Hydrodehalogenation of alkyl iodides with base-mediated hydrogenation and catalytic transfer hydrogenation: Application to the asymmetric synthesis of N-protected α-methylamines

Article abstract of DOI:10.1021/jo500911v

We report a very mild synthesis of N-protected α-methylamines from the corresponding amino acids. Carboxyl groups of amino acids are reduced to iodomethyl groups via hydroxymethyl intermediates. Reductive deiodination to methyl groups is achieved by hydrogenation or catalytic transfer hydrogenation under alkaline conditions. Basic hydrodehalogenation is selective for the iodomethyl group over hydrogenolysis-labile protecting groups, such as benzyloxycarbonyl, benzyl ester, benzyl ether, and 9-fluorenyloxymethyl, thus allowing the conversion of virtually any protected amino acid into the corresponding N-protected α-methylamine.

Full text of DOI:10.1021/jo500911v

Note
pubs.acs.org/joc
Open Access on 08/12/2015
Hydrodehalogenation of Alkyl Iodides with Base-Mediated
Hydrogenation and Catalytic Transfer Hydrogenation: Application to
the Asymmetric Synthesis of N‑Protected α‑Methylamines
Pijus K. Mandal, J. Sanderson Birtwistle, and John S. McMurray*
Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, 1901 East Road, Houston, Texas
77054, United States
S
* Supporting Information
ABSTRACT: We report a very mild synthesis of N-protected α-methylamines
from the corresponding amino acids. Carboxyl groups of amino acids are
reduced to iodomethyl groups via hydroxymethyl intermediates. Reductive
deiodination to methyl groups is achieved by hydrogenation or catalytic
transfer hydrogenation under alkaline conditions. Basic hydrodehalogenation is
selective for the iodomethyl group over hydrogenolysis-labile protecting groups, such as benzyloxycarbonyl, benzyl ester, benzyl
ether, and 9-fluorenyloxymethyl, thus allowing the conversion of virtually any protected amino acid into the corresponding N-
protected α-methylamine.
n the field of peptidomimetic drug development, the goal is
to incorporate nonproteinogenic amino acid surrogates into
to a variety of amino acids, including bis-Boc histidine, Boc-
Tyr(Me), and Boc-Ser(Bn). The side-chain benzyl protecting
group of serine was removed by the Raney nickel. Khono et al.
reported the synthesis of (R)-2-amino-1-(4-methoxyphenyl)-
propane starting with tyrosine in which the amino, side-chain
hydroxyl, and carboxyl groups were protected with benzylox-
ycarbonyl, methyl, and ethyl groups, respectively (Cbz-
Tyr(Me)-OEt).4 The carboxyl ester was reduced to the
hydroxymethyl group with NaBH4. After activation as a tosyl
ester, the tosylate was reduced with Zn powder in the presence
of NaI in refluxing aqueous dimethoxyethane. The Cbz group
was stable to these conditions, and it was subsequently
removed using standard hydrogenation. Quagliato et al.
reduced the carboxyl group of free amino acids using LiBH4,
followed by Boc protection of the amino group.11 The
hydroxymethyl group was transformed to an iodomethyl
group with I2 and polymer supported triphenylphosphine.
The iodomethyl group was reduced to the methyl group using
L-Selectride. Some of these methods required elevated
temperatures, and not all amino and side-chain protecting
groups were stable to all of the reduction steps. We, therefore,
sought a methodology that could be used to convert α-amino
acids bearing standard protecting groups to N-protected and
“side-chain”-protected α-methylamines.
I
candidate compounds to introduce new ligand−receptor
interactions, to reduce proteolytic susceptibility, and to increase
bioavailability. α-Methylamines represent a class of amino acid
replacements in which the carboxyl group of the amino acid is
converted to a methyl group and which, therefore, can serve as
C-terminal amino acid mimics. Indeed, our laboratory reported
that replacing the CONHBn group of a C-terminal Gln-NHBn
with a methyl group increased cellular potency approximately
50-fold in a set of STAT3 phosphorylation inhibitors1 (Figure
1). In addition to peptidomimetics, α-methylamines are
components of several important drug classes, such as
adrenergic receptor agonists,2−5 α-methylhistamine and ana-
logues,6,7 inhibitors of phenylethanolamine N-methyl trans-
ferase,8 amphetamine analogues,9 dopamine analogues,10
potassium channel modulators,11 and cathepsin K inhibitors,12
to name but a few (Figure 1).
Complete reduction of the carboxyl group of α-amino acids
to a methyl group is a common strategy for the stereospecific
synthesis of α-methylamines. This is a multistep process, and
typical strategies involve reduction of the carboxyl group to a
hydroxymethyl group, followed by derivatization to moieties
that are further reduced to the methyl group. The following
examples illustrate varying approaches to the several steps in
the synthesis. Starting with L-histidinol (in which the carboxyl
group of histidine was reduced to the hydroxymethyl group),
Friary et al. converted the hydroxyl group to the chloride, then
reduced the chloromethyl group with catalytic transfer
hydrogenolysis using ammonium formate in refluxing meth-
anol.7 Donner reduced free carboxyl groups of N-Boc-protected
amino acids with borane to hydroxymethyl groups and
converted these to the corresponding ethyl thioethers via
tosylates.13 Desulfurization with Raney nickel afforded the N-
Boc-protected α-methylamine. This methodology was applied
Our laboratory reported a catalytic transfer hydrogenation
(CTH) method using triethylsilane (TES) and 10% Pd/C to
remove benzyl-type protecting groups and to reduce nitro
groups, imines, azides, and both conjugated and nonconjugated
multiple bonds under neutral conditions.14 Though a wide
variety of functional groups were reduced, TES/Pd−C-
mediated reduction of organic halides was not explored.
Herein, we report that CTH as well as conventional
Received: April 24, 2014
© XXXX American Chemical Society
A
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The Journal of Organic Chemistry
Note
Figure 1. α-Methylamines utilized in pharmacological applications.
hydrogenation under alkaline conditions is an efficient and
chemoselective method of hydrodehalogenation of alkyl iodides
derived from the carboxyl groups of protected α-amino acids to
produce chiral α-methylamines.
