A Modular Construction of Epidithiodiketopiperazines

Article abstract of DOI:10.1021/acs.orglett.9b01770

Epidithiodiketopiperazines (ETPs) possess remarkably diverse biological activities and have attracted significant synthetic attention. The preparation of analogues is actively pursued; however, they are structurally challenging, and more direct and modular methods for their synthesis are desirable. To this end, the utility of a bifunctional triketopiperazine building block for the straightforward synthesis of ETPs is reported. A modular strategy consisting of enolate alkylation followed by site-selective nucleophile addition enables the concise synthesis of (±)-hyalodendrin and a range of analogues.

Full text of DOI:10.1021/acs.orglett.9b01770

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
A Modular Construction of Epidithiodiketopiperazines
Thomas N. Snaddon,* Toya D. Scaggs, Colin M. Pearson, and James W. B. Fyfe
‡
‡
‡,†
Department of Chemistry, Indiana University, 800 East Kirkwood Avenue, Bloomington, Indiana 47405, United States
S Supporting Information
*
ABSTRACT: Epidithiodiketopiperazines (ETPs) possess re-
markably diverse biological activities and have attracted
significant synthetic attention. The preparation of analogues
is actively pursued; however, they are structurally challenging,
and more direct and modular methods for their synthesis are
desirable. To this end, the utility of a bifunctional
triketopiperazine building block for the straightforward synthesis of ETPs is reported. A modular strategy consisting of
enolate alkylation followed by site-selective nucleophile addition enables the concise synthesis of (±)-hyalodendrin and a range
of analogues.
ynthetic routes to epidithiodiketopiperazines (ETPs) have
been intensely pursued. These fungal metabolites comprise
0 distinct families that are all characterized by a synthetically
ETP synthesis continues to present significant synthetic
challenges, which restrict their widespread potential to address
biological problems. In order to remedy this, we herein report
an experimentally straightforward, concise, and modular
protocol for the preparation of ETPs.
S
2
imposing disulfide-bridged diketopiperazine (DKP) (Figure
1
1
a). The unusually stable transannular disulfide embedded
within this heteroatom-rich motif 1 possesses a 0° CSSC
dihedral angle, which demands a fully eclipsed arrangement of
lone pairs on the adjacent S atoms and confers significant
The synthesis of ETPs 9 typically involves the elaboration of
+
preassembled diketopiperazines 8 via electrophilic (S ) or
−
11
nucleophilic (S ) incorporation (Figure 1b). However,
achieving site selectivity, functional group tolerance, and
necessary syn stereoselectivity using such strategies can be
challenging. Furthermore, the assembly of DKPs comprising
different amino acids, as well as the preparation of bespoke
amino acids themselves, can be challenging and requires
2
strain energy. This allows ETPs to engage in redox cycling to
produce reactive oxygen species, ligate and eject Zn(II), or
participate in rapid and reversible disulfide exchange reactions
3
with the cysteine residues of proteins. The ETP core is solely
responsible for the diversity of observed biological activities.
For example, the enantiomers of hyalodendrin 2 are naturally
occurring and have been isolated from different fungal sources,
and they exhibit enantiomer-specific antimicrobial and
1
2
13
significant synthetic investment.
Triketopiperazines
(TKPs) are rigid scaffolds that possess only one enolizable
site. This removes the issue of site-selective enolization that
complicates diketopiperazine (DKP) elaboration and should
permit straightforward alkylation via the derived enolate 11
4
antiviral/antibacterial activities. Similarly, the annulated
5
6
ETPs dehydrogliotoxin 3 and glionitrin 4 constitute
antipodal forms and differ only in arene decoration. The
former exhibits antibacterial activity, whereas the latter is
antibiotic/antitumor active. Chetomin 5, a rare heterodimeric
indole containing two different ETP core units, has attracted
(
Figure 1c). In addition, site-selective nucleophilic carbonyl
addition is possible due dipole minimization of the 1,4-
configured bis-amide motif, which confers disparate carbonyl
electrophilicities to the vicinal dicarbonyl motif within the
TKP (see 11). Tertiary alcohols resulting from nucleophile
addition would serve as precursors to electrophilic N-
acyliminium ions, which can be trapped by pendant sulfur
14
7
significant interest as a chemotherapeutic agent. It is a potent
in vitro and in vivo inhibitor of hypoxia inducible factor 1α
(
HIF-1α), a transcription factor that is essential to the growth
15
3
g,8
nucleophiles to forge the challenging transannular disulfide.
of solid tumors.
Non-natural ETPs have also attracted
9
We expected that successful exploitation of this bifunctional
reactivity within a common S-substituted TKP (10) would
result in the straightforward preparation of both natural and
non-natural N,N′-dimethyl ETPs (12). Herein, we report the
successful realization of this goal in which a single TKP
precursor can be elaborated via chemoselective functionaliza-
tion events.
significant attention. Overman and co-workers have devel-
oped NT-1721 (6), a candidate ETP with potent activity
against acute myeloid leukemia.
