The stereoselective construction of E- and Z-Δ-Ile from E-dehydroamino acid ester: the synthesis of the phomopsin A tripeptide side chain

Article abstract of DOI:10.1039/c5cc08458j

The stereoselective synthesis of the phomopsin A tripeptide side chain was achieved by using methyl 2-(((benzyloxy)carbonyl)amino)-2-(diphenoxyphosphoryl)acetate as a common synthetic precursor for the synthesis of E-Δ-dehydroisoleucine and E-Δ-aspartate.

Full text of DOI:10.1039/c5cc08458j

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The stereoselective construction of E- and Z-D-Ile
from E-dehydroamino acid ester: the synthesis of
the phomopsin A tripeptide side chain†
Cite this:DOI: 10.1039/c5cc08458j
Received 12th October 2015,
Accepted 26th November 2015
Yoko Yasuno, Akito Nishimura, Yoshifumi Yasukawa, Yuma Karita, Yasufumi Ohfune
and Tetsuro Shinada*
DOI: 10.1039/c5cc08458j
www.rsc.org/chemcomm
The stereoselective synthesis of the phomopsin A tripeptide side
chain was achieved by using methyl 2-(((benzyloxy)carbonyl)amino)-2-
(diphenoxyphosphoryl)acetate as a common synthetic precursor for
the synthesis of E-D-dehydroisoleucine and E-D-aspartate.
Phomopsin A (1) was isolated from the fungus species Diaporthe
toxica as the main mycotoxin of lupinosis (Fig. 1).1 Phomopsin A
(1) and its natural congener, phomopsin B (2), are potent
inhibitors of microtubule depolymerization at o1 mM.2 Phomopsin
A (1) and B (2) are comprised of four dehydroamino acids (Dhaas)
and two highly oxidized unusual amino acids. Their characteristic
structures and potent pharmacological activities have attracted
Fig. 1 Structures of phomopsin A and B.
much attention as a synthetic target.3–5 The first total synthesis
3
´
of phomopsin B (2) was achieved by Wandless et al. Joullie et al.
reported the synthesis of the tripeptide side chain.5 The total
synthesis of the structurally more complex phomopsin A (1) has
not been reported yet.
The stereoselective synthesis of the tripeptide side chain is
one of the challenging synthetic tasks in view of its stereo
control and linkage. Previously, the synthesis was accomplished
by the stereoselective dehydration of b-hydroxyisoleucine 4 and
b-hydroxyaspartate 5 as surrogates for the E-D-Ile and E-D-Asp
moieties, respectively (Fig. 2).5,6 In the precedent route, the
geometrical control depends on the reaction mode of the
b-elimination and the stereochemistry of 4 and 5. To elaborate
Fig. 2 Structures of a,b-unsaturated amino acid precursors.
the requisite stereochemistry, 4 and 5 were selectively prepared sequentially introduced from the C-terminal of 6 and 8.
in several steps. Herein, we would like to report a new synthetic Conversion of 7 to 8 involves the construction of the E-D-Ile8–12
route to access the tripeptide side chain. Our approach is moiety. To achieve this challenging task, we tackled an
characterized by simplifying the synthetic route with a-(diphenyl- unprecedented approach by a series of sequential transformations:
phosphono)glycine 3 as a common synthetic precursor and the (i) E-selective olefination of 7, (ii) Z-selective iodination of the
stereocontrolled construction of the E-D-Ile and E-D-Asp moieties resulting E-dehydroamino acid, and (iii) the Negishi cross-
on the peptide side chain under mild conditions.
coupling reaction. It was anticipated that the remaining E-D-Asp
Our strategy is outlined in Scheme 1. In consideration of the moiety would be stereoselectively prepared from 9 by our original
instability of the NH2-free dehydroamino acid ester,7 3 was synthetic method to access E-dehydroamino acid esters using 3.13
A model study for the synthesis of E-8 from 7 was examined
by the synthesis of E- and Z-D-Ile 13 from 3 (Scheme 2). The
Graduate School of Science, Osaka City University, 3-3-138, Sugimoto, Sumiyoshi,
E-selective Horner–Wadsworth–Emmons reaction of 313 with
Osaka 558-8585, Japan
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c5cc08458j
propanal in the presence of DBU and MgBr2ÁOEt2 gave E-11
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undesired side reactions such as the competitive b-H elimination
from an Et–Pd species might decrease the catalytic ability. This
was solved by switching the ligand to TMEDA, which is known
to be an effective ligand to suppress the side reaction by the
saturation of the coordination sphere of the Pd catalyst.15
Gratifyingly, the cross-coupling process was extremely improved
by using TEMDA and a robust Pd catalyst, Pd–PEPPSIt–IPr, to
give Z-13 in 99% yield. The stereochemistry of Z-D-Ile 13 was
determined by NOESY experiments and comparing its NMR
data with those of E-D-Ile 13.8
The above new method is characterized by the mild reaction
conditions and the use of E-11 as a superior substrate to Z-11
for the initial iodination reaction. The use of E-11 in the
iodination reaction is quite rare. Support for the synthetic
advantage of E-Dhaas in the iodination reaction came from
the following comparative experiments of E-11 and Z-11
(Scheme 3). The treatment of Z-11 with NIS gave a new
