Synthesis of (Z)-fluoroalkene dipeptide isosteres utilizing organocopper-mediated reduction of γ,γ-difluoro-α,β-enoates

Article abstract of DOI:10.1016/S0040-4039(00)01924-9

γ,γ-Difluoro-α,β-enoates are reduced with organocopper reagents to afford the corresponding γ-fluoro-β,γ-enoates. This organocopper-mediated reduction was applied to the synthesis of (Z)-fluoroalkene dipeptide isosteres.

Full text of DOI:10.1016/S0040-4039(00)01924-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 285–287
Synthesis of (Z)-fluoroalkene dipeptide isosteres utilizing
organocopper-mediated reduction of g,g-difluoro-a,b-enoates
Akira Otaka,* Hideaki Watanabe, Etsuko Mitsuyama, Akira Yukimasa, Hirokazu Tamamura and
Nobutaka Fujii
Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan
Received 2 October 2000; revised 18 October 2000; accepted 27 October 2000
Abstract—g,g-Difluoro-a,b-enoates are reduced with organocopper reagents to afford the corresponding g-fluoro-b,g-enoates.
This organocopper-mediated reduction was applied to the synthesis of (Z)-fluoroalkene dipeptide isosteres. © 2000 Elsevier
Science Ltd. All rights reserved.
Replacement of scissile amide bonds in peptides with
the corresponding nonhydrolyzable cognates, has
gained much attention in medicinal and organic chem-
istry,1 and it has facilitated the development of peptide-
based drugs. Extensive synthetic studies on dipeptide
mimetics possessing nonhydrolyzable peptide bond ana-
logues have been reported by others, and we have also
been engaged in the synthesis of (E)-alkene dipeptide
isosteres using organocopper-mediated SN2% reactions.2
Although such (E)-alkene isosteres closely approximate
parent peptide bonds in three-dimensional structure,
they lack corresponding hydrogen bonding or dipolar
interactions. Therefore, fluoro-3 or trifluomethylalkene4
dipeptide isosteres have been proposed as potentially
better alkene mimetics, and much effort has been di-
rected toward their synthesis (Fig. 1).
a-fluorovinylphosphonate.6 This finding is the first ex-
ample of copper-mediated reduction of molecules con-
taining the g,g-difluoro-a,b-enoate moiety where one
fluorine works as a leaving group. We speculated that
this organocopper-mediated reaction should be applica-
ble to molecules possessing substituents other than the
phosphono group, to afford g-fluoro-b,g-enoates. This
hypothesis encouraged us to examine the feasibility of
this unprecedented reduction to the synthesis of
fluoroalkene dipeptide isosteres.
We chose a,a-difluoro-b-hydroxy esters 2 as potential
precursors, and anticipated subjecting these to a se-
quence of reactions consisting of copper-mediated re-
duction followed by transformation of the hydroxy
group to an amino functionality, which would lead to
desired fluoroalkene isosteres (Scheme 1).
In the course of our synthetic studies on difluoro-
methylphosphono pThr (phosphothreonine) mimetics,5
we found that reaction of 3-(diethylphosphonodifl-
uoromethyl)but-2-enoate with methyl copper reagents
affords an organocopper-mediated reduction product,
Reaction of aldehydes with BrZnCF2CO2Et in THF
afforded the a,a-difluoro-b-hydroxy esters 2. Protection
of the hydroxy group with TBSOTf–2,6-lutidine, fol-
lowed by DIBAL-H reduction and subsequent Horner–
R2
F
R2
O
R2
O
R2
H
N
H
N
H
N
H
N
N
H
N
H
R1
O
R1
O
R1
(E)-alkene isosteres
O
R1
(Z)-F-alkene isosteres
O
natural peptide bonds
Figure 1. Peptide bonds and their alkene-type isosteres.
Keywords: fluoroalkene; dipeptide isosteres; organocopper-mediated reduction.
* Corresponding author. Tel.: +81-75-753-4571; fax: +81-75-753-4570; e-mail: aotaka@pharm.kyoto-u.ac.jp
0040-4039/01/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01924-9

