Interrupted fischer indolization approach toward the communesin alkaloids and perophoramidine

Article abstract of DOI:10.1021/ol302023q

A concise approach toward the total synthesis of the communesin alkaloids and perophoramidine is reported. The strategy relies on the use of the interrupted Fischer indolization to build the tetracyclic indoline core of the natural products. Studies to probe the scope and limitations of this plan are presented. Although the methodology does not tolerate a C8-allyl substituent en route to the challenging vicinal quaternary stereocenters, variation at C7 and on the C ring is permitted.

Full text of DOI:10.1021/ol302023q

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Interrupted Fischer Indolization Approach
toward the Communesin Alkaloids and
Perophoramidine
Alex W. Schammel, Grace Chiou, and Neil K. Garg*
Department of Chemistry and Biochemistry, University of California, Los Angeles,
California 90095-1569, United States
neilgarg@chem.ucla.edu
Received July 20, 2012
ABSTRACT
A concise approach toward the total synthesis of the communesin alkaloids and perophoramidine is reported. The strategy relies on the use of the
interrupted Fischer indolization to build the tetracyclic indoline core of the natural products. Studies to probe the scope and limitations of this plan
are presented. Although the methodology does not tolerate a C8-allyl substituent en route to the challenging vicinal quaternary stereocenters,
variation at C7 and on the C ring is permitted.
The communesin family of natural products and pero-
phoramidine have been popular targets for chemical
synthesis (Figure 1).1 Communesins A (1) and B (2) were
isolated in 1993 by Numata and co-workers from a
Penicillium mold found growing on the marine algae
Enteromorpha intestinalis.2 Over the past decade, several
additional communesin alkaloids (e.g., 3ꢀ8) have been
discovered,3 in addition to perophoramidine (9).4 Some of
the communesins exhibit moderate insecticidal activity,
whereas communesin B (2) also shows activity against the
P-388 leukemia cell line (ED50 = 0.88 μM).5 Furthermore,
9 is cytotoxic toward the HCT116 colon cancer cell line
(IC50 = 60 μM).4
The alkaloids 1ꢀ9 possess a number of structural fea-
tures that render them attractive and challenging targets
for total synthesis. Communesins 1ꢀ8 bear a heptacyclic
skeleton, which contains a heterocycle-fused indoline core.
Other characteristics of these natural products include the
vicinal quaternary centers at C7 and C8 and two aminal
linkages at C6 and C9.6 Perophoramidine (9) is similar to
the communesins, although it lacks the seven-membered G
ring and has an opposite sense of relative stereochemistry
with respect to C7 and C8. Additionally, perophoramidine
(9) is more highly oxidized in comparison to the commu-
nesins as noted by the aromatic halogenation pattern and
presence of amidine functional groups instead of aminals.
Synthetic endeavors toward these natural products have
(1) (a) Siengalewicz, P.; Gaich, T.; Mulzer, J. Angew. Chem., Int. Ed.
2008, 47, 8170–8176. (b) Zhang, D.; Song, H.; Qin, Y. Acc. Chem. Res.
2011, 44, 447–457. (c) Zuo, Z.; Ma, D. Isr. J. Chem. 2011, 51, 434–441.
(2) Numata, A.; Takahashi, C.; Ito, Y.; Takada, T.; Kenzo, K.;
Usami, Y.; Matsumura, E.; Imachi, M.; Ito, T.; Hasegawa, T. Tetra-
hedron Lett. 1993, 34, 2355–2358.
(3) (a) Jadulco, R.; Edrada, R. A.; Ebel, R.; Berg, A.; Schaumann,
K.; Wray, V.; Steube, K.; Proksch, P. J. Nat. Prod. 2004, 67, 78–81. (b)
Hayashi, H.; Matsumoto, H.; Akiyama, K. Biosci. Biotechnol. Biochem.
2004, 68, 753–756. (c) Dalsgaard, P. W.; Blunt, J. W.; Munro, M. H. G.;
Frisvad, J. C.; Christophersen, C. J. Nat. Prod. 2005, 68, 258–261.
(4) Verbitski, S. M.; Mayne, C. L.; Davis, R. A.; Concepcion, G. P.;
Ireland, C. M. J. Org. Chem. 2002, 67, 7124–7126.
(5) (a) Ratnayake, A. S.; Yoshida, W.; Mooberry, S. L.; Hemscheidt,
T. K. J. Org. Chem. 2001, 66, 8717. (b) Erratum: Ratnayake, A. S.;
Yoshida, W. Y.; Mooberry, S. L.; Hemscheidt, T. K. J. Org. Chem. 2003,
68, 1640.
