Identification of a novel Michael acceptor group for the reversible addition of oxygen- and sulfur-based nucleophiles. Synthesis and reactivity of the 3-alkylidene-3H-indole 1-oxide function of Avrainvillamide

Article abstract of DOI:10.1021/ja0372006

The 3-alkylidene-3H-indole 1-oxide functional group found in the naturally occurring alkaloid avrainvillamide has been synthesized by a cross coupling-reductive condensation sequence and found to undergo reversible addition of oxygen- and sulfur-based nucleophiles. Copyright

Full text of DOI:10.1021/ja0372006

Published on Web 09/12/2003
Identification of a Novel Michael Acceptor Group for the Reversible Addition
of Oxygen- and Sulfur-Based Nucleophiles. Synthesis and Reactivity of the
3-Alkylidene-3H-indole 1-Oxide Function of Avrainvillamide
Andrew G. Myers* and Seth B. Herzon
Department of Chemistry and Chemical Biology, HarVard UniVersity, Cambridge, Massachusetts 02138
Received July 10, 2003; E-mail: myers@chemistry.harvard.edu
Scheme 1a
Functional groups that bond covalently to active-site nucleophiles
frequently form the basis for the design of potent and selective
enzyme inhibitors, and those that form covalent bonds reversibly
(e.g., carbonyl groups, boronic esters) can be especially valuable
in pharmaceutical development.1 In studies directed toward the
synthesis of the alkaloids avrainvillamide (1) and stephacidin B
(2), we have identified the 3-alkylidene-3H-indole 1-oxide group
as a new function that is capable of reversible covalent bond
formation with heteroatom-based nucleophiles.
a Reaction conditions: (a) I2 (3 equiv), DMAP (0.2 equiv), CCl4-
pyridine, 49 °C, 96%. (b) Pd2(dba)3 (0.05 equiv), 2-nitrophenylboronic acid
(1 equiv), 2-(di-t-butylphosphino)biphenyl (0.20 equiv), Ba(OH)2‚8H2O (3.0
equiv), THF-H2O, 38 °C, 73%. (c) 2-iodonitrobenzene (2 equiv), Pd2(dba)3
(0.025 equiv), Cu (powder, 5 equiv), DMSO, 70 °C, 70%. (d) Zn (dust, 2.7
equiv), 1 M NH4Cl (2.2 equiv), EtOH, 48 °C, 64%.
Avrainvillamide and stephacidin B, formally a dimer of 1 (vide
infra), have been separately identified in culture media from various
strains of Aspergillus. Both compounds exhibit antiproliferative
activity, and 1 is reported to exhibit antimicrobial activity against
multidrug-resistant bacteria.2 Avrainvillamide is apparently the first
natural product with a 3-alkylidene-3H-indole 1-oxide function; our
synthetic efforts were therefore initially directed toward the
development of a viable strategy to introduce this group. A process
that forms the nitrogen heterocycle with C-C bond formation
between carbon 3 (R in structure 1) and the arene ring was
recognized to be especially convergent in the context of targets 1
and 2. A two-step organometallic coupling-reductive condensation
sequence was envisioned (Scheme 1).3
To implement the proposed two-step process, the model substrate
3 was prepared by iodination4 of 4,4,6,6-tetramethylcyclohex-2-
en-1-one5 (96%, Scheme 1). A Suzuki coupling of 3 with 2-nitro-
phenylboronic acid then afforded the R-arylated ketone 4 in 73%
yield (Scheme 1).6 Alternatively, 4 could be formed from 3 in 70%
yield by using 2-iodonitrobenzene as the coupling partner in the
presence of Pd2(dba)3 and copper powder.7 Reductive condensation
of 4 was accomplished in the presence of activated zinc powder,8
providing the 3-alkylidene-3H-indole 1-oxide 5 in 48% yield, as
well as the (separable) byproducts 6 (9%) and 7 (7%). Spectroscopic
data supported the assignment of the major product as 5; this
assignment was confirmed by single-crystal X-ray analysis
(Figure 1).
Figure 1. Capped-stick and space-filling models of 5 from X-ray data.
Control experiments demonstrated that the (unstable) byproduct 7
was formed slowly from 5 under the reaction conditions; however,
the yield was low (10%), and paths connecting 4 and 7 not involving
5 are readily envisioned. In practice, byproducts 6 and 7 were minor,
and 5 was easily purified chromatographically.
Solutions of 5 in benzene or chloroform were found to be quite
stable when protected from light (vide infra); however, in methanol
a surprisingly facile, reversible 1,5-addition of solvent to the R,â-
unsaturated nitrone group occurred (eq 1).9 At 23 °C in pure
methanol-d4, the half-life for the conversion of 5 to 8 (Nu ) OCD3)
was approximately 5 h. The equilibrium between 5 and 8 was
significantly temperature dependent. At equilibrium, the ratio of 8
(Nu ) OCD3) to 5 was 2:1 at 23 °C and 10:1 at -20 °C (7 days
