DNA-Compatible [3 + 2] Nitrone-Olefin Cycloaddition Suitable for DEL Syntheses

Article abstract of DOI:10.1021/acs.orglett.9b00017

The limited scope of DNA-compatible chemistry restricts the types of chemical features that can be incorporated into DNA-encoded libraries (DELs). Here, a method to synthesize DNA-conjugated polycyclic isoxazolidines via a [3 + 2] nitrone-olefin cycloaddi

Full text of DOI:10.1021/acs.orglett.9b00017

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
DNA-Compatible [3 + 2] Nitrone−Olefin Cycloaddition Suitable for
DEL Syntheses
Christopher J. Gerry,† Zhenhua Yang, Michele Stasi, and Stuart L. Schreiber*
,‡
‡
‡
,†,‡
†Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, United
States
‡
Chemical Biology and Therapeutics Science Program, Broad Institute, 415 Main Street, Cambridge, Massachusetts 02142, United
States
*
S Supporting Information
ABSTRACT: The limited scope of DNA-compatible chemistry restricts the types of chemical features that can be incorporated
into DNA-encoded libraries (DELs). Here, a method to synthesize DNA-conjugated polycyclic isoxazolidines via a [3 + 2]
nitrone−olefin cycloaddition is described. The reaction is compatible with many olefin-containing substrates and diverse N-
alkylhydroxylamines. The ability to perform subsequent DNA ligation and PCR amplification was also confirmed. This
methodology facilitates the synthesis of DELs containing topographically complex compounds with underexplored chemical
features.
DNA-encoded libraries (DELs) of small molecules can
We identified the intramolecular [3 + 2] nitrone−olefin
cycloaddition as a transformation that can fill some of the
structural gaps in current DELs. Earlier reports have shown
1
,2
facilitate the identification of protein “binders” in affinity-
3
−6
based biochemical assays.
DELs combine synthetic organic
20,21
chemistry and DNA barcoding to generate libraries of
compounds that are each covalently linked to a unique,
amplifiable tag that records the synthetic reactions from
this reaction to be water- and DNA-compatible,
though it
has never been used for DEL synthesis, and previous DNA-
compatible examples were performed using DNA-templated
7
20
which individual compounds derive. DELs are most often
synthesis with activated olefins and preformed nitrones.
2
used to identify molecules that engage an immobilized
From a structural standpoint, this reaction converts sp -rich
8
3
protein target. This strategy has yielded binders of
starting materials to sp -rich isoxazolidines containing at least
9
therapeutically relevant proteins such as kinases, phospha-
two stereogenic elements. The isoxazolidine motif is rarely
found in DELs, but it resides in several alkaloid natural
1
0
11
12
tases, G-protein-coupled receptors, and others.
22,23
It is possible that the full potential of DEL-mediated target-
products and other bioactive compounds.
Furthermore,
based screening has not been realized because, despite recent
unlike most other ring-forming reactions (e.g., ring-closing
metathesis), it can introduce appendage diversity via
condensation of N-alkylhydroxylamines with aldehydes or
ketones to form nitrones in situ. The ability to perform ring
closure and appendage diversification simultaneously is
appealing because split−pool synthesis often makes post-
reaction purification challenging. Therefore, DEL pathways
should be limited to a handful of steps to mitigate buildup of
DNA damage and unwanted byproducts, among other
13−16
advances in DNA-compatible chemistry,
the types of
1
7
structural features found in DELs remain limited. To
generate libraries, DNA-encoded compounds are often
synthesized in parallel with their barcodes using split−pool
synthesis. The presence of DNA and water during synthesis,
however, restricts the chemistry that may be used to build
DELs. Many robust and commonly used transformations
1
8
(
e.g., cross-couplings, amidations, and S Ar reactions) tend
N
24
2
factors.
to produce compounds rich in sp -hybridized carbons.
We first synthesized on-DNA salicylaldehyde derivative 1
and treated it with methylhydroxylamine; we used the
double-stranded DNA “headpiece” commonly used in split−
Therefore, significant gaps exist in the types of molecular
19
architectures found in DELs. In an effort to address these
shortcomings, a novel, open-source collaboration involving a
small group of scientists at the Novartis Institutes for
BioMedical Research and the Broad Institute was recently
established. The work reported here describes an early
example of this collaboration.
