Synthesis of HDAC Substrate Peptidomimetic Inhibitors Using Fmoc Amino Acids Incorporating Zinc-Binding Groups

Article abstract of DOI:10.1021/acs.orglett.9b00885

Syntheses of Fmoc amino acids having zinc-binding groups were prepared and incorporated into substrate inhibitor H3K27 peptides using Fmoc/^tBu solid-phase peptide synthesis (SPPS). Peptide 11, prepared using Fmoc-Asu(NHO^tBu)-OH, is a

Full text of DOI:10.1021/acs.orglett.9b00885

This is an open access article published under a Creative Commons Attribution (CC-BY)
License, which permits unrestricted use, distribution and reproduction in any medium,
provided the author and source are cited.
Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of HDAC Substrate Peptidomimetic Inhibitors Using Fmoc
Amino Acids Incorporating Zinc-Binding Groups
Amit Mahindra,† Christopher J. Millard,‡ Iona Black,† Lewis J. Archibald,† John W. R. Schwabe,‡
and Andrew G. Jamieson*,†
†School of Chemistry, University of Glasgow, Joseph Black Building, University Avenue, Glasgow G12 8QQ, U.K.
‡Leicester Institute of Structural and Chemical Biology, Department of Molecular and Cell Biology, University of Leicester, Leicester
LE1 7RH, U.K.
S
* Supporting Information
ABSTRACT: Syntheses of Fmoc amino acids having zinc-binding groups were prepared and incorporated into substrate
inhibitor H3K27 peptides using Fmoc/tBu solid-phase peptide synthesis (SPPS). Peptide 11, prepared using Fmoc-
Asu(NHOtBu)-OH, is a potent inhibitor (IC50 = 390 nM) of the core NuRD corepressor complex (HDAC1−MTA1−RBBP4).
The Fmoc amino acids have the potential to facilitate the rapid preparation of substrate peptidomimetic inhibitor (SPI) libraries
in the search for selective HDAC inhibitors.
believed to have distinct roles in gene expression.8 Under-
pigenetic regulation of gene expression is a key process in
Ethe cell that facilitates changes in heritable phenotype standing the regulation of HDAC activity in the context of
corepressor complexes presents a promising strategy to
understand the specific role of each complex on gene
expression.
without a change in DNA sequence. Gene expression is, in
part, regulated by the acetylation state of lysine residues in
histone protein tails that coordinate the packaging of DNA
into chromatin. Two different classes of lysine-modifying
enzymes, the histone deacetylases (HDACs) and the histone
acetyltransferases (HATs), are responsible for applying and
removing this post-translational modification.1,2 HDAC
enzymes have been found to deacetylate other nonhistone
proteins and in this context can also be referred to as KDACs.3
Modifications in HDAC function have been linked to
numerous diseases including neurological disorders, muscular
dystrophy, cardiac hypertrophy, cancer, and HIV infection.4
There are 18 human HDAC enzymes, which have been
subdivided into four different classes, based on their sequence
homology with yeast proteins.5 The majority of cellular protein
acetylation (70−80%) is performed by the class I (1, 2, 3, and
8) HDACs, so an understanding of their specific role in cell
biochemistry is important and will provide insight into the
epigenetic working of the cell.6,7 Most class I HDAC enzymes
(1, 2, and 3) must be recruited to larger corepressor complexes
to be fully active. There are at least five corepressor complexes
(NuRD, CoREST, MiDAC, SIN3, SMRT/NCoR), and all are
Four HDAC inhibitors have been FDA approved for clinical
application including Vorinostat (SAHA), Romidepsin
(FK228, a prodrug), Belinostat (PXD-101), and Panobinostat
(LBH-589, Farydak), with at least 20 others in clinical trials.9
Unfortunately, these inhibitors are nonspecific across various
HDACs, and lack of specificity contributes to the cytotoxicity
observed in clinical trials.10 Therefore, there is a persistent
need to develop isoform-specific and complex-selective HDAC
inhibitors.
