Total synthesis of (+)-suaveolindole: Establishment of its absolute configuration

Article abstract of DOI:10.1021/ja075100k

This communication describes two approaches toward the total synthesis of (+)-suaveolindole. The initial strategy uses a 6-exo-Heck cyclization to generate a transient sp³ carbopalladate. This intermediate was successfully coupled with an indole 3-stannane to assemble the majority of the carbon framework of the natural product. However, due to problems described herein, this interesting route was not viable. To reach our target, lessons learned from the first strategy directed us to develop a significant extension of the Ireland ester enolate rearrangement in which the tetra-substituted isopropylidene group and the α-disposed carboxymethyl function are introduced in a single event. This key reaction enables a remarkably concise inaugural synthesis of (+)-suaveolindole. Copyright

Full text of DOI:10.1021/ja075100k

Published on Web 08/14/2007
Total Synthesis of (+)-Suaveolindole: Establishment of Its Absolute
Configuration
Emile J. Velthuisen† and Samuel J. Danishefsky*,†,‡
Laboratory for Bioorganic Chemistry, Sloan-Kettering Institute for Cancer Research, 1275 York AVenue,
New York, New York 10021, and Department of Chemistry, Columbia UniVersity, HaVemeyer Hall, 3000 Broadway,
New York, New York 10027
Received July 10, 2007; E-mail: s-danishefsky@ski.mskcc.org
Scheme 1. Original Synthetic Strategy toward Suaveolindole
Historically, small molecule natural products (SMNPs) as well
as structures derived from or inspired by SMNPs have played a
large role in the discovery of novel antibiotics to improve human
health.1 One need go no further than â-lactams (cf. penicillin and
cephalosporin), aminoglycosides (the streptomycin family), mac-
rolides (cf. erythromycin and its congeners), anthracyclines (cf.
tetracyclines), and vancomycin to establish this point. With the
apparent curtailment of pharma’s commitment to SMNP discovery
platforms, there have come fewer new antibiotic leads for optimiza-
tion. It was in this setting that our group took an interest in the
indolic isoprenoid, suaveolindole (1). Isolated in microgram quanti-
ties from the fruit of the plant Greenwayodendron suaVeolens,
suaveolindole demonstrates activity against the gram-positive
bacteria Bacillus subtilis (MIC 4 µg/mL), Staphylococcus aureus
(MIC 8 µg/mL), and methicillin-resistant S. aureus (MIC 8 µg/
mL).2 While the antibiotic data reported for 1 are not yet
development worthy, its activity against gram-positive bacteria drew
our attention. Clearly, increasing concern as to the problem of
antibiotic resistance adds urgency to the need for evaluating new
candidate structure types for advancement.
Scheme 2. Unsuccessful Route toward Suaveolindolea
While our long-term motivation in identifying 1 as a total-
synthesis candidate was that of molecular editing1 directed to
enhancement of its gram-positive antibacterial activity, the novel
structure of the natural product encouraged us to explore some
unconventional approaches for its synthesis. We began with the
thought, first incubated in our lab in 1983, that a substrate
represented as 2, could undergo palladative insertion (see 3) en
route to cyclization (see 4).3 Continuing from this line of conjecture,
we wondered whether cross-coupling of the initial transient sp3
species, 4, with a suitably protected indole, primed at its â-position
with a tin- or boron-based moiety (see 5), would afford 6. From
there, we hoped to reach 1, possibly via substructure type 7.
