Synthesis of a Novel Rhizobitoxine-Like Triazole-Containing Amino Acid

Article abstract of DOI:10.1055/s-0036-1588300

The synthesis of the four stereoisomers of a new 1,2,3-triazole analogue of rhizobitoxine from serine is described. The key step is a Huisgen 1,3-dipolar cycloaddition on an ethynylglycine synthon.

Full text of DOI:10.1055/s-0036-1588300

SYNLETT
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9
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6
-
5
2
1
4
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4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2016, 27, A–D
letter
A
T. Boibessot et al.
Letter
Synlett
Synthesis of a Novel Rhizobitoxine-Like Triazole-Containing Amino
Acid
Thibaut Boibessota
David Bénimèlisa
Marion Jeanb
ethynylglycine
synthon
O
NBoc
6 steps
Zohra Benfoddaa
Patrick Meffre*a
NHBoc
N
2 steps
CO2CH3
NHBoc
HO
CO2H
+
N
HO
N
a Université de Nîmes, EA7352 CHROME,
Rue du Dr G. Salan, 30021 Nîmes Cedex 1, France
patrick.meffre@unimes.fr
b Aix Marseille Univ, CNRS, Centrale Marseille, iSm2,
Marseille, France
NH2
D- or L-serine
CO2CH3
NHBoc
4 stereoisomers
dr >90:10
ee = 97.2–99.5%
N3
4 steps
Received: 10.06.2016
Accepted after revision: 05.08.2016
Published online: 18.08.2016
therefore have potential applications in agronomy and bio-
technology.13,14
Synthesis of such unusual amino acids is a challenge, es-
pecially because of the enol ether reactivity.1,15,16 Therefore,
there is a need for readily accessible stable structural ana-
logues. 1,2,3-Triazole derivatives have gained a recent inter-
est in medicinal chemistry because they are pharmaco-
phores with good stability and high aqueous solubility,17–21
particularly in the area of peptidomimetics22 and are readi-
ly accessible by the Huisgen 1,3-dipolar cycloaddition in-
volving an alkyne and an azide.23–26
In this paper, we describe the synthesis of a new tri-
azole-containing amino acid analogue of rhizobitoxine in
protected form (compound (1S,2S)-2) from serine (Figure 2)
where the central enol ether linkage in rhizobitoxine is re-
placed by the robust 1,2,3-triazole linker in such a way that
there is no longer β,γ-unsaturation to the amino acid moi-
ety. This analogue should be a stable analogue compared to
unstable vinylglycine derivatives and, based on reported
mechanisms of inhibition, such an unusual amino acid
could be a potential inhibitor of PLP-dependent en-
zymes.27,28
DOI: 10.1055/s-0036-1588300; Art ID: st-2016-d0381-l
Abstract The synthesis of the four stereoisomers of a new 1,2,3-tri-
azole analogue of rhizobitoxine from serine is described. The key step is
a Huisgen 1,3-dipolar cycloaddition on an ethynylglycine synthon.
Key word rhizobitoxine, triazole amino acid, Huisgen cycloaddition,
ethynylglycine synthon, chiral HPLC
Rhizobitoxine 1 (Figure 1) is an unusual amino acid that
belongs to the β,γ-enol ether family, a γ-substituted sub-
class of the naturally occurring vinylglycines.1 It has been
initially regarded as a phytotoxin because it induces chloro-
sis in soybeans.2–4
NH2
O
HO
O
O
NH3
Figure 1 Rhizobitoxine (1)
Rhizobitoxine is a metabolic product secreted by symbi-
otic bacteria such as Rhizobium japonicum (now Bradyrhi-
zobium elkanii)5–7 or the plant pathogen Pseudomonas an-
dropogonis (now Burkholderia andropogonis).8 Rhizobit-
oxine, which is a structural analogue of cystathionine,
inhibits two pyridoxal phosphate (PLP) dependent en-
zymes: cystathionine β-lyase,5,9 involved in the methionine
biosynthesis pathway and 1-aminocyclopropane-1-carbox-
ylate (ACC) synthase10 involved in ethylene biosynthesis in
plants. It inhibits the production of ethylene,11 a gaseous
stress phytohormone, and plays a positive role in establish-
ing symbiosis between B. elkanii and its host legume by
ethylene inhibition.12 As plant growth regulators or inhibi-
tors of sulfur assimilation, rhizobitoxine and analogues
NHBoc
CO2CH3
NHBoc
2
HO
N
1
N
N
Figure 2 Protected triazole containing analogue of rhizobitoxine
[(1S,2S)-2]
Retrosynthetic analysis shows that this compound
should be accessible using a Huisgen 1,3-dipolar cycloaddi-
tion of azide (S)-3 with alkyne (S)-4 (Figure 3).
