A Bioinspired Synthesis of Polyfunctional Indoles

Article abstract of DOI:10.1002/anie.201806490

Polyfunctional indoles bearing substituents at C5 and C6 are prevalent in natural products, pharmaceuticals, agrochemicals, and materials. Owing to the remoteness of the C5 and C6 positions, indoles of this family can be difficult to prepare, and often require multistep syntheses. Herein, we describe a concise process that converts simple derivatives of tyrosine into 5,6-difunctionalized indoles by direct oxidation of C?H, N?H, and O?H bonds. Our work draws inspiration from the biosynthetic polymerization of tyrosine to make melanin pigments, but makes an important departure to provide well-defined indole heterocycles.

Full text of DOI:10.1002/anie.201806490

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Accepted Article
Title: A Bioinspired Synthesis of Polyfunctional Indoles
Authors: Jean-Philip George Lumb, Zheng Huang, Ohhyeon Kwon,
Haiyan Huang, Aziz Fadli, Xavier Marat, and Magali Moreau
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201806490
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A Bioinspired Synthesis of Polyfunctional Indoles
Zheng Huang[a], Ohhyeon Kwon[a], Haiyan Huang[a], Aziz Fadli[b], Xavier Marat[b], Magali Moreau[c],
Jean-Philip Lumb[a],*
Dedication In memory of Professor Allan Hay.
Abstract: Poly-functional indoles bearing substituents at C5 and C6
are prevalent in natural products, pharmaceuticals, agrochemicals
and materials. Due to the remote nature of the C5 and C6 positions,
indoles of this family can be difficult to prepare, and often require
multi-step syntheses. Herein, we describe a concise process that
converts phenethyl-amino-phenols into 5, 6-di-functionalized indoles
by direct oxidation of C-H, N-H and O-H bonds. Our work draws
inspiration from the biosynthetic polymerization of tyrosine to make
melanin pigments, but makes an important departure to provide well-
defined indole heterocycles.
The indole heterocycle is
a key functional element of
pharmaceuticals, fragrances, agrochemicals, pigments and
materials.1 Its importance has motivated over a century of
research leading to many indole syntheses and many strategies
to functionalize the indole core (Scheme 1A).2 While each
possess their own set of advantages and limitations, remotely
functionalized indoles, with differentiated handles at C5 and C6,
remain difficult to prepare.2e Whereas the C2 and C3 positions are
inherently nucleophilic, and the C4 and C7 positions accessible
by directing groups, the C5 and C6 positions are remote, and
difficult to differentiate.2e Indoles of this family are typically
prepared by ring forming reactions,2a-c but these can suffer from
poor regioselectivity, require multi-step syntheses and be difficult
to diversify. This challenge has motivated recent efforts to expand
the C-H functionalization toolbox, and strategies to functionalize
C5 and C6 of indole are now emerging.3 These impressive
advances notwithstanding, the expedient synthesis of poly-
functional indoles remains a goal of considerable interest.4
Scheme 1. A) Challenges of synthesizing polyfunctional indoles. B) First step
of the melanogenic pathway. C) This Work: Bio-inspired indole synthesis.
coupled to the reduction of 3/2 O2, and converts Tyr into 5, 6-
dihydroxy-indole-2-carboxylic acid (DHICA) or 5, 6-
dihydroxyindole (DHI). By forming the C-N bond by
dehydrogenative coupling, the pathway makes readily available
phenethyl-amino-phenols starting materials for the synthesis of
indoles. Related cyclization reactions are notoriously difficult,6
and reflect the relative strength of the C-H and N-H bonds of the
starting material.7 The melanogenic pathway overcomes these
challenges by disrupting aromaticity,8,9 and highlights the utility of
O2 as both an atom transfer agent and as an acceptor of hydrogen.
