Unique Stereoselective Homolytic C?O Bond Activation in Diketopiperazine-Derived Alkoxyamines by Adjacent Amide Pyramidalization

Article abstract of DOI:10.1002/chem.201803284

Simple monocyclic diketopiperazine (DKP)-derived alkoxyamines exhibit unprecedented activation of a remote C?O bond for homolysis by amide distortion. The combination of strain-release-driven amide planarization and the persistent radical effect (PRE) enables a unique, irreversible, and quantitative trans→cis isomerization under much milder conditions than typically observed for such homolysis-limited reactions. This isomerization is shown to be general and independent of the steric and electronic nature of both the amino acid side chains and the substituents at the DKP nitrogen atoms. Homolysis rate constants are determined, and they significantly differ for both the labile trans diastereomers and the stable cis diastereomers. To reveal the factors influencing this unusual process, structural features of the kinetic trans diastereomers and thermodynamic cis diastereomers are investigated in the solid state and in solution. X-ray crystallographic analysis and computational studies indicate substantial distortion of the amide bond from planarity in the trans-alkoxyamines, and this is believed to be the cause for the facile and quantitative isomerization. Thus, these amino-acid-derived alkoxyamines are the first examples that exhibit a large thermodynamic preference for one diastereomer over the other upon thermal homolysis, and this allows controlled switching of configurations and configurational cycling.

Full text of DOI:10.1002/chem.201803284

A Journal of
Accepted Article
Title: Unique stereoselective homolytic C-O bond activation in
diketopiperazine-derived alkoxyamines via adjacent amide
pyramidalization
Authors: Tynchtyk Amatov, Harish Jangra, Radek Pohl, Ivana
Cisarova, Hendrik Zipse, and Ullrich Jahn
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To be cited as: Chem. Eur. J. 10.1002/chem.201803284
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10.1002/chem.201803284
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Unique stereoselective homolytic C-O bond activation in
diketopiperazine-derived alkoxyamines via adjacent amide
pyramidalization
Tynchtyk Amatov, [a, b] Harish Jangra,[b] Radek Pohl,[a] Ivana Cisařová,[c] Hendrik Zipse,*[b] Ullrich
Jahn*[a]
Abstract: Simple monocyclic diketopiperazine (DKP)-derived
alkoxyamines exhibit an unprecedented activation of a remote C-O
bond for homolysis by amide distortion. The combination of strain
release-driven amide planarization and the persistent radical effect
(PRE) enable a unique, irreversible and quantitative trans®cis
isomerization under much milder conditions than typically observed
for such homolysis-limited reactions. This isomerization is shown to
be general and independent of the steric and electronic nature of both
amino acid side chains and substituents at the DKP nitrogen atoms.
Homolysis rate constants have been determined and they significantly
differ for both, the labile trans-diastereomers and the stable cis-
diastereomers. To reveal the factors influencing this unusual process,
structural features of the kinetic trans- and thermodynamic cis-
diastereomers were investigated in the solid state and in solution. X-
ray crystallographic analysis and computational studies indicate a
substantial distortion of the amide bond from planarity in the trans-
alkoxyamines, which is the cause for the facile and quantitative
isomerization. Thus, these amino acid-derived alkoxyamines are the
first examples that exhibit a large thermodynamic preference for one
diastereomer over the other upon thermal homolysis, which allows
controlled switching of configurations and configurational cycling.
proposed the structure of bridgehead-nitrogen bearing lactams,
2-quinuclidone and its one-carbon shorter homologue,[6] as early
as 1938 and pointed out the disruption of the amide resonance in
such twisted amides for the first time because of violation of
Bredt’s rule.[7] Since then the chemistry of distorted amides,
mostly incorporated into medium-sized bridged lactam
architectures, has captured the imagination of chemists.[8] The
unambiguous synthesis of 2-quinuclidonium tetrafluoroborate by
Stoltz et al.[9,10] was a landmark achievement more than 68 years
after Lukeš’s publication.[11] Significant weakening of the N–C(O)
bond is the most important consequence of amide nitrogen
pyramidalization. The β-lactam antibiotic penicillin is a prime
example of a distorted amide, making it the warhead against
harmful bacteria, which saved countless human lives.[12] Very
recently, a considerable interest in applications of non-planar
amides I, which are not part of bridged lactam motives,[13] in
transition-metal catalyzed N–C(O) bond activation by oxidative
addition and coupling via acylmetal species II has emerged; its
facility is a result of ground-state destabilization of the distorted
amide bond (Figure 1).[14-16] This strategy can also be diverted to
decarbonylation of acylmetal species and subsequent cross-
coupling, thus formally activating the C–C(O) bond as a
consequence
of
N–C(O)
insertion.[17]
Amide
bond
pyramidalization may also affect the strength of adjacent bonds.