Many cyclic peptide HDAC inhibitors exist in nature such as
CHAP31 and Apicidin A, which show class I selective HDAC
inhibition in the nanomolar range (Figure 1).11 These
inhibitors function by coordinating with the HDAC active
site zinc through a side chain that has zinc binding properties
such as a hydroxamic acid or ethyl ketone. Recently, we
reported a linear substrate peptidomimetic inhibitor (SPI)
Received: March 12, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00885
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Figure 2. Structure of amino acids for SPPS.
Different types of ZBG have been selected to fine-tune the
binding affinity with the active site zinc atom, in the search for
selective and less toxic HDAC inhibitors. We selected two
ZBGs, a ketone with relatively low predicted binding affinity
and hydroxamic acid with strong binding affinity.16 The length
of the aliphatic side chain in these amino acids is based on the
distance between the α-carbon and the side-chain carbonyl on
the acetyl lysine residue.17 The crystal structure of the
H4K16Asu peptide bound to HDAC1−MTA1 validates this
as the correct length and side chains of longer and shorter
length have previously been demonstrated to have limited
potency.12
Several methods have been reported for the synthesis of
nonproteinogenic α-amino acids: Strecker synthesis,18 Grubbs
metathesis,19 alkylation of glycine derivatives,20 and oxazo-
lones.21 Initially we focused our attention on the synthesis of
the Fmoc amino acids using Grubbs cross metathesis as the
key step to prepare the required side-chain functionality. Due
to extremely poor yields (5−7% for cross metathesis due to
homocoupling) we turned our attention to alkylation of glycine
derivatives first reported by Belokon and co-workers.22 This
method provided an efficient and highly stereoselective way to
prepare the amino acids required for this work and results in
the desired Fmoc-protected amino acid analogues required for
solid-phase peptide synthesis.
Figure 1. Examples of HDAC inhibitors having zinc binding groups.
based on the histone H4 sequence (H4K16Asu) which inhibits
the HDAC1−MTA1 complex with IC50 366 nM (Figure 1).12
Despite their attractiveness as tool compounds and as
potential therapeutic lead compounds, the synthesis of this
type of peptide still poses a significant challenge. Numerous
synthetic strategies have been reported to prepare these
peptides; however, they all involve complex multistep
syntheses. For example, the multistep solution-phase syntheses
of CHAP31 and Apicidin A have been reported but require the
purification of intermediates.13−15 Furumai et al. reported the
synthesis of CHAP31 starting from Z-D-proline and requires
purification after each peptide coupling. The unnatural Asu
amino acid was initially introduced as the benzyl-protected
ester. Following peptide N- to C-terminal macrocyclization the
Asu side-chain benzyl-protecting group was removed, and the
activated carboxylic acid reacted with hydroxylamine to
provide the desired hydroxamic acid (AsuNHOH). This
synthetic strategy is only appropriate for peptides such as
CHAP31 and Apicidin A with aliphatic amino acid residues.
However, histone peptides that incorporate reactive amino
acid side chains would require a complex orthogonal
protection strategy.
Recently, our group reported a linear inhibitor peptidomi-
metic (H4K16Asu) using solid-phase peptide synthesis (SPPS)
using hydroxylamine resin.12 The reported method required a
multistep procedure starting from the Fmoc−oxooctanoic
acid−OAll (prepared via Grubbs cross metathesis). The
desired peptide was synthesized with a poor overall yield of
1%. The foremost limitation in moving forward to generate
this type of peptide-based inhibitor is the lack of availability of
the nonproteogenic zinc binding Fmoc-protected amino acids
that would provide straightforward synthetic access to this class
of molecules via standard Fmoc/tBu SPPS.
The chiral NiII Schiff base complex (S)-Ni-Gly-2FBPB 1 was
prepared by a modified version of our previously reported
route (Supporting Information Scheme S1).23,24 Alkylation of
(S)-Ni-Gly-2FBPB 1 required orthogonally protected electro-
philes compatible with basic conditions for the amino acid
synthesis and also Fmoc/tBu SPPS (Figure 2).25 The alkylation
reaction was initially attempted using electrophiles 6-bromo-N-
(trityl)hexanamide (2a) (Table 1, entry 1) and 6-bromo-N-
(THP)hexanamide (2b) (Table 1, entry 2) and resulted in
degradation of the product under the reaction conditions and
low yields. Stereoselective alkylation was achieved using 6-
bromo-N-(tert-butoxy)hexanamide (2c) to provide the desired
product 3 in 57% yield (Table 1, entry 3). The reaction
conditions were optimized by increasing the equivalents of
base (3 equiv) to provide complex 3 diastereoselectively (94:6
d.r.) (Table 1, entry 4). At reduced temperature no
bisalkylation was observed. The NiII Schiff base complex 3
was isolated in excellent yield and in diastereomerically pure
1
form (as confirmed by H and 19F NMR and LCMS) as a red
As part of our ongoing research program to develop SPIs, we
developed the synthesis of Fmoc amino acids having side
chains with functional groups suitable for zinc binding. Here
we describe the development of an asymmetric synthesis of
these Fmoc-AAs (Figure 2), which are compatible building
blocks with standard Fmoc/tBu SPPS.
