Thiourea-catalyzed enantioselective addition of indoles to pyrones: Alkaloid cores with quaternary carbons

Article abstract of DOI:10.1021/ja508523g

We report the development of a catalytic method for the enantioselective addition of indoles to pyrone-derived electrophiles. Arylpyrrolidino-derived thioureas catalyze the addition with high stereoselectivity in the presence of catalytic quantities of an achiral Bronsted acid. The indole-pyrone adducts feature a quaternary stereocenter and represent an unusual class of indolines bearing structural resemblance to the hybrid natural product pleiocarpamine.

Full text of DOI:10.1021/ja508523g

Communication
pubs.acs.org/JACS
Thiourea-Catalyzed Enantioselective Addition of Indoles to Pyrones:
Alkaloid Cores with Quaternary Carbons
Charles S. Yeung,†,§ Robert E. Ziegler,‡,§ John A. Porco, Jr.,*,‡ and Eric N. Jacobsen*,†
†Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, United
States
‡Department of Chemistry and Center for Chemical Methodology and Library Development (CMLD-BU), Boston University,
Boston, Massachusetts 02215, United States
S
* Supporting Information
Table 1. Catalyst Structure Optimization Studies
ABSTRACT: We report the development of a catalytic
method for the enantioselective addition of indoles to
pyrone-derived electrophiles. Arylpyrrolidino-derived thi-
oureas catalyze the addition with high stereoselectivity in
the presence of catalytic quantities of an achiral Brønsted
acid. The indole−pyrone adducts feature a quaternary
stereocenter and represent an unusual class of indolines
bearing structural resemblance to the hybrid natural
product pleiocarpamine.
omplex indole alkaloids are important compounds that
Cpossess a wide range of bioactivities. For instance,
pleiomaltinine is a hybrid natural product that features both
indoline and γ-pyrone functionalities and exhibits an impressive
ability to reverse multidrug resistance in vincristine-resistant
cells.1 Recently, we described a synthetic approach to
pleiomaltinine through a Brønsted acid-promoted indole−
pyrone annulation (Figure 1) involving a putative quinone
methide-like intermediate.2 Inspired by both the structural and
biological uniqueness of pleiomaltinine and the relative scarcity
of enantioselective catalytic transformations involving quinone
Conditions: [1] = 0.05 M, 3 days. All reactions were conducted on a
0.05 mmol scale. Isolated yields are reported. Enantioselectivities of
the O-mesylated derivative of 3a were determined by HPLC analysis
on commercial chiral columns. See the Supporting Information for
a
details. No BzOH was added.
methide intermediates,3 we sought to explore the development
of a general asymmetric annulation of indoles and pyrones. The
established ability of neutral hydrogen-bond donors to catalyze
enantioselective transformations of cationic intermediates
through anion-binding mechanisms4 led us to consider whether
the cooperative action of a chiral thiourea and an achiral
Brønsted acid5 could promote stereoselective additions of
nucleophilic indoles to cationic pyrone-derived quinone
methide-like intermediates. In such a transformation, the
formation of a chiral ion pair could render the formal
nucleophilic addition step enantioselective to afford a chiral
indoline bearing a quaternary carbon stereocenter at C3
Figure 1. An indole−pyrone annulation approach to pleiomaltinine
and a proposed enantioselective variant.
Received: August 19, 2014
Published: September 12, 2014
© 2014 American Chemical Society
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Table 2. Substrate Scope of Indole−Pyrone Additions
Figure 2. Variation of the Brønsted acid cocatalyst. Conditions: [1] =
a
0.05 M, 3 days. The reaction was conducted at 0 °C. Isolated yields
are reported. Enantioselectivities of the O-mesylated derivative of 3a
were determined by HPLC analysis on commercial chiral columns. See
the Supporting Information for details.
Figure 3. Variation of the pyrone precursor. Conditions: [1] = 0.05 M,
3 days. Isolated yields are reported. Enantioselectivities of the O-
mesylated derivative of 3a were determined by HPLC analysis on
commercial chiral columns. See the Supporting Information for details.
Conditions: [1] = 0.05 M, 3 days. Products were derivatized to the
corresponding O-mesylates (3 equiv of RSO2Cl, 5 equiv of NEt3,
CH2Cl2, overnight) for isolation and ee determination. Products 3b
and 3l were derivatized to O-tosylates. Isolated yields of the
corresponding sulfonates are reported. All reactions were conducted
on a 0.1 mmol scale. Enantioselectivities were determined by HPLC
analysis on commercial chiral columns. See the Supporting
a
Information for details. The reaction was conducted on a 0.05
mmol scale with 1.09 equiv of indole.
(Figure 1).6,7 We describe here the successful development of
this strategy.
Using the benzoic acid-catalyzed reaction of pyrone
precursor 1 and 1,2,3,4-tetrahydrocarbazole (2a) as a model,8
we evaluated several chiral urea and thiourea derivatives that
have been utilized previously with success in Brønsted acid-
cocatalyzed reactions.5 While promising levels of enantiose-
lectivity and reactivity were obtained with different classes of
neutral hydrogen-bond-donor catalysts (Table 1),9 particularly
high ee’s were observed with thiourea derivatives bearing a t-
leucine arylpyrrolidino amide component (7).10 Through a
systematic investigation of such substituted arylpyrrolidino