As illustrated with tert-butyloxycarbonyl-leucine (Scheme 1),
protected amino acids were reduced to the corresponding β-
Conventional hydrogenation in MeOH/THF over 10% Pd−
C in the presence of 1.5−2 equiv of DIEA also resulted in
reductive deiodination to the α-methyl group. This suggested
that the formation of HI poisons the Pd catalyst and that DIEA
neutralizes the acid. Dehydrohalogenation of iodomethyl
intermediates is complete in 4 h for both reduction methods
as judged by reverse phase HPLC.
a
Scheme 1.
Reductive deiodination of alkyl iodides derived from a variety
of protected amino acids was performed under both conditions,
CTH with TES/Pd−C and conventional hydrogenation with
H2/Pd−C, in the presence of DIEA (Table 1). These basic
conditions are selective for deiodination and leave untouched
benzyl-based amino or hydroxyl protecting groups, such as
benzyloxycarbonyl (Z), benzyl ester (OBzl) and benzyl ether,
and 9-fluorenyloxymethyl (Fmoc), which are cleaved by
standard hydrogenation reactions. Thus, our methodology
allows the preparation of α-methylamines containing a wide
variety of protected functionalities, e.g., the side-chain amino
group of lysine (entry 6), the side-chain carboxyl group
glutamic acid (entry 7), and by inference aspartic acid, the
hydroxyl groups of tyrosine and serine (entries 8 and 9,
respectively), the indole of tryptophan (entry 10), and the
imidazole of histidine (entry 11). In our studies, we have
chosen to keep the amino α-protecting groups intact for
stability on storage. At the appropriate time, these protecting
groups can be removed using standard deprotection conditions.
Oba and colleagues introduced deuterium in leucine
derivatives by free-radical-mediated Bu3SnD/AIBN reduction
of methyl iodides.19,20 In a similar vein, we found that the
iodine atom could be readily replaced with a deuterium using
TES-d in the catalytic transfer hydrogenation reaction, as
illustrated for Fmoc-PheψCH2D (5e) in Scheme 2. Although
methanol is a potential hydrogen source, no trace of the
trihydrogen species was found, indicating that, during TES-
mediated CTH, triethylsilane is the sole source of hydrogen.
In the case of 4-iodophenylalanine, mass spectroscopic
analysis of the hydrogenation reactions, using both H2 and
TES, at various time points revealed that the aromatic side
chain is deiodinated first. This is in keeping with dehalogena-
tion of aromatic halides with hydrogenation, which is known to
a
Reagents and conditions. (i) a, IBCF, NMM, −15 °C; b, NaBH4,
quantitative; (ii) I2, Ph3P, imidazole 67%; (iii) H2, or TES, Pd/C,
DIEA (see Table 1 for yields).
amino alcohols by activation of the carboxyl group as a mixed
carbonic anhydride (MCA) using iso-butyl chloroformate
(IBCF), followed by in situ reduction with sodium borohy-
dride.15−17 The hydroxyl group was replaced by an iodide by
treatment with iodine, triphenylphosphine, and imidazole to
give the iodomethyl intermediate, 1c.18
Using standard CTH conditions, addition of TES to a stirred
suspension of 1c in MeOH/THF in the presence of 10% Pd−C
under argon resulted in the immediate evolution of hydrogen
gas, as is normally observed.14 However, there was no evidence
of deiodination, even after stirring for the extended reaction
time of 24 h. Conventional hydrogenation in MeOH/THF in
the presence of 10% Pd−C also failed to reduce the iodo
intermediate. Interestingly, addition of 2 equiv of the tertiary
amine, diisopropylethylamine (DIEA), to the TES Pd/C-
mediated CTH reaction resulted in complete reduction of the
iodide to the corresponding N-Boc-α-methylamine (1d).
B
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Note
Table 1. Yields of the Conversion of α-Iodomethylamines to
α-Methylamines by Base-Mediated Dehydrohalogenation
Scheme 2
conditions are not selective with respect to the reduction of
nitro groups.
To test for epimerization of the α-carbon during these
procedures, we converted both L- and D-Boc-Thr(Bn)-OH to
the corresponding α-methylamines, 12d and 13d, respectively,
using both H2 and TES conditions. As threonine has two chiral
centers, it was reasoned that the potential diastereomers
resulting from the synthesis would be readily detected. Chiral
HPLC indicated the presence of single diastereomers. Neither
1H nor 13C NMR spectra indicated the presence of more than
one stereoisomer. As further proof, the Boc group was removed
from 12d and the α-methylamine was derivatized with
Mosher’s reagent to give a product with three stereocenters
(14, Scheme 3). Chiral HPLC of the unpurified product
Scheme 3
showed one peak, and 1H and 19F NMR showed only one set of
resonances. Thus, the chirality of the α-carbon remains intact
during all phases of the transformation. This is in keeping with
the work of Quagliato et al., who reported that reduction of α-
iodomethylamines derived from N-Boc-amino acids either with
H2/Pearlman’s catalyst or with L-Selectride to form α-
methylamines did not epimerize the α-carbon.11
In summary, dehydrohalogenation of the alkyl amines
derived from N-protected amino acids can be accomplished
by conventional hydrogenolysis or CTH in the presence of a
tertiary amine. Hydrogenation under alkaline conditions leaves
intact side-chain protecting groups, thus allowing the
conversion of virtually any protected amino acid into the
corresponding α-methylamine. Removal of the amino protect-
ing group would permit facile incorporation into peptidomi-
metic or other drug candidates.
EXPERIMENTAL SECTION
■
Preparation of N-Protected β-Amino Alcohols (General
Procedure).16,17 The preparation of Boc-LeuψCH2OH, 1b, is given
as an example. A solution of Boc-Leu-OH (4.34 g, 18.8 mmol) in dry
THF (40 mL) was cooled to −10 °C under an argon atmosphere. N-
Methylmorpholine (NMM) (2.5 mL, 22.6 mmol, 1.2 equiv) was
added, followed by dropwise addition of isobutyl chloroformate (2.9
mL, 22.6 mmol, 1.2 equiv). After stirring at −10 °C for 10 min, the
reaction was allowed to increase to room temperature over 60 min.
