Access to a welwitindolinone core using sequential cycloadditions

Article abstract of DOI:10.1021/ol901499b

Image Presented A concise approach to the core skeleton of the welwitindolinone alkaloids was developed on the basis of sequential cycloaddition reactions. First, a palladium catalyzed enantioselective [6 + 3] trimethylenemethane cycloaddition onto a trop

Full text of DOI:10.1021/ol901499b

ORGANIC
LETTERS
2009
Vol. 11, No. 16
3782-3785
Access to a Welwitindolinone Core
Using Sequential Cycloadditions
Barry M. Trost* and Patrick J. McDougall
Department of Chemistry, Stanford UniVersity, Stanford, California 94305-5080
bmtrost@stanford.edu
Received July 1, 2009
ABSTRACT
A concise approach to the core skeleton of the welwitindolinone alkaloids was developed on the basis of sequential cycloaddition reactions.
First, a palladium catalyzed enantioselective [6 + 3] trimethylenemethane cycloaddition onto a tropone nucleus was used to generate the
requisite bicyclo[4.3.1]decadiene. Subsequent modifications to the cycloadduct allowed for an intramolecular [4 + 2] cycloaddition to generate
the oxindole and complete the core of the natural product family.
The palladium-catalyzed trimethylenemethane (Pd-TMM)
cycloaddition reaction represents a highly effective tool for
Scheme 1. Enantioselective Pd-TMM [6 + 3] Cycloadditions
the rapid synthesis of complex carbocycles.1 A rather useful
extension to the widely studied [3 + 2] cycloaddition to
electron-deficient olefins is a [6 + 3] cycloaddition to a
tropone nucleus, providing access to functionalized
bicyclo[4.3.1]decadienes.2 Building upon our disclosures of
enantioselective [3 + 2] Pd-TMM cycloadditions controlled
using phosphoramidite ligands,3 we have recently rendered
the [6 + 3] cycloaddition enantioselective as well, thus
enabling access to stereodefined bicyclo[4.3.1]decadienes in
an efficient manner (Scheme 1).4
The advent of such methodology opens the door for a
unique, enantioselective synthesis of bioactive molecules
possessing the [4.3.1] bicyclic motif. Of these, we chose to
initiate a program to develop a synthesis of the welwitin-
dolinone B and C class of marine alkaloids (1-7; Figure
1).5 These particular compounds are characterized by a highly
functionalized [4.3.1] bicyclic carbon skeleton containing an
oxindole, two quaternary stereocenters, and multiple sensitive
functional groups. While the bioactivity of these molecules
varies, the more potent of these, N-methylwelwitindolinone
(1) (a) Trost, B. M. Angew. Chem., Int. Ed. Engl. 1986, 25, 1–20. (b)
Trost, B. M. Pure Appl. Chem. 1988, 60, 1615–1626.
(2) (a) Trost, B. M.; Seoane, P. R. J. Am. Chem. Soc. 1987, 109, 615–
617.
(3) (a) Trost, B. M.; Stambuli, J. P.; Silverman, S. M.; Schworer, U.
J. Am. Chem. Soc. 2006, 128, 13328–13329. (b) Trost, B. M.; Cramer, N.;
Silverman, S. M. J. Am. Chem. Soc. 2007, 129, 12396–12397. (c) Trost,
B. M.; Silverman, S. M.; Stambuli, J. P. J. Am. Chem. Soc. 2007, 129,
12398–12399.
(5) (a) 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. (b) Jimenez, J. I.; Huber, U.; Moore, R. E.;
Patterson, G. M. L. J. Nat. Prod. 1999, 62, 569–572.
(4) Trost, B. M.; McDougall, P. J.; Hartmann, O.; Wathen, P. T. J. Am.
Chem. Soc. 2008, 130, 14960–14961.
10.1021/ol901499b CCC: $40.75
Published on Web 07/16/2009
 2009 American Chemical Society

