Progress toward the total synthesis of N-methylwelwitindolinone B isothiocyanate

Article abstract of DOI:10.1021/ol5020043

Progress toward the welwitindolinone alkaloid N-methylwelwitindolinone B isothiocyanate is reported. A key reaction to synthesize the [4.3.1] bicycle embedded in the core of the molecule is a furan type 2 intramolecular Diels-Alder reaction with a tetrasubstituted dienophile, which sets the two vicinal quaternary centers present in the natural product. The sterically encumbered cycloaddition precursor was synthesized using a Horner-Wadsworth-Emmons reaction followed by a Suzuki cross-coupling reaction. Finally, introduction of the secondary alkyl chloride was achieved by a regio- and diastereoselective opening of a [2.2.1] oxobicycloheptane functionality.

Full text of DOI:10.1021/ol5020043

Letter
pubs.acs.org/OrgLett
Terms of Use
Progress toward the Total Synthesis of N‑Methylwelwitindolinone B
Isothiocyanate
Leah Cleary, Jennifer Pitzen, John A. Brailsford, and Kenneth J. Shea*
Department of Chemistry, University of California, Irvine, 1102 Natural Sciences 2, Irvine, California 92697-2025, United States
S
* Supporting Information
ABSTRACT: Progress toward the welwitindolinone alkaloid N-methylwelwitindolinone B isothiocyanate is reported. A key
reaction to synthesize the [4.3.1] bicycle embedded in the core of the molecule is a furan type 2 intramolecular Diels−Alder
reaction with a tetrasubstituted dienophile, which sets the two vicinal quaternary centers present in the natural product. The
sterically encumbered cycloaddition precursor was synthesized using a Horner−Wadsworth−Emmons reaction followed by a
Suzuki cross-coupling reaction. Finally, introduction of the secondary alkyl chloride was achieved by a regio- and
diastereoselective opening of a [2.2.1] oxobicycloheptane functionality.
he welwitindolinone alkaloids were isolated from the blue-
green algae (cyanobacteria) Hapalosiphon welwischii,
methylwelwitindolinone B isothiocyanate (2), welwitindolinone
B isothiocyanate (3), and 3-epi-welwitindolinone B isothiocya-
nate (4) were not surveyed for their bioactivities.
T
Westiella intricata, Fischerella muscicola, and Fischerella major
(Figure 1).1 These molecules have been of significant interest
Because of their intriguing structures and bioactivities, the
welwitindolinones have become popular synthetic targets.
Welwitindolinone A isonitrile (1) was the first of these
alkaloids to be synthesized, with the Baran and Wood groups
each publishing innovative approaches to accomplish its total
synthesis.3 Other efforts toward the welwitindolinones have
mainly focused on the synthesis of MDR inhibitor 7, with
numerous groups reporting approaches to the core of the
[4.3.1] bicyclic welwitindolinones.4 The Rawal group reported
the synthesis of 75 following their groundbreaking synthesis of
N-methylwelwitindolinone D isonitrile (not pictured).6 Fur-
thermore, they also employed their enolate arylation strategy in
the synthesis of 20,21-dihydro N-methylwelwitindolinone B
isothiocyanate.7 The Garg group has likewise synthesized
several members of the welwitindolinone alkaloids, while the
Martin group has completed a formal synthesis intercepting a
late-stage Rawal intermediate.8 There have been no reports of
the total synthesis of any of the welwitindolinones B.
Figure 1. Representative members of the welwitindolinone alkaloids.
to the synthetic chemistry community because of the challenges
associated with synthesizing the densely packed, highly
functionalized cyclohexane or cyclohexene core present in
these alkaloids as well as their interesting bioactivities.
Several of the welwitindolinones were found to possess
significant activity after isolation and screening of their
biological properties.2 The lipophilic extract of W. intricata
was found to be fungicidal, and upon purification, welwitindo-
linone A isonitrile (1) was identified as an antifungal agent.
