Divergent Access to Histone Deacetylase Inhibitory Cyclopeptides via a Late-Stage Cyclopropane Ring Cleavage Strategy. Short Synthesis of Chlamydocin

Article abstract of DOI:10.1021/acs.orglett.9b03305

A unified step-economical strategy for accessing histone deacetylase inhibitory peptides is proposed, based on the late-stage installation of multiple zinc-binding functionalities via the cleavage of the strained cyclopropane ring in the common pluripoten

Full text of DOI:10.1021/acs.orglett.9b03305

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Divergent Access to Histone Deacetylase Inhibitory Cyclopeptides
via a Late-Stage Cyclopropane Ring Cleavage Strategy. Short
Synthesis of Chlamydocin
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Gabor Zoltan Elek, Kaur Koppel, Dzmitry M. Zubrytski, Nele Konrad, Ivar Jarving, Margus Lopp,
and Dzmitry G. Kananovich*,†
†Tallinn University of Technology, School of Science, Department of Chemistry and Biotechnology, Akadeemia tee 15, 12618
Tallinn, Estonia
‡Belarusian State University, Department of Organic Chemistry, Leningradskaya 14, 220050 Minsk, Belarus
S
* Supporting Information
ABSTRACT: A unified step-economical strategy for access-
ing histone deacetylase inhibitory peptides is proposed, based
on the late-stage installation of multiple zinc-binding
functionalities via the cleavage of the strained cyclopropane
ring in the common pluripotent cyclopropanol precursor. The
efficacy of the proposed diversity-oriented approach has been
validated by short stereoselective synthesis of natural product
chlamydocin, containing a challenging-to-install fragment of
(2S,9S)-2-amino-8-oxo-9,10-epoxydecanoic acid (Aoe) and a
range of its analogues, derivatives of 2-amino-8-oxodecanoic
and 2-aminosuberic acids.
has attracted a great deal of attention.6 It has been shown that
istone deacetylase (HDAC) enzymes serve as epigenetic
Hgene expression mediators via the regulation of the inhibitory potential and selectivity profile of the peptide
HDAC inhibitors can be further diversified by the modification
of ZBG or the amino acid sequence.1,6
deacetylation/acetylation of histone proteins within eukaryotic
cells.1 Dysfunction of HDAC enzymes is associated with
numerous severe physiological processes like cancer, neuro-
degeneration, and metabolic disorders,2 thus making them a
validated target for therapeutic intervention. Several naturally
occurring cyclopeptides with extremely high inhibitory activity
against zinc-dependent HDAC enzymes are known.3 Their
structural organization is archetypal and includes a cyclic cap
that is responsible for interaction with the peripheral binding
site of the enzyme, a hydrophobic spacer, and a zinc-binding
group (ZBG) to capture a zinc ion in the catalytic pocket
(Figure 1).1,3 The spacer with ZBG is approximately isosteric
with acetylated lysine, suggesting that it mimics an acetylated
histone protein.3 Several natural cyclopeptides [chlamydocin
(1),4a HC-toxin,4b trapoxins,4c WF-3161,4d etc.] contain the
epoxy ketone function as a zinc-binding motif in the side chain
of (2S,9S)-2-amino-8-oxo-9,10-epoxydecanoic acid (Aoe).
