Synthesis of C3-Alkylated Indoles on DNA via Indolyl Alcohol Formation Followed by Metal-Free Transfer Hydrogenation

Article abstract of DOI:10.1021/acs.orglett.9b02132

3-Alkylated indole cores have been found in countless natural products and many biologically active compounds, including pharmaceuticals. In this report, a highly efficient approach to C3-alkylated indole derivatives on DNA via indolyl alcohol formation f

Full text of DOI:10.1021/acs.orglett.9b02132

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Synthesis of C3-Alkylated Indoles on DNA via Indolyl Alcohol
Formation Followed by Metal-Free Transfer Hydrogenation
Pinwen Cai, Guanyu Yang, Lanzhou Zhao, Jinqiao Wan, Jin Li, and Guansai Liu*
Discovery Chemistry Unit, HitGen Inc., Building 6, No. 8 Huigu 1st East Road, Tianfu International Bio-Town, Shuangliu District,
Chengdu 610200, Sichuan, P. R. China
*
S Supporting Information
ABSTRACT: 3-Alkylated indole cores have been found in countless natural products and many biologically active compounds,
including pharmaceuticals. In this report, a highly efficient approach to C3-alkylated indole derivatives on DNA via indolyl
alcohol formation followed by metal-free transfer hydrogenation is developed. This on-DNA C3 alkylation approach is attractive
because library compounds can be constructed from simple aldehydes or acid functionalized aldehydes, which are
widely commercially available.
NA-encoded chemical libraries (DECL) have increasingly
D
become one of the most powerful hit generation
1
methods in early drug discovery. The technology combines
the powers of molecular biology, combinatorial chemistry,
high-throughput sequencing and advanced informatics, provid-
ing access of broad chemical diversity through affinity
selection. A number of novel small molecule ligands have
been generated from DECL selection toward a diverse set of
2
3
4
5
therapeutic targets, such as RIPK1, IDE, Wip1, PAD-4,
6
7
8
9
10
11
TNKS1, TNF-α, BTK, PAR2, DDR1, p38MAPK,
1
2
β2AR, etc.
While the results from DEL selection have been impressive,
substantial challenges to fully realize the potential of this
technology remain. One of the most fundamental challenges is
the development of new DNA compatible chemistry or
utilization of known DNA compatible chemistry to construct
leadlike structures. The needs of diverse and leadlike
structures continually drive the efforts in the development of
new DNA compatible reactions.
Figure 1. Pharmaceuticals containing C3-alkylated indoles.
structures in DECL. To this end, we report a new strategy for
the synthesis of C3-alkylated indole derivatives on DNA.
Building blocks underlie the chemical foundation of library
diversity. The chemical diversity of one DECL strongly
depends on the availability of building blocks suitable for
DNA compatible reactions. We hypothesized that C3-alkylated
indoles can be assembled in two steps starting from simple
1
3
The chemical space of bioactive compounds and natural
products contains a large variety of heterocyclic structures.
Indole is one of the most significant structural components of
pharmaceuticals. Statistically, C3 of indole is the most
substituted position in indole-containing drugs; 88% indole-
containing drugs were reported to be substituted at the C3
1
6
indoles and aldehydes (Figure 2), which are widely
commercially available and diverse. We proposed that C3-
alkylated indoles can be constructed from either DNA-
appended indoles or DNA-appended aldehydes through
indolyl alcohol formation followed by Hantzsch ester hydro-
genation. This “two tagging points” approach may facilitate
1
4
position. Many of them are C3-alkylated indoles (Figure 1).
Although many methods have been developed for functional-
15
ization of indoles in small molecule synthesis, no such
methods have been reported to construct such important
Received: June 20, 2019
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02132
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 2. Optimization of the Conditions of the Hantzsch
Ester Hydrogenation
a
b
entry
1
2
buffer (mM)
3
(%)
18
c
c
phosphate buffer (200)
phosphate buffer (200)
acetate buffer (2400)
d
90
90
Figure 2. Strategy for the synthesis of C3-alkylated indole. (A) DNA
was appended on the indole ring. (B) DNA was appended on
aldehydes.
e
3
a
All reactions were carried out with 3 (20 nmol) in THF/H O (1/4,
0 μL). The final DNA concentration was 0.4 mM. Concentrations
2
5
listed in the table were final concentrations in reaction mixtures.
target−binder interactions by partially avoiding steric
b
c
Conversion determined by LC-MS. Starting buffer stock: pH 5.5
17
hindrances caused by oligonucleotide tags.
d
phosphate buffer (250 mM). 3 was purified with additional spin
We first investigated the formation of indolyl alcohol from
DNA-linked indole and benzaldehyde. Use of phosphate buffer
or borate buffer alone resulted in negligible formation of
desired product 3 (Table 1, entries 1 and 2). Use of borate
e
filtration. Starting buffer stock: pH 4.8 acetate buffer (3 M).
precipitation. In this case, use of this phosphate buffer alone
produced desired products 4 in only 18% conversion yield
(
Table 2, entry 1), with large amounts of starting material left.
