Formal syntheses of naturally occurring welwitindolinones

Article abstract of DOI:10.1021/ol301424h

The formal syntheses of N-methylwelwitindolinone C isothiocyanate, N-methylwelwitindolinone C isonitrile, N-methylwelwitindolinone D isonitrile, 3-hydroxy-N-methylwelwitindolinone C isothiocyanate, and 3-hydroxy-N- methylwelwitindolinone C isonitrile are reported. The synthesis features several novel processes, including a Lewis acid mediated coupling between a benzylic-type heteroaromatic alcohol and a highly functionalized silyl ketene acetal, an intramolecular enolate arylation, and a regioselective, Pd(0)-catalyzed π-allylic cyclization of a γ-benzoyloxy enone moiety that is revealed by unmasking a furan ring.

Full text of DOI:10.1021/ol301424h

ORGANIC
LETTERS
2012
Vol. 14, No. 15
3834–3837
Formal Syntheses of Naturally Occurring
Welwitindolinones
Tsung-hao Fu, William T. McElroy, Mariam Shamszad, and Stephen F. Martin*
Department of Chemistry and Biochemistry, The University of Texas at Austin, Austin,
Texas 78712, United States
sfmartin@mail.utexas.edu
Received May 23, 2012
ABSTRACT
The formal syntheses of N-methylwelwitindolinone C isothiocyanate, N-methylwelwitindolinone C isonitrile, N-methylwelwitindolinone D
isonitrile, 3-hydroxy-N-methylwelwitindolinone C isothiocyanate, and 3-hydroxy-N-methylwelwitindolinone C isonitrile are reported. The
synthesis features several novel processes, including a Lewis acid mediated coupling between a benzylic-type heteroaromatic alcohol and a
highly functionalized silyl ketene acetal, an intramolecular enolate arylation, and a regioselective, Pd(0)-catalyzed π-allylic cyclization of a
γ-benzoyloxy enone moiety that is revealed by unmasking a furan ring.
Several novel indole alkaloids, including N-methylwel-
witindolinone C isothiocyanate (1) and N-methylwelwitin-
dolinone C isonitrile (2), were isolated by Moore and co-
workers from the extracts of the blue-green cyanobacteria
Hapalosiphon wetwitschii and Westiella intracta in 1994
(Figure 1).1 These compounds, which were collectively
named welwitindolinones and possess a unique bicyclo-
[4.3.1]decane ring system, were isolated together with the
related fisherindoles and hapalindoles, and a putative bio-
genetic relationship among these alkaloids was proposed.1
The related alkaloids 3-hydroxy-N-methylwelwitindolinone
C isothiocyanate (3), 3-hydroxy-N-methylwelwitindolinone
C isonitrile (4), and N-methylwelwitindolinone D isonitrile
(5) with the same skeletal framework were later isolated
from the cyanophytes Fischerella muscicola and Fischerella
major.2 These natural products exhibit a number of useful
biological properties, including antifungal and larvicidal
activities, microtubule depolymerization, and the ability to
reverse P-glycoprotein-mediated multidrug drug resistance
(MDR) in human cancer cells.3
Figure 1. Representative welwitindolinone alkaloids.
Owing to their novel structures and exciting biological
activities, the welwitindolinone family of natural products
has captured the attention of many in the synthetic com-
munity, and these efforts have been chronicled in numerous
publications over the past 15 years.4 Despite these extensive
efforts, 1,5,6 2,6,7 3,6,7 4,6,7 and 58 succumbed to total synthesis
only very recently. We now report the details of some of our
work in the area that has culminated in the formal syntheses
of the naturally occurring welwitindolinones 1À5.
(1) Stratmann, K.; Moore, R. E.; Bonjouklian, R.; Deeter, J. B.;
Patterson, G. M. L.; Shaffer, S.; Smith, C. D.; Smitka, T. A. J. Am.
Chem. Soc. 1994, 116, 9935–9942.
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J. Nat. Prod. 1999, 62, 569–572.
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Moore, R. E. Mol. Pharmacol. 1995, 47, 241–247. (b) Zhang, X. Q.;
Smith, C. D. Mol. Pharmacol. 1996, 49, 288–294.
r
10.1021/ol301424h
Published on Web 07/25/2012
2012 American Chemical Society