In considering this challenge, we were drawn to the biosynthesis
of indoles that occurs during melanogenesis (Scheme 1B and see
Scheme S1 for a detailed description of the pathway).5 Melanin is
a ubiquitous biopolymer that comes from oxidative polymerization
of L-Tyrosine (Tyr) catalyzed by the enzyme tyrosinase. While it
is a pathway more naturally aligned with the material sciences,1f
its initial stages consist of an indole synthesis that is exceptionally
efficient. The net transformation is a 6 e | 6 H+ oxidation that is
Despite its efficiency, melanogenesis is not an attractive pathway
to indoles. The catechols DHI and DHICA oxidize more easily
than Tyr, so under the oxidizing conditions of their synthesis, they
polymerize to poorly defined materials.1f Even in cases where the
use of stoichiometric oxidants can interrupt the process,10 the
underlying properties of catechols make DHI and DHICA
problematic candidates for an indole platform. Catechols are
acidic, sensitive towards oxidation, have a high affinity for metals
and are difficult to differentiate. A more attractive indole would
protect the C6 O-H group, leaving C5 O-H as a directing group to
functionalize C4 (Scheme 1C). In combination with the directing
effects of the N-H, a platform of this kind might allow selective
functionalization at any of the heterocycle’s remaining C-H bonds,
and create an attractive entry point for the synthesis of poly-
[a]
Z. Huang, O. Kwon, H. Huang, Prof. Dr. J.-P. Lumb
Department of Chemistry, McGill University
801 Sherbrooke Street West, Montreal, QC H3A 0B8, Canada
E-mail: jean-philip.lumb@mcgill.ca
A. Fadli, X. Marat
L’Oréal Research and Innovation
Aulnay-sous-Bois, France
M. Moreau
[b]
[c]
L’Oréal Research and Innovation
Clark NJ, USA
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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Scheme 2. Description of optimized process and scope. a) Unless otherwise noted, reactions were carried out using 1 mmol of starting material. b) Isolated
yields were calculated based on 0.5 mmol as the theoretical maximum of product. c) Reaction performed on 200 mmol of starting material. d) N-Boc tyrosine tert-
butyl ester was used as starting material. e) Reaction performed on 50 mmol of starting material. f) Starting material is a 3:1. mixture of diastereomers.
functional indoles.4 The successful development of this platform
forms the basis of our work, which interfaces the melanogenic
pathway with modern C-H functionalization logic.11
(indole numbering). This occurs with complementary
regioselectivity to our previous work, which selectively
functionalizes the less electron rich carbonyl at C5.13,15 By using
camphor sulfonic acid (CSA), it is possible to promote the
formation of Q2 while leaving the tert-butyl-carbonate (Boc)
protecting group intact. In the presence of sulfuric acid (H2SO4),
however, Boc deprotection liberates the ammonium salt Q3,
which undergoes cyclization when the pH is adjusted with sodium
phosphate (Na3PO4).16 A series of proton transfers restore
aromaticity and provide indole 1a in 66 % isolated yield.17 Overall,
the process functionalizes 4 C-H bonds, 1 N-H bond and the O-H
bond of methanol to convert an inexpensive building block into an
indole with a free phenol at C5, an aryl ether at C6 and a methyl
ester at C2. It can be operated on 200 mmol scale, so that > 13 g
of 1a are produced in a single pass. We have prepared more than
100 g of 1a, which is a benchtop stable solid, whose structure was
confirmed by X-ray analysis (See Section 8 in the Supporting
Information). The reaction does not require sophisticated
glassware, the catalyst components are commercially available
and inexpensive, and it is complete within hours at room
temperature. These are mild conditions for the oxidation of
aromatic C-H bonds, particularly when forming C-O or C-N