9a,b
Finally, Matile and co-
workers have employed the unique properties of ETPs for
10
strain-promoted intracellular probe delivery (e.g., 7). This
occurs with such extraordinary cellular uptake efficiencies that
endosomal capture is avoided, leading to ETPs being
harnessed as “unstoppable” transporters for thiol-mediated
cellular uptake. Overall, it is clear that with such unique
reactivity and properties ETPs will continue to serve as target
compounds for therapeutic development and as design
scaffolds for chemical biology applications. However, bespoke
We began our investigations into the use of TKPs as useful
synthetic intermediates by targeting the simplest of the ETPs,
Received: May 20, 2019
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01770
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 1. Synthesis of (± )-Hyalodendrin 2
a
Conditions: (a) LiHMDS, THF, −78 °C, S-[[(tert-
butyldimethylsilyl)oxy]methyl] 4-methylbenzenesulfonothioate, 85%;
(
b) LiHMDS, THF, DMPU, 0 °C, BnBr, 84%; (c) TBAF, TrSCl,
THF, 85%; (d) MeMgBr, THF, −78 °C; (e) PTSA, DCM, 58% (over
two steps); (f) OsO , NMO, acetone/H O, 89%; (g) BF ·OEt ,
4
2
3
2
DCM, −78 °C to rt, 70%.
1
9
corresponding desulfenylated product. Fortunately, this
could be overcome by trapping the thiolate in situ; dropwise
addition of TBAF to a solution of 15 and tritylsulfenyl chloride
(
TrSCl) in THF resulted in rapid and clean conversion to
trityl-protected disulfide 16. Next, and in line with our
synthetic design we required site selective addition of an
appropriate nucleophile to the vicinal dicarbonyl moiety. After
significant experimentation we established that treatment with
methylmagnesium bromide gave tertiary alcohols 17 exclu-
sively as an inconsequential 1:1 mixture of diastereomers.
Organocopper and organozinc nucleophiles were ineffective
whereas organolithium regents resulted a myriad of products
Figure 1. (a) Selected natural and non-natural ETPs. (b) ETP
synthesis from DKP derived from parent amino acids. (c) Modular
ETP synthesis which exploits the bifunctional reactivity of
triketopiperazines (TKPs).
16
(
±)-hyalodendrin 2 (Scheme 1). This naturally occurring
phenylalanine−serine-derived ETP exhibits enantiomer-specif-
ic antimicrobial and antiviral/antibacterial activity. Beginning
with N,N′-dimethyl triketopiperazine 13, which was readily
+
presumably due to the highly oxophilicity of Li . Thereafter,
dehydration upon treatment of this mixture with a
stoichiometric quantity of p-toluenesulfonic acid afforded a
3:1 mixture of both the desired dehydrated product 18 and the
17
prepared in two steps from sarcosine methyl ester, we sought
to install a suitably protected thiol, which would later serve as
an anchor for transannular disulfide assembly. Treatment of 13
with LiHMDS followed by trapping of the resulting enolate
20
corresponding bridged disulfide product. However, employ-
ment of substoichiometric quantities of p-toluenesulfonic acid
effectively suppressed disulfide formation and reliably provided
the alkene 18 in 58% (over two steps). Upjohn dihydroxylation
followed by treatment of the resulting diols 19 (dr 1:1) with
BF ·OEt delivered (±)-hyalodendrin (2) in 70% yield via the
1
8
with Clive’s silyl ether protected sulfenating reagent
efficiently provided S-substituted TKP 14 in excellent yield
on 5 g scale. A second enolization with LiHMDS was then
performed, and the resulting S-substituted enolate was trapped
with benzyl bromide to provide the fully substituted carbon 15
that constitutes the phenylalanine subunit of hyalodendrin 2.
Due to the limited solubility of the intermediate lithium
enolate, the addition of DMPU to this second enolate
alkylation was necessary to ensure consistently high yields.
The next step involved installation of the crucial disulfide.
Deprotection with a range of fluoride sources (TBAF, KHF2,
HF, HF·pyr, CsF) was efficient; however, the instability of
resulting thiol precluded efficient stepwise reaction with
tritylsulfenyl chloride and resulted in mixtures of 16 and the
3
2
21
putative N-acyliminium ion 20. In order to ensure efficient
epidisulfide formation, purification of the intermediate diols 19
was necessary; direct exposure of the crude diols to BF ·OEt
3
2
resulted in drastically lower conversion. Attempts to replace
2
2
BF ·OEt with Hf(OTf)4, a milder Lewis acid, were
3
2
unsuccessful and resulted in no reaction.
Our synthesis of (±)-hyalodendrin 2 establishes the utility
of bifunctional S-substituted triketopiperazine 14, and we next
sought to exploit this in an operationally straightforward and
modular synthesis of a focused library of ETP analogues of
B
DOI: 10.1021/acs.orglett.9b01770
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. ETP Analogues Synthesized from Common TKP 14
general structure 22 (Scheme 2). Starting from 14,
diversification via a modular three-step alkylation/disulfide
formation/Grignard addition−ring closure sequence provided
a range of ETP analogues in useful yield on preparative scale.