(6) Compounds 1ꢀ9 are numbered in a manner that is consistent with
that of Numata et al. (see ref 2).
(7) (a) May, J. A.; Zeidan, R. K.; Stoltz, B. M. Tetrahedron Lett.
2003, 44, 1203–1205. (b) Crawley, S. L.; Funk, R. L. Org. Lett. 2003, 5,
3169–3171. (c) May, J. A.; Stoltz, B. M. Tetrahedron 2006, 62, 5262–
5271. (d) Yang, J.; Song, H.; Xiao, X.; Wang, J.; Qin, Y. Org. Lett. 2006,
8, 2187–2190. (e) Crawley, S. L.; Funk, R. L. Org. Lett. 2006, 8, 3995–
3998. (f) Sabahi, A.; Novikov, A.; Rainier, J. D. Angew. Chem., Int. Ed.
2006, 45, 4317–4320. (g) George, J. H.; Adlington, R. M. Synlett 2008,
2093–2096.
r
10.1021/ol302023q
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led to several promising routes,7 in addition to a few
recently completed total syntheses by the groups of
Weinreb,8 Funk,9 Ma,10 and Qin.11
Figure 2. Interrupted Fischer indolization methodology and
approach toward alkaloids 1ꢀ9.
intermediates for our total synthesis objectives but also
an opportunity to study the scope and limitations of the
interrupted Fischer indolization methodology. Herein, we
report the outcome of the interrupted Fischer indolization
reaction as variations in the N,O-acetal coupling fragment
(at C7, C8, or C3) are considered.
Figure 1. Communesins (1ꢀ8) and perophoramidine (9).
The first point of variation we explored was the sub-
stituent at C7 of the N,O-acetal component, as a C7-
aminoethyl substituent would be necessary for the synthe-
sis of the communesin family of natural products and
also for perophoramidine (Scheme 1). Acetal 16, a readily
available known compound,16 was treated with TMSOTf
En route to the total synthesis of compounds 1ꢀ9 and a
variety of other alkaloids, we have developed a cascade
reaction that provides access to fused indoline scaffolds.12
The transformation, termed the “interrupted Fischer13ꢀ15
indolization”, allows for aryl hydrazines 10 and latent
aldehydes 11 to be converted to indoline products 12
(Figure 2). The reaction is operationally simple and broad
in scope, requires mild reaction conditions, and has shown
utility in synthesis.12 In our initial attempts, we found that
the interrupted Fischer indolization of N-methylphenylhy-
drazine (13) with N,O-acetal 14 efficiently delivered tetra-
cycle 15.12a,b Of note, this reaction provides rapid access
to the 6,5,6,6 FꢀEꢀDꢀC ring system of the communesins
and perophoramidine and provides a unique approach to
these highly sought after alkaloids.
€
in the presence of Hunig’s base to afford enol ether 17 as
an inconsequential mixture of E/Z isomers. Subsequently,
enol ether 17 underwent a hetero-DielsꢀAlder reaction
with sulfonamide 1817 to deliver the desired N,O-acetal
substrate 19 in 70% yield. In the interrupted Fischer
indolization reaction, treatment of 19 with N-methylphe-
nylhydrazine (13) furnished tetracycles 20 and 21 in a com-
bined 67% yield (approximately 3:1 ratio of 20 to 21).18
Thus, we were able to construct the key indoline scaffold,
which bears a nitrogen functional handle useful for the
synthesis of the communesin alkaloids.
Encouraged by these results, we also explored the inter-
rupted Fischer indolization of two reaction partners that
could plausibly allow for assembly of the seven-membered
G ring of the communesins. Thus, hydrazine 2219 under-
went reaction with N,O-acetal 2320 to provide tetracyclic
indoline 24 in 54% yield (Scheme 2). Subsequent removal
of the phthalyl group was achieved upon treatment of 24
with hydrazine monohydrate to give primary amine 25.
With the aim of forging the G ring via a PictetꢀSpengler
cyclization,21 amine 25was condensed with3-methylbut-2-
enal to furnish imine 26. Unfortunately our efforts to
By further varying the reaction partners in the key
interrupted Fischer indolization reaction, we envisioned
that more highly functionalized derivatives of 15 could be
readily accessible. This would provide not only advanced
(8) Liu, P.; Seo, J. H.; Weinreb, S. M. Angew. Chem., Int. Ed. 2010,
49, 2000–2003.
(9) Fuchs, J. R.; Funk, R. L. J. Am. Chem. Soc. 2004, 126, 5068–5069.