6
pool DEL synthesis. Our initial experiments suggested that
Received: January 2, 2019
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00017
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
conversion to the desired isoxazolidine 2 could be increased
by raising the reaction temperature (Table 1, entries 1 and
Table 2. Scope of Hydroxylamine with Substrate 1*
Table 1. Initial Optimization of On-DNA [3 + 2]
Nitrone−Olefin Cycloaddition
time
(h)
temp
(°C)
MeNHOH
(equiv)
buffer
g
h
entry
buffer
vol
2 (%)
a
a
a
1
2
3
4
5
6
7
8
9
12
12
12
12
12
4
4
12
4
70
90
100
70
90
90
90
90
90
90
90
90
25
25
25
25
100
25
25
25
25
25
25
Na HPO
2
2
2
0.1
2
0.5
0.1
0.5
2
70
88
84
2
4
4
4
Na HPO
2
f
Na HPO
2
b
pyrrolidine
54
64
86
93
a
Na HPO
2
4
a
4
Na HPO
2
c
c
NaH PO
2
4
4
f
NaH PO
81
2
d
NaH PO
90
71
91
2
4
d
1
1
1
0
1
2
4
4
4
NaH PO
8
2
8
2
4
e
NaOAc
NaOAc
e
25
>98
a
b
c
1
.0 M aq buffer (pH 9.2). 0.2 M DMA solution. 1.0 M aq buffer
d
e
(
pH 4.2). 0.1 M aq buffer (pH 5.9). 0.1 M aq buffer (pH 5.0).
f
g
Significant DNA damage observed. Compared to amount of 1 stock
h
solution (0.8 mM) added. Determined by UPLC-MS.
2
). Performing the reaction at 100 °C, however, resulted in
decomposition of the DNA barcode via depurination that was
detectable by UPLC-MS analysis (Table 1, entry 3). Using
organic base (Table 1, entry 4) or additional equivalents of
hydroxylamine (Table 1, entry 5) resulted in low conversion
and substantial byproduct formation. Although high con-
versions could be achieved in 4 h at 90 °C in basic phosphate
buffer (Table 1, entry 6), even higher conversions were
observed in acidic phosphate buffer (Table 1, entry 7). The
substrate was more prone to depurination in acidic
conditions (Table 1, entry 8), so milder buffering systems
were explored (Table 1, entries 9−12). Ultimately, 8 vol of
*
0
.1 M NaOAc buffer yielded the highest conversion (Table 1,
Reactions carried out with 35 equiv of hydroxylamine (50 mM in
DMSO) in 0.1 M NaOAc aq buffer (pH 5.0) for 8 h (2 h at 40 °C
entry 12). The cis ring fusion of 2 was confirmed via NMR-
based characterization of an off-DNA analogue (see
Supporting Information for details).
a
b
then 6 h at 90 °C). 140 equiv of hydroxylamine. 50% phthalimide,
c
37% free amine. Determined by UPLC-MS.
We then studied the compatibility of this transformation
with additional hydroxylamines; the reaction conditions were
modified slightly to account for the increased complexity and
steric bulk of the nitrone intermediates (Table S1). Whereas
methyl-, ethyl-, and n-hexylhydroxylamine afforded clean
conversions to the desired isoxazolidines (Table 2, entries
independent of the hydroxylamine in the reaction, was an
oxime-containing product likely derived from interception of
the nitrone intermediate by an exogenous nucleophile. Both
products are consistent with the increased steric bulk of the
nitrone slowing the rate of the intramolecular cyclization.
Steric bulk of tBuNHOH (Table 2, entry 5) hindered the
[3 + 2] cycloaddition and condensation to the nitrone;
however, increasing the amount of hydroxylamine 4-fold
(Table 2, entry 6) yielded substantially higher isoxazolidine
1
−3), byproducts were observed when 1 was treated with
iPrNHOH (Table 2, entry 4). We identified one species as
the obligatory nitrone intermediate; it had the same mass as
the desired isoxazolidine product and appeared to convert to
it over time (Figure S1). The other species, which was
B
DOI: 10.1021/acs.orglett.9b00017
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
formation. Cyclopentyl- and cyclohexylhydroxylamine
achieved 88 and 82% conversion, respectively (Table 2,
entries 7 and 8), both of which were higher than that of
iPrNHOH (77%). These differences in reactivity underscore
the outsized impact of steric effects upon the success of the
reaction.
