Tandem reduction-olefination of triethyl 2-acyl-2-fluoro-2-phosphonoacetates and a synthetic approach to Cbz-Gly-Ψ[(Z)-CF{double bond, long}C]-Gly dipeptide isostere

Article abstract of DOI:10.1016/j.tet.2006.09.096

(Z)-α-Fluoro-α,β-unsaturated esters (Z)-7a-f were stereoselectively prepared by a tandem reduction-olefination of triethyl 2-acyl-2-fluoro-2-phosphonoacetates 6a-f with NaBH₄ in EtOH. A concise synthesis of Cbz-Gly-Ψ[(Z)-CF{double bond, long}C]-Gly (26) as a dipeptide isostere was achieved via the tandem reduction-olefination of the corresponding 2-acyl-2-fluoro-2-phosphonoacetate 20.

Full text of DOI:10.1016/j.tet.2006.09.096

Tetrahedron 62 (2006) 11881–11890
Tandem reduction–olefination of triethyl 2-acyl-2-fluoro-2-
phosphonoacetates and a synthetic approach to Cbz-Gly-
J[(Z)-CF]C]-Gly dipeptide isostere
*
Shigeki Sano, Yoko Kuroda, Katsuyuki Saito, Yukiko Ose and Yoshimitsu Nagao
Graduate School of Pharmaceutical Sciences, The University of Tokushima, Sho-machi, Tokushima 770-8505, Japan
Received 2 September 2006; revised 26 September 2006; accepted 27 September 2006
Available online 25 October 2006
Abstract—(Z)-a-Fluoro-a,b-unsaturated esters (Z)-7a–f were stereoselectively prepared by a tandem reduction–olefination of triethyl
2-acyl-2-fluoro-2-phosphonoacetates 6a–f with NaBH4 in EtOH. A concise synthesis of Cbz-Gly-J[(Z)-CF]C]-Gly (26) as a dipeptide
isostere was achieved via the tandem reduction–olefination of the corresponding 2-acyl-2-fluoro-2-phosphonoacetate 20.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
We have demonstrated the HWE reaction of various
aldehydes with 2-fluoro-2-diethylphosphonoacetic acid (4)
with i-PrMgBr in THF.13 However, the HWE reactions
resulted in satisfactory Z-selectivities only for aromatic
and a,b-unsaturated aldehydes. Consequently, we describe
herein a tandem reduction–olefination of triethyl 2-acyl-2-
fluoro-2-phosphonoacetates 6a–f for the stereoselective syn-
thesis of (Z)-a-fluoro-a,b-unsaturated esters (Z)-7a–f.33 In
addition, to expand the application of this methodology,
we achieved a concise synthesis of Cbz-Gly-J[(Z)-
CF]C]-Gly (26) as a dipeptide isostere based on the tandem
reduction–olefination. It is well known that fluoroolefins
play an important role as amide isosteres, from the stand-
point of mimicking of the steric demand, bond lengths,
and bond angles.34–49 Namely, (Z)-fluoroolefins mimic the
(s-Z)-amide bonds, as shown in Figure 1.
There is currently much interest in the synthesis of a-fluoro-
a,b-unsaturated carbonyl compounds as valuable building
blocks for biologically active compounds.1–6 Recent efforts
in our laboratory have focused on the stereoselective
Horner–Wadsworth–Emmons (HWE) reactions for the
synthesis of a,b-unsaturated esters or a,b-unsaturated
carboxylic acids using HWE reagents,7–17 such as
methyl bis(2,2,2-trifluoroethyl)phosphonoacetate (1),18 bis-
(2,2,2-trifluoroethyl)phosphonoacetic acid (2),15,19 triethyl
2-fluoro-2-phosphonoacetate (3),20 and 2-fluoro-2-diethyl-
phosphonoacetic acid (4).3 Although, the stereoselective
synthesis of (E)-a-fluoro-a,b-unsaturated esters utilizing
the HWE reaction of phosphonoacetate 3 with aldehydes
is well known,21–32 there are few reports on the stereoselec-
tive HWE reaction, which was successfully employed in the
synthesis of (Z)-a-fluoro-a,b-unsaturated esters.
R1
R1
F
O
N
=
O
P
O
P
R2
R2
H
H
CF3CH2O
CF3CH2O
CF3CH2O
CF3CH2O
CO2Me
CO2H
(Z)-fluoroolefin
(s-Z)-amide
1
2
Figure 1. (Z)-Fluoroolefins mimic the (s-Z)-amide bonds.
O
O
EtO
P
EtO
EtO
2. Results and discussion
P
CO2Et
CO2H
EtO
F
F
2.1. Tandem reduction–olefination of triethyl 2-acyl-2-
fluoro-2-phosphonoacetate
3
4
Triethyl2-acyl-2-fluoro-2-phosphonoacetates 6a–fwerepre-
pared by the treatment of commercially available triethyl 2-
fluoro-2-phosphonoacetate (3) with n-BuLi (1.05 mol equiv)
in THF at 0 ꢀC, followed by acylation of the resulting
Keywords: Reduction; Olefination; Fluorine; Phosphonoacetates; a-Fluoro-
a,b-unsaturated esters; Dipeptide isosteres.
* Corresponding author. Tel.: +81 88 633 7273; fax: +81 88 633 9503;
e-mail: ssano@ph.tokushima-u.ac.jp
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.09.096

11882
S. Sano et al. / Tetrahedron 62 (2006) 11881–11890
O
P
F
EtO
EtO
R
H
F
iii
CO2Et
O
CO2Et
R
i, ii
O
P
(Z)-7a–f
6a: 58%, 6b: 60%, 6c: 77%
6d: 60%, 6e: 52%, 6f: 54%
EtO
EtO
CO2Et
(CH2)2
F
3
a: R =
d: R = t-Bu
e: R = Ph
i, iv
H
R
F
b: R = Ph(CH2)2
c: R = cyclohexyl
CO2Et
(E)-7a–f
f: R = 2-Naph
Scheme 1. Reagents and conditions: (i) n-BuLi, THF, 0 ꢀC, 1 h; (ii) RCOCl 5a–f, THF, 0 ꢀC, a: 2 h, b: 1 h, c: 5 h, d: 6 h, e: 1 h, f: 1 h; (iii) NaBH4, EtOH,
ꢁ78 ꢀC to rt (Table 1); (iv) RCHO 8a–f, THF, rt (Table 2).
lithium enolate with acyl chlorides 5a–f (1.05 mol equiv)
in 52–77% yields (Scheme 1). Tandem reduction–olefina-
tion of phosphonoacetates 6a–f with NaBH4 (1 mol equiv)
in EtOH was then examined, as shown in Scheme 1 and
Table 1. In the case of phosphonoacetate 6a, NaBH4
(1 mol equiv) was added to the solution of 6a in EtOH
at ꢁ78 ꢀC, and the mixture was then stirred for 2 h, after
which the temperature was allowed to rise to room
temperature. After 1 h of stirring at room temperature,
(Z)-a-fluoro-a,b-unsaturated ester (Z)-7a was obtained in
83% yield as the sole stereoisomer (Table 1, entry 1).
Excellent Z-selectivity was also achieved in all the other
tandem reduction–olefination reactions with phosphono-
acetates 6b–f (Table 1, entries 2–6). The disappearance
of the starting phosphonoacetates 6a–f was conveniently
monitored by thin-layer chromatographic (TLC) analysis,
and after that the reaction temperature was raised to com-
plete the olefination of the resulting pro-(Z)-oxyanion in-
termediate (Fig. 2). The reduction of phosphonoacetates
6c,d with bulky acyl groups was slower than that of phos-
phonoacetates 6a,b,e,f, and the tandem reduction–olefina-
tion of phosphonoacetate 6d was achieved at ꢁ78 ꢀC for
18 h without an increase in temperature (Table 1, entries
3 and 4). High volatility of (Z)-a-fluoro-a,b-unsaturated
ester (Z)-7d caused an inaccurate yield (Table 1, entry 4).
Moderate yields of (Z)-a-fluoro-a,b-unsaturated esters
(Z)-7e,f were probably attributable to the high lability of
the starting phosphonoacetates 6e,f (Table 1, entries 5 and 6).
On the other hand, ordinary E-selective HWE reactions of
phosphonoacetate 3 with aldehydes 8a–f were performed
under n-BuLi conditions at room temperature. As antici-
pated, (E)-a-fluoro-a,b-unsaturated esters (E)-7a–f were ob-
tained as major products in each corresponding reaction
(Scheme 1, Table 2). That is to say, a complementarity of
stereoselectivity was found between the HWE reaction of
phosphonoacetate 3 with aldehydes 8a–f and the tandem
reduction–olefination of phosphonoacetate 6a–f. The geom-
etry and the diastereomeric ratios of olefins 7a–f were
confirmed on the basis of the coupling constants between
fluorine and the adjacent olefinic proton (3JH,F), and the in-
tegration of appropriate proton absorptions was obtained by
1H NMR (300 or 400 MHz) analysis, respectively.