crystalline solid after automated flash column chromatography.
Decomplexation of 3 was achieved under basic conditions
using 8-hydroxyquinoline to give the amino acid L-Asu-
(NHOtBu) 4 and chiral auxiliary (2S)-FBPB, which can be
recycled.26 Finally, L-Asu(NHOtBu) 4 was N-protected using
N-(9-fluoromethoxycarbonyloxy)succinimide to provide the
B
DOI: 10.1021/acs.orglett.9b00885
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Screening of Protecting Groups for Alkylation of 1
to Generate Fmoc-L-Asu(NHOtBu)-OH
Scheme 2. Synthesis of Fmoc-L-Aon 9 (R = −CH3) and
Fmoc-L-Aod 10 (R = −C2H5)
Chiral integrity was then analyzed by chiral HPLC. As evident
from the chromatograms of L- and D-Asu(NHOtBu), we
conclude that chirality is retained, and the protocol described
herein did not result in any racemization (e.e. > 99%).
The synthesis of these amino acids 5, 9, and 10 was achieved
on scale to provide gram quantities of the bench-stable Fmoc-
protected amino acid building blocks. The foremost advantage
of these amino acids (AAs) is that they can be incorporated at
any position in a peptide sequence using standard Fmoc/tBu
SPPS conditions. These Fmoc amino acid building blocks
therefore facilitate the rapid generation of peptide inhibitors.
The Fmoc-AA building blocks 5, 9, and 10 were then used
to synthesize histone tail derived SPIs using SPPS.
Heptapeptide SPI 11 based on residues 23−29 of the
unstructured tail region of histone H3 and incorporating the
non-native amino acid L-Asu(NHOtBu)-OH in place of K27Ac
was prepared by microwave-assisted Fmoc/tBu SPPS on Rink
Amide resin (Scheme 3). The histone H3K27Ac (23−29)
peptide 14 was also produced as a negative control. Finally, the
peptides were cleaved from resin and underwent global
deprotection under acidic conditions.
desired Fmoc-L-Asu(NHOtBu)-OH 5 in excellent 98% yield
(Scheme 1).27
Scheme 1. Synthesis of Fmoc-L-Asu(NHOtBu)-OH (5)
An impurity corresponding to the hydroxymate t-butyl-
protected peptide byproduct was identified in the crude sample
following cleavage of peptide 11 from the solid support.
Extended deprotection reaction times (up to 48 h) or
increased temperature (up to 40 °C) results in hydrolysis of
the hydroxamic acid. Hydroxamic acid peptides 11 were
obtained when cleavage was performed with [TFA/TIPS/
DCM (98:1:1)] for 24 h, providing SPIs 11 in good 29% yield
following purification by reverse-phase high-performance
liquid chromatography (RP-HPLC).
During acid-mediated cleavage of peptide 12 in the presence
of TIPS scavenger, silicon hydride reduction of the ketone
functionality occurs, followed by esterification to provide the
trifluoroacetate ester (Supporting Information Scheme S5) as
detected by LCMS. Water-mediated hydrolysis of the ester
then takes place and results in formation of the corresponding
alcohol.29 Therefore, TIPS was excluded from the cleavage
cocktail for peptides 12 and 13, containing ketone
functionality, and successful cleavage and deprotection were
achieved using TFA/DCM (95:5, v/v) for 3 h.