Alkyne (S)-4 is an ‘ethynylglycine synthon’.29,30 It is syn-
thesized from D-serine in six steps using Garner aldehyde
(R)-531,32 as a key precursor (Scheme 1). Two principal
methods have been described to synthesize alkyne 4 from
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

B
T. Boibessot et al.
Letter
Synlett
CO2H
NH2
L-Serine
i
CO2CH3
HO
CO2CH3
N3
HO
NBoc
O
NHBoc
(S)-8
NHBoc
(S)-3
(S)-4
ii or iii
Figure 3 Precursors of the Huisgen 1,3-dipolar cycloaddition for tri-
azole formation in (1S,2S)-2
CO2CH3
NHBoc
N3
iv
CO2CH3
NHBoc
RO
(S)-3
+
(S)-9a: R = Ts
(S)-9b: R = Ms
aldehyde 5: the Bestmann–Ohira and the the Corey–Fuchs
strategies.29 We decided here to use the Bestmann–Ohira
strategy using diazophosphonate 6 for this aldehyde-to-
alkyne transformation, as this was well-known in our labo-
ratory.33 In 2002, we described the one-pot synthesis of
ethynylglycine synthon 4 in 70% in 72 hours.34 This proce-
dure involving in situ formation of diazophosphonate 6 is
convenient on a small scale (0.95 mmol of aldehyde 5) but
we noticed a dramatic increase of the reaction time when
performed on a larger scale. Therefore, we decided to re-
turn to the original strategy35 with preparation of diazo-
phosphonate 6 prior to the homologation. After flash chro-
matography, the ethynylglycine synthon 4 was obtained in
83% yield on 22 mmol scale (lit.35 80% on 11 mmol scale)
(Scheme 1).
CO2CH3
H2C
NHBoc
10
Scheme 2 Reagents and conditions: (i) see ref.31; (ii) TsCl, Et3N, 4-DMAP
(cat.), Me3NHCl (cat.), CH2Cl2, 0 °C, 2 h, 68%; (iii) MsCl, Et3N, CH2Cl2, 0 °C,
0.5 h, 64%; (iv) NaN3, DMF, see Table 1.
yield). The results of the transformation from (S)-9a and
(S)-9b to (S)-3 are summarized in Table 1. The best reaction
conditions in our hands for nucleophilic substitution were
using sodium azide in DMF at 70 °C for a short reaction
time (Table 1, entry 2). Under these reaction conditions,
azide (S)-3 was obtained from p-toluenesulfonate (S)-9a in
39% yield, together with alkene 10 in 37% yield, resulting
from an elimination reaction. Changing from p-toluenesul-
fonate 9a to methanesulfonate 9b, or lowering reaction
temperature did not improve the yield for 3 (Table 1). We
obtained enantiomer (R)-3 under the same conditions (Ta-
ble 1, entry 2) through (R)-9a from D-serine with identical
yields and opposite specific rotation. It is worth noting that
Shelly et al.38 reported the formation of compound (S)-3
from methanesulfonate (S)-9b (NaN3, DMF, 50 °C, 0.5 h; un-
der the same conditions as Table 1, entry 4) in 56% yield but
with a lower specific rotation. Moreover, Friscourt et al. re-
ported the formation of the benzyl ester analogue of 3
(NaN3, DMF, 40°C, 2 h) in only 18% yield.39 All these obser-
vations show that this transformation is somewhat capri-
cious.
