Total synthesis of (-)- N -methylwelwitindolinone C isothiocyanate

Article abstract of DOI:10.1021/ja206538k

We report the first total synthesis of (-)-N-methylwelwitindolinone C isothiocyanate. Our route features a number of key transformations, including an indolyne cyclization to assemble the [4.3.1]-bicyclic scaffold, as well as a late-stage intramolecular nitrene insertion to functionalize the C11 bridgehead carbon en route to the natural product.

Full text of DOI:10.1021/ja206538k

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Total Synthesis of (À)-N-Methylwelwitindolinone C Isothiocyanate
Alexander D. Huters, Kyle W. Quasdorf, Evan D. Styduhar, and Neil K. Garg*
Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095, United States
S Supporting Information
b
ABSTRACT: We report the first total synthesis of (À)-N-
methylwelwitindolinone C isothiocyanate. Our route fea-
tures a number of key transformations, including an indo-
lyne cyclization to assemble the [4.3.1]-bicyclic scaffold, as
well as a late-stage intramolecular nitrene insertion to
functionalize the C11 bridgehead carbon en route to the
natural product.
Figure 1. [4.3.1]-Bicyclic welwitindolinones 1À3.
he welwitindolinones are a unique class of natural products
isolated from the blue-green algae Hapalosiphon welwitschii
Scheme 1
T
and Westiella intricata.1 Ten welwitindolinones have been identi-
fied to date, nine of which possess [4.3.1]-bicyclic cores (e.g., 1À3,
Figure 1).2 Although compact in size, each of these natural
products contains a dense array of functionality that has plagued
synthetic efforts for nearly two decades. To date, more than 10
laboratories have reported progress toward the bicyclic
welwitindolinones.3,4 Whereas these exhaustive efforts have re-
sulted in several elegant methods for bicycle generation, comple-
tion of these targets has remained a formidable challenge. In fact,
the only total synthesis of a [4.3.1]-bicyclic welwitindolinone was
recently achieved by Rawal and co-workers, with their break-
through synthesis of (()-3 in 2011.5
With the aim of synthesizing alkaloids 1À3 and other family
members, we selected 1 as our initial synthetic target. Of note,
welwitindolinone 1 was uniquely found to reverse P-glycoprotein-
mediated multiple drug resistance (MDR) to a variety of anti-
cancer drugs inhuman cancercell lines andisthereforea promising
lead for the treatment of drug-resistant tumors.6 The densely
functionalized bicyclic framework of 1 presents numerous syn-
thetic challenges, including a 3,4-disubstituted oxindole, a heavily
substituted cyclohexyl ring, and a bridgehead isothiocyanate sub-
stituent at C11. In this Communication, we report the first total
synthesis of (À)-N-methylwelwitindolinone C isothiocyanate (1).
Retrosynthetically, it was envisioned that 1 would be derived
from bicycle 4 through late-stage functionalization of the C11
bridgehead position (Scheme 1). In turn, intermediate 4 would
arise from indole precursor 5 by introduction of the vinyl chloride
and oxindole moieties. In the key complexity-generating step, the
[4.3.1]-bicycle would be fashioned through intramolecular addi-
tion of an enolate onto an in situ-generated “indolyne” species (see
transition structure 6).7 The use of an indolyne intermediate8,9 was
considered advantageous as the high reactivity of the aryne would
permit the assembly of the congested C4ÀC11 bond linkage,
where a tertiary center would be introduced adjacent to the C12
quaternary stereocenter. Of note, the indolynewould be inherently
electrophilic, representing an uncommon umpolung of the indole’s
typical reactivity. Bromoindole 7 was thought to be a suitable
precursor to the desired indolyne via the classic dehydrohalogena-
tion method for aryne generation. Finally, cyclohexyl derivative 8
and indole 9 were identified as suitable starting fragments.
Our synthesis commenced with the concise preparation of the
key [4.3.1]-bicycle (Scheme 2). (S)-Carvone (10) was elaborated
to enone 11 using the robust five-step procedure reported by
Natsume in the enantiomeric series.10 Subsequent pivalate cleavage,
followed by I2-promoted addition of bromoindole 9,11 furnished
adduct 12 in 54% yield over two steps.12 TBS protection of 12
provided silyl ether 13, which in turn was employed in the critical
indolyne cyclization. To our delight, treatment of 13 with NaNH2
and t-BuOH in THF at ambient temperatures3p,13 led to indolyne