Zinc-binding ethyl ketone and carboxylate functions are
present in apicidines,4e in their 2-amino-8-oxodecanoic
(Aoda) and 2-aminosuberic acid (Asu) structural units,
respectively (Figure 1). The structural principles of such
peptides have been translated into HDAC inhibitory drugs
approved by the Food and Drug Administration for cancer
treatment (e.g., Vorinostat, Belinostat, and Romidepsin).5 Due
to the significance of HDAC inhibitors as therapeutic agents,
the clarification of the HDAC enzyme function and design of
more selective inhibitors, especially on the level of isoforms,
A number of methods have been reported for the synthesis
of Aoda7 and Asu8 building blocks, compatible with peptide
synthesis under the standard Boc/Fmoc/Cbz protocols. In
contrast, a vulnerable epoxide functionality, along with an
additional chiral center, requires advanced synthetic planning
for the Aoe-containing peptides. For example, the first total
synthesis of chlamydocin and trapoxin B was implemented by
Schmidt9 and later by Schreiber10 via multistep sequences from
(R,R)-tartaric acid-derived precursors. The Rich group utilized
epoxidation of the corresponding racemic allylic alcohol under
Sharpless conditions,11 while Baldwin exploited free radical
homologation of 2-amino-5-iodopentanoic acid.12 More
recently, the Kazmaier group reported the synthesis of several
Aoe-containing cyclopeptides via chelate enolate Claisen
rearrangement.13
Despite these creative contributions, synthesis of similar
targets via the distinct multistep protocols from the diverse
building blocks hampers access to the realm of HDAC
inhibitory peptides. Therefore, the development of a step-
economical and general synthetic strategy is highly desired for
the preparation of the corresponding molecular libraries.1,6
Due to the interest of our group in cyclopropanol chemistry,
Received: September 18, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03305
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
of the cyclopropane and the presence of an electron-donating
hydroxyl group facilitate ring opening with a range of
electrophilic and radical species.15 These reactions typically
occur under mild conditions well tolerated by other
functionalities, which makes the cyclopropanol motif suitable
for late-stage cleavage. Herein, we demonstrate for the first
time the utilization of the cyclopropanol unit as an efficient
pluripotent group for diversity-oriented synthesis, which is
validated by a concise divergent synthesis of natural product
chlamydocin 1 (Figure 1), and a set of its known analogues1,6
with histone deacetylase inhibitory activity.
Implementation of our approach requires a single universal
building block, 2-amino-7-(1-hydroxycyclopropyl)heptanoic
acid (Acyha). A carbon skeleton of the latter was assembled
by cross-metathesis of two readily available alkene partners,
protected (S)-allyl glycine 4 and alkene 6 with a masked
cyclopropanol functionality (Scheme 1).
Both 4 and 6 can be accessed from commercial starting
materials via a short high-yield reaction sequence. The N-
terminus of (S)-allyl glycine (3) was masked with a range of
protective groups (Boc, Cbz, and Fmoc) followed by the
esterification of the C-terminus to provide amino acid coupling
partners 4a−c. TBS-protected cyclopropanol 6 was easily
prepared in multigram quantities in three steps and 90%
overall yield from ethyl 5-bromovalerate (5) via the
consequent Kulinkovich cyclopropanation, silylation, and
HBr elimination steps.
Figure 1. Examples of natural HDAC inhibitors with different zinc-
binding groups (ZBGs) in the side chain.
Because the metathesis of alkene partners 4 and 6 is of type
I,17 its statistical nature and the fast inactivation of the Grubb’s
catalyst afforded rather low yields of cross-coupling product 7a
in the initial runs. After optimization (see the Supporting
Information), we were able to increase the yield of target
product 7a to 75% by using only 1 mol % of the second
generation of the Hoveyda−Grubbs catalyst and a 5-fold excess
of readily available alkene 6. Under optimal conditions, cross-
coupled products 7a−c, decorated with orthogonal protecting
groups at the N- and C-termini, were smoothly prepared in
71−75% yields. The reduction of the double bond and
debenzylation of the C-terminus (for Fmoc analogue 7b) by
hydrogenation afforded protected Acyha derivatives 8a and 8b
in quantitative yields with an intact cyclopropane moiety. It
should be noted that the TBS-protected cyclopropanol unit
cannot tolerate strong acids, as was evidenced by the fast
transformation of 8a into the corresponding Aoda derivative 9a
under typical Boc removal conditions (TFA/CH2Cl2), even
prior to the removal of the Boc group itself (see the Supporting
Information).
we noticed that all the required zinc-binding motifs [ethyl
ketone, carboxylate, and even (S)-epoxy ketone] can be
straightforwardly generated from the same cyclopropanol
moiety, thus offering the required general approach (Figure
2). Cyclopropanols are easily available14 and versatile synthetic
intermediates,15 with continuously emerging new applications
in the synthesis of natural products.16 The internal ring strain
Considering the protecting group compatibility issues, Cbz-
carboxylic acid 10c was selected for the total synthesis of
chlamydocin (Scheme 2).
Extensive studies of the synthesis of chlamydocin9,11−13 and
its Aoda/Asu analogues6c−h led us to select this macrocycle as
the first target to validate our approach. The most efficient
strategy for the closure of its macrocyclic ring involved
macrolactamization at the C-terminus of D-proline.9b There-
fore, Aib-Phe-D-Pro-OMe tripeptide 11 was prepared from the
corresponding amino acids in 73% total yield over four steps
by using standard peptide coupling protocols (see the
Supporting Information).12,13c
Next, the TBTU-mediated peptide coupling of 11 with
Acyha derivative 10c afforded tetrapeptide 12 in 96% yield.
