y.; Nakajo, E.; Saegusa, T. Synth. Commun. 1986, 16,
1073.
(7) For a review, see: Hu, X. E. Tetrahedron 2004, 60, 2701.
(8) For recent synthetic applications of HNTf2, see: (a) Kuhnert, N.;
Peverley, J.; Robertson, J. Tetrahedron Lett. 1998, 39, 3215. (b) Zhang,
L.; Kozmin, S. A. J. Am. Chem. Soc. 2004, 126, 10204.
Org. Lett., Vol. 8, No. 18, 2006
3997

1
nation of the H NMR spectrum of 26 revealed that the
secondary product was in fact enamine 27, indicating that
the intramolecular 7-exo-dig closure proceeded spontane-
ously, albeit slowly, at room temperature. The ease of this
cyclization clearly reflects the highly encumbered environ-
ment around the C(5) ethynyl substituent. The structure and
stereochemistry of this unusual enamine was secured by
X-ray crystallographic analysis. Finally, the second aminal
functionality was installed by hydrolysis of the ester moiety
of enamine 27 (Scheme 8). The resulting acid was converted
Scheme 6
Scheme 8
This methodology was now sufficiently developed for its
intended application. Our paramount concern was whether
the cycloaddition would still take place in the presence of
the C(12a) ethynyl substituent. To that end, we prepared
carbamate 25 from 4-ethynyl-1-methyltryptamine (15)11
using the same procedure as that employed for carbamate
16. To our delight, treatment of the aziridine 25 with TBAF
cleanly delivered the desired endo cycloadduct 26 (Scheme
7). However, we observed that the cycloadduct 26 underwent
to the mixed anhydride and then treated with sodium azide
to effect a facile Curtius rearrangement to bisaminal 28.14
In conclusion, we have demonstrated that aza-ortho-
xylylenes can be generated at ambient temperatures via acid-
or base-induced cleavage of 2-(2-acylaminophenyl)aziridines
and then intercepted with indoles in intramolecular hetero
Diels-Alder reactions. The generality of this cascade type
of transformation warrants further investigation because both
the tetrahydroquinoline and the â-phenethylamine privileged
structures are simultaneously constructed. Moreover, this
methodology has expedited the construction of a hexacyclic
substructure of communesin B that also possesses the
bisaminal functionality. Efforts directed toward the comple-
tion of the total synthesis are underway and will be reported
in due course.
Scheme 7
Acknowledgment. We appreciate the financial support
provided by the National Institutes of Health (GM28663).
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.
OL061461D
(12) (a) For a related example of a gold-catalyzed intramolecular
hydroamination of an arylalkyne, see: Kadzimirsz, D.; Hildebrandt, D.;
Merz, K.; Dyker, G. Chem. Commun. 2006, 661. For the cyclization of
â-ketoesters with alkynes using this catalyst, see: (b) Kennedy-Smith, J.
J.; Staben, S. T.; Toste, F. D. J. Am. Chem. Soc. 2004, 126, 4526.
(13) For another example of a bridgehead enamine, see: Kirby, A. J.;
Komarov, I. V.; Wothers, P. D.; Feeder, N. Angew. Chem., Int. Ed. 1998,
37, 785.
a slow transformation to a secondary product. Consequently,
the alkyne 26 was immediately treated with a gold(I)
catalyst12 to provide the enamine 2713 via a 7-exo-dig ring
closure with the nearby piperidine nitrogen. Further exami-
(14) For the preparation of N-acylhemiaminals via Curtius rearrange-
ments, see: (a) Roush, W. R.; Marron, T. G. Tetrahedron Lett. 1993, 34,
5421. (b) Smith, A. B.; Safonov, I. G.; Corbett, R. M. J. Am. Chem. Soc.
2002, 124, 11102.
(11) Prepared in four steps (see Supporting Information) from the known
4-formyl-1-(triisopropylsilyl)gramine; see: Chauder, B.; Larkin, A.; Snieck-
us, V. Org. Lett. 2002, 4, 815.
3998
Org. Lett., Vol. 8, No. 18, 2006