Synthesis of amino acids Fmoc-L-Aon-OH 9 and Fmoc-L-
Aod-OH 10 was achieved using the same route and with
electrophiles 7-bromoheptan-2-one (6a) and 8-bromooctan-3-
one (6b), which were prepared from commercially available 6-
bromohexanoic acid (Supporting Information Schemes 3 and
4) via Weinreb amides.28 Alkylation of NiII Schiff base complex
1 with 6a or 6b followed by decomplexation and Fmoc
protection gave the desired amino acids [9 (R = −CH3), 10 (R
= −C2H5)] with excellent yield at each step (Scheme 2).
To access the chiral integrity of 5, the Fmoc-D-Asu-
(NHOtBu)-OH 5a isomer was produced for comparison.
C
DOI: 10.1021/acs.orglett.9b00885
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Synthesis of Peptide (H3K27) Incorporating Fmoc-L-Asu(NHOtBu)-OH
SPIs 11−14 were assessed in a fluorescence-based inhibition
assay to determine potency as HDAC inhibitors (Table 2). SPI
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.9b00885.
Table 2. Synthesis of H3K27 Peptidomimetics via SPPS
sequence
yield (%)
purity (%)
IC50
Ac-KAARAsuSA-NH2 11
Ac-KAARAodSA-NH2 12
Ac-KAARAonSA-NH2 13
Ac-KAARK(Ac)SA-NH2 14
29
32
28
34
99
99
99
99
390 nM
17 μM
ND
Experimental procedures and characterization data for
all compounds, copies of 1H,13C, COSY, HSQC, and 19
F
NMR spectra for building blocks, and analytical HPLC
traces for peptides (PDF)
ND
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: andrew.jamieson.2@glasgow.ac.uk.
ORCID
11 incorporating the hydroxamic acid amino acid has an IC50
=
390 nM against the HDAC1−MTA1−RBBP4 corepressor
complex, which is comparable to our previously reported SPI
based on the H4 peptide sequence.12 SPI 12 incorporating the
ethyl ketone amino acid side chain has an IC50 = 17 μM.
Unexpectedly, SPI 13 with methyl ketone side chain was
inactive at the tested concentration. The lower activity of SPIs
12−13 can be attributed to the lower zinc binding affinity of
ketones. In the future these amino acids will be incorporated in
various histone tails to generate a library to identify important
binding interactions through additional crystal structure
studies. The cell permeability of these peptides will also be
investigated to determine their usefulness as cellular probes.
In summary, we have developed the synthesis of three novel
Fmoc amino acids incorporating zinc binding group side
chains. The foremost advantage of these amino acid building
blocks is that they can be incorporated at any position in a
peptide sequence using standard Fmoc/tBu SPPS. As proof of
principle a series of SPIs based on the structure of the
H3K27Ac tail were synthesized by SPPS. One of these
analogues 11 was active (IC50 = 390 nM) against the core
NuRD corepressor complex (HDAC1−MTA1−RBBP4). This
synthetic strategy has the potential to facilitate the rapid
generation of peptide-based HDAC inhibitor libraries.
Andrew G. Jamieson: 0000-0003-1726-7353
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the University of Glasgow and the EPSRC (Research
Project Grant EP/N034295/1) for financial support of this
research. L.A. thanks the EPSRC for a studentship (EP/
M506539/1 and EP/N509668/1). JWRS is supported by a
Senior Investigator Award (WT100237) from the Wellcome
Trust. JWRS is a Royal Society Wolfson Research Merit Award
holder. The authors also thank Andrew Monaghan (high-
resolution mass spectrometry, University of Glasgow) for
technical assistance.
REFERENCES
■
(1) (a) Allfrey, V. G.; Faulkner, R.; Mirsky, A. E. Proc. Natl. Acad.
Sci. U. S. A. 1964, 51, 786−794. (b) Struhl, K. Genes Dev. 1998, 12,
599−606. (c) Biel, M.; Wascholowski, V.; Giannis, A. Angew. Chem.,
Int. Ed. 2005, 44, 3186−3216. (d) Narita, T.; Weinert, B. T.;
Choudhary, C. Nat. Rev. Mol. Cell Biol. 2019, 20, 156−174.