Table 2. HWE reactions of 2-fluoro-2-phosphonoacetate 3 with aldehydes
8a–fa
Entry
Aldehyde
Yield (%)b
E:Zc
1
2
3
4
5
6
8a
8b
8c
8d
8e
8f
78 (7a)
77 (7b)
81 (7c)
37 (7d)d
84 (7e)
93 (7f)
88:12 (7a)
92:8 (7b)e
91:9 (7c)
97:3 (7d)e
93:7 (7e)
89:11 (7f)
a
THF, rt, 20 h, 3/n-BuLi/8 (1.2:1.2:1 molar ratio).
Isolated yields.
a
Table 1. Tandem reduction–olefination of 6a–f with NaBH4
b
c
d
e
Determined by 1H NMR (300 or 400 MHz, CDCl3) analysis.
High volatility.
Entry Phosphonoacetate Temperature/time
Yield
(%)b
E:Zc
Determined by 1H NMR (400 MHz, C6D6) analysis.
1
2
3
4
5
6
6a
6b
6c
6d
6ee
6fe
ꢁ78 ꢀC/2 h to rt/1 h 83 (7a) 0:100 (7a)
ꢁ78 ꢀC/2 h to rt/1 h 76 (7b) <1:>99 (7b)
ꢁ78 ꢀC/18 h to rt/1 h 84 (7c) 9:91 (7c)
We also subjected a series of phosphonoacetates 9a–c to the
tandem reduction–olefination. Phosphonoacetates 10a–c
were prepared by the treatment of phosphonoacetates 9a–c
with n-BuLi (1.05 mol equiv) in THF at 0 ꢀC, followed by
acylation of the resulting lithium enolate with 3-phenyl-
propionyl chloride (5b) (1.05 mol equiv) (Scheme 2). Under
ꢁ78 ꢀC/18 h
58 (7d)d 4:96 (7d)
ꢁ78 ꢀC/2 h to rt/1 h 59 (7e) 0:100 (7e)
ꢁ78 ꢀC/1 h to rt/1 h 63 (7f) <1:>99 (7f)
a
b
c
d
e
EtOH, 6/NaBH4 (1:1 molar ratio).
Isolated yields.
Determined by 1H NMR (300 or 400 MHz, CDCl3) analysis.
High volatility.
Labile compounds.
O
P
X
O
P
Ph
EtO
EtO
EtO
EtO
CO2Et
O
iii
i, ii
X
CO2Et
H
CO2Et
X
O
P
O
P
F
F
10a–c
EtO
EtO
EtO
EtO
9a–c
(E)-11a–c
Ph
CO2Et
CO2Et
10a: 36%
O
O
R
H
10b: 73%
10c: 13%
a: X = H, b: X = Me, c: X = i-Pr
H
R
pro-(Z)-oxyanion
pro-(E)-oxyanion
Scheme 2. Reagents and conditions: (i) n-BuLi, THF, 0 ꢀC, 1 h; (ii)
PhCH2CH2COCl (5b), THF, 0 ꢀC, a: 30 min, b: 3 h, c: 20 h; (iii) NaBH4,
EtOH, ꢁ78 ꢀC to rt (Table 3).
Figure 2. Pro-(Z)- and pro-(E)-oxyanion intermediate in tandem reduction–
olefination of 6a–f.

S. Sano et al. / Tetrahedron 62 (2006) 11881–11890
11883
a
Table 3. Tandem reduction–olefination of 10a–c with NaBH4
diastereoselective reduction with NaBH4. In fact, Burton
and Thenappan reported in 1991 that the use of NaBH4 as
a reducing agent of 6e at room temperature led to a mixture
of two geometrical isomers (E:Z¼52:48).53 In our experi-
ment, an apparent decrease in Z-selectivity (E:Z¼16:84,
63% yield) was also found in the tandem reduction–olefina-
tion of 6b at room temperature (Scheme 4).
Entry Phosphonoacetate Temperature/time
Yield
(%)b
E:Zc
1
2
3
4
10a
10b
10c
10c
ꢁ78 ꢀC/2 h to rt/1 h 48 (11a)d 100:0 (11a)
ꢁ78 ꢀC/20 h to rt/1 h 49 (11b) 93:7 (11b)
e
ꢁ78 ꢀC/6 h
—
9 (11c)
—
56:44 (11c)
0 ꢀC/20 h
a
b
c
d
e
EtOH, 10/NaBH4 (1:1 molar ratio).
Isolated yields.
O
P
F
Determined by 1H NMR (400 MHz, CDCl3) analysis.
3-Phenyl-1-propanol (19%) was obtained.
No reaction.
EtO
Ph
CO2Et
OH
EtO
F
+
i
O
P
F
CO2Et
H
14
EtO
EtO
Ph
CO2Et
O
(Z)-7b
the same reaction conditions of the tandem reduction–olefi-
nation described above, phosphonoacetates 10a,b provided
a,b-unsaturated esters 11a,b in E:Z ratios of 100:0 and
93:7, respectively (Table 3, entries 1 and 2). According to
Cahn–Ingold–Prelog (CIP) priority, each major stereoiso-
mer of a,b-unsaturated esters 11a,b was assigned as the E-
configuration, while (E)-11a,b and (Z)-7a–f refer to the
same geometry. Thus, the olefinic proton and the ester moi-
ety of (E)-11a,b and (Z)-7a–f are on the same side of the
double bond. However, the reaction of phosphonoacetate
10c with a bulky isopropyl group instead of the H, F, or Me
group appeared to suffer, as indicated by the low stereoselec-
tivity and the low yield (Table 3, entries 3 and 4). The geom-
etry of olefin 11a was confirmed on the basis of the coupling
constants (3JH,H¼15.6 Hz) of 1H NMR (400 MHz) analysis
between both olefinic protons. The geometry of olefins 11b,c
was determined on the basis of the chemical shift of the
olefinic proton by application of Tobey–Pascual substituent
shielding constants.50–52 The diastereomeric ratios of olefins
11a–c were also confirmed on the basis of the integration of
appropriate proton absorptions by 1H NMR (400 MHz) anal-
ysis. It is worth noting that the tandem reaction of 10a with
NaBH4 afforded 3-phenyl-1-propanol (13) in 19% yield as
a by-product together with 48% of (E)-a,b-unsaturated ester
(E)-11a (Table 3, entry 1). That is to say, reduction of phos-
phonoacetate 10a furnished the pro-(E)-oxyanion intermedi-
ate, from which a retro-aldol type reaction would take place
under the basic conditions to give the 3-phenylpropionalde-
hyde (8b). The aldehyde 8b would be reduced by NaBH4 to
3-phenyl-1-propanol (13), immediately (Scheme 3).
ii
6b
Ph
(Z)-7b
iii
or iv
14
Scheme 4. Reagents and conditions: (i) NaBH4, EtOH, ꢁ78 ꢀC, 18 h; (ii)
NaBH4, EtOH, rt, 2 h; (iii) NaBH4, EtOH, rt, 1 h; (iv) n-BuLi, THF, rt, 1 h.
Next, we tried to isolate the oxyanion intermediate of the
tandem reduction–olefination reaction of 6a–f. In the case
of 6b, the tandem reduction–olefination at ꢁ78 ꢀC gave
a fortuitous mixture of (Z)-7b and alcohol 14. Chromato-
graphic separation and isolation of the products afforded
(Z)-7b (44%, E:Z¼<1:>99) and alcohol 14 (46%), as shown
in Scheme 4. 13C NMR analysis (75 MHz) of alcohol 14
strongly suggested that the alcohol was obtained in a dia-
stereomerically pure form. In addition, treatment of alcohol
14 with NaBH4 (1 mol equiv) in EtOH at room temperature
resulted in the formation of (Z)-7b with an E:Z ratio of
<1:>99 in 80% yield. On the other hand, the addition of
n-BuLi (1 mol equiv) to a solution of alcohol 14 in THF at
room temperature gave (Z)-7b in 80% yield with a slightly
lower stereoselectivity (E:Z¼8:92). It can therefore be pre-
sumed that a retro-aldol type reaction is involved here that
is similar to the reaction of 10a. Unfortunately, 3-phenyl-
1-propanol (13) was not obtained as a by-product in the re-
action with NaBH4. A decrease in the stereoselectivity of
the olefination of alcohol 14 under n-BuLi conditions com-
pared with that under NaBH4 conditions may be ascribed to
the ordinary E-selective HWE reaction of a small amount of
aldehyde 8b with phosphonoacetate 3 formed by a retro-
aldol type reaction of pro-(Z)-oxyanion intermediate.
O
P
H
O
P
O
EtO
EtO
H
Ph
CO2Et
O
EtO
EtO
H
CO2Et
CO2Et
H
10a
Ph
H
On the basis of the experimental results described above, ex-
cellent Z-selectivity of this tandem reduction–olefination of
6a–f to a-fluoro-a,b-unsaturated esters 7a–f should be the
result of highly diastereoselective reduction. When a possi-
ble Felkin–Anh type transition state is envisioned,54–60 the
attack of hydride preferentially involves the conformation
A of phosphonoacetates 6a–f, not B, to minimize steric inter-
actions, as indicated in the Newman projections (Fig. 3).