structure could conceivably be elaborated to any of the
natural products 1-7.
Ideally, a tropone system bearing a 2-amino-5-ester
substitution pattern, as in compound 12, would provide the
most straightforward synthetic approach. However, in order
to attain high levels of regioselectivity for the TMM
cycloaddition, the unusual isophthalimide group was re-
quired.4 Unfortunately, this unstable protecting group led to
numerous difficulties in carrying out further synthetic
transformations. As a result, our attention turned to the
potential of a late-stage installation of the bridgehead amine
using an intramolecular nitrenoid insertion into the C11-H
bond.10 This, in turn, enabled the use of a tropone lacking
the 2-amino group (11), known to be highly successful in
[6 + 3] cyclodadditions.4
Figure 1. Selected welwitindolinone B and C alkaloids.
Studies began with the construction of several 4-substituted
tropones beginning from cycloheptatriene 14 (Scheme 3),
C isothiocyanate (1), acts as a powerful antagonist for the
overexpression of P-glycoprotein, offering a potential thera-
peutic benefit against multiple drug-resistant tumors.6
Although a total synthesis of any member of this class of
compounds has yet to be accomplished,7 several approaches
to a core structure have been reported.8 The majority of these
syntheses rely on using an intact oxindole or indole moiety
as a starting point, followed by stepwise construction of the
bicyclo[4.3.1]decane core. In contrast, we envisioned a novel
approach that would rely on a series of sequential cycload-
ditions to rapidly build the common core structure 8 (Scheme
2). Central to this theme was an enantioselective [6 + 3]
Scheme 3. Preparation of the Tropone Intermediates
Scheme 2. Retrosynthetic Analysis
easily prepared by the cyclopropanation/ring expansion of
anisole.11 Barium hydroxide mediated hydrolysis delivered
acid 15, which could be readily functionalized as desired.12
Ideally, a tropone bearing the imidofuran ring (19) would
offer the most straightforward approach. However, oxidation
of the corresponding cycloheptatriene 16 to tropone 19
proved difficult. Use of a more electron-deficient amidofuran
possessing a methyl ester9b was then explored. Standard
(6) (a) Smith, C. D.; Zilfou, J. T.; Stratmann, K.; Patterson, G. M. L.;
Moore, R. E. Mol. Pharmacol. 1995, 47, 241–247. (b) Zhang, X.; Smith,
C. D. Mol. Pharmacol. 1996, 49, 288–294.
(7) Two total syntheses of the biosynthetically related welwitindolinone
A isonitrile have been reported: (a) Baran, P. S.; Richter, J. M. J. Am. Chem.
Soc. 2005, 127, 15394–15396. (b) Reisman, S. E.; Ready, J. M.; Hasuoka,
A.; Smith, C. J.; Wood, J. L. J. Am. Chem. Soc. 2006, 128, 1448–1449.
(8) Reviews: (a) Avendan˜o, C.; Mene´ndez, J. C. Curr. Org. Synth. 2004,
1, 65–82. (b) Brown, L. E.; Konopelski, J. P. Org. Prep. Proced. Int. 2008,
40, 411–445. Recent progress: (c) Boissel, V.; Simpkins, N. S.; Bhalay, G.
Tetrahedron Lett. 2009, 50, 3283–3286. (d) Tian, X.; Huters, A. D.; Douglas,
C. J.; Garg, N. K. Org. Lett. 2009, 11, 2349–2351.
cycloaddition that would rapidly construct the bicyclic
fragment 10 from a suitable tropone (11 or 12) and the cyano
TMM donor 13. Based on work by Padwa,9 an intramolecu-
lar [4 + 2] cycloaddition reaction between a pendent
amidofuran and the endocyclic olefin would then be used to
generate the oxindole core 8 in a single operation. This core
Org. Lett., Vol. 11, No. 16, 2009
3783

amide coupling conditions and N-methylation gave inter-
mediate 17, which was oxidized13 to the tropone 20 in 54%
overall yield. While the methyl ester would require eventual
removal to generate the natural product series, it was thought
that such an amidofuran would offer a method to access
synthetic analogues, as well as providing an additional handle
for the proposed nitrenoid insertion at C11. Nonetheless, to
expand our synthesis options to allow for a later stage
installation of the unsubstituted amidofuran, tropone 21
bearing the easily cleaved p-methoxybenzyl group (PMB)
was also prepared in good yield from cycloheptatriene 18.
Palladium-catalyzed [6 + 3] cycloadditions of both
tropones 20 and 21 were conducted using the (bis)biphenyl
pyrrolidine ligand L114 (see Scheme 1). Tropone 20
reacted to give the desired cycloadduct 22 as a single
regio- and diastereomer in 60% yield and high (94% ee)
enantioselectivity (Scheme 4). Concurrently, the 4-PMB
Scheme 5. Elaboration of Adduct 22
microwave conditions promoted the intramolecular [4 + 2]
cycloaddition to provide alcohol 25 as a single diastere-
omer,15 albeit in moderate yield. While it was hoped that
dehydration to the oxindole core would be spontaneous,
treatment of the unstable intermediate with the dehydrating
agent developed by Burgess16 proved necessary to give the
completed core structure 26.17
Scheme 4. Asymmetric [6 + 3] Cycloadditions
In considering the conversion of TMM adduct 23 to the
core structure, the next stage of the synthesis called for
installation of the amidofuran and a thermal [4 + 2]
cycloaddition to generate the oxindole. As before, isomer-
ization of the exocyclic olefin was readily accomplished with
catalytic DMAP to give the R,ꢀ-unsaturated nitrile 27 in
excellent yield (Scheme 6). Removal of the PMB group
ester tropone 21 delivered the cycloadduct 23 in better
yield (80%) and comparable enantioselectivity. Both
cycloadducts 22 and 23 were independently carried
forward to the natural product core to illustrate the
effectiveness of our synthetic approach.
Scheme 6. Elaboration of Adduct 23
Already possessing the amidofuran, cycloadduct 22 was
poised to undergo the anticipated [4 + 2] cycloaddition to
generate the oxindole core. However, as predicted, a facile
[3,3] sigmatropic rearrangement occurred upon heating.4 To
avoid this, chemoselective derivatizations of the exocyclic
olefin, such as oxidation, were attempted yet remain a
challenge for this synthetic route. Fortunately, isomerization
of the double bond to the endocyclic position using catalytic
DMAP proved facile, giving compound 24 in high yield
(Scheme 5). Gratifyingly, heating this intermediate under
(9) (a) Padwa, A.; Brodney, M. A.; Dimitroff, M. J. Org. Chem. 1998,
63, 5304–5305. (b) Padwa, A.; Dimitroff, M.; Waterson, A. G.; Wu, T. J.
Org. Chem. 1997, 62, 4088–4096. (c) Lynch, S. M.; Bur, S. K.; Padwa, A.
Org. Lett. 2002, 4, 4643–4645. (d) Padwa, A.; Wang, Q. J. Org. Chem.
2006, 71, 3210–3220.
followed by coupling with N-Boc-amidofuran 299c gave the
Diels-Alder precursor 30 in good yield. Heating of imid-
ofuran 30 in toluene at reflux temperature promoted the
intramolecular cycloaddition to give oxabicycle 31 as a single
diastereomer in almost quantitative yield. Not surprisingly,
(10) Espino, C. G.; Wehn, P. M.; Chow, J.; Du Bois, J. J. Am. Chem.
Soc. 2001, 123, 6935–6936.
(11) Anciaux, A. J.; Demonceau, A.; Noels, A. F.; Hubert, A. J.; Warin,
R.; Teyssie, P. J. Org. Chem. 1981, 46, 873–876.
(12) See the Supporting Information for details.
(13) Bartels-Keith, J. R.; Johson, A. W.; Langeman, A. J. Chem. Soc.
1952, 4461–4466.
3784
Org. Lett., Vol. 11, No. 16, 2009

