E-Selective Horner-Wadsworth-Emmons reaction of 2-OBO-cyclopentanone for the synthesis of rac-N-Cbz-Gly-Ψ[(E)-CF=C]-Pro-OH dipeptide isostere

Article abstract of DOI:10.1016/j.tetlet.2014.06.063

The Horner-Wadsworth-Emmons reactions of ethyl 2-fluoro-2- diethylphosphonoacetate with 2-(4-methyl-2,6,7-trioxabicyclo[2.2.2]octan-1-yl) cyclopentanone (2-OBO-cyclopentanone) using n-butyllithium furnished the corresponding tetra-substituted fluoroolefin in an E-selective manner (E:Z = 95:5). A facile synthesis of rac-N-Cbz-Gly-Ψ[(E)-CF=C]-Pro-OH as a dipeptide isostere was achieved based on the E-selective Horner-Wadsworth-Emmons reaction.

Full text of DOI:10.1016/j.tetlet.2014.06.063

Tetrahedron Letters 55 (2014) 4480–4483
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
E-Selective Horner–Wadsworth–Emmons reaction
of 2-OBO-cyclopentanone for the synthesis
of rac-N-Cbz-Gly-W[(E)-CF@C]-Pro-OH dipeptide isostere
⇑
Shigeki Sano , Tomoya Matsumoto, Michiyasu Nakao
Graduate School of Pharmaceutical Sciences, The University of Tokushima, Sho-machi, Tokushima 770-8505, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The Horner–Wadsworth–Emmons reactions of ethyl 2-fluoro-2-diethylphosphonoacetate with 2-
(4-methyl-2,6,7-trioxabicyclo[2.2.2]octan-1-yl)cyclopentanone (2-OBO-cyclopentanone) using n-butyl-
lithium furnished the corresponding tetra-substituted fluoroolefin in an E-selective manner
Received 13 May 2014
Revised 10 June 2014
Accepted 16 June 2014
Available online 20 June 2014
(E:Z = 95:5). A facile synthesis of rac-N-Cbz-Gly-
achieved based on the E-selective Horner–Wadsworth–Emmons reaction.
Ó 2014 Elsevier Ltd. All rights reserved.
W[(E)-CF@C]-Pro-OH as a dipeptide isostere was
Keywords:
Horner–Wadsworth–Emmons reaction
Fluoroolefin
Proline
OBO ester
E-Selective
Fluoroolefins are important structural units and have become
critical components of the bioisosteres used in medicinal chemis-
try, where they provide superior isosteric and isoelectronic
replacements for peptide amide bonds.1–9 Hence, tetra-substituted
(E)- or (Z)-fluoroolefins are of special interest from the viewpoint
of constructing dipeptide mimetics containing the C-terminal pro-
line residue. There are several reports concerning the synthesis of
fluoroolefin isosteres of proline-containing dipeptides via Wittig-
type olefination,10–14 Julia-Kocienski olefination,15 or Peterson
olefination9,16–18 of cyclopentanone derivatives. However, stereo-
selective syntheses of (E)- or (Z)-Xaa-W[CF@C]-Pro-OH (Xaa = a-
mino acids) as an (s-E)- or (s-Z)-amide bond surrogate are much
less common and still pivotal issues to be addressed. We have
already reported synthesis of the N-Cbz-Gly-W[(Z)-CF@CH]-Gly-
OH dipeptide isostere based on the tandem reduction-olefination
of the corresponding ethyl 2-acyl-2-fluoro-2-diethylphosphono-
acetate with excellent Z-selectivity (Scheme 1).19,20 However, this
method is not applicable to the stereoselective synthesis of
of a fluorinated pseudo-dipeptide analogue, rac-N-Cbz-Gly-W[(E)-
CF@C]-Pro-OH [rac-(E)-1]. It is worth noting that proline is the only
amino acid that can be found in the s-E (cisoid) conformation at the
Xaa-Pro linkage (cis-proline turn).21–23
The first step of our experiments consisted in developing a
novel cyclopentanone, 2-(4-methyl-2,6,7-trioxabicyclo[2.2.2]octan
-1-yl)cyclopentanone (2-OBO-cyclopentanone, 2) as a substrate of
the E-selective HWE reaction. 2-OBO-cyclopentanone (2), which
has a bulky bicyclic protecting group for a carboxylic acid moiety,
was successfully obtained from methyl 2-oxocyclopentanecarb-
oxylate (3) in 5 steps as shown in Scheme 3. Reduction of b-keto-
ester 3 with sodium borohydride followed by saponification
afforded b-hydroxy carboxylic acid 5. Esterification of the cesium
salt of 5 with 1-(bromomethyl)-1-methylcyclobutane furnished
b-hydroxy ester 6. Construction of the OBO ester moiety of 7 was
achieved by treatment of 6 with a catalytic amount of boron tri-
fluoride etherate. Finally, oxidation of 7 with sulfur trioxide–pyri-
dine complex gave the desired cyclopentanone 2 with a bulky OBO
ester group at the C-2 position. The bicyclic OBO ester is readily
convertible into a carboxy group by mild aqueous acid treatment
followed by alkaline hyrolysis.24,25
tetra-substituted fluoroolefins, such as N-Cbz-Gly-W[(E)- or (Z)-
CF@C]-Pro-OH [(E)- or (Z)-1] (Scheme 2). As part of our continuing
exploration of the stereoselective preparation of fluoroolefins, we
herein describe the first successful outcome of E-selective Horn-
er–Wadsworth–Emmons (HWE) reactions leading to the synthesis
We next carried out the HWE reaction of ethyl 2-fluoro-2-
diethylphosphonoacetate (8) and 2-OBO-cyclopentanone (2) in
the presence of an ordinary base at 0 °C (Table 1). Treatment of a-
fluorophosphonate 8 and 2-OBO-cyclopentanone (2) with n-butyl-
lithium in anhydrous THF at 0 °C afforded (E)-tetra-substituted
⇑
Corresponding author. Tel.: +81 88 633 7273; fax: +81 88 633 9503.
E-mail address: ssano@tokushima-u.ac.jp (S. Sano).
http://dx.doi.org/10.1016/j.tetlet.2014.06.063
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