This Felkin–Anh model considers that the transition state
mostly resembles the ketones and hydrides.61 The tandem
reduction–olefination of 10a,b to a,b-unsaturated esters
11a,b is also stereoselective, and the stereoselective out-
come may be understood in terms of the similar Felkin–
Anh type conformation of 10a,b (conformation C), as shown
in Figure 3. In the case of phosphonoacetate 10c (X¼i-Pr),
Ph
(E)-11a
pro-(E)-oxyanion
O
P
EtO
EtO
CHO
CO2Et
Ph
OH
Ph
12
8b
13
Scheme 3. Tandem reduction–olefination of 10a and by-product 13.
2.2. Mechanistic consideration of tandem
reduction–olefination
As stated above, we performed the reduction step in the
tandem reduction–olefination of phosphonoacetates 6a–f
at ꢁ78 ꢀC to better differentiate a transition state for the

11884
S. Sano et al. / Tetrahedron 62 (2006) 11881–11890
acyl chloride 19 in a quantitative yield. Acylation of phos-
EtO
EtO
(CH2)2
O
O
a: R =
d: R = t-Bu
e: R = Ph
EtO
P
EtO
P
< <
phonoacetate 3 then afforded triethyl 2-acyl-2-fluoro-2-
phosphonoacetate 20 via treatment with acyl chloride 19
under n-BuLi conditions at ꢁ78 ꢀC in THF. As expected,
phosphonoacetate 20 was easily converted to (Z)-a-fluoro-
a,b-unsaturated ester 21 by the tandem reduction–olefina-
tion with NaBH4 in EtOH with excellent stereoselectivity
(E:Z¼0:100) at ꢁ78 ꢀC in 63% yield (two steps).
R
F
O
CO2Et
O
F
R
CO2Et
b: R = Ph(CH2)2
c: R = cyclohexyl
f: R = 2-Naph
H
H
A
B
(Z)-7a–f
(E)-7a–f
EtO
EtO
O
O
EtO
P
EtO
P
Reduction of the (Z)-a-fluoro-a,b-unsaturated ester 21 gave
the corresponding primary alcohol 22 in 93% yield. The
hydroxyl group of 22 was successively transformed to the
protected amino group of 23 under Mitsunobu reaction
conditions.63–65 In this reaction, PPh3, N-carbobenzoxy-2-
nitrobenzenesulfonamide (N-Cbz-NsNH), and alcohol 22
were dissolved in CH2Cl2 and diethyl azodicarboxylate
(DEAD) in toluene was slowly added to the solution. How-
ever, when DEAD was first reacted with the phosphine,
a poor result was obtained. Next, Cbz-protected 24 was ob-
tained in 95% yield (two steps) by chemoselective deprotec-
tion of the 2-nitrobenzenesulfonyl (Ns) group of 23 with
4-tert-butylthiophenol in the presence of K2CO3 in DMF.
Deprotection of the TBDPS group of 24 with tetra-n-butyl-
ammonium fluoride (TBAF) in THF cleanly produced the
primary alcohol 25 in 92% yield. Finally, oxidation of alco-
hol 25 with an excess amount of Jones reagent in acetone
delivered Cbz-Gly-J[(Z)-CF]C]-Gly (26) as a dipeptide
isostere in 80% yield.
a: X = H
Ph
Ph
< <
O
CO2Et
O
X
b: X = Me
X
CO2Et
H
H
C
D
(E)-11a,b
(Z)-11a,b
Figure 3. Plausible conformations of 6a–f and 10a,b for diastereoselective
reduction with NaBH4.
the reduction is slightly stereoselective because the two pos-
sible conformations C and D are equally important.
2.3. Synthesis of Cbz-Gly-J[(Z)-CF]C]-Gly
as a dipeptide isostere
The chemistry described above was extended to the prepara-
tion of dipeptide isosteres. A possible strategy for the syn-
thesis of Cbz-Gly-J[(Z)-CF¼C]-Gly (26) as a dipeptide
isostere via Z-selective tandem reduction–olefination of tri-
ethyl 2-acyl-2-fluoro-2-phosphonoacetate 20 with NaBH4
is shown in Scheme 5. Our synthesis began with a ring open-
ing reaction of the commercially available b-propiolactone
(15), followed by protection of the resultant alcohol 16
with tert-butyldiphenylsilyl chloride (TBDPSCl) in the pres-
ence of imidazole according to the procedure of Ley and
co-workers (96% yield).62 Alkaline hydrolysis of the methyl
ester 17 with aqueous EtOH solution of NaOH furnished car-
boxylic acid 18 (99% yield). Upon treatment with oxalyl
chloride in CH2Cl2, carboxylic acid 18 provided the desired
3. Conclusion
We described here the tandem reduction–olefination of 2-
acyl-2-fluoro-2-phosphonoacetates 6a–f, as a novel one-
pot reaction, for the preparation of a-fluoro-a,b-unsaturated
esters 7a–f with excellent Z-selectivity. Furthermore, a con-
cise synthesis of Cbz-Gly-J[(Z)-CF]C]-Gly (26) as a di-
peptide isostere was achieved by virtue of an application
of this reaction.
i
ii
iii
HO
TBDPSO
TBDPSO
O
CO2Me
16
CO2Me
CO2H
O
15
17
18
iv
TBDPSO
COCl
v
O
P
F
19
EtO
F
vi
ix
vii
CO2Et
O
EtO
OTBDPS
EtO2C
O
P
21
EtO
EtO
OTBDPS
20
CO2Et
F
3
Ns
F
F
F
H
viii
xi
x
HO
OTBDPS
OH
N
OTBDPS
N
OTBDPS
Cbz
Cbz
22
23
24
F
F
H
N
H
N
xii
CO2H
Cbz
Cbz
25
26
Scheme 5. Reagents and conditions: (i) NaOMe, MeOH, 50 ꢀC, 4 h; (ii) TBDPSCl, imidazole, CH2Cl2, rt, 14 h; (iii) 1 N NaOH, EtOH, rt, 6 h; (iv) (COCl)2,
CH2Cl2, rt, 15 h; (v) n-BuLi, THF, ꢁ78 ꢀC, 1 h; (vi) 19, THF, ꢁ78 ꢀC, 1 h; (vii) NaBH4, EtOH, ꢁ78 ꢀC, 2 h to rt, 1 h; (viii) LiAlH4, THF, 0 ꢀC, 30 min; (ix)
PPh3, N-Cbz-NsNH, DEAD, CH2Cl2, rt, 1 h; (x) 4-tert-BuC6H4SH, K2CO3, DMF, rt, 15 min; (xi) TBAF, THF, rt, 45 min; (xii) Jones reagent, acetone, rt, 30 min.

S. Sano et al. / Tetrahedron 62 (2006) 11881–11890
11885
2
1
1
4. Experimental
65.3 (d, JC,P¼6.9 Hz), 98.5 (dd, JC,F¼208.6 Hz, JC,P
¼
154.4 Hz), 126.3 (s), 128.4 (s), 128.5 (s), 140.2 (s), 162.0
2
2
4.1. General
(d, JC,F¼22.4 Hz), 197.8 (d, JC,F¼23.0 Hz); IR (neat)
1757, 1732, 1265, 1018 cmꢁ1; EIMS calcd for C17H24FO6P
MW 374.1295, found m/z 374.1295 (M+). Anal. Calcd for
C17H24FO6P: C, 54.54; H, 6.46. Found: C, 54.57; H, 6.46%.
All melting points were determined on a Yanagimoto micro
melting point apparatus and are uncorrected. IR spectra were
obtained using a JASCO FT/IR-420 IR Fourier transform
spectrometer. H NMR (400 or 300 MHz) and 13C NMR
4.2.3. Triethyl 3-cyclohexyl-2-fluoro-3-oxo-2-phosphono-
propanoate (6c). Colorless oil; 1H NMR (400 MHz, CDCl3)
d 1.13–1.49 (14H, m), 1.63–1.96 (5H, m), 2.98–3.10 (1H,
m), 4.25–4.40 (6H, m); 13C NMR (75 MHz, CDCl3) d 14.0
1
(100 or 75 MHz) spectra were recorded on JEOL JNM-
AL400 and JEOL JNM-AL300 spectrometers, respectively.
Chemical shifts are given in d values (parts per million)
using tetramethylsilane (TMS) as an internal standard.
Electron impact mass spectra (EIMS) were recorded on
a JEOL JMS SX-102A spectrometer. Electron spray ioniza-
tion mass spectra (ESIMS) were recorded on a Waters LCT
Premier spectrometer. Elemental combustion analyses were
performed using a Yanagimoto CHN CORDER MT-5. All
reactions were monitored by TLC employing 0.25-mm silica
gel plates (Merck 5715; 60 F254). Preparative TLC (PTLC)
was performed on 0.5-mm silica gel plates (Merck 5744;
60 F254). Column chromatography was carried out on silica
gel [Kanto Chemical 60N (spherical, neutral); 63–210 mm].
Anhydrous THF, CH2Cl2, MeOH, and DMF were used as
purchased from Kanto Chemical. Anhydrous EtOH was
commercially obtained from Wako Pure Chemical Industry.
All aldehydes and acyl chlorides were distilled prior to use.
All other reagents were used as purchased.
