Synthesis and Analysis of Natural-Product-Like Macrocycles by Tandem Oxidation/Oxa-Conjugate Addition Reactions

Article abstract of DOI:10.1002/chem.201900620

As traditional small-molecule drug discovery programs focus on a relatively narrow range of chemical space, most human proteins are viewed as unreachable targets. Consequently, there is a strong interest in expanding the chemical space in drug discovery b

Full text of DOI:10.1002/chem.201900620

A Journal of
Accepted Article
Title: Synthesis and Analysis of Natural Product-Like Macrocycles via
Tandem Oxidation/Oxa-Conjugate Addition Reactions
Authors: Jiyong Hong, Hyunji Lee, Kayla Sylvester, and Emily
Derbyshire
This manuscript has been accepted after peer review and appears as an
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To be cited as: Chem. Eur. J. 10.1002/chem.201900620
Link to VoR: http://dx.doi.org/10.1002/chem.201900620
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10.1002/chem.201900620
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COMMUNICATION
Synthesis and Analysis of Natural Product-Like Macrocycles via
Tandem Oxidation/Oxa-Conjugate Addition Reactions
Hyunji Lee,[a] Kayla Sylvester,[b] Emily R. Derbyshire[a, b] and Jiyong Hong*[a]
Abstract: Since traditional small-molecule drug discovery programs
focus on a relatively narrow range of chemical space, the majority of
human proteins are viewed as intractable. As a consequence, there
is strong interest in expanding the chemical space in drug discovery
beyond traditional small molecules. Here, we report a preparation of
a natural product-like macrocyclic library with chemical diversity by
exploiting the tandem allylic oxidation/oxa-conjugate addition and
macrocyclization reactions. Cheminformatic analyses demonstrate
that our tetrahydropyran-containing macrocyclic library shows a
significant overlap with natural products in chemical space. We
expect that our approach to the natural product-like tetrahydropyran-
containing macrocyclic library will be applicable in designing libraries
that may probe more deeply into natural product-like space.
containing macrocyclic library with chemical diversity that
overlaps with natural products. Herein, we describe the
preparation and cheminformatic analysis of a natural product-
like, THP-containing macrocyclic library.
As illustrated in Scheme 1, our strategy exploited the tandem
allylic oxidation/oxa-conjugate addition.[7] We envisioned that the
incorporation of various building blocks would rapidly increase
skeletal diversity by allowing the modification of ring sizes and
scaffolds, the utilization of different macrocylization methods
would incorporate various functionalities into macrocycles, and
finally the appendage diversification would further modulate
physicochemical properties of macrocycles.
Tetrahydropyran
Construction
Skeletal
Diversification
S
S
H
S
H
S
O
More than 80–85% of all human proteins has been often
regarded as 'undruggable'.[1] This is mainly due to the fact that a
majority of synthetic libraries in small molecule drug discovery
programs address a relatively narrow range of chemical space.[2]
H
R
+
via the tandem
oxidation/oxa-
conjugate addition
reaction
via incorporation of
amino acids, olefins,
acetylenes, and
CO2H
O
OH
H
R
OPMB
aromatic rings
OPMB
Appendage
Diversification
S
H
S
S
S
As
a consequence, there is great interest in navigating
Macrocyclization
underexplored chemical space and identifying small molecule
modulators for the large number of conventionally intractable
drug targets.[3]
- reduction
- macrolactonization
- CuAAC
- ring-closing metathesis
- enyne metathesis
- Sonogashira coupling
O
O
- HWE olefination
- methylenation
- acylation
O
H
O
H
H
O
H
X
H
O
R
NH
R
NH
R
NH
- glycosylation
- nucleophilic aromatic substitution
- pyridone synthesis
Y
In this regard, macrolides are an attractive class of natural
products since they often occupy distinct parts of the chemical
space posed between conventional drug-like molecules and
biologics. Therefore, the molecular diversity and complexity of
macrocyclic natural products have provided inspiration for
innovative chemical probe and drug design.[4] With the
recognition of the therapeutic potential of macrocyclic
compounds, there have been growing interests in generating
macrocyclic libraries by using various strategies.[5] Although
some progress in the macrocyclic library synthesis has been
made in recent years, a need still exists for effective strategies
that enable to generate natural product-like macrocycle scaffolds
with structural and stereochemical diversity.