S. Sano et al. / Tetrahedron Letters 55 (2014) 4480–4483
4481
Table 1
HWE reactions of 8 with 2-OBO-cyclopentanone (2)
Scheme
1. Tandem
reduction-olefination
of
ethyl
2-acyl-2-fluoro-2-
diethylphosphonoacetate.
Entry
Base
Solventa
Yieldb (%)
E:Zc
1
2
3
4
5
6
7
8
9
n-BuLi
NaH
THF
THF
THF
THF
THF
Et2O
i-Pr2O
t-BuOMe
n-Hexane
Toluene
83
20
88
98
7
14
62
78
63
76
81:19
68:32
83:17
71:29
48:52
86:14
89:11
91:9
LHMDS
NHMDS
KHMDS
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
92:8
88:12
10
a
b
c
The initial concentration of 2 was 0.08 M.
Isolated yields.
Determined by 1H NMR (400 MHz, CDCl3) analysis.
Scheme 2. N-Cbz-Gly-W[(E)- or (Z)-CF@C]-Pro-OH as an amide bond surrogate.
fluoroolefin (E)-9 (E:Z = 81:19) as shown in Table 1 (entry 1). The
ratios of E/Z isomers of 9 were determined by appropriate signals
in the 1H NMR (400 MHz, CDCl3) spectra of fluoroolefin 9. Use of
lithium hexamethyldisilazide (LHMDS) slightly increased the pref-
erence for (E)-9 (entry 3). However, the stereoselectivity was mark-
edly decreased in the reaction with other bases, such as sodium
hydride, sodium hexamethyldisilazide (NHMDS), and potassium
hexamethyldisilazide (KHMDS) (entries 2, 4, and 5). We therefore
chose n-butyllithium as a suitable base, because the reaction by-
products are notable in the reaction with LHMDS. Furthermore,
the solvent had a remarkable effect on the stereoselectivity, afford-
ing a higher E/Z ratio (E:Z = 91:9) and isolated yield (78%) in tert-
butyl methyl ether (entry 8).
Table 2
HWE reactions of 8 with 2-OBO-cyclopentanone (2)
Entry
8 and n-BuLi (mol equiv)
2 (M)a
Yieldb (%)
E:Zc
1
2
3
4
5
6
7
8
1.2
1.2
1.2
1.2
1.2
1.2
1.5
1.8
2
0.15
0.08
0.04
0.02
0.01
0.005
0.02
0.02
0.02
0.02
86
78
84
85
65
11
81
94
92
71
91:9
91:9
93:7
94:6
95:5
93:7
94:6
95:5
94:6
58:42e
9
10d
1.2
a
b
c
Initial concentration.
Isolated yields.
Determined by 1H NMR (400 MHz, CDCl3) analysis.
d
e
2-TOM-cyclopentanone (10) was employed instead of 2.
Ethyl (E)- and (Z)-2-fluoro-2-(2-TOM-cyclopentylidene)acetates [(E)- and (Z)-
11] were obtained.
Scheme 3. Synthesis of 2-OBO-cyclopentanone (2).

