Design, synthesis and characterization of structurally dynamic cyclic: N, S -acetals

Article abstract of DOI:10.1039/d0cc03503c

We report the synthesis, characterization and comparison of a series of electronically perturbed, cyclic N,S-acetals. Inspired by electrophilic auxiliaries utilized for amine capture and concomitant peptide ligation, we studied these N,S-acetal systems and evaluated their propensity to generate zwitterionic intermediates in situ. Certain N,S-acetals in this study exhibit structurally dynamic properties through a solvent and pH-dependent ability to ring-open and ring-close via C1-S bond ionization at room temperature.

Full text of DOI:10.1039/d0cc03503c

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Design, synthesis and characterization of structurally dynamic
cyclic N,S-acetals
Received 00th January 20xx,
Accepted 00th January 20xx
Emily K. Kirkeby and Andrew G. Roberts*
DOI: 10.1039/x0xx00000x
We report the synthesis, characterization and comparison of a (4, X = S or Se) and an amine partner (5) under aqueous
series of electronically perturbed, cyclic N,S-acetals. Inspired by conditions. First, a transiently generated hemiaminal int-6’
electrophilic auxiliaries utilized for amine capture and undergoes X-to-N acyl shift, followed by the release of a
concomitant peptide ligation, we studied these N,S-acetal systems peptide (6) with an amide bond at Xaa–Xaa.9 ACL is a useful
and evaluated their propensity to generate zwitterionic alternative for peptide ligation between sterically encumbered
intermediates in situ. Certain N,S-acetals in this study exhibit partners (e.g., Val–Val), as well as for C-terminal partners
structurally dynamic properties through a solvent and pH- considered to be epimerization prone (e.g., Phe–Val). Although
dependent ability to ring-open and ring-close via C1–S bond enabling, the electrophilic benzaldehyde component (4) must
ionization at room temperature.
be
Chemical protein synthesis via peptide ligation methodologies
is an enabling technology utilized for the advancement of
biochemical discovery.1 Native chemical ligation (NCL)2 is the
most frequently employed method to chemically join peptide
sequences (Fig. 1A). This dependable ligation requires
synthetic or semisynthetic access3 to a C-terminal peptide
thioester 1 and an N-terminal Cys peptide 2. The reaction
proceeds with a transthioesterification event, followed by an
S-to-N acyl shift (int-3) to access ligated protein 3a with an
amide bond at Xaa–Cys, W = SH.2,4 If desired, the Cys residue
can be chemoselectively dethiylated, 3a, W = SH  3b, W = H,
providing Ala at the ligation site—a powerful advance referred
to as Ala ligation (Fig. 1A).5,6 A recent meta-analysis7a revealed
that the two-step Ala ligation is used more frequently than
NCL alone, due to the greater frequency of Ala (9% total
abundance) compared with Cys residues (<2%) within
proteins.7 Naturally low Cys residue abundance has prompted
the development of chemical methods for ligation at
alternative sites, Xaa–Xaa, where Xaa is an ‘acyl donor’ and Xaa
is an ‘acyl acceptor’.1,6
Among the Cys-independent methodologies,8 the
development of aldehyde capture ligation (ACL) by Arora9a and
Li9b represent a major advance toward the ideal of sequence-
independent ligation (4, X = S or Se, Fig. 1B). The method
leverages the chemoselective reactivity of an electrophilic C-
terminal thioester-9 or selenoester-9b benzaldehyde derivative
Department of Chemistry, University of Utah, 315 South 1400 East, Salt Lake City,
Utah 84112, United States. e-mail: roberts@chem.utah.edu
†Electronic Supplementary Information (ESI) available: For ESI, including full
procedures and characterization data, 1H and 13C NMR spectra, crystallographic
data in CIF format (CCDC 2001038, 2001039, and 2001040) and computational
information, see DOI: 10.1039/x0xx00000x
Figure 1 Native chemical ligation (A) and aldehyde capture ligation (B) inspire the
design and characterization of a dynamic class of cyclic N,S-acetal molecules (C).