Scattered examples document C–N σ-bond cleavage reactions in
twisted amides of type V and VI under reductive, oxidative and
alkylative conditions as reported by the Aube[18,19] and
Szostak[20,21] groups. The pKA of the αC–H bond to the carbonyl
group is dramatically lowered, and as a result of amide nitrogen
pyramidalization in VII its use in aldol additions is enabled.[22,23]
Similar effects were observed by Lloyd-Jones and Booker-Milburn
in sterically hindered amides such as VIII,[24] which undergo rapid
proton switch via a twisted conformer because of their enhanced
αC–H acidity.
Introduction
The amide bond is one of the best-studied linkages because of its
profound implications on the structure and functions of
biomolecules as well as organo- and biocatalysts.[1] Strong
nN→π*C=O interaction, which is responsible for its planar nature,
and hydrogen bonding abilities are central to making the amide
unit a powerful conformation-controlling element.[2,3] Deviation
from the planar geometry greatly alters both the physical and
chemical properties of amide containing molecules.[4,5] Lukeš
The strain associated with disruption of amide bond geometry
should in principle also have significant implications for the C-Q
bond strengths other than C-H bonds in I and enable their
activation. This has been so far widely neglected; no studies exist.
However, this principle may lay out new avenues for the design of
catalytic and thermal reactions for selective functionalization of
amide containing natural products and feedstock materials. We
recently introduced alkoxyamines IX as DKP-radical surrogates
and applied them in the synthesis of diverse bridged DKP motives,
which are present in numerous biologically active alkaloids.[25-27]
This transformation is controlled by the persistent radical effect
(PRE),[28-31] a powerful principle that governs the selective radical
coupling between transient and persistent radical species X and
[a]
[b]
[c]
Dr. T. Amatov, Dr. R. Pohl, Dr. U. Jahn
Institute of Organic Chemistry and Biochemistry,
Academy of Sciences of the Czech Republic
Flemingovo náměstí 2, 16610 Prague (Czech Republic)
E-mail: ullrich.jahn@uochb.cas.cz
Dr. T. Amatov, H. Jangra, Prof. Dr. H. Zipse
Ludwig Maximilian University
Department of Chemistry
Butenandstrasse 5-13, 81377 München (Germany) E-mail:
zipse@cup.uni-muenchen.de
Dr. I. Cisařová
Department of Inorganic Chemistry, Faculty of Science,
Charles University in Prague
Hlavova 2030/8, 12843 Prague (Czech Republic)
XI. The homolysis of alkoxyamines is
phenomenon, which is applied in nitroxide-mediated
a well-appreciated
Supporting information for this article is given via a link at the end of
the document.
1
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10.1002/chem.201803284
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polymerization (NMP),[32-34] tin-free radical transformations[35] as
well as in materials research, which is a testament to the power
of PRE. However, the vast majority of these transformations
require temperatures beyond 100 °C to proceed, which prohibits
their application under milder conditions. Thus, an enormous
interest exists in designing more labile alkoxyamines,[36]
homolysis of which can be triggered by external stimuli under
controlled conditions.[37,38] Such labile alkoxyamines have been
suggested as novel theranostic agents, applying transient and
highly reactive alkyl radicals to irreversibly damaging unhealthy
cells and using the simultaneously formed persistent nitroxide
radicals as diagnostic tools.[39,40] For such biological applications,
the structure of alkoxyamines should play an important role;
ideally it should be biocompatible and assist binding to desired
biological targets, a feature that is not given in current compounds
of this type. Given that DKPs constitute a large class of
biologically active medicinally privileged scaffolds,[41-43] we
hypothesized that a combination of amino acid-derived DKPs with
nitroxides may prove attractive for potential biomedical
applications as theranostic agents.
element for configurational switching to cis-IX by a radical
mechanism.
Results
®
Preparative trans cis isomerization reactions.
During a temperature screening to find optimum conditions for
PRE-mediated cyclization reactions, a trans-cis isomerization of
DKP alkoxyamines was discovered. Heating a 5:1 trans/cis
mixture of 1[44] in tBuOH at 80 ºC for 2 h provided pure cis-1,
whose spectral data matched the minor component in the original
mixture (Figure 2A). Both isomers of 1 were individually
crystallized and their configurations were confirmed by X-ray
crystallography (Figure 3). Similarly, an inseparable 11:1 trans-
2/cis-2 mixture with a benzyl group, converged to pure cis-2.
Enantiomerically pure tryptophan-derived DKP trans-3, bearing
N-Me groups, also isomerized cleanly to the cis-isomer upon
heating without compromising the residing stereocenter. It is
noteworthy that the isomerization proceeded quantitatively
regardless of the steric features of the nitrogen substituents.
