Total synthesis of (±)-welwitindolinone A isonitrile

Article abstract of DOI:10.1021/ja057640s

A highly stereoselective total synthesis of the alkaloid natural product welwitindolinone A isonitrile has been completed. The synthesis utilizes a chloronium ion mediated semi-pinacol rearrangement to simultaneously install the C10 quaternary center and neopentyl chlorine and a novel anionic cyclization to construct the spiro-oxindole with complete stereocontrol. Copyright

Full text of DOI:10.1021/ja057640s

Published on Web 01/11/2006
Total Synthesis of (()-Welwitindolinone A Isonitrile
Sarah E. Reisman, Joseph M. Ready,‡ Atsushi Hasuoka, Catherine J. Smith, and John L. Wood*
Sterling Chemistry Laboratory, Department of Chemistry, Yale UniVersity, New HaVen, Connecticut 06520-8107
Received November 9, 2005; E-mail: john.wood@yale.edu
Scheme 1
Welwitindolinone A isonitrile (1) is one of several related
oxindole-containing alkaloids isolated from blue-green algae by
Moore and co-workers in 1994.1 Among the known welwitindoli-
nones, the only one comprised of a highly functionalized spiro-
cyclobutane oxindole carbon skeleton is 1, and consequently, it has
been postulated to serve as the biosynthetic precursor to the
remaining congeners (cf. welwitindolinones C and D in Scheme
1).1a Although isolation and structural characterization of the
welwitindolinones was driven by their biological activities (1 is an
antifungal agent), our interest in 1 was piqued by its densely packed
and diverse array of synthetically challenging functional groups.2
Herein we report an efficient total synthesis of (()-1 that exempli-
fies the strategic and methodological advances molecules of this
complexity inspire.
From a retrosynthetic perspective (Scheme 1), we initially
envisioned an approach wherein the vinyl isonitrile is derived from
a ketone (2).3 Although this disconnection reveals a number of
standard bond forming strategies, there appeared to be a paucity
of methods capable of efficiently delivering the requisite C3 and
C12 all-carbon quaternary centers. To address this deficiency, we
developed a mild SmI2-mediated synthesis of spiro-oxindoles
(Scheme 1, boxed structures) that enables access to 2 from cyclic
urethane 4 via aryl isocyanate 3 (vide infra).4 In addition to
providing a new oxindole synthesis, these initial investigations
Scheme 2
demonstrated that known cyclohexadiene 6 could be readily
converted to hydroxy-enone 5 (six steps and 56% overall yield), a
compound we viewed as a potential precursor to 4.
Having outlined a general approach and developed a method for
assembling the oxindole,4 we began considering specific tactics for
the stereocontrolled introduction of both the C12 quaternary center
and the adjacent neopentyl chlorine found in key intermediate 4.
hydroxy-enone 5 using a sequence that begins with TIPS protection
followed by sequential treatment of the derived enone with LHMDS
(to transiently protect the cyclic urethane as the lithium amide),
L-selectride, and N-phenyltriflimide. The derived enol triflate (10)
was then subjected to Pd-catalyzed CO insertion in the presence
of methanol to provide enoate 11, which was treated with excess
methylmagnesium bromide/anhydrous cerium trichloride to deliver
12. After considerable experimentation with a variety of chlorine
sources, we were delighted to find that treatment of 12 with dilute
aqueous sodium hypochlorite and cerium trichloride heptahydrate6
induces rearrangement of 12 to a single chloro-ketone diastereomer
(13) in 78% isolated yield!
Having successfully implemented the semi-pinacol chemistry,
we next installed the C12 vinyl moiety and advanced to cyclization
precursor 4 by first desilylating 13 under mild conditions using
aqueous fluorosilicic acid7 in warm acetonitrile. The resulting
â-hydroxy ketone was reduced using tetramethylammonium triac-
etoxyborohydride8 to give a single diastereomer of diol 14, a
crystalline solid which proved suitable for single-crystal X-ray
diffraction, thus providing definitive proof that the semi-pinacol
rearrangement had furnished the desired relative stereochemistry.9
Rather than address these challenges separately, we devised an
approach wherein a chloronium ion induced semi-pinacol rear-
rangement delivers both simultaneously (see 7 f 8 f 9 in Scheme
2).5 In this event, the C12/C13 relative stereochemistry would be
dictated by mechanism (methyl migration anti to chloronium ion),
while the overall stereocontrol would derive from diastereoface
selective formation of the intermediate chloronium ion. Importantly,
since both potential migrating groups of tertiary alcohol 7 are
methyl, success would depend only upon chloronium ion facial
selectivity. Given the rigid, bicyclic nature of 7, diastereoface