3
(s), 16.4 (d, JC,P¼6.2 Hz), 25.3 (s), 25.6 (s), 25.7 (s), 28.1
(s), 28.6 (d, 4J¼1.2 Hz), 46.4 (s), 63.3 (s), 65.1 (d,
2JC,P¼6.9 Hz), 65.2 (d, JC,P¼6.9 Hz), 98.5 (dd, JC,F
¼
2
1
1
2
209.3 Hz, JC,P¼156.3 Hz), 162.3 (d, JC,F¼22.4 Hz),
2
201.8 (d, JC,F¼22.4 Hz); IR (neat) 1756, 1726, 1271,
1097, 1022 cmꢁ1; EIMS calcd for C15H26FO6P MW
352.1451, found m/z 352.1473 (M+). Anal. Calcd for
C15H26FO6P: C, 51.13; H, 7.44. Found: C, 50.97; H, 7.30%.
4.2.4. Triethyl 2-fluoro-4,4-dimethyl-3-oxo-2-phosphono-
pentanoate (6d). Colorless oil; 1H NMR (400 MHz, CDCl3)
d 1.24 (9H, d, J¼1.7 Hz), 1.25–1.45 (9H, m), 4.25–4.45 (6H,
m); 13C NMR (75 MHz, CDCl3) d 14.0 (s), 16.4 (d,
3JC,P¼6.2 Hz), 25.8 (d, JC,F¼5.0 Hz), 45.8 (dd, J¼2.5,
4
3
2
2
3.7 Hz), 63.3 (s), 65.0 (d, JC,P¼6.9 Hz), 65.1 (d, JC,P
¼
1
1
6.9 Hz), 99.9 (dd, JC,F¼214.2 Hz, JC,P¼158.8 Hz), 162.5
2
2
(d, JC,F¼22.4 Hz), 203.6 (d, JC,F¼21.8 Hz); IR (neat)
1752, 1716, 1268, 1245, 1022 cmꢁ1; EIMS calcd for
C13H24FO6P MW 326.1295, found m/z 326.1308 (M+).
Anal. Calcd for C13H24FO6P: C, 47.85; H, 7.41. Found: C,
47.41; H, 7.18%.
4.2. Acylation of triethyl 2-fluoro-2-phosphonoacetate
(3) with 3-phenylpropionyl chloride (5b)
A 1.6 mol/l solution of n-BuLi (4.9 ml, 13.0 mmol) in n-hex-
ane was added to a stirred solution of phosphonoacetate 3
(1.5 ml, 12.4 mmol) in anhydrous THF (20 ml) at 0 ꢀC under
argon. The mixture was stirred at 0 ꢀC for 1 h, and then
3-phenylpropionyl chloride (5b) (1.16 ml, 13.0 mmol) was
slowly added to the solution. After being stirred at 0 ꢀC for
1 h, the reaction mixture was treated with 5% HCl (10 ml)
and then extracted with AcOEt (50 mlꢂ3). The extract
was washed with brine, dried over anhydrous MgSO4, fil-
tered, and concentrated in vacuo. The oily residue was puri-
fied by silica gel column chromatography [n-hexane–AcOEt
(1:1)] to afford 6b (1.68 g, 60%) as a colorless oil.
4.2.5. Triethyl 2-fluoro-3-oxo-2-phosphono-3-phenylpro-
panoate (6e). Colorless oil; H NMR (400 MHz, CDCl3)
d 1.26 (3H, t, J¼7.1 Hz), 1.32–1.41 (6H, m), 4.22–4.46
(6H, m), 7.42–7.55 (2H, m), 7.57–7.65 (1H, m), 7.95–8.03
(1H, m), 8.07–8.14 (1H, m); ESIMS calcd for C15H21FO6P
MW 347.1060, found m/z 347.1031 (M++H).
1
4.2.6. Triethyl 2-fluoro-3-(2-naphthyl)-3-oxo-2-phospho-
nopropanoate (6f). Colorless oil; 1H NMR (400 MHz,
CDCl3) d 1.26 (3H, t, J¼7.1 Hz), 1.32–1.43 (6H, m),
4.14–4.51 (6H, m), 7.53–7.67 (2H, m), 7.83–7.93 (2H, m),
7.94–8.03 (2H, m), 8.60 (1H, s); ESIMS calcd for
C19H23FO6P MW 397.1216, found m/z 397.1190 (M++H).
4.2.1. Triethyl 5-cyclopentyl-2-fluoro-3-oxo-2-phospho-
nopentanoate (6a). Colorless oil; 1H NMR (400 MHz,
CDCl3) d 1.02–1.15 (2H, m), 1.31–1.41 (9H, m), 1.45–
1.82 (9H, m), 2.77 (2H, dt, J¼3.2, 7.3 Hz), 4.23–4.40 (6H,
m); 13C NMR (75 MHz, CDCl3) d 14.0 (s), 16.3 (d,
4.2.7. Triethyl 3-oxo-5-phenyl-2-phosphonopentanoate
(10a). Yellow oil; H NMR (400 MHz, CDCl3) d 1.20–
1
3
3JC,P¼6.2 Hz), 16.4 (d, JC,P¼6.2 Hz), 25.1 (s), 28.9 (d,
1.39 (9H, m, keto- and enol-tautomer), 2.86–3.36 (4H, m,
keto- and enol-tautomer), 3.86–4.33 (6H, m, keto- and
enol-tautomer), 3.86–4.33 (1H, m, keto-tautomer), 7.14–
7.33 (5H, m, keto- and enol-tautomer), 13.70 (1H, s, enol-
tautomer); IR (neat) 1738, 1703, 1580, 1433, 1236, 1077,
3J¼2.5 Hz), 32.5 (s), 37.9 (s), 39.4 (s), 63.4 (s), 65.2
2
2
1
(d, JC,P¼6.9 Hz), 65.3 (d, JC,P¼6.9 Hz), 98.5 (dd, JC,F
¼
1
2
208.6 Hz, JC,P¼155.7 Hz), 162.2 (d, JC,F¼23.7 Hz),
2
199.0 (d, JC,F¼23.0 Hz); IR (neat) 1758, 1733, 1270,
1022 cmꢁ1; EIMS calcd for C16H28FO6P MW 366.1608,
1025, 976 cmꢁ1
; EIMS calcd for C17H25O6P MW
found m/z 366.1606 (M+).
356.1389, found m/z 356.1403 (M+).
4.2.2. Triethyl 2-fluoro-3-oxo-5-phenyl-2-phosphonopen-
tanoate (6b). Colorless oil; H NMR (400 MHz, CDCl3)
4.2.8. Triethyl 2-methyl-3-oxo-5-phenyl-2-phosphono-
pentanoate (10b). Colorless oil; 1H NMR (400 MHz,
1
3
d 1.25–1.40 (9H, m), 2.90–2.97 (2H, m), 3.07–3.14 (2H,
m), 4.18–4.35 (6H, m), 7.15–7.33 (5H, m); 13C NMR
CDCl3) d 1.23–1.36 (9H, m), 1.63 (3H, d, JH,P¼15.6 Hz),
2.89–3.17 (4H, m), 4.08–4.28 (6H, m), 7.15–7.34 (5H, m);
¼
3
3
(75 MHz, CDCl3) d 13.9 (s), 16.3 (d, JC,P¼6.2 Hz), 28.8
13C NMR (75 MHz, CDCl3) d 13.9 (s), 16.3 (d, JC,P
3
2
3
2
(d, J¼2.5 Hz), 40.2 (s), 63.3 (s), 65.2 (d, JC,P¼6.9 Hz),
6.2 Hz), 16.4 (d, JC,P¼6.2 Hz), 17.1 (d, JC,P¼5.6 Hz),

11886
S. Sano et al. / Tetrahedron 62 (2006) 11881–11890
3
3
30.0 (s), 42.0 (s), 62.2 (s), 63.4 (d, 1JC,P¼133.3 Hz), 63.3 (d,
(1H, q, J¼7.2 Hz), 5.98 (1H, dd, JH,F¼33.9 Hz, JH,H¼
2
2JC,P¼6.9 Hz), 63.5 (d, JC,P¼6.9 Hz), 126.1 (s), 128.4 (s),
9.7 Hz); IR (neat) 2929, 2854, 1736, 1673, 1304,
1087 cmꢁ1; EIMS calcd for C11H17FO2 MW 200.1213,
found m/z 200.1218 (M+).
2
128.5 (s), 140.9 (s), 168.5 (d, JC,P¼3.7 Hz), 200.8 (d,
2JC,P¼1.9 Hz); IR (neat) 1732, 1716, 1455, 1257, 1106,
1048, 1021, 970 cmꢁ1; EIMS calcd for C18H27O6P MW
370.1545, found m/z 370.1546 (M+).
4.3.4. Ethyl (Z)-2-fluoro-4,4-dimethyl-2-pentenoate [(Z)-
7d].69,70 Colorless oil; H NMR (300 MHz, CDCl3) d 1.20
1
4.2.9. Triethyl 2-isopropyl-3-oxo-5-phenyl-2-phosphono-
pentanoate (10c). Colorless oil; 1H NMR (400 MHz,
CDCl3) d 1.12 (3H, d, J¼6.8 Hz), 1.19 (3H, d, J¼6.8 Hz),
1.25–1.38 (9H, m), 2.61–2.77 (1H, m), 2.86–3.05 (4H, m),
4.05–4.31 (4H, m), 4.25 (2H, q, J¼7.1 Hz), 7.10–7.34
(5H, m); 13C NMR (75 MHz, CDCl3) d 14.0 (s), 16.3 (d,
(9H, d, J¼0.7 Hz), 1.33 (3H, t, J¼7.2 Hz), 4.26 (2H, q,
3
J¼7.2 Hz), 6.06 (1H, d, JH,F¼38.7 Hz); IR (neat) 1735,
1671, 1282, 1205, 1095 cmꢁ1; EIMS calcd for C9H15FO2
MW 174.1056, found m/z 174.1060 (M+).
