Straightforward access to N-trifluoromethyl amides, carbamates, thiocarbamates and ureas

Article abstract of DOI:10.1038/s41586-019-1518-3

Amides and related carbonyl derivatives are of central importance across the physical and life sciences^1,2. As a key biological building block, the stability and conformation of amides affect the structures of peptides and proteins as well as their biological function. In addition, amide-bond formation is one of the most frequently used chemical transformations^3,4. Given their ubiquity, a technology that is capable of modifying the fundamental properties of amides without compromising on stability may have considerable potential in pharmaceutical, agrochemical and materials science. In order to influence the physical properties of organic molecules—such as solubility, lipophilicity, conformation, pK_a and (metabolic) stability—fluorination approaches have been widely adopted^5–7. Similarly, site-specific modification with isosteres and peptidomimetics⁸, or in particular by N-methylation⁹, has been used to improve the stability, physical properties, bioactivities and cellular permeabilities of compounds. However, the N-trifluoromethyl carbonyl motif—which combines both N-methylation and fluorination approaches—has not yet been explored, owing to a lack of efficient methodology to synthesize it. Here we report a straightforward method to access N-trifluoromethyl analogues of amides and related carbonyl compounds. The strategy relies on the operationally simple preparation of bench-stable carbamoyl fluoride building blocks, which can be readily diversified to the corresponding N–CF₃ amides, carbamates, thiocarbamates and ureas. This method tolerates rich functionality and stereochemistry, and we present numerous examples of highly functionalized compounds—including analogues of widely used drugs, antibiotics, hormones and polymer units.

Full text of DOI:10.1038/s41586-019-1518-3

Letter
https://doi.org/10.1038/s41586-019-1518-3
Straightforward access to N-trifluoromethyl
amides, carbamates, thiocarbamates and ureas
thomas Scattolin1, Samir Bouayad-Gervais1 & Franziska Schoenebeck1*
Amides and related carbonyl derivatives are of central importance a lack of efficient methodology to synthesize it. Here we report a
across the physical and life sciences1,2. As a key biological building straightforward method to access N-trifluoromethyl analogues of
block, the stability and conformation of amides affect the structures amides and related carbonyl compounds. The strategy relies on
of peptides and proteins as well as their biological function. In the operationally simple preparation of bench-stable carbamoyl
addition, amide-bond formation is one of the most frequently used fluoride building blocks, which can be readily diversified to the
chemical transformations3,4. Given their ubiquity, a technology corresponding N–CF3 amides, carbamates, thiocarbamates and
that is capable of modifying the fundamental properties of ureas. This method tolerates rich functionality and stereochemistry,
amides without compromising on stability may have considerable and we present numerous examples of highly functionalized
potential in pharmaceutical, agrochemical and materials compounds—including analogues of widely used drugs, antibiotics,
science. In order to influence the physical properties of organic hormones and polymer units.
molecules—such as solubility, lipophilicity, conformation, pKa and
Amide units are present in many pharmaceutical compounds3, for
(metabolic) stability—fluorination approaches have been widely example atorvastatin (Lipitor) and ledipasvir (Harvoni), which are
adopted5–7. Similarly, site-specific modification with isosteres and among the best-selling drugs worldwide to date10 (Fig. 1). Compound
peptidomimetics8, or in particular by N-methylation9, has been used families that are closely related to amides—such as carbamates and
to improve the stability, physical properties, bioactivities and cellular ureas—are similarly influential, finding applications as insecticides,
permeabilities of compounds. However, the N-trifluoromethyl in polymers (foams, elastomers, polyurethanes), as preservatives, in
carbonyl motif—which combines both N-methylation and cosmetics and in pharmaceuticals (for example, as chemotherapeutic
fluorination approaches—has not yet been explored, owing to and anti-HIV agents)11–13
.
a
OH
OH
O
HO2C
O
O
N
N
Me
Me
N
H
OH
O2S
O
O
O
O
N
H
HO
HN
S
H
N
H
H
Ph
R
O
Atorvastatin (Lipitor)
cardiovascular disease
Darunavir
HIV treatment
Penicillin
antibiotic
F
H2N
b
N
HN
O
O
O
O
H
N
N
O
HN
O
N
H
N
O
N
OMe
3
5
H
H
n
n
O
Polyurethane
plastics
Nylon (6,6)
F
F
Ledipasvir
hepatitis C
c
O
O
O
S
N
N
O
CF3
CF3
NH
N
F
N
N
O
O
O
CF3
Bench-stable
N
N
H
N
CF3
CF3
HN
MeO
O
Fig. 1 | Selected examples of amides and related compounds, and this
work. a, Selected pharmaceutical compounds containing an amide or a
carbamate group. b, Representative materials containing an amide or a
carbamate group. c, Our approach to accessing N–CF3 carbonyl families
from a bench-stable building block.