The precipitated NMM hydrochloride was filtered off, and the filtrate
cooled to −10 °C. NaBH4 (1.07 g, 28.2 mmol, 1.5 equiv) was added.
After 15 min, the reaction was quenched with 2% KHSO4 (25 mL)
until the effervescence ceased. Ethyl acetate (200 mL) was added, and
the solution was washed with water (200 mL) and 5% NaHCO3 (100
mL), followed by brine (100 mL), before drying over MgSO4. Filtering
a
Yields are calculated from weights of final products after chromato-
b
graphic purification. The N-protected α-methylamine was not
separable from nonpolar, silane-based side products resulting from
the TES in the CTH reaction.
be very rapid.21 Attempts to deiodinate the iodomethyl
derivative of 4-nitrophenylalanine, using both procedures,
resulted in mixtures of compounds, indicating that the
C
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Note
and removal of the solvent under reduced pressure gave the protected
amino alcohol of sufficient purity to proceed to the next reaction.
Analysis was done by TLC and/or HPLC and NMR.
(m, 1H), 3.4 (m, 1H), 3.5 (m, 1H), 4.2 (t, J = 7.0 Hz, 1H), 4.41 (m,
2H), 4.93 (d, J = 9.0 Hz, 1H), 5.1 (s, 2H), 7.27−7.42 (m, 9H), 7.6 (d,
J = 7.5 Hz, 2H), 7.75 (d, J = 8.0 Hz, 2H). 13C NMR (75 MHz,
CDCl3): δ 13.5, 30.1, 30.6, 47.3, 50.3, 66.6, 66.8, 120.0, 125.0, 127.1,
127.7, 128.3, 128.4, 128.6, 135.7, 141.3, 143.8, 155.6, 172.8. HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C27H27INO4 556.0985; Found
556.1021.
Z-Tyr(Bn)ψCH2I, 8c. Yield 2.3 g, 89%, starting from 5.2 mmol of 8b.
1H NMR (300 MHz, CDCl3) δ 2.68 (dd, J = 8.0 and 13.2 Hz, 1H), 2.8
(dd, J =5.6 and 13.2 Hz, 1H), 3.13 (dd, J = 3.34 and10.5 Hz,1H), 3.35
(dd, J = 3.5 and 9.4 Hz, 1H), 3.6 (m, 1H), 4.86 (d, J = 8.0 Hz, 1H),
5.00 (s, 2H), 5.05 (s, 2H), 6.8 (d, J = 8.1 Hz, 2H), 7.1 (d, J = 8.1 Hz,
2H), 7.25−7.6 (m, 10H). 13C NMR (75 MHz, CDCl3): δ 157.9, 155.4,
137.0, 136.3, 133.3, 133.2, 131.3, 131.2, 130.2, 129.6, 129.0, 128.8,
128.7, 128.6, 128.6, 128.2, 128.1, 128.0, 127.5, 115.1, 70.1, 66.9, 51.7,
39.7, 13.5. HRMS (ESI-TOF) m/z:[M + NH4]+ Calcd for
C24H28IN2O3 519.1145; Found 519.1154.
Alternate Procedure: Preparation of Boc-Leucinol, 1b. In this
case, a procedure different from the above was utilized. Leucine methyl
ester hydrochloride (1 equiv; 27.5 mmol) and Boc-anhydride (1.5
equiv; 41.3 mmol) were dissolved in CH2Cl2 (135 mL), and
triethylamine (1.5 equiv, 41.3 mmol, 5.5 mL) was added. The mixture
was stirred for 3 h at room temperature. The solution was washed with
2% KHSO4 (100 mL) and 5% NaHCO3 (100 mL), followed by brine
(50 mL), before drying over MgSO4. Removal of the solvent under
reduced pressure gave the Boc-leucine methyl ester as a clear oil. The
Boc-leucine methyl ester and NaBH4 (4 equiv, 88.9 mmol) were
dissolved in dry THF (110 mL) under an argon atmosphere, and
methanol (24 equiv, 22 mL) was added dropwise. The vigorous
effervescence was controlled by a cold water bath. After 3 h, the
volume of the solution was reduced under reduced pressure to ca. 80
mL and quenched with water (100 mL) before extracting with ethyl
acetate (2 × 100 mL). The extract was washed with brine (100 mL)
and dried over MgSO4. Filtering and removal of the solvent gave the
product as a clear oil.
Fmoc-Ser(Bn)ψCH2I, 9c. Yield 1.8 g, 72%, starting from 4.95 mmol
1
of 9b. H NMR (300 MHz, CDCl3) δ 3.38 (m, 2H),3.5 (m, 1H), 3.7
(m, 1H), 3.8 (m, 1H), 4.2 (t, J = 7.4 Hz, 1H), 4.42 (m, 2H), 4.52 (s,
2H), 5.2 (d, J = 8.2 Hz, 1H), 7.27−7.42 (m, 9H), 7.6 (d, J = 7.5 Hz,
2H), 7.75 (d, J = 7.5 Hz, 2H). 13C NMR (75 MHz, CDCl3): δ 47.3,
51.1, 67.0, 70.4, 73.5, 120.1, 125.1, 127.1, 127.8, 127.8, 128.0, 128.2,
128.6, 137.6, 141.4, 143.9, 155.6. HRMS (ESI-TOF) m/z: [M + H]+
Calcd for C25H25INO3 514.0879; Found 514.0890.