4.3.5. Ethyl (Z)-2-fluoro-3-phenyl-2-propenoate [(Z)-
3
3
1
3JC,P¼2.5 Hz), 16.4 (d, JC,P¼1.9 Hz), 19.0 (d, JC,P
¼
7e].67,68 Colorless oil; H NMR (400 MHz, CDCl3) d 1.39
3
2
7.5 Hz), 19.1 (d, JC,P¼5.0 Hz), 30.2 (s), 32.7 (d, JC,P
¼
(3H, t, J¼7.1 Hz), 4.36 (2H, q, J¼7.1 Hz), 6.92 (1H, d,
2
2
3.1 Hz), 63.0 (d, JC,P¼6.9 Hz), 63.3 (d, JC,P¼7.5 Hz),
3JH,F¼35.2 Hz), 7.33–7.44 (3H, m), 7.61–7.68 (2H, m); 13
C
1
2
72.1 (d, JC,P¼129.5 Hz), 126.1 (s), 128.42 (s), 128.45 (s),
NMR (75 MHz, CDCl3) d 14.2, 61.9, 117.5 (d, JC,F
4.4 Hz), 128.8, 129.7, 130.3 (d, JC,F¼8.1 Hz), 131.2 (d,
¼
167.8 (d, 2JC,P¼3.7 Hz), 201.4 (d, 2JC,P¼1.9 Hz); IR (neat)
1716, 1255, 1226, 1047, 967 cmꢁ1; EIMS calcd for
C20H31O6P MW 398.1858, found m/z 398.1877 (M+).
4
1
2
3JC,F¼4.4 Hz), 148.6 (d, JC,F¼267.2 Hz), 161.4 (d, JC,F
¼
34.3 Hz); IR (neat) 3060, 2983, 2939, 1730, 1660, 1496,
1450, 1371, 1282, 1201, 1101 cmꢁ1; ESIMS calcd for
C11H11NaFO2 MW 217.0641, found m/z 217.0626 (M++Na).
4.3. Tandem reduction–olefination of triethyl 5-cyclo-
pentyl-2-fluoro-3-oxo-2-phosphonopentanoate (6a)
4.3.6. Ethyl (Z)-2-fluoro-3-(2-naphthyl)-2-propenoate
[(Z)-7f]. Colorless solid (CHCl3–n-hexane), mp 60–61 ꢀC;
1H NMR (400 MHz, CDCl3) 1.41 (3H, t, J¼7.1 Hz), 4.38
To a solution of phosphonoacetate 6a (100 mg, 0.273 mmol)
in EtOH (7 ml) was added a solution of NaBH4 (10.3 mg,
0.273 mmol) in EtOH (3 ml) at ꢁ78 ꢀC under argon. After
stirring at ꢁ78 ꢀC for 2 h, the reaction mixture was allowed
to warm to room temperature and then was stirred for 1 h.
The mixture was treated with aqueous solution saturated
with NH4Cl (5 ml) and then extracted with AcOEt
(20 mlꢂ3). The extract was washed with brine, dried over
anhydrous MgSO4, filtered, and concentrated in vacuo.
The oily residue (E:Z¼0:100) was purified by silica gel
column chromatography [n-hexane–AcOEt (19:1)] to afford
(Z)-7a (48 mg, 83%) as a colorless oil.
3
(2H, q, J¼7.1 Hz), 7.09 (1H, d, JH,F¼35.2 Hz), 7.45–7.57
(2H, m), 7.75–7.91 (4H, m), 8.10 (1H, s); 13C NMR
2
(75 MHz, CDCl3) d 14.2, 61.9, 117.7 (d, JC,F¼5.0 Hz),
4
126.6, 126.8 (d, JC,F¼8.1 Hz), 127.3, 127.7, 128.5, 128.6,
4
3
128.68, 128.74, 130.8 (d, JC,F¼8.1 Hz), 133.4 (d, JC,F
¼
1
2
33.0 Hz), 147.2 (d, JC,F¼267.8 Hz), 161.5 (d, JC,F
¼
34.2 Hz); IR (KBr) 3421, 3371, 3062, 2985, 1726, 1655,
1373, 1254, 1099, 1022 cmꢁ1; ESIMS calcd for C15H14FO2
MW 245.0978, found m/z 245.0983 (M++H). Anal. Calcd
for C15H13FO2: C, 73.76; H, 5.36. Found: C, 73.43; H, 5.55%.
4.3.1. Ethyl (Z)-5-cyclopentyl-2-fluoro-2-pentenoate [(Z)-
7a]. Colorless oil; 1H NMR (300 MHz, CDCl3) d 1.00–1.20
(2H, m), 1.33 (3H, t, J¼7.1 Hz), 1.39–1.68 (6H, m), 1.70–
1.87 (3H, m), 2.52 (2H, q, J¼7.6 Hz), 4.28 (2H, q,
4.3.7. Ethyl (E)-5-phenyl-2-pentenoate [(E)-11a].72 Color-
less oil; 1H NMR (400 MHz, CDCl3) d 1.28 (3H, t,
J¼7.1 Hz), 2.45–2.61 (2H, m), 2.71–2.86 (2H, m), 4.18
(2H, q, J¼7.1 Hz), 5.85 (1H, d, J¼15.6 Hz), 7.00 (1H, dt,
J¼6.6, 15.6 Hz), 7.14–7.40 (5H, m); IR (neat) 1719, 1653,
1267, 1197, 1039 cmꢁ1; EIMS calcd for C13H16O2 MW
204.1150, found m/z 204.1121 (M+). Anal. Calcd for
C13H16O2: C, 76.44; H, 7.90. Found: C, 76.19; H, 7.92%.
3
3
J¼7.1 Hz), 6.13 (1H, dt, JH,F¼33.5 Hz, JH,H¼8.1 Hz);
IR (neat) 1735, 1679, 1455, 1371, 1311, 1083 cmꢁ1; EIMS
calcd for C12H19FO2 MW 214.1369, found m/z 214.1348
(M+). Anal. Calcd for C12H19FO2: C, 67.26; H, 8.94. Found:
C, 66.89; H, 8.82%.
4.3.8. Ethyl (E)-2-methyl-5-phenyl-2-pentenoate [(E)-
1
4.3.2. Ethyl (Z)-2-fluoro-5-phenyl-2-pentenoate [(Z)-
7b].66,67,71 Colorless oil; 1H NMR (400 MHz, CDCl3)
11b].73 Colorless oil; H NMR (400 MHz, CDCl3) d 1.29
(3H, t, J¼7.1 Hz), 1.78 (3H, s), 2.41–2.56 (2H, m), 2.69–
2.82 (2H, m), 4.19 (2H, q, J¼7.1 Hz), 6.81 (1H, dt, J¼1.2,
7.3 Hz), 7.15–7.33 (5H, m); IR (neat) 1709, 1649, 1266,
d 1.32 (3H, t, J¼7.1 Hz), 2.51–2.61 (2H, m), 2.76 (2H, t,
3
J¼7.3 Hz), 4.27 (2H, q, J¼7.1 Hz), 6.14 (1H, dt, JH,F
¼
33.2 Hz, JH,H¼7.6 Hz), 7.10–7.34 (5H, m); 13C NMR
1116, 1080 cmꢁ1
; EIMS calcd for C14H18O2 MW
3
3
(75 MHz, CDCl3) d 14.4, 26.0 (d, JC,F¼2.5 Hz), 34.45 (d,
218.1307, found m/z 218.1281 (M+). Anal. Calcd for
C14H18O2: C, 77.03; H, 8.31. Found: C, 76.75; H, 8.33%.
4JC,F¼1.9 Hz), 61.5, 119.5 (d, JC,F¼11.2 Hz), 126.29,
2
128.20, 128.31, 128.53, 140.59, 148.21 (d, 1JC,F¼256.6 Hz),
160.8 (d, 2JC,F¼35.5 Hz); IR (neat) 1733, 1679, 1455, 1371,
1313, 1105 cmꢁ1; EIMS calcd for C13H15FO2 MW
222.1056, found m/z 222.1051 (M+). Anal. Calcd for
C13H15FO2: C, 70.25; H, 6.80. Found: C, 69.79; H, 6.74%.