Among macrocyclic natural products, tetrahydropyran (THP)-
containing macrocycles are an interesting class of natural
products with a wide range of biological activities (Supporting
Information Figure S1).[6] Intrigued by the great potential of THP-
containing macrocycles in the development of chemical probes
and therapeutics, we embarked on the construction of a THP-
Scheme 1. Outline of our approach to the construction of a THP-containing
natural product-like macrocyclic library.
The construction of the THP-containing macrocyclic library
started with the preparation of the allylic alcohols (3a and 3b) for
the tandem allylic oxidation/oxa-conjugate addition reaction
(Scheme 2). Chiral epoxides (2a and 2b)[8] were coupled to the
known 1,3-dithiane 1[7a] to afford 3a and 3b.[7] The one-pot allylic
oxidation/oxa-conjugate addition/oxidation[7] of 3a and 3b in the
presence of MnO2 and dimethyltriazolium iodide provided the
desired 2,6-cis-THP methyl esters (5a and 5b) in a single step
with excellent stereoselectivity (d.r.>20:1). Upon basic hydrolysis
of 5a and 5b, the resulting 2,6-cis-THP carboxylic acids (6a and
6b) were coupled to various amino acids, dipeptides, or amines
to afford a set of macrolactonization substrates (8a–f and 10a,b).
To incorporate unsaturation and further increase the ring size,
the resulting aldehyde 4 from the oxa-conjugate addition step
was treated with (carbethoxymethylene)triphenylphosphorane to
afford the (E)-a,b-unsaturated ester 5c. Then, basic hydrolysis
of 5c followed by coupling of the resulting carboxylic acid 6c to
an amine provided the hydroxy ester 12.
[a]
[b]
H. Lee, Prof. Dr. E. R. Derbyshire, Prof. Dr. J. Hong
Department of Chemistry, Duke University
Durham, NC 27708 (USA)
E-mail: jiyong.hong@duke.edu
K. Sylvester, Prof. Dr. E. R. Derbyshire
Department of Molecular Genetics and Microbiology, Duke
University Medical Center
Durham, NC 27710 (USA)
Supporting information for this article is given via a link at the end of
the document.
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10.1002/chem.201900620
Chemistry - A European Journal
COMMUNICATION
21b followed by azide installation completed the preparation of
22a and 22b. Other alkyne azide 24 was prepared from 8c in a
similar manner.
S
H
S
S
S
S
H
S
S
H
S
ii)
i)
i)
O
O
H
OH
O
H
OH
H
H
O
OH
O
4
3a (67%)
1
3b (53%)
OPMB
PMBO
TBS
OPMB
(R1 = –CH2CH2CH2–)
vii) (84% for 2 steps)
ii), iii)
ii), iii)
R1S
SR1
R1S
SR1
H
R1S
SR1
R1S
SR1
O
O
S
H
S
O
S
H
S
S
S
O
H
O
H
O
H
R1
O
O
O
O
NH
H
O
H
H
HN
O
H
O
H
O
N3
OPMB
CO2R2
CO2R2
O
Ph
HN
O
HN
O
O
Ph
O
O
H
PMBO
H
H
H
Ph
O
Ph
O
2a, R1 = H
2b, R1 = OTBS
O
I
14a
O
O
13
14b
14c
CO2R2
OPMB
OPMB
PMBO
TBS
5c, R2 = Me
5a, R2 = Me
5b, R2 = Me
i)
ii), iii)
i)
ii), iii)
i)
ii), iv), v)
viii)
iv)
iv)
6c, R2 = H (80%)
6a, R2 = H (88% for 3 steps)
6b, R2 = H (68% for 3 steps)
6a
ii), vi)
SR1
i)
v)
S
v)
v)
R1S
SR1
R1S
H
SR1
R1S
H
SR1
R1S
H
S
H
S
S
H
S
H
S
H
O
O
H
O
H
O
O
O
H
O
H
N
OPMB
H
O
O
OPMB
Ph
O
HN
O
O
H
OPMB
H
O
R3
NH
R3
O
CO2H
H
O
R3
F
O
O
O
OR4
21a, R3 = H
21b, R3 = CH2OBn
R3
O
11, R4 = PMB
12, R4 = H
OR4
vi)
PMBO
TBS
9a,b
O
Ph
O2N
7a–f, R4 = PMB