Preparation of Protected Amino Iodides (General Proce-
dure).18 The preparation of Boc-LeuψCH2I, 1c, is provided as an
example. Iodine (7.99 g, 27.6 mmol, 2 equiv) was added to triphenyl
phosphine (7.23 g, 27.6 mmol, 3 equiv) and imidazole (3.13 g, 46
mmol, 5 equiv) dissolved in CH2Cl2 (60 mL), and the mixture was
stirred for 30 min. Boc-leucinol (2.00 g, 9.2 mmol, 1 equiv) dissolved
in CH2CL2 (20 mL) was added dropwise. After 2 h, the white
precipitate was filtered and the filtrate was washed with brine (2 × 100
mL) before drying over MgSO4. Removal of the solvent under reduced
pressure gave a brown solid that was purified by silica gel
chromatography using 10−20% ethyl acetate in hexane. Yield 2.0 g,
67%, starting from 9.2 mmol of 1b. Identical to that reported by
Caputo et al.22 1H NMR (300 MHz, CDCl3) δ 0.93−1.00 (m, 6H),
1.36 (t, J = 7.0 Hz, 2H), 1.46 (s, 9H), 1.57−1.72 (m, 1H), 3.26−3.33
(m, 1H), 3.36−3.52 (m, 2H), 4.5 (brs, 1H).
Fmoc-Trp(Boc)ψCH2I, 10c. Yield 1.4 g, 57%, starting from 4.0 mmol
1
of 10b. H NMR (600 MHz, CDCl3) δ 1.71 (s, 9H), 2.98 (m, 1H),
3.09 (m, 1H), 3.32(m, 1H),3.48 (m, 1H),3.9 (m, 1H), 4.27 (t, J = 7.0
Hz,1H), 4.41−4.49 (m, 2H), 5.1 (d, J = 7.75 Hz, 1H),7.3−7.46 (m,
7H), 7.56−7.63 (m, 3H), 7.7 (d, J = 8.0 Hz, 1H), 7.8 (d, J = 7.6 Hz,
2H), 8.18 (s, 1H). 13C NMR (150 MHz, CDCl3): δ 155.6, 149.6,
143.8, 141.3, 135.5, 130.2, 127.8, 127.1, 125.1, 124.7, 124.2, 122.8,
120.1, 119.1, 115.7, 115.4, 83.8, 67.0, 50.3, 47.2, 30.5, 28.2, 13.4.
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C31H32IN2O4 623.1407;
Found 623.1409.
Fmoc-His(Boc)ψCH2I, 11c. Yield 1.6 g, 63%, starting from 4.4 mmol
1
Z-LeuψCH2I, 2c. Yield 2.5 g, 88%, starting from 7.96 mmol of 2b.
of 11b. H NMR (500 MHz, CDCl3) δ 1.63 (s, 9H), 2.90 (m, 1H),
1H NMR (300 MHz, CDCl3) δ 0.90−0.94 (m, 6H), 1.36 (m, 2H),
3.04 (m, 1H), 3.26 (m, 1H), 3.39 (m. 1H), 3.97 (m, 1H), 4.26 (m,
1H), 4.38 (m, 2H), 6.06 (d, J = 8.1 Hz, 1H), 7.29 (s, 1H), 7.32−7.35
(m, 2H), 7.41−7.43 (m, 2H), 7.61−7.64 (m, 2H), 7.78 (d, J = 7.5.Hz,
2H), 8.08 (s, 1H). 13C NMR (125 MHz, CDCl3) δ: 155.6, 146.8,
143.9, 141.3, 138.6, 137.0, 127.7, 127.1, 125.2, 120.0, 115.1, 85.9, 66.9,
50.9, 47.2, 31.6, 27.9, 18.9, 10.9. HRMS (ESI-TOF) m/z: [M + H]+
Calcd for C26H29IN3O4 574.1203; Found 574.1214.
1.62 (m, 1H), 3.26 (m, 1H), 3.4−3.54 (m, 2H), 4.9 (d, J = 9.0 Hz,
1H), 5.1 (s, 2H), 7.3−7.38 (m, 5H). 13C NMR (75 MHz, CDCl3): δ
15.4, 22.5, 22.7, 24.7, 44.2, 48.5, 66.9, 128.1, 128.2, 128.6, 136.4, 155.6.
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C14H21INO2 362.0617;
Found 362.0662.
Boc-PheψCH2I, 3c. Yield 2.16 g, 65%, starting from 9.2 mmol of 3b.
Identical to that reported by Quagliato et al.11 and Caputo et al.22 1H
NMR (300 MHz, CDCl3) δ 1.45 (s, 9H), 2.8 (dd, J = 8.1 and 13.2 Hz,
1H), 2.93 (dd, J = 5.7 and 13.5 Hz, 1H), 3.18 (dd, J = 4.0 and 10.1 Hz,
1H), 3.42 (dd, J = 4.1 and 10.0 Hz, 1H), 3.62 (m, 1H), 4.7 (brs, 1H),
7.25−7.36 (m, 5H).
Z-PheψCH2I, 4c. Yield 1.2 g, 85%, starting from 4.2 mmol of 4b.
Identical to that reported by Caputo et al.22 1H NMR (300 MHz,
CDCl3) δ 2.82 (dd, J = 8.0 and 13.6 Hz, 1H), 2.95 (dd, J = 6.0 and
13.9 Hz, 1H), 3.2 (dd, J = 4.0 and10.3 Hz, 1H), 3.43 (dd, J = 4.4 and
10.1 Hz, 1H), 3.71 (m, 1H), 4.95 (d, J = 7.7 Hz, 1H), 5.1 (s, 2H),
7.22−7.43 (m 10H).
Boc-L-Thr(OBzl)ψCH2I, 12c. Yield 1.0 g, 73%, starting from 3.4
1
mmol of Boc-L-Thr(OBzl)-CH2OH. H NMR (600 MHz, CDCl3) δ
1.22 (d, J = 6.3 Hz, 3H), 1.44 (s, 9H), 3.24−3.3 (m, 2H), 3.72 (m,
1H), 4.02 (m, 1H), 4.41 (d, J = 11.3 Hz, 1H), 4.63 (d, J = 11.3 Hz,
1H), 5.00(d, J = 9.0 Hz, 1H), 7.27−7.38 (m, 5H). 13C NMR (75 MHz,
CDCl3): δ 6.9, 16.7, 28.4, 56.3, 71.3, 73.5, 79.7, 127.9, 128.0, 128.5,
138.0, 155.5. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C16H25INO3 406.0879; Found 406.0872.
