Synthetic autocatalysts show organocatalysis of other reactions

Article abstract of DOI:10.1039/b916836b

A molecule capable of both autocatalysis and organocatalysis was synthesized. The autocatalytic activity results from the self-complementary recognition sites provided by hydrogen bonding between heterocyclic subunits and the organocatalysis resides in an embedded thiourea function. The behavior of the molecule suggests both replication and metabolism can be engineered into synthetic compounds.

Full text of DOI:10.1039/b916836b

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Synthetic autocatalysts show organocatalysis of other reactionsw
Seiji Kamioka, Dariush Ajami and Julius Rebek Jr.*
Received (in Austin, TX, USA) 14th August 2009, Accepted 16th October 2009
First published as an Advance Article on the web 2nd November 2009
DOI: 10.1039/b916836b
A molecule capable of both autocatalysis and organocatalysis
was synthesized. The autocatalytic activity results from the self-
complementary recognition sites provided by hydrogen bonding
between heterocyclic subunits and the organocatalysis resides in
an embedded thiourea function. The behavior of the molecule
suggests both replication and metabolism can be engineered into
synthetic compounds.
locate the molecular recognition involved in the formation of
2. Specifically, a competition between thymine isothiocyanate
4a (an electrophile that has a recognition site) and N-methylated
thymine isothiocyanate 4b (an electrophile that lacks a recognition
site) was performed with a xanthene diaminopyridine unit 3a
(a nucleophile that has recognition site). The results showed
that the thiourea 2a was formed in greater amounts (thiourea
2a : N-methylated thiourea 2b = 68 : 32, a 4 2-fold preference).
When the product was present at the beginning of the
competition, the preference increased (Table 1) and in the case
where the isocyanates were added slowly at low temperatures
(conditions where associations leading to templation by 2a
are favored) the preference rose to 10 : 1. This indicated that
molecular recognition was involved in the reaction and the
product enhanced its own formation. Competition experiments
of 4a and 4b with the xanthene methyl ester unit 3b (which
lacks a recognition site) showed no preference for the two
isothiocyanates (see ESIw).
The organocatalytic activity of 2a was established by
Michael additions and transfer hydrogenation to a nitroolefin
(Fig. 3 and 4). The thiourea 2a catalyzed the Michael addition
of thiophenol to the nitroolefin in quantitative yield in a
matter of minutes (see ESIw). Thiourea 2a also catalyzed the
addition of 2,4-pentanedione to the nitroolefin in 90% yield in
the presence of 5 equivalents of triethylamine in 28 h. Using 2a
and the Hantzsch ester as the hydride source, the nitroolefin
was reduced in high yield (94%). The catalytic activity of 2a,
while modest, was comparable to that reported elsewhere.6
Additional experiments indicate that the organocatalytic
ability of 2a is decreased by dimerization under these conditions.
Experiments with the N-methyl compound 2b (which cannot
dimerize) show somewhat improved (roughly two-fold) activity
in the initial part of the reactions (Fig. 3 and 4). Control
experiments using either subunit (amine 3a or isothiocyanate 4a)
Molecules capable of self-replication accommodate a wide
range of structures, from nucleic acids1,2 and peptides3 to
any number of wholly synthetic compounds.4 All of these
show the characteristic of autocatalysis based on molecular
recognition. While ribozymes and proteins are well-studied
catalysts for reactions other than replication, the synthetic
structures—despite the surging current activity in organo-
catalysis—are not; only a single case has been presented.5 This
research was undertaken to find synthetic molecules capable of
both autocatalysis and organocatalysis. Here we report the
behavior of a system that incorporates a Jacobsen-type6
catalyst.
Earlier7 we introduced the self-replicating compound 1
(Fig. 1). The structure of 1 suggested that it could accommodate
a thiourea subunit, a much-admired and versatile function
in organocatalysis, without compromising the features that
contribute to its autocatalytic activity. This includes the self-
complementary recognition sites provided by the hydrogen
bonding arrays of the pyrimidine and diaminotriazene and
their presentation on a xanthene scaffold in a manner that