1Institute of Organic Chemistry, RWTH Aachen University, Aachen, Germany. *e-mail: franziska.schoenebeck@rwth-aachen.de
1 0 2 N A t U r e V O L 5 7 3 S e P t e M B e r 2 0 1 9
|
|
| 5

Letter reSeArCH
O
nBu
O
O
COOBn
O
N
N
O
O
O
O
AgF
Me
Me
F
N
S
F
N
NCS
+
H
Cl3CO
OCCl3
RT, MeCN
F
N
CF3
CF3
CF3
32, 74%a
31, 71%
Penicillin core
O
Oxybuprocaine (anaesthetic)
Boc
N
Via:
AgF
O
Me
Me
Ag2S
O
O
F
N
F
N
F
F
F
F
Cl3CO
OCCl3
AgF
N–
F
CF3
N
CF3
Me
AgF
OMe
Boc
33, 77%
34, 98%
Melatonin precursor
Mexiletine (heart disease)
NC
O
MeO
O
Ph
Br
O
O
O
O
N
O
F
N
F
N
F
N
F
N
F
N
Me
F
N
CF3
CF3
CF3
CF3
CF3
3, 80%
CF3
1, 98%
2, 91%
4, 95%b
6, 96%
5, 86%
NO2
Cl
O
O
Ph
O
O
O
S
F
N
F
N
F
N
F
N
OBn
F
N
F
N
OTf
CF3
CF3
CF3
CF3
CF3
CF3
OMe
O
7, 96%
9, 92%
8, 99%
10, 93%
11, 95%
12, 97%
Cl
Br
CO2Me
O
CF3
O
O
O
O
O
O
N
F
F
N
F
N
F
N
Ph
F
N
N
I
F
N
F
3
CF3
O
CF3
CF3 OMe
CF3
CF3
CF3
14, 81%
17, 93%b
18, 90%
13, 92%
15, 93%
16, 97%
CF3
N
O
OAc
OMe
SO2Me
F
O
O
O
O
O
O
O
F
N
F
N
F
N
F
N
SMe
F
N
F
N
CF3
CF3
CF3
CF3
CF3
CF3
19, 99%
20, 94%
23, 93%
21, 91%
22, 96%
24, 80%
NO2
O
OtBu
O
O
O
O
O
N
OMe
OtBu
OMe
OtBu
O
N
F
N
F
N
F
N
F
N
F
N
F
N
CF3
CF3
O
CF3
O
CF3
O
CF3
O
CF3
29, 60%a,b
30, 87%b
25, 98%
26, 96%
27, 92%
28, 90%
Fig. 2 | Synthesis of N-trifluoromethyl carbamoyl building blocks.
Proposed mechanism using isothiocyanates (1.0 equiv.), BTC (0.4 equiv.)
and AgF (5.0 equiv.) in acetonitrile at room temperature (RT) to generate a
wide range of compounds. aQuantified by 1H NMR analysis. bReaction was
carried out at 50 °C. OTf, triflate.
Despite the well established enabling effects of both N-methylation key stereocentres2. The indirect synthesis of the N–CF3 carbonyl motif is
and fluorination, the N-trifluoromethylated amide motif has so far therefore likely to be a much more promising approach.
remained essentially unexplored. The most common strategy for the
Only a few low-functionality N–CF3 amides have been prepared
generation of amide bonds involves joining a primary or secondary previously; yields were moderate, and the reactions required toxic or
amine with a suitable carbonyl electrophile14. However, this approach highly electrophilic reagents, or involved intermediates that are difficult
is unlikely to provide general access to N–CF3 amides, not only because to make18,19. These methods are incompatible with additional reactive
secondary trifluoromethylated amines—that is, H–N(R)(CF3)—are functional groups or stereocentres, and also do not provide access to the
difficult to synthesize15, but also because non-aromatic examples are wider N–CF3 carbonyl families. We envisioned that a building-block
likely to have poor stability, resulting from the elimination of fluo- approach would probably be the most enabling. As such, we focused
ride (and overall HF) assisted by the nitrogen lone pair16. Our group our research on the development of a simple method to access a robust
recently developed an efficient method to convert secondary amines precursor, which could then potentially be modified to produce various
(R2N–H) to the corresponding tertiary trifluoromethyl amines N–CF3 carbonyl compounds.