NH2
i
NBoc
HO
O
CO2H
CHO
D-Serine
(R)-5
NBoc
iii
O
+
O
O
P
O
O
P
ii
OCH3
OCH3
OCH3
OCH3
(S)-4
N2
7
6
Scheme 1 Reagents and conditions: (i) see ref.31,32; (ii) NaH, toluene
then 4-acetamidobenzenesulfonyl azide, THF, 72%, see ref.36; (iii) K2CO3,
MeOH, 83%.
The diazophosphonate 6 was synthesized from phos-
phonate 7 with minor modifications of the procedure de-
scribed by Pietruszka and Witt.36 It was obtained in 72%
yield (lit.36 77%) (Scheme 1).
Table 1 Results of the NaN3 Nucleophilic Substitution on (S)-9a and
(S)-9ba
Entry
Starting
material
T(°C)
Time (h)
Yield of
(S)-3 (%)
Yield of
10 (%)
Azide (S)-3 was synthesized from protected L-serine (S)-
8.31 We first envisaged synthesizing azide 3 by a nucleophil-
ic substitution on reactive sulfonic ester derivatives of alco-
hol 8 (Scheme 2). The conversion of alcohol (S)-8 into p-tol-
uenesulfonate (S)-9a was performed using the conditions
described by Jackson and Perez-Gonzales37 to obtain (S)-9a
in 68% yield, and the results were in agreement with the lit-
erature (lit.37 64–69%). Conversion of (S)-8 into methanesul-
fonate (S)-9b was performed using the conditions of Shetty
et al.38 and allowed (S)-9b to be obtained in 64% yield after
column chromatography purification (lit.38 81%, crude
1
2
3
4
(S)-9a
(S)-9a
(S)-9b
(S)-9b
20
70
20
50
5
33
39
25
25
35
37
55
29
0.17
24
0.5
a See Scheme 2, reaction conditions (iv).
We then tried the direct formation of azide (S)-3 using a
Mitsunobu reaction as described by Stanley et al.40 (Scheme 3).
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

C
T. Boibessot et al.
Letter
Synlett
The four stereoisomers of compound 2 were synthe-
sized using the same strategy as described above from D-
and L-serine with analogous results (see Supporting Infor-
mation).44
CO2CH3
CO2CH3
i
HO
N3
NHBoc
(S)-8
NHBoc
(S)-3
Scheme 3 Reagents and conditions: (i) Ph3P/DIAD/DPPA
After a screening of several chiral stationary phases by
HPLC, Lux-Cellulose-2, and Chiralpak AZ-H were found to
be efficient for baseline separation of the mixture of the
four stereoisomers of 11 and 2, respectively, thus allowing
the determination of the diastereomeric ratio and the enan-
tiomeric excess of each isomer (Table 2). For all compounds,
diastereomeric ratios were found to be greater than 90:10
and the enantiomeric excesses were higher than 96% (see
Supporting Information)
(1.14/1.28/1.14), THF, 0 °C, 41%.
Azide (S)-3 was obtained in 41% yield from (S)-8 (lit.40
69%) although with a cumbersome purification by column
chromatography to isolate a somewhat impure material as
observed on the NMR spectrum. We decided therefore to
pursue the synthesis using pure compound 3 obtained fol-
lowing conditions described in Scheme 2,Table 1, entry 2.