adducts 14 and 15 in a combined 46% yield (2.5:1 ratio).14,15
Although O-arylated product 15 was observed,16 the major product
14 possesses the desired [4.3.1]-bicyclic framework of the natural
product and is available in gram quantities.17 Moreover, it was
believed that bicycle 14 was suitably functionalized to allow for the
ultimate completion of the natural product synthesis.
Received: July 14, 2011
Published: August 07, 2011
r
2011 American Chemical Society
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dx.doi.org/10.1021/ja206538k J. Am. Chem. Soc. 2011, 133, 15797–15799
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Scheme 2
Scheme 4
been used to construct five-membered oxazolidinones fused to
cyclohexyl rings.24 Although use of Rh catalysis furnished ketone 4
rather than the desired product 20,25 Ag catalysis24b,c was found to
be more effective. Upon treatment of 19 with AgOTf, bathophe-
nanthroline, and PhI(OAc)2 in CH3CN at elevated temperatures,
the desired nitrene insertion took place to deliver oxazolidinone 20
as the major product. Ketone 4 was also recovered and could be
recycled through our synthetic route. Nonetheless, hydrolysis of 20
followed by IBX oxidation generated the penultimate intermediate
21. With aminoketone 21 in hand, final introduction of the
isothiocyanate3m,26 furnished 1. Spectral data for synthetic 1 were
identical in all respects to those reported for the natural product.1a,27
In summary, we have achieved the first total synthesis of N-
methylwelwitindolinone C isothiocyanate (1). Our enantiospe-
cific route proceeds in 17 steps from known carvone derivative 11
and features a number of key transformations, including (a) an
indolyne cyclization to assemble the [4.3.1]-bicycle, (b) late-
stage introduction of the vinyl chloride and oxindole moieties,
and (c) a nitrene insertion reaction to functionalize the sterically
congested C11 bridgehead position. Our synthesis of (À)-(1)
validates the use of indolynes as intermediates in complex
molecule synthesis and provides a promising entryway to the
other [4.3.1]-bicyclic welwitindolinones.
Scheme 3
Having assembled the bicyclic framework of the natural product,
we focused efforts on introduction of the vinyl chloride and oxindole
moieties (Scheme 3). Desilylation of 14, followed by DessÀMartin
oxidation, smoothly furnished diketone 16. Subsequently, a se-
quence involving triflation and Pd-catalyzed stannylation provided
vinyl stannane 17.18 Exposure of 17 to CuCl2 in dioxane afforded
vinyl chloride 18.19 To arrive at the necessary oxindole, a two-step
procedure involving sequential C2 bromination and hydrolysis was
employed to deliver late-stage intermediate 4.7
With intermediate 4 lacking only the isothiocyanate substituent,
we turned our attention to functionalization of the sterically con-
gested C11 bridgehead position.20 Unfortunately, attempts to sub-
stitute C11 through intermolecular processes were unsuccessful.21
As a workaround, we postulated that an intramolecular nitrene
CÀH insertion might be more fruitful.22,23 Ketone reduction of 4
proceeded efficiently using i-Bu2AlH to furnish a secondary alcohol
intermediate as a single diastereomer (Scheme 4). Subsequent
carbamoylation furnished 19,23 the key substrate for the critical
CÀH insertion reaction. The cyclization of carbamate 19 was
attempted using a variety of reaction conditions that had previously
’ ASSOCIATED CONTENT
S
Supporting Information. Detailed experimental proce-
b
dures and compound characterization data. This material is
available free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
neilgarg@chem.ucla.edu
’ ACKNOWLEDGMENT
The authorsare grateful to the NIH-NIGMS (R01 GM090007),
Boehringer Ingelheim, DuPont, Eli Lilly, Amgen, the University of
15798
dx.doi.org/10.1021/ja206538k |J. Am. Chem. Soc. 2011, 133, 15797–15799

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California, Los Angeles, the ACS Organic Division (fellowship to
K.W.Q.), Bristol-Myers Squibb (fellowship to K.W.Q.), and the
Foote Family (fellowships to A.D.H. and K.W.Q.) for financial
support. We thank the Garcia-Garibay laboratory (UCLA) for
access to instrumentation, Prof. Justin Du Bois for helpful discus-
sions, Dr. John Greaves (UC Irvine) for mass spectra, and Xia Tian,
Haoxuan Wang, and Sonam Kumar for experimental assistance.
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