A) Previous two-electron (O)C–N and distal bond activation modes in twisted amides
O
O
R
N
Nu
n+2
[M]
Q
Q
(Ref. 14-16)
(Ref. 17)
Nu
R
III
II
[M]n
Oxidative addition
Nu
–CO
Q
Nu
IV
O
R
R
σC-N cleavage
H
O
Q
(Ref. 18-21)
N
H
N
I
N
O
Twisted/distorted
amides
V
VI
Facilitated deprotonation by
increased αC-H acidity
O
N
O
H
R
N
S
Me
H
(Ref. 22-24)
N
Ag
VII
H
Nu
VIII
B) This work: Distorted amides facilitate C–O homolysis and irreversible isomerization
stronger
C-O bond
weakened distorted
planar
amide
C-O bond
amide
O
O
O
O
R
R
R
R
N
O
O
R
N
N
N
N
N
70-90 °C
XI
N
N
N
R1
R1
R1
R
O
O
O
trans-IX
X
cis-IX
Figure 1. A) Known examples of amide twisting-mediated bond activation
modes. B) Proposed selective homolytic cleavage of an adjacent C–O bond
controlled by amide bond distortion.
Herein we report that trans-substituted diketopiperazine-derived
alkoxyamines trans-IX are indeed a step on the way to this goal,
since homolysis starts surprisingly at temperatures as low as
70 °C for tertiary alkoxyamines and even below room temperature
for quaternary alkoxyamines. Preparative, structural and
computational studies demonstrate that deviation of the amide
bonds from planarity is the cause for the significant weakening of
the adjacent C–O bond. This effect can be used as a steering
Figure 2. A) Thermal trans®cis isomerization of DKP-derived alkoxyamines. B)
Comparison of the 1H NMR spectra of a 1:1 trans/cis-4 mixture before heating
(blue) and after heating (maroon).
2
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Hybridization and steric bulk of the C-substituent also did not
influence the direction of the isomerization, since a 1:1 trans/cis
mixture of aliphatic L-leucine-derived alkoxyamine 4 cleanly and
quantitatively isomerized on heating at 90 °C as revealed by their
1H NMR spectra (Figure 2B). These results show that the radical
as the origin of unusually strong C–ON bonds in those cases,
which was also supported by computational studies, revealing the
importance of hyperconjugative interactions between the lone pair
of the oxygen atom of the alkoxyamine and the antibonding σ*-
orbital of the neighboring αC–heteroatom bond.[49]
coupling
during
isomerization
occurs
with
exclusive
Several features of the solid-state structures are noteworthy
(Table 1). The bond lengths of the C4–OTMP unit vary in a rather
small range of 0.01 Å (Atom numbering of X-ray structures in
Figure 3) and are somewhat shorter than in comparable simpler
cyclic a-carbonyl substituted alkoxyamines (cyclic ketones[50]
1.454 Å, esters[51] 1.435 Å), but longer than a-amino-substituted
alkoxyamines. Surprisingly, the C3-N2 distance varies and is,
except for trans-3, longer than in the corresponding cis-isomers,
whereas the C1–N1 bond lengths do not differ very much in both
isomers.
The C3,N2,C21,C2 dihedral angles of the trans-DKP units as
visualized in Figure 3 surprisingly show with 157-165°, a strong
deviation from planarity, whereas the same dihedral angle
amounts to 172-178° in the corresponding cis-isomers. At the
same time, the dihedral angles involving the nitrogen atom N1
also deviate, but not that strongly. Notable twisting of the N2–C(O)
amide bond with twist angles τ = 9.1o and 9.8o, respectively, is
also observed in trans-1 and trans-5. The twist angles go in
opposite directions for both nitrogen atoms in that they are larger
at N2 in the trans-isomers, but except for cis-3 larger at N1 in the
cis-isomers.
diastereoselectivity, thus the isomerization of diketopiperazine
alkoxyamines is unidirectional toward the cis-isomers regardless
of the steric and electronic features of nitrogen and carbon
substituents.
Solid state and solution structures of trans- and cis-DKP
alkoxyamines.
X-Ray crystallographic investigation of DKP alkoxyamines cis-1
and trans-1, cis-2, cis-3 and trans-3, cis-4 and trans-5
unambiguously confirmed the relative trans-configuration of the
alkyl and alkoxyamine substituents in the starting DKP
alkoxyamines and their cis-configuration in the products (Figure
3). None of the crystallographically determined structures reveals
significant steric interactions of the substituents. An immediately
recognizable feature in all molecular structures is that the
alkoxyamine unit always occupies a pseudoaxial position in both
trans- and cis-diastereomers. NOE experiments for cis-1 and
trans-1 as well as cis-2 and trans-2 pairs also support a strong
bias for axial orientation of the alkoxyamine unit in solution (See
the Supporting information (SI), Figure S1). The large difference
in thermodynamic stability and the dramatic difference in the C–
ON bond strengths of cis- and trans-diastereomers of
Pyramidalization of the N2 atom is significant as determined by
alkoxyamines 1-4 should have a significant stereoelectronic origin. calculation of the classical Winkler-Dunitz distortion parameter χN2
[52]
It has been noted in the literature that simple alkoxyamines having
a heteroatom in the α-position such as α-alkoxy, α-ethylaminyl
and α-phenylsulfanyl substituents have small homolysis rate
constants kd, and consequently high carbon-oxygen bond
dissociation energies BDE(C–ON), which however, poorly
correlate with the BDE(C–H) of the corresponding non-
and χN1
.
