Total Synthesis of (±)-Perophoramidine

Article abstract of DOI:10.1021/ja049569g

The first total synthesis of racemic perophoramidine is described. The key step features the highly stereoselective introduction of the vicinial quaternary centers via base-promoted carbon-carbon bond formation between a 3-alkylindole and a 3-bromo-3-alkylindolin-2-one. This transformation presumably proceeds through a conjugate addition or Diels-Alder cycloaddition of the 3-alkylindole with a 3-alkylindol-2-one intermediate. Copyright

Full text of DOI:10.1021/ja049569g

Published on Web 04/02/2004
Total Synthesis of (()-Perophoramidine
James R. Fuchs and Raymond L. Funk*
Department of Chemistry, PennsylVania State UniVersity, UniVersity Park, PennsylVania 16802
Received January 24, 2004; E-mail: rlf@chem.psu.edu
Perophoramidine1 and communesin B2 are two architecturally
Scheme 1
intriguing natural products related by their presumed biosynthetic
origin from two molecules of tryptamine. Their structural differen-
ces are substantial, however, since perophoramidine (1) embodies
a bis-amidine rather than the bis-aminal functionality present in
communesin B, (2) lacks the azepine ring system of communesin
B, (3) possesses a trans- rather than cis-stereochemical relationship
of the vicinal quaternary centers, and (4) contains halogenated
aromatic rings.
Scheme 2
Accordingly, the structural features and biological properties3
of these natural products have elicited activity directed toward their
chemical synthesis.4 Indeed, we recently reported that the hexacyclic
substructure 3 of communesin B could be rapidly assembled by an
intramolecular cycloaddition of the indole, N-acyl-aza-o-xylylene
intermediate 2, in turn, generated from carbonate 1 (Scheme 1).4c
This result led us to contemplate the union of the two tryptamine
moieties in the putative biosynthetic pathway through an analogous
hetero Diels-Alder reaction of the prenylated tryptamine 4 with
an oxidized tryptamine, 3-(2-aminoethyl)indol-2-one (5).5 The
resulting exo-cycloadduct 6 would be expected to undergo a rapid
transamidation reaction with the strained bridged bicyclic lactam
to afford the spirolactam 7. Reduction of the lactam carbonyl and
cyclizations with the primary amine nitrogen would then afford
the complete ring system of communesin B.
Scheme 3
The viability of this type6 of “biomimetic” approach rests on
the ability to generate and trap the quasi-antiaromatic indol-2-one.
While we are not aware of any reactions in the literature where
this intermediate has been explicitly stated or deliberately generated,
numerous examples can be found that suggest that it may have
been.7 In view of this precedent, we were gratified to discover that
subjection of 3-bromo-3-methylindolin-2-one (8)8 and 3-methylin-
dole (10) to the Kitagawa reaction conditions7b afforded the
indolenine 13 (Scheme 2) as a mixture of stereoisomers (74:26).
Moreover, the stereoselectivity could be significantly improved (95:
5) by employing cesium carbonate in methylene chloride, a protocol
reported by Corey for the generation of acyclic N-acyl-aza-o-
xylylenes.9 Thermodynamic control does not appear to be operative
here since resubjection of the minor isomer to these reaction
conditions afforded none of the major isomer. The direct formation
of intermediate 12 via a conjugate addition pathway involving the
putative indol-2-one intermediate 9 is in accord with the observed
solvent and counterion effects. However, it is also possible that
Lewis acid catalysis modulates the stereoselectivity en route to
cycloadduct 11 which undergoes subsequent ring opening to 12.10
The elucidation of the stereochemistry of indolenines 13 was a
prerequisite for the orientation of our synthetic effort toward the
appropriate natural product target, perophoramidine/communesin
B. Toward that goal, the readily separable major isomer of
indolenine 13 was converted into the conformationally less mobile
aminal 16 (Scheme 3). Thus, tosylation of the lactam functionality
followed by treatment of the resulting imide 14 with basic methanol
effected ring opening and subsequent closure of the tosylamide
anion of 15 upon the indolenine functionality to afford aminal 16.
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10.1021/ja049569g CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Scheme 4
as well as the fortuitous removal of the BOC protecting group. As
anticipated, deprotection of nosylamide 24 according to the
Fukuyama protocol11 was accompanied by attack of the resulting
methylamine from the easily accessible R-face of the imidate to
introduce the more basic of the two amidine functionalities. The
remaining amidine was then installed upon oxidation (MnO2 or
DDQ) to furnish racemic perophoramidine whose 1H and 13C
spectral characteristics were identical to those previously published.1
In conclusion, we have discovered that 3-alkylindoles undergo
base-promoted alkylation reactions with 3-bromo-3-alkylindolin-
2-ones.7 This methodology facilitated the first total synthesis of
the cytotoxic agent perophoramidine through the early stage, highly