8a–f, R4 = H
15
17
19
vi)
ii), iv), v)
SR1
i)
ii), iii), vii)
ii), viii), ix), x)
SR1
R1S
H
SR1
R1S
SR1
R1S
R1S
(R5 = –CH2CH2CH2–)
R5S
H
SR5
R3
=
R5S
SR5
R5S
SR5
HN
MeO2C
O
O
O
H
O
H
O
H
F
H
O
H
N
H
H
O
H
O
O
O
Ph
O
O
N3
O
O
R2
H
O
O
NH
HN
O
H
H
H
H
O
O
O
NH
R3
HN
O
HN
O
HN
MeO2C
HO
16a–c
PivOHN
O
Ph
O
MeO2C
HO
HO
Ph
Ph
O2N
MeO2C
R5S
MeO2C
R5S
8a
8b
8c
22a, R3 = H
22b, R3 = CH2OBn
OH
18
20
SR5
SR5
R5S
SR5
HN
R2
=
N
H
16a
R1S
H
SR1
R1S
H
SR1
MeO2C
O
O
O
O
O
O
H
H
H
H
H
H
H
N
N
H
OH
MeO2C
OH
Ph MeO2C
OH
OBn MeO2C
8f
HN
O
HN
O
O
ix), xi)
O
iv), v)
O
O
H
N
H
N
8c
H
H
HN
N
16b
16c
Ph
OH
N3
H
N
HN
O
HN
O
MeO2C
Ph
8d
8e
O
O
O
O
N
H
O
R5S
SR5
R5S
SR5
23
24
O
O
O
R5S
H
SR5
HN
H
N
O
MeO2C
MeO2C
OBn
O
H
O
H
O
H
O
H
H
Scheme 3. Preparation of linear precursors to macrocycles. Reagents and
conditions: i) amine linkers, HATU, i-Pr2NEt, CH2Cl2, 25 °C; ii) DDQ,
CH2Cl2/H2O (10/1), 25 °C; (iii) DCC, DMAP, CH2Cl2, 25 °C; iv) p-TsCl, Et3N,
DMAP, CH2Cl2, 25 °C; (v) NaN3, DMF, 50 °C; vi) allyl bromide, NaH, THF, 0 to
25 °C; vii) TBAF, THF, –20 °C; viii) ethyl 2-bromomethylacrylate, NaH, THF, 0
to 25 °C; ix) 1 N LiOH, THF/H2O (2/1), 25 °C; x) PivO–NH2·TfOH, EDC·HCl,
pyridine, CH2Cl2, 25 °C; xi) propargyl bromide, K2CO3, DMF, 25 °C.
HN
O
O
HN
O
R4O
TBS
R4O
CO2R6
TBS
CO2R6
OH
MeO2C
12
N
HN
O
O
H
N
H
N
Ph
9a, R4 = PMB
R6 = Me
10a, R4 = R6 = H
9b, R4 = PMB
R6 = Me
10b, R4 = R6 = H
O
iv), vi)
iv), vi)
Scheme 2. Preparation of THPs via the tandem allylic oxidation/oxa-conjugate
addition reaction. Reagents and conditions: i) 2a or 2b, t-BuLi, THF/HMPA
(10/1), –78 °C, 1 h; ii) MnO2, CH2Cl2, 25 °C, 18–24 h; iii) dimethyltriazolium
iodide, MnO2, DBU, MeOH, CH2Cl2, 4Å MS, 25 °C, 24 h; iv) 1 N LiOH,
THF/H2O (2/1), 25 °C, 17–24 h; v) amine linkers, HATU, i-Pr2NEt, CH2Cl2,
With macrocyclization substrates in hand, we set out to
explore the macrocyclization step in order to prepare macrocycle
skeletons with various functional groups (Scheme 4). First,
hydrolysis of the ester 8d followed by macrolactonization of the
resulting hydroxy carboxylic acid in the presence of 2-methyl-6-
nitrobenzoic anhydride[9] smoothly proceeded to give the desired
macrolactone 25 in 89% for 2 steps (Scheme 4a).[10] In a similar
manner, the macrolactonization substrates (8a–f, 12, and 10a,b)
smoothly underwent the Shiina macrolactonization (see the
Supporting Information for details). The Cu(I)-catalyzed
azide/alkyne cycloaddition reaction[11] of 14c provided the
triazole 26 (Scheme 4b).[12] Other alkyne azides (22a,b and 24)
also gave the desired triazoles in good yields (see the
Supporting Information for details). The ring-closing metathesis
of 16c and 14a gave the desired macrocyclic products 27 and
28, respectively (Scheme 4c and 4d). The alkynyl macrocycle 29
was prepared by the intramolecular Sonogashira coupling
reaction of the iodo alkyne 14b (Scheme 4e). The intramolecular
nucleophilic aromatic substitution of the 4-fluoro-3-nitroarene 19
25 °C, 18–24 h; vi) DDQ, CH2Cl2/H2O (10/1), 25 °C,
1 h; vii)
(carbethoxymethylene)triphenylphosphorane, CH2Cl2, 25 °C, 15 h; viii) 1 N
LiOH, THF/MeOH/H2O (2/1/1), 40 °C, 1 h.