In all characterized trans-alkoxyamines, a significant
pyramidalization of N2 with χN2 = 14.6-22.1° was found and N1 is
also distorted, though with χN1 = 5.5-11.3° less strongly. In
contrast, deviation from planarity of both amide nitrogen atoms is
small in the cis-isomers, except for cis-2. These data collectively
demonstrate significant amide bond twisting and pyramidalization
in all trans-alkoxyamine diastereomers, whereas the distortion is
much less marked in all cis-isomers.
alkoxyamine-substituted
precursors.[45-48]
The
common
rationalization for these observations invoked the anomeric effect
Figure 3. X-ray structures of alkoxyamines cis/trans-1, cis-2, cis/trans-3, cis-4 and trans-5. The insets show the Newman projection of the DKP core along the N2–
C(O) and N1–C(O) bonds for trans-1, the common numbering scheme of the DKP skeleton and the definition of the important C3,N2,C21,C2 dihedral angle. For
trans-5, R1 = trans-CH=CHPh, R2 = Ph.
3
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Table 1. Important structural/distortion parameters of alkoxyamines 1-5 characterized by X-ray crystallography.
trans-1
1.436
1.355
1.351
157.9
169.0
cis-1
cis-2
trans-3
1.429
1.344
1.354
165.0
174.4
cis-3
cis-4
trans-5
Parameter
1.429
1.341
1.354
178.3
174.7
1.428
1.344
1.355
171.9
179.2
1.433
1.340
1.352
177.0
174.9
1.426
1.345
1.363
178.1
178.2
1.429
1.351
1.350
165.0
170.9
d(C4
d(C3
d(C1
–
–
–
OTMP) (Å)
N2) (Å)
N1) (Å)
Dihedral angle C3,N2,C21,C2 (°)
Dihedral angle C1,N1,C14,C4 (°)
Sum of angles at N2 (at N1) (°)
356
360
(360)
2.7
360
358
360
(360)
1.8
360
360
3.4
358
(359)
9.1
(360)
3.0
(360)
3.3
(359)
9.8
Twist angle (τ) at N2 (at N1) (°)
(0.5)
22.1
(8.2)
1.8
(10.1)
8.2
(7.4)
14.6
1.6
(8.6)
1.8
(5.1)
15.0
3.1
χN2 (°)
5.5
11.3
5.3
0.7
5.1
1.8
9.2
χN1 (°)
Computational study of the structural effects in
alkoxyamines 1.
The relative importance of anomeric effect and amide
pyramidalization for the observed reactivity for DKP-derived
alkoxyamines cis-1 and trans-1 was first evaluated by optimizing
their structures at the B3LYP/6-31G(d) level of theory and
comparing them with the X-ray crystallographic results, which are
in good agreement (see SI, Figures S7). Subsequently, the
magnitude of these interactions was quantified using the Natural
Bond Orbital (NBO) analysis at the B3LYP/6-31G(d) level of
theory (Figure 4 and SI, Figure S21 and Table S3). Indeed, the
alkoxyamine oxygen lone pair interacts favorably with the
neighboring C–N, C–C, and C–H bonds, speaking for an
anomeric effect.
However, the cumulative energies for these interactions as well
as their individual components are essentially identical for both
isomers (–75 kJ/mol for cis-1 vs. –74 kJ/mol for trans-1), which
implies that the stability difference of trans- vs. cis-diastereomers
must have other origins than the anomeric effect. The strongest
donor/acceptor interactions in these systems concern the C3/N2
amide resonance interaction, which amounts to 308 kJ/mol in cis-
1, but to only 284 kJ/mol in trans-1. This difference is
accompanied by larger differences in amide bond planarity in
these two stereoisomers, where the calculated (O)C3–N2–C21–
C2 dihedral angles amount to 166° in trans-1 and 175° in cis-1.
These values differ somewhat from the experimentally obtained
157.9° and 178.3° but show the trend very well.
Figure 4. Important hyperconjugation interactions (in kJ/mol, NBO) in cis-1 and
trans-1 calculated at the B3LYP/6-31G(d) level of theory.