4482
S. Sano et al. / Tetrahedron Letters 55 (2014) 4480–4483
The effect of the concentration of substrate was also investi-
gated. The initial concentration of 2-OBO-cyclopentanone (2) in
all the reactions in Table 1 was 0.08 M. In order to optimize the
initial concentration of 2-OBO-cyclopentanone (2), we carried out
the HWE reaction of
a-fluorophosphonate 8 under various initial
concentrations of 2 as shown in Table 2. At lower initial concentra-
tions of cyclopentanone 2, the E/Z ratios of the resulting
tetra-substituted fluoroolefin 9 were slightly increased up to
95:5 (entries 3–6). Finally, the most satisfactory E/Z ratio
(E:Z = 95:5) and isolated yield (94%) were obtained in the HWE
reaction of 2-OBO-cyclopentanone (2) with 1.8 equiv of ethyl 2-flu-
oro-2-diethylphosphonoacetate (8) and 1.8 equiv of n-butyllithium
in tert-butyl methyl ether at 0 °C (entry 8).26,27 On the other hand,
the HWE reactions of 2-{[(triisopropylsilyl)oxy]methyl}cyclo-
pentanone (2-TOM-cyclopentanone, 10) and phosphonate 8 with
n-butyllithium in anhydrous tert-butyl methyl ether at 0 °C
resulted in the formation of the corresponding fluoroolefin 11 with
a modest E/Z ratio (71% yield, E:Z = 58:42). In light of the more
moderate E-selectivity of the HWE reaction of cyclopentanone 10
compared to 2, we hypothesized that the stereochemical outcome
with enhanced E-selectivity in the n-butyllithium-promoted HWE
reaction of
due to the bulkiness of the OBO moiety of 2, as depicted in Figure 1.
Whether the HWE reaction exhibits -facial selectivity is
a-fluorophosphonate 8 and cyclopentanone 2 was
p
unknown, but both approaches favor the formation of (E)-9 by vir-
tue of the steric hindrance caused by pseudo-equatorial OBO or
pseudo-axial methine hydrogen at the C2 position of 2. Although
the reaction mechanism for the HWE reaction of a-fluorophospho-
nate 8 is not fully understood, it is believed that these steps for the
olefination are irreversible in analogy with the HWE reaction of
Still’s reagent.28–38
Scheme 4. Synthesis of rac-N-Cbz-Gly-W[(E)-CF@C]-Pro-OH [rac-(E)-1].
The dipeptide isostere, rac-N-Cbz-Gly-W[(E)-CF@C]-Pro-OH
[rac-(E)-1], was synthesized conveniently from the (E)-9
(E:Z = 94:6) by the sequence shown in Scheme 4. The reduction
of (E)-9 with lithium aluminum hydride followed by treatment
with saturated aqueous solution of tartaric acid afforded the corre-
sponding triol (E)-12 in 92% yield. The allylic hydroxy group of (E)-
12 was converted to the protected amino group of (E)-13 via the
Mitsunobu
reaction.19,39
Deprotection
of
the
2-nito-
robenzenesulfonyl (Ns) group of (E)-13 with 4-tert-butylthiophe-
nol in the presence of potassium carbonate in DMF furnished
Cbz-protected (E)-14 in 77% yield (two steps). Finally, hydrolysis
of (E)-14 under aqueous alkaline conditions furnished rac-N-Cbz-
Figure 2. NOE correlations for (E)- and (Z)-12.
Gly-W[(E)-CF@C]-Pro-OH [rac-(E)-1] as a single diastereomer in
In summary, we developed a novel efficient method for the
preparation of the (E)-tetra-substituted fluoroolefin (E)-9 from
ethyl 2-fluoro-2-diethylphosphonoacetate (8) and 2-OBO-
cyclopentanone (2) in the presence of n-butyllithium. In addition,
86% yield. The geometries of (E)- and (Z)-9 were confirmed by
means of proton homonuclear Overhauser enhancement (NOE)
experiments (300 MHz, CDCl3) of the corresponding triols (E)-
and (Z)-12 derived from an E/Z mixture of 9 (Fig. 2).
rac-N-Cbz-Gly-W[(E)-CF@C]-Pro-OH [rac-(E)-1] was readily syn-
thesized from (E)-9. Efforts toward the synthesis of the optically
pure (E)-1 and other dipeptide isosteres containing the C-terminal
proline residue are ongoing in our laboratories, and the results of
these studies will be reported in due course.
Acknowledgments
This work was supported in part by a Grant for the Regional
Innovation Cluster Program (Global Type) promoted by MEXT.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.06.
063. These data include MOL files and InChiKeys of the most
important compounds described in this article.
Figure 1. Plausible transition states for the HWE reaction of
and cyclopentanone 2.
a-fluorophosphonate 8

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4483
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3
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