We then tested hydroxylamines containing functional
groups other than saturated hydrocarbons. Benzyl-containing
hydroxylamines were very successful (Table 2, entries 9 and
reaction profiles. Though treatment of 8 and 10 with
iPrNHOH resulted in low isoxazolidine formation, in each
case, the only other major product was the nitrone
intermediate. Nitrile 11, on the other hand, always generated
a complex mixture of products that could not be easily
identified or distinguished by UPLC-MS analysis alone.
Finally, sulfone 12 afforded moderate isoxazolidine formation
with all three hydroxylamines.
Having seen that activated olefins accelerate on-DNA
cyclizations dramatically, we studied the hydroxylamine scope
further with 6 and 8−10 (Table 3). We tailored the reaction
parameters for each substrate to yield maximal isoxazolidine
formation under the mildest possible conditions; 9 achieved
very similar results with the harsher conditions associated
with 8 and 10 (Table S2), which suggests 8−10 (or
derivatives) could be pooled for DEL synthesis.
Using these optimized conditions, treatment with methyl-
and n-alkylhydroxylamines largely resulted in excellent
isoxazolidine formation (Table 3, entries 1−12). Experiments
with ester 6 were less successful due to incomplete
consumption of starting material and the formation of
saponification byproducts; this trend continued throughout
the study. All substrates yielded slightly lower conversions
with iPrNHOH (Table 3, entries 13−16). Lower conversions
still were seen with tBuNHOH (Table 3, entries 17−20) due
to sluggish nitrone formation and cyclization. Cyclopentylhy-
droxylamine behaved similarly to iPrNHOH (Table 3, entries
1
0), but an electrophilic 2-pyridine derivative yielded high
amounts of oxime (Table 2, entry 11). Free and protected
amines are compatible with the reaction, though we observed
some phthalimide deprotection (Table 2, entries 12 and 13).
N-hydroxy-L-ornithine generated high levels of oxime (Table
2
, entry 14), potentially via an intramolecular 5-exo-tet
cyclization to generate the on-DNA oxime and the presumed
ornithine-derived proline. A bulky sulfone-containing reagent
initially afforded low consumption of 1, but additional
hydroxylamine furnished excellent results (Table 2, entries
1
5 and 16). Finally, treatment with aromatic hydroxylamines
resulted in no isoxazolidine formation (Table 2, entries 17
and 18).
Next, we studied the effect of olefin substitution. Ten
additional on-DNA substrates (3−12) were synthesized, and
each was initially tested with three hydroxylamines (Figure
1
). Due to the sensitivity of the reaction to steric effects (see
Table 2, entries 1−8), all experiments with prenylated 3
resulted in poor isoxazolidine formation.
21−24), but reactions with the bulkier cyclohexyl reagent
were superior due to decreased oxime formation (Table 3,
entries 25−28). Next, reactions with benzyl-containing
hydroxylamines proceeded smoothly (Table 3, entries 29−
3
6). Most experiments with the pyridine-containing reagent,
however, suffered from high rates of oxime formation, though
was sufficiently reactive to undergo cyclization before this
9
side reaction could occur (Table 3, entries 37−40). Both free
and phthalimide-protected amines were again tolerated
(
Table 3, entries 41−48), and minimal deprotection was
observed under these milder conditions. N-hydroxy-L-
ornithine generally furnished high amounts of oxime
byproduct and complex reaction profiles (Table 3, entries
4
9−52), but the sulfone-containing hydroxylamine yielded
excellent results (Table 3, entries 53−56). We did not
observe products of conjugate additionwhich is a known
25
DNA-compatible reaction in any experiment.
Compatibility of this transformation with several com-
monly used functional groups in DNA-compatible chem-
istryfree and protected amines, carboxylic acids, and aryl
halideshighlights its utility for DEL design. In strategically
designed on-DNA chemical pathways, these chemical handles
Figure 1. Conversions to isoxazolidines for on-DNA substrates 3−
1
2. Reactions carried out with 40 equiv of hydroxylamine (50 mM
(
e.g., the carboxylic acid of 8) would be functionalized either
in DMSO) in 1.0 M NaOAc aq buffer (pH 5.0) for 8 h at 40 °C.
before or after cyclization to enable to the construction of
large, combinatorial DELs containing rare structural features.