The homolysis rate constants kd showed dramatic differences for
trans- and cis-diastereomers of alkoxyamines 1 and 2. The
isomerization of trans-1 was monitored by 1H NMR spectroscopy
at four different temperatures and the experimental data fit to first-
order kinetics (Figure 5A, 5B). Homolysis of trans-1 was
reasonably fast and is rate determining, since no observable
cyclization took place compared to formation of cis-1 when it was
heated in the 75-85 °C temperature range, which allowed
determination of its kinetics (Table 2, Figure 5, Figure S2). The
activation enthalpy was determined to be ΔH‡ = 128 kJ/mol and
the corresponding activation entropy to ΔS‡ = 54 J/(K´mol); the
activation energy amounts to Ea = 131 kJ/mol using the Arrhenius
equation.
Kinetics of isomerization, reductive radical quenching and
cyclization of alkoxyamines 1 and 2.
With solid structural information at hand, DKP alkoxyamines 1 and
2 were studied with respect to their potential for radical generation
under mild conditions by determination of their homolysis,
reduction and cyclization kinetics.
4
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homolysis for trans-1 is slightly higher than the +109 kJ/mol
calculated from the experimentally determined activation
parameters (Table 2).
Table 2. Kinetic data for the thermal isomerization of trans-1 and trans-2.
trans-1
∆G‡
kd´10–4
T
t1/2
(s–1
)
(kJ/mol)
(K)
(min)
343.15
348.15
353.15
358.15
1.6
3.3
6.1
11
72
35
19
11
109.3
109.0
108.8
108.5
∆H‡
∆S‡
A
Ea
(s–1
)
(kJ/mol)
131
(kJ/mol)
(J/(K´mol)
13.5´1015
128
54
trans-2
∆G‡
kd´10–4
T
t1/2
(s–1
)
(kJ/mol)
(K)
(min)
343.15
353.15
358.15
2.9
10
19
40
11
6
107.7
107.2
106.9
∆H‡
∆S‡
A
Ea
(s–1
)
(kJ/mol)
128
(kJ/mol)
(J/(K´mol)
9.83´1015
125
52
Quaternary DKP alkoxyamines remained so far elusive, any
attempt to isolate them failed so far. Their formation can be
inferred experimentally from successful cyclization reactions that
culminated in an approach to asperparaline C.[27] To define the
reasons for their instability and to draw conclusions that may lead
to the design of DKP alkoxyamines that only slowly homolyze at
physiological temperatures, quaternary DKP alkoxyamines trans-
q1 and cis-q1 with fully substituted carbon atoms were
computationally investigated (Figure 6B) and compared to the
isomers of 1 (Figure 6A). On one hand, both the stereoelectronic
and thermodynamic trends are conserved compared to 1.
Significant pyramidalization of the N2-atom in trans-q1 is
observed with a dihedral angle (O)C3–N2–C21–C2 amounting to
166° compared to 171° in cis-q1 (see SI, Figs. S22-S24, Tables
S4 and S6). On the other hand, coupling of the transient tertiary
DKP radical with persistent TEMPO becomes endergonic for
trans-q1 and at the same time the activation barrier for homolysis
is significantly reduced in both isomers, thus making DKP-derived
quaternary alkoxyamines q1 extremely labile (see SI, Figs. S25-
S27 and Table S9). These results, however, clearly point to
opportunities to design DKP alkoxyamines with a defined
homolysis range, if the homolysis rate constant of at least the cis-
isomer can be decreased by increasing the C-O bond strength
through optimizing the substitution pattern at C2.
Figure 5. A) A typical 1H NMR profile of the vinylic proton region at 80 °C. B)
Kinetic traces for the isomerization of trans-1 between 70 °C and 85 °C.
The isomerization of trans-2, bearing a benzyl side chain, to cis-2
was similarly studied and shown to proceed ca. 1.6 times faster
than isomerization of trans-1 (Table 2 and Figure S3). The
activation enthalpy of ΔH‡ = 125 kJ/mol and activation entropy of
ΔS‡ = 52 J/(K´mol) for the overall transformation translate into an
activation energy of Ea = 128 kJ/mol (Figure S4). In the 70-85 °C
temperature range the homolysis of the cis-diastereomers must
be at least 2-3 orders of magnitude slower or even negligible
compared to homolysis of the trans-diastereomer, i.e.
kd(trans)>>kd(cis) (vide infra). This allows approximation of the
observed rate constants for the isomerization process to the
homolysis rate constants of the trans-diastereomers, i.e.
kobs~kd(trans)
.