Table 1. Optimization of the Conditions of Indolyl Alcohol
Formation
If the sample of conjugate 3 was purified by spin filtration
using Millipore Amicon Ultra-15 Centrifugal Filter Units, the
pH of the reaction solution was kept at 5.5−6 and the
conversion can reach 96% (Table 2, entry 2). Then, we
realized that it would be time-consuming and cost inefficient to
purify thousands of samples by spin filtration in DEL building
block validation and planned to keep acidic conditions by
using highly concentrated sodium acetate buffer to overwhelm
the pH effects of salt residues from the last step. Finally,
conjugate 4 was obtained in an excellent yield when purified 3
was treated with Hantzsch ester in acetate buffer (Table 2,
entry 3).
a
,
bc
entry
2 (mM)
buffer (mM)
base (mM)
3
(%)
d
1
2
3
4
5
6
67
67
67
67
200
200
phosphate (83)
−
−
3
e
borate (83)
borate (83)
borate (83)
borate (83)
10
33
78
91
91
e
K CO (67)
2
3
e
NaOH (67)
NaOH (200)
NaOH (133)
e
−
With the established conditions in hand, we investigated C3
alkylations of indoles with a wide range of aldehydes and
indoles (Scheme 1). The standard conditions were found to be
tolerant of many different functional groups on benzaldehydes,
and various heterocyclic aldehydes, giving medium to excellent
yields over two steps (Scheme 1, 7a−7o). Aliphatic aldehydes,
a
All reactions were carried out with 1 (20 nmol) in DMSO/H O (1/
2
2
, 60 μL). The final DNA concentration was 0.33 mM.
Concentrations listed in the table were the final concentrations in
reaction mixtures. Conversion determined by LC-MS. Parts of the
target products were dehydrated in LC-MS (TM-18). which were also
calculated into desired products. Starting buffer stock: pH 5.5
phosphate buffer (250 mM). Starting buffer stock: pH 9.4 borate
b
c
d
especially with a secondary carbon (CH ) adjacent to
e
2
aldehydes, gave very low yields (some examples shown in
the Supporting Information). However, some cyclic aliphatic
aldehydes afforded desired products with moderate to good
yields (Scheme 1, 7p and 7q). The main reason for the low
transformations of aliphatic aldehydes was relatively low
conversions in the step of indolyl alcohol formation possibly
due to low stabilities of aliphatic aldehydes under strong basic
conditions. Notably, a carboxylic acid group was also tolerable
in this transformation (Scheme 1, 7r and 7s), although 400
mM instead of 200 mM starting sodium hydroxide was used to
overwhelm acidic effects of small molecules. This provided an
optional way for DECL design by introducing another variants
such as amines via amide formation. We also applied the
optimal conditions to different DNA-linked indoles (Scheme 1,
7t−7z). Most of them gave excellent conversions except
conjugate 7v, in which the DNA tagging point was adjacent to
the reaction site.
buffer (250 mM).
buffer with addition of inorganic base K CO provided 3 in a
2
3
medium conversion (Table 1, entry 3). Encouraged by the
results, we began increasing the pH by adding NaOH (Table 1,
entries 4 and 5), which revealed a clear trend toward enhanced
conversion under increasingly basic conditions; 91% con-
version can be finally achieved using a combination of borate
buffer and NaOH (Table 1, entry 5). Under this circumstance,
the pH of the solution was tested at 12.8, which had already
overwhelmed the buffer capacity of the borate buffer.
Ultimately, use of NaOH solely instead of a combination of
borate buffer and NaOH by keeping the pH around 12.8
cleanly provided 3 in 91% conversion (Table 1, entry 6).