To the best of our knowledge, there is only one prece-
dent describing a Huisgen 1,3-dipolar cycloaddition using
an ethynylglycine synthon as substrate. It is one example
(with no further application of the product) in a methodol-
ogy report of a click reaction between in situ generated
β-azido styrenes from cinnamic acid using CAN/NaN3 and
alkynes to form N-styryl triazoles.41
The Huisgen 1,3-dipolar cycloaddition between
ethynylglycine synthon (S)-4 and azide (S)-3 was per-
formed using classical conditions42 (Scheme 4, path a): L-
Ascorbate, CuSO4 in the mixture of tert-butanol/water and
yielded the desired 1,2,3-triazole (2S,4S)-11 in 70% yield.
Deprotection of the oxazolidine with APTS monohydrate in
methanol43 furnished the final compound (1S,2S)-2 in 17%
yield with 55% recovery of starting material. The overall
yield from (S)-4 was 12%.
In order to increase the global yield, inversion of the or-
der of the two final steps was examined (Scheme 4, path b).
Opening the oxazolidine ring in (S)-4 using the same condi-
tions as before yielded the protected amino alcohol (S)-12
in 48% yield with recovery of starting material (S)-4 in 32%
yield. Subsequent Huisgen cycloaddition then led to the
same compound (1S,2S)-2 in 65% yield, with a 92:8 diaste-
reomeric ratio and an enantiomeric excess higher than
99.5% (vide infra). Using this strategy, the overall yield from
(S)-4 increased to 31%.
Table 2 Diastereomeric Ratio and Enantiomeric Excess for Stereoiso-
mers of 11 and 2
Isomer
dr
10:1
ee (%)
Isomer
dr
11:1
ee (%)
(2S,4R)-11
(2R,4S)-11
(2S,4S)-11
(2S,4R)-11
99.5
96.2
99.5
99.5
(1S,2S)-2
(1R,2R)-2
(1S,2R)-2
(1R,2S)-2
99.5
99.5
99.5
97.2
16:1
14:1
9:1
10:1
14:1
9:1
a Determined by chiral HPLC.
Deprotection of compounds 2 and biological evaluation
of their activity on PLP-dependant enzymes are under in-
vestigation in our laboratory, and the results will be report-
ed in due course.
Acknowledgment
We gratefully thank the French ‘Ministère de l’Éducation Nationale,
de l’Enseignement Supérieur et de la Recherche’ for financial support.
Dr Nicolas Vanthuyne (Aix-Marseille Université, Plateforme de Chro-
matographie Chirale, ISM2 – UMR7313 – Chirosciences) is acknowl-
edged for fruitful collaboration.
Supporting Information
NBoc
Supporting information for this article is available online at
O
CO2CH3
2
N
http://dx.doi.org/10.1055/s-0036-1588300.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
4
path a
N
NHBoc
N
(2S, 4S)-11
ii
i
References and Notes
NBoc
NHBoc
O
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CO2CH3
2
HO
N
1
N
NHBoc
N
ii
(S)-4
NHBoc
i
(1S, 2S)-2
HO
path b
(S)-12
Scheme 4 Reagents and conditions: (i) azide (S)-3, L-ascorbate (0.2
equiv), CuSO4 (0.1 equiv), t-BuOH–H2O (1:1), 70%, (path a), 65% (path
b); (ii) PTSA-H2O, MeOH, 20 °C, 2 h, 17% (path a), 48% (path b).
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Letter
Synlett
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(S)-Methyl
2-[(tert-Butoxycarbonyl)amino]-3-(4-{(S)-1-
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[(tert-butoxycarbonyl)amino]-2-hydroxyethyl}-1H-1,2,3-
triazol-1-yl)propanoate [(1S,2S)-2, (Scheme 4, Path a]
To a solution of (2S, 4S)-11 (0.337 g, 0.72 mmol) in MeOH (5 mL)
was added PTSA·H2O (0.137 g, 0.72 mmol). The reaction
mixture was stirred for 2 h at room temperature and sat. aq
NaHCO3 solution (40 mL) was poured into the solution. The
aqueous solution was extracted with EtOAc (3 × 40 mL). The
organic phases were combined, washed with sat. aq NaHCO3
solution (40 mL), sat. aq NaCl solution (40 mL), dried over
MgSO4, filtered, and concentrated under reduced pressure. The
residue was purified by flash column chromatography (silica
gel, EtOAc–PE = 0:100, increasing to 100:0, v/v) to give the
desired compound (1S, 2S)-2 (0.053 g, 17%) as a white solid and
recovered starting material (2S, 4S)-11 (0.184 g, 55%).