D
DOI: 10.1021/acs.orglett.9b00885
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(2) (a) Perri, F.; Longo, F.; Giuliano, M.; Sabbatino, F.; Favia, G.;
Ionna, F.; Addeo, R.; Scarpati, G. D. V.; Di Lorenzo, G.; Pisconti, S.
Crit. Rev. Oncol. Hematol. 2017, 111, 166−172. (b) Conley, B. A.;
Wright, J. J.; Kummar, S. Cancer 2006, 107, 832−840. (c) Bernstein,
B. E.; Meissner, A.; Lander, E. S. Cell 2007, 128, 669−681.
(3) Choudhary, C.; Kumar, C.; Gnad, F.; Nielsen, M. L.; Rehman,
M.; Walther, T. C.; Olsen, J. V.; Mann, M. Science 2009, 325, 834−
840.
(4) (a) Fraga, M. F.; Ballestar, E.; Villar-Garea, A.; Boix-Chornet,
M.; Espada, J.; Schotta, G.; Bonaldi, T.; Haydon, C.; Ropero, S.;
Petrie, K.; Iyer, N. G.; et al. Nat. Genet. 2005, 37, 391−400.
(b) Esteller, M. N. Engl. J. Med. 2008, 358, 1148−1159.
(c) Falkenberg, K. J.; Johnstone, R. W. Nat. Rev. Drug Discovery
2014, 13, 673−691.
(5) (a) Gregoretti, I.; Lee, Y.-M.; Goodson, H. V. J. Mol. Biol. 2004,
338, 17−31. (b) Witt, O.; Deubzer, H. E.; Milde, T.; Oehme, I.
Cancer Lett. 2009, 277, 8−21. (c) New, M.; Olzscha, H.; La Thangue,
N. B. Mol. Oncol. 2012, 6, 637−656.
(6) (a) Haberland, M.; Montgomery, R. L.; Olson, E. N. Nat. Rev.
Genet. 2009, 10, 32−42. (b) Yang, X. J.; Seto, E. Nat. Rev. Mol. Cell
Biol. 2008, 9, 206−218.
(15) (a) Dose, A.; Sindlinger, J.; Bierlmeier, J.; Bakirbas, A.; Schulze-
Osthoff, K.; Einsele-Scholz, S.; Hartl, M.; Essmann, F.; Finkemeier, I.;
Schwarzer, D. Angew. Chem., Int. Ed. 2016, 55, 1192−1195. (b) Wu,
M.; Hayward, D.; Kalin, J. H.; Song, Y.; Schwabe, J. W. R.; Cole, P. A.
eLife 2018, 7, 37231. (c) Maolanon, A. R.; Kristensen, H. M.; Leman,
L. J.; Ghadiri, M. R.; Olsen, C. A. ChemBioChem 2017, 18, 5−49.
(16) (a) Chen, K.; Xu, L.; Wiest, O. J. Org. Chem. 2013, 78, 5051−
5055. (b) McCarren, P.; Hall, M. L.; Whitehead, L. Chem. Biol. Drug
Des. 2012, 80, 203−214.
(17) Finnin, M. S.; Donigian, J. R.; Cohen, A.; Richon, V. M.;
Rifkind, R. A.; Marks, P. A.; Breslow, R.; Pavletich, N. P. Nature 1999,
401, 188.
(18) (a) Harada, K. Nature 1963, 200, 1201. (b) Yet, L. Angew.
Chem., Int. Ed. 2001, 40, 875−877. (c) Wang, J.; Liu, X.; Feng, X.
Chem. Rev. 2011, 111, 6947−6983.
(19) (a) Miller, S. J.; Blackwell, H. E.; Grubbs, R. H. J. Am. Chem.
Soc. 1996, 118, 9606−9614. (b) Chatterjee, A. K.; Choi, T.-L.;
Sanders, D. P.; Grubbs, R. H. J. Am. Chem. Soc. 2003, 125, 11360−
11370. (c) Wang, Z. J.; Spiccia, N. D.; Jackson, W. R.; Robinson, A. J.
J. Pept. Sci. 2013, 19, 470−476.
(20) (a) O’Donnell, M. J.; Bennett, W. D.; Wu, S. J. Am. Chem. Soc.
