Angewandte
Communications
Chemie
How to cite: Angew. Chem. Int. Ed. 2021, 60, 11120–11126
International Edition:
German Edition:
Prebiotic Chemistry
Chiral Amplification of Phosphoramidates of Amines and Amino
Acids in Water
Abstract: The origin of biomolecular homochirality continues
to be one of the most fascinating aspects of prebiotic chemistry.
Various amplification strategies for chiral compounds to
enhance a small chiral preference have been reported, but
none of these involves phosphorylation, one of natureꢁs
essential chemical reactions. Here we present a simple and
robust concept of phosphorylation-based chiral amplification
of amines and amino acids in water. By exploiting the
difference in solubility of a racemic phosphoramidate and its
enantiopure form, we achieved enantioenrichment in solution.
Starting with near racemic, phenylethylamine-based phosphor-
amidates, eeꢁs of up to 95% are reached in a single amplifi-
cation step. Particularly noteworthy is the enantioenrichment
of phosphorylated amino acids and their derivatives, which
might point to a potential role of phosphorus en-route to
prebiotic homochirality.
length scales.[3] Focusing on chiral amplification, we now
discovered that phosphorylation of chiral amines to phos-
phoramidates results in an exceptional large difference in
solubility between enantiomers and racemates allowing read-
ily enhancement of enantiomeric excess (ee) up to 95% in
a single dissolution step in water.
It should be emphasized that in the past decades several
approaches to chiral amplification have been reported and
various distinct mechanism proposed in the context of
prebiotic chemistry[2,3] such as asymmetric autocatalysis,[4]
preferred crystallization[5–7] and amplification in supramolec-
ular systems.[8,9] As for any model system on the origin of the
building blocks of life,[10] as well as selection and amplification
mechanisms (including the chiral amplification presented
here), a note of caution is appropriate regarding the relevance
and nature of the molecules, transformations and conditions
as recently discussed by Kitadai and Maruyama[11] in view of
the inherent uncertainty associated with prebiotic chemistry.
Approaches to achieve amplification and enrichment of
homochirality, following the intriguing model proposed by
Frank[12a] nearly 70 years ago, and investigations into non-
linear effects by Kagan,[8d,f,12b] include asymmetric autocatal-
ysis pioneered by Soai,[4] and various physical models[13] based
on differences in solubility of enantiomers and racemic
compounds,[14a–e] crystallization[15] or sublimation[16] (i.e. con-
glomerates vs. racemates),[14f,g,17] aggregation behavior,[8]
amplification through supramolecular chirality[8] and supra-
molecular self-amplifying catalysis.[9] Especially the attrition-
enhanced deracemization involving conglomerates (through
Ostwald ripening),[5] following the fascinating initial results by
Viedma,[6] enabled various groups[7] to demonstrate how to
readily obtain solid phase homochirality.
H
omochirality, the single handedness of its essential build-
ing blocks such as amino acids, carbohydrates and DNA, is
a characteristic of biological systems and is known as “a
signature of life”.[1] The origin of homochirality ranks among
the most fundamental questions directly associated with
biogenesis and represents a key challenge in prebiotic
chemistry.[2] The presence of single enantiomers is considered
a prerequisite for chemical evolution and several theoretical
and experimental approaches towards the emergence of
biomolecular homochirality point to two fundamental
issues: i) the symmetry breaking event to yield an imbalance
of enantiomers,[3] and ii) the amplification mechanism(s) to
sustain and propagate a small chiral bias to provide a large set
of chiral building blocks and induce chirality at different
To arrive at enantiomer-enriched compounds in solution
advantage is taken of the eutectic model[14b,18] with selective
partitioning of enantiomers between liquid and solid phase
and preferred crystallization of racemic (heterochiral) mate-
rial. The models, mechanism and experimental demonstration
of solution phase amplification were explored by Morowitz,[19]
Breslow,[14a,d,e] Blackmond,[14b,18] Hayashi[14c] and others[20] for,
for example, amino acids and applied in chirality transfer in,
for instance, catalytic asymmetric aldol reactions.[14b] Taking
advantage of the sensitivity of molecular composition in a co-
crystallization process to achiral additives as shown by
Lahav,[21] Blackmond and co-workers developed elegant
methods to modify eutectic ee values resulting in enhanced
solution phase enantiomeric enrichments of several amino
acids.[14b,c]
ˇ
[*] V. Daskovꢀ, Dr. J. Buter, Dr. A. K. Schoonen, F. de Vries,
Prof. Dr. B. L. Feringa
Stratingh Institute for Chemistry, University of Groningen
Nijenborgh 4, 9747 AG Groningen (The Netherlands)
E-mail: b.l.feringa@rug.nl
Dr. M. Lutz
Crystal and Structural Chemistry, Bijvoet Centre for Biomolecular
Research, Utrecht University
Padualaan 8, 3584 CH Utrecht (The Netherlands)
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
ꢁ 2021 The Authors. Angewandte Chemie International Edition
published by Wiley-VCH GmbH. This is an open access article under
the terms of the Creative Commons Attribution Non-Commercial
NoDerivs License, which permits use and distribution in any
medium, provided the original work is properly cited, the use is non-
commercial and no modifications or adaptations are made.
As part of our ongoing program on chiral amplifica-
tion[8f,16a,22] and addressing the challenge to design potential
11120
ꢀ 2021 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH
Angew. Chem. Int. Ed. 2021, 60, 11120 –11126