286
A. Otaka et al. / Tetrahedron Letters 42 (2001) 285–287
F
F
F
F
F
F
R1
R1
R1
ii
iv
i
iii
CO2R2
R1-CHO
CO2Et
CO2Et
OH
OTBS
OTBS
1a (R1 = Ph)
1b (R1 = Bn)
2a (R1 = Ph)
2b (R1 = Bn)
3a (R1 = Ph)
3b (R1 = Bn)
4a (R1 = Ph, R2 = Et)
4b (R1 = Bn, R2 = But)
v
F
F
F
vi
F
R1
Bn
Bn
CO2But
CO2R2
CO2But
+
Ph
CO2But
X
N3
OTBS
OH
6 (from 5b)
5a (R1 = Ph, R2 = Et)
5b (R1 = Bn, R2 = But)
5c (from 4b)
Scheme 1. (i) BrZnCF2CO2Et, THF; (ii) TBSOTf, 2,6-lutidine, CH2Cl2; (iii) DIBAL-H, CH2Cl2–toluene, then
(EtO)2P(O)CH2CO2Et (or But), LiCl, diisopropylethylamine, CH3CN; (iv) Me2Cu(CN)Li2·2LiBr·2LiCl, THF–Et2O; (v) TBAF,
THF; (vi) MsCl, pyridine, DMAP, CH2Cl2, then NaN3, DMF or Ph3P, DEAD, diphenylphosphoryl azide, THF.
Wadsworth–Emmons (HWE) olefination of the re-
sulting aldehydes, gave the requisite enoates 4 pos-
sessing (E)-geometry. Reduction of phenyl-substituted
enoate 4a with Me2Cu(CN)Li2·2LiBr·2LiCl (4 equiv.,
which was the most effective organocopper reducing
reagent in our previous study6), in THF–Et2O at
−78°C for 15 min, yielded the corresponding reduction
product 5a possessing (Z)-fluoroalkene geometry† in
96% yield. On the other hand, similar reaction of
benzyl-substituted enoate 4b, gave a mixture of desired
reduction product 5b and fluorodiene 5c (5b: 5c=4:1).
Furthermore, attempted transformation of the hydroxy
functionality in reduction product 6 to an azide group
using an SN2-azide replacement (MsCl–base, then
NaN3) or Mitsunobu reaction (Ph3PꢀDEADꢀ
diphenylphosphoryl azide)7 met with failure. Similarly,
intermolecular azide replacement of a,a-difluoro-b-
hydroxy esters 2 resulted in no satisfactory result. These
results necessitated an alternative synthetic approach
(Scheme 2), wherein we planned to introduce an amino
group via intramolecular Mitsunobu reaction8 prior to
undertaking essentially the same sequence of reactions,
involving organocopper-mediated reduction as stated
above.
(E)-geometry. Reduction of 11b with Me2Cu-
(CN)Li2·2LiBr·2LiCl (4 equiv.)‡ in THF–Et2O at
−78°C for 15 min, proceeded unequivocally to yield the
desired (Z)-fluoroalkene dipeptide isostere,† BocꢀPhe-
C[(Z)-CFꢁCH]-GlyꢀOEt (12b) in 85% isolated yield
without formation of the fluorodiene. Similarly, 11c
was subjected to the organocopper-mediated reduction
to give BocꢀVal-C[(Z)-CFꢁCH]-GlyꢀOEt (12c) in 95%
yield. Utilization of the second synthetic route is crucial
for introduction of the amino group and suppression of
undesired fluorodiene formation.
Allmendingers’ pioneering study on fluoroalkene
isosteres, employed aldol reaction of a-fluoro-a,b-un-
saturated aldehydes with ester enolates, followed by the
introduction of nitrogen functionality by an Overman
rearrangement.3 Alternatively, synthetic methodologies
employing fluoroolefination reactions of aldehydes or
ketones with a-fluoroacetate derivatives, have also been
reported.9 Conceptually distinct from the above pub-
lished methodologies, our presented protocol is new
due to its strategy of using organocopper-mediated
reduction. Since enantioselective syntheses of Boc-pro-
tected d-amino-g,g-difluoro-a,b-enoate10 and a,a-di-
fluoro-b-hydroxy ester11 have been reported, our
methodology extends to the synthesis of enantiomeri-
cally pure versions. In conclusion, methodology has
been presented herein which utilizes organocopper-
mediated reduction to provide access to fluoroalkene
dipeptidomimetics. Additional studies to extend this
methodology to other XaaꢀC[(Z)-CFꢁCH]-Gly type
isosteres (in this study Xaa=Phe or Val) and
stereoselevtive versions, are currently underway and
will be reported in due course.
Starting from the a,a-difluoro-b-hydroxy esters 2b or
2c, treatment with NaOH in THF–H2O, followed by
coupling of p-anisidine using bis(2-oxo-3-oxazolidinyl)-
phosphinic chloride and diisopropylethylamine, pro-
vided the corresponding a,a-difluoro-b-hydroxy amides
7. Intramolecular Mitsunobu reaction of
7 with
Ph3PꢀDEAD in THF, gave b-lactams 8. Ring-opening
of 8 with NaOH in THF–H2O, followed by esterifica-
tion, afforded p-methoxyphenyl (PMP)-protected a,a-
difluoro-b-amino esters 9. Removal of the PMP group
with CAN in MeCN–H2O and subsequent introduction
of the Boc-protecting group, gave Boc-protected a,a-
difluoro-b-amino esters 10. Reduction of 10 to the
corresponding aldehydes with DIBAL-H (2 equiv.) in
CH2Cl2–toluene at −78°C, followed by HWE reaction,
gave d-amino-g,g-difluoro-a,b-enoates 11 possessing
‡ To a solution of CuCN (59 mg, 0.66 mmol) and LiCl (56 mg, 1.32
mmol) in THF (1.7 ml) was added MeLi·LiBr in Et2O (1.5 M, 0.88
ml) at −78°C. The mixture was allowed to warm to 0°C and stirred
at this temperature for 1–2 min. After re-cooling to −78°C, 11b (60
mg, 0.17 mmol) in THF (1.5 ml) was added. After being stirred at
−78°C for 15 min, the reaction was quenched by addition of sat.
NH4Cl–28% NH4OH solution. After usual work-up followed by
flash chromatographic purification, 48 mg (85% yield) of compound
12b was obtained.
† Coupling constants of 5a, 5b, 12b and 12c (3JHF=35.0, 36.5, 36.7
and 36.6 Hz, respectively) are consistent with those of a-fluorovinyl
groups possessing a (Z)-configuration (3JHFcis=33–38 Hz).3