bonds.6
We have previously demonstrated that
a combination of
[Cu(CH3CN)4](PF6) (abbreviated CuPF6) and N, N′-di-tert-
butylethylenediamine (DBED) recreates many aspects of the
tyrosinase mechanism, but with one important exception
(Scheme 2A).12 In the absence of a protein matrix, oxygenation of
Boc-Tyr-OMe produces Cu(II)-semiquinone radical (SQ) as
opposed to a free ortho-quinone. SQ engages in a rate-limiting,
oxidative C-O coupling with the starting phenol to provide ortho-
quinone Q1 in yields that approach 95%. This is a net 6 e | 4 H+
oxidation that has an identical redox stoichiometry to the complete
oxidation of Tyr to DHI or DHICA (Scheme 1B). As a result, it
differs from the 4 e | 2 H+ oxidation catalyzed by tyrosinase. This
important difference allows us to compartmentalize the oxidase
and cyclase phases of our process, and avoid redox-exchange
between catechols and ortho-quinones.13 The sensitive 5, 6-di-
functionalzed heterocycle can thus be formed in a subsequent,
redox neutral cyclization, in the absence of the Cu-catalyst and
O2. ortho-quinone Q1 differentiates its two carbonyls as an , β-
unsaturated ketone and a vinylogous ester. Therefore, under
carefully optimized conditions (See Table S2-S5 in the Supporting
Information),14 the vinylogous ester undergoes substitution with
methanol to provide para-quinone Q3 with a methyl ether at C6
A variety of 1o and 2o alcohols can be used in place of methanol
to install C6 aryl ethers (Scheme 2B), including allyl and benzyl
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Scheme 3. Synthetic Applications. Conditions: a) [Ir(COD)(OMe)]2 (0.5 - 1.5 mol%), dtbpy (1 - 3 mol%), B2Pin2 (1.0 - 1.4 equiv), THF, 60 - 80 °C, 4 - 18 h. b)
DMAP (10 mol%), Boc2O (1.1 equiv), THF, rt, 2.5 h, 83%. c) NBS (1.0 equiv), THF, 0 oC - rt, 2 h. d) MOMCl (3.0 equiv), DIPEA (3.0 equiv), MeCN, rt, 4 h, 73%. e)
Pd(PPh3)4 (2 mol%), NaBH4 (2.0 equiv), THF, rt, 4 h, 70%. f) Tf2O (1.2 equiv), NEt3 (2 equiv), CH2Cl2, 0 oC - rt, 2 h. g) Pd(OAc)2 (3 mol%), XPhos (6 mol%), B2Pin2
(1.1 equiv), KOAc (3 equiv), dioxane, 80 oC, 12 h. h) Cu2O (10 mol%), NH4OH (28 wt% aq., 2.5 equiv), NaI (2 equiv), MeOH, O2 balloon, rt, 4 h, 83%. i) TBAF (1.2
equiv), HOAc (2.4 equiv), THF, 0 oC - rt, 2 h, 94%. j) DMAP (10 mol%), ClHSiiPr2 (1.1 equiv), NEt3 (1.5 equiv), CH2Cl2, rt, 4h, 77%, 96% brsm. k) TBSCl (1.1 equiv),
imidazole (1.5 equiv), CH2Cl2, rt, 2h; then neat 180 oC, 15 min, 89%. l) [Ir(COD)(OMe)]2 (1.5 mol%), dtbpy (3 mol%), B2Pin2 (1.4 equiv), dioxane, 80 °C, 18 h. See
SI for more experimental details.
ethers 1d and 1f, prepared on 9 and 11 g scale, respectively. We
do not observe transesterification when the methyl ester of Tyr is
replaced with an ethyl ester (1g), and cyclization of the
corresponding tert-butyl ester produces free carboxylic acid 1h by
in situ deprotection. We observe decreased stability of the
relatively electron rich N-H indole lacking the C2 carboxylate (1i),
which is challenging to purify and store. However, the
corresponding N-benzyl derivative 1j is easier to manipulate, and
it can be delivered in good yield by cyclization of the
corresponding Boc-, benzyl-derivative of the aminophenol.
Likewise, indoles with substituents at C2 and C3 are smoothly
prepared as their N-benzyl derivatives (1l-1o). Ongoing efforts
are directed towards tyrosine derivatives bearing substituents at
C2 or C3, which are currently incompatible with our optimized
conditions of ortho-oxygenation.
example, borylation can be directed to C2 or C3 by employing the
conditions of Hartwig and Smith to form 4 and 5 on free N-H indole
218 or Boc-protected derivative 3,19 respectively (Scheme 3a). To
borylate at C4, we take advantage of the C5-phenol to employ
Hartwig’s silyl-directed borylation,20 which provides 14 in 93%
yield in the presence of the free N-H indole (Scheme 3b).