(R2N–CF3)17. However, this methodology is applicable only for nucleop-
Our studies commenced with the finding that subjecting isothi-
hilic secondary amines, and leaves electron-deficient N–H sites in amides ocyanates to silver fluoride leads to their formal desulfurization;
untouched. Considering the stability of amides, any direct chemical see Supplementary Information for mechanistic investigations. We sug-
modification is likely to require relatively harsh reaction conditions and gest that a difluoromethyl imine20 is generated in the process (Fig. 2),
therefore would be of limited applicability. Indeed, the N-methylation of and that the use of additional silver fluoride might enable the genera-
amides already presents synthetic challenges, such as the racemization of tion of a nucleophilic derivative that could then potentially be trapped
5
S e P t e M B e r 2 0 1 9 | V O L 5 7 3 | N A t U r e | 1 0 3

reSeArCH Letter
Stability in NaOH (pH 14, RT, 6 h)
O
O
MgX
Ph
Ph
Ph
O
O
O
F
N
N
Toluene, RT,
10 min
≤
CF3
<
CF3
Et
N
H
Et
N
Et
N
CH3
CF3
35, 89%
O
OAc
Cl
Br
Boc
O
O
Me
O
N
O
N
O
OMe
CF3
S
Me
N
N
OBn
N
N
CF3
nBu
N
SMe
CF3
CF3
N
CF3
Boc
CF3
41, 74%
36, 41%
38, 86%
39, 75%
40, 93%
37, 30%
Melatonin derivative
Paracetamol derivative
O
CO2Me
Cl
SO2Me
Me
Br
OMe
nBu
O
CF3
N
O
O
O
O
nBu
Br
N
nBu
N
Me
N
N
N
OTf
N
5
CF3
CF3
O
S
CF3
CF3
CF3 Me
CF3
47, 82%
Nylon (6,6) derivative
Br
45, 71%
42, 74%
43, 97%
46, 68%
44, 83%
Br
Br
CF3
N
O
N
O
O
CF3
O
Br
Br
O
OtBu
OtBu
N
O
OtBu
Bu
N
O
R
N
N
CF3
48, 73%
Microporous organic polymer derivative
N
CF3
O
CF3
O
CF3
O
CF3
49, 97%
Kevlar derivative
53, 72%, >99% e.e.
51, 97%, >99% e.e. (R = Ph)
52, 79% (R = nBu)
50, 69%, 96% e.e.
O
O
O
O
O
OtBu
OtBu
OtBu
OtBu
OtBu
N
N
N
CF3
N
CF3
N
CF3
O
CF3
O
O
O
CF3
O
N
tBuO
57, 91%, 99% e.e.
58, 87%, 98% e.e.
56, 65%, >99% e.e.
54, 92%, >99% e.e.
55, 39%
O
Pd-catalysed late-stage amination
O
O
O
OtBu
OtBu
(i)
OtBu
(i)
N
N
N
tBuO
CF3
O
CF3
O
MeO
CF3
O
N
H
Br
N
H
O
O
59, 61%, >99% e.e.
60, 37%, 94:6 d.r.
61, 38%, 88:12 d.r.
Late-stage deprotection and peptide coupling
Ph
O
O
O
O
O
H
N
(ii)
H
N
(ii)
N
OEt
OtBu
N
OMe
N
CF3
CF3
O
CF3
O
O
NH
63, 57%, 98:2 d.r.
62, 91%, >99% e.e.