More intriguing was the discovery that N-methylwelwitindoli-
none C isothiocyanate (7) reverses multiple drug resistance
(MDR) in vinblastine-resistant breast and ovarian cancer cells
by inhibiting P-glycoprotein. While welwitindolinone C
isothiocyanate (5) and N-methylwelwitindolinone C isonitrile
(6) were also found to possess MDR activities, N-
Our group has previously investigated a furan type 2
intramolecular Diels−Alder (T2IMDA) reaction approach
toward the synthesis of 7 (Scheme 1).9 Alkylation of oxindole
8 with alcohol 9 leads to the formation of cycloaddition
precursor 10 which then cyclizes to provide 11. The core of 7
was rapidly formed through this methodology as a single
diastereomer, with the C3 stereocenter setting the other four
Received: July 9, 2014
© XXXX American Chemical Society
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Scheme 1. Previous Work towards the Synthesis of N-
Methylwelwitindolinone C Isothiocyanate (7) Reported by
the Shea Lab
Scheme 3. Synthesis of the Core of Welwitindolinone B
stereocenters formed in the product. One drawback of this
cycloaddition is that it was not possible to use a more sterically
encumbered tetrasubstituted alkene, because furan alcohol 9 is
prone to decomposition in the presence of stronger Lewis acids
that were necessary to increase the reactivity with a more
sterically hindered alkene. We reasoned that it might be
beneficial to switch strategies and use a more robust furan diene
to target 2.
We proposed that we could improve our strategy and target
welwitindolinones B by incorporating the C12 quaternary
center through a similar furan T2IMDA with a tetrasubsituted
alkene and a furan diene without a silyl protected alcohol
(Scheme 2). Retrosynthetically, we envisioned that 2 could be
Scheme 2. Retrosynthetic Analysis of 2
ester 15 produced oxindole 20 in good overall yield. The
tetracyclic [4.3.1] core of the welwitindolinones was then
rapidly obtained via an alkylation−T2IMDA reaction cascade.
In one pot, oxindole 20 was converted to silyl ketene aminal 21
which was then treated with excess TBSOTf and furan alcohol
16 to furnish cycloadduct 22 as a single diastereomer with the
relative stereochemistry at the C3 position of the oxindole
epimeric to that of natural product 2.10 The bridgehead alkene
of cycloadduct 22 was reduced with complete diastereoselec-
tivity, and oxabicycloheptane 23 was then chlorinated stereo-
and regioselectively.11 To confirm the chloride stereochemistry,
alcohol 24 was lactonized (26) and the single crystal X-ray
structure proved that the chlorinated product was formed as the
desired α-epimer. Alcohol 24 could alternatively be oxidized to
form chloroketone 25. However, conditions for methylation to
install the final quaternary center proved elusive, favoring
byproducts of alkylation at C3 or elimination of the chloride.
The difficulties we encountered while attempting late-stage
installation of the quaternary center further highlighted the
need to extend the furan T2IMDA reaction methodology to
include tetrasubstituted alkenes.
synthesized through the functionalization of chlorohydrin 12.
The chlorohydrin would be advanced from cycloadduct 13
which would be formed after the T2IMDA reaction of
cycloaddition precursor 14. Alkylation of oxindole 15 with
furan alcohol 16 would provide cycloaddition precursor 14.
Preparation of the core of welwitindolinone B was
successfully accomplished through a T2IMDA reaction of a
model system, which provided a platform to test late-stage
chloride installation (Scheme 3). We chose alkene 19 because it
was easily accessible and would provide a substrate to test some
of the final functional group manipulations. The synthesis
commenced by converting N-methyl-4-bromooxindole (18) to
the silyl ketene aminal, followed by lithium halogen exchange
and transmetalation to provide pinacol borane 15. Suzuki cross-
coupling of bromomalonate-derived alkene 19 and boronic
After extensive trials and optimization, we found a Horner−
Wadsworth−Emmons/Suzuki cross-coupling strategy was
optimal to synthesize alkene 31 (Scheme 4). To this end,
aldehyde 2712 was treated with lithiated phosphonate 2813
B
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relative stereochemistry and in good overall yield. Moreover,
oxindole 31 is the most densely functionalized dienophile
reported for use in a T2IMDA reaction to date. Cycloadduct 32
was then diastereoselectively reduced with concomitant benzyl
group deprotection to afford alcohol 33. The X-ray crystal
structure of 33 confirmed the relative stereochemistry (Figure
2). Silyl protection of alcohol 33 was followed by a LiBH4
Scheme 4. Synthesis of Tetrasubsituted Alkene 30 through a
Horner−Wadsworth−Emmons/Suzuki Cross-Coupling
Strategy
Figure 2. Crystal structure of 33.
furnishing a separable mixture of trisubstituted alkene 29 in a
6:1 ratio favoring the desired Z isomer.14 Acrylate 29 was then
brominated through a two-step sequence to provide vinyl
bromide 30. Suzuki cross-coupling of the bromide and oxindole
15 furnished sterically encumbered dienophile 31 in excellent
yield.15 The sequence conveniently provides a large quantity of
the tetrasubstituted alkene for elaboration toward welwitindo-
linone B (2).