this cycloaddition occurred at much lower temperature and
with greatly improved yield as compared to the more
electron-deficient amidofuran system discussed above. The
BCl3, bromocatechol borane, [Rh(COD)Cl]29d) were also
examined without much success. Ultimately, two useful
conditions were identified: Burgess reagent could be used
to dehydrate and leave the Boc group intact to generate
oxindole 34, and alternatively, use of catalytic Yb(OTf)3
could deliver the N-H oxindole core 35 as a single
component in moderate yield.
In summary, a particularly concise strategy for the
synthesis of the core of several welwitindolinone alkaloids
derives from the combination of the asymmetric [6 + 3] Pd-
TMM cycloaddition to form the bridged [4.3.1]bicycle with
the [4 + 2] cycloaddition-dehydration to form the oxindole
bicycle. The examples presented provided the complete
tetracyclic ring system in less than 10 steps beginning with
anisole. Efforts are underway to elaborate these intermediates
and complete the synthesis of several of the more bioactive
members in this group of natural products.
1
configuration was tentatively assigned as shown using H
NMR analysis. Somewhat surprisingly, however, this com-
pound remained as the oxabicycle 31 and did not undergo
dehydration to the oxindole even after prolonged reaction
times.
As previously demonstrated by Padwa,9d the electron-
withdrawing properties of the Boc group were likely
preventing the spontaneous opening and dehydration of
the oxabicycle. Thus, removal of the Boc group was
expected to lead directly to the formation of the desired
oxindole. Interestingly, while confirming the hypothesis,
the common removal technique employing TFA also led
to hydrolysis of the nitrile to provide primary amides 32
and 33 (Table 1). Several alternate reagents (BF3·OEt2,
Acknowledgment. We thank the NSF and NIH (Grant
GM 33049) for generous support of our programs. P.J.M.
thanks the American Cancer Society for a Postdoctoral
Fellowship.
Table 1. Completion of Oxindole Core
Supporting Information Available: Full characterization
and NMR spectra of all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL901499B
(14) A commercially available phosphoramidite (Aldrich Chemical Co.,
Inc., Catalog no. 665290) could also be used, although it gave low ee. See
the Supporting Information.
(15) Due to the unstable nature of intermediate 25, the configuration
was not rigourously established.
(16) Burgess, E. M.; Penton, H. R.; Taylor, E. A.; Williams, W. M.
Organic Syntheses; Wiley: New York, 1988; Collect. Vol. 6, p 788.
(17) A single-step conversion of intermediate 24 to oxidole 26 was also
possible using the Burgess reagent at high temperature; however, purification
of the product was difficult.
reagents
TFA
BF3·OEt3
Burgess reagent
Yb(Otf)3
compd
yield (%)
32 and 33
34 and 35
34
not determined
determined
48
50
35
Org. Lett., Vol. 11, No. 16, 2009
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