selectivity was anticipated; however, of concern was the likelihood
that chlorination would occur from the least hindered convex face
and result in formation of the undesired stereoisomer (not shown).
Though somewhat speculative, we hoped to override this intrinsic
bias and promote formation of the illustrated chloronium ion (8,
Scheme 2) by installing a sufficiently large protecting group (R)
on the C11 secondary hydroxyl.
Implementing this approach required a tertiary allylic alcohol
substrate (12) which, as outlined in Scheme 3, was prepared from
‡ Current address: Department of Biochemistry, The University of Texas
Southwestern Medical Center at Dallas.
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10.1021/ja057640s CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3
Scheme 4
this synthesis inspired the development of new methods for the
construction of spiro-oxindoles and improved procedures for
chloronium ion induced semi-pinacol rearrangement. To our
knowledge, this represents the first example of a chloronium ion
induced semi-pinacol rearrangement in the context of a natural
product total synthesis and demonstrates the utility of this reaction
for the synthesis of R-chloro-quaternary centers, such as those found
in the welwitindolinones and related natural products.
Selective dehydration of the less-hindered C20 alcohol in 14
using Martin sulfurane10 was followed by oxidation of the remaining
alcohol using the Dess-Martin periodinane11 to give cyclization
precursor 4 in good yield. Treatment of ketone 4 with DBU induced
elimination of CO2 to furnish the aniline, which was converted in
situ (phosgene/Et3N) to the corresponding isocyanate (3, Scheme
1). In accord with our preliminary studies,4 exposure of the crude
isocyanate to a preformed mixture of SmI2 and LiCl in THF at
-78 °C delivered oxindole 2 in 75% yield with complete diaste-
reocontrol. The stereochemical assignment was confirmed by single-
crystal X-ray diffraction and is consistent with bond formation on
the less-hindered convex face of the bicyclo[4.2.0]octane skeleton.9
With oxindole 2 in hand, we initiated efforts to install the vinyl
isonitrile. Unfortunately, 2 proved to be a remarkably unreactive
intermediate, and all attempts to convert it to the natural product
failed.12 As a result, we refocused our efforts on an approach
wherein the C11 nitrogen would be introduced prior to oxindole
formation. To this end, urethane 4 was converted to oxime 15 via
a one-pot Boc-protection/CO2-elimination sequence that was fol-
lowed by treatment of the derived enone with methoxylamine
hydrochloride in pyridine at 65 °C. Unfortunately, R,â-unsaturated
oximes of this type proved unreactive toward the previously
described SmI2-mediated reductive cyclization, therefore neces-
sitating development of an alternative method for accessing the
oxindole. At this juncture, we recognized that a similar cyclization
could potentially be applied to isocyano-isocyanate 18 by taking
advantage of the known propensity of isonitriles to undergo
R-deprotonation when exposed to strong base (Scheme 4).13 Access
to the requisite cyclization substrate (18) was gained from 15 via
sodium cyanoborohydride reduction followed by formylation, SmI2-
mediated N-O bond cleavage, Boc-deprotection, and one-pot
dehydration/isocyanate generation (phosgene/Et3N).14,15 Importantly,
the reduction of 15 occurs exclusively from the convex face, thus
furnishing a pseudoaxial C11 proton that is poised for subsequent
deprotonation. With regard to the latter, we were pleased to find
that exposure of crude isocyano-isocyanate 18 to LHMDS at -78
°C provided 1 as a single diastereomer in moderate yield.
Acknowledgment. Financial support was provided by Bristol-
Myers Squibb, Yamanouchi, Merck, Amgen, Pfizer, and the NIH
(Grant No. 1 R01 CA/GM 93591-01A). S.E.R. thanks Bristol-Myers
Squibb for a graduate student fellowship. J.M.R. was the recipient
of a NIH postdoctoral fellowship. In addition, we acknowledge and
thank C.D. Incarvito for X-ray crystallographic analysis.
Supporting Information Available: Experimental and character-
ization details (PDF, CIF). This material is available free of charge
via the Internet at http://pubs.acs.org.
References
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(12) Screening included (but was not limited to) N-nucleophiles, such as
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(13) Hoppe, D. Angew. Chem., Int. Ed. Engl. 1974, 13, 789-804.
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In conclusion, we have developed an efficient synthesis of (()-1
(2.5% overall yield with an average yield of 81%). Importantly,
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