Our approach to the welwitindolinones 1À5 is outlined
in retrosynthetic format in Scheme 1 and features refunction-
alization of the advanced common intermediate 6, which is
accessed by the stereoselective methylation of the dienolate
derived from 7. We envisioned that the tetracycle 7 could be
formed via a novel allylic alkylation of enone 8. Although
there are a plethora of examples of π-allylic alkylations,9 we
are aware of no precedent for a Pd(0)-catalyzed π-allylic
alkylation of a γ-acyloxy enone moiety as found in 8 that
proceeds R to the carbonyl group. This construction would
thus represent a novel advance that could prove to be of
broader utility. The synthesis of 8 from 9 features formation
of the tricyclic core of the welwitindolinones by an enolate
arylation, which is precedented in our earlier work in the
area,4v and the oxidative unmasking of a furan ring to reveal
the latent γ-acyloxy enone subunit. Access to 9 then requires
trapping of the carbocation generated from the known
alcohol 114v with the π-nucleophile 10 via a vinylogous
Mannich-like reaction10 utilizing methodology that we pre-
viously developed specifically for this bond forming step.11
Scheme 1. Retrosynthetic Approach to Welwitindolinone
Alkaloids
~
ꢀ
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The first task required the synthesis of the silyl ketene
acetal 10. In the event, γ-alkylation of the dianion of
methyl acetoacetate (12)12 with furfuryl chloride (13)13
furnished ketoester 14 (Scheme 2). Subsequent deprotona-
tion of 14 with NaHMDS followed by trapping with
TMSCl gave 10 as a single isomer,14 which was used
directly without purification.
The methyl ketone 15, which was prepared from com-
mercially available 4-bromoindole in two steps,4v was
treated with methylmagnesium bromide to give the some-
what labile alcohol 11, which was treated immediately with
silyl ketene acetal 10 in the presence of TMSOTf to deliver
ketoester9 asa mixture(ca. 4:1) ofketoand enoltautomers
in 60% yield over two steps (Scheme 3). Construction of
the seven-membered carbocyclic ring was then achieved to
give 16 in 89% yield via a Pd(0)-catalyzed intramolecular
enolate arylation that was optimally promoted with PEPP-
SI-IPr15 in the presence of NaOt-Bu. Initial attempts to
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Org. Lett., Vol. 14, No. 15, 2012
3835

The selective oxidative cleavageof the furan moietyof 17
proved tobe considerablymorechallenging thanoriginally
anticipated, primarily because of competing halogenation
of the indole ring. Numerous reagents and conditions were
screened. Br2 and dibromohydantoin in aqueous solvents
gave low yields of 18 along with significant amounts of
overbrominated products in which bromine atoms had
been introduced onto the indole ring. Use of N-chlorosuc-
cinimide (NCS) in aqueous solvents led only to chlorina-
tion of the furan and indole rings; no aldehyde was
detected in the reaction mixtures. MeReO3/urea hydrogen
peroxide oxidized the indole moiety while leaving the furan
ring intact.16 Dimethyldioxirane (DMDO) and magne-
sium monoperoxyphthalate (MMPP) gave mixtures of
products, whereas use of singlet oxygen produced the
Z-isomer of 18 in only about 20% yield.
Scheme 2. Synthesis Silyl Ketene Acetal 10
We eventually discovered that treating 17 with N-bro-
mosuccinimide (NBS) in aqueous DMF gave aldehyde 18
in 34% yield, together with 7% of a brominated derivative
of 18 and 6% of a brominated derivative of 17. Selective
reduction of the aldehyde moiety in 18 was initially some-
what problematic because mixtures of 1,2- and 1,4-reduc-
tion products were formed. However, we discovered that
Scheme 3. Synthesis of Benzoate 20
17
tert-BuNH2BH3 reduced 18 to give alcohol 19 in 82%
yield, and no overreduction of the ketone moiety was
observed. O-Benzoylation of alcohol 19 with BzCl gave
20, thereby setting the stage for the pivotal intramolecular
π-allylic alkylation. Although the acetate analog of 20 was
also prepared, it was found to be less stable and gave lower
yields in the cyclization.
Deprotection of the silyl enol ether moiety in 20 with
TBAF provided the enol 21, which was treated directly
with Bu3SnOMe18 and Pd2dba3 in the presence of trifur-
ylphosphine to deliver a mixture (5.8:1:3.5) of enones 22
and 23and vinyl ketone 7 (Scheme 4). Whenthismixture of
22, 23, and 7 was deprotonated with freshly prepared
NaHMDS under equilibrating conditions, the dienolate
thus generated was methylated with MeI to furnish 6 as a
single diastereomer. The structure of 6 was unequivocally
established by X-ray crystallography. At this stage, the
entire carbon skeleton of the welwitindolinones 1À5 had
been assembled, but several functional group manipula-
tions were needed.
The primary challenge at this juncture was the conver-
sion of the ketone functional group into the vinyl chloride
24, and a number of one-step methods are known. How-
ever, in a number of preliminary experiments, we found
that treating ketone 6 with PCl5,19 WCl6,20 PPh3/CCl4,21
(16) Finlay, J.; McKervey, M.; Gunaratne, H. Tetrahedron Lett.
1998, 39, 5651–5654.
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4051–4054.
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J. Chem. Soc. 1952, 1419–1425.
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selectively oxidize the furan ring in 16 were unsuccessful
because the enol moiety in 16 cyclized onto the intermedi-
ate unsaturated keto aldehyde, thus leading to unwanted
byproducts. This troublesome side reaction was avoided
simply by protecting 16 as its tert-butyldimethylsilyl enol
ether 17. In practice, the enolate arylation and enol pro-
tection steps were performed without purification of the
intermediate 16.
Chem. 2007, 72, 2216–2219.
3836
Org. Lett., Vol. 14, No. 15, 2012