We next set out to optimize the reaction condition for the
Hantzsch ester hydrogenation (Table 2). During chemistry
optimization, we realized that the slightly acidic condition was
critical for this transformation. Conjugate 3, which was
obtained by one ethanol precipitation in the step of indolyl
alcohol formation, was dissolved in pH 5.5 phosphate buffer,
but unexpectedly, the pH of the solution was tested as 7−8,
possibly due to salt residues in the last step after one ethanol
Having demonstrated the wide substrate scope study of C3
alkylation with DNA-linked indoles, we next turned to test
reactions between DNA-linked aldehydes and indoles as
building blocks (Table 3). It is unexpected that only 11%
desired product 10 was obtained with the condition of borate
buffer and sodium hydroxide at 60 °C. Instead, bis-addition
B
DOI: 10.1021/acs.orglett.9b02132
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Substrate Scope of Indolyl Alcohol Formation
and Hantzsch Ester Hydrogenation
Table 3. Optimization of the Conditions of Indolyl Alcohol
Formation
b
9
temp
(°C)
10 (10a)
a
entry
(mM) buffer (mM) base (mM)
(%)
c
1
2
3
4
200
200
133
133
borate (83) NaOH (200)
60
25
25
25
11 (89)
96 (3.6)
99 (0)
c
borate (83) NaOH (200)
c
borate (83) NaOH (133)
−
NaOH (133)
99 (0)
a
All reactions were carried out with 8 (20 nmol) in DMSO/H O (1/
2
2
, 60 μL). The final DNA concentration was 0.33 mM.
Concentrations listed in the table were final concentrations in
reaction mixtures. Conversion determined by LC-MS. Starting
b
c
buffer stock: pH 9.4 borate buffer (250 mM).
compound 10a was observed as a major byproduct. We
decreased the reaction temperature and the amounts of indole
and bases. Quantitative desired product 10 was obtained as
shown in entry 3. As discussed previously, NaOH solely was
finally used instead of a combination of borate buffer and
NaOH, giving the desired 10 in 99% conversion.
Several acid functionalized aldehydes that were appended on
DNA were screened under the above established condition
followed by Hantzsch ester hydrogenation. Both aromatic and
aliphatic aldehydes were shown to be tolerant and gave
acceptable conversions over two steps (Scheme 2).
Scheme 2. Substrate Scope of Indolyl Alcohol Formation
a
and Hantzsch Ester Hydrogenation
a
Condition of step 1: 40 μL of DNA (200 mM sodium hydroxide
solution, pH 12.8, 20 nmol), 20 μL of indole (400 mM in DMSO), rt,
4
h, 1:2 DMSO/H O. Condition of step 2: 40 μL of DNA (3 M
2
acetate buffer, pH 4.8, 20 nmol), 10 μL of Hantzsch ester (100 mM in
THF), rt, 12 h, 1:4 THF/H O.
2
a
Conditions of step 1: 40 μL of DNA (200 mM sodium hydroxide
To confirm positions of alkylation, two control experiments
with 3-methylindole as a starting material were carried out
under the optimal conditions (Scheme 3). No desired
alkylation product was obtained. The results indirectly
indicated that the alkylation happens at position 3 of indole,
not on DNA backbones or on other positions of indoles.
solution, pH 12.8, 20 nmol), 20 μL of aldehyde (600 mM in DMSO),
b
6
0 °C, 12 h, 1:2 DMSO/H O. Conditions of step 2: 40 μL of DNA
2
(
3 M acetate buffer, pH 4.8, 20 nmol), 10 μL of Hantzsch ester (100
c
mM in THF), rt, 12 h, 1:4 THF/H O. A 400 mM sodium hydroxide
2
solution instead of a 200 mM sodium hydroxide solution was used in
step 1.
C
DOI: 10.1021/acs.orglett.9b02132
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Control Experiments To Confirm Positions of
Scheme 6. Proposed DEL Structures and Estimated Size
Alkylation
that C3-alkylated indoles can be constructed from either DNA-
appended indoles or DNA-appended aldehydes through
indolyl alcohol formation followed by Hantzsch ester hydro-
genation. This on-DNA C3 alkylation approach is attractive
because library compounds can be constructed from simple
aldehydes or bifunctional acid aldehydes, which are widely
commercially available and diverse. This is an instructive
example of covering leadlike substituted core structures into
DNA-encoded chemical libraries to increase molecular
diversity. Continued efforts in chemistry development to
introduce more privileged structures in DECL will be reported
in due course.
