Synthesis of α,α-Difluorinated Phosphonate pSer/pThr Mimetics via Rhodium-Catalyzed Asymmetric Hydrogenation of β-Difluorophosphonomethyl α-(Acylamino)acrylates

Article abstract of DOI:10.1021/acs.orglett.8b01151

A novel and facile synthetic strategy for α,α-difluorinated phosphonate mimetics of phosphoserine/phosphothreonine utilizing rhodium-catalyzed asymmetric hydrogenation was developed. The dehydrogenated substrate β-difluorophosphonomethyl α-(acylamino)acrylates were first prepared from protected serine/threonine followed by asymmetric hydrogenation using the rhodium-DuPhos catalytic system to generate the chiral center(s). These important phosphonate building blocks were successfully incorporated into phosphatase-resistant peptides, which displayed similar inhibition to the 14-3-3 ζ protein as the parent pSer/pThr peptides.

Full text of DOI:10.1021/acs.orglett.8b01151

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of α,α-Difluorinated Phosphonate pSer/pThr Mimetics via
Rhodium-Catalyzed Asymmetric Hydrogenation of
β‑Difluorophosphonomethyl α‑(Acylamino)acrylates
Hong-Xue Chen,† Jie Kang,† Rong Chang, Yun-Lai Zhang, Hua-Zhen Duan, Yan-Mei Li,
and Yong-Xiang Chen*
Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Department of Chemistry,
Tsinghua University, Beijing 100084, China
S
* Supporting Information
ABSTRACT: A novel and facile synthetic strategy for α,α-
difluorinated phosphonate mimetics of phosphoserine/phos-
phothreonine utilizing rhodium-catalyzed asymmetric hydro-
genation was developed. The dehydrogenated substrate β-
difluorophosphonomethyl α-(acylamino)acrylates were first
prepared from protected serine/threonine followed by asymmetric hydrogenation using the rhodium−DuPhos catalytic system
to generate the chiral center(s). These important phosphonate building blocks were successfully incorporated into phosphatase-
resistant peptides, which displayed similar inhibition to the 14-3-3 ζ protein as the parent pSer/pThr peptides.
erine/threonine phosphorylation is a key protein post-
translational modification that regulates diverse cellular
S
signaling pathways.1 Many cellular protein−protein interactions
(PPIs) are mediated by domains that recognize and bind to
motifs containing phosphorylated serine or threonine residues.2
Phosphoproteins and phosphopeptides have provided useful
tools for elucidating the biological function of phosphorylation
and regulating pSer/pThr involved PPIs.3 However, the
phosphate moiety is hydrolytically labile to phosphatases in a
cellular context.4 To circumvent this limitation, some
phosphatase-inert mimetics, in which a nonhydrolyzable
methylene (CH2) or difluoromethylene (CF2) unit replaces
phosphoryl ester oxygen, have been developed for many
biological studies and therapeutics designs.4,5 In comparison
with methyl phosphonates, the physicochemical properties of
difluoromethyl phosphonates are more similar to those of the
corresponding phosphates.6 However, the syntheses of CF2-
substituted pSer/pThr mimetics, especially in a form suitable
for solid-phase peptide synthesis (SPPS) (Figure 1), are still
rather challenging.
Figure 1. Structures of difluoromethyl phosphonate mimetics of pSer
and pThr.
preparation of CF2-substituted pSer mimetic 1, among several
synthetic approaches8,9 the recently reported one employed the
reaction of a chiral aziridine with the lithium anion of diethyl
difluoromethylenephosphonate.5e,9a However, the chiral azir-
idine needs to be prepared either through enzymatic
desymmetrization of prochiral N-protected serinol or via a
five-step synthesis from serine.10 Thus, it is of great interest to
develop a general facile synthetic strategy toward both CF2-
pThr 2 and CF2-pSer 1.
The construction of a secondary CF2 phosphonate unit along
with two stereocenters largely increases the difficulty of
generating a CF2-substituted pThr mimetic than the pSer
one. Dating back to previous pioneering work, there are only a
few synthetic strategies available. Berkowitz’s group reported
that a stereoselective synthesis of CF2-pThr 2 relied on
diastereomerization in a deprotection step7 (Scheme 1A).