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Journal Name
R1
synthesized using the redox-neutral sulfenylation chemistry
View Article Online
H
O
R1
described by Seidel and co-workers.11DaOTI:h10is.10a3c9i/dD-0pCroC0m3o50te3Cd
1
N
HOAc
HS
S
reaction
combines
commercially
available
1,2,3,4-
NH
PhCH3, 60 ºC
R2
tetrahydroisoquinolines (9a-9c) reacted with prepared 2-
mercaptobenzaldehydes (10a-10c) (see the ESI†). All seven
N,S-acetal variants 8a-8g were purified by trituration with
ethyl acetate and isolated as solids in useful yields, with
derivatives 8d-8g being previously unknown. Preliminary
studies using 1H NMR spectroscopy (500 MHz, CDCl3) to
characterize 8b, 8c, and 8d were perplexing. We observed
spectral line broadening in the upfield region ( ppm, 4.75-
2.25), while the downfield regions ( ppm, 10.0-5.5) were
resolved as one would expect. Despite being previously
characterized,11a the spectroscopic anomalies in comparative
1H NMR spectra for 8a and 8b were not explained. Overall, the
phenomenal spectral features observed for 8b, 8c, and 8d
were seemingly incongruent with comparative data for 8a, 8e,
8f, and 8g. However, the general observations based on data
appeared to be naturally in line with our initial hypotheses
concerning C1–S ionization susceptibility. Further investigation
revealed an intriguing dynamic behavior exhibited by the study
of 8b, 8c and 8d in solvents of varied polarity.
R2
9a R1 = H
10a R2 = H
(8), 8a R1 = H, R2 = H
(63%, over two steps)a
9b R1 = OMe
9c R1 = NO2
10b R2 = OMe
10c R2 = NO2
MeO
MeO
N
N
N
S
S
S
NO2
NO2
8b (44%)
over two steps
8c (77%)
over two steps
8d (63%)
over two steps
O2N
O2N
N
S
N
S
N
S
OMe
OMe
8e (33%)
over two steps
8f (55%)
8g (26%)
over three steps
Scheme 1 Redox-neutral synthesis and study of seven N,S-acetal derivatives.
aYields are reported following multistep transformations that utilize crude 2-
mercaptobenzaldehydes (10a-10c).
A comparative analysis of 1H NMR spectra (500 MHz, CDCl3,
 ppm, 4.75-2.25) for 8a-top and 8b-middle (Fig. 2) serves to
emphasize the impact that a single methoxy group exhibits on
the N,S-acetal system. Null system 8a exhibits complete
resolution for each diastereotopic methylene proton: Hb (4.56,
d, J = 16.6 Hz, 1H), Hb’ (3.96, d, J = 16.6 Hz, 1H), Hcc’ (3.22, m,
synthetically prepared and the stoichiometric auxiliary is
ultimately discarded as 7 (X = S or Se) along with other
unknown derivatives. These issues present the opportunity to
design a dynamic, small molecule organocatalyst to facilitate
concomitant transthioesterification and amine trapping
reactions for procedurally improved sequence-independent
peptide ligation (Fig. 1C).8,9,10 Inspired by the productive
reactivity of N,O-hemiaminal int-6’,9a we envisioned the study
of a class of cyclic N,S-acetal molecules (8) designed with
latent ambiphilicity. We hypothesize that a cyclic N,S-acetal (8)
will exist in dynamic equilibrium with ‘open’ form zwitterion
int-8, revealing benzylic iminium (electrophilic, + at C1) and
aryl thiolate functionalities.11 An informed understanding of
2H), Hdd’ (2.86, m, 2H). The respective methylene protons, Hbb’
,
Hcc’, and Hdd’, in the methoxy variant (8b) exhibit significant
line broadening, despite total resolution of the methoxy group,
CH3O- (3.79, s, 3H), and the downfield region ( (ppm), 10.0-
5.5). Intriguingly, this odd behavior is subject to changes in
1
solvent polarity (see ESI† Fig. S-2, Fig. S-3). Analysis of the H
NMR spectrum of 8b in benzene-d6 (500 MHz, C6D6) exhibits
total resolution (Fig. 2, bottom), including for respective
int-8, could facilitate the development of
organocatalyzed thioacyl aminolysis reaction, 1 + 5  6, via
proposed ternary adduct int-8’, under aqueous
conditions.9,10,12 We posited that controlled permutation and
evaluation of electronics at positions R1 and R2 (8) would
enable the discovery of a dynamic class of molecules. Through
reactivity and spectroscopic characterization studies, we
reveal the dynamic properties and reactivity exhibited by
certain N,S-acetal variants (8).