derivatives, we found that new catalysts bearing the m-terphenyl
motif11 promoted the indole−pyrone addition with >95% ee
Figure 4. Proposed catalytic cycle.
(7d and 7e). Thiourea 7e was ultimately selected for further
evaluation in the addition of various indole nucleophiles to γ-
pyrone precursor 1 (Table 2). Both electron-withdrawing (3b−
f) and electron-donating (3g−j) substituents on the indole ring
were well-tolerated, indicating that the nucleophilicity of the
reactive 3-position of the indole is not critical for high
enantioselectivity.12 Variation of both the 2- and 3-substituents
on the indole was also possible (3k−m), although substitution
at the 3-position was necessary to avoid rearomatization to an
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achiral product. The absolute configuration of (R)-3a was
established unambiguously by X-ray crystallography, and all of
the derivatized adducts were assigned by analogy.
ACKNOWLEDGMENTS
■
Financial support from the National Institutes of Health (GM-
099920 to J.A.P. and GM-43214 to E.N.J.), a postdoctoral
fellowship from NSERC (C.S.Y.), and a graduate fellowship
from Vertex Pharmaceuticals, Inc. (R.E.Z.) are gratefully
acknowledged. We thank Professor Scott Schaus and Neil
Lajkiewicz (Boston University) for helpful discussions, Won
Seok Ham and Dennis Dobrovolsky (Harvard University) for
experimental assistance, and Dr. Shao-Liang Zheng (Harvard
University) for crystal structure determination. Research at the
Center for Chemical Methodology and Library Development at
Boston University (CMLD-BU) was supported by NIH Grant
GM-067041.
Several experiments were carried out with the goal of
shedding light on the mechanism of catalysis and enantioin-
duction in this indole−pyrone addition reaction. Variation of
the identity or the amount of the Brønsted acid cocatalyst had
remarkably little effect on the reaction outcome (Figure 2),
suggesting that the acid does not participate directly in the
enantiodetermining step. In contrast, variation of the leaving
group on the pyrone precursor was found to impact the
enantioselectivity, as the chlorinated analogue 8 underwent the
reaction to afford adduct 3a with 84% ee using catalyst 7b while
the benzoyl derivative 9 proved unreactive (Figure 3). Finally,
the N-methylated analogue of 2a reacted with 1 in the presence
of chiral thiourea 7e to afford only racemic cycloaddition
product, revealing a crucial role of the indole N−H in the
catalytic mechanism. Taken together, these findings are most
consistent with an enantiodetermining step involving specific
interactions between the catalyst and both the pyrone leaving
group and the indole N−H moiety. We propose that 1
undergoes desilylation in the presence of the Brønsted acid. A
cationic quinone methide-like intermediate is then generated by
anion abstraction by the thiourea catalyst, with general base
activation of the indole in the stereodetermining addition step
(Figure 4).13 Additional attractive interactions (e.g., π−π or C−
H−π) between the cationic electrophile and the catalyst
pyrrolidine substituent are suggested by the dependence of the
reaction enantioselectivity on the nature of that aromatic
group.11 A mechanistic picture emerges that bears resemblance
to that invoked previously in the ring-opening reaction of
episulfonium ions with indole nucleophiles,5b thereby suggest-
ing a possible general principle for enantioselective additions of
indoles to cationic electrophiles.
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In summary, we have uncovered a highly enantioselective
method for the addition of 3-substituted indoles to γ-pyrone-
derived electrophiles, providing a route to simplified
pleiomaltinine analogues bearing a defined quaternary stereo-
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ASSOCIATED CONTENT
* Supporting Information
■
S
Complete experimental procedures, characterization data,
additional discussion of catalyst optimization and substrate
scope, and crystallographic information (CIF) for compound
(R)-3a. This material is available free of charge via the Internet
at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
porco@bu.edu
■
(6) We have found that indolenines bearing γ-pyrone functionalities
preferentially adopt the ring-closed form in settings where the indole
nitrogen is alkylated (cf. pleiomaltinine, ref 2) and the open form
when the indole lacks an N substitutent (cf. 3a). The position of this
equilibrium is expected to depend strongly on medium effects and
specific hydrogen-bonding interactions.
jacobsen@chemistry.harvard.edu
Author Contributions
§C.S.Y. and R.E.Z. contributed equally.
Notes
(7) For examples of indolines containing quaternary stereocenters,
The authors declare no competing financial interest.
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(9) Products were derivatized to the corresponding O-mesylates or
O-tosylates for isolation and ee determination. See the Supporting
Information for a detailed summary of catalyst screening and
optimization efforts.
(10) Catalysts with the general structure of 7 have proven effective in
a wide variety of enantioselective reactions. For examples, see refs 4e,
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mechanism, as proposed in Figure 4, to afford the observed open
product directly or via a concerted [4 + 2] cycloaddition pathway with
subsequent ring opening.
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