Angewandte
Chemie
DOI: 10.1002/anie.201310905
Asymmetric Catalysis
Chiral Anion Phase Transfer of Aryldiazonium Cations: An
Enantioselective Synthesis of C3-Diazenated Pyrroloindolines**
Hosea M. Nelson, Solomon H. Reisberg, Hunter P. Shunatona, Jigar S. Patel, and F. Dean Toste*
Abstract: Herein is reported the first asymmetric utilization of
aryldiazonium cations as a source of electrophilic nitrogen.
This is achieved through a chiral anion phase-transfer
pyrroloindolinization reaction that forms C3-diazenated pyr-
roloindolines from simple tryptamines and aryldiazonium
tetrafluoroborates. The title compounds are obtained in up to
99% yield and 96% ee. The air- and water-tolerant reaction
allows electronic and steric diversity of the aryldiazonium
electrophile and the tryptamine core.
a wide scope of valuable halogenated products in high
yields and excellent enantioselectivities.[1f–m] Inspired by the
substrate generality exhibited by CAPT halo-functionaliza-
tion and other oxidative reactions,[1n,o] it has been a long-
standing goal in our research group to identify additional
cationic electrophiles amenable to this strategy (Scheme 1b).
We were specifically interested in cations comprised of
À
electrophilic nitrogen atoms, as asymmetric electrophilic C N
bond formation remains a synthetic challenge.[2] Aryldiazo-
nium salts were recognized as candidates, as their N-electro-
philicity has been exploited to diazenate several classes of
carbon nucleophiles in a nonstereoselective fashion, including
aromatic compounds,[3] enolates,[4] and heteroaromatic com-
pounds.[5] Reports of Gomberg–Bachmann–Hey biaryl syn-
theses[3b] and azo-coupling reactions[3a,c] that utilize aryldi-
azoniums under phase-transfer conditions further encouraged
our efforts in this area. Furthermore, although azo com-
pounds have been utilized extensively in materials science,[6]
commodities,[7] and chemical biology[8] for their photochem-
ical properties, studies of enantioenriched diazenes within
these contexts are rare.
Chiral anion phase-transfer (CAPT) catalysis has recently
arisen as an effective strategy in enantioselective catalysis
(Scheme 1a).[1] In particular, electrophilic halo-functionaliza-
tion reactions of alkenes using Selectfluor (Scheme 1b) and
its derivatives have proven broadly effective, delivering
When considering transformations suitable for providing
proof-of-principle for CAPT of diazonium cations, we were
drawn to several enantioselective pyrroloindolinization reac-
tions[9,10] and recent total syntheses in which C3-diazenated
pyrroloindolines were key intermediates (prepared in a six-
step diastereoselective sequence).[11] Furthermore, Zhang and
Antilla have recently reported a highly efficient and enantio-
slective method for the preparation of C3-hydrazinated
pyrroloindolines[9] utilizing azodicarboxylate electrophiles;
however, no such transformation using diazonium cations to
directly provide C3-diazenated products in either a racemic or
an asymmetric fashion has been reported.
We envisioned that CAPT of an insoluble aryldiazonium
salt would provide a soluble chiral ion pair poised for attack at
the terminal diazonium nitrogen atom by tryptamine
1 (Scheme 1c). The resulting enantioenriched indolinium
intermediate (2) could then cyclize to yield the desired
pyrroloindoline structural motif 3. Herein we report the
successful execution of this synthetic hypothesis to enable the
preparation of highly enantioenriched pyrroloindolines from
simple tryptamine derivatives, thereby providing the first
Scheme 1. a) General chiral anion phase-transfer process, b) cationic
reagents employed, and c) application of chiral anion phase-transfer
catalysis to pyrroloindolinization.
[*] Dr. H. M. Nelson, S. H. Reisberg, H. P. Shunatona, J. S. Patel,
Prof. Dr. F. D. Toste
Department of Chemistry, University of California at Berkeley
Latimer Hall, Berkeley, CA (USA)
E-mail: fdtoste@berkeley.edu
À
example of catalytic, enantioselective C N bond formation
by utilizing aryldiazonium cations as an electrophilic source of
nitrogen.
[**] We gratefully acknowledge NIHGMS (R01 GM104534) for financial
support. H.M.N. would like to acknowledge the UNCF and Merck
for generous funding. S.H.R. would like to acknowledge the Amgen
Foundation for generous funding. We would like to thank Pascal
Tripet for useful discussions.
As a consequence of the demonstrated success of the
benzamide group in CAPT catalysis,[1h–k] our efforts began
with the readily prepared tryptamine derivative 4 (Table 1).
We were pleased to find that exposure of tryptamine 4 to
3 equivalents of Na3PO4, 1 equivalent of phenyldiazonium
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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