a general,
dd’
cc’
8a, 1H NMR (500 MHz, CDCl3)
N
bb’
S
8a
b
b’
cc’
dd’
dd’
8b, 1H NMR (500 MHz, CDCl3)
MeO
cc’
N
bb’
In our study, we envisioned electronic perturbations that
would affect ionization of the C1–S bond in N,S-acetal 8.11a We
designed a series of N,S-acetals (8a-8g) using Hammett
substituent constants to predict ionization susceptibility a
priori (Scheme 1).13 In other words, we anticipate an N,S-acetal
(8) with an electron donating substituent at R1 (e.g., R1 = OMe)
and/or an electron withdrawing substituent at R2 (e.g., R2 =
NO2) to favor C1–S bond ionization relative to either converse
case. The comparative study and characterization of N,S-
acetals organized into two groups, group I: 8b, 8c, 8d, and,
group II: 8e, 8f, 8g, relative to the parent null, 8a, might offer
further insight. Accordingly, designed N,S-acetals were
S
8b
b
b’
cc’
dd’
8b, 1H NMR (500 MHz, C6D6)
b
b’
c
c’
dd’
2 | J. Name., 2012, 00, 1-3
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Figure 2 Characterization of N,S-acetals (8a, 8b) by 1H NMR spectroscopy.
To further understand this solvent-dependent dynamic
behavior, we reasoned that a zwitterionic intermediate int-8
may be directly observable spectroscopically or inferred by
trapping either the benzylic iminium or thiolate functionalities
to form a stable derivative. Thus, we developed an
View Article Online
DOI: 10.1039/D0CC03503C
methylene protons: Hb (4.21, d, J = 16.6 Hz, 1H), Hb’ (3.56, d, J =
16.6 Hz, 1H), CH3O- (3.29, s, 3H), Hc (3.22, td, J = 11.8, 4.3 Hz,
1H), Hc’ (2.94, ddd, J = 18.2, 12.0, 6.6 Hz, 1H), Hdd’ (2.37, m,
2H).
A.
Intriguingly, select variants 8b, 8c and 8d (group I) in the
series exhibit dynamic properties observable by 1H NMR
spectroscopy (see ESI†).11,14 In the exemplary case of methoxy-
substituted variant, 8b, we observe significant 1H signal
broadening for methylene positions Hbb’, Hcc’ and Hdd’ in CDCl3
at ambient conditions. Contrarily, the entire 1H spectrum is
resolved in benzene-d6. This solvent-controlled dynamicity is
b
b’
cc’
dd’
dd’
MeO
cc’
21 ºC
–5 °C
N
bb’
Ha
S
8b, dynamic mixture
–15 °C
–25 °C
–35 °C
–45 °C
cooling
21 °C to –45 °C
observed by
also
temperature
dependent.
For
example,
the
characterization of 8b by variable temperature 1H NMR
demonstrates that cooling from 21 C (broadened signals) to –
45 C in CDCl3 results in spectral resolution (Fig. 3A, see ESI†
Fig. S-1).
1H NMR in CDCl3
S
MeO
b
b’
cc’
dd’
N
We attribute these observations to a dynamic equilibrium
of interconverting antiperiplanar and synperiplanar
diastereoisomers (Fig. 3B). The respective nomenclatures
describe the relationship between the lone pair at nitrogen
and the C1–S bond. The depicted antiperiplanar conformer
Ha
8b-antiperiplanar
favored diastereomer
B.