These results are fully supported by a computational investigation
performed at the (U)B2PLYP/G3MP2Large//(U)B3LYP/6-31G(d)
level in combination with the SMD continuum model for DMSO
solution (Figure 6A, and SI, Figures S11-S13 and Table S8): DKP
alkoxyamine cis-1 is in Gibbs free energy terms 12.1 kJ/mol more
stable than trans-1 at 298.15 K. The barrier for radical pair
formation amounts to +120.5 kJ/mol for trans-1, whereas that for
cis-1 is with +126.1 kJ/mol as expected higher. The barrier for
5
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Figure 6. Solvation-corrected Gibbs energy (ΔGsol-sp, kJ/mol) profile for A) trans®cis isomerization of DKP-alkoxyamine 1 and B) its hypothetical quaternary
analog q1, both calculated at the (U)B2PLYP/G3MP2Large//(U)B3LYP/6-31G(d) level of theory. Single point solvation energies were calculated for DMSO at the
SMD/(U)B3LYP/6-31G(d) level of theory.
The assumption that homolysis of the cis-diastereomers of 1 and
2 is negligible at lower temperatures is additionally supported by
a radical reduction experiment (Figure 7A). Heating the 11:1
trans/cis-2 mixture in the presence of excess thiophenol (13
the temperature range between 90 °C and 115 °C (Table 3, Figure
S5). It is noteworthy that under these conditions potential
cyclization reactions of both substrates were not observed,
showing that the rate of reduction is orders of magnitude faster.[54-
58] Comparison of these values with the homolysis rate constants
for trans-2 (cf. Table 2) shows that homolysis of cis-2 at 90 °C is
1.5 times slower than the homolysis of trans-2 at 70 °C, whereas
the homolysis of cis-1 at 90 °C is 1.8 times slower compared to
trans-1 at 70 °C. This confirms that the thermodynamic preference
for the cis-configuration is undoubtedly a consequence of a
significant difference in the bond dissociation energies (BDE) of
the C–O bond between the trans- and cis-isomers as was also
confirmed by the computational study.
1
equivalents) at 70 °C and monitoring by H NMR spectroscopy
showed that isomerization to cis-2 effectively competed with
radical reduction by thiophenol. Moreover, when trans-2 was fully
consumed, the ratio of cis-2 to reduced DKP red-2 was ca. 50:50,
and most importantly it remained essentially constant on further
heating for three hours. In contrast, heating cis-2 with thiophenol
under identical conditions, but at 110 °C leads to clean formation
of fully reduced DKP red-2 (Figure 7B). Taken together, these
experiments convincingly demonstrate that cis-2 does not
undergo homolysis of the C–O bond at 70 °C.
Knowing the homolysis rate constants kisom~kd(trans) for trans-
isomers 1 and 2 (cf. Table 2), and that isomerization is not
competing upon homolysis of cis-isomers because of clean
pseudo-first order reduction (Figure 7B), kd(cis) for cis-1 and cis-2
were obtained applying the method developed by Edeleva et
al.,[53] which is based on thermolysis of alkoxyamines in the
presence of excess PhSH. A clean first-order consumption of cis-
1 and cis-2 took place and rate constants kd(cis) were obtained in
To determine the relative facility of the isomerization reaction of
the isomers of 1 and potential subsequent C-C bond formation
reactions, the cyclization kinetics were determined by thermolysis
of pure cis-1 in the absence of PhSH at 100 °C, 110 °C and 115 °C
1
and monitoring the progress by H NMR spectroscopy (See the
SI, Figure S6).
A clean first-order decay of the signals
corresponding to cis-1 and the appearance of signals
corresponding to 6-exo-trig cyclization products syn/anti-6 and 7-
endo-trig cyclization product 7 was observed (Figure 8A). The
6
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cyclization was slow at 100 °C and required ca. three hours to
reach completion. However, the rate of cyclization increased
eightfold at 115 °C. The obtained rate constants for the first-order
decay of cis-1 were with 3.7´10–4 s–1, 1.6´10–3 s–1, and 2.8´10–3
s–1 at 100 °C, 110 °C and 115 °C, respectively, slightly smaller
than those determined for reduction in the presence of thiophenol
(cf. Table 3).
pair. The barrier for 7-endo cyclization is somewhat higher at
+82.8 kJ/mol, in full agreement with the formation of 6-exo
products syn/anti-6 as the major products under the experimental
conditions.[21]
Table 3. Kinetic data for the thermal homolysis of cis-1 and cis-2 in the
presence of excess PhSH.