We then sought to employ our T2IMDA strategy to
diastereoselectively set the two vicinal quaternary centers of
31 (Scheme 5). Alkene 31 was alkylated with furan alcohol 16.
In this case the cycloaddition was found to be slow so the
reaction was quenched at −78 °C to avoid decomposition of
the intermediate triene. The triene was immediately subjected
to cycloaddition conditions, and we were pleased to find that
BF3·OEt2 catalyzed the formation of cycloadduct 32 as a single
isomer with the vicinal quaternary centers set with the correct
mediated reduction and DMP oxidation of ester 34 to aldehyde
36. Wittig olefination of aldehyde 36 cleanly provided alkene
37. At this stage we were disappointed to find that the
previously established chlorination conditions did not provide
any of the desired chlorohydrin 38. Likewise, subjecting
aldehyde 36 or alcohol 33 to the chlorination conditions did
not furnish any of the desired products. Alternatively, attempts
to chlorinate 34 were more fruitful if the reaction conditions
were modified to use dichloroethane and heated to 80 °C;
however, chlorination was accompanied by a Friedel−Crafts
acylation reaction to form cyclopentene 39 (Scheme 6).
Improved conditions for the chlorination are still under
investigation with alternate substrates.
Scheme 6. Chlorination of 34
Scheme 5. Furan Type 2 Intramolecular Diels−Alder
Reaction with Tetrasubsituted Alkene 30 and Elaboration
toward 2
Several other acids were also assayed to find alternate
conditions for the chlorination of ether 34, and we were excited
to find that AcCl in the presence of catalytic ZnCl2 provided a
modest yield of chlorinated product 40.16 Efforts to optimize
the reaction conditions were not fruitful; however, this
chlorination procedure offers an alternative strategy to
eventually complete the total synthesis.
The welwitindolinone alkaloids remain a source of vibrant,
new chemistry, and these molecules continue to be a challenge
to synthetic organic chemists. We have established conditions
to synthesize the carbon skeleton of welwitindolinone B and
were able to set three out of five stereocenters using a furan
T2IMDA reaction including the two vincinal quaternary
centers. The major challenge left to complete the welwitindo-
linones B is the development of a reaction sequence to
C
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an installation of the isothiocyanate. Our progress toward the
synthesis of N-methylwelwitindolinone B isothiocyanate (2)
represents a concise and novel entry into this family of
alkaloids.
ASSOCIATED CONTENT
* Supporting Information
■
(5) Allan, K. M.; Kobayashi, K.; Rawal, V. H. J. Am. Chem. Soc. 2012,
134, 1392−1395.
S
(6) Bhat, V.; Allan, K. M.; Rawal, V. H. J. Am. Chem. Soc. 2011, 133,
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Experimental details and procedures, compound character-
1
ization data, copies of H and 13C NMR spectra for new
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compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: kjshea@uci.edu.
Notes
The authors declare no competing financial interest.
(9) Brailsford, J. A.; Lauchli, R.; Shea, K. J. Org. Lett. 2009, 11, 5330−
5333.
ACKNOWLEDGMENTS
■
(10) Although the stereocenter at the C3 carbon is epimeric to the
natural product, this can be rectified through a late stage epimerization.
Evidence of epimerization of the C3 stereocenter can be found in ref 7.
(11) Borthwick, A. D.; Curry, D. J.; Poynton, A.; Whalley, W. B.;
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(12) Denmark, S. E.; Seierstad, M.; Herbert, B. J. Org. Chem. 1999,
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The authors would like to thank Dr. Joseph Ziller (UC Irvine)
for assistance obtaining X-ray crystal structures. We are also
grateful for funding from Allergan (Allergan Graduate Fellow-
ship, L.C.), UC Irvine (Dissertation Fellowship, L.C.), and
Vertex (Vertex Scholar Fellowship, J. P.).
(13) Nawrath, T.; Schulz, S.; Gerth, K.; Mueller, R. Chem. Biodiversity
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