The co-injection experiment by LC-MS and HPLC of 13a
from on-DNA synthesis of C3-alkylated indole and authentic
1
8
sample 18 from off-DNA synthesis followed by the
installation of DNA was carried out (Scheme 4). Two samples
Scheme 4. Off-DNA Synthesis of Authentic Sample 18
gave identical LC-MS and HPLC traces (see the detailed
information in the Supporting Information). This method
indirectly confirmed the characterization of desired on-DNA
product 13a.
To understand whether this newly developed methodology
is DEL compatible, C3 alkylaton of indoles on long DNA
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02132.
(
headpiece-primer-code 1) and its post-enzymatic ligation
Details of experimental procedures, copies of HPLC
traces, and MS and NMR spectra (PDF)
were evaluated (Scheme 5; see the detailed information in the
Scheme 5. C3 Alkylation of Indoles on Long DNA and Post-
Enzymatic Ligation
AUTHOR INFORMATION
Corresponding Author
■
*
E-mail: gs.liu@hitgen.com.
ORCID
Guansai Liu: 0000-0001-8925-6093
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors acknowledge Fang Jiao at HitGen Inc. for
assistance on HPLC purification of DNA samples and Zhao
Wang and Ping Li at HitGen Inc. for quantitative polymerase
chain reaction experiments. This work was funded internally by
HitGen Inc.
Supporting Information). Indolyl alcohol formation and
Hantzsch ester hydrogenation were evaluated against DNA
materials with indole or benzaldehyde that were linked to 33
bp double-stranded DNA. The chemical yields were found to
be consistent with yields on short DNA. No evidence of DNA
decomposition was detected by LC-MS or gel electrophoresis.
The product underwent efficient enzymatic ligation with a
DNA tag to produce 21 and 24. The quantitative polymerase
chain reaction experiment was also conducted, and no DNA
damage was observed (see the Supporting Information).
Under the newly developed conditions of on-DNA C3
alkylation of indoles, a DECL was proposed and the synthesis
is under way (Scheme 6). Introducing three cycles of diversity
brought the expected size to 30 million with commercially
available building blocks as shown in Scheme 6.
REFERENCES
■
(
(
1) For selected recent reviews on DNA encoded chemical libraries,
see: (a) Neri, D.; Lerner, R. A. Annu. Rev. Biochem. 2018, 87, 479.
b) Lerner, R. A.; Brenner, S. Angew. Chem., Int. Ed. 2017, 56, 1164.
(c) Arico-Muendel, C. C. MedChemComm 2016, 7, 1898. (d) Good-
now, R. A., Jr; Dumelin, C. E.; Keefe, A. D. Nat. Rev. Drug Discovery
2017, 16, 131. (e) Zimmermann, G.; Neri, D. Drug Discovery Today
016, 21, 1828. (f) Franzini, R. M.; Randolph, C. J. Med. Chem. 2016,
9, 6629. (g) Dickson, P.; Kodadek, T. Org. Biomol. Chem. 2019, 17,
676.
2
5
4
(
2) Harris, P. A.; King, B. W.; Bandyopadhyay, D.; Berger, S. B.;
Campobasso, N.; Capriotti, C. A.; Cox, J. A.; Dare, L.; Dong, X.;
Finger, J. N.; Grady, L. C.; Hoffman, S. J.; Jeong, J. U.; et al. J. Med.
Chem. 2016, 59, 2163.
(
3) Maianti, J. P.; McFedries, A.; Foda, Z. H.; Kleiner, R. E.; Du, X.
In summary, we report herein a highly efficient approach to
constructing C3-alkylated indoles on-DNA. We demonstrated
Q.; Leissring, M. A.; Tang, W. J.; Charron, M. J.; Seeliger, M. A.;
Saghatelian, A.; Liu, D. R. Nature 2014, 511, 94.
D
DOI: 10.1021/acs.orglett.9b02132
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(
4) Ding, Y.; O’Keefe, H.; DeLorey, J. L.; Israel, D. I.; Messer, J. A.;
Molander, G. A. J. Am. Chem. Soc. 2019, 141, 3723. (s) Flood, D. T.;
Asai, S.; Zhang, X. J.; Wang, J.; Yoon, L.; Adams, Z. C.; Dillingham, B.
C.; Sanchez, B. B.; Vantourout, J. C.; Flanagan, M. E.; Piotrowski, D.
W.; Richardson, P. F.; Green, S. A.; Shenvi, R. A.; Chen, J. S.; Baran,
P. S.; Dawson, P. E. J. Am. Chem. Soc. 2019, 141, 9998.
(14) Vitaku, E.; Smith, D. T.; Njardarson, J. T. J. Med. Chem. 2014,
57, 10257.