Analytical Data
1
Rf = 0.26 (EtOAc); mp 55–57 °C. H NMR (300 MHz, CDCl3): δ =
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Parang, K. Bioorg. Med. Chem. Lett. 2011, 21, 449.
(21) Lebeau, A.; Abrioux, C.; Bénimèlis, D.; Benfodda, Z.;
1.42 [s, 18 H, C(CH3)3], 2.89 (br s, 1 H, OH), 3.79 (s, 3 H, CO2CH3),
3.84–3.87, 4.10–4.12 (2 m, 2 H, CH2O), 4.70–4.86 (m, 4 H, 2 CH,
CH2N), 5.43 (br s, 1 H, NH), 5.59 (br s, 1 H, NH), 7.57 (s, 1 H, CHtri-
azole). 13C NMR (75 MHz, CDCl3): δ = 28.4, 28.5 [2 s, 18 H,
C(CH3)3], 48.2 (CH), 51.5 (CH2N), 53.4 (CO2CH3), 53.9 (CH), 65.0
(CH2O), 80.1 [C(CH3)3], 81.0 [C(CH3)3], 123.9 (CHtriazole), 147.1
Meffre,
P.
Med.
Chem.
2016,
12,
DOI:
10.2174/1573406412666160404125718.
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20
(Ctriazole), 155.2 (NCO2), 155.8 (NCO2), 169.5 (CO2CH3). [α]D
+49.9 (c 0.91, CHCl3). HRMS (ES+): m/z [M + H]+ calcd for
C
18H32N5O7: 430.2302; found: 430.2303. HPLC: purity = 99.6%,
tR = 12.43 min. IR: 3358, 2362, 2338, 1742, 1683 cm–1
.
Nitrogen inversion in the oxazolidine ring or slow interconver-
sion of both amide or carbamate conformers of compounds 4,
11, and 2 causes considerable line broadening and duplication
1
of signals in the H NMR and 13C NMR spectra (see Supporting
Information).
General Synthetic Procedure for Click-Chemistry Reaction
for the Synthesis of 2
(S)-Methyl 2-[(tert-Butoxycarbonyl)amino]-3-(4-{(S)-1-[(tert-
butoxycarbonyl)amino]-2-hydroxyethyl}-1H-1,2,3-triazol-1-
yl)propanoate [(1S,2S)-2, Scheme 4, Path b)
Azide 3 (0.420 g, 1.72 mmol) and alkyne 12 (0.318 g, 1.72
mmol) were dissolved in a mixture of t-BuOH–H2O (10 mL, 1:1,
v/v). Sodium L-asborbate (0.068 g, 20 mol%) and CuSO4·5H2O
(0.041 g, 10 mol%) were added. The reaction mixture was
stirred at room temperature for 24 h, the solution was concen-
trated under vacuum and diluted with H2O (70 mL). The
aqueous phase was extracted with EtOAc (3 × 50 mL). The
organic phases were combined, dried over MgSO4, filtered, and
concentrated under reduced pressure. The residue was purified
by flash chromatography (silica gel, EtOAc–PE = 0:100, increas-
ing to 100:0, v/v) to give the desired compound (1S,2S)-2 as a
white solid (0.480 g, 65% yield). The compound exhibited the
same analytical properties as described above.
(39) Friscourt, F.; Fahrni, C. J.; Boons, G.-J. J. Am. Chem. Soc. 2012, 134,
18809.
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M.; Bräuner-Osborne, H.; Taylor, D. K.; Abell, A. D. Bioorg. Med.
Chem. Lett. 2010, 20, 7512.
See Supporting Information for the characterization data of
other products.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D