Boc-D-Thr(OBzl)ψCH2I, 13c. Yield 1.04 g, 76%, starting from 3.4
1
mmol of Boc-D-Thr(OBzl)-CH2OH. H NMR (600 MHz, CDCl3) δ
1.22 (d, J = 6.3 Hz, 3H), 1.44 (s, 9H), 3.24−3.3 (m, 2H), 3.72 (m,
1H), 4.02 (m, 1H), 4.40 (d, J = 11.3 Hz, 1H), 4.63 (d, J = 11.3 Hz,
1H), 5.00(d, J = 9.0 Hz, 1H), 7.27−7.38 (m, 5H). 13C NMR (75 MHz,
CDCl3): δ 6.9, 16.7, 28.4, 56.3, 71.3, 73.5, 79.7, 127.9, 128.0, 128.5,
138.0, 155.5. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C16H25INO3 406.0879; Found 406.0882.
Dehalogenation of N-Protected β-Amino Iodides (General
Procedure). The conversion of Boc-LeuψCH2I, 1c, to Boc-LeuψCH3,
1d, is given as an example.
Fmoc-PheψCH2I, 5c. Yield 2.3 g, 85%, starting from 5.2 mmol of
5b. Identical to that reported by Caputo et al.22 1H NMR (300 MHz,
CDCl3) δ 3.0−2.8 (m, 2H), 3.2 (dd, J = 3.6 and 10.0 Hz, 1H), 3.45
(dd, J = 4.2 and 10.2 Hz, 1H), 3.7 (m, 1H), 4.24 (t, J = 6.8 Hz, 1H),
4.42 (d, J = 6.7 Hz, 2H), 4.93 (d, J = 8.1 Hz, 1H), 7.26−7.36 (m, 7H),
7.4−7.46 (m, 2H), 7.56−7.62 (m, 2H), 7.8 (d, J = 7.5 Hz, 2H).
Z-Lys(Boc)ψCH2I, 6c. Yield 2.0 g, 76%, starting from 5.46 mmol of
1
6b. H NMR (300 MHz, CDCl3) δ 1.3−1.6 (m, 15H), 3.1 (m, 2H),
3.31 (m, 1H), 3.41 (m, 2H), 4.6 (brs, 1H), 5.0 (brs, 1H), 5.1 (s, 2H),
7.3−7.4 (m, 5H). 13C NMR (75 MHz, CDCl3): δ 14.1, 22.8, 28.5,
29.7, 34.6, 40.1, 50.4, 66.9, 79.1, 128.1, 128.2, 128.6, 136.3, 155.7,
156.1. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C19H30IN2O4
477.1250; Found 477.1288.
Method A, Conventional Hydrogenation. Boc-LeuψCH2I, 1c
(2.00 g, 6.11 mmol, 1 equiv), and DIEA (1.60 mL, 9.17 mmol, 1.5
equiv) were dissolved in a mixture of THF (27 mL) and methanol (55
mL), and 10% palladium on charcoal (0.200 g) was added. The
mixture was hydrogenated at 49 psi and room temperature for 24 h in
a Parr apparatus. The solvent was removed, and the residue was
dissolved in 100 mL of EtOAc and filtered through Celite. The filtrate
Fmoc-Glu(OBn)ψCH2I, 7c. Yield 1.3 g, 68%, starting from 3.5 mmol
1
of 7b. H NMR (300 MHz, CDCl3) δ1.9 (m, 2H), 2.43 (m, 2H), 3.3
D
dx.doi.org/10.1021/jo500911v | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
was concentrated under vacuum, and the crude product was purified
by silica gel chromatography eluting with 10−20% ethyl acetate in
hexane.
Method B, Catalytic Transfer Hydrogenation with TES. Boc-
LeuψCH2I, 1c (0.700 g, 2.14 mmol1 equiv, 2.14 mmol), triethylsilane
(3.4 mL, 21.4 mmol; 10 equiv), and DIEA (0.56 mL, 3.21 mmol, 1.5
equiv) were dissolved in a mixture of THF (24 mL) and methanol (47
mL), and 10% palladium on charcoal (70 mg) was added into it. The
mixture was stirred at room temperature for 24 h.
The solvent was removed under vacuum, and the residue was
dissolved in 50 mL of EtOAc and filtered through Celite. Solvent was
removed, and the crude was then purified by silica gel chromatography
as above.
Z-Tyr(Bn)ψCH3, 8d. Yield: Method A: 0.295 g, 78%; Method B:
0.310 g, 83%, starting from 1.0 mmol of 8c. H NMR (600 MHz,
1
CDCl3) δ 1.14 (d, J = 7.0 Hz, 3H), 2.7 (m, 1H), 2.8 (m, 1H), 3.98 (m,
1H), 4.62 (m, 1H), 5.07 (s, 2H), 5.11 (s, 2H), 6.93 (d, J = 8.5 Hz,
1H), 7.10 (d, J = 8.0 Hz, 1H), 7.33−7.42 (m, 6H), 7.45−7.48 (m,
3H), 7.52−7.55 (m, 1H), 7.58−7.63 (m, 2H). 13C NMR (150 MHz,
CDCl3): δ 157.5, 137.1, 133.3, 133.2, 131.3, 130.5, 130.2, 129.4, 129.1,
128.8, 128.7, 128.6, 128.5, 128.1, 127.9, 127.5, 114.8, 70.0, 66.5, 48.1,
41.9, 20.2. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C24H26NO3
376.1913; Found 376.1942.
Fmoc-Ser(OBn)ψCH3, 9d. Yield: Method A: 0.345 g, 92%; Method
B: 0.330 g, 88%, starting from 0.97 mmol of 9c. 1H NMR (300 MHz,
CDCl3) δ 1.21 (d, J = 6.0 Hz, 3H), 3.45 (m, 2H), 3.92 (m, 1H), 4.2 (t,
J = 7.0 Hz, 1H), 4.38 (d, J = 7.0 Hz, 2H), 4.52 (m, 2H), 4.98 (brs,
1H),7.25−7.43 (m, 9H), 7.6 (d, J = 7.5 Hz, 2H), 7.75 (d, J = 7.5 Hz,
2H). 13C NMR (75 MHz, CDCl3): δ 18.1, 47.3, 66.6, 73.1, 73.2, 120.0,
125.1, 127.0, 127.6, 127.7, 127.8, 128.5, 138.1, 141.3, 144.0, 155.9.