A. Otaka et al. / Tetrahedron Letters 42 (2001) 285–287
287
PMP = p-methoxyphenyl
F
R
H
N
F
F
F
F
F
F
F
R
R
R
OEt
iv
ii
iii
i
CO2Me
N
OH
O
NHPMP
OH
O
PMP
O
OMe
2b (R = Bn), 2c (R = Pri)
7b (R = Bn), 7c (R = Pri)
8b (R = Bn), 8c (R = Pri)
9b (R = Bn), 9c (R = Pri)
F
F
F
F
F
vi
v
R
R
R
CO2Me
CO2Et
CO2Et
NHBoc
10b (R = Bn), 10c (R = Pri)
NHBoc
11b (R = Bn), 11c (R = Pri)
NHBoc
12b (R = Bn), 12c (R = Pri)
Scheme 2. (i) NaOH, THF–H2O, then bis(2-oxo-3-oxazolidinyl)-phosphinic chloride, p-anisidine, diisopropylethylamine, CH2Cl2;
(ii) Ph3P, DEAD, THF; (iii) NaOH, THF–H2O, then H2SO4, MeOH; (iv) CAN, MeCN–H2O, then (Boc)2O, THF; (v)
DIBAL-H, CH2Cl2–toluene, then (EtO)2P(O)CH2CO2Et, LiCl, diisopropylethylamine, CH3CN; (vi) Me2Cu(CN)Li2·2LiBr·2LiCl,
THF–Et2O.
Acknowledgements
3. (a) Allmendinger, T.; Furet, P.; Hungerbu¨hler, E. Tetra-
hedron Lett. 1990, 31, 7297. (b) Allmendinger, T.; Felder,
E.; Hungerbu¨hler, E. ibid. 1990, 31, 7301.
We thank Dr. Terrence R. Burke, Jr., NCI, NIH,
Frederick, MD 21702-1201, for proofing the
manuscript and providing useful comments. This work
was supported in part by The Japan Health Sciences
Foundation and Grants-in-Aid for Scientific Research
from the Ministry of Education, Science and Culture of
Japan.
4. Wipf, P.; Henninger, T. C.; Geib, S. J. J. Org. Chem.
1998, 63, 6088.
5. Otaka, A.; Mitsuyama, E.; Kinoshita, T.; Tamamura, H.;
Fujii, N. J. Org. Chem. 2000, 65, 4888.
6. Otaka, A.; Mitsuyama, E.; Watanabe, H.; Tamamura,
H.; Fujii, N. Chem. Commun. 2000, 1081.
7. Lal, B.; Pramanik, B. N.; Manhas, M. S.; Bose, A. K.
Tetrahedron Lett. 1977, 1977.
8. Nakayama, K.; Kawato, H. C.; Inagaki, H.; Nakajima,
R.; Kitamura, A.; Someya, K.; Ohta, T. Org. Lett. 2000,
2, 977.
References
9. (a) Bartlett, P. A.; Otake, A. J. Org. Chem. 1995, 60,
3107. (b) Welch, J. T.; Lin, J. Tetrahedron 1996, 52, 291.
10. Berts, W.; Luthman, K. Tetrahedron 1999, 55, 13819.
11. (a) Braun, M.; Vonderhagen, A.; Waldmu¨ller, D. Liebigs
Ann. 1995, 1447. (b) Andre´s, J. M.; Mart´ınez, M. A.;
Pedrosa, R.; Pe´rez-Encabo, A. Synthesis 1996, 1070. (c)
Iseki, K.; Kuroki, Y.; Asada, D.; Takahashi, M.; Kishi-
moto, S.; Kobayashi, Y. Tetrahedron 1997, 53, 10271.
1. For reviews on peptidomimetics: Peptidomimetics Proto-
cols; Kazmierski, W. M., Ed.; Humana Press: Totowa,
New Jersey, 1999, and references cited therein.
2. Tamamura, H.; Yamashita, M.; Nakajima, Y.; Sakano,
K.; Otaka, A.; Ohno, H.; Ibuka, T.; Fujii, N. J. Chem.
Soc., Perkin Trans. 1 1999, 2983, and references cited
therein.
.