4.3.9. Ethyl (Z)-2-methyl-5-phenyl-2-pentenoate [(Z)-
1
11b].74 Colorless oil; H NMR (400 MHz, CDCl3) d 1.30
(3H, t, J¼7.1 Hz), 1.89 (3H, d, J¼1.2 Hz), 2.68–2.83 (4H,
m), 4.19 (2H, q, J¼7.1 Hz), 5.96 (1H, dt, J¼1.2, 7.1 Hz),
7.15–7.33 (5H, m); IR (neat) 1702, 1652, 1125,
1028 cmꢁ1; EIMS calcd for C14H18O2 MW 218.1307, found
m/z 218.1304 (M+). Anal. Calcd for C14H18O2: C, 77.03; H,
8.31. Found: C, 76.63; H, 8.36%.
4.3.3. Ethyl (Z)-3-cyclohexyl-2-fluoro-2-propenoate [(Z)-
1
7c].68 Colorless oil; H NMR (300 MHz, CDCl3) d 1.09–
1.42 (9H, m), 1.60–1.82 (5H, m), 2.49–2.64 (1H, m), 4.27

S. Sano et al. / Tetrahedron 62 (2006) 11881–11890
11887
4.3.10. Mixture of ethyl (E)-2-isopropyl-5-phenyl-2-pen-
tanoate [(E)-11c] and ethyl (Z)-2-isopropyl-5-phenyl-2-
pentanoate [(Z)-11c].75 Colorless oil; 1H NMR (400 MHz,
CDCl3) d 1.04 (6H, d, J¼6.8 Hz, E-isomer), 1.11 (6H, d,
J¼6.8 Hz, Z-isomer), 1.30 (3H, t, J¼7.1 Hz, E- and Z-iso-
mer), 2.45–2.91 (5H, m, E- and Z-isomer), 4.11–4.27 (2H,
m, E- and Z-isomer), 5.73 (1H, t, J¼7.3 Hz, Z-isomer),
6.61 (1H, t, J¼7.1 Hz, E-isomer), 7.11–7.36 (5H, m, E-
and Z-isomer); EIMS calcd for C16H22O2 MW 246.1620,
found m/z 246.1598 (M+). Anal. Calcd for C14H18O2: C,
78.01; H, 9.00. Found: C, 77.66; H, 9.01%.
4.4.3. Ethyl (E)-3-cyclohexyl-2-fluoro-2-propenoate [(E)-
7c].30,77 Colorless oil; 1H NMR (300 MHz, CDCl3) d 1.02–
1.44 (9H, m), 1.60–1.82 (5H, m), 2.94–3.10 (1H, m), 4.29
3
3
(1H, q, J¼7.2 Hz), 5.76 (1H, dd, JH,F¼22.0 Hz, JH,H
¼
10.3 Hz); IR (neat) 2929, 2852, 1729, 1300, 1213 cmꢁ1
EIMS calcd for C11H17FO2 MW 200.1213, found m/z
;
200.1207 (M+).
4.4.4. Ethyl (E)-2-fluoro-4,4-dimethyl-2-pentenoate [(E)-
7d].70 Colorless oil; 1H NMR (400 MHz, CDCl3) d 1.22 (9H,
s), 1.36 (3H, t, J¼7.1 Hz), 4.30 (2H, q, J¼7.1 Hz), 5.93 (1H,
3
d, JH,F¼28.6 Hz); IR (neat) 1735, 1651, 1374, 1348,
4.3.11. Ethyl 2-diethylphosphono-2-fluoro-3-hydroxy-5-
phenylpentanoate (14). Colorless prism (Et2O–n-hexane),
mp 66.5–67.5 ꢀC; 1H NMR (300 MHz, CDCl3) d 1.24 (3H,
t, J¼7.0 Hz), 1.32 (3H, t, J¼7.0 Hz), 1.34 (3H, t,
J¼7.0 Hz), 1.54–1.71 (1H, m), 1.93–2.11 (1H, m), 2.60–
2.79 (1H, m), 2.85–3.03 (1H, m), 3.40 (1H, br s), 4.09–
4.42 (7H, m) 7.10–7.34 (5H, m); 13C NMR (75 MHz,
1252 cmꢁ1; EIMS calcd for C9H15FO2 MW 174.1056,
found m/z 174.1030 (M+).
4.4.5. Ethyl (E)-2-fluoro-3-phenyl-2-propenoate [(E)-
1
7e].26,71 Colorless oil; H NMR (400 MHz, CDCl3) d 1.24
(3H, t, J¼7.1 Hz), 4.25 (2H, q, J¼7.1 Hz), 6.92 (1H, d,
3JH,F¼22.2 Hz), 7.30–7.36 (3H, m), 7.44–7.47 (2H, m);
13C NMR (75 MHz, CDCl3) d 13.8, 61.6, 117.5 (d,
CDCl3) d 13.9 (s), 16.25 (d, 3JC,P¼5.3 Hz), 16.28 (d, 3JC,P
¼
4
3
4
5.3 Hz), 31.6 (d, JC,F¼1.3 Hz), 32.2 (dd, JC,F¼4.7 Hz,
2JC,F¼25.5 Hz), 128.0, 128.7, 129.6 (d, JC,F¼2.5 Hz),
2
3
1
3JC,P¼8.4 Hz), 62.4 (s), 64.2 (d, JC,P¼6.9 Hz), 64.6 (dd,
131.0 (d, JC,F¼9.3 Hz), 147.0 (d, JC,F¼255.3 Hz), 160.5
4JC,F¼1.3 Hz, 2JC,P¼6.9 Hz), 71.8 (d, 2JC,F¼19.9 Hz), 98.0
(d, JC,F¼36.7 Hz); IR (neat) 3058, 2983, 2939, 1732,
2
(dd, 1JC,F¼204.9 Hz, 1JC,P¼160.7 Hz), 125.9 (s), 128.3 (s),
1656, 1494, 1448, 1375, 1284, 1230, 1132, 1022 cmꢁ1
ESIMS calcd for C11H11NaFO2 MW 217.0641, found m/z
;
2
2
128.4 (s), 141.2 (s), 165.8 (dd, JC,F¼22.7 Hz, JC,P
¼
2.2 Hz); IR (KBr) 3314, 1756, 1601, 1444, 1396,
1255 cmꢁ1; EIMS calcd for C17H26O6FP MW 379.1451,
found m/z 376.1439 (M+). Anal. Calcd for C17H26O6FP:
C, 54.25; H, 6.96. Found: C, 54.17; H, 6.84%.
217.0657 (M++Na).
4.4.6. Ethyl (E)-2-fluoro-3-(2-naphthyl)-2-propenoate
[(E)-7f]. Colorless solid (CHCl3–n-hexane), mp 32–34 ꢀC;
1H NMR (400 MHz, CDCl3) d 1.23 (3H, t, J¼7.1 Hz),
3
4.4. HWE reaction of triethyl 2-fluoro-2-phosphono-
acetate (3) with 3-phenylpropionaldehyde (8b)
4.25 (2H, q, J¼7.1 Hz), 7.07 (1H, d, JH,F¼22.2 Hz),
7.46–7.72 (3H, m), 7.77–7.90 (3H, m), 7.94 (1H, s); 13C
NMR (75 MHz, CDCl3)
d
13.9, 61.6, 121.6 (d,
4
To a solution of phosphonoacetate 3 (201 ml, 0.99 mmol) in
anhydrous THF (10 ml) was added a solution of n-BuLi
(1.58 mol/l in n-hexane, 0.63 ml, 0.99 mmol) at 0 ꢀC under
argon. After being stirred at 0 ꢀC for 1 h, 3-phenylpropion-
aldehyde (8b) (110 ml, 0.83 mmol) was slowly added to the
solution at 0 ꢀC. After being stirred at room temperature for
20 h, the reaction mixture was treated with 5% HCl (3 ml)
and then extracted with AcOEt (20 mlꢂ3). The extract was
washedwithbrine, driedoveranhydrousMgSO4, filtered, and
concentrated in vacuo. The oily residue (E:Z¼92:8) was
purified by silica gel column chromatography [n-hexane–
AcOEt–acetone (100:4:1)] to afford a diastereomeric mixture
of (E)-7b and (Z)-7b (142 mg, 77%) as a colorless oil.
2JC,F¼26.8 Hz), 126.3, 126.7, 127.1 (d, JC,F¼2.5 Hz),
4
127.5, 127.6, 128.2, 128.3, 128.4, 129.5 (d, JC,F¼3.7 Hz),
3
1
133.0 (d, JC,F¼23.7 Hz), 147.1 (d, JC,F¼255.3 Hz),
2
160.5 (d, JC,F¼36.1 Hz); IR (neat) 3056, 2983, 1730,
1651, 1506, 1468, 1375, 1336, 1226, 1132, 1020 cmꢁ1
;
ESIMS calcd for C15H14FO2 MW 245.0978, found m/z
245.0970 (M++H). Anal. Calcd for C15H13FO2: C, 73.76;
H, 5.36. Found: C, 73.45; H, 5.49%.
4.5. Synthesis of Cbz-Gly-J[(Z)-CF]C]-Gly (26)
4.5.1. Methyl 3-hydroxypropionate (16).62 To a solution of
sodium methoxide (146 mg, 2.65 mmol) in anhydrous MeOH
(8 ml) was added b-propiolactone (15) (1.9 g, 26.5 mmol) at
room temperature under argon. After being stirred at 50 ꢀC
for 4 h, the reaction mixture was submitted to filtration
through a silica gel short column (Et2O). The filtrate was con-
centrated in vacuo to afford 16 (2.74 g, quant.) as a colorless
oil. 1H NMR (400 MHz, CDCl3) d 2.36 (1H, s, OH), 2.59 (2H,
t, J¼5.6 Hz), 3.72 (3H, s), 3.88 (2H, t, J¼5.6 Hz); 13C NMR
(100 MHz, CDCl3) d 36.6, 51.7, 58.2, 173.3.