Otaka’s group described a synthetic approach toward CF2-pThr
2 utilizing Oppolzer’s sultam chiral auxiliary, which first
constructed the β-stereocenter utilizing diastereoselective
hydrogenation of the olefinic sultam−imide phosphonate
derivative followed by stereoselective amination of the α-
carbon8 (Scheme 1A). A more facile synthetic route with higher
total yield and fewer steps remains in demand. As for the
In Otaka’s route,8 one of key steps is constructing a β-
stereocenter by utilizing diastereoselective hydrogenation of
olefinic phosphonate derivative. It inspired us to consider the
possibility of simultaneously constructing two stereocenters in
CF2-pThr 2 by employing olefinic asymmetric hydrogenation.
Moreover, we noticed that the enantioselective catalyzed
hydrogenation of β-alkyl α-(acylamino)acrylates has emerged
as a valuable synthetic tool for the preparation of enantiopure
Received: April 11, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01151
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Previous and Present Synthetic Strategies for
CF2-Substituted pThr Mimetic
Scheme 2. Synthesis of N-Fmoc-Protected CF2-pSer 3
Otaka’s procedures.8 The resultant prochiral substrate 7 was
then asymmetrically hydrogenated to construct an α-stereo-
center using the Rh−DuPhos system14 (consisting of the
catalyst Rh(COD)2BF4 and the ligand (S,S)-Et-DuPhos for
enantioselective hydrogenation of α-(acylamino)acrylate to
obtain the (S)-α-stereocenter11c), yielding S-form difluoro-
methyl phosphonate 8 as a predominant product with 90% ee,
characterized by chiral HPLC (Supporting Information, SI).
The phosphonate 8 was subsequently deprotected by trifluoro-
acetic acid (TFA) and treated with Fmoc-OSu to give the N-
Fmoc-protected final product 3. The total yield of this synthetic
route is over 35%, which is a significant improvement compared
with previous strategies.9
Next, we applied this strategy to the synthesis of N-Fmoc-
protected CF2-pThr 4 starting from N-Boc-protected L-
threonine α-tert-butyl ester (Scheme S1). Meanwhile, to ensure
that E-form prochiral hydrogenation substrate S3 is the
predominant product, the β-halogenation step was slightly
modified by a shift to use N-bromosuccinimide (NBS) and
lithium bis(trimethylsilyl)amide (LiN(TMS)2) instead of NIS
and TEA, as previously reported.17 However, the asymmetric
hydrogenation of the tetrasubstituted substrate S3 was
unsuccessful. Over 80% of the substrate was not converted,
even after the hydrogen pressure, reaction temperature, and
amount of catalysts were increased (Table S1).
It seemed that the addition of the methyl group into the β-
carbon of the substrate caused the failure of asymmetric
hydrogenation due to steric hindrance. According to some
successful attempts of Rh-catalyzed asymmetric hydrogenation
of similar tetrasubstituted substrates,11a,d,14,17a we estimated
that the substitution of the bulky protection groups Boc and
tert-butyl ester by small protection groups such as acetyl and
methyl ester might improve the efficiency of asymmetric
hydrogenation. Therefore, L-threonine α-methyl ester hydro-
chloride was chosen as the starting material instead (Scheme
3). First, it was treated with acetic anhydride and sodium
α-amino acids derivatives in the past decades.11 This kind of
reaction is usually processed through a rhodium-chelating
intermediate involving chiral phosphorus ligand, the CC
double bond, and the acyl CO group of the substrate.11a As a
result, the conformation of the α-stereocenter in the product is
related to that of the ligand, while the β-stereocenter is
determined by the CC double-bond configuration.12 Thus,
we came up with a new strategy to apply this powerful reaction
for the asymmetric synthesis CF2-pSer 1/CF2-pThr 2 and their
derivatives. Herein, we report a general synthetic strategy with
high total yields to construct N-Fmoc-protected CF2-
substituted pSer mimetic 3 and pThr mimetic 4, which were
designed in a form suitable for SPPS, starting from
commercially available Ser and Thr derivatives via rhodium-
catalyzed asymmetric hydrogenation of β-difluorophosphono-
methyl α-(acylamino)acrylates (Scheme 1B).