However, we decided to exploit an opportunity to complete
the formal syntheses of the welwitindolinones 1À5 by inter-
cepting a pivotal intermediate that Rawal has converted into
these natural products. In the event, global reduction of 6
with LiAlH4 gave an intermediate triol that underwent facile
oxidation with Dess-Martin periodinane to furnish aldehyde
25 in 89% yield over two steps (Scheme 5). Spectral data
Scheme 4. Side Chain Elaboration
Scheme 5. Completion of Formal Synthesis
(1H and 13C NMR) for the synthetic 25 thus obtained are
consistent with those reported.8 Inasmuch as Rawal and
co-workers have converted 25 into welwitindolinones 1À5,6,8
its preparation by the route outlined in this account con-
stitutes a formal synthesis of these alkaloids.
In summary, the formal syntheses of welwitindolinones
1À5 were successfully completed by the independent
synthesis of the aldehyde 25, a key intermediate in Rawal’s
syntheses of these alkaloids.6,8 The synthesis features a
number of interesting steps. The first of these is a Lewis
acid mediated coupling that involves a variant of a viny-
logous Mannich reaction in which a benzylic-type carbo-
cation is trapped by a highly functionalized π-nucleophile.
Other highlights include an intramolecular enolate aryla-
tion to form a seven-membered ring and a novel, regiose-
lective π-allylic alkylation of a γ-acyloxy enone moiety to
construct the tetracyclic core of the welwitindolinones.
P(OPh)3/Cl2,22 and Sc(OTf)3/AcCl23 under a variety of
established conditions and modifications thereof did not
furnish any of the desired vinyl chloride 24. Other proto-
cols for transforming ketones into vinyl chlorides were also
examined. For example, the reaction of hydrazones with
NCS is known to generate vinyl chlorides.24 Initial efforts
to prepare the hydrazone of 6 led solely to extensive
reduction of the pendant vinyl group, which presumably
occurred because dimide was generated in situ. However,
even when 6 was treated with hydrazine under rigorous
exclusion of oxygen and trace metals, no hydrazone for-
mation was observed, even under forcing conditions that
led to the formation of uncharacterizable mixtures. Be-
cause this protocol was used successfully by Rawal to
prepare the vinyl chloride of a closely related ketone,
additional work is perhaps indicated.6 The ketone 6 was
also converted into its vinyl triflate by sequential reaction
with LiHMDS and Comins’ reagent, but preliminary at-
tempts to convert this triflate to a vinyl stannane following a
protocol used by Garg5 for a related substrate were un-
successful. Rawal observed an unusual rearrangement for a
closely related enol triflate having a bridgehead aldehyde
instead of an ester,4z although we observed no such reaction.
We continue to explore methods to effect the conversion of
ketone 6 into the vinyl chloride 24 in order to complete a total
synthesis of N-methylwelwitindolinone C isothiocyanate (1).
Acknowledgment. We thank the National Institutes of
Health (GM 25439) and the Robert A. Welch Foundation
(F-0652) for their generous support of this research. We
are also grateful to Vince Lynch (The University of Texas)
for X-ray crystallography and Steve Sorey (The University
of Texas) for NMR spectroscopy.
Supporting Information Available. Experimental pro-
1
cedures and H NMR spectra for all new compounds,
plus CIF file representing X-ray coordinates for com-
pound 6, are included. This material is available free of
charge via the Internet at http://pubs.acs.org.
(23) Su, W.; Jin, C. Org. Lett. 2007, 9, 993–996.
(24) Mori, H.; Tsuneda, K. Chem. Pharm. Bull. 1963, 11, 1413–1417.
The authors declare no competing financial interest.
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