Compound 8 was synthesized as described.4 Eventually, we
arrived at conditions under which it indeed underwent apparent
sequential 6-exo-Heck cyclization (cf. 4) followed by sp3 Stille
coupling with stannane 9 to afford a 4:1 mixture of indole 10 and
its C11 epimer (not shown here).5 Upon exposure to hydroboration/
oxidation conditions,6 a single stereoisomer was isolated. The
relative configuration was determined by NOESY experiments to
be that shown in 11.
a Key: (a) Pd2dba3 (2.5 mol %), Ph3As (5 mol %), Bu4NCl, DMF, 105
°C, (55%); (b) i) BH3‚THF, ii) NaBO3‚4H2O, (56%).
group. It was further hoped that the methyl group at C12 would
adopt a pre-equatorial disposition. Indeed, these expectations might
well have accounted for the actual preference observed in the
formation of 10. However, the selectivity of the process was not
high (∼4:1), presumably owing to relatively modest “A-value”
preferences for a pre-equatorially disposed C12 methyl group in this
context.
Hydroboration of 10 had led cleanly to 11 as shown (Scheme
2). The double-bond face anti to the indole function was more
accessible to attack by the hydroborating agent than was the syn
counterpart. Thus, the syn stereochemical relationship between C11
and C12 is that required to reach 1. However, the C16-C11
stereoconnectivity is inopportune. Moreover, serious difficulties
were encountered in preliminary experiments intended to introduce
the isopropylidene group at C15 from structures derived from 11.
Indeed, we took note of a general paucity of effective methods for
installation of tetra-substituted isopropylidene functions exocyclic
to a ring in multifunctional settings.8 In summary then, the key
mechanistically driven projections adumbrated in Scheme 1 had
been reduced to practice and are likely to be valuable in the future.
However, a viable route to suaveolindole itself had eluded us.
The preliminary efforts toward suaveolindole, summarized above,
were not without teaching value. They served to focus our thinking
around the C11-C15 sector and how to achieve the exocyclic
isopropylidene pattern while providing the required configurations
The basis for our initial expectations regarding the stereochem-
istry of the cyclization step (see 3f4) is implied in our rendering
of the relevant structures (see Scheme 1). Thus, it was anticipated
that the Heck cyclization course would be one in which suprafacial
insertion of the palladium carbon σ-bond into the methylene group
would have maximum eclipsing overlap.7 Moreover, the neopentyl
metal bond would adopt a “quasi-axial” bias (see 4), thereby
minimizing the allylic A(1,3) strain with respect to the CH2OR
† Sloan-Kettering Institute for Cancer Research.
‡ Columbia University.
9
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10.1021/ja075100k CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3. Synthesis of (+)-Suaveolindolea
protecting group provided synthetic (+)-suaveolindole (1), whose
spectroscopic properties (1H NMR, 13C NMR, optical rotation16)
are fully consistent with those found for the natural product. In
addition, the fully synthetic material exhibits the same type of
antibacterial activity as the naturally occurring suaveolindole.4 Since
the synthesis started from a known chiral intermediate (i.e., (R)-
12), we are able to thus assign the absolute configuration of the
natural product as shown.17
In summary, this communication describes the first total synthesis
of (+)-suaveolindole. The concise and efficient nature of the route
allows for the synthesis of enantiopure material in significant
quantities to support further biological assays and the generation
of analogues. Results of these efforts will be described in due course
as well as other applications of the logic of this synthesis.
a Key: (a) 4-bromo-1-butene, Mg, THF; (b) PCC, CH2Cl2, (47% from
12); (c) O3, MeOH, Me2S, (88%); (d) 2-iodoaniline, Pd(OAc)2 (5 mol %),
DABCO, DMF, (68%); (e) TsCl, TBAB, aq NaOH/benzene, (91%); (f) i)
CuI, MeLi; ii) PhNTf2, Et2O/THF; (g) CO, Pd(PPh3)4, i-Pr2EtN, MeOH/
DMF, (45% from 15); (h) MeLi, Et2O, (84%); (i) Ac2O, i-Pr2EtN, DMAP,
CH2Cl2, (83%); (j) LiHMDS, TMSCl, THF, -78 °C, (56%); (k) i) oxalyl
chloride, DMF (cat.), CH2Cl2; (ii) CH2N2, i-Pr2EtN, THF (62%); (l)
CF3CO2Ag, Et3N, THF/H2O, (74%); (m) naphthalene, Na, DME, (94%).