N
S
R2
(8b-antiperiplanar,
shown)
is
presumed
to
be
MeO
MeO
Ha
thermodynamically favored, the nitrogen lone pair is oriented
anti to the C1–S bond, this is also confirmed by x-ray
crystallography (Fig. 3B, for x-ray structures of 8a and 8d, see
ESI†). This type of stereospecific dynamicity has been
previously described for alkaloid N,O-acetal systems and
highlights the importance of stereochemistry at nitrogen.15 In
the parent null case, 8a (R1 = H, R2 = H), and for group II
variants (8e, 8f, and 8g) interconversion from antiperiplanar to
synperiplanar form at room temperature is presumed to be
disfavored. These N,S-acetals, 8a, 8e, 8f and 8g, exhibit fully
resolved 1H NMR spectra in both CDCl3 and benzene-d6.
However, in the methoxy substituted case 8b (shown), this
interconversion is proposed to be facile and this room
temperature equilibration is responsible for the signal
broadening observed in CDCl3. Benzene-d6 is hypothesized to
destabilize the zwitterionic int-8b, precluding the
interconversion of the antiperiplanar and synperiplanar
diastereoisomers. These observations distinguish the chemical
dynamicity of group I N,S-acetals (8b, 8c, 8d) and the
importance of electronic perturbations to their reactivity.
Using theory-based computation to study mechanism,
Houk, Seidel and coworkers previously suggested int-8a to be
the penultimate intermediate en route to the formation of 8a
from the reaction of 9a with 10a (Scheme 1).11a Accordingly,
relative energy values obtained from quantum mechanical
modelling11 of N,S-acetals, 8a, 8d, 8g, and their respective
zwitterionic forms, int-8a (R1 = H, R2 = H), int-8d (R1 = OMe, R2
= NO2) and int-8g (R1 = NO2, R2 = OMe), support a C1–S bond
ionization susceptibility rank of: 8d > 8a > 8g (see ESI† Fig. S-7).
This relative comparison of the extremely polarized cases, 8d
and 8g, is consistent with our qualitative spectroscopic
observations. A solution of N,S-acetal 8d in CDCl3 at room
temperature is structurally dynamic, whereas variant 8g is not.
8b- (shown) and 8d-
antiperiplanar
thermodynamically favored
c
d
b
N
S
R2
int-8b, R2 = H and int-8d, R2 = NO2
8b- and 8d-
synperiplanar
Ha
MeO
N
N
S
R2
S
MeO
Ha
R2
Figure 3 (A) Variable temperature 1H NMR spectroscopy in CDCl3, 21 C to –45
C, demonstrates 8b-antiperiplanar as the favored diastereomer; (B) Proposed
equilibration of two diastereoisomeric forms: Impact of electronics and
stereoelectronics on structural dynamics (8b and 8d).
understanding of dynamic reactivity for group I N,S-acetals, 8b,
8c and 8d, under more extreme conditions (Scheme 2). The
reaction of 8b [16 mM] under acidic conditions, a. neat
CF3CO2H, or b. 10 equiv CF3CO2H in CDCl3, forms the
protonated form of int-8b rapidly, <1 min for condition b, and
1
quantitatively (> 95% purity H NMR). This benzylic iminium
int-8b is characterized by H, 13C and 2-D NMR experiments
1
(see ESI† Fig. S-4, Fig. S-5, Fig. S-6). Notably, the methine Ha
and C1 signals are diagnostic (500 MHz, CDCl3), as signals shift
from N,S-acetal 8b (Ha = 6.14 ppm, C1 = 67.1 ppm) to benzylic
iminium int-8b (Ha = 8.57 ppm, C1 = 163.9 ppm). As expected,
methylene signals, Hb, Hc and Hd, for int-8b are homotopic and
fully resolved. Similar ring-opening results are observed for the
additional group I N,S-acetal variants, 8c and 8d (see ESI†).
This N,S-acetal (8b) ionization process is reversible (Scheme
2). Titration of crude int-8b from CDCl3 experiment (condition
b) with 10 equiv triethylamine (condition c) quantitatively
1
reforms the ‘closed’ form, N,S-acetal 8b, as observed by H
NMR spectroscopy (see ESI† Fig. S-4). Interestingly, reclosure is
also affected by altering the polarity of the solvent mixture.