In order to introduce a variety of functional groups to the
macrocycle skeletons, we envisioned to use a series of
macrocyclization reactions. Towards this objective, we prepared
the macrocyclization substrates (14a–c, 16a–c, 18, 20, 22a, 22b,
and 24) as shown in Scheme 3. The carboxylic acid 6a was
coupled to the propynyl L-phenylalaninate to give the propynyl
ester 13. After PMB deprotection, the resulting alcohol was
converted to the butenoate, 3-iodobenzoate, and azide (14a–c).
PMB deprotection of 6a, allylation, and coupling to terminal
alkenes gave the dienes (16a–c) in 95–99% yields. The
common intermediate 6a was further converted to 18 and 20
following standard procedures. PMB deprotection of 21a and
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10.1002/chem.201900620
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afforded the biaryl ether 30 in 81% yield (Scheme 4f). When we
attempted the Rh(III)-catalyzed C−H activation/heterocyclization
of w-alkynyl a-substituted acrylic hydroxamate,[13] we observed
the formation of the two isomeric pyridones 31a and 31b
physical properties, chemical reactivity, and biological activity of
the parent compounds.[15] To further expand the diversity of the
macrocyclic library, we carried out acylations and glycosylations
of 33b to give 34a–e (Scheme 5).
(Scheme 4g).[14] As illustrated above,
a diverse set of
macrocyclization reactions was successfully used to introduce
various functionalities to the macrocycle skeletons.
O
S
H
S
H
i)
O
O
H
H
(a) Macrolactonization
O
HN
O
O
HN
O
H
N
H
N
(R = –CH2CH2CH2–)
RS
SR
RS
H
SR
H
Ph
Ph
O
O
1. 1 N LiOH
THF/H2O, 25 ℃, 1 h
O
O
25
32 (85%)
O
O
H
H
2. MNBA, DMAP
CH2Cl2 (1 mM), 25 ℃, 24 h
89% for 2 steps
OH
ii)
iii)
iv)
CO2Me
HN
O
O
HN
O
H
N
H
N
MeO2C
Ph
Ph
OH
CH2
O
8d
25
O
O
(b) Cu-catalyzed Azide/Alkyne Cycloaddition
O
O
O
H
H
H
H
H
H
RS
SR
RS
SR
O
HN
O
O
O
HN
O
HN
O
H
N
H
N
H
N
CuI, i-Pr2NEt
THF (1 mM)
Ph
Ph
33c (77%)
O
Ph
O
O
O
O
H
O
H
H
O
H
33a (24%,
35% brsm)
33b (97%)
O
reflux, 24 h
61%
O
N3
N
HN
O
HN
O
N
Ph
Ph
N
v) or vi)
R =
O
OAc
14c
26
O
O
AcO
AcO
OAc
OAc
(c) Ring-closing Metathesis
OR
RS
SR
34a (55%)
34b (41%)
RS
H
SR
H
O
O
O
O
O
O
Grubbs II
CH2Cl2 (1 mM)
34d (29%)
OAc
O
O
NH
O
NH
H
H
H
H
reflux, 19 h
87%
OAc
O
Ph
16c
O
Ph
O
HN
O
H
N
OAc
34e (13%)
O
O
Ph
O
11
O
27
O
34c (62%)
O
34a–e
(d) Enyne Metathesis
RS
SR
H
RS
SR
O
O
O
Grubbs II, ethylene
CH2Cl2 (1 mM)
Scheme 5. Appendage diversification by acylation and glycosylation.