Chiu, C. H.; Skinner, S. R.; Matico, R. E.; Murray-Thompson, M. F.;
Li, F.; Clark, M. A.; Cuozzo, J. W.; Arico-Muendel, C.; Morgan, B. A.
ACS Med. Chem. Lett. 2015, 6, 888.
(
5) Lewis, H. D.; Liddle, J.; Coote, J. E.; Atkinson, S. J.; Barker, M.
D.; Bax, B. D.; Bicker, K. L.; Bingham, R. P.; Campbell, M.; Chen, Y.
H.; Chung, C.; Craggs, P. D.; Davis, R. P.; et al. Nat. Chem. Biol.
2
(
015, 11, 189.
6) Samain, F.; Ekblad, T.; Mikutis, G.; Zhong, N.; Zimmermann,
M.; Nauer, A.; Bajic, D.; Decurtins, W.; Scheuermann, J.; Brown, P. J.;
Hall, J.; Graslund, S.; Schuler, H.; Neri, D.; Franzini, R. M. J. Med.
Chem. 2015, 58, 5143.
7) Li, Y.; De Luca, R.; Cazzamalli, S.; Pretto, F.; Bajic, D.;
Scheuermann, J.; Neri, D. Nat. Chem. 2018, 10, 441.
8) Cuozzo, J. W.; Centrella, P. A.; Gikunju, D.; Habeshian, S.;
(15) For selected research papers on C3 functionalization of indoles,
́
́
see: (a) García-García, C.; Ortiz-Rojano, L.; Alvarez, S.; Alvarez, R.;
Ribagorda, M.; Carreno, M. C. Org. Lett. 2016, 18, 2224. (b) Li, B.;
̌
̈
̈
Zhang, B. B.; Zhang, X. Y.; Fan, X. S. Chem. Commun. 2017, 53, 1297.
(c) Chen, G.; Zhang, X.; Jia, R.; Li, B.; Fan, X. Adv. Synth. Catal.
2018, 360, 3781. (d) Wolfard, J.; Xu, J.; Zhang, H. M.; Chung, C. K.
Org. Lett. 2018, 20, 5431. (e) Pi, C.; Yin, X. H.; Cui, X. L.; Ma, Y. W.;
Wu, Y. Org. Lett. 2019, 21, 2081.
(
(
Hupp, C. D.; Keefe, A. D.; Sigel, E. A.; Soutter, H. H.; Thomson, H.
A.; Zhang, Y.; Clark, M. A. ChemBioChem 2017, 18, 864.
(
M.; Cuozzo, J. W.; Dekker, N.; Dumelin, C. E.; Ferguson, A.; Fiez-
Vandal, C.; Geschwindner, S.; et al. SLAS Discovery 2018, 23, 429.
(
(16) Chen, C.; Feng, H. X.; Li, Z. L.; Cai, P. W.; Liu, Y. K.; Shan, L.
H.; Zhou, X. L. Tetrahedron Lett. 2014, 55, 3774.
(17) Ottl, J.; Leder, L.; Schaefer, J. V.; Dumelin, C. E. Molecules
2019, 24, 1629.
(18) Guo, Q. X.; Peng, Y. G.; Zhang, J. W.; Song, L.; Feng, Z.; Gong,
L. Z. Org. Lett. 2009, 11, 4620.
9) Brown, D. G.; Brown, G. A.; Centrella, P.; Certel, K.; Cooke, R.
10) Richter, H.; Satz, A. L.; Bedoucha, M.; Buettelmann, B.;
Petersen, A. C.; Harmeier, A.; Hermosilla, R.; Hochstrasser, R.;
Burger, D.; Gsell, B.; Gasser, R.; Huber, S.; Hug, M. N.; Kocer, B.;
Kuhn, B.; Ritter, M.; Rudolph, M. G.; Weibel, F.; Molina-David, J.;
Kim, J.-J.; Santos, J. V.; Stihle, M.; Georges, G. J.; Bonfil, R. D.;
Fridman, R.; Uhles, S.; Moll, S.; Faul, C.; Fornoni, A.; Prunotto, M.
ACS Chem. Biol. 2019, 14, 37.