to achieve). Warming a cold (-20 °C) solution of 8 and 5 at
equilibrium quickly reestablished equilibrium at the higher tem-
perature (23 °C), now from the product side (8 f 5). Removal of
methanol in vacuo led to complete and clean reversal of adduct
formation (8 f 5). Addition of methanol to 5 was found to be
catalyzed by both base (NaOCH3, 10 mol %, equilibrium <10 min,
23 °C) and acid (CH3CCO2H, 10 mol %, t1/2 ≈ 1 h, 23 °C; Cl3-
CCO2H, 10 mol %, equilibrium < 10 min, 23 °C). As expected,
small amounts (e10 mol %) of catalyst did not perturb the
Deuterium-labeling experiments (see Supporting Information)
established that product 5 had been formed with the expected
connectivity, that is, with nitrogen bonding to the carbonyl carbon
(this was also shown for 4 f 7), but, interestingly, in the formation
of the N-hydroxy indole byproduct 6, nitrogen was shown to bond
to the â-carbon of enone 4 (potentially a 5-endo-trig closure).
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C O M M U N I C A T I O N S
equilibrium between 5 and 8; however, stoichiometric quantities
of sodium methoxide did (8:5 ) 100:1 at equilibrium, 10 equiv of
NaOCH3).
In an effort to explore the potentially greater generality of
nucleophilic additions to R,â-unsaturated nitrones, the nitrones
derived from the condensation of N-phenylhydroxylamine with (E)-
cinnamaldehyde13 and (E)-4,4-dimethyl-2-pentenal were prepared
and subjected to conditions leading to adduct formation with 5
described above. However, in neither case was nucleophilic addition
observed. By and large, the acyclic R,â-unsaturated nitrones were
found to be unreactive. These observations might point toward the
importance of the formation of the aromatic indole structure in
5 f 8, a driving force that would be lacking in acyclic R,â-
unsaturated nitrones. Thus far, our studies have identified the
3-alkylidene-3H-indole 1-oxide group as both necessary and
sufficient to function as a novel Michael acceptor group for oxygen-
and sulfur-based nucleophiles. There is as yet no evidence that this
reactivity plays any role in the biological activity of 1 (or 2),
although our findings are certainly intriguing in this regard.
Thiols were also found to add cleanly and reversibly to 5 in the
presence of a base, but not without. For example, addition of
4-methoxybenzenethiol (1.2 equiv) to 5 in the presence of triethy-
lamine-d15 (0.2 equiv) in CD2Cl2 at 23 °C afforded the 1,5-adduct
(8, Nu ) SC6H4OCH3) quickly (<15 min) and quantitatively (1H
NMR analysis). Under similar conditions, addition of thiophenol
(8, Nu ) SC6H5) proceeded to afford a 9:1 ratio of adduct to starting
material, whereas the ratio was >98:2 at -40 °C (1H NMR analysis,
k8f5 ) 0.25 ( 0.15 s-1 M-1 at -40 °C).10 Neither addition was
significantly affected by the presence (or absence) of oxygen. The
1,5-adducts were highly labile toward silica gel, to the extent that
they could not be purified chromatographically without inducing
complete reversal (8 f 5).
Other transformations of 5 of note include its reduction with
NaBH4 in methanol (8, Nu ) H, 89%) and its photochemical
rearrangement under ambient light or, more rapidly, upon direct
irradiation (200 W Hg lamp) to form the lactam 9 (eq 2, 67%).11
The latter transformation may involve an intermediate oxaziridine,
as is frequently proposed in the photochemistry of nitrones.12
Acknowledgment. We thank Dr. Shaw G. Huang and William
E. Collins for assistance with NMR analysis, and Andrew Haidle
for solving the crystal structure of 5. S.B.H. acknowledges the
National Science Foundation for a predoctoral fellowship. This work
was supported by a grant from the National Institutes of Health.
Supporting Information Available: Experimental procedures for
the preparation of all new compounds, tabulated spectral data, and X-ray
data of 5 (PDF and CIF). This material is available free of charge via
the Internet at http://pubs.acs.org.
References
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In contrast to the facile addition of oxygen- and sulfur-based
nucleophiles that was observed, all potential nitrogen-based nu-
cleophiles examined to date (e.g., n-propylamine, formamide,
2-pyrrolidinone, 2-hydroxypyridine, 2-trimethylsilyloxypyrroline)
have failed to produce detectable levels of adducts in reactions with
5. Given the steric hindrance about the â-position of 5 (see Figure
1), it is remarkable that any nucleophilic addition occurs at all.
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