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J. Name., 2013, 00, 1-3 | 3
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Treatment of crude int-8b from CDCl3 experiment (condition b)
with 100 equiv CH3OH (condition d) reforms N,S-acetal 8b as
observed by thin-layer chromatography and 1H NMR
Notes and references
‡ CCDC 2001038 (8a), 2001039 (8b) and 2001040 (8d) contain
the supplementary crystallographic data for this paper. The data
can be obtained free of charge from The Cambridge
View Article Online
DOI: 10.1039/D0CC03503C
500 MHz, CDCl3
MeO
Crystallographic
Data
Centre
via
Ha
6.14 ppm
67.1 ppm
N
1
www.ccdc.cam.ac.uk/getstructures.
Ha
C1
S
8b
dynamic mixture
1
2
(a) S. B. H. Kent, J. Pept. Sci., 2015, 21, 136–138; (b) S. Kent, Bioorg.
Med. Chem. 2017, 25, 4926–4937.
P. E. Dawson, T. W. Muir, I. Clark-Lewis and S. B. Kent, Science 1994,
266, 776–779; (b) T. M. Hackeng, J. H. Griffin and P. E. Dawson, P. E.,
Proc. Natl. Acad. Sci. USA 1999, 96, 10068–10073.
a. neat CF3CO2D, or
c. add
Et3N
b. 10 equiv CF3CO2D,
CDCl3 (shown)
500 MHz, CDCl3
d
MeO
c
Ha
8.57 ppm
3
4
5
T. W. Muir, D. Sondhi and P. A. Cole, Proc. Natl. Acad. Sci. USA, 1998,
95, 6705–6710.
E. C. B. Johnson and S. B. Kent, J. Am. Chem. Soc., 2006, 128, 6640–
6646.
(a) L. Z. Yan, and P. E. Dawson, J. Am. Chem. Soc., 2001, 123, 526–533;
(b) Q. Wan, and S. J. Danishefsky, Angew. Chem. Int. Ed., 2007, 46,
9248–9252.
1
N
163.9 ppm
C1
b
Ha
SD
int-8b
zwitterionic form
CF3CO2
d. add
CH3OH
R1
D
int-11b, R1 = OMe
X = OMe, OCOCF3
adduct mixture
1
N
8b
+
X
Ha
SD
CF3CO2
6
7
(a) H. M. Burke, L. McSweeney and E. M. Scanlan, Nature Comm.,
2017, 8, 15655. (b) S. Kulkarni, J. Sayers, B. Premdjee and R. J.
Payne, Nature Rev. Chem., 2018, 2, 0122.
Scheme 2 N,S-acetal 8b, C1–S ionization, chemically induced formation of
zwitterion int-8b and reactivity.
(a) V. Agouridasa, O. E. Mahdib, M. Cargoëta and O. Melnyk, Bioorg.
Med. Chem. 2017, 25, 4938–4945; (b) M. T. Jacobsen, P. W. Erickson,
M. S. Kay, Bioorg Med Chem. 2017, 25, 4946–4952.
(a) Y. Chow and X. Li, Tetrahedron Lett., 2015, 56, 3715–3720; (b) J.
Yang, J. Zhao, J. Sci. China Chem. 2018, 61, 97–112.
(a) M. Raj, H. Wu, S. L. Blosser, M. A. Vittoria and P. S. Arora, J. Am.
Chem. Soc., 2015, 127, 6932–6940; (b) C. L. Tung, C. T. T. Wongab and
X. Li, Org. Biomol. Chem., 2015, 13, 6922–6926.
spectroscopy. Anticipated in situ formed adducts consistent
with N,O-acetals (11b, X = OMe or OCOCF3) are not detected.16
Further studies will evaluate the propensity of benzylic
iminium int-8b to undergo addition-type reactions with various
nucleophiles, including amines, alcohols and thiols.16,17
Collectively, these results suggest that the development of pH
controlled, buffered conditions may permit systematic N,S-
acetal opening and closure reactivity. Further studies will
involve the generation and reactivity characterization of N,S-
acetal derived scaffold–peptide adducts (e.g., int-8’, Fig. 1C)
toward the development of an organocatalysis platform for
sequence-independent peptide ligation.18 The understanding
of
8
9
10 For selected related approaches, see: (a) S. Leleu, M. Penhoat, A.
Bouet, G. Dupas, C. Papamicaël, F. Marsais and V. Levacher, V. J. Am.