stereoselective introduction of the vicinial quaternary centers.
Current effort is directed toward delineating the mechanism and
stereocontrol elements of this reaction as well as its application in
other total synthesis endeavors.
Acknowledgment. We thank Professors Samuel Danishefsky
and Ken Feldman for helpful discussions. We appreciate the
financial support provided by the National Institutes of Health
(GM28553).
Supporting Information Available: Spectroscopic data and ex-
perimental details for the preparation of all new compounds. This
material is available free of charge via the Internet at http://pubs.acs.org.
References
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(2) (a) Isolated from the fungal strain Penicillium sp. (P-388, ED50 ) 0.88
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aminal and methyl ester proton resonances, which thereby estab-
lishes the trans relationship of the methyl substituents.
On the basis of this result, a “biomimetic” strategy for the total
synthesis of perophoramidine was envisaged analogous to the one
outlined for communesin B in Scheme 1. To that end, we were
gratified to discover that the indole 178 and 3-bromoindolin-2-one
188 could be coupled (Scheme 4) without deleterious consequence
due to the replacement of the methyl substituents of the previously
discussed model system (Scheme 2) with functionalized side chains
and/or the bromine substituent on the aromatic ring of oxindole 18
(89%, dr > 20:1). The lactam 19 was converted into the corre-
sponding BOC-imide derivative that underwent a cascade reaction
sequence upon reduction of the azido functionality involving
transamidation and closure of the resulting carbamate upon the
indolenine to deliver the aminal 20. The opportunity to introduce
the chloro substituents now presented itself since the aromatic rings
were differentially activated for electrophilic aromatic substitution.
Thus, chlorination of aminal 20 followed by nosylation of the lactam
functionality proceeded uneventfully to afford the imide 21. Next,
the silyloxy functionality of 21 was converted into the azido group
present in 22 by the straightforward reaction sequence. It should
be noted here that the N-methyl lactam analogous to 22 was also
prepared during the course of this investigation, although all
attempts to convert it to the corresponding amidine via an intra-
molecular Staudinger reaction failed. Consequently, the imide 22
was subjected to the second transamidation reaction in the synthetic
sequence, and the newly generated p-nosylamide was selectively
methylated in preference to the six-membered lactam to afford the
pentacyclic compound 23. Treatment of lactam 23 with Meerwein’s
reagent effected its conversion into the corresponding imidate 24
(3) Communesin B was observed to disrupt microfilaments in cultured
mammalian cells,2b and perophoramidine induces apoptosis via PARP-1
cleavage,1 a signal of irreparable DNA damage, see: D’Amours, D.;
Sallmann, F. R.; Dixit, V. M.; Poirier, G. G. J. Cell Sci. 2001, 114, 3771.
(4) Perophoramidine: (a) Artman, G. D.; Weinreb, S. M. Org. Lett. 2003, 5,
1523. Communesin B: (b) May, J. A.; Zeidan, R. K.; Stoltz, B. M.
Tetrahedron Lett. 2003, 44, 1203. (c) Crawley, S. L.; Funk, R. L. Org.
Lett. 2003, 5, 3169.
(5) Stoltz and co-workers have proposed a very similar biosynthetic route
through the cycloaddition of indol-2-one 5 with N-methylaurantioclavine,
i.e, the azepine analogue of indole 4, see ref 4b.
(6) For the seminal examples of proposed alkaloid biosynthesis (calycantha-
ceous) originating from tryptamine dimers, see: (a) Robinson, R.; Teuber,
H. J. Chem. Ind. 1954, 783. (b) Woodward, R. B.; Yang, N. C.; Katz, T.
J. Proc. Chem. Soc. 1960, 76. Indeed, the gross structure of perophor-
amidine was predicted, albeit, bearing aminals instead of amidines
(northern aminal dimethylated) and lacking the halogen substituents. It
was subsequently synthesized, see: (c) Hendrickson, J. B.; Rees, R.;
Go¨schke, R. Proc. Chem. Soc. 1962, 383.
(7) (a) For example, the substitution reaction of an 3-alkyl-3-chloroindolin-
2-one with KCN might proceed by an elimination-addition pathway rather
than direct displacement. Labroo, R. B.; Labroo, V. M.; King, M. M.;
Cohen, L. A. J. Org. Chem. 1991, 56, 3637. (b) More pertinent to our
specific application is the Kitagawa synthesis of the antibiotic trisindoline
by the silver carbonate-promoted replacement of the two bromine
substituents of 3,3-dibromoindolin-2-one with two indole moieties.
Kobayashi, M.; Aoki, S.; Gato, K.; Matsunami, K.; Kurosu, M.; Kitagawa,
I. Chem. Pharm. Bull. 1994, 42, 2449.
(8) See Supporting Information for the preparation of this compound.
(9) Steinhagen, H.; Corey, E. J. Angew. Chem., Int. Ed. 1999, 38, 1928.
(10) Alternative pathways for the formation of indolenines 13 other than direct
displacement can also be envisaged, for example, one involving transfer
alkylation. For an instructive example, see: Melvin, L. S.; Trost, B. M.
J. Am. Chem. Soc. 1972, 94, 1790.
(11) Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett. 1995, 36, 6373.
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