4.4.1. Ethyl (E)-5-cyclopentyl-2-fluoro-2-pentenoate
[(E)-7a]. Colorless oil; 1H NMR (400 MHz, CDCl3)
d 1.01–1.16 (2H, m), 1.35 (3H, t, J¼7.1 Hz), 1.39–1.69 (6H,
m), 1.70–1.86 (3H, m), 2.52 (2H, q, J¼7.8 Hz), 4.30 (2H, q,
3
3
J¼7.1 Hz), 5.94 (1H, dt, JH,F¼21.7 Hz, JH,H¼8.1 Hz); IR
(neat) 1729, 1666, 1375, 1342, 1220, 1126 cmꢁ1; EIMS calcd
for C12H19FO2 MW 214.1369, found m/z 214.1349 (M+).
4.4.2. Ethyl (E)-2-fluoro-5-phenyl-2-pentenoate [(E)-
4.5.2. Methyl 3-(tert-butyldiphenylsilyloxy)propanoate
(17). To a solution of 16 (1.24 g, 11.9 mmol) in anhydrous
CH2Cl2 (50 ml) were added imidazole (1.62 g, 23.8 mmol)
and tert-butylchlorodiphenylsilane (3.1 ml, 11.9 mmol) at
room temperature under argon. After being stirred at room
temperature for 14 h, an aqueous solution saturated with
NH4Cl (20 ml) was added and then extracted with CHCl3
(70 mlꢂ3). The extract was dried over anhydrous MgSO4,
1
7b].76 Colorless oil; H NMR (400 MHz, CDCl3) d 1.34
(3H, t, J¼7.1 Hz), 2.70–2.93 (4H, m), 4.28 (2H, q,
3
3
J¼7.1 Hz), 5.93 (1H, dt, JH,F¼21.3 Hz, JH,H¼8.1 Hz),
7.15–7.40 (5H, m); IR (neat) 1730, 1455, 1375, 1261,
1024 cmꢁ1; EIMS calcd for C13H15FO2 MW 222.1056,
found m/z 222.1066 (M+). Anal. Calcd for C13H15FO2: C,
70.25; H, 6.80. Found: C, 70.08; H, 6.84%.

11888
S. Sano et al. / Tetrahedron 62 (2006) 11881–11890
filtered, and evaporated in vacuo to afford an oily residue,
which was purified by chromatography on silica gel column
[n-hexane–AcOEt (15:1)] to give 17 (3.92 g, 96%) as a color-
The extract was dried over anhydrous MgSO4, filtered, and
concentrated in vacuo. The oily residue (E:Z¼0:100) was
purified by silica gel column chromatography [n-hexane–
AcOEt (15:1)] to afford 21 (2.94 mg, 63%) as a colorless
1
less oil. H NMR (400 MHz, CDCl3) d 1.03 (9H, s), 2.58
1
(2H, t, J¼6.3 Hz), 3.68 (3H, s), 3.94 (2H, t, J¼6.3 Hz),
7.35–7.50 (6H, m), 7.62–7.74 (4H, m); 13C NMR
(75 MHz, CDCl3) d 19.1, 26.7, 37.7, 51.5, 59.8, 127.7,
129.7, 133.5, 135.5, 172.1; IR (neat) 3072, 3049, 2931,
2858, 1745, 1589, 1471, 1429, 1362, 1194, 1111,
1008 cmꢁ1; ESIMS calcd for C20H27O3Si MW 343.1729,
found m/z 343.1761 (M++H). Anal. Calcd for C20H26O3Si:
C, 70.13; H, 7.65. Found: C, 69.72; H, 7.71%.
oil. H NMR (400 MHz, CDCl3) d 1.05 (9H, s), 1.33 (3H,
t, J¼7.1 Hz), 2.45–2.54 (2H, m), 3.74 (2H, t, J¼6.4 Hz),
3
4.28 (2H, q, J¼7.1 Hz), 6.23 (1H, dt, JH,F¼33.4 Hz,
3JH,H¼7.6 Hz), 7.33–7.49 (6H, m), 7.62–7.71 (4H, m); 13
C
NMR (75 MHz, CDCl3) d 14.1, 19.2, 26.8, 27.8 (d,
4
3JC,F¼2.5 Hz), 61.5, 62.1 (d, JC,F¼2.5 Hz), 117.5 (d,
2JC,F¼11.8 Hz), 127.7, 129.7, 133.5, 135.5, 148.7 (d, 1JC,F
1732, 1682, 1589, 1471, 1427, 1371, 1313, 1111 cmꢁ1
¼
256.0 Hz), 160.7 (d, 2JC,F¼36.1 Hz); IR (neat) 3072, 2931,
;
4.5.3. 3-(tert-Butyldiphenylsilyloxy)propanoic acid (18).
To a solution of 17 (3.92 g, 11.4 mmol) in EtOH (15 ml)
was added 1 N NaOH (11.4 ml), and the resulting mixture
was stirred at room temperature for 6 h. The reaction mix-
ture was concentrated in vacuo, acidified with 10% HCl,
and then extracted with CHCl3 (50 mlꢂ3). The extract was
dried over anhydrous MgSO4, filtered, and evaporated
in vacuo to afford 18 (3.74 g, 99%) as a white powder. Mp
ESIMS calcd for C23H29FNaO3Si MW 423.1768, found
m/z 423.1748 (M++Na). Anal. Calcd for C23H29FO3Si: C,
68.97; H, 7.30. Found: C, 68.67; H, 7.46%.
The geometry and the diastereomeric ratio of 21 were con-
firmed on the basis of the coupling constant between fluorine
and the adjacent olefinic proton (3JH,F¼33.4 Hz), and the in-
tegration of appropriate proton absorptions was obtained by
1H NMR (400 MHz) analysis. The corresponding E-isomer
of 21 was prepared by HWE reaction of phosphonoacetate
3 and 3-(tert-butyldiphenylsilyloxy)propanal78,79 utilizing
n-BuLi as a colorless oil. E-Isomer of 21: 1H NMR
(400 MHz, CDCl3) d 1.04 (9H, s), 1.33 (3H, t, J¼7.1 Hz),
2.73–2.82 (2H, m), 3.74 (2H, t, J¼6.1 Hz), 4.28 (2H, q,
1
95–97 ꢀC (CHCl3–n-hexane); H NMR (400 MHz, CDCl3)
d 1.04 (9H, s), 2.60 (2H, t, J¼6.3 Hz), 3.95 (2H, t,
J¼6.3 Hz), 7.35–7.51 (6H, m), 7.63–7.75 (4H, m), 10.18–
11.51 (1H, br s, CO2H); 13C NMR (75 MHz, CDCl3)
d 19.1, 26.7, 37.6, 59.5, 127.7, 129.7, 133.3, 135.5, 178.3;
IR (KBr) 3261, 3070, 2929, 2858, 1587, 1469, 1427, 1390,
1109, 1045, 1008 cmꢁ1; ESIMS calcd for C19H24NaO3Si
MW 351.1392, found m/z 351.1392 (M++Na). Anal. Calcd
forC19H24O3Si: C, 69.47;H, 7.36. Found:C, 69.36;H, 7.65%.
3
3
J¼7.1 Hz), 6.05 (1H, dt, JH,F¼21.2 Hz, JH,H¼7.8 Hz),
7.33–7.48 (6H, m), 7.62–7.68 (4H, m); 13C NMR
(75 MHz, CDCl3) d 14.1, 19.2, 26.8, 29.0 (d, 3JC,F¼5.0 Hz),
4
2
61.3, 62.7 (d, JC,F¼2.5 Hz), 120.5 (d, JC,F¼19.3 Hz),
4.5.4. 3-(tert-Butyldiphenylsilyloxy)propanoyl chloride
(19). Oxalyl chloride (2.1 ml, 24.4 mmol) was added to a so-
lution of 18 (4.0 g, 12.2 mmol) in anhydrous CH2Cl2 (50 ml)
under argon. After being stirred at room temperature for
15 h, the reaction mixture was evaporated to dryness
in vacuo to afford 19 (4.22 g, quant.) as a white powder,
which was used without further purification. 1H NMR
(400 MHz, CDCl3) d 1.04 (9H, s), 3.07 (2H, t, J¼5.9 Hz),
3.96 (2H, t, J¼5.9 Hz), 7.33–7.51 (6H, m), 7.63–7.75 (4H,
m); IR (KBr) 3072, 2931, 2886, 2857, 1793, 1471, 1427,
1390, 1361, 1110 cmꢁ1; ESIMS calcd for C19H24ClO2Si
MW 347.1234, found m/z 347.1240 (M++H).