We have shown that this methodology can achieve high
yields with a variety of substrates, but to be suitable for DEL
synthesis, it must also leave the DNA barcode capable of
a
3
5 equiv of hydroxylamine for 2 h at 40 °C then 6 h at 90 °C.
To determine if favorable electronics could outweigh the
penalty of increased steric bulk, we synthesized DNA-linked
substrates featuring a variety of electron-withdrawing groups
on the reactive olefin (4−12; Figure 1). For each substrate,
significant product formation was observed after 8 h at just
26
undergoing enzymatic DNA ligation and PCR amplification.
To assess postreaction DNA integrity (Figure 2), we
performed cycloadditions with 1, 9, and 10 using each
scaffold’s optimized reaction conditions. Then, we ligated an
oligonucleotide to the reaction products to generate a
barcode comparable in size to those found in a 3-cycle
DEL. Finally, we successfully amplified all three barcodes by
4
0 °C. Under these mild conditions, saponification was
observed with esters 4−7. Of these four substrates, isopropyl
ester 6 exhibited the lowest susceptibility to hydrolysis.
Substrates 8−10 often yielded high conversions and simple
C
DOI: 10.1021/acs.orglett.9b00017
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Table 3. Scope of Hydroxylamine with 6 and 8−10*
*
a
b
c
Reaction conditions: 100 equiv of hydroxylamine (50 mM in DMSO) in 1.0 M NaOAc aq buffer (pH 5.0). 8 h at 50 °C. 8 h at 60 °C. 4 h at 40
d
e
°C. 250 equiv of hydroxylamine. Determined by UPLC-MS; green = 80−100%; yellow = 50−79%; red = 0−49%; N.D. = not determined.
PCR and detected no loss of informational integrity (Figures
S2−S5).
In conclusion, we have developed a DNA-compatible [3 +
2
] nitrone−olefin cycloaddition capable of generating
polycyclic isoxazolidines. This transformation routinely
eclipses 80% product formation with a variety of N-
alkylhydroxylamines and olefin-containing substrates, which
makes it appealing for DEL construction. We also confirmed
that three sets of our optimized reaction conditions did not
damage the DNA barcode or prevent subsequent ligation and
amplification steps required for DEL synthesis.
Figure 2. Schematic for three-step assessment of DNA integrity.
DNA attached to cycloaddition substrates 1, 9, and 10 successfully
underwent DNA ligation and PCR amplification after [3 + 2]
nitrone−olefin cycloaddition.
D
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Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
DELs that incorporate this transformation may begin to fill
some of the structuraland perhaps functionalgaps left by
current on- and off-DNA small-molecule libraries. Efforts to
leverage this reaction most effectively for DEL synthesis are
ongoing, and we aim to describe these at a later date.
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AUTHOR INFORMATION
Corresponding Author
(8) Decurtins, W.; Wichert, M.; Franzini, R. M.; Buller, F.; Stravs,
M. A.; Zhang, Y.; Neri, D.; Scheuermann, J. Automated Screening
for Small Organic Ligands Using DNA-Encoded Chemical Libraries.
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■
*
E-mail: stuart_schreiber@harvard.edu.
(
9) Yang, H.; Medeiros, P. F.; Raha, K.; Elkins, P.; Lind, K. E.;
ORCID
Lehr, R.; Adams, N. D.; Burgess, J. L.; Schmidt, S. J.; Knight, S. D.;
et al. Discovery of a Potent Class of PI3Kα Inhibitors with Unique
Binding Mode via Encoded Library Technology (ELT). ACS Med.
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Stuart L. Schreiber: 0000-0003-1922-7558
Author Contributions
C.J.G. and S.L.S. designed the research and wrote the
manuscript. C.J.G., Z.Y., and M.S. performed off-DNA
chemistry. C.J.G. performed all on-DNA chemistry, molecular
biology experiments, and data analysis. All authors have
contributed to editing the manuscript.