Reagents and conditions: i) MeI, CaCO3, MeCN/H2O (3/1), reflux, 22 h; ii)
TMSCl, BrCH2CH2Br, Zn, CH2Br2, TiCl4, –40 to 25 °C, 4 h; iii) NaBH4, MeOH,
–40 °C, 1 h; iv) methyl diethylphosphonoacetate, THF, 0 to 25 °C, 1 h; v) (S)-
citronellic acid, sorbic acid, or palmitic acid, EDC·HCl, DMAP, DMF, 25 °C, 16
h; vi) b-D-glucose pentaacetate or a-D-mannose pentaacetate, BF3·OEt2,
CH2Cl2, reflux or 0 to 25 °C, 17–21 h.
O
NH
O
NH
H
H
H
reflux, 17 h
68%
O
Ph
O
O
O
Ph
O
O
O
14a
28
(e) Sonogashira Cross-coupling
RS
SR
H
RS
SR
Pd(PPh)4, Et2NH
MeCN (1 mM)
O
O
O
O
H
O
H
O
H
O
O
HN
O
HN
O
50 ℃, 19 h
58%
Ph
Ph
Upon completing the construction of the macrocyclic library,
we carried out cheminformatic analyses using principal
component analysis (PCA) and principal moment of inertia (PMI)
in order to assess the molecular diversity of our macrocyclic
library (THP-MC Library Set).[6b] In addition to our macrocyclic
library set, we compiled 50 top-selling small-molecule drugs
(Drug Set), 75 diverse natural products (Natural Product Set),
and 36 macrocyclic natural products (Macrocyclic NP Set) for
PCA and PMI analyses. We examined 20 structural and
physicochemical properties of 195 compounds (see the
Supporting Information for details). Examination of the
component loadings in PCA indicated that the main contributors
of the PC1 axis are molecular weight and number of oxygens
and hydrogen bonding acceptors, while the greatest contributors
of the PC2 axis are hydrophobicity and calculated aqueous
solubility. In PC1 vs. PC2 plot (Figure 1a), the members of our
macrocyclic library shift in a negative direction along the PC1
axis compared to the small-molecule drugs, covering a distinct
region of the chemical space and considerably overlapping with
macrocyclic natural product space. In plots PC1 vs. PC3 (Figure
1b) and PC3 vs. PC2 (Figure 1c), the macrocyclic library
members are positioned between drug space and macrocyclic
natural product space. Our PMI analysis showed that the
macrocyclic library possesses decreased rod-like character
O
O
14b
29
I
(f) Nucleophilic Aromatic Substitution
RS
SR
RS
SR
O
K2CO3
DMF (10 mM)
O
H
F
H
O
H
O
H
O
O
O
Ph
NH
O
O
Ph
NH
70 ℃, 2 h
81%
O
O
O
O
O2N
O2N
OH
19
30
(g) Pyridone Synthesis
RS
SR
RS
H
SR
H
RS
H
SR
[Cp*RhCl2]2 (10 mol%)
CsOAc (2 equiv)
O
O
H
H
O
O
O
H
O
+
MeOH (5 mM)
reflux, 30 min
54% (31a+31b)
O
HN
NH
O
O
NH
Ph
O
Ph
O
Ph
O
HN
O
O
N
H
PivOHN
O
20
31a
31b
Scheme 4. Examples of the reactions used in the macrocyclization step.
After the macrocyclization, we further diversified the
macrocycles by using 1,3-dithiane as a latent functional group
for a carbonyl, hydroxy, or olefinic group (Scheme 5). Upon 1,3-
dithiane deprotection of 25, the corresponding ketone 32 was
successfully transformed to 33a–c. Glycosylated or acylated
macrolides are abundant in natural products since glycosylation
and acylation modifications have significant effects on the
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10.1002/chem.201900620
Chemistry - A European Journal
COMMUNICATION
compared to the drug set, while extending more into sphere-like
space and overlapping with natural products (Figure 1d).