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C25H26NO3 388.1913;
Found 388.1924.
Fmoc-Trp(Boc)ψCH3, 10d. Yield: Method A: 0.124 g, 77%; Method
B: 0.135 g, 84%, starting from 0.32 mmol of 10c. 1H NMR (600 MHz,
CDCl3) δ 1.22 (m, 2H), 1.69 (s, 9H), 2.82 (m, 1H), 3.03 (m, 1H),
4.15 (m, 1H), 4.24 (m, 1H), 4.4−4.48 (m, 2H), 4.87 (m, 1H), 7.28
(m, 1H), 7.30−7.37 (m, 3H), 7.40−7.48 (m, 3H),7.57−7.61 (m, 2H),
7.66 (m, 1H), 7.79 (m, 2H), 8.16 (s, 1H). 13C NMR (150 MHz,
CDCl3): δ 155.8, 149.7, 144.0, 141.3, 130.9, 127.7, 127.1, 125.1, 124.4,
123.9, 122.6, 120.0, 119.3, 116.9, 115.3, 83.6, 66.6, 47.3, 47.0, 32.2,
28.2, 20.5. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C31H33N2O4
497.2440; Found 497.2456.
Fmoc-His(Boc)ψCH3, 11d. Yield: Method A: 0.200 g, 85%; Method
B: 0.190 g, 81%, starting from 0.53 mmol of 11c. 1H NMR (600 MHz,
CDCl3) δ 1.22 (d, J = 6.0 Hz, 3H), 1.62 (s, 9H), 2.75 (m, 1H), 2.82
(m, 1H), 4.08 (m, 1H), 4.25 (m, 1H), 4.34 (m, 1H), 4.40 (m, 1H),
5.63 (d, J = 6.5 Hz, 1H), 7.20 (s, 1H), 7.31−7.34 (m, 2H), 7.39−7.43
(m, 2H), 7.60−7.63 (m, 2H), 7.78 (d, J = 7.5 Hz, 2H), 8.06 (s, 1H).
13C NMR (150 MHz, CDCl3): δ 155.8, 147.0, 144.1, 141.3, 136.7,
127.6, 127.0, 125.2, 120.0, 114.5, 85.5, 66.6, 47.3, 46.8, 34.2, 27.9, 20.5.
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C26H30N3O4 448.2236;
Found 448.2257.
Boc-LeuψCH3, 1d. Yield: Method A: 1.1 g, 88%, starting from 6.11
mmol of 1c; Method B: 0.391 g, 91%, starting from 2.14 mmol of 1c.
1H NMR (300 MHz, CDCl3) δ 4.26 (bs, 1H), 3.70 (bs, 1H), 1.68 (m,
1H), 1.43 (s, 9H), 1.36 (m, 2H), 1.10 (d, J = 7.0 Hz, 2H), 0.92 (m,
6H). 13C NMR (125 MHz, CDCl3): δ 155.3, 78.9, 77.3, 77.0, 76.8,
46.7, 44.7, 28.6, 28.4, 25.0, 22.7, 22.6, 21.8. HRMS (ESI-TOF) m/z:
[M + Na]+ Calcd for C11H23NNaO2 224.1626; Found 224.1616.
Z-NHLeuψCH3, 2d. Yield: Method A: 1.2 g, 64%, starting from 8.03
1
mmol of 2c. H NMR (300 MHz, CDCl3) δ 7.37−7.29 (m, 5H),
5.13−5.04 (m, 2H), 4.51 (d, J = 8.0 Hz, 1H), 3.82−3.77 m, 1H),
1.69−1.60 (m, 1H), 1.39−1.16 (m, 2H), 1.14 (d, J = 7.0 Hz, 3H), 0.93
(m, 6H). 13C NMR (125 MHz, CDCl3): δ 155.8, 136.7, 128.6, 128.2,
128.2, 128.1, 128.1, 66.5, 46.6, 45.3, 25.0, 22.8, 22.5, 21.8. HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C14H22NO2 236.1651; Found
236.1611.
Boc-PheψCH3, 3d.11 Yield: Method A: 1.23 g, 91%, starting from
5.73 mmol of 3c. 1H NMR (300 MHz, CDCl3) δ 7.24−7.17 (m, 5H),
4.36 (bd, 1H), 3.91 (m, 1H), 2.87 (m, 2H), 1.45 (s, 9H), 1.14 (d, J =
7.0 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 155.2, 138.3, 129.7,
129.5, 129.3, 128.6, 128.5, 128.3, 126.5, 126.3, 49.1, 47.4, 43.0, 28.4,
20.2, 19.1. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
C14H21NNaO2 258.1470; Found 258.1471.
Z-PheψCH3, 4d. Yield: Method A: 0.28 g, 81%, starting from 1.27
mmol of 4c; Method B: 0.310 g, 76%, starting from 1.52 mmol of 4c.
1H NMR (300 MHz, CDCl3) δ 7.40−7.15 (m, 10H), 5.09 (s, 2H),
4.60 (m, 1H), 4.00 (m, 1H), 2.8 (m, 2H), 1.14(d, J = 7.0 Hz, 3H). 13
C
Fmoc-PheψCH2D, 5e. To a stirred suspension of Fmoc-phenyl-
alanino iodide (100 mg, 0.21 mmol), DIPEA (0.1 mL, 0.63 mmol),
dissolved in a mixture of 10 mL of THF−MeOH (9:1), and 10% Pd−
C (10 mg), was added Et3SiD (10 equiv; 0.3 mL). It was stirred at
room temperature for 12 h (HPLC analysis showed quantitative
conversion), and the mixture was then centrifuged. The supernatant
was then concentrated and purified by RPHPLC. The pure fractions
were then collected and lyophilized to get a white solid (48 mg, Yield:
65%). 1H NMR (600 MHz, CDCl3) δ 1.14 (s, 2H), 2.76 (m, 1H), 2.86
(m, 1H), 4.03 (m, 1H), 4.24 (t, J = 6.5 Hz, 1H), 4.37 (m, 1H), 4.48
(m, 1H), 4.65 (m,1H), 7.20 (m, 2H), 7.26 (m, 1H), 7.31−7.36 (m,
4H), 7.44 (m, 2H), 7.60 (m, 2H), 7.80 (d, J = 7.5 Hz, 2H). 13C NMR
(150 MHz, CDCl3): δ 155.6, 144.0, 141.4, 137.9, 129.5, 128.4, 127.7,
127.1, 126.5, 125.1, 125.0, 120.0, 66.4, 47.9, 47.4, 42.7. HRMS (ESI-
TOF) m/z: [M + H]+ Calcd for C24H23DNO2 359.1870; Found
359.1886.