First, a range of electrophiles was explored for the initial
alkylation of the lithium enolate derived from 14 (step A,
substituents in red). Benzyl derivatives bearing substitution at
the ortho, meta, and para positions (23−26) were well
tolerated, with both electron deficient (24) and electron rich
19 → 2) this Lewis acid was ineffective for the conversion of
1,2-diols 19; however, it functions effectively here in the rapid
and chemoselective activation of lone tertiary alcohols.
We next explored the nucleophile scope by treating
benzylated and trityl-protected disulfide TKP 15 with a
range of Grignard reagents, prior to epidisulfide formation.
Both alkyl and aryl Grignard reagents performed well within
the reaction and in each case the corresponding ETP was
obtained with useful efficiency. Addition of i-butylmagnesium
bromide to the benzyl-substituted TKP 15 resulted exclusively
(
25) and halogenated (23, 26) providing similar levels of
efficiency. Disubstituted benzylic (28), π-extended naphthylic
27), and N-heterocyclic (29) electrophiles could also be
in hydride delivery and gave the phenylalanine−glycine
(
11f
containing ETP 32
following ring closure, whereas the
employed, albeit in more modest yield.
Allylic and propargylic halides are also effective electrophiles
11f
addition of methylmagnesium bromide afforded 33, the
deoxygenated serine−alanine analogue of hyalodendrin, via the
two-step sequence. Acetal-protected and allyl Grignard
reagents provided ETPs 34 and 35, respectively, with
functional handles for further manipulation. The nucleophilic
addition of benzylmagnesium bromide was also successful and
provided the C2-symmetric phenylalanine−phenylalanine-
(
30 and 31) and provide potential handles for further
functionalization within the context of broader SAR studies.
These differentially alkylated TKPs were then converted to the
corresponding ETPs via trityl disulfide formation, followed by
site-selective nucleophilic addition of methylmagnesium bro-
mide and hafnium(IV) triflate-mediated ring closure using a
11c,d,f
22
containing ETP 36.
Finally, aromatic nucleophiles with
modification of Movassaghi’s protocol. The use of milder and
more functional group tolerant Hf(OTf) , where the number
of equivalents of could be reduced from 10 to 1.5 equiv is
noteworthy. During our hyalodendrin synthesis (cf. Scheme 2
various substitution patterns and functionality were also
effective and gave ETPs 37−40 in good yield. These are
particularly noteworthy as they would otherwise require
4
C
DOI: 10.1021/acs.orglett.9b01770
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ASSOCIATED CONTENT
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AUTHOR INFORMATION
Corresponding Author
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*
(6) Park, H. B.; Kwon, H. C.; Lee, C.-H.; Yang, H. O. Glionitrin A,
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Thomas N. Snaddon: 0000-0003-1119-0332
Present Address
†
School of Chemistry, University of St. Andrews, North
Haugh, St. Andrews, KY16 9ST, U.K.
Author Contributions
(
d) Fujimoto, H.; Sumino, M.; Okuyama, E.; Ishibashi, M.
‡
T.D.S., C.M.P., and J.W.B.F. contributed equally.
Immunomodulatory Constituents from an Ascomycete, Chaetomium
Notes
seminudum. J. Nat. Prod. 2004, 67, 98−102.
(
8) Kung, A. L.; Zabludoff, S. D.; France, D. S.; Freedman, S. J.;
The authors declare no competing financial interest.
Tanner, E. A.; Viera, A.; Cornell-Kenyon, S.; Lee, J.; Wang, B.; Wang,
J.; Memmert, K.; Naegeli, H. U.; Petersen, F.; Eck, M. J.; Bair, K. W.;
Wood, A. W.; Livingston, D. M. Small Molecule Blockade of
Transcriptional Coactivation of the Hypoxia-Inducible Factor Path-
way. Cancer Cell 2004, 6, 33−43.
(9) (a) Kowolik, C. M.; Lin, M.; Xie, J.; Overman, L. E.; Horne, D.
A. NT1721, a Novel Epidithiodiketopiperazine, Exhibits Potent in
vitro and in vivo Activity Against Acute Myeloid Leukemia. Oncotarget
ACKNOWLEDGMENTS
■
We thank Dr. Dung T. Do (Indiana University) for exploratory
experimental efforts. We gratefully acknowledge Indiana
University and the National Institutes of Health
(
R01GM121573) for generous financial support.
2
016, 7, 86186−86197. (b) Baumann, M.; Dieskau, A. P.; Loertscher,
DEDICATION
This manuscript is dedicated to Dr. John Mayer.
■
B. M.; Walton, M. C.; Nam, S.; Kie, J.; Horne, D. A.; Overman, L. E.
Tricyclic Analogues of Epidithiodioxopiperazine Alkaloids with
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(
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(
2
4
(
E
DOI: 10.1021/acs.orglett.9b01770
Org. Lett. XXXX, XXX, XXX−XXX