Chem. Soc., 2005, 127, 15668–15669; (b) H. Wu, Handoko, M. Raj
and P. S. Arora, Org. Lett., 2017, 19, 5122–5125; (c) Handoko, S.
Satishkumar, N. R. Panigrahi and P. S. Arora, J. Am. Chem. Soc., 2019,
141, 15977–15985.
11 (a) C. L. Jarvis, M. T. Richers, M. Breugst, K. N. Houk and D. Seidel,
Org. Lett. 2014, 16, 3556–3559; (b) M. T. Richers, M. Breugst, A. Yu,
A. Y. Platonova, A. Ullrich, A. Dieckmann, K. N. Houk and D. Seidel, J.
Am. Chem. Soc. 2014, 136, 6123–6135.
12 At appropriate concentrations, unhindered thioacyl aminolysis
ligations can proceed uncatalyzed. Intramolecular thioacyl
aminolysis reactions can also be efficient, see: (a) R. J. Payne, S.
Ficht, W. A. Greenberg and C.-H. Wong, Angew. Chem. Int. Ed., 2008,
47, 4411–4415; (b) Y. Li, A. Yongye, M. Giulianotti, K. Martinez-
Mayorga, Y. Yu and R. A. Houghten, J. Comb Chem., 2009, 11, 1066–
1072.
group I N,S-acetal (8b, 8c, 8d) reactivity may also have
implications for the control of nucleophile capture and release
events important to X,S-acetal systems (X = O or N)19 and
dynamic covalent chemistry derived materials.20
We are grateful for financial support from the University
of Utah. Computational resources were provided by the Center
for High Performance Computing at the University of Utah. We
thank Lori D. Digal for helpful discussions. We also thank
Samantha Grosslight and Dr. Jolene P. Reid (Sigman
Laboratory) for assistance with computations, Dr. Ryan
VanderLinden for x-ray crystallographic analyses and Dr. Peter
Flynn of the University of Utah for assistance with variable
temperature NMR experiments. NMR results included in this
report were recorded at the David M. Grant NMR Center, a
University of Utah Core Facility. Funds for construction of this
center and the helium recovery system were obtained from
the University of Utah and the National Institutes of Health
(NIH) awards 1C06RR017539-01A1 and 3R01GM063540-17W1,
respectively. NMR instruments were purchased with support
of the University of Utah and the NIH award 1S10OD25241-01.
13 C. Hansch, A. Leo, R. W. Taft, Chem. Rev., 1991, 91, 165–195. (σpara
:
H– = 0, MeO– = -0.27, O2N– = 0.78)
14 R. G. Bryant, J. Chem. Educ., 1983, 60, 933.
15 B. Herberich, J. D. Scott and R. M. Williams, Bioorg. Med. Chem.
2000, 8, 523–532.
16 J. Dhineshkumar, M. Lamani, K. Alagiri, and K. R. A. Prabhu, Org.
Lett., 2013, 15, 1092–1095.
17 For a representative method, see: T. Suga, S. Iizuka and T. Akiyama,
Org. Chem. Front. 2016, 3, 1259.
18 Preliminary studies support the dynamic reactivity of N,S-acetals
with amino acids. For example, an aqueous solution of 8a (1 equiv)
and H-Gly-OH (2 equiv) generates a tentatively assigned Gly-adduct
int-11a (Scheme 2, X = Gly-OH, R1 = H) as observed by UPLC-MS
([M+Gly-OH+H]+: 329.13; obsd: 329.30)
19 For a representative example, see: L. R. Malins, J. N. deGruyter, K. J.
Robbins, P. M. Scola, M. D. Eastgate, M. R. Ghadiri, P. S. Baran, J.
Am. Chem. Soc., 2017, 139, 5233–5241.
20 Y. Zhang and O. Ramström, Chem. Eur. J., 2014, 20, 3288–3291.
Conflicts of interest
There are no conflicts to declare.
4 | J. Name., 2012, 00, 1-3
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