We are grateful to Dr. Amanda Hargrove and Zhengguo Cai for
assistance with PMI analysis and to Duke University for funding
this work. NMR spectra were acquired at Duke University NMR
Spectroscopy Center funded by NSF, NIH, NC Biotechnology
Center, and Duke University.
8.0
5.0
a
Drug Set
b
Natural Product Set
Macrocyclic NP Set
THP-MC Library Set
4.0
3.0
6.0
4.0
2.0
2.0
1.0
Conflict of interest
0.0
0.0
-1.0
-2.0
-3.0
-4.0
-5.0
-2.0
-4.0
-6.0
-8.0
The authors declare no conflict of interest.
Keywords: chemical diversity • macrocycles • natural products •
tandem oxidation/oxa-conjugate addition • tetrahydropyrans
PC 1
PC 1
6.0
4.0
1.0
0.9
0.8
0.7
0.6
0.5
rod
sphere
c
d
[1]
T. I. Oprea, C. G. Bologa, S. Brunak, A. Campbell, G. N. Gan, A.
Gaulton, S. M. Gomez, R. Guha, A. Hersey, J. Holmes, et al., Nat. Rev.
Drug Discovery 2018, 17, 317–332.
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7735; d) S. Alihodžić, M. Bukvić, I. J. Elenkov, A. Hutinec, S. Koštrun, D.
Pešić, G. Saxty, L. Tomašković, D. Žiher, in Progress in Medicinal
Chemisry, Vol. 57 (Eds.: D. R. Witty, B. Cox), Elsevier, 2018, pp. 113–
233.
disk
-10.0
-12.0
I1/I3
PC 3
Figure 1. Principal component analysis (PCA) and principal moment of inertia
(PMI) plots. (a) PCA plot of PC1 vs. PC2; (b) PCA plot of PC1 vs. PC3; (c)
PCA plot of PC3 vs. PC2; (d) PMI plot illustrating the three-dimensional shape
diversity of the compound sets.
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To demonstrate the potential of the macrocyclic library for
chemical probe and therapeutic development, we tested the
anticancer activity of the macrocycles in Huh7 cells (see the
Supporting Information for details). Additional biological
evaluations of the macrocyclic library in long non-coding RNAs,
transcription factors, patient-derived xenograft tumors, and
fungal infection are in progress. The assay data will be reported
in due course.
In summary, we report a strategy for the generation of a
structurally diverse macrocyclic library based on our allylic
oxidation/oxa-conjugate addition method. Cheminformatic
analyses demonstrate that our THP-containing macrocyclic
library shows a significant overlap with natural products. Insights
gained from such analyses will be useful in designing future
libraries that may probe more deeply into natural product-like
space. Since there exist a number of readily available chiral
epoxides and functionalized 1,3-dithianes, we expect that our
approach can be expanded to a larger size of macrocycle library
with a high level of structural diversity. Moreover, it is possible to
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tools in developing chemical probes[16] to dissect important
biological processes as well as in targeting traditionally
challenging 'undruggable' drug targets.
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[10] The yield for the macrolatonization reaction was highly dependent on
the length, rigidity, and substituent pattern of w-hydroxy carboxylic
acids; see the Supporting Information for details.
[11] H. C. Kolb, M. G. Finn, K. B. Sharpless, Angew. Chem., Int. Ed. 2001,
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[12] The yield for the Cu(I)-catalyzed azide/alkyne cycloaddition reaction
was dependent on the length of azide akynes. We also observed the
Acknowledgements
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formation of head-to-tail dimeric triazoles; see the Supporting
Information for details.
[15] A. C. Weymouth-Wilson, Nat. Prod. Rep. 1997, 14, 99–110.
[16] S. L. Schreiber, J. D. Kotz, M. Li, J. Aubé, C. P. Austin, J. C. Reed, H.
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[14] The structures of the isomeric pyridines were determined by NMR
spectroscopic analysis; see the Supporting Information for details.
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Natural product-like macrocycles were
efficiently assembled via the tandem
allylic oxidation/oxa-conjugate addition
and macrocyclization reactions. The
macrocyclic library displayed a
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significant overlap with natural
products in chemical space.
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