64, 93%, 92:8 d.r. (2 steps)
(2 steps)
Fig. 3 | Synthesis of N-trifluoromethylated amides from trifluoromethyl acid, dichloromethane, RT, 2 h; step 2: HBTU, DIPEA, amino acid, RT,
carbamic fluorides and derivatization. Amides are accessed by reaction
of R–N(CF3)COF (1.0 equiv.) with RMgX (1.2 equiv.) in toluene at room
temperature for 10 min. Reaction conditions: (i) Pd(OAc)2 (10 mol%)/
BINAP (15 mol%), Cs2CO3, toluene, 110 °C, 3 h; (ii) step 1: trifluoroacetic
16 h. BINAP, 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl; DIPEA,
diisopropylethylamine, HBTU, 3-[bis(dimethylamino)methyliumyl]-3H-
benzotriazol-1-oxide hexafluorophosphate; d.r., diastereomeric ratio; e.e.,
enantiomeric excess.
by a suitable carbonyl electrophile to yield an N-trifluoromethylated procedure—starting from readily accessible isothiocyanates (R–NCS)
carbonyl motif in a single step. In view of safety and practicability, we along with excess silver fluoride and the solid reagent BTC—might
used the solid reagent bis(trichloromethyl) carbonate (BTC) as the car- enable the direct synthesis of N-trifluoromethylcarbamoyl fluorides,
bonyl source, and found that we could readily convert it to the carbonyl which could then potentially serve as building blocks for further
difluoride with silver fluoride. As such, we were hopeful that a one-pot derivatization.
1 0 4
| N A t U r e | V O L 5 7 3 | 5 S e P t e M B e r 2 0 1 9

Letter reSeArCH
F
a
O
O
O
COOBn
Ph
OMe
Cl
Br
O
MeO
O
S
O
O
O
O
N
H
Me
N
OMe
N
N
N
N
H
N
N
H
N
MeO
N
H
N
N
N
S
H
CF3
CF3
CF3
CF3
CF3
O
O
65, 71%
67, 81%
Potential antibiotic (penicillin core)
66, 80%
68, 63% (2 steps)
69, 94%
Aspartame derivative
HO
O
nBu
O
Et
N
Ph
Fmoc
NH
O
O
O
O
O
Et
O
O
CF3
tBu
O
MeO
Me
HO
N
N
H
N
N
N
N
H
N
Ph
N
H
N
3
OMe
O
CF3
CF3
CF3
CF3
N
H
O
70, 61%a
72, 80%
73, 67% (2 steps)
74, 87%
71, 77%
HO
Oxybuprocaine derivative
CO2Me
OMe
O
O
O
O
OMe
N
N
N
N
N
N
N
H
N
N
CF3 OMe
Me
CF3
CF3
O
CF3
Me
75, 89%
77, 79%
78, 92%
76, 97%
O
b
S
CF3
O
N
O
O
O
CF3
OMe
Ph
O
O
NO2
O
H
O
O
O
N
79, 99%
Br
O
O
O
O
CF3
O
O
N
O
N
O
O
O
N
CF3
OMe
CF3
CF3 Cl
O
N
83, 98%
84, 74%b
81, 79%
82, 67%
CF3
Mexiletine derivative
(heart disease)
80, 79%b
H
O
OtBu
O
O
O
O
H
H
O
OMe
O
N
I
O
N
EtO
N
O
CF3
CF3
CF3 CN
O
N
85, 88%
88, 85%
86, 78%
CF3
87, 83%
Oestrone derivative
Cbz protection
Fmoc protection
NO2
Cl
N
O
N
O
NuH
Nu–
THF, RT, 1 h
Na+
N
O
89, 96%
N
F
N
CH2Cl2, DIEA
CF3
CF3
DMAP (cat),
RT, 15 h
Nonlinear optical material (dye) derivative
Me
Me
c
Cl
Br
Boc
O
O
O
N
SO2Me
O
O
N
O
MeO
S
N
S
N
O
S
N
S
N
Me
N
S
N
CF3
NHBoc
CF3
CF3
Br
CF3 OMe
O
CF3
91, 74%
92, 88%
93, 87%
90, 86%
94, 86%
Penicillin G
Ph
O
CO2H
O
N
O
N
S
H
Se
N
R
CF3
Overlay of minimum energy conformers of
95, 86%
N–Me vs N–CF3 penicillin G
Fig. 4 | Syntheses of additional N–CF3 derivatives. a, Ureas are prepared
from R–N(CF3)COF (1.0 equiv.), NuH with catalytic DMAP (0.1 equiv.)
in dichloromethane at RT. b, Carbamates are prepared in analogy to ureas.
NaNu (1.2 equiv.) in tetrahydrofuran (THF) at RT. aQuantified by 1H NMR
analysis. bReaction was carried out with tBuOK as base. Calculated log P
(where P is the partition coefficient) for penicillin G: 3.46 (N–CF3), 2.49
c, Thio- and selenocarbamates are prepared with R–N(CF3)COF (1.0 equiv.), (N–Me), 1.40 (N–H).