1
127.7, 129.7, 133.5, 135.5, 147.7 (d, JC,F¼251.6 Hz),
2
160.9 (d, JC,F¼36.1 Hz); IR (neat) 3072, 2931, 2858,
1732, 1427, 1375, 1325, 1217, 1111 cmꢁ1; ESIMS calcd
for C23H29FNaO3Si MW 423.1768, found m/z 423.1800
(M++Na). Anal. Calcd for C23H29FO3Si: C, 68.97; H,
7.30. Found: C, 68.80; H, 7.29%.
4.5.6. (Z)-5-(tert-Butyldiphenylsilyloxy)-2-fluoropent-2-
en-1-ol (22). To a solution of 21 (458 mg, 1.14 mmol) in an-
hydrous THF (10 ml) was added LiAlH4 (91 mg, 2.4 mmol)
at 0 ꢀC under argon. After being stirred at 0 ꢀC for 30 min,
the reaction mixture was treated with 5% HCl (10 ml) and
then extracted with CHCl3 (50 mlꢂ3). The extract was dried
over anhydrous MgSO4, filtered, and concentrated in vacuo.
The oily residue was purified by silica gel column chroma-
tography [n-hexane–AcOEt (4:1)] to afford 22 (380 mg,
93%) as a colorless oil. 1H NMR (400 MHz, CDCl3)
d 1.05 (9H, s), 2.28–2.43 (2H, m), 3.69 (2H, t, J¼6.6 Hz),
4.5.5. Ethyl (Z)-5-(tert-butyldiphenylsilyloxy)-2-fluoro-
pent-2-enoate (21). A 1.6 mol/l solution of n-BuLi
(7.6 ml, 12.2 mmol) in n-hexane was added to a stirred solu-
tion of phosphonoacetate 3 (2.4 ml, 11.6 mmol) in anhy-
drous THF (30 ml) at ꢁ78 ꢀC under argon. The mixture
was stirred at ꢁ78 ꢀC for 1 h, and then a solution of acyl
chloride 19 (4.22 g, 12.2 mmol) in anhydrous THF (30 ml)
was added to the solution. After being stirred at ꢁ78 ꢀC
for 1 h, the reaction mixture was treated with 5% HCl
(40 ml) and then extracted with CHCl3 (100 mlꢂ3). The
extract was dried over anhydrous MgSO4, filtered, and con-
centrated in vacuo to give an oily residue.
3
3
4.08 (2H, dd, JH,F¼15.6 Hz, JH,H¼6.4 Hz), 4.90 (1H, dt,
3
3JH,F¼36.9 Hz, JH,H¼7.6 Hz), 7.32–7.48 (6H, m), 7.57–
7.72 (4H, m); 13C NMR (75 MHz, CDCl3) d 19.2, 26.8,
3
2
27.0 (d, JC,F¼3.7 Hz), 61.4 (d, JC,F¼32.4 Hz), 63.0 (d,
4JC,F¼1.9 Hz), 104.6 (d, JC,F¼13.7 Hz), 127.6, 129.6,
2
1
133.8, 135.6, 158.4 (d, JC,F¼255.4 Hz); IR (neat) 3356,
3072, 2931, 2858, 1714, 1589, 1471, 1427, 1390, 1111,
1020 cmꢁ1; ESIMS calcd for C21H28FO2Si MW 359.1843,
found m/z 359.1879 (M++H). Anal. Calcd for C21H27FO2Si:
C, 70.35; H, 7.59. Found: C, 70.06; H, 7.39%.
To a solution of the crude 20 in EtOH (30 ml) was added a so-
lution of NaBH4 (439 mg, 11.6 mmol) in EtOH (30 ml) at
ꢁ78 ꢀC under argon. After stirring at ꢁ78 ꢀC for 2 h, the re-
action mixture was allowed to warm to room temperature
and then was stirred for 1 h. The mixture was treated with
an aqueous solution saturated with NH4Cl (50 ml), concen-
trated in vacuo, and then extracted with CHCl3 (100 mlꢂ3).
4.5.7. Benzyl (Z)-5-(tert-butyldiphenylsilyloxy)-2-fluoro-
pent-2-enylcarbamate (24). To a solution of 22 (500 mg,
1.40 mmol) in anhydrous CH2Cl2 (15 ml) were added

S. Sano et al. / Tetrahedron 62 (2006) 11881–11890
11889
PPh3 (475 mg, 1.81 mmol) and N-Cbz-NsNH (610 mg,
1.81 mmol), and then a 2.2 mol/l solution of DEAD
(823 ml, 1.81 mmol) in toluene was added slowly at room
temperature under argon. After being stirred at room temper-
ature for 1 h, the reaction mixture was concentrated in vacuo.
The crude solid was purified by silica gel column chromato-
graphy [n-hexane–AcOEt (4:1)] to afford crude 23 (1.03 g)
as a yellow oil, which was used without further purification.
mixture was stirred at room temperature for 30 min, 2-prop-
anol (1 ml) was added to it and the resulting mixture was
then stirred until the color of the reaction mixture disap-
peared. After filtration, the filtrate was concentrated in vacuo
and then treated with an aqueous solution saturated with
NaHCO3 (20 ml), washed with CHCl3 (20 ml). The aqueous
layer was acidified with 10% HCl (10 ml) and then extracted
with AcOEt (50 mlꢂ5). The extract was dried over anhy-
drous MgSO4, filtered, and concentrated in vacuo to afford
26 (85 mg, 80%) as a white powder. Mp 74–75 ꢀC
To a solution of 23 (360 mg) in anhydrous DMF (3 ml) were
added K2CO3 (220 mg, 1.60 mmol) and 4-tert-butylthiophe-
nol (116 ml, 0.69 mmol) at room temperature under argon.
After being stirred at room temperature for 15 min, the reac-
tion mixture was treated with 5% HCl (10 ml) and then
extracted with CHCl3 (20 mlꢂ3). The extract was dried
over anhydrous MgSO4, filtered, and concentrated in vacuo.
The oily residue was purified by silica gel column chromato-
graphy [n-hexane–AcOEt (7:1)] to afford 24 (230 mg, 95%)
1
(CHCl3–n-hexane); H NMR (400 MHz, DMSO) d 3.02
(2H, d, J¼7.1 Hz), 3.25–3.43 (1H, br s, NH), 3.76 (2H, dd,
3
3JH,F¼12.7 Hz, JH,H¼5.9 Hz), 4.90–5.09 (3H, m), 7.26–
7.45 (5H, m), 12.16–12.63 (1H, br s, CO2H); 13C NMR
3
(75 MHz, CD3OD) d 29.7 (d, JC,F¼5.6 Hz), 42.0 (d,
2
2JC,F¼33.6 Hz), 67.7, 100.6 (d, JC,F¼12.5 Hz), 128.8,
1
129.0, 129.5, 138.2, 158.7, 158.9 (d, JC,F¼257.2 Hz),
174.6; IR (KBr) 3313, 2956, 1687, 1550, 1271, 1167,
1140, 1053, 993 cmꢁ1; ESIMS calcd for C13H14FNNaO4
MW 290.0805, found m/z 290.0821 (M++Na). Anal. Calcd
for C13H14FNO4: C, 58.42; H, 5.28; N, 5.24. Found: C,
57.98; H, 5.42; N, 4.93%.
1
as a colorless solid. Mp 44–45 ꢀC (CHCl3–n-hexane); H
NMR (400 MHz, CDCl3) d 1.04 (9H, s), 2.16–2.52 (2H,
3
m), 3.66 (2H, t, J¼6.6 Hz), 3.86 (2H, dd, JH,F¼14.9 Hz,
3JH,H¼5.9 Hz), 4.68–4.97 (2H, m, olefinic proton and NH),
5.11 (2H, s), 7.28–7.53 (11H, m), 7.61–7.69 (4H, m); 13C
NMR (75 MHz, CDCl3) d 19.2, 26.8, 27.0 (d, 3JC,F¼3.7 Hz),
41.7 (d, 2JC,F¼31.8 Hz), 62.9 (d, 4JC,F¼2.5 Hz), 66.9, 104.2
Acknowledgements
2
(d, JC,F¼13.7 Hz), 127.6, 128.08, 128.11, 128.5, 129.6,
1
133.7, 135.5, 136.3, 156.10, 156.12 (d, JC,F¼255.4 Hz);
This work was partially supported by a Grant-in-Aid for
Scientific Research (C) from the Japan Society for the
Promotion of Science. A research grant from the Research
Foundation for Pharmaceutical Sciences is also greatly
appreciated.
IR (neat) 3334, 3070, 2931, 2858, 1714, 1518, 1427, 1390,
1250, 1111 cmꢁ1; ESIMS calcd for C29H35FNO3Si MW
492.2383, found m/z 492.2370 (M++H). Anal. Calcd for
C29H34FNO3Si: C, 70.84; H, 6.97; N, 2.85. Found: C,
70.61; H, 6.98; N, 2.81%.
References and notes
4.5.8. Benzyl (Z)-2-fluoro-5-hydroxypent-2-enylcar-
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0.927 mmol) in THF was added to a stirred solution of 24
(380 mg, 0.77 mmol) in anhydrous THF (20 ml) at room
temperature under argon. The mixture was stirred at room
temperature for 45 min, after which the reaction mixture
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tract was washed with brine, dried over anhydrous MgSO4,
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(2H, t, J¼6.1 Hz), 3.90 (2H, dd, JH,F¼14.4 Hz, JH,H
¼
6.1 Hz), 4.86 (1H, dt, 3JH,F¼36.4 Hz, 3JH,H¼7.3 Hz), 4.95–
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