Alternatively, N-H directed borylation at C7 under Smith’s
conditions21 occurs when the C5-OH is protected as the TBS
ether (Scheme 3a). Differentiation at C5 and C6 provides either
of the free phenols, and using the triflate at C5, we can prepare
boronate 17 using Miyaura and Buchwald’s conditions (Scheme
3c).22 The corresponding halides or pseudo halides can be
prepared with similar levels of control. Bromination is selective for
C4 when the C5-OH group is free and the nitrogen is protected
with a Boc-group (see 13, Scheme 3b)), but it is selective for C3
when the nitrogen is free and the C5-OH is protected as the silyl
ether (see 14, Scheme 3a). The C7-iodide (not shown) is readily
prepared by iodination of 8,23 and triflates 15 or 16 can be installed
selectively from the corresponding phenols (Scheme 3c). It is also
possible to use N-H/O-H direction sequentially and prepare bi-
The directing abilities of the N-H of the indole and the C5 O-H
allow selective C-H functionalization at each of the remaining
positions on the indole heterocycle to provide a streamlined
synthesis of poly-functional building blocks (Scheme 3). For
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functional building blocks 19-21 (Scheme 3d). This includes N-H
directed borylation at C7 following O-H directed C4 bromination,
or O-H directed C4 borylation following N-H directed C7
borylation/iodination. Alternatively, sequential N-H directed
bromination at C3 followed by N-H directed C7 borylation provides
the C3-C7 bidirectional building block 21. Most of these C-H
functionalization reactions have been conducted on gram scale,
and reliably provide useful quantities of the polyfunctional indoles
(see Scheme 3 and the Supporting Information for details).
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The substitution pattern of these indoles maps directly onto a
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molecules. This includes bis-benzyl ether 22, which is a known
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regioselective entry into C5/C6 (indole numbering) differentiated
indoloquinones, which attract interest due to the biological activity
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In summary, we have described an efficient synthesis of poly-
functional indoles that interfaces bio-inspiration with C-H
functionalization logic. We have addressed the challenge of
C5/C6 differentiation with a uniquely efficient and bio-inspired
cyclization of phenethyl-amino-phenols. The resulting indoles
allow us to direct C-H functionalization at each of the
heterocycle’s remaining positions with complete regiocontrol.
Given the power of modern cross-coupling technologies and the
prevalence of indoles, these building blocks should serve as
attractive starting materials for a range of applications.
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Acknowledgements
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Financial support was provided by the Natural Sciences and
Engineering Council of Canada (Discovery Grant for J.-P. L.) and
L’Oréal. We thank McGill University Faculty of Science (Milton
Leong Fellowship in Science to Z. H.) and the Heather Munroe-
Blum Fellowship in Green Chemistry (Fellowship to O. K.). We
thank Dr. Thierry Maris (University of Montreal) for help with X-ray
crystallography.
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Keywords: indole • C-H functionalization • melanogenesis •
copper catalysis • aerobic catalysis
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Entry for the Table of Contents
Layout 2:
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Z. Huang[a], O. Kwon[a], H. Huang[a], A.
Fadli[b], X. Marat[b], M. Moreau[c], J.-P.
Lumb[a],*
Page No. – Page No.
A Bioinspired Synthesis of
Polyfunctional Indoles
Poly-functional indoles bearing substituents at C5 and C6 are prevalent in natural
products, pharmaceuticals, agrochemicals and materials, but they remain difficult to
prepare. Herein, we describe a concise process that converts phenethyl-amino-
phenols into 5, 6-di-functionalized indoles by direct oxidation of C-H, N-H and O-H
bonds. Our work draws inspiration from the biosynthetic polymerization of tyrosine
to make melanin pigments, but makes an important departure to provide well-defined
indole heterocycles with high efficiency.
This article is protected by copyright. All rights reserved.