5
S e P t e M B e r 2 0 1 9 | V O L 5 7 3 | N A t U r e | 1 0 5

reSeArCH Letter
When we reacted biphenyl isothiocyanate with the solid reagent BTC methodology, although peptides consisting solely of N–CF3 analogues
and silver fluoride in acetonitrile for 16 h at room temperature, we of naturally occurring α-amino acids are not yet accessible.
obtained the corresponding N-trifluoromethylcarbamoyl fluoride 1
We examined the conformational properties of 35 relative to those
in 98% yield (Fig. 2). Notably, 1 proved to be stable to moisture and of the N–Me analogue by 1H nuclear magnetic resonance (NMR) spec-
oxygen and could be stored on the bench. Previous synthetic routes had troscopy. Although evidence of rotamers was visible in the spectrum
allowed the formation of only low-functionality analogues, in moder- of the N–Me derivative at ≤5°C, the spectrum of the corresponding
ate yields, and using toxic reagents such as mercury salts and fluoro- N–CF3 amide (35) showed the presence of rotamers at temperatures
phosgene gas21. Encouraged by the efficiency of the transformation, we lower than −45°C; this indicates that rotation is less restricted in the
tested whether N-trifluoromethylcarbamoyl fluorides of greater molec- N–CF3 amide series. These observations are consistent with the
ular complexity and functionality would also be accessible. The trans- observed infrared carbonyl stretching frequencies of these compounds
formation proved to be very general (Fig. 2) and numerous functional and with our calculations of bond lengths, which indicate that the C–N
groups were tolerated, such as tertiary amines (32), amides (31), nitriles bond is longest in the N–CF3 amide. Our computational study of the
(6), esters (15), sulfones (20), thioethers (19), halogens (2, 11, 13 N–CF3 analogue of the antibiotic penicillin G (Fig. 4) indicated that the
and 18), nitro (7) and diazo (25) groups. Free alcohols, acids or primary analogous conformation to that of the corresponding N–Me or N–H
amines required a protecting group. Optically pure protected amino motifs was favoured, and predicted higher partition coefficients and
acids could also be transformed with retention of stereochemistry pKa values for the N–CF3 analogue; see Supplementary Information.
(26–30). The substrates underwent efficient transformation at room
We next explored the feasibility of synthesizing N–CF3 carbonyl
temperature (or at slightly higher temperatures) and, after precipitation heteroatom motifs. The carbamoyl fluorides were not reactive towards
of the salt by-products with diethyl ether, the products were readily weaker nucleophiles unless a catalytic amount of 4-dimethylamino-
purified by filtration through Celite.
pyridine (DMAP)23 was added as well as base; this then enabled their
With these building blocks in hand, we next set out to develop meth- transformation to the corresponding carbamates or ureas (Fig. 4).
odology for their conversion to compounds from the broader carbonyl The use of stronger nucleophiles—such as alkoxides, thiolates or sele-
families. We could readily access N-trifluoromethyl amides from these nolates—resulted in efficient transformation at room temperature with-
carbamoyl fluoride precursors through the straightforward addition of out the need for additives. As such, a diverse library of more than thirty
a Grignard reagent at room temperature (Fig. 3). Of the solvents that examples of N-trifluoromethyl carbamates, -ureas, -thiocarbamates,
we tested in this context (dichloromethane, diethyl ether, toluene and and -selenocarbamates with rich functionality could be generated
tetrahydrofuran), toluene proved to be the most effective. Alkyl, aro- in a rapid and operationally simple manner (Fig. 4). Notable exam-
matic and heterocyclic substituents were efficiently introduced within ples are the N–CF3 analogues of oxybuprocaine 70 (an anaesthetic),
10 minutes, even in the presence of sterically demanding ortho-substit- aspartame (65) and the penicillin derivative 6724, as well as analogues
uents (for example, 45). The reactivity of the carbamoyl fluorides was of the widely used protecting groups tert-butyloxycarbonyl (Boc),
sufficiently high as to outcompete metal–halogen exchange, enabling benzyloxycarbonyl (Cbz) and fluorenylmethyloxycarbonyl (Fmoc)
the syntheses of halogenated amides 39, 43 and 45, which could serve (80, 84, 86 and 87), the pharmaceutical compound mexiletine 82 (used
as valuable platforms for further derivatization (see below). We also in the treatment of heart disease), the carbohydrate 81, an analogue of
synthesized the N-trifluoromethyl analogues of the hormone melatonin the hormone oestrone (85), and the diazo derivative 89, which is an
(37), the pain-relief drug paracetamol (36), and key structural units analogue of the nonlinear optical material Disperse Orange 3.