(10) (a) Zuo, Z.; Ma, D. Angew. Chem., Int. Ed. 2011, 50, 12008–
12011. (b) Zuo, Z.; Xie, W.; Ma, D. J. Am. Chem. Soc. 2010, 132, 13226–
13228.
(11) (a) Yang, J.; Wu, H.; Shen, L.; Qin, Y. J. Am. Chem. Soc. 2007,
129, 13794–13795. (b) Wu, H.; Xue, F.; Xiao, X.; Qin, Y. J. Am. Chem.
Soc. 2010, 132, 14052–14054.
(12) (a) Boal, B. W.; Schammel, A. W.; Garg, N. K. Org. Lett. 2009,
11, 3458–3461. (b) Schammel, A. W.; Boal, B. W.; Zu, L.; Mesganaw, T.;
€
€
Garg, N. K. Tetrahedron 2010, 66, 4687–4695. (c) C-elebi-Olc-um, N.;
Boal, B. W.; Huters, A. D.; Garg, N. K; Houk, K. N. J. Am. Chem. Soc.
2011, 133, 5752–5755. (d) Zu, L.; Boal, B. W.; Garg, N. K. J. Am. Chem.
Soc. 2011, 133, 8877–8879. (e) Schammel, A. W.; Chiou, G.; Garg, N. K.
J. Org. Chem. 2012, 77, 725–728.
~
(16) (a) Paz Munoz, M.; de la Torre, M. C.; Sierra, M. A. Adv. Synth.
ꢀ
Catal. 2010, 352, 2189–2194. (b) Kowalski, P.; Jaskowska, J. Arch.
Pharm. (Weinheim, Ger.) 2012, 345, 81–85.
(17) Steinhagen, H.; Corey, E. J. Angew. Chem., Int. Ed. 1999, 38,
1928–1931.
(18) The formation of NMe and NH products is consistent with
previous observations in the interrupted Fischer indolization; see
ref 12a, 12b.
(19) Srivastava, S.; Ruane, P. H.; Toscano, J. P.; Sullivan, M. B.;
Cramer, C. J.; Chiapperino, D.; Reed, E. C.; Falvey, D. E. J. Am. Chem.
Soc. 2000, 122, 8271–8278.
(13) For reviews of the classic Fischer indole synthesis, see: (a)
Robinson, B. Chem. Rev. 1963, 63, 373–401. (b) Robinson, B. Chem.
Rev. 1969, 69, 227–250.
(14) For seminal studies of the Fischer indole synthesis, see: (a)
Fischer, E.; Jourdan, F. Ber. 1883, 16, 2241–2245. (b) Fischer, E.; Hess,
O. Ber. 1884, 17, 559–568.
(15) For the use of the interrupted Fischer indolization to access
flustramine derivatives, see: Bunders, C.; Cavanagh, J.; Melander, C.
Org. Biomol. Chem. 2011, 9, 5476–5481.
(20) Carbamylated N,O-acetal 23 was employed in this study because
it was found to be more readily removable compared to the N-Ts group.
B
Org. Lett., Vol. XX, No. XX, XXXX

shown in Scheme 3. Commercially available aniline 28
was converted to sulfonamide 29, which, in turn, under-
went reduction upon treatment with lithium aluminum
hydride to furnish alcohol 30. Oxidation of alcohol 30 with
PCC yielded aldehyde 31, which was elaborated to alcohol
32 by the addition of allyl magnesium bromide. Treatment
of alcohol 32 with thionyl chloride provided benzylic
chloride 33, which was the substrate for the hetero-
DielsꢀAlder reaction. In the event, the desired C8 sub-
stituted acetal 34 was obtained, albeit in modest yield.23
Attempts to effect the interrupted Fischer indolization on
this substrate to arrive at 35 proved fruitless, despite
exhaustive efforts using a variety of acid-mediated condi-
tions, in addition to several arylhydrazine coupling
partners.24 Although this route proved ineffective for our
planned total synthesis, these efforts reveal a steric limita-
tion of the interrupted Fischer indolization methodology.