spot on TLC, which was supposed to be the imine intermediate
16.16 The starting material was consumed after 2 h. Without
the isolation of 16, the crude imine was subjected to the base-
promoted isomerization reaction with DABCO to provide Z-12
in 74% yield. Under the conditions, no starting material was
recovered. It was conceivable that undesired side reactions
might compete during the course of the imine formation. To
accelerate the rate of imine formation, we turned our attention
to E-11. It is anticipated that E-11 would be more reactive than
Z-11 because of its higher torsional strain caused by the steric
repulsion between the ethyl and methoxycarbonyl groups.
To assess the reactivity of E-11 with NIS, iodination reactions
of E-11 and Z-11 were conducted in CD2Cl2. The conversion
ratios were analysed by 1H-NMR. We found that the conversion
of E-11 to the imine intermediate 1616 was superior to that of
Z-11 [conversion ratio after 0.5 h: 89% vs. 37%]. Moreover,
treatment of E-11 with NIS for 2 h followed by the DABCO-
promoted isomerization gave Z-12 in 83% yield. These results
indicated the potential synthetic utility of E-Dhaas for the
advanced iodination substrate. The synthetic advantage was
proved by the synthesis of the tripeptide side chain shown in
Scheme 4.
Scheme 1 Synthetic plan.
[E : Z = 88 : 12] in 87% yield. The treatment of 11 with NIS and
DABCO14 provided the thermodynamically stable Z-iodide 12 as
a single isomer in 86% yield. The Negishi cross-coupling
reaction of Z-12 with Me2Zn in the presence of 5 mol% of
Pd(PPh3)2Cl2 in THF at room temperature proceeded smoothly
to give E-13 as the sole product in 93% yield. The stereochemistry
of E-13 was confirmed by NOESY analysis and a comparison with
its authentic 13C-NMR data.8 It is noteworthy that NHCbz, the
methoxycarbonyl group, and N-acyl enamine moieties were
tolerated under the mild conditions. The synthetic utility was
successfully displayed in the synthesis of Z-13 from 3. The
E-selective olefination of 3 and acetaldehyde provided E-14
[E : Z = 78 : 22, 99% yield],13 followed by the iodination reaction
to give Z-15 in 63% yield. In contrast to the facile cross-coupling
of Z-12 with Me2Zn in the Negishi reaction, that of Z-15 with
Et2Zn resulted in a moderate yield (46%). We supposed that
The synthesis of the tripeptide side chain was commenced
with the coupling reaction of 17 with 3,4-D-Pro 6. The removal
of the Cbz group of 3 under the hydrogenation reaction
Scheme 2 Synthesis of E-D-Ile 13 and Z-D-Ile 13.
Scheme 3 Comparative experiments of E-11 and Z-11.
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coupling precursor 22. The peptide bond forming reaction of 22
with 17 provided 9 in 56% yield without any olefin isomerization.
The synthesis of the phomopsin A tripeptide side chain E-23 was
furnished by the E-selective Dhaa forming reaction developed by
us.13 Phosphonate 9 was condensed with 10 in the presence of
DBU/ZnCl2 to afford E-23 in 80% yield. The removal of the Boc
groups of 23 with TFA provided a 4.3 : 1 mixture of E-24 and Z-24.
The mixture was purified by preparative TLC to give E-24 in 35%
yield with the inseparable E/Z-mixture (18% yield). The E-geometry
of the resulting D-Asp moiety was confirmed by the comparison of
the chemical shift values of the olefinic protons (E: 6.05 ppm and
Z: 5.46 ppm).13
In summary, we have developed a novel synthetic route to
access the phomopsin A tripeptide side chain 24 in 12 steps
from 3. The synthesis could be simplified by the use of
a-(diphenylphosphono)glycine 3 as a common surrogate of
E-D-Ile and E-D-Asp moieties. The carbon–carbon bond forming
reactions on the peptide chain were successfully achieved under the
mild conditions. Studies in the development of the total synthesis of
phomopsin A and D-Ile-containing natural products18 as well as
studies from the view point of chemical biology19 of D-Ile-containing
biologically active molecules are in progress.
TS gratefully acknowledges financial support from the Scientific
Research of Innovative Areas, Chemical Biology of Natural Products,
the Ministry of Education, Culture, Sports, Science and Technology
(No. 23102009), and the Japan Society for the Promotion of
Science (KAKENHI No. 23228001 and 25282233). YY gratefully
acknowledges financial support by the Sasagawa Scientific
Research Grant from The Japan Science Society.
Scheme 4 Synthesis of the tripeptide side chain 24. Reagent and conditions:
(a) H2, Pd/C, HCl in MeOH, EtOAc; (b) 6, EDCI, DMAP, CH2Cl2, DMF, 55% over
2 steps; (c) propanal, DBU, MgBr2ÁOEt2, THF, 91% (E:Z = 74 : 26); (d) NIS,
CHCl3, 50 1C then DABCO, rt, 74% (Z only); (e) Pd–PEPPSIt–IPr, Me2Zn, THF,
94%. (f) LiOHÁH2O, THF/H2O, 50 1C; (g) allyl bromide, Cs2CO3, DMF, 86% over
2 steps; (h) Boc2O, DMAP, CH2Cl2, quant.; (i) Pd(PPh3)4, morpholine, THF; (j) 7,
EDCI, DMAP, CH2Cl2/DMF, 56% over 2 steps; (k) 10, DBU, ZnCl2, THF, 80%,
and (l) TFA, CH2Cl2 then preparative TLC, 35%.
Notes and references
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´
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