cis-1
∆G‡
T
kd´10–4
t1/2
(s–1
2.8
9.7
47
)
(kJ/mol)
(K)
(min)
363.15
373.15
388.15
41.1
12.0
2.4
114.2
113.7
113.1
∆H‡
∆S‡
A
Ea
(s–1
)
(kJ/mol)
132
(kJ/mol)
(J/(K´mol)
2.92´1015
129
41
cis-2
∆G‡
kd´10–4
T
t1/2
(s–1
1.9
4.0
16
)
(kJ/mol)
(K)
(min)
363.15
373.15
383.15
388.15
62.1
28.6
7.3
115.9
115.5
115.2
115.0
30
3.9
∆H‡
∆S‡
A
Ea
(s–1
)
(kJ/mol)
132
(kJ/mol)
(J/(K´mol)
1.69´1015
129
36
Discussion
The 15-22° deviation of the amide nitrogen atom from planarity in
trans-DKP alkoxyamines 1-5, which are normal ring-sized
lactams, is a significant distortion for an amide bond.[59] Nitrogen
atom pyramidalization in DKPs was observed before, however
only in proline- or pipecolic acid-fused DKPs, where it is enforced
by the conformation of the pyrrolidine and piperidine rings.[60,61] In
the monocyclic DKP alkoxyamines reported here, amide
pyramidalization is the main contributor to the significantly more
facile homolysis of trans-diastereomers compared to their cis-
isomers. Strain release as a result of planarization of the distorted
amide bond and concomitant conjugation with the incipient radical
center leads to a significant lowering of the transition state energy
required for homolytic bond cleavage. It is significant that ground-
state destabilization of the amide bond in trans-alkoxyamines
leads to a decrease of the strength of a bond, which is two skeletal
bonds away. This C–O bond weakening is conceptually different
from the amide bond twisting-induced C–N weakening of adjacent
nitrogen substituents or the distorted N–C(O) bond itself.[62,63] To
the best of our knowledge, such a mechanism for adjacent bond
activation is very rare.[64] A computational investigation of
Figure 7. Kinetic traces of thermolysis of trans-2 and cis-2 in the presence of
excess radical scavenger PhSH. A) Competitive fast isomerization vs. hydrogen
abstraction upon thermolysis of trans-2 with excess PhSH at 70 °C. B)
Thermolysis of pure cis-2 in the presence of PhSH at 110 °C.
This indicates that cyclization rates are in the same range as
reduction, and therefore a mechanism for the overall cyclization
can be derived, which proceeds via a slow homolysis of cis-1
followed by a slightly faster radical cyclization, which is terminated
by fast radical coupling of the bicyclic radical intermediates with
TEMPO. This is supported by calculations at the
(U)B2PLYP/G3MP2large//(U)B3LYP/6-31G(d)
level
in
combination with the SMD continuum model for DMSO (Figure 8B
and SI, Figs. S14-S20). The Gibbs free energy barrier for 6-exo
cyclization starting from the corresponding DKP radical derived
from cis-1 amounts to only 70.5 kJ/mol, which is thus over 50
kJ/mol less than the barrier for formation of the respective radical
7
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quaternary DKP alkoxyamine analogs shows that substituent
effects offer opportunities to significantly modulate the
temperature window at which controlled homolysis can occur,
thus providing prospect for future theranostic applications.
Figure 8. Thermal cycloisomerization of cis-1 to bridged DKPs syn/anti-6 and 7. A) First order decay of cis-1 and formation of cyclization products 6 and 7 at 100 °C.
B) ΔGsol-sp profile in kJ/mol for the cyclization steps calculated at the (U)B2PLYP/G3MP2Large//(U)B3LYP/6-31G(d) level of theory. Single point solvation energies
were calculated for DMSO at the SMD/(U)B3LYP/6-31G(d) level of theory.
A second potential prospect is the possibility of temporary
information or energy storage by alkoxyamines (Figure 9), since
the DKP skeleton red-A can be charged by deprotonation and
oxygenation under kinetically controlled conditions providing
trans-substituted alkoxyamines trans-A with often good
diastereoselectivity (a). Thermal isomerization to the strain-free
cis-diastereomers cis-A leads to release (b) and reductive
removal of the alkoxyamine is restoring the original state red-A
(c). In this way the system might be multiple times recycled.
Significantly, this process occurs exclusively by directed
configurational switching.
Diastereomeric excess has been previously noted for
stereoisomeric alkoxyamines upon reversible homolysis and
coupling,[65,66] where an achiral nitroxide radical couples to a chiral
carbon-centered radical (Figure 10A). However, none of the so far
investigated diastereomeric acyclic alkoxyamines 8-10, described
by Marque and Ananchenko,[67] Moad and Rizzardo,[68] or
Georges[69] exhibited large diastereomeric preferences on
thermal homolysis/radical coupling reactions. Only sterically very
crowded SG1-derived alkoxyamines 9 equilibrated up to a 6:1
mixture when a 1:1 diastereomeric mixture or the individual
diastereomers were heated at 100 °C. The most promising
examples for directed isomerizations proved to be so far the cyclic
sialic acid-derived anomeric alkoxyamines 11, recently reported
by Crich, providing a 7:1 ratio of α/β-anomers at 90 °C depending
on the protecting groups.[70,71] Alkoxyamines 11 are also
interesting in that the nitroxide unit is attached to a natural product
core structure, providing the bias, but it shows that a simple cyclic
constraint as in 11 is not sufficient to induce complete
isomerization. However, combining the cyclic constraint with
strain induced by amide distortion in DKP alkoxyamines (Figure
10B) provides the necessary driving force for a unidirectional
three-point redox-fueled switching system based on central
chirality (cf. Figure 9).