(
11) Petersen, L. K.; Blakskjær, P.; Chaikuad, A.; Christensen, A. B.;
Dietvorst, J.; Holmkvist, J.; Knapp, S.; Korinek, M.; Larsen, L. K.;
Pedersen, A. E.; Rohm, S.; Sløk, F. A.; Hansen, N. J. V.
MedChemComm 2016, 7, 1332.
12) Ahn, S.; Kahsai, A. W.; Pani, B.; Wang, Q. T.; Zhao, S.; Wall, A.
̌
̈
(
L.; Strachan, R. T.; Staus, D. P.; Wingler, L. M.; Sun, L. D.; Sinnaeve,
J.; Choi, M.; Cho, T.; Xu, T. T.; Hansen, G. M.; et al. Proc. Natl. Acad.
Sci. U. S. A. 2017, 114, 1708.
(
13) For selected research papers on the development of DNA
compatible reactions, see: (a) Li, X.; Liu, D. R. Angew. Chem., Int. Ed.
004, 43, 4848. (b) Chouikhi, D.; Ciobanu, M.; Zambaldo, C.;
Duplan, V.; Barluenga, S.; Winssinger, N. Chem. - Eur. J. 2012, 18,
2698. (c) Franzini, R. M.; Samain, F.; Abd Elrahman, M.; Mikutis,
2
1
G.; Nauer, A.; Zimmermann, M.; Scheuermann, J.; Hall, J.; Neri, D.
Bioconjugate Chem. 2014, 25, 1453. (d) Ding, Y.; Clark, M. A. ACS
Comb. Sci. 2015, 17, 1. (e) MacConnell, A. B.; McEnaney, P. J.;
Cavett, V. J.; Paegel, B. M. ACS Comb. Sci. 2015, 17, 518. (f) Satz, A.
L.; Cai, J.; Chen, Y.; Goodnow, R.; Gruber, F.; Kowalczyk, A.;
Petersen, A.; Naderi-Oboodi, G.; Orzechowski, L.; Strebel, Q.
Bioconjugate Chem. 2015, 26, 1623. (g) Li, Y.; Gabriele, E.; Samain,
F.; Favalli, N.; Sladojevich, F.; Scheuermann, J.; Neri, D. ACS Comb.
Sci. 2016, 18, 438. (h) Ding, Y.; Franklin, G. J.; DeLorey, J. L.;
Centrella, P. A.; Mataruse, S.; Clark, M. A.; Skinner, S. R.;
Belyanskaya, S. ACS Comb. Sci. 2016, 18, 625. (i) Fan, L.; Davie,
C. P. ChemBioChem 2017, 18, 843. (j) Thomas, B.; Lu, X.;
Birmingham, W. R.; Huang, K.; Both, P.; Reyes Martinez, J. E.;
Young, R. J.; Davie, C. P.; Flitsch, S. L. ChemBioChem 2017, 18, 858.
(
k) 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.; Richardson, P.; Liu, Z. Q.; Qin, T.; Blackmond, D. G.; Baran, P. S.
Proc. Natl. Acad. Sci. U. S. A. 2018, 115, E6404. (l) Wang, X.; Sun, H.;
Liu, J.; Dai, D.; Zhang, M.; Zhou, H.; Zhong, W.; Lu, X. Org. Lett.
2
018, 20, 4764. (m) Lu, X.; Roberts, S. E.; Franklin, G. J.; Davie, C. P.
MedChemComm 2017, 8, 1614. (n) Lu, X.; Fan, L.; Phelps, C. B.;
Davie, C. P.; Donahue, C. P. Bioconjugate Chem. 2017, 28, 1625.
(
o) Satz, A. L.; Cai, J.; Chen, Y.; Goodnow, R.; Gruber, F.;
Kowalczyk, A.; Petersen, A.; Naderi-Oboodi, G.; Orzechowski, L.;
Strebel, Q. Bioconjugate Chem. 2015, 26, 1623. (p) Kolmel, D. K.;
Loach, R. P.; Knauber, T.; Flanagan, M. E. ChemMedChem 2018, 13,
132. (q) Du, H.-C.; Simmons, N.; Faver, J. C.; Yu, Z.; Palaniappan,
̈
2
M.; Riehle, K.; Matzuk, M. M. Org. Lett. 2019, 21, 2194. (r) Phelan, J.
P.; Lang, S. B.; Sim, J.; Berritt, S.; Peat, A. J.; Billings, K.; Fan, L. J.;
E
DOI: 10.1021/acs.orglett.9b02132
Org. Lett. XXXX, XXX, XXX−XXX