(10) Gilmartin, A. G.; Faitg, T. H.; Richter, M.; Groy, A.; Seefeld,
M. A.; Darcy, M. G.; Peng, X.; Federowicz, K.; Yang, J.; Zhang, S.-
Y.; et al. Allosteric Wip1 Phosphatase Inhibition through Flap-
Subdomain Interaction. Nat. Chem. Biol. 2014, 10, 181.
(11) Ahn, S.; Kahsai, A. W.; Pani, B.; Wang, Q. T.; Zhao, S.; Wall,
Notes
A. L.; Strachan, R. T.; Staus, D. P.; Wingler, L. M.; Sun, L. D.; et al.
Allosteric “Beta-Blocker” Isolated from a DNA-Encoded Small
Molecule Library. Proc. Natl. Acad. Sci. U. S. A. 2017, 114 (7),
The authors declare the following competing financial
interest(s): S.L.S. is a member of the Board of Directors of
the Genomics Institute of the Novartis Research Foundation
1
(
708−1713.
̌
12) Salamon, H.; Klika Skopic, M.; Jung, K.; Bugain, O.;
́
(
GNF); a shareholder and member of the Board of Directors
Brunschweiger, A. Chemical Biology Probes from Advanced DNA-
Encoded Libraries. ACS Chem. Biol. 2016, 11 (2), 296−307.
(13) Wang, J.; Lundberg, H.; Asai, S.; Martín-Acosta, P.; Chen, J.
S.; Brown, S.; Farrell, W.; Dushin, R. G.; O’Donnell, C. J.;
Ratnayake, A. S.; et al. Kinetically Guided Radical-Based Synthesis of
C(Sp 3)−C(Sp 3) Linkages on DNA. Proc. Natl. Acad. Sci. U. S. A.
of Jnana Therapeutics; a shareholder of Forma Therapeutics;
a shareholder of and adviser to Decibel Therapeutics and
Eikonizo Therapeutics; an adviser to Eisai, Inc., the Ono
Pharma Foundation, and F-Prime Capital Partners; and a
Novartis Faculty Scholar.
2
(
018, 115 (28), E6404−E6410.
14) Li, H.; Sun, Z.; Wu, W.; Wang, X.; Zhang, M.; Lu, X.; Zhong,
ACKNOWLEDGMENTS
■
W.; Dai, D. Inverse-Electron-Demand Diels−Alder Reactions for the
We thank Liam Hudson, Jeremy Mason, and Matthias
Westphal (Novartis Postdoctoral Scholars), Shawn Nelson
Jr., Wenyu Wang, and Bruce Hua (Broad Institute) for
helpful discussions. We also thank Patrick O’Hearn (Broad),
Jennifer Poirier (Novartis), Philip Michaels (Novartis), and
John Capece (Novartis) for analytical support. Bennett Meier
Synthesis of Pyridazines on DNA. Org. Lett. 2018, 20 (22), 7186−
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(
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15) Wang, X.; Sun, H.; Liu, J.; Dai, D.; Zhang, M.; Zhou, H.;
Zhong, W.; Lu, X. Ruthenium-Promoted C−H Activation Reactions
between DNA-Conjugated Acrylamide and Aromatic Acids. Org.
Lett. 2018, 20 (16), 4764−4768.
(
Broad) provided critical feedback on the manuscript. This
(16) Ruff, Y.; Berst, F. Efficient Copper-Catalyzed Amination of
DNA-Conjugated Aryl Iodides under Mild Aqueous Conditions.
MedChemComm 2018, 9 (7), 1188−1193.
work was supported by NIH R01GM038627 and
R35GM127045 (to S.L.S.) and the Novartis Institutes for
BioMedical Research. C.J.G. is supported by a National
Science Foundation Graduate Research Fellowship
(17) Franzini, R. M.; Randolph, C. Chemical Space of DNA-
Encoded Libraries. J. Med. Chem. 2016, 59 (14), 6629−6644.
(18) Satz, A. L.; Cai, J.; Chen, Y.; Goodnow, R.; Gruber, F.;
(
DGE1144152). S.L.S. is a member of the Novartis Faculty
Kowalczyk, A.; Petersen, A.; Naderi-Oboodi, G.; Orzechowski, L.;
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to DNA Encoded Libraries. Bioconjugate Chem. 2015, 26 (8), 1623−
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