NMR (125 MHz, CDCl3): δ 155.6, 137.9, 136.6, 129.5, 128.6, −128.4,
128.1, 126.5, 66.51, 48.0, 42.8, 20.2. HRMS (ESI-TOF) m/z: [M +
H]+ Calcd for C17H20NO2 270.1494; Found 270.1536.
Fmoc-PheψCH3, 5d. Yield: Method A: 0.340 g, 89%, starting from
1.03 mmol of 5c; Method B: 1.105 g, 82%, starting from 3.66 mmol of
5c. 1H NMR (300 MHz, CDCl3) δ 7.80 (d, J = 7.5 Hz, 2H), 7.58 (m,
2H), 7.43−7.15 (m, 9H), 4.59 (bd, 1H), 4.48−4.18 (m, 4 H), 2.83 (m,
2H), 1.14 (d, J = 7.0 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ =
155.6, 144.0, 141.4, 137.9, 129.6, 128.4, 127.7, 127.1, 126.5, 125.1,
125.1, 120.0, 66.4, 48.0, 47.3, 42.7, 20.2. HRMS (ESI-TOF) m/z: [M
+ H]+ Calcd for C24H24NO2 358.1807; Found 358.1829.
Z-Lys(Boc)ψCH3, 6d. Yield: Method A: 0.795 g, 83%, starting from
2.85 mmol of 6c; Method B: 0.24 g, 65%, starting from 1.06 mmol of
6c. 1H NMR (300 MHz, CDCl3) δ 7.36−7.30 (m, 5H), 5.08 (s, 2H),
4.57 (m, 2H), 3.73 (m, 1H), 3.11 (m, 2H), 1,27−1.54 (m, 15H), 1.14
(d, J = 7.0 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 156.1, 155.9,
136.6, 128.5, 128.2, 128.1, 66.5, 47.0, 40.3, 36.7, 29.8, 23.1, 21.3.
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C19H31N2O4 351.2284;
Found 351.2285.
Fmoc-Glu(OBn)ψCH3, 7d. Yield: Method A: 0.28 g, 90%, starting
from 0.72 mmol of 7c; Method B: 0.383 g, 81%, starting from 1.1
mmol of 7c. 1H NMR (300 MHz, CDCl3) δ 7.77 (d, J = 7.5 Hz, 2H),
7.59 (d, 2H, J = 7.5 Hz), 7.43−7.30 (m, 9H), 5.10 (s, 2H), 4.62 (d, J =
8.7 Hz, 2H), 4.40 (d, J = 7.0 Hz, 2H), 4.00 (t, J = 7.0 Hz, 1H), 3.77
(m, 1H), 2.43 (t, J = 7.5 Hz, 2H), 1.60−1.93 (m, 2H), 1.18 (d, J = 7.0
Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 173.4, 155.9, 144.0, 143.9,
141.3, 135.9, 128.6, 128.3, 127.70, 127.52, 127.46, 127.07, 125.1,
120.22, 120.00, 66.4, 66.4, 60.46, 47.3, 46.9, 31.9, 31.1, 21.4. HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C27H28NO4 430.2018; Found
430.2011.
Boc-L-Thr(OBzl)ψCH3, 12d. Yield: Method A: 0.30 g, 88%; Method
B: 0.28 g, 81%, starting from 1.23 mmol of Boc-L-Thr(OBzl)-CH2I
1
(12c). H NMR (600 MHz, CDCl3): δ 1.16−1.18 (m, 6H). 1.44 (s,
9H), 3.5 (m, 1H), 3.72 (m, 1H), 4.42 (d, J = 11.6 Hz, 1H), 4.6 (d, J =
11.6 Hz, 1H), 4.73 (m, 1H), 7.25−7.36 (m, 5H). 13C NMR (75 MHz,
CDCl3): δ 16.1, 18.1, 28.4, 50.3, 71.0, 78.9, 127.6, 127.7, 128.3, 138.6,
155.8. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C16H26NO3
280.1913; Found 280.1914. Chiral HPLC Rt: 22.06 min. (Chiralpak IC
Column; mobile phase: water/MeCN, gradient 55−75% MeCN/50
min, 0.5 mL/min, monitored at 254 nm).
Boc-D-Thr(OBzl)ψCH3, 13d. Yield: Method A: 0.29 g, 84%; Method
B: 0.276 g, 80%, starting from 1.23 mmol of Boc-D-Thr(OBzl)-CH2I
1
(13c). H NMR (600 MHz, CDCl3) δ1.16−1.18 (m, 6H), 1.44 (s,
9H), 3.5 (m, 1H), 3.72 (m, 1H), 4.42 (d, J = 11.6 Hz, 1H), 4.61 (d, J =
11.6 Hz, 1H), 4.74 (m, 1H), 7.26−7.36 (m, 5H). 13C NMR (75 MHz,
E
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The Journal of Organic Chemistry
Note
CDCl3): δ 16.1, 18.1, 28.4, 50.2, 71.0, 78.9, 127.6, 127.7, 128.3, 138.6,
155.8. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C16H26NO3
280.1913; Found 280.1917. Chiral HPLC Rt: 22.86 min. (Chiralpak IC
Column; mobile phase: water/MeCN, gradient 55−75% MeCN/50
min, 0.5 mL/min, monitored at 254 nm).
(9) Nichols, D. E.; Snyder, S. E.; Oberlender, R.; Johnson, M. P.;
Huang, X. J. Med. Chem. 1991, 34, 276−281.