Acknowledgment. We dedicate this paper to the many contri-
butions of Robert Ireland in the field of organic synthesis. Support
for this research was provided by the National Institutes of Health
(CA103823). We thank Drs. Dave Maloney and Pavel Nagorny
for helpful discussions and Rebecca Lambert for editorial assistance.
We also thank Dr. George Sukenick, Hui Fang, Sylvi Rusli, (NMR
Core Facility, Sloan-Kettering Institute), and Dr. Cliff Soll (Hunter
College) for mass spectral analysis. Additionally, we thank Sequoia
Sciences for providing us with an authentic sample of suaveolindole
and performing biological assays upon synthetic (+)-suaveolindole.
at carbons 11, 12, and 16. Of course, for drug development
purposes, we also sought access to enantiopure material, hopefully
without recourse to resolution. The heart of our new plan, at the
level of relative stereochemistry, was the thought that perhaps the
issue of C11-C16 stereoconnectivity could be linked to that of
fashioning the exocyclic double bond. This line of inquiry led us
to project a fairly bold extension of the Ireland ester enolate
rearrangement.9 We asked whether the incipient nucleophilic carbon
of a silyl ketene acetal, derived from the acetate of a tertiary allylic
alcohol (e.g., 17), can deliver its two-carbon carboxymethyl
“payload” in acceptable yield to an unsaturated neopentylic carbon
(e.g., 18). By appropriate pattern recognition,10 we anticipated that
the usual γ,δ-olefinic acyl relationship associated with the family
of Claisen rearrangements could be converted to the required δ,ꢀ-
connectivity through a one-carbon homologation (see 18f1).
Realization of these notions in the context of a remarkably concise
inaugural total synthesis of suaveolindole is set forth in Scheme 3.
We began by modification of a known procedure to generate 13
(Scheme 3).11 Formation of indole was accomplished by ozonolysis
of the terminal olefin of 13 and subsequent annulation of aldehyde
14 with 2-iodoaniline.12 Following protection of the indole,
intermediate 15 was in hand. At this stage, the all-carbon quaternary
stereocenter was efficiently installed through conjugate addition of
LiMe2Cu to the enone 15.13 Subsequent trapping of the resulting
enolate as an enol triflate provided compound 16 in 9:1 dr.
We now turned to the preparation of the Claisen precursor, 17.
The carbon framework for the isopropylidene group was installed
in two steps through carbomethoxylation of enol triflate14 16 and
treatment with excess MeLi. The resulting tertiary allylic alcohol
was then acetylated in preparation for the key Ireland-Claisen
reaction. In the event, upon treatment of allylic acetate 17 with
LiHMDS/TMSCl at -78 °C, the desired rearrangement proceeded
smoothly, providing 18 as a single stereoisomer in 56% yield. The
stereoselectivity of the reaction likely originates from approach of
the intermediate silyl ketene acetal from the R-face of the molecule,
thereby minimizing abutments with the indole moiety. The relative
stereochemical assignment of 18 was made on the basis of NOESY
experiments on the methyl ester derivative.4 We note that this
unprecedented use of the Ireland-Claisen reaction allowed for
concurrent formation of the C16 stereocenter and the isopro-
pylidene moiety in a single step. Carboxylic acid 18 was then
homologated in a two-step Arndt-Eistert sequence, which pro-
ceeded in 46% overall yield.15 Finally, removal of the indole
Supporting Information Available: Experimental procedures and
compound characterization data. This material is available free of charge
via the Internet at http://pubs.acs.org.
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(16) Although not originally reported in the isolation paper, we obtained a
rotation of [R]22D ) +26° (c ) 1.0, CD3OD) for authentic suaveolindole
generously supplied by Sequoia Sciences. This compared to a rotation of
[R]22 ) +32° (c ) 1.0, CD3OD) for the synthetic material (+)-1.
D
(17) The absolute configuration of (+)-1 is (R,R,S) for C11, C12, and C16
respectively.
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