Following this strategy, we chose commercially available N-
Boc-protected L-serine α-tert-butyl ester as a starting material
for the synthesis of N-Fmoc-protected CF2-pSer 3 (Scheme 2).
The substrate was first treated with methanesulfonyl chloride
and triethylamine to give a sulfonic ester intermediate, followed
by β-elimination in the existence of 1,8-diazabicyclo[5.4.0]-
undec-7-ene (DBU) to yield a dehydroalanine derivative 5.13
Next, the β-hydrogen was substituted with an iodo group using
N-iodosuccinimide (NIS) and triethylamine (TEA) according
to previously reported procedures14 to afford Z-form β-
iodoacrylate 615 as the predominant product (Z/E = 94:6),
whose conformation actually has no effect on the chirality of
the final product 3. The difluoromethylenephosphonate group
was introduced to 6 via a Cu(I)-mediated coupling6b,16 with
diethylphosphonodifluoromethyl zinc bromide according to
Scheme 3. Synthesis of N-Fmoc-Protected CF2-pThr 13
B
DOI: 10.1021/acs.orglett.8b01151
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Organic Letters
Letter
carbonate followed by refluxing to afford Z-form N-acetyl
dehydrobutrate 9.18 Then the conversion of 9 to β-
bromodehydrobutrate 10 employed NBS and LiN(TMS)2 as
mentioned above. The subsequent coupling of 10 and
difluoromethylenephosphonate was performed according to
the same procedure in the synthesis of protected CF2-pSer 3.
The resultant product, E-form prochiral substrate 11 (the
conformation was confirmed by NOESY, SI), was then
hydrogenated under catalysis of the Rh-(S,S)-Et-DuPhos
system to yield the desired form difluoromethylenephospho-
nate 12 with 89% ee. As we found that it was unable to remove
the N-acetyl group and methyl ester group while maintaining
the phosphonyl ethyl ester of 12, the compound was fully
deprotected by refluxing in hydrochloride14 and subsequently
treated with Fmoc-OSu to give the final product 13 with a free
phosphonate. The overall yield of this synthetic strategy is
about 25%, more efficient than previous reactions.7,8
peptide interaction. For Pep-CF2pS 14, the phosphonyl ethyl
ester groups were removed by using a mixture of BSTFA,
TBAI, and BF3·Et2O in DCM prior to peptide detachment
from the resin.8 Finally, the peptides were cleaved from the
resin by a mixture of TFA, TIS, and water (95:2.5:2.5 (v)) with
all side-chain protection groups removed. After purification by
preparative HPLC, the peptides were characterized by
analytical HPLC and ESI-MS (SI). In addition, the control
peptides Pep-pThr 16 containing natural pThr and non-
phosphorylated Pep-Thr 17 (Figure 2A) were prepared
following the same synthetic strategy.
Subsequently, we applied fluorescence polarization to
measure the binding affinities of these peptides with 14-3-3 ζ
protein, respectively. Each fluorescent peptide (14, 15, 16, and
17) was dissolved and diluted in buffer A (50 mM Tris, 100
mM NaCl, pH = 7.5) to a final concentration of 100 nM and
then mixed with an increasing concentration of 14-3-3 ζ protein
until the polarization value of those peptides reached saturation.
The nonphosphorylated Pep-Thr 17 exhibited no obvious
change in its polarization value, while all other peptides
displayed a sharp increase in polarization signals, indicating the
association between those peptides and the protein. These
polarization signals were fitted to the saturation titration
equation (eq 1, SI)21 to achieve Kd values. As shown in Figure
2B, Pep-CF2pS 14 exhibited a Kd value of 0.34 0.04 μM when
binding with 14-3-3 ζ protein, reflecting a similar affinity to the
parent peptide RLYHpSLPA (a Kd value of 0.46 μM5a).