(10) Gorczynski, R. J.; Anderson, W. G.; Stout, D. M. J. Med. Chem.
1981, 24, 835−839.
(11) Quagliato, D. A.; Andrae, P. M.; Matelan, E. M. J. Org. Chem.
2000, 65, 5037−5042.
Preparation of Mosher’s Adduct, 14. Boc deprotection of 12d
(100 mg) was done by treating with 0.5 mL of trifluoroacetic acid
(TFA) for 1 h. Excess TFA was removed under vacuum and stripped
off residual amount with CCl4. The crude TFA salt (50 mg, 0.28
mmol) was then dissolved in 1.0 mL of dry CH2Cl2. To this solution,
cooled in ice, 120 μL of triethylamine (0.84 mmol) followed by 52 μL,
(0.28 mmol) of (S)-(+)-α-methoxy-α-trifluoromethylphenylacetyl
chloride (Mosher’s acid chloride), was added. After completion, as
monitored by reverse phase HPLC, 100 μL of water was added and
the mixtures were passed through a short silica gel column that was
washed with an additional 10 mL of CH2Cl2. The organic eluate was
concentrated under vacuum, yielding a colorless oil. (82 mg, 75%). 1H
NMR (500 MHz, CDCl3) δ 1.18 (d, J = 6.7 Hz, 3H), 1.2 (d, J = 6.3
Hz, 3H), 3.4 (s, 3H), 3.56 (m, 1H), 4.1 (m, 1H), 4.43 (d, J = 11.8 Hz,
1H), 4.65 (d, J = 11.8 Hz, 1H), 7.0 (d, J = 8.5 Hz, 1H), 7.26−7.41 (m,
8H), 7.50−7.55 (m, 2H). 19F NMR (470 MHz, CDCl3) δ −68.75 (s,
3F). HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C21H25F3NO3
396.1787; Found 396.1790. Chiral HPLC Rt: 26.64 min. (Chiralpak IC
Column; mobile phase: water/MeCN, gradient 50−80% MeCN/30
min, 0.5 mL/min, monitored at 254 nm).
(12) Barrett, D. G.; Deaton, D. N.; Hassell, A. M.; McFadyen, R. B.;
Miller, A. B.; Miller, L. R.; Payne, J. A.; Shewchuk, L. M.; Willard, D.
H., Jr.; Wright, L. L. Bioorg. Med. Chem. Lett. 2005, 15, 3039−3043.
(13) Donner, B. G. Tetrahedron Lett. 1995, 36, 1223−1226.
(14) Mandal, P. K.; McMurray, J. S. J. Org. Chem. 2007, 72, 6599−
6601.
(15) Bandgar, B. P.; Modhave, R. K.; Wadgaonkar, P. P.; Sande, A. R.
J. Chem. Soc., Perkin Trans. 1 1996, 1993−1994.
(16) Kokotos, G. Synthesis 1990, 299−301.
(17) Rodriguez, M.; Linares, M.; Doulut, S.; Heitz, A.; Martinez, J.
Tetrahedron Lett. 1991, 32, 923−926.
(18) Mondal, S.; Fan, E. Synlett 2006, 306−308.
(19) Oba, M.; Kobayashi, M.; Oikawa, F.; Nishiyama, K.; Kainosho,
M. J. Org. Chem. 2001, 66, 5919−5922.
(20) Oba, M.; Terauchi, T.; Miyakawa, A.; Kamo, H.; Nishiyama, K.
Tetrahedron Lett. 1998, 39, 1595−1598.
(21) Anwer, M. K.; Spatola, A. F. Tetrahedron Lett. 1985, 26, 1381−
1384.
(22) Caputo, R.; Cassano, E.; Longobardo, L.; Palumbo, G.
Tetrahedron 1995, 51, 12337−12350.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra of alkyl iodides and final α-
methylamines, 19F NMR spectrum of 14, and HPLC chromato-
grams of compounds 12d, 13d, and 14. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: jmcmurra@mdanderson.org.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the American Asthma Foundation (Award
Number: 11-0360) and the Center for Targeted Therapy for
support of this work. We also acknowledge the NCI Cancer
Center Support Grant P30 CA016672 at MDACC for support
of the NMR facility and the Translational Chemistry Core
Facility, which provided mass spectrometry.
REFERENCES
■
(1) Mandal, P. K.; Gao, F.; Lu, Z.; Ren, Z.; Ramesh, R.; Birtwistle, J.
S.; Kaluarachchi, K. K.; Chen, X.; Bast, R. C.; Liao, W. S.; McMurray, J.
S. J. Med. Chem. 2011, 54, 3549−3563.
(2) Dallanoce, C.; Frigerio, F.; De, A. M.; Dorsch, S.; Klotz, K.-N.;
De, M. C. Bioorg. Med. Chem. 2007, 15, 2533−2543.
(3) Bloom, J. D.; Dutia, M. D.; Johnson, B. D.; Wissner, A.; Burns, M.
G.; Largis, E. E.; Dolan, J. A.; Claus, T. H. J. Med. Chem. 1992, 35,
3081−3084.
(4) Kohno, H.; Iwakuma, T.; Yamada, K. Synth. Commun. 1998, 28,
1935−1945.
(5) Fuso, L.; Mores, N.; Valente, S.; Malerba, M.; Montuschi, P. Curr.
Med. Chem. 2013, 20, 1477−1495.
(6) Lipp, R.; Arrang, J. M.; Garbarg, M.; Luger, P.; Schwartz, J. C.;
Schunack, W. J. Med. Chem. 1992, 35, 4434−4441.
(7) Friary, R. J.; Mangiaracina, P.; Nafissi, M.; Orlando, S. C.;
Rosenhouse, S.; Seidl, V. A.; Shih, N. Y. Tetrahedron 1993, 49, 1993−
1996.
(8) Ye, Q.; Grunewald, G. L. J. Med. Chem. 1989, 32, 478−486.
F
dx.doi.org/10.1021/jo500911v | J. Org. Chem. XXXX, XXX, XXX−XXX