The here reported complete thermodynamic preference for the
cis-isomer irrespective of steric and electronic factors is unique
for 3,6-disubstituted DKPs. Except for fused proline-derived
DKPs,[72] such high thermodynamic bias was observed only for a
few N-alkyl-N’-acyl DKPs because of the specific distal effect of
the N-acyl carbonyl group.[73]
Figure 9. An overall reversible introduction of amide distortion into DKPs, its
redox-neutral planarization and reductive restoration.
Recently, it has been suggested that the additive Winkler-Dunitz
parameter (∑τ+χN) describes amide bond distortions more
accurately based on the linear correlation between (∑τ+χN) and
8
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N–C(O) bond lengths or differences in N-/O-protonation
products as well as a significant amide bond distortion from
planarity in the trans-DKP alkoxyamines, but much less in their
cis-isomers. Kinetic investigations of the isomerization by 1H NMR
spectroscopy revealed the rate constants of homolysis and
allowed determination of the activation parameters for both, the
trans-isomers and cis-isomers of two representative alkoxyamine
pairs. These studies showed that isomerization of the initial trans-
isomer to the more stable cis-isomer is faster than any follow-up
transformation such as radical reduction or cyclization. Quantum
chemical calculations proved to be very valuable in rationalizing
the importance of structural and reactivity parameters governing
the isomerization and further transformations. On this basis, they
also allow the prediction of structure and reactivity of more labile,
not isolable quaternary DKP alkoxyamines. The studies reported
here have many implications. Generation of the kinetic trans-
isomers having defined absolute configuration with good
selectivity allows energy uptake through significant amide
distortion, which can be released by quantitative thermal
isomerization; significant are the complete stereoselectivity and
stability under ambient conditions. The here gained knowledge
may serve as a foundation for applications of this novel class of
amino acid derived alkoxyamines for the design of smart and
functional small molecules, in polymerization processes to access
amino acid-derived or -terminated polymers, and as versatile
amino acid surrogates. Studies toward envisioned applications of
these alkoxyamines are ongoing in these laboratories and will be
reported in due course.
aptitude.[74,75] The maximum possible value for
a
fully
perpendicular amide bond amounts to ∑τ+χN = 150°. Compared
to this value, the total distortion in our most non-planar DKP trans-
1 amounts to only 31.2° and our results thus show that even a
small additive amide distortion of one fifth of the maximum value
suffices in normal-sized lactams to trigger interesting and unusual
reactivity. The here reported additive distortion values are similar
to those found in sterically hindered amides VIII reported by Lloyd-
Jones and Booker-Milburn and in N-acylazetidines studied by
Ohwada[76] and Szostak.[77]
Acknowledgements
Generous financial support by the Institute of Organic Chemistry
and Biochemistry of the Czech Academy of Sciences (RVO:
61388963), the COST action CM1201 “Biomimetic Radical
Chemistry”, the Gilead Sciences & IOCB Research Center and
the European Regional Development Fund; OP RDE; Project:
Chemical
biology
for
drugging
undruggable
targets
(ChemBioDrug) (No.CZ.02.1.01/0.0/0.0/16_019/0000729) is
gratefully acknowledged. I.C. thanks the Ministry of Education,
Youth and Sports of the Czech Republic (MSM0021620857) for
financial support.
Figure 10. A) Previous thermal isomerization of diastereomeric alkoxyamine
motives. B) Irreversible isomerization by strain release in a conformationally
constrained cycle.
Keywords: alkoxyamines • distorted amide • isomerization •
radicals • persistent radical effect
Conclusions
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groups attached to the DKP nitrogen atoms. Structural studies
with the help of X-ray crystallography unambiguously confirmed
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10
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Entry for the Table of Contents (Please choose one layout)
Layout 1:
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Strain release drives isomerization:
Amide pyramidalization in
Tynchtyk Amatov, Harish Jangra, Radek
Pohl, Ivana Císařová, Hendrik Zipse*
and Ullrich Jahn*
diketopiperazine-derived trans-
alkoxyamines is the reason for facile
homolytic bond cleavage at mild
temperatures and quantitative
isomerization to cis-isomers with
nearly planar amide geometry.
Page No. – Page No.
Unique stereoselective homolytic C-O
bond activation in diketopiperazine-
derived alkoxyamines via adjacent
amide pyramidalization
11
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