The hydrogenation of the double bond in the latter was
conveniently performed in flow mode with the simultaneous
Figure 2. Conventional and proposed strategies for accessing HDAC
inhibitory peptides.
B
DOI: 10.1021/acs.orglett.9b03305
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 1. Synthesis of Protected 2-Amino-7-(1-hydroxycyclopropyl)heptanoic Acid (Acyha) Derivatives
a
Reagents and conditions for 4a: (a) Boc2O, NaHCO3, MeOH, sonification; (b) K2CO3, MeI, acetone. Reagents and conditions for 4b: (a)
FmocOSu, K2CO3, dioxane/H2O; (b) BnBr, NaHCO3, DMF. Reagents and conditions for 4c: (a) CbzCl, NaHCO3, H2O; (b) K2CO3, MeI,
acetone. Reagents and conditions for 6: (c) EtMgBr, Ti(Oi-Pr)4, Et2O; (d) TBSCl, imidazole, THF; (e) t-BuOK, THF. HG-II = Hoveyda−Grubbs
catalyst, second generation.
a
Scheme 2. Stereodivergent Synthesis of Chlamydocin (1) and Its Epimer epi-1
a
Reagents and conditions: (a) TBTU, HOBT, Et3N in CH2Cl2; (b) NaOH in THF/H2O; (c) 10% Pd/C, H2 in MeOH, H-Cube (60 °C, 60 bar);
(d) HATU, DIEA in DMF; (e) 1 M TBAF in THF; (f) air, 0.5 mol % Mn(acac)3 in THF, 0 °C, 2 h, then poly-D-leucine/SiO2, DBU, −25 °C, 48 h;
(g) air, 0.5 mol % Mn(acac)3 in THF, 0 °C, 2 h, then poly-L-leucine/SiO2, DBU, −25 °C, 48 h.
removal of the Cbz group, yielding tetrapeptide 13 in
quantitative yield after the hydrolytic release of free carboxylate
at the D-proline terminus. HATU-enabled macrocyclization
afforded macrocyclic tetrapeptide 14 in 56% yield. Finally, the
removal of the TBS group in 14 produced the key intermediate
15 with an unmasked cyclopropanol functionality. The latter
was transformed into the corresponding (S)-epoxy ketone.18
The aerobic oxidation of 15 catalyzed by 0.5 mol % Mn(acac)3
followed by treatment with DBU in the presence of silica-
supported poly-D-leucine afforded chlamydocin 1 in 78% yield.
The same transformation performed with poly-L-leucine as a
chiral mediator led to the corresponding (R)-epoxide epimer
C
DOI: 10.1021/acs.orglett.9b03305
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
epi-1, thus demonstrating stereochemical divergence. Both
transformations yielded the corresponding macrocycles as
almost pure (S)- and (R)-diastereoisomers, according to the
chiral HPLC analysis [dr >95:5 (see the Supporting
Information)]. The measured specific rotation for synthetic 1
([α]D = −140°) was close to the reported for the natural
sample ([α]D = −147.5°).4a The (S)-configuration of the chiral
center in the epoxide moiety of 1 was proven by CD
spectroscopy (Scheme 2), showing a negative Cotton effect
with a maximum at ∼290 nm for (S)-stereoisomer 1, and an
accordingly positive absorption band for its (R)-counterpart
epi-1, in full accord with the literature data.9,11
Following our method, the natural product chlamydocin was
prepared in an affordable 26% overall yield over 10 steps
[counted as the longest linear sequence from 3 (see Scheme
S1)]. Even more important is the fact that our approach
creates a shortcut to a series of chlamydocin analogues by
exploiting the pluripotency of the cyclopropanol function in
common precursor 15, as demonstrated by a series of
successful cyclopropane cleavage reactions (Scheme 3).
ketone 21.24 A side chain of 2-aminosuberic acid (Asu) in
compound 22 was installed by the fast and high-yield oxidation
of cyclopropanol 15 with bis(trifluoroacetoxy)iodobenzene
(PIFA) in acetic acid.25 Known bioactive Asu derivatives6,8
have also been prepared. Oxidation of 15 with PIFA in ethanol
afforded the corresponding ethyl ester6c 23. We also developed
a one-pot protocol for the synthesis of amides (see Scheme S2)
via intermediate generation of mixed anhydrides from
cyclopropanols in aprotic media.25d Thus, oxidation of
cyclopropanol 15 with PhI(O2CAr)2 (Ar = 2,4,6-trichlor-
ophenyl) in CH2Cl2 followed by addition of BnONH2
produced benzyl-protected hydroxamic acid 24 in 75% yield.