allows the molecule to act as a template for its own formation.
The thiourea inserted as in 2 offers two hydrogen bond
donors that have been used to catalyze8 Diels–Alder reactions,9
Michael additions,10 Friedel–Crafts alkylations,11 and transfer
hydrogenations12 but these donors do not appear likely to
interfere with the replication sites of the pyrimidine or triazene.
A tertiary amine near the thiourea is known to activate
nucleophiles in organocatalysis and is likewise compatible
with the intended autocatalysis. The key step in the synthesis
is shown in Fig. 2, where the thiourea function emerges during
the reaction of amine 3 with the isothiocyanate 4.
Establishing the autocatalytic activity was challenging, as
the coupling reaction of isothiocyanate 4 and amine 3 was too
fast to follow with conventional kinetic methods at NMR
concentrations. Instead, we used competition experiments to
The Skaggs Institute for Chemical Biology and Department of
Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Rd,
La Jolla, California, 92037, USA. E-mail: jrebek@scripps.edu;
Fax: +1-858-784-2876; Tel: +1-858-784-2250
w Electronic supplementary information (ESI) available: Synthesis of
2a, b, 5 and substrates and characterization by spectroscopic data. See
DOI: 10.1039/b916836b
Fig. 1 Line drawings of the previously reported self-replicator 1, and
proposed autocatalytic molecule with implanted organocatalysis site 2.
The self-complementary recognition sites are shown in the box, where
the pyrimidine and diaminotriazene form three hydrogen bonds.
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Fig. 3 Effects of catalysts on Michael additions using 2,5-pentane-
dione as a nucleophile. The concentration of the product (mM) is
plotted against time (hours).
Fig. 2 The synthesis of autocatalytic and organocatalytic molecules.
Both 2b and 5 lack recognition sites and were used as controls.
Table 1 Competition reactions between thymine isothiocyanate 4a
and N-methylated thymine isothiocyanate 4b with xanthene diamino-
pyridine unit 3a
Entry Catalyst 2a (%) Yield of 2a + 2b (%)a Ratio (2a : 2b)b
1
0
91
94
95
92
87
68 : 32
74 : 26
90 : 10
74 : 26
92 : 8
2
25
25
50
50
3c
4
5c
a
b
Isolation by column chromatography. Ratios were determined by
c
HPLC after column chromatography. These reactions were
performed using high dilution conditions of isothiocyanates 4. The
yields and ratios of products have been corrected for the addition of 2a
at the start of the experiments.
alone did not show catalysis of these reactions, but the
combination of 3a and 4a showed the same activity as 2a
itself. Accordingly, the organocatalytic activity requires the
thiourea function and the formation of 2a is much faster than
the Michael reactions. In these cases, the reaction conditions
for autocatalysis and organocatalysis are quite similar; to our
knowledge, a system in which the product of an autocatalytic
reaction is able to catalyze other unrelated reactions is
unprecedented.
Fig. 4 The organocatalyzed reduction of a nitroolefin. The concentration
of the resulting product (mM) is plotted against reaction progress (days).
should, be considered as starting points for the autocatalytic
reproduction of catalytic capabilities as proposed by
Eschenmoser.15 In the meantime a ‘‘top down’’ approach
involving potential precursors16 to the RNA world with
information sequences related to peptide nucleic acids also
shows promise.
In the RNA world, genetic information and chemical
catalysis were purportedly housed in a single type of molecule.
Less complex and more stable structures than RNA were
likely nearer life’s origins, but any candidates proposed are
expected to show functions related to both genetics and to
metabolism.13 We described here a small, synthetic structure
that exhibits both self-replication and activity as a catalyst for
organic transformations. This represents a ‘‘bottom up’’
approach from minimalist structures but opens an avenue to
reaction cycles that can generate molecular complexity.14 The
behavior of 2a suggests there may be a broad range of
structures—quite unrelated to nucleic acids—that can, and
We are grateful to the Skaggs Institute. S. K. is a Skaggs
Post-doctoral Fellow.
Notes and references
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8 For reviews on urea- or thiourea-based organocatalysts, see:
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7326 | Chem. Commun., 2009, 7324–7326