of macromolecules, including the bis(N-(trifluoromethyl)amides) 47
Consistent with our findings for N–CF3 amides, the reaction of
and 49—the building blocks of the N–CF3 analogues of nylon (6,6) and chiral carbamoyl fluorides proceeded with retention of stereochemis-
Kevlar, respectively—and 48, which is an analogue of a microporous try: the synthesis of carbamate 87 resulted in no detectable racemiza-
organic polymer precursor. Moreover, carbamoyl fluorides derived tion, despite the use of DMAP and a reaction time of 15 h. Similarly,
from amino acids could also be converted to the corresponding amides, the optically pure ureas 66 and 77 were synthesized with ≤5%
provided that they were protected with a tert-butyl ester group. Notably, racemization.
the stereochemistry was retained, resulting in amides 50–59 and 62 in
high yields and excellent enantioselectivities (96–99% enantiomeric general method to access the N-trifluoromethylcarbonyl family. The
excess). properties and stability of the N–CF3 carbonyl motif set the stage for
In summary, we describe an operationally simple, safe, robust and
The wider applications of these compounds will depend both on the its enabling effects to be harnessed across various disciplines, ranging
properties induced by the CF3 substituent and on the overall stability from fighting diseases (pharmaceuticals) and resistances (antibiotics,
of this class of compounds. Among the compounds we prepared, we herbicides) to creating novel materials (polymers, coatings) and manip-
observed no decomposition either of the carbamoyl fluorides or of the ulating biological processes.
final target compounds. To assess the stability of the N–CF3 amides,
we subjected amide 35 to a solution of HCl (pH 1) or a solution of
NaOH (pH 14) at room temperature for 6 h (in acetonitrile/water). We
observed essentially no decomposition in acid and only a small amount
of decomposition in base, whereas the corresponding N–Me amides
showed more decomposition in base and the N–H analogue showed
substantial decomposition in base (see Supplementary Figs. 1–11). The
analogous acid and base tests on 46 and the nylon derivative 47 showed
no decomposition. This suggests that the N-trifluoromethyl amides are
rather robust and that they appear to be more stable than their N–H
amide counterparts.
Data availability
The authors declare that the data supporting the findings of this study are available
within the paper and its supplementary information files.
Online content
Any methods, additional references, Nature Research reporting summaries, source
data, extended data, supplementary information, acknowledgements, peer review
information; details of author contributions and competing interests are available
at https://doi.org/10.1038/s41586-019-1518-3.
Received: 18 December 2018;Accepted: 9 July 2019;
Published online 4 September 2019.
Consistent with this observed stability, we found that various
follow-up synthetic transformations were also possible: the palladium-
catalysed amination22 of 59 with amino acids proceeded smoothly, and
tolerated prolonged heating at 110°C. Subjecting amide 62 to 20% tri-
fluoroacetic acid in dichloromethane (to achieve ester cleavage), fol-
lowed by peptide couplings under typical conditions, we obtained the
corresponding peptides 63 and 64 in excellent yields. As such, pep-
tides containing the N–CF3 moiety can be readily prepared with this
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Acknowledgements We acknowledge RWTH Aachen University for financial
support, and K. Deckers and T. Sperger for assistance and discussions.
Additional information
Supplementary information is available for this paper at https://doi.org/
10.1038/s41586-019-1518-3.
Author contributions T.S. and S.B.-G. performed the experiments. S.B.-G.
undertook the calculations. All authors analysed the data and contributed to the
preparation of the manuscript. F.S. wrote the manuscript.
Correspondence and requests for materials should be addressed to F.S.
Peer review information Nature thanks Scott Bagley, Jonathan Clayden and the
other, anonymous, reviewer(s) for their contribution to the peer review of this
work.
Competing interests A patent application has been submitted by RWTH
Aachen University for this methodology, with T.S. and F.S. as inventors
(2018112315090400DE).
Reprints and permissions information is available at http://www.nature.com/
reprints.