1989, 111, 2353−2355. (b) Belokon, Y. N.; Bespalova, N. B.;
(7) (a) Micelli, C.; Rastelli, G. Drug Discovery Today 2015, 20, 718−
735. (b) Kelly, R.; Chandru, A.; Watson, P.; Song, Y.; Blades, M.;
Robertson, N.; Jamieson, A. G.; Schwabe, J. W. R.; Cowley, S. M. Sci.
Rep. 2018, 8, 14690.
̌
́
Churkina, T. D.; Císarova, I.; Ezernitskaya, M. G.; Harutyunyan, S. R.;
̌
́
Hrdina, R.; Kagan, H. B.; Kocovsky, P.; Kochetkov, K. A.; Larionov,
O. V.; et al. J. Am. Chem. Soc. 2003, 125, 12860−12871.
̃
(c) Sorochinsky, A. E.; Acena, J. L.; Moriwaki, H.; Sato, T.;
(8) (a) Kalin, J. H.; Wu, M.; Gomez, A. V.; Song, Y.; Das, J.;
Hayward, D.; Adejola, N.; Wu, M.; Panova, I.; Chung, H. J.; Kim, E.;
Roberts, H. J.; Roberts, J. M.; Prusevich, P.; Jeliazkov, J. R.; Roy
Burman, S. S.; Fairall, L.; Milano, C.; Eroglu, A.; Proby, C. M.;
Dinkova-Kostova, A. T.; Hancock, W. W.; Gray, J. J.; Bradner, J. E.;
Valente, S.; Mai, A.; Anders, N. M.; Rudek, M. A.; Hu, Y.; Ryu, B.;
Schwabe, J. W. R.; Mattevi, A.; Alani, R. M.; Cole, P. A. Nat. Commun.
2018, 9, 53. (b) Watson, P. J.; Fairall, L.; Schwabe, J. W. R. Mol. Cell.
Endocrinol. 2012, 348, 440−449. (c) Millard, C. J.; Watson, P. J.;
Fairall, L.; Schwabe, J. W. R. Trends Pharmacol. Sci. 2017, 38, 363−
377.
(9) (a) Duvic, M.; Talpur, R.; Ni, X.; Zhang, C.; Hazarika, P.; Kelly,
C.; Chiao, J. H.; Reilly, J. F.; Ricker, J. L.; Richon, V. M.; Frankel, S. R.
Blood 2007, 109, 31−39. (b) Butler, L. M.; Zhou, X.; Xu, W. S.;
Scher, H. I.; Rifkind, R. A.; Marks, P. A.; Richon, V. M. Proc. Natl.
Acad. Sci. U. S. A. 2002, 99, 11700−11705. (c) Taori, K.; Paul, V. J.;
Luesch, H. J. Am. Chem. Soc. 2008, 130, 1806−1807. (d) Sawas, A.;
Radeski, D.; O’Connor, O. A. Ther. Adv. Hematol. 2015, 6, 202−208.
(e) Atadja, P. Cancer Lett. 2009, 280, 233−241.
Soloshonok, V. A. Amino Acids 2013, 45, 691−718.
(21) (a) Wang, T.; Yu, Z.; Hoon, D. L.; Phee, C. Y.; Lan, Y.; Lu, Y. J.
Am. Chem. Soc. 2016, 138, 265−271. (b) Cabrera, S.; Reyes, E.;
Aleman, J.; Milelli, A.; Kobbelgaard, S.; Jørgensen, K. A. J. Am. Chem.
Soc. 2008, 130, 12031−12037. (c) Fisk, J. S.; Mosey, R. A.; Tepe, J. J.
Chem. Soc. Rev. 2007, 36, 1432−1440.
(22) Belokon, Y. N.; Bakhmutov, V. I.; Chernoglazova, N. I.;
Kochetkov, K. A.; Vitt, S. V.; Garbalinskaya, N. S.; Belikov, V. M. J.
Chem. Soc., Perkin Trans. 1 1988, 2, 305−312.
(23) Aillard, B.; Robertson, N. S.; Baldwin, A. R.; Robins, S.;
Jamieson, A. G. Org. Biomol. Chem. 2014, 12, 8775−8782.
(24) Li, B.; Zhang, J.; Xu, Y.; Yang, X.; Li, L. Tetrahedron Lett. 2017,
58, 2374−2377.
(25) Wuts, P. G.; Greene, T. W. In Greene’s protective groups in
organic synthesis; John Wiley & Sons, 2006.
(26) Yuan, G.; Lingfang, K.; Yingchun, L. Method for preparing
chiral alpha-unnatural amino acid by transition metal complex, Patent
China, 2013.
̈
(27) Obkircher, M.; Stahelin, C.; Dick, F. J. Pept. Sci. 2008, 14, 763−
(10) (a) Kang, S. P.; Ramirez, J.; House, L.; Zhang, W.; Mirkov, S.;
Liu, W.; Haverfield, E.; Ratain, M. J. A. Pharmacogenet. Genomics
2010, 20, 638−641. (b) Garcia-Manero, G.; Minden, M.; Estrov, Z.;
Verstovsek, S.; Newsome, W. M.; Reid, G.; Besterman, J.; Li, Z.;
Pearce, L.; Martell, R. J. Clin. Oncol. 2006, 24, 337. (c) Mottamal, M.;
Zheng, S.; Huang, T. L.; Wang, G. Molecules 2015, 20, 3898−3941.
(11) (a) Han, J. W.; Ahn, S. H.; Park, S. H.; Wang, S. Y.; Bae, G. U.;
Seo, D. W.; Kwon, H. K.; Hong, S.; Lee, H. Y.; Lee, Y. W.; Lee, H. W.
Cancer Res. 2000, 60, 6068−6074. (b) Yoshida, M.; Furumai, R.;
Nishiyama, M.; Komatsu, Y.; Nishino, N.; Horinouchi, S. Cancer
Chemother. Pharmacol. 2001, 48, S20−S26. (c) Newkirk, T. L.;
Bowers, A. A.; Williams, R. M. Nat. Prod. Rep. 2009, 26, 1293−1320.
(d) Mwakwari, S.; Patil, V.; Guerrant, W.; K Oyelere, A. Curr. Top.
Med. Chem. 2010, 10, 1423−1440.
766.
(28) (a) Jones, P.; Altamura, S.; De Francesco, R.; Paz, O. G.;
Kinzel, O.; Mesiti, G.; Monteagudo, E.; Pescatore, G.; Rowley, M.;
̈
Verdirame, M.; Steinkuhler, C. J. Med. Chem. 2008, 51, 2350−2353.
(b) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815−3818.
(c) Qu, B.; Collum, D. B. J. Org. Chem. 2006, 71, 7117−7119.
(29) (a) Doyle, M. P.; DeBruyn, D. J.; Donnelly, S. J.; Kooistra, D.
A.; Odubela, A. A.; West, C. T.; Zonnebelt, S. M. J. Org. Chem. 1974,
39, 2740−2747. (b) Kursanov, D. N.; Parnes, Z. N.; Bassova, G. I.;
Loim, N. M.; Zdanovich, V. I. Tetrahedron 1967, 23, 2235−2242.
(c) Doyle, M. P.; West, C. T. J. Org. Chem. 1975, 40, 3835−3838.
(12) Watson, P. J.; Millard, C. J.; Riley, A. M.; Robertson, N. S.;
Wright, L. C.; Godage, H. Y.; Cowley, S. M.; Jamieson, A. G.; Potter,
B. V.; Schwabe, J. W. R. Nat. Commun. 2016, 7, 11262.
(13) (a) Furumai, R.; Komatsu, Y.; Nishino, N.; Khochbin, S.;
Yoshida, M.; Horinouchi, S. Proc. Natl. Acad. Sci. U. S. A. 2001, 98,
87−92. (b) Komatsu, Y.; Tomizaki, K. Y.; Tsukamoto, M.; Kato, T.;
Nishino, N.; Sato, S.; Yamori, T.; Tsuruo, T.; Furumai, R.; Yoshida,
M.; Horinouchi, S. Cancer Res. 2001, 61, 4459−4466.
(14) (a) Mou, L.; Singh, G. Tetrahedron Lett. 2001, 42, 6603−6606.
(b) Berst, F.; Ladlow, M.; Holmes, A. B. Chem. Commun. 2002, 5,
508−509.
E
DOI: 10.1021/acs.orglett.9b00885
Org. Lett. XXXX, XXX, XXX−XXX