However, Pep-CF2pT 15 displayed a Kd value of 0.27 0.04
μM, which indicates a much higher binding affinity with the
protein than the naturally phosphorylated Pep-pThr 16 (4.44
0.73 μM). A possible explanation to this difference is that the β-
methyl group of pThr in Pep-pThr 16 might break some
hydrogen bonds nearby between peptide and protein, but the
fluorine atoms in Pep-CF2pT 15 could act as hydrogen bond
acceptors, thus recovering some broken hydrogen bonds.
In addition, we have also evaluated the interaction between
these peptides and 14-3-3 ζ in the presence of alkaline
phosphatase (ALP), indicating that phosphonate-containing
peptides could be successful replacement of corresponding
phosphopeptides as useful tools in cellular context (Figure S4,
SI).
To demonstrate the applicability of the obtained N-Fmoc-
protected CF2-substituted pSer/pThr mimetics 3/13 in Fmoc
SPPS, we used them in the synthesis of two phosphopeptide
mimetics Pep-CF2pS 14 and Pep-CF2pT 15 derived from the
substrate sequence of 14-3-3 ζ protein (RLYHpSLPA)19
(Figure 2A). In our previous work,5a we incorporated the
In summary, we have developed a novel, practical and
efficient strategy to synthesize CF2-substituted pSer and pThr
mimetics via the Rh-DuPhos system catalyzed asymmetric
hydrogenation. Before our present work, only the Berkowitz
and the Otaka strategies could reach the difluoromethyl
phosphonate mimetic of phosphothreonine, while both
strategies spend a number of steps in constructing the α,β-
dual-chiral-center structure. Our strategy significantly improves
the total yield by constructing two chiral centers in one step
through asymmetric hydrogenation of the acrylate substrate,
which is achieved using a serial of common reactions under
mild conditions starting from commercially available amino
acid derivatives. Furthermore, we proved that the Fmoc-
protected CF2-substituted pSer/pThr mimetics can be used in
SPPS to generate phosphatase-inert substrate peptides of 14-3-
3 ζ, which display similar binding efficacy with the parent
sequence. Since this strategy could be efficient in large-scale
acquisition of the pSer/pThr mimetics, we envisage that it has
broad applicability in generating phosphatase-inert phospho-
peptides/phosphoproteins used as valuable in vivo tools for
probing phosphorylation’s role and manipulating pSer/pThr
involved PPIs.
Figure 2. (A) Structures of the synthesized fluorescent peptides. (B)
Fluorescence polarization measurements of the fluorescent peptides,
respectively. Kd values of all peptides except Pep-Thr 17 were
generated by fitting to eq 1 (SI).
CH2-substituted pSer mimetic into this substrate peptide
instead of pSer. The resultant phosphatase-resistant peptide
retained 14-3-3 ζ binding efficacy similar to the parent pSer-
containing peptide. According to the known procedures,20 we
chose rink amide MBHA resin for peptide anchoring to create
an amide C-terminus, followed by peptide elongation via
standard Fmoc SPPS. In order to evaluate the binding affinity
of the peptides to 14-3-3 ζ by fluorescence polarization, we also
introduced 5(6)-carboxyfluorescein (5(6)-FAM) to the N-
terminus of the peptides. In addition, a triglycerol linker was
inserted between the 5(6)-FAM group and the amino acid
sequence to minimize the effect of FAM on the protein−
C
DOI: 10.1021/acs.orglett.8b01151
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b01151.
■
S
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Experimental procedures and detailed characterization
data of all new compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: chen-yx@mail.tsinghua.edu.cn.
ORCID
Yan-Mei Li: 0000-0003-1215-5010
Yong-Xiang Chen: 0000-0003-3518-0139
Author Contributions
†H.-X.C. and J.K. contributed equally.
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Z. Synth. Commun. 2016, 46, 977−982.
(14) Roff, G. J.; Lloyd, R. C.; Turner, N. J. J. Am. Chem. Soc. 2004,
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Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
This work is supported by grants from the National Natural
Science Foundation of China (91753122, 21672125). We thank
Prof. Dr. Qiang Liu (Department of Chemistry, Tsinghua
University) for assistance with hydrogenation facilities.
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