Compound 24 is the immediate precursor of the correspond-
ing free hydroxamic acid,6d known as a strong HDAC
inhibitor.6,8
In conclusion, here we demonstrate the first use of a
cyclopropanol functionality as a powerful pluripotent inter-
mediate for diversity-oriented synthesis, on both stereo-
chemical and functional diversity levels. The expedient
synthesis of the natural product chlamydocin, its (R)-epoxide
epimer, and several chlamydocin analogues has verified the
efficacy of our approach for accessing Aoe-, Aoda-, and Asu-
containing HDAC inhibitory peptides, including their ZBG-
modified congeners. Due to the broad spectrum of chemical
transformations provided by the rapidly evolving field of
cyclopropanol chemistry,15,16 further advances in the last-stage
diversification from the single cyclopropanol precursor can be
expected, which are suitable for the generation of bioactive
molecular libraries in general and HDAC inhibitory peptides in
particular.
Scheme 3. Divergent Preparation of Aoda- and Asu-
Containing Chlamydocin Analogues by Late-Stage Ring
a
Cleavage of the Common Cyclopropane Precursor 15
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b03305.
Experimental procedures and characterization data for
new compounds and copies of NMR spectra, HPLC
chromatograms, and CD spectra (PDF)
a
Reagents and conditions: (a) TFA, CH2Cl2, 24 h; (b) Togni reagent,
AUTHOR INFORMATION
10 mol % [Cu(CH3CN)4]BF4, 20 min; (c) SelectFluor, 20 mol %
AgF, C6H6/H2O, reflux, 4 h; (d) air, Cu(OAc)2, MeOH, 3 h; (e) air,
Cu(OAc)2, MeSO2Na, MeOH, 3 h; (f) air, Cu(OAc)2, piperidine,
MeOH, 45 min; (g) PIFA, acetic acid, 30 min; (h) PIFA, ethanol, 30
min; (i) PhI(O2CAr)2 (Ar = 2,4,6-trichlorophenyl), CH2Cl2, 2 h, then
NH2OBn (10 equiv), 10 h. All reactions were carried out at rt unless
noted otherwise. TFA = trifluoroacetic acid, and PIFA =
■
Corresponding Author
*E-mail: dzmitry.kananovich@taltech.ee.
ORCID
Margus Lopp: 0000-0002-8041-2595
Dzmitry G. Kananovich: 0000-0002-2664-4491
Notes
b
iodosobenzene bis(trifluoroacetate). Compound 16 was prepared
directly from TBS-protected cyclopropanol 14.
The authors declare no competing financial interest.
Cyclopropanols undergo facile rearrangement to the
corresponding carbonyl compounds in the presence of acid
or base catalysts.15c Therefore, the transformation of TBS-
protected cyclopropanol 14 to Aoda-containing cyclopepti-
de6c,e 16 was achieved in 80% yield by treatment with TFA in
CH2Cl2. In view of the importance of fluorinated compounds
in medicinal chemistry,19 including 18F PET imaging,20 late-
stage trifluoromethylation21 and fluorination22 were success-
fully performed to afford fluorinated Aoda analogues 17 and
18. A number of functionalized ketones have been prepared via
the copper-catalyzed aerobic oxidation of the cyclopropanol
moiety,23 e.g., vinyl ketone 19, γ-ketosulfone 20, and β-amino
ACKNOWLEDGMENTS
■
Funding from the Centre of Excellence in Molecular Cell
Engineering (Grant 2014-2020.4.01.15-0013), the Estonian
Ministry of Education and Research (Grant IUT19-32), and
TalTech (Grant B58) is gratefully acknowledged. Support
from COST Action CA15106 “C−H Activation in Organic
Synthesis” (CHAOS) is gratefully acknowledged. This work
has been partially supported by ASTRA “TUT Institutional
Development Program for 2016-2022” Graduate School of
Functional Materials and Technologies (2014-2020.4.01.16-
D
DOI: 10.1021/acs.orglett.9b03305
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