Scheme 1. Interrupted Fischer Indolization of 19
Scheme 3. Attempted Interrupted Fischer Indolization of
C8-Allylated Compound 34
Scheme 2. Interrupted Fischer Indolization of 22 þ 23 and
Further Elaboration to 26
arrive at pentacycle 27 through a PictetꢀSpengler cycliza-
tion have been unsuccessful to date.22
We also prepared a derivative of N,O-acetal 34 lacking
the C8 allyl substituent and tested its viability in the
Other aspects of the interrupted Fischer indolization we
aimed to test involved substitution at C8 for the eventual
installation of the C7/C8 vicinal quaternary stereocenters,
in addition to the aryl bromide substituent present in
perophoramidine. Our route to a suitable substrate is
(23) This hetero-DielsꢀAlder reaction was hampered by the compe-
titive formation of diene i, which presumably forms from elimination of
the benzylic chloride. Efforts to suppress the formation of i were not
undertaken because of the difficulty of the subsequent interrupted
Fischer indolization.
(21) For reviews of the PictetꢀSpengler reaction, see: (a) Cox, E. D.;
€
Cook, J. M. Chem. Rev. 1995, 95, 1797–1842. (b) Stokigt, J.; Antonchick,
A. P.; Wu, F.; Waldmann, H. Angew. Chem., Int. Ed. 2011, 50, 8538–
8564. ForPictetꢀSpengler reactions on similar systems, see: (c) Mahboobi,
S.; Eluwa, S.; Koller, M.; Popp, A.; Schollmeyer, D. J. Heterocycl. Chem.
2000, 37, 1177–1185. (d) Somei, M.; Teranishi, S.; Yamada, K.; Yamada, F.
Chem. Pharm. Bull. 2001, 49, 1159–1165. (e) Yamada, K.; Namerikawa, Y.;
Haruyama, T.; Miwa, Y.; Yanada, R.; Ishikura, M. Eur. J. Org. Chem.
2009, 5752–5759.
(24) MOM ether ii was also prepared but unfortunately proved
ineffective in the interrupted Fischer indolization reaction under a
variety of conditions.
(22) Attempts to form the G ring through intermediate 26 led to
hydrolysis of the imine, thus returning 25. Base induced PictetꢀSpengler
reaction attempts led to the recovery of starting material (see ref 21e).
Further efforts to introduce the G ring of the communesins are
underway.
Org. Lett., Vol. XX, No. XX, XXXX
C

steps from commercially available materials, is expected to
serve as a precursor to perophoramidine (9).26
Scheme 4. Synthesis of Trihalotetracycle 40
In summary, we have established a promising synthetic
strategy toward the communesin alkaloids and perophor-
amidine. The approach involves the use of the interrupted
Fischer indolization methodology, which in turn enables
the rapid assembly of tetracyclic scaffolds that are remi-
niscent of the cores of the desired natural products.
Although the methodology does not tolerate a C8-allyl
substituent en route to the challenging vicinal quaternary
stereocenters, variation at C7 and on the C ring is per-
mitted. Current efforts are dedicated to further elucidating
the subtleties of the interrupted Fischer indolization meth-
odology in the synthesis of indoline-containing natural
products.
interrupted Fischer indolization reaction (Scheme 4).
Alcohol 30 was treated with thionyl chloride to provide
benzylic chloride 36 in 95% yield. Subsequent reaction
of alkyl chloride 36 with enol ether 17 under basic condi-
tions provided N,O-acetal 37 in significantly higher yield
compared to the reaction of the C8-allylated material
(see Scheme 3, 33 þ 17 f 34).23 Fortunately, treatment of
N,O-acetal 37 with phenylhydrazine (38) in the presence
of TFA in dichloroethane generated tetracycle 39 in 68%
yield.25 The success of this transformation supports the
notion that the interrupted Fischer indolization reaction of
34 fails (see Scheme 3) due to steric considerations. Finally,
tetracycle 39 was exposed to NCS to furnish trihalotetra-
cycle 40.9 Intermediate 40, which is available in only six
Acknowledgment. The authors are grateful to the Na-
tional Science Foundation (CHE-0955864 and graduate
fellowship to G.C.), Boehringer Ingelheim, DuPont, Eli
Lilly, Amgen, AstraZeneca, Roche, the Sloan Foundation,
and the University of California, Los Angeles for financial
support. We thank Laura Shim (UCLA) for experimental
assistance and the GarciaꢀGaribay laboratory (UCLA)
for the generous access to instrumentation. These studies
were supported by shared instrumentation grants from
the NSF (CHE-1048804) and the National Center for
Research Resources (S10RR025631).
Supporting Information Available. Experimental de-
tails and compound characterization data. This material
is available free of charge via the Internet at http://pubs.
acs.org.
(25) The use of AcOH/H2O conditions for this transformation failed
to deliver the desired product 39.
(26) Intermediate 40 may plausibly be elaborated by initial benzylic
oxidation to functionalize C8, followed by further manipulations.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX