Diastereoselective synthesis of highly functionalized fluoroalkene dipeptide isosteres and its application to Fmoc-based solid-phase synthesis of a cyclic pentapeptide mimetic

Article abstract of DOI:10.1016/j.tet.2008.02.076

A diastereoselective and divergent method for synthesis of a highly functionalized (Z)-fluoroalkene dipeptide isosteres has been developed. The key feature of this synthetic method is an efficient one-pot reaction involving reduction/asymmetric alkylation

Full text of DOI:10.1016/j.tet.2008.02.076

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 4332e4346
www.elsevier.com/locate/tet
Diastereoselective synthesis of highly functionalized fluoroalkene
dipeptide isosteres and its application to Fmoc-based solid-phase
synthesis of a cyclic pentapeptide mimetic
Tetsuo Narumi, Kenji Tomita, Eriko Inokuchi, Kazuya Kobayashi,
*
Shinya Oishi, Hiroaki Ohno, Nobutaka Fujii
Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
Received 23 January 2008; received in revised form 22 February 2008; accepted 22 February 2008
Available online 4 March 2008
Abstract
A diastereoselective and divergent method for synthesis of a highly functionalized (Z)-fluoroalkene dipeptide isosteres has been developed.
The key feature of this synthetic method is an efficient one-pot reaction involving reduction/asymmetric alkylation via transmetalation, which
produces trans-amide type (Z)-fluoroalkenes flanking two stereogenic centers in high yields, with excellent (Z)-selectivity and diastereoselec-
tivity. Practical Fmoc-based solid-phase synthesis of a specific CXCR4 antagonistic pseudopeptide 25 containing (Z)-fluoroalkene isostere is
also described.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Fluoroalkene; Peptide isosteres; Transmetalation; CXCR4 antagonist
1. Introduction
bonds,4a,b which is difficult by other means such as NMR anal-
ysis or X-ray diffraction, and for the precise functional analy-
sis of the role of each peptide bond5 (Fig. 1).
Replacement of native hydrolyzable peptide bonds with
non-hydrolyzable mimetics is an established approach toward
overcoming the major limitations of peptides, including poor
bioavailability and short physiological half-life due to rapid
proteolysis, which limit their use as therapeutic or chemical
probes.1 Furthermore, conformationally restricted analogs of
biologically active peptides represent an attractive structural
motif leading to the more effective agents.
Alkene-type dipeptide isosteres (ADIs),2 whose design is
based on the partial double-bond character of the peptide
bond in its most stable conformation, have been thought to
be ideal dipeptide mimetics. ADIs possessing an (E)- or (Z)-al-
kene unit3 with increased lipophilicity relative to native dipep-
tides are resistant to enzymatic cleavage. Because of their
fixed cis/trans conformation, ADIs can be used as chemical
probes for determining the bioactive conformation of peptide
Xaa
O
O
H
N
N
H
Yaa
Native Peptide Bond
Xaa
O
Yaa
H
Xaa
O
O
H
N
HN
N
H
N
O
O
Yaa
Xaa
X
O
Yaa
Xaa
X
N
H
HN
Yaa
Peptide Bond Isosteres
X = H, Alkene Dipeptide Isosteres (ADIs)
X = F, Fluoroalkene Dipeptide Isosteres (FADIs)
* Corresponding author. Tel.: þ81 75 753 4551; fax: þ81 75 753 4570.
E-mail address: nfujii@pharm.kyoto-u.ac.jp (N. Fujii).
Figure 1. Native peptide bond and its corresponding isosteres.
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.02.076

T. Narumi et al. / Tetrahedron 64 (2008) 4332e4346
4333
Over the past 15 years, we have engaged in the syntheses of
several types of ADIs and have developed diastereoselective
methods toward synthesis of (E)-Alkene Dipeptide Isosteres
(EADIs),2a (Z)-Alkene Dipeptide Isosteres (ZADIs),3 Trisub-
stituted Alkene Dipeptide Isosteres (TADIs),4a,b and Xaae
Pro isosteres6 utilizing organocopper-mediated SN20 alkylation
as a key reaction. These methodologies have been applied to
the preparation of biologically active peptidomimetics.2c,3e,4a
The studies have revealed that a simple alkene unit is not
always sufficient for replacement of peptide bond probably be-
cause of (1) the lack of a hydrogen-bonding site, (2) a smaller
dipole moment [mpeptide bond¼3.6 D vs malkene¼0.1 D], and (3)
flexible f- and j-angle rotations due to the lack of steric inter-
actions between the carbonyl oxygen and the side chain on the
b-carbon.
can be trapped in situ by an alkyl halide, resulting in the for-
mation of a-substituted fluoroalkene isosteres 3a.12b The reac-
tion with samarium diiodide (SmI2) in the presence of t-BuOH
easily provides fluoroalkene isosteres 3b, and the replacement
of t-BuOH with carbonyl compounds such as aldehydes or
ketones provides a-substituted fluoroalkene isosteres 3c via
aldol reactions of Sm dienolates.12d Although this reductive
defluorination is useful for the regio- and stereoselective
formation of the (Z)-fluoroalkene unit, the method has not
addressed the stereoselective construction of the a-side chain.
F
F
R1
CO2Et
NHBoc
1
RCuLn or SmI2
On the other hand, in 1986, Abraham et al. reported a theo-
retical and crystallographic study of fluoroalkene as peptide
bond analog.7a They have shown that the fluoroalkene unit
could be a more effective peptide bond analog than a simple
alkene unit due to the presence of a highly electronegative
F
R1
OEt
OM
NHBoc
2
dienolate intermediate
M = Cu, Li, or Sm
fluorine substituent with a larger dipole moment [mFealkene
1.4 D].8 The van der Waals radii of the fluorine atom
¼
˚
(1.47 A) is sufficiently close to that of the oxygen atom
9
(1.52 A), thus it favors the induction of the steric restriction
of f- and j-dihedral angles. A computational study with water
molecules has revealed that the fluoroalkene moiety can be in-
volved in hydrogen-bonding interactions.10
˚
Aldol
Alkylation
Reaction
M = Sm
Protonation
M = Li or Cu
R3
OH
F
R2
F
In spite of their potency as dipeptide mimetics, difficulties
in the stereoselective and divergent synthesis of fluoroalkene
isosteres have hampered their application to biologically ac-
tive peptides.7b,d,f,12e,g As such, there is an upsurge of interest
in the development of efficient methodologies to synthesize a-
substituted fluoroalkene isosteres. For the synthesis of fluo-
roalkene isosteres, it is necessary to stereoselectively construct
a (Z)- or (E)-fluoroalkene unit as well as to control the config-
uration of two stereogenic centers at the a- and d-positions. It
is more desirable to introduce a variety of ‘functionalized’ al-
kyl side chains, which play important roles in bioactivity.
Although numerous synthetic approaches to fluoroalkene
isosteres have been developed including classical olefination
reactions such as the Peterson reaction,7c,e the aldol condensa-
tion,7d and the HornereWadswortheEmmons reaction,7f only
a few examples of diastereoselective synthesis of FADIs have
been reported to date. Recently, Pannecoucke’s group have
provided a practical route for synthesis of FADIs using a tem-
perature-controlled Negishi-coupling reaction11 and asymmet-
ric reductive amination of a-fluoroenones7g as key
transformations. This approach has significant advantages in
synthesizing both (E)- and (Z)-isomer.
F
R1
R1
R1
CO2Et
CO2Et
CO2Et
NHBoc
NHBoc
NHBoc
3a
3b
3c
Scheme 1. Synthesis of fluoroalkene dipeptide isosteres by reductive defluori-
nation/enolate trapping methodology.
In this paper, we describe a diastereoselective, divergent,
and practical approach for the synthesis of highly functional-
ized fluoroalkene isosteres utilizing an efficient one-pot reac-
tion involving organocopper-mediated reduction/asymmetric
alkylation via transmetalation. Its application to Fmoc-based
solid-phase peptide synthesis (SPPS) of a fluoroalkene iso-
stere-containing potential CXCR4 antagonist is also presented.
2. Results and discussion
2.1. Diastereoselective synthesis of L-Vale(D/L)-Xaa type
(Z)-fluoroalkene dipeptide isosteres by one-pot reaction
involving organocopper-mediated reduction/asymmetric
alkylation via transmetalation
Alternatively, we12 and Taguchi’s group13 have indepen-
dently developed effective approaches to (Z)-fluoroalkene iso-
steres via a reductive defluorination reaction of a,b-enoates 1
possessing two fluorine atoms at the g-positions, in which or-
ganocopper reagents derived from CuX (X¼CN or I) and the
MeLi$LiBr complex were utilized for carbonefluorine bond
cleavage via a single electron transfer mechanism12d,14,15
(Scheme 1). In these reactions, the dienolate intermediates 2
On the basis of our previous study on reductive defluorina-
tion shown in Scheme 1,12b,d we envisioned extending this ap-
proach to the diastereoselective synthesis of (Z)-fluoroalkene
isosteres as depicted in Scheme 2. It was our expectation
that formation of the fluoroalkene-containing dienolates carry-
ing a chiral auxiliary by organocopper- or SmI2-mediated re-
duction of g,g-difluoro-a,b-unsaturated carbonyl compounds
4, followed by trapping with electrophiles, would result in

4334
T. Narumi et al. / Tetrahedron 64 (2008) 4332e4346
Table 1
Reduction of g,g-difluoro-a,b-N-enoyl sultam 12a with organocopper reagents
regio- and stereoselective construction of (Z)-fluoroalkene iso-
steres 5. This synthetic strategy can be extended to diastereo-
selective syntheses of (L,L), (L,D), (D,L), and (D,D)-type isosteres
by simply using an appropriate starting material and a chiral
auxiliary. Introduction of various alkyl groups at the a-posi-
tion in the final stage would allow diversity-oriented synthesis
of (Z)-fluoroalkene isosteres.
a
and SmI2
F
F
F
RCuLn
SmI2
XS
XS
NHBoc
12a
O
NHBoc
13
O
Entry
Reagentsb
Additives (equiv)
Yieldd (%)
de
52
74
95
85
81
87
c
F
R2
1
2
3
4
5
6
7
a
SmI2
d
d
1) Organocopper- or
F
F
R1
XC
R1
X C
Me3CuLi2$LiI
Me2Cu(CN)Li2
Me2CuLi$LiI
Me2CuLi$LiI
Me2CuLi$LiI
Me2CuLi$LiI
SmI2-Mediated Reduction
d
d
2) Asymmetric Alkylation
One-Pot Reaction
NHBoc
4
O
NHBoc
5
O
HMPA (10)
TMSCl (4)
BF3$OEt2 (4)
XC: Chiral Auxiliary
F
R2
R1
OH
Cleavage of Chiral Auxiliary
Unless otherwise stated, the reactions were carried out with 4 equiv of the
NHBoc
O
reagent at ꢀ78 ꢁC for 30 min.
6
b
Organocopper reagents include other Li salts (LiCl and/or LiBr).
(Z)-Fluoroalkene Isosteres
c
0 ꢁC, 60 min, with 6 equiv of SmI2.
Isolated yield.
A mixture of unidentified compounds was obtained.
d
Scheme 2. Planned diastereoselective synthesis of (Z)-fluoroalkene dipeptide
isosteres.
e
the reduction of N-enoyl sultam, which has a different electron
density compared with the corresponding enoates with a single
electron reductant. In this regard, we first examined the orga-
nocopper- or SmI2-mediated reduction of 12a without any al-
kyl halides (Table 1). We previously reported that the reaction
of the enoates with SmI2 gave better results than using organo-
copper reagents.12d The reduction of the enoyl sultam 12a with
SmI2 only afforded a mixture of unidentified products (entry
1). In contrast, organocopper reagents were effective in pro-
ducing the reduced product 137h (entries 2e7): the reaction
with a higher order cuprate (Me3CuLi2$LiI$3LiBr) produced
13 in moderate yield (entry 2).18 The reactions using either
the cyano Gilman reagent (Me2CuLi$LiCN$2LiBr) or the Gil-
man reagent (Me2CuLi$LiI$2LiBr), which shows lower elec-
tron-donating ability,15 proceeded more smoothly to give 13
with yields of 74% and 95%, respectively (entries 3 and 4).
We examined the introduction of additives such as HMPA,
TMSCl, and BF3$OEt2; however, no obvious differences in re-
activity or in chemical yield were observed (entries 5e7).
Based on these results, the Gilman reagent was chosen as a sin-
gle electron reductant.19
The synthetic sequence leading to the key N-enoyl sultam
intermediates 12 is illustrated in Scheme 3. The known a,a-di-
fluoro-b-amino ester 9,12d prepared from isobutyl aldehyde 7
by a Rh-catalyzed ReformatskyeHonda reaction,16 was sub-
jected to hydrogenolysis with Pd(OH)2/CeH2 in the presence
of (Boc)2O, affording the Boc-protected ester 10.12d The re-
sulting ester 10 was converted to the desired N-enoyl sultam
12a in 89% yield, by a sequence of reactions involving reduc-
tion by DIBALH and HornereWadswortheEmmons coupling
with (S)-N-[(diethoxyphosphono)acetyl]camphorsultam 11a,17
with exclusive E-selectivity. The diastereomer 12b was also
prepared using (R)-sultam derivative 11b in 96% yield.
1. MS 4Å, 0 °C
2. RhCl(PPh3)3, Et2Zn,
BrCF2CO2Et, 0 °C
F
F
Ph
CO2Et
OMe
HN
+
CHO
7
H2N
OMe
58%
8
Ph
9
F
F
1. DIBALH, -78 °C
Pd(OH)2/C,
(Boc)2O, H2
F
F
X
2. 11, LiCl, i-Pr2NEt
CO2Et
NHBoc
10
NHBoc
O
96%
EtO
EtO
X
P
O
Next, trapping of the Cu or Li dienolate intermediate 14a,
generated from 12a by organocopper-mediated reduction
with methyl iodide to construct a stereogenic center at the
a-position (Scheme 4) was investigated. Direct treatment of
14a with methyl iodide yielded only a complex mixture. As
this unsuccessful result might be attributed to the low reactiv-
ity of Cu or Li dienolate 14a toward alkylation, the next step
was to use the more reactive Sn dienolate.20 After reduction of
O
12a: X = XS (89%)
12b: X = XR (96%)
11a: X = XS
11b: X = XR
O2S
N
XS
=
N
XR
=
S
O2
Scheme 3. Synthesis of key substrates 12 for one-pot reduction/asymmetric
alkylation.
2) HMPA
3) Ph3SnCl
4) MeI
F
Me
F
In order to achieve consecutive one-pot reduction/asym-
metric alkylation, the following two-step sequence was
needed: (1) the reduction of 12a to give the Li or Cu dienolate
intermediate; (2) trapping of the dienolate intermediate with
an alkyl halide in a regio- and stereoselective fashion. How-
ever, to the best of our knowledge, there is no example of
.
XS
XS
OM
1) Me2CuLi LiI
12a
-78 °C, 30 min
NHBoc
O
NHBoc
15a
14a
93%, >95% de
Scheme 4. Diastereoselective synthesis of L-ValeL-Ala (Z)-fluoroalkene iso-
stere by one-pot reduction/asymmetric alkylation via transmetalation.

T. Narumi et al. / Tetrahedron 64 (2008) 4332e4346
4335
Table 2
Diastereoselective synthesis of (Z)-fluoroalkene isosteres by one-pot organocopper-mediated reduction/transmetalation/asymmetric alkylation
F
F
R
XS
M
XS
NHBoc
O
O
NHBoc
O
(L,L)-type isosteres
14a
F
F
X
RCuLn
NHBoc
O
12a : X = XS
12b : X = XR
F
F
R
XR
M
XR
O2S
XR
=
N
=
N
XS
S
NHBoc
NHBoc
O
O2
(L,D)-type isosteres
14b
Entry
1
Electrophiles
MeI
Substrates
Productsa (%)
% deb
F
Me
XS
12a
12b
12a
>95
NHBoc
O
c
15a (93)
F
Me
XR
2
3
MeI
BnBr
BnBr
95
95
NHBoc
O
c
15b (69)
F
Bn
XS
NHBoc
O
O
c
16a (93)
F
Bn
XR
4
5
6
7
12b
12a
12b
12a
91
>95
92
NHBoc
c
16b (77)
CO2t-Bu
F
XS
O
Br
CO2t-Bu
CO2t-Bu
NHBoc
c
17a (80)
CO2t-Bu
F
XR
O
Br
NHBoc
17b (75)
c
dd
d
Br
CO2Me
OMe
F
Br
8
12b
93
XR
MeO
NHBoc
O
c
18b (77)
F
XS
>95
Br
9
12a
NHBoc
19a (99)
O
c
(continued on next page)

4336
T. Narumi et al. / Tetrahedron 64 (2008) 4332e4346
Table 2 (continued)
Entry
Electrophiles
Substrates
Productsa (%)
% deb
F
XR
Br
10
11
12b
91
NHBoc
19b (86)
O
O
c
F
XS
12a
12a
12a
>95
Br
NHBoc
20a (99)
c
F
Br
XS
12
13
91
NHBoc
O
c
21a (99)
CO2Me
F
XS
91
Br
CO2Me
NHBoc
O
c
22a (94)
Br
F
Br
14
12b
92
XR
Br
NHBoc
O
c
23b (71)
a
Isolated yield.
Determined by RP-HPLC of purified products.
b
c
A trace amount of either g-alkylated products or E-isomer was detected by RP-HPLC.
Reduced product 13 was obtained.
d
12a with Me2CuLi$LiI$2LiBr, sequential treatment with
HMPA, triphenyltin chloride, and methyl iodide, regioselec-
tively produced an a-methyl fluoroalkene isostere 15a in
93% yield with exclusive Z-selectivity. RP-HPLC analysis
showed that the a-methylation proceeded with >95% de.21
With these results in hand, the scope of this one-pot re-
duction/asymmetric alkylation via transmetalation with vari-
ous alkyl halides was examined (Table 2). In all cases,
good to excellent yields of a-alkylated fluoroalkene isosteres
were obtained with excellent diastereo- and Z-selectivity.
Successive treatments of N-enoyl sultam 12a with the orga-
nocopper reagent, HMPA, triphenyltin chloride, and benzyl
bromide proceeded smoothly to yield L-ValeL-Phe isostere
16a in 93% yield and 95% de (entry 3). This one-pot strategy
also showed comparable reactivity and selectivity to the cor-
responding (R)-sultam 12b to provide L-ValeD-Phe isostere
16b in 77% yield and 91% de (entry 4). The use of tert-butyl
bromoacetate as an electrophile produced an L-ValeL-
Asp(Ot-Bu) isostere 17a in 80% isolated yield and >95%
de (entry 5); also (L,D)-type 17b in 75% isolated yield and
92% de (entry 6). For the synthesis of the L-ValeD-Glu fluo-
roalkene isostere, however, use of methyl 3-bromopropionate
gave reduced product 13 with no alkylated product (entry 7).
Treatment of dienolate 14b with p-methoxybenzyl bromide
proceeded smoothly to give an L-ValeD-Tyr(Me) fluoroal-
kene isostere 18b in 77% isolated yield and 93% de (entry
8). As expected, this one-pot strategy can also be applied
to the synthesis of fluoroalkene isosteres of unnatural amino
acids. Trapping of the dienolates 14a and 14b with allyl bro-
mide afforded L-ValeL-Gly(allyl) isostere 19a (99% yield,
>95% de, entry 9) and (L,D) isostere 19b (86% yield, 91%
de, entry 10), respectively. In a similar manner, the reaction
of dienolates 14a with 1-bromo-2-methyl-2-propene (meth-
allyl bromide) also yielded an L-ValeL-(g0-dehydro)Leu iso-
stere 20a in 99% yield and >95% de (entry 11). The use of
2-(bromomethyl)naphthalene and methyl 4-bromocrotonate
stereoselectively gave the corresponding a-alkylated fluoroal-
kene isosteres 21a and 22a (entries 12 and 13). Synthesis of
a fluoroalkene isostere 23b bearing an aryl bromide moiety is
of significant synthetic value with respect to the further elab-
oration. For such purposes, we attempted to trap the dieno-
lates 14b with p-bromobenzyl bromide, chemoselectively
affording the corresponding isostere 23b in 71% yield and
92% de (entry 14).
The de of each product was determined by RP-HPLC. Flu-
oroolefinic geometries of all the products were established by
1H NMR,22 and the absolute configurations of the alkyl groups
at the a-position were determined by circular dichroism

T. Narumi et al. / Tetrahedron 64 (2008) 4332e4346
4337
NH
1. RCuL
n
F
Arg
Nal
2. HMPA, Ph3SnCl
3. allyl Br
F
F
H2N
H2N
R1
XS
O
R1
R1
XS
N
H
0.1 M THF: 66%, >95% de
00.01 M THF: 97%, >95% de
N
H
NHBoc
O
NHBoc
29
O
NH
O
30
O
X
Gly
H
=
O
TBSO
Scheme 6. One-pot reaction of N-enoyl sultam 29.
H
N
N
N
H
Arg
NH
Tyr
OH
we speculated that the TBS group would be removed by the
fluoride anion, which is generated by organocopper-mediated
reduction. However, the addition of TMSCl to trap the fluorine
anion was not effective for improvement of the yield. Consid-
ering that the good to high yields shown in Table 2 might be
attributed to the relatively small scale of the reaction
(<100 mg), we next attempted the reaction under more dilute
conditions. Slow addition of sultam 29 (0.01 M in THF) to
Me2CuLi$LiI$2LiBr, subsequent transmetalation, and asym-
metric alkylation proceeded readily to give the a-allyl sultam
30 (97% yield, >95% de).
FC131 (24): X = -CO-NH-
FCN001 (25): X = - [(Z)-CF=CH]-
Figure 2. FC131 and its cyclic fluoroalkene pseudopeptide (FCN001). Nal¼
L-3-(2-naphthyl)alanine.
measurements with an empirical rule after converting to the
corresponding methyl esters.23
2.2. Diastereoselective synthesis of L-ArgeL-Arg
(Z)efluoroalkene isosteres and its application to a cyclic
pseudopeptide analog of specific CXCR4 antagonist, FC131
Next, synthesis of Fmoc-protected isostere 34 having a 3-
hydroxypropyl group was investigated (Scheme 7). The a-allyl
sultam 30 was subjected to disiamylborane [(Sia)2BH]-medi-
ated hydroboration, readily producing the corresponding alkyl
borane compound. Mild oxidation conditions were required
for conversion of the alkyl borane to the corresponding alco-
hol, since the chiral auxiliary would be cleaved easily by hy-
droperoxide anion. The use of aqueous 20% AcOK and 50%
H2O2 in THF was entirely successful, chemoselectively effect-
ing the desired conversion to give the desired alcohol 31 in
69% isolated yield on a small scale (<100 mg). However,
upon increasing the reaction scale (2000 mg), the chiral auxil-
iary was cleaved to produce the corresponding hydroxy acid in
44% yield, along with the desired alcohol 31 in 30% yield.
Under more dilute THF conditions, with slow addition of
the minimum amount of aqueous 20% AcOK and 50%
H2O2 provided 31 in good conversion. To employ Fmoc-based
SPPS, the conversion of N-Boc to the N-Fmoc group was at-
tempted. The alcohol 31 was protected with TBSCl in
CH2Cl2 to yield the TBS ether 32, which was converted to
the corresponding acid under basic conditions without epime-
rization at the a-carbon. The resulting acid 33 was subjected to
several conditions to remove the Boc group in the presence of
TBS ethers; however, all attempted conditions [TFA, 0 ꢁC;
Efforts were then made to apply the developed methodol-
ogy to synthesize a fluoroalkene-containing pseudopeptide.
Previously, bioactivity investigations replacing the L-ArgeL-
Nal and L-NaleGly peptide bonds of the specific CXCR4 an-
tagonistic peptide, FC131 [cyclo(eD-Tyr-Arg-Arg-Nal-Glye)]
24,24 were carried out.2c Replacement of the amide-bonds with
(E)-alkene isosteres led to a significant loss of CXCR4 antag-
onistic activity. On the other hand, the importance of the am-
ide bond between Arg and Arg has not been studied. To this
end, FCN001 (25) was designed bearing an Arg-Arg fluoro-
alkene isostere, which is a mimetic of 24 (Fig. 2).
Our synthesis began with commercially available 4-(tert-
butyldimethylsilyloxy)butan-1-ol 26 (Scheme 5). Swern oxi-
dation of the alcohol 26, and subsequent ReformatskyeHonda
reaction gave ester 27 in a synthetically acceptable yield
(39%). Cleavage of the chiral auxiliary of 27 by hydrogenation
in the presence of (Boc)2O, reduction of the resulting Boc-pro-
tected ester 28 with DIBALH, and coupling with (S)-sultam
derivative 11a produced the desired sultam 29.
F
F
R1
1. (COCl)2, DMSO,
Et3N, -78 °C
2. 8, MS 4Å, 0 °C;
RhCl(PPh3)3,
BrCF2CO2Et, Et2Zn
39%
CO2Et
OH
TBSO
HN
27
OMe
26
Ph
R1
=
TBSO
OH
1. DIBALH, -78 °C
F
F
Pd(OH)2/C,
(Boc)2O, H2
F
F
F
F
R1
TBSCl,
R1
XS
R1
2. 11a, LiCl, i-Pr2NEt
R1
XS
R1
XS
imidazole
CO2Et
NHBoc
28
(Sia)2BH
30
73%
85%
NHBoc
29
O
83%
(2 steps)
NHBoc
O
O
NHBoc
O
31
32
R1
=
TBSO
F
Scheme 5. Synthesis of N-enoyl sultam 29.
R1
F
R1
1N-LiOH,
50% H2O2
R1
OH
R1
OH
One-pot reaction of sultam 29 with allyl bromide in a larger
scale (>1500 mg) yielded the desired a-allyl sultam 30
(Scheme 6). Despite its excellent diastereoselectivity (>95%
de), the chemical yield of the one-pot reaction was relatively
low compared with the results shown in Table 2. Initially,
NHBoc
NHFmoc
34
O
33
Scheme 7. Conversion of a-allyl sultam 30 to Fmoc-protected fluoroalkene
isostere.

4338
T. Narumi et al. / Tetrahedron 64 (2008) 4332e4346
HCl/AcOEt, 0 ꢁC;25 ZnBr2;26 etc.] produced the desilylated
products with no detectable amount of the desired amine.
Attention was next turned to synthesis of an L-OrneL-Orn
isostere 36 by introduction of two nitrogen functionalities
(Scheme 8), which could be converted to guanidino groups us-
ing 1H-pyrazole-1-carboxamidine hydrochloride. Thus, bis-
TBS ether 32 was cleaved readily by aqueous 3.28 N H2SiF6
to give the diol, which was subsequently subjected to the Mit-
sunobu reaction with NsNHBoc,27 leading to the formation of
bis(sulfonamide) 35 in 85% yield. The sulfonamide 35 was
converted to the corresponding acid under basic conditions,
which was subjected to cleavage of the three Boc groups
with TFA followed by Fmoc protection to give desired isostere
36 with the L-OrneL-Orn sequence (94% in 3 steps).
peptide 40 with diphenylphosphoryl azide (DPPA)29 and
NaHCO3 in DMF, led to the formation of protected cyclic
pseudopeptide 41 with a 64% isolated yield based on the ini-
tial resin-loading. Completion of the synthesis of FCN001 thus
required three further transformations: removal of the t-Bu
group with aqueous 95% TFA, deprotection of bis-Ns groups
with b-mercaptoethanol and DBU in DMF,30 and guanidina-
tion of the resulting diamine. These functional group modifica-
tions thus provided the expected cyclic pseudopeptide
FCN001 25 bearing an L-ArgeL-Arg fluoroalkene isostere in
8% overall yield from 41. During the synthesis of 25 via
Fmoc-base SPPS, cyclization, deprotection, and guanidina-
tion, neither isomerization of double bonds nor epimerization
of stereogenic centers was detected.
3. Conclusion
1. 1N-LiOH,H2O2
R2
R1
2. TFA,0 °C
F
F
3. Fmoc-OSu,Et3N
R1
XS
R2
OH
In conclusion, we have developed an effective one-pot
methodology for the diastereoselective synthesis of (Z)-fluo-
roalkene dipeptide isosteres, which are potential trans-peptide
bond mimetics. This synthetic procedure consists of three suc-
cessive steps: (1) organocopper-mediated reduction of N-enoyl
sultam bearing two fluorine atoms at the g-position, (2) trans-
metalation of the Li or Cu dienolate intermediate to the more
reactive tin dienolates, and (3) Oppolzer sultam-assisted ster-
eoselective trapping of the dienolate intermediate with alkyl
halides. Our methodology features smooth a-alkylation to pro-
duce fluoroalkene isosteres in good to excellent yields with
high diastereoselectivity. Since a broad range of reactive alkyl
halides can be used to trap the tin dienolate intermediates,
many natural and unnatural amino acid-containing isosteres
can be prepared. Moreover, cyclic pseudopeptide 25, which
contains the L-ArgeL-Arg isostere, was synthesized utilizing
Fmoc-based SPPS with no detectable quantity of the epimer-
ized product at the a-position. To the best of our knowledge,
this is the first example successfully applying fluoroalkene
isosteres with stereogenic centers at both the a- and the d-
position to Fmoc-based SPPS. A biological evaluation of
FCN001 is currently underway and will be reported in due
course.
94%
O
O
R1 =
NHBoc
NHFmoc
36
32
TBSO
1. H2SiF6
Ns
N
R2 =
2. DEAD,PPh3,
NsNHBoc
85%
H
Ns
N
35 R1 =
Boc
Scheme 8. Synthesis of Fmoc-protected OrneOrn fluoroalkene isostere 36.
Finally, synthesis of a cyclic pseudopeptide utilizing Fmoc-
based SPPS and well-established cyclic peptide synthesis
protocols28 was investigated (Scheme 9). Fmoc-amino acid-
containing fluoroalkene isostere 36 was coupled onto the resin
38. A protected peptide resin 39 was treated with 1,1,1,3,3,3-
hexafluoro-2-propanol (HFIP)eCH2Cl2 (3:7) to afford the side
chain-protected pseudopeptide 40. Cyclization of linear
A (Nal)
37 R = H-Gly-
38 R = H-Nal-Gly-
A = Fmoc-based SPPS
A [Fmoc-Orn(Ns)-Ψ-Orn(Ns)-OH] (36)
Resin
R
Cl
=
Ψ = [(Z)-CF=CH]
A [D-Tyr(t-Bu)]
(39)
H-D-Tyr(t-Bu)-Orn(Ns)-Ψ-Orn(Ns)-Nal-Gly
4. Experimental
HFIP-CH2Cl2 (3:7)
4.1. General
H-D-Tyr(t-Bu)-Orn(Ns)-Ψ-Orn(Ns)-Nal-Gly-OH (40)
1H NMR spectra were recorded using a JEOL AL-400 and
JEOL ECA-500 spectrometer. Chemical shifts are reported in
d (ppm) relative to TMS (in CDCl3) or solvent peak (in D2O,
CD3OD) as internal standard. 13C NMR spectra were recorded
using a JEOL AL-400 and JEOL ECA-500, and referenced to
the residual CHCl3 signal. 19F NMR spectra were recorded us-
ing a JEOL AL-400 and JEOL ECA-500, and referenced to the
residual CFCl3 signal (dF 0.00 ppm). Exact mass (HRMS)
spectra were recorded on a JMS-HX/HX 110A mass spectrom-
eter. Optical rotations were measured with a JASCO sodium
automatic polarimeter P-1020. Infrared (IR) spectra were ob-
tained on a JASCO FT/IR-4100 FT-IR spectrometer with
DPPA, NaHCO3
(64% based on resin)
cyclo[-D-Tyr(t-Bu)-Orn(Ns)-Ψ-Orn(Ns)-Nal-Gly-] (41)
1. 95% TFA-H2O
2. β-mercaptoethanol, DBU
3. Et3N,
N
.
HCl
N
H2N
NH
FCN001 (25)
(8% from 41)
Scheme 9. Synthesis of FCN001 via Fmoc-based SPPS.

T. Narumi et al. / Tetrahedron 64 (2008) 4332e4346
4339
JASCO ATR PRO410-S. For flash chromatography, Wakosil
C-300, C-300E, and silica gel 60H (silica gel for thin-layer
chromatography, Merck) were employed.
48.7, 53.0, 58.1 (t, J¼25.7 Hz), 65.1, 80.0, 120.1 (t,
J¼246.2 Hz), 124.8 (t, J¼8.3 Hz), 138.5 (t, J¼26.1 Hz),
155.7, 162.2; 19F NMR (376 MHz, CDCl3) d ꢀ107.5 (dt,
J¼249.7, 14.0 Hz), ꢀ105.5 (dt, J¼252.4, 11.4 Hz); HRMS
(FAB), m/z calcd for C23H37F2N2O5S ([MþH]þ) 491.2391,
found 491.2398.
4.2. (5S,2E)-5-[N-(tert-Butoxycarbonyl)amino]-4,4-difluoro-
6-methylhept-2-enoyl (S)-sultam (12a)
To a solution of the ester 1012d (687 mg, 2.00 mmol) in
CH2Cl2 (20 mL) at ꢀ78 ꢁC under argon was added dropwise
a solution of DIBALH in toluene (0.93 M, 3.44 mL,
3.20 mmol), and the mixture was stirred for 2 h at ꢀ78 ꢁC.
The reaction was quenched with aqueous 0.5 N Rochelle salt
and extracted with Et2O. The extract was washed with brine
and dried over MgSO4. Concentration under reduced pressure
gave the aldehyde as an oil, which was used immediately in
the next step without purification. To a stirred solution of
(S)-D-N-(diethoxyphosphonoacetyl)camphorsultam (970 mg,
2.46 mmol) in CH3CN (15 mL) at 0 ꢁC under argon were
added LiCl (112 mg, 2.60 mmol) and i-Pr2NEt (452 mL,
2.60 mmol). After stirring for 30 min, a solution of the above
aldehyde in CH3CN (5 mL) was added to the mixture at 0 ꢁC,
and the mixture was stirred for 2 h at 0 ꢁC and for 12 h at room
temperature. The reaction was quenched with saturated NH4Cl
and extracted with Et2O. The extract was washed with brine
and dried over MgSO4. Concentration under reduced pressure
followed by flash chromatography over silica gel with n-hex-
aneeAcOEt (5:1) gave the title compound 12a (845 mg, 89%
yield) as a colorless oil: [a]2D3 ꢀ73.6 (c 1.05, CHCl3); IR
(ATR): 3376 (NHCO), 1712 (CO), 1686 (CO), 1330 (NSO2),
4.4. General procedure for one-pot reduction/asymmetric
alkylation via transmetalation. synthesis of (2R,5S,3Z)-5-[N-
(tert-butoxycarbonyl)amino]-4-fluoro-2,6-dimethylhept-3-
enoyl (S)-sultam (15a)
To a suspension of CuI (64.0 mg, 0.335 mmol) in THF
(1 mL) at ꢀ78 ꢁC under argon was added dropwise a solution
of MeLi$LiBr complex in Et2O (1.5 M, 0.45 mL,
0.670 mmol), and the mixture was stirred for 10 min at 0 ꢁC.
To the solution of the above organocopper reagent at
ꢀ78 ꢁC was added dropwise a solution of the N-enoyl sultam
12a (40.0 mg, 0.0815 mmol) in THF (1.5 mL). The mixture
was stirred for 30 min at ꢀ78 ꢁC and HMPA (233 mL,
1.34 mmol) was added dropwise to the mixture. After stirring
for 30 min at ꢀ78 ꢁC, a solution of triphenyltin chloride
(64.6 mg, 0.168 mmol) in THF (1.5 mL) was added dropwise,
and the mixture was then stirred for 30 min at ꢀ40 ꢁC. Methyl
iodide (95 mL, 0.670 mmol) was added dropwise and the mix-
ture was stirred for 20 h at ꢀ40 ꢁC. The reaction was
quenched at ꢀ40 ꢁC by addition of a 1:1 saturated NH4Cle
28% NH4OH solution (4 mL) and the mixture was stirred at
room temperature for additional 30 min. The mixture was
extracted with Et2O and the extract was washed with brine
and dried over MgSO4. Concentration under reduced pressure
followed by flash chromatography over silica gel with n-hex-
aneeAcOEt (5:1) gave the title compound 15a (36.9 mg, 93%
yield) as a colorless oil: [a]2D4 ꢀ95.5 (c 0.945, CHCl3); IR
(ATR): 3370 (NHCO), 1698 (CO), 1333 (NSO2), 1165
1
1164 (NSO2); H NMR (400 MHz, CDCl3) d 0.90e0.99 (m,
6H), 0.99 (s, 3H), 1.17 (s, 3H), 1.32e1.49 (m, 2H), 1.43 (s,
9H), 1.90e1.98 (m, 3H), 2.04e2.17 (m, 3H), 3.43e3.55 (m,
2H), 3.92e4.03 (m, 2H), 4.70 (d, J¼10.5 Hz, 1H), 6.87 (dt,
J¼15.4, 11.5 Hz, 1H), 7.01 (d, J¼15.4 Hz, 1H); 13C NMR
(100 MHz, CDCl3) d 16.6, 19.8, 20.7, 20.8, 26.4, 27.3, 28.2
(3C), 32.9, 38.3, 44.7, 47.8, 48.7, 53.0, 58.2 (t, J¼24.8 Hz),
65.1, 79.9, 120.1 (t, J¼246.6 Hz), 124.9 (t, J¼7.9 Hz), 138.4
(t, J¼26.5 Hz), 155.7, 162.2; 19F NMR (376 MHz, CDCl3)
d ꢀ107.4 (dt, J¼249.7, 11.9 Hz), ꢀ105.3 (dt, J¼251.0,
13.4 Hz); HRMS (FAB), m/z calcd for C23H37F2N2O5S
([MþH]þ) 491.2391, found 491.2385.
1
(NSO2); H NMR (400 MHz, CDCl3) d 0.92e0.94 (m, 6H),
0.97 (s, 3H), 1.16 (s, 3H), 1.19e1.41 (m, 2H), 1.33 (d,
J¼7.1 Hz, 3H), 1.44 (s, 9H), 1.81e1.96 (m, 4H), 2.02e2.06
(m, 2H), 3.42e3.52 (m, 2H), 3.86e3.97 (m, 1H), 3.89 (t,
J¼6.1 Hz, 1H), 4.12e4.19 (m, 1H), 4.70 (d, J¼9.8 Hz, 1H),
5.02 (dd, J¼37.8, 9.0 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 18.4, 19.3, 19.8, 20.8 (2C), 26.4, 28.3 (3C), 30.4, 32.8,
35.9, 38.3, 44.6, 47.7, 48.4, 53.0, 57.4 (d, J¼26.5 Hz), 65.0,
79.6, 105.9 (d, J¼11.6 Hz), 155.7, 157.4 (d, J¼251.6 Hz),
173.8; 19F NMR (376 MHz, CDCl3) d ꢀ119.63 (dd, J¼37.8
22.8 Hz); HRMS (FAB), m/z calcd for C24H40FN2O5S
([MþH]þ) 487.2642, found 487.2636.
4.3. (5S,2E)-5-[N-(tert-Butoxycarbonyl)amino]-4,4-difluoro-
6-methylhept-2-enoyl (R)-sultam (12b)
By use of a procedure similar to that described for the prep-
aration of (S)-sultam derivative 12a, the ester 10 (687 mg,
2.00 mmol) was converted into the title compound 12b
(913 mg, 96% yield) as a colorless oil: [a]2D4 þ44.7 (c 1.14,
CHCl3); IR (ATR): 3400 (NHCO), 1709 (CO), 1684 (CO),
1334 (NSO2), 1165 (NSO2); 1H NMR (400 MHz, CDCl3)
d 0.92e1.00 (m, 6H), 0.98 (s, 3H), 1.17 (s, 3H), 1.35e1.47
(m, 2H), 1.43 (s, 9H), 1.86e1.98 (m, 3H), 2.07e2.18 (m,
3H), 3.43e3.55 (m, 2H), 3.91e4.03 (m, 2H), 4.68 (d,
J¼11.0 Hz, 1H), 6.89 (dt, J¼15.4, 11.0 Hz, 1H), 7.01 (d,
J¼15.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 16.8, 19.8,
20.7, 20.8, 26.4, 27.3, 28.2 (3C), 32.8, 38.3, 44.6, 47.8,
4.5. (2S,5S,3Z)-5-[N-(tert-Butoxycarbonyl)amino]-4-fluoro-
2,6-dimethylhept-3-enoyl (R)-sultam (15b)
By use of a procedure similar to that described for the prep-
aration of BoceL-ValeL-Ala FADI derivative 15a, the (R)-sul-
tam derivative 12b (40.0 mg, 0.0838 mmol) was converted
into the title compound 15b (28.0 mg, 69% yield): [a]D24
þ49.2 (c 1.13, CHCl3); IR (ATR): 3383 (NHCO), 1703
(CO), 1335 (NSO2), 1166 (NSO2); 1H NMR (400 MHz,

4340
T. Narumi et al. / Tetrahedron 64 (2008) 4332e4346
CDCl3) d 0.83e0.86 (m, 6H), 0.90 (s, 3H), 1.09 (s, 3H), 1.17e
1.33 (m, 2H), 1.26 (d, J¼7.1 Hz, 3H), 1.37 (s, 9H), 1.77e1.89
(m, 4H), 1.97e1.99 (m, 2H), 3.42e3.52 (m, 2H), 3.81 (t,
J¼6.3 Hz, 1H), 3.90e3.99 (m, 1H), 4.06e4.14 (m, 1H),
4.62 (d, J¼9.3 Hz, 1H), 4.99 (dd, J¼37.2, 8.8 Hz, 1H); 13C
NMR (100 MHz, CDCl3) d 17.8, 19.2, 19.8, 19.9, 20.8,
26.4, 28.3 (3C), 30.2, 32.8, 35.9 (d, J¼4.1 Hz), 38.3, 44.6,
47.7, 48.4, 53.0, 56.8 (d, J¼27.3 Hz), 65.0, 79.5, 105.2 (d,
J¼11.6 Hz), 155.1, 157.7 (d, J¼260.7 Hz), 173.6; 19F NMR
(376 MHz, CDCl3) d ꢀ117.2 (dd, J¼37.2, 18.6 Hz); HRMS
(FAB), m/z calcd for C24H38FN2O5S ([MꢀH]ꢀ) 485.2491,
found 485.2491.
4.8. (2R,5S,3Z)-5-[N-(tert-Butoxycarbonyl)amino]-2-(2-tert-
butoxy-2-oxoethyl)-4-fluoro-6-methylhept-3-enoyl (S)-
sultam (17a)
By use of a procedure similar to that described for the prep-
aration of BoceL-ValeL-Ala FADI derivative 15a, the (S)-sul-
tam derivative 12a (40.0 mg, 0.0838 mmol) was converted
into the title compound 17a (46.6 mg, 80% yield) as a colorless
oil: [a]2D6 ꢀ81.7 (c 1.01, CHCl3); IR (ATR): 3369 (NHCO),
1703 (CO), 1337 (NSO2), 1164 (NSO2); 1H NMR
(400 MHz, CDCl3) d 0.92e0.94 (m, 6H), 0.96 (s, 3H), 1.21
(s, 3H), 1.25e1.47 (m, 2H), 1.41 (s, 9H), 1.43 (s, 9H),
1.82e1.94 (m, 4H), 2.00e2.06 (m, 1H), 2.12e2.16 (m, 1H),
2.51 (dd, J¼16.0, 5.7 Hz, 1H), 2.82 (dd, J¼16.0, 8.2 Hz,
1H), 3.41e3.51 (m, 2H), 3.88e3.98 (m, 2H), 4.33e4.39 (m,
1H), 4.72 (d, J¼9.8 Hz, 1H), 4.90 (dd, J¼36.3, 9.3 Hz, 1H);
13C NMR (100 MHz, CDCl3) d 18.4, 19.2, 19.9, 20.6, 26.5,
28.0 (3C), 28.3 (3C), 30.5, 32.8, 37.8 (d, J¼3.3 Hz), 37.9,
39.2, 44.6, 47.8, 48.5, 52.9, 57.4 (d, J¼25.7 Hz), 65.1, 79.6,
81.0, 103.5 (d, J¼12.4 Hz), 155.0, 158.5 (d, J¼262.3 Hz),
169.8, 171.7; 19F NMR (376 MHz, CDCl3) d ꢀ117.1 (br s);
HRMS (FAB), m/z calcd for C29H46FN2O7S ([MꢀH]ꢀ)
585.3015, found 585.2998.
4.6. (2R,5S,3Z)-2-Benzyl-5-[N-(tert-butoxycarbonyl)amino]-
4-fluoro-6-methylhept-3-enoyl (S)-sultam (16a)
By use of a procedure similar to that described for the prep-
aration of BoceL-ValeL-Ala FADI derivative 15a, the (S)-sul-
tam derivative 12a (40.0 mg, 0.0838 mmol) was converted
into the title compound 16a (43.6 mg, 93% yield) as a colorless
oil: [a]2D5 ꢀ82.5 (c 1.51, CHCl3); IR (ATR): 3370 (NHCO),
1698 (CO), 1333 (NSO2), 1164 (NSO2); 1H NMR
(400 MHz, CDCl3) d 0.70 (s, 3H), 0.86e0.90 (m, 9H),
1.13e1.36 (m, 2H), 1.45 (s, 9H), 1.69e2.04 (m, 6H), 2.79
(dd, J¼13.2, 7.6 Hz, 1H), 3.11 (dd, J¼12.9, 8.1 Hz, 1H),
3.34e3.42 (m, 2H), 3.77 (br, 1H), 3.89 (dt, J¼23.3, 9.0 Hz,
1H), 4.45 (q, J¼8.1 Hz, 1H), 4.64 (d, J¼9.5 Hz, 1H), 4.97
(dd, J¼35.6, 9.5 Hz, 1H), 7.14e7.26 (m, 5H); 13C NMR
(100 MHz, CDCl3) d 18.4, 19.1, 19.8, 20.4, 26.4, 28.3 (3C),
30.4, 32.7, 38.2, 40.4, 43.0, 44.6, 47.5, 48.1, 53.0, 57.6 (d,
J¼24.8 Hz), 65.0, 79.5, 104.3 (d, J¼12.4 Hz), 126.6, 128.2
(2C), 129.5 (2C), 137.5, 155.1, 158.2 (d, J¼261.5 Hz),
172.3; 19F NMR (376 MHz, CDCl3) d ꢀ119.4 to ꢀ119.1 (br
m); HRMS (FAB), m/z calcd for C30H44FN2O5S ([MþH]þ)
563.2955, found 563.2965.
4.9. (2S,5S,3Z)-5-[N-(tert-Butoxycarbonyl)amino]-2-(2-tert-
butoxy-2-oxoethyl)-4-fluoro-6-methylhept-3-enoyl (R)-
sultam (17b)
By use of a procedure similar to that described for the prep-
aration of BoceL-ValeL-Ala FADI derivative 15a, the (R)-sul-
tam derivative 12b (40.0 mg, 0.0838 mmol) was converted
into the title compound 17b (37.0 mg, 75% yield): [a]D23
þ39.5 (c 1.06, CHCl3); IR (ATR): 3367 (NHCO), 1702
(CO), 1335 (NSO2), 1162 (NSO2); 1H NMR (500 MHz,
CDCl3) d 0.87e0.92 (m, 6H), 0.96 (s, 3H), 1.21 (s, 3H),
1.24e1.46 (m, 2H), 1.41 (s, 9H), 1.43 (s, 9H), 1.86e2.16
(m, 6H), 2.51e2.56 (m, 1H), 2.78e2.84 (m, 1H), 3.39e3.50
(m, 2H), 3.90e4.07 (m, 2H), 4.33e4.38 (m, 1H), 4.66 (d,
J¼9.8 Hz, 1H), 4.91 (dd, J¼36.2, 9.3 Hz, 1H); 13C NMR
(125 MHz, CDCl3) d 17.6, 19.2, 19.9, 20.6, 26.5, 28.0 (3C),
28.3 (3C), 29.9, 32.8, 37.7 (d, J¼3.3 Hz), 37.9, 39.1, 44.6,
47.8, 48.5, 52.9, 56.7 (d, J¼29.0 Hz), 65.1, 79.6, 81.0, 102.8
(d, J¼12.4 Hz), 155.1, 159.0 (d, J¼264.0 Hz), 169.8, 171.7;
19F NMR (376 MHz, CDCl3) d ꢀ114.7 (dd, J¼36.2,
15.5 Hz); HRMS (FAB), m/z calcd for C29H46FN2O7S
([MꢀH]ꢀ) 585.3015, found 585.3016.
4.7. (2S,5S,3Z)-2-Benzyl-5-[N-(tert-butoxycarbonyl)amino]-
4-fluoro-6-methylhept-3-enoyl (R)-sultam (16b)
By use of a procedure similar to that described for the prep-
aration of BoceL-ValeL-Ala FADI derivative 15a, the (R)-sul-
tam derivative 12b (40.0 mg, 0.0838 mmol) was converted
into the title compound 16b (36.2 mg, 77% yield): [a]D26
þ21.9 (c 0.825, CHCl3); IR (ATR): 3379 (NHCO), 1701
(CO), 1334 (NSO2), 1165 (NSO2); 1H NMR (400 MHz,
CDCl3) d 0.75 (s, 3H), 0.77e0.81 (m, 6H), 0.89 (s,
3H), 1.10e1.35 (m, 2H), 1.44 (s, 9H), 1.74e1.99 (m, 6H),
2.76e2.81 (m, 1H), 3.11e3.16 (m, 1H), 3.34e3.44 (m,
2H), 3.77 (br, 1H), 3.94e4.02 (m, 1H), 4.48 (q, J¼8.3 Hz,
1H), 4.64 (d, J¼9.8 Hz, 1H), 4.93 (dd, J¼36.2, 9.2 Hz, 1H),
7.13e7.28 (m, 5H); 13C NMR (100 MHz, CDCl3) d 17.6,
18.9, 19.8, 20.5, 26.4, 28.3 (3C), 30.2, 32.8, 38.2, 40.3, 42.9,
44.6, 47.6, 48.1, 53.0, 56.7 (d, J¼29.0 Hz), 65.0, 79.5, 103.6
(d, J¼12.4 Hz), 126.6, 128.2 (2C), 129.4 (2C), 137.5, 155.1,
158.7 (d, J¼262.3 Hz), 172.3; 19F NMR (376 MHz, CDCl3)
d ꢀ115.88 (dd, J¼36.2, 17.6 Hz); HRMS (FAB), m/z calcd for
C30H42FN2O5S ([MꢀH]ꢀ) 561.2804, found 561.2797.
4.10. (2S,5S,3Z)-5-[N-(tert-Butoxycarbonyl)amino]-4-fluoro-
2-(4-methoxybenzyl)-6-methylhept-3-enoyl (R)-sultam (18b)
By use of a procedure similar to that described for the prep-
aration of BoceL-ValeL-Ala FADI derivative 15a, the (R)-sul-
tam derivative 12b (50.0 mg, 0.102 mmol) was converted into
the title compound 18b (50.2 mg, 77% yield) as a colorless oil:
[a]2D4 þ24.6 (c 1.31, CHCl3); IR (ATR): 1701 (CO), 1335
1
(NSO2), 1165 (NSO2); H NMR (500 MHz, CDCl3) d 0.74
(s, 3H), 0.89 (s, 3H), 0.79e0.83 (m, 6H), 1.26e1.35 (m,

T. Narumi et al. / Tetrahedron 64 (2008) 4332e4346
4341
2H), 1.44 (s, 9H), 1.75e1.98 (m, 6H), 2.73e2.77 (m, 1H),
4.13. (2R,5S,3Z)-5-[N-(tert-Butoxycarbonyl)amino]-4-fluoro-
3.03e3.08 (m, 1H), 3.34e3.42 (m, 2H), 3.75e3.76 (m, 4H),
3.96e4.03 (m, 1H), 4.41e4.45 (m, 1H), 4.66 (d, J¼9.6 Hz,
1H), 4.92 (dd, J¼35.2, 9.3 Hz, 1H), 6.77 (d, J¼8.4 Hz, 2H),
7.13 (d, J¼8.4 Hz, 2H); 13C NMR (125 MHz, CDCl3)
d 17.6, 19.0, 19.8, 20.4, 26.4, 28.3 (3C), 30.2, 32.8, 38.2,
39.6, 43.2, 44.6, 47.5, 48.1, 53.0, 55.2, 56.7 (d, J¼29.4 Hz),
65.0, 79.5, 103.7 (d, J¼12.6 Hz), 113.7 (2C), 129.6, 130.4
(2C), 155.1, 158.4, 158.6 (d, J¼262.1 Hz), 172.4; 19F NMR
(376 MHz, CDCl3) d ꢀ116.01 (dd, J¼35.2, 16.6 Hz); HRMS
(FAB), m/z calcd for C31H44FN2O6S ([MꢀH]ꢀ) 591.2910,
found 591.2905.
6-methyl-2-(2-methylprop-2-enyl)hept-3-enoyl (S)-
sultam (20a)
By use of a procedure similar to that described for the prep-
aration of BoceL-ValeL-Ala FADI derivative 15a, the (S)-sul-
tam derivative 12a (78.2 mg, 0.159 mmol) was converted into
the title compound 20a (82.7 mg, 99% yield) as a colorless oil:
[a]2D3 ꢀ89.7 (c 1.09, CHCl3); IR (ATR): 3381 (NHCO), 1698
(CO), 1333 (NSO2), 1163 (NSO2); 1H NMR (500 MHz,
CDCl3) d 0.92e0.93 (m, 6H), 0.96 (s, 3H), 1.15 (s, 3H),
1.24e1.40 (m, 2H), 1.44 (s, 9H), 1.77e2.04 (m, 9H), 2.15e
2.19 (m, 1H), 2.57e2.61 (m, 1H), 3.41e3.51 (m, 2H),
3.87e3.95 (m, 2H), 4.32e4.37 (m, 1H), 4.73 (s, 3H), 4.89
(dd, J¼36.4, 8.9 Hz, 1H); 13C NMR (125 MHz, CDCl3)
d 18.5, 19.2, 19.8, 20.6, 21.7, 26.4, 28.3 (3C), 30.3, 32.7,
38.3, 39.5, 42.6, 44.6, 47.7, 48.2, 53.0, 57.5 (d, J¼25.8 Hz),
65.1, 79.4, 104.5 (d, J¼12.0 Hz), 113.7, 141.7, 155.0, 158.0
(d, J¼262.7 Hz), 172.7; 19F NMR (470 MHz, CDCl3)
d ꢀ119.4 to ꢀ119.33 (m); HRMS (FAB), m/z calcd for
C27H42FN2O5S ([MꢀH]ꢀ) 525.2804, found 525.2809.
4.11. (2R,5S,3Z)-5-[N-(tert-Butoxycarbonyl)amino]-4-fluoro-
6-methyl-2-(prop-2-enyl)hept-3-enoyl (S)-sultam (19a)
By use of a procedure similar to that described for the prep-
aration of BoceL-ValeL-Ala FADI derivative 15a, the (S)-
sultam derivative 12a (40.0 mg, 0.0838 mmol) was converted
into the title compound 19a (42.9 mg, 99% yield) as a colorless
oil: [a]2D2 ꢀ81.0 (c 1.06, CHCl3); IR (ATR): 3380 (NHCO),
1699 (CO), 1335 (NSO2), 1166 (NSO2); 1H NMR
(400 MHz, CDCl3) d 0.92e0.94 (m, 6H), 0.97 (s, 3H), 1.16
(s, 3H), 1.21e1.40 (m, 2H), 1.44 (s, 9H), 1.76e1.94 (m,
4H), 1.97e2.09 (m, 2H), 2.31e2.40 (m, 1H), 2.49e2.59 (m,
1H), 3.42e3.52 (m, 2H), 3.83e3.97 (m, 2H), 4.22 (q,
J¼9.8 Hz, 1H), 4.72 (d, J¼9.8 Hz, 1H), 4.90e5.09 (m, 3H),
5.67e5.84 (m, 1H); 13C NMR (100 MHz, CDCl3) d 18.5,
19.2, 19.8, 20.8, 26.4, 28.3 (3C), 30.3, 32.8, 38.3, 38.6,
40.7, 44.6, 47.7, 48.3, 53.0, 57.5 (d, J¼26.5 Hz), 65.2, 79.5,
104.1 (d, J¼11.6 Hz), 117.8, 134.0, 155.1, 158.0 (d,
J¼263.2 Hz), 172.4; 19F NMR (376 MHz, CDCl3) d ꢀ119.0
(dd, J¼36.2, 23.8 Hz); HRMS (FAB), m/z calcd for
C26H40FN2O5S ([MꢀH]ꢀ) 511.2647, found 511.2629.
4.14. (2R,5S,3Z)-5-[N-(tert-Butoxycarbonyl)amino]-4-fluoro-
6-methyl-2-(naphth-2-ylmethyl)hept-3-enoyl (S)-sultam (21a)
By use of a procedure similar to that described for the prep-
aration of BoceL-ValeL-Ala FADI derivative 15a, the (S)-sul-
tam derivative 12a (50.0 mg, 0.105 mmol) was converted into
the title compound 21a (64.0 mg, 99% yield) as a colorless oil:
[a]2D4 ꢀ71.8 (c 1.41, CHCl3); IR (ATR): 3368 (NHCO), 1710
(CO), 1678 (CO), 1341 (NSO2), 1160 (NSO2); 1H NMR
(CDCl3) d 0.21 (s, 3H), 0.74 (s, 3H), 0.85e0.89 (m, 6H),
1.19e1.30 (m, 2H), 1.44 (s, 9H), 1.55e1.61 (m, 2H), 1.73e
1.92 (m, 4H), 2.97e3.01 (m, 1H), 3.24e3.31 (m, 3H), 3.72
(br s, 1H), 3.88e3.96 (m, 1H), 5.03 (dd, J¼36.6, 8.9 Hz,
1H), 7.38e7.43 (m, 3H), 7.64 (s, 1H), 7.72e7.76 (m, 3H);
13C NMR (125 MHz, CDCl3) d 18.4, 19.1, 19.6, 19.7, 26.3,
28.3 (3C), 30.4, 32.7, 38.1, 40.7, 43.0 (d, J¼3.0 Hz), 44.5,
47.3, 48.0, 52.9, 57.6 (d, J¼25.8 Hz), 64.9, 79.5, 104.5 (d,
J¼13.8 Hz), 125.3, 125.7, 127.4, 127.5, 127.8, 127.9, 127.9,
132.5, 133.4, 135.0, 155.1, 158.2 (d, J¼263.3 Hz), 172.3;
19F NMR (470 MHz, CDCl3) d ꢀ118.9 (br s); HRMS
(FAB), m/z calcd for C34H44FN2O5S ([MꢀH]ꢀ) 611.2960,
found 611.2958.
4.12. (2S,5S,3Z)-5-[N-(tert-Butoxycarbonyl)amino]-4-fluoro-
6-methyl-2-(prop-2-enyl)hept-3-enoyl (R)-sultam (19b)
By use of a procedure similar to that described for the prep-
aration of BoceL-ValeL-Ala FADI derivative 15a, the (R)-sul-
tam derivative 12b (40.0 mg, 0.0838 mmol) was converted
into the title compound 19b (37.1 mg, 86% yield) as a colorless
oil: [a]2D4 þ34.3 (c 0.900, CHCl3); IR (ATR): 3380 (NHCO),
1699 (CO), 1334 (NSO2), 1165 (NSO2); 1H NMR
(400 MHz, CDCl3) d 0.90e0.93 (6H), 0.97 (s, 3H), 1.16 (s,
3H), 1.25e1.40 (m, 2H), 1.44 (s, 9H), 1.85e2.08 (m, 6H),
2.34e2.41 (m, 1H), 2.51e2.58 (m, 1H), 3.41e3.52 (m, 2H),
3.86e3.97 (m, 1H), 3.99e4.07 (m, 1H), 4.23 (dt, J¼9.0,
6.8 Hz, 1H), 4.69 (d, J¼9.8 Hz, 1H), 4.91e5.09 (m, 3H),
5.70e5.81 (m, 1H); 13C NMR (100 MHz, CDCl3) d 17.8,
19.1, 19.9, 20.8, 26.4, 28.3 (3C), 30.2, 32.8, 38.6, 38.7,
40.7, 44.6, 47.7, 48.3, 53.0, 56.8 (d, J¼28.1 Hz), 65.2, 79.5,
103.5 (d, J¼12.4 Hz), 117.8, 134.1, 155.1, 158.4 (d,
J¼262.3 Hz), 172.3; 19F NMR (376 MHz, CDCl3) d ꢀ115.8
(dd, J¼36.2, 17.6 Hz); HRMS (FAB), m/z calcd for
C26H40FN2O5S ([MꢀH]ꢀ) 511.2647, found 511.2647.
4.15. (2R,5S,3Z)-5-[N-(tert-Butoxycarbonyl)amino]-4-fluoro-
2-(4-methoxy-4-oxobut-2-enyl)-6-methylhept-3-enoyl (S)-
sultam (22a)
By use of a procedure similar to that described for the prep-
aration of BoceL-ValeL-Ala FADI derivative 15a, the (S)-sul-
tam derivative 12a (50.0 mg, 0.105 mmol) was converted into
the title compound 22a (56.3 mg, 94% yield) as a colorless oil:
[a]2D3 ꢀ68.8 (c 1.30, CHCl3); IR (ATR): 3371 (NHCO), 1703
(CO), 1335 (NSO2), 1165 (NSO2); 1H NMR (500 MHz,
CDCl3) d 0.90e0.94 (m, 6H), 0.96 (s, 3H), 1.11 (s,
3H), 1.31e1.43 (m, 2H), 1.44 (s, 9H), 1.85e2.07 (m, 6H),

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T. Narumi et al. / Tetrahedron 64 (2008) 4332e4346
2.44e2.50 (m, 1H), 2.66e2.72 (m, 1H), 3.42e3.52 (m, 2H),
3.70 (s, 3H), 3.86e3.98 (m, 2H), 4.29e4.33 (m, 1H), 4.70
(d, J¼9.7 Hz, 1H), 4.96 (dd, J¼36.2, 9.1 Hz, 1H), 5.86 (d,
J¼15.6 Hz, 1H), 6.82e6.88 (m, 1H); 13C NMR (125 MHz,
CDCl3) d 18.4, 19.2, 19.8, 20.6, 26.4, 28.3 (3C), 30.3, 32.8,
36.8, 38.3, 40.1 (d, J¼3.0 Hz), 44.6, 47.7, 48.4, 51.4, 53.0,
57.5 (d, J¼25.8 Hz), 65.2, 79.6, 103.6 (d, J¼12.6 Hz),
123.7, 144.0, 155.1, 158.6 (d, J¼263.9 Hz), 166.2, 171.7;
19F NMR (470 MHz, CDCl3) d ꢀ117.3 to ꢀ117.2. (m);
HRMS (FAB), m/z calcd for C28H42FN2O7S ([MꢀH]ꢀ)
569.2702, found 569.2709.
stirring at 0 ꢁC for 1 h, the reaction was quenched with satu-
rated NaHCO3. The mixture was filtered over Celite and the
filtrate was extracted with AcOEt. The extract was washed
with saturated NaHCO3 and brine, and dried over MgSO4.
Concentration under reduced pressure followed by flash chro-
matography over silica gel with n-hexaneeAcOEt (40:1) gave
the title compound 27 (8.69 g, 39% yield) as a colorless oil:
[a]2D4 ꢀ33.9 (c 1.28, CHCl3); IR (ATR): 1770 (CO), 1758
1
(CO); H NMR (500 MHz, CDCl3) d ꢀ0.10 (m, 6H), 0.77
(s, 9H), 1.33e1.15 (m, 5H), 1.48e1.42 (m, 1H), 1.68e1.60
(m, 1H), 3.28e3.25 (m, 4H), 3.39e3.31 (m, 3H), 4.25e4.16
(m, 3H), 7.28e7.15 (m, 5H); 13C NMR (125 MHz, CDCl3)
d ꢀ5.4 to ꢀ5.5 (2C), 13.8, 18.2, 25.8, 26.3, 28.9, 56.3
(t, J¼22.5 Hz), 58.4, 59.7, 62.5 (d, J¼6.6 Hz), 77.8, 117.7
(t, J¼256.7 Hz), 127.7, 128.0, 128.3, 140.3, 164.1 (t, J¼
32.4 Hz); 19F NMR (470 MHz, CDCl3) d ꢀ110.5 (dd,
J¼256.7, 10.2 Hz), ꢀ112.6 (dd, J¼256.8, 12.6 Hz); HRMS
(FAB), m/z calcd for C23H38F2NO4Si ([MꢀH]ꢀ) 458.2544,
found 458.2566.
4.16. (2S,5S,3Z)-2-(4-Bromobenzyl)-5-[N-(tert-butoxy-
carbonyl)amino]-4-fluoro-6-methylhept-3-enoyl (R)-
sultam (23b)
By use of a procedure similar to that described for the prep-
aration of BoceL-ValeL-Ala FADI derivative 15a, the (R)-sul-
tam derivative 12b (50.0 mg, 0.105 mmol) was converted into
the title compound 23b (47.8 mg, 71% yield) as a colorless oil:
[a]2D4 þ25.1 (c 1.12, CHCl3); IR (ATR): 1703 (CO), 1337
4.18. Ethyl (3S)-3-[N-(tert-butoxycarbonyl)amino]-6-(tert-
butyldimethylsiloxy)-2,2-difluorohexanoate (28)
1
(NSO2), 1165 (NSO2); H NMR (500 MHz, CDCl3) d 0.72
(s, 3H), 0.80e0.84 (m, 6H), 0.90 (s, 3H), 1.21e1.45 (m,
2H), 1.44 (s, 9H), 1.70e1.98 (m, 6H), 2.74e2.78 (m, 1H),
3.04e3.08 (m, 1H), 3.35e3.43 (m, 2H), 3.78 (br s, 1H),
3.97e4.03 (m, 1H), 4.42e4.47 (m, 1H), 4.65 (d, J¼9.6 Hz,
1H), 4.92 (dd, J¼35.9, 9.2 Hz, 1H), 7.10 (d, J¼8.2 Hz, 2H),
7.35 (d, J¼8.3 Hz, 2H); 13C NMR (125 MHz, CDCl3)
d 17.6, 19.0, 19.7, 20.2, 26.4, 28.3 (3C), 30.1, 32.8, 38.2,
39.7, 42.8, 44.6, 47.6, 48.2, 53.0, 56.7 (d, J¼28.2 Hz), 65.1,
79.6, 103.3 (d, J¼13.2 Hz), 120.6, 131.3 (2C), 131.3 (2C),
136.5, 155.1, 159.0 (d, J¼263.9 Hz), 172.0; 19F NMR
(376 MHz, CDCl3) d ꢀ115.4 (dd, J¼35.9, 15.5 Hz); HRMS
(FAB), m/z calcd for C30H41BrFN2O5S ([MꢀH]ꢀ) 639.1909,
found 639.1902.
To a solution of the ester 27 (7.05 g, 15.2 mmol) in EtOH
(50.0 mL) were added 20% Pd(OH)2/C (1.11 g, 1.58 mmol)
and (Boc)2O (7.26 g, 33.3 mmol), and the suspension was
stirred for 12 h under H2 at room temperature. The mixture
was filtered through a pad of Celite and the filtrate was con-
centrated under reduced pressure, followed by flash chroma-
tography over silica gel with n-hexaneeAcOEt (40:1) to
give the title compound 28 (5.47 g, 85% yield) as a colorless
oil: [a]2D2 ꢀ13.9 (c 1.16, CHCl3); IR (ATR): 3364 (NHCO),
1
1770 (CO), 1717 (CO); H NMR (500 MHz, CDCl3) d 0.00
(s, 6H), 0.84 (s, 9H), 1.29 (t, J¼7.2 Hz, 3H), 1.37e1.66 (m,
12H), 1.78e1.84 (m, 1H), 3.56e3.63 (m, 2H), 4.17e4.29
(m, 3H), 4.85 (d, J¼10.2 Hz, 1H); 13C NMR (125 MHz,
CDCl3) d ꢀ5.7 (2C), 13.6, 18.0, 23.7, 25.6 (3C), 27.9 (3C),
28.2, 52.3 (dd, J¼27.6, 23.4 Hz), 61.8, 62.6, 79.6, 114.4 (t,
J¼255.2 Hz), 155.0, 163.1 (dd, J¼33.3, 30.9 Hz); 19F NMR
(376 MHz, CDCl3) d ꢀ113.6 (dd, J¼256.6, 8.3 Hz), ꢀ119.8
(dd, J¼256.6, 18.6 Hz); HRMS (FAB), m/z calcd for
C19H36F2NO5Si ([MꢀH]ꢀ) 424.2336, found 424.2343.
4.17. Ethyl (3S)-6-(tert-butyldimethylsiloxy)-2,2-difluoro-3-
{N-[(1R)-(2-methoxy-1-phenylethyl)]amino}hexanoate (27)
To a solution of oxalyl chloride (7.45 g, 58.7 mmol) in
CH2Cl2 (120 mL) at ꢀ78 ꢁC under argon was added dropwise
a solution of DMSO (3.82 mL, 53.8 mmol) in CH2Cl2
(84 mL). After 10 min, 4-(tert-butyldimethylsilyloxy)-1-buta-
nol 26 (10.2 g, 48.9 mmol) in CH2Cl2 (72 mL) was added
dropwise. After 0.5 h, Et3N (33.8 mL, 244.5 mmol) was added
dropwise. After stirring at ꢀ78 ꢁC for 1 h, the mixture was di-
luted with CH2Cl2 (200 mL). The diluted mixture was washed
with saturated NH4Cl and brine, and dried over MgSO4. Con-
centration under reduced pressure gave an oily aldehyde,
which was used immediately in the next step without purifica-
tion. A solution of the above aldehyde and amine 8 in THF
(263 mL) was stirred at 0 ꢁC for 4 h under argon in the pres-
4.19. (5S,2E)-5-[N-(tert-Butoxycarbonyl)amino]-8-(tert-
butyldimethylsiloxy)-4,4-difluorooct-2-enoyl (S)-sultam (29)
By use of a procedure similar to that described for the prep-
aration of the (S)-sultam derivative 12a, the ester 28 (5.49 mg,
12.9 mmol) was converted into the title compound 29 (5.83 g,
73% yield) as a colorless oil: [a]2D0 ꢀ59.8 (c 1.33, CHCl3); IR
(ATR): 3370 (NHCO), 1713 (CO), 1692 (CO), 1332 (NSO2),
1
1165 (NSO2); H NMR (400 MHz, CDCl3) d 0.00 (s, 6H),
˚
ence of activated molecular sieves 4 A. To the mixture were
0.84 (s, 9H), 0.94 (s, 3H), 1.12 (s, 3H), 1.30e1.44 (m, 12H),
1.48e1.65 (m, 2H), 1.77e1.94 (m, 4H), 2.06e2.08 (m,
2H), 3.39e3.50 (m, 2H), 3.54e3.61 (m, 2H), 3.88e3.91 (m,
1H), 3.94e4.03 (m, 1H), 4.56 (d, J¼10.2 Hz, 1H), 6.79e
6.87 (m, 1H), 6.95 (d, J¼15.3 Hz, 1H); 13C NMR
successively added a suspension of RhCl(PPh3)3 (2.07 g,
2.24 mmol) in THF (20 mL), a solution of BrCF2CO2Et
(9.96 mL, 48.9 mmol) in THF (20 mL), and a solution of
Et2Zn in n-hexane (1.0 M, 195.6 mL, 195.6 mmol). After

T. Narumi et al. / Tetrahedron 64 (2008) 4332e4346
4343
(100 MHz, CDCl3) d ꢀ5.5 (2C), 18.1, 19.6, 20.7, 24.3, 25.8
(3C), 26.2, 28.0 (3C), 28.4, 32.6, 38.1, 44.5, 47.6, 48.5,
52.8, 54.0 (t, J¼27.3 Hz), 62.0, 64.9, 79.6, 119.6 (t,
J¼245.4 Hz), 125.2, 137.7 (t, J¼26.5 Hz), 155.2, 161.9; 19F
NMR (376 CDCl3) d ꢀ108.1 (dt, J¼248.3, 10.3 Hz), ꢀ110.8
(dt, J¼248.3, 12.4 Hz). Anal. Calcd for C29H50F2N2O6SSi:
C, 56.10; H, 8.12; N, 4.51. Found: C, 56.20; H, 8.14; N, 4.45.
1.84e1.95 (m, 4H), 2.04e2.06 (m, 2H), 3.40e3.50 (m, 2H),
3.56e3.64 (m, 4H), 3.85e3.88 (m, 1H), 4.04e4.21 (m, 2H),
4.75 (d, J¼8.3 Hz, 1H), 4.97 (dd, J¼36.4, 9.0 Hz, 1H); 13C
NMR (125 MHz, CDCl3) d ꢀ5.4 (2C), ꢀ5.3 (2C), 18.2,
18.3, 19.9, 20.8, 25.9 (3C), 26.0 (3C), 26.4, 28.3 (3C), 28.7,
28.8, 29.9, 30.7, 32.9, 38.4, 41.0, 44.6, 47.7, 48.3, 51.7 (d,
J¼27.6 Hz), 53.0, 62.5 (2C), 65.1, 79.5, 103.9 (d,
J¼12.0 Hz), 154.9, 158.7 (d, J¼261.5 Hz), 173.0; 19F NMR
(470 MHz, CDCl3) d ꢀ120.7 (dd, J¼36.4, 19.3 Hz); HRMS
(FAB), m/z calcd for C38H70FN2O7SSi2 ([MꢀH]ꢀ) 773.4432,
found 773.4454.
4.20. (2R,5S,3Z)-5-[N-(tert-Butoxycarbonyl)amino]-8-(tert-
butyldimethylsiloxy)-4-fluoro-2-(prop-2-enyl)oct-3-enoyl (S)-
sultam (30)
By use of a procedure similar to that described for the prep-
aration of BoceL-ValeL-Ala FADI derivative 15a, the (S)-sul-
tam derivative 29 (1.01 g, 1.62 mmol) was converted into the
title compound 30 (1.03 g, 97% yield) as a colorless oil:
[a]2D1 ꢀ71.9 (c 1.11, CHCl3); IR (ATR): 3352 (NHCO),
3300 (NHCO), 1716 (CO), 1695 (CO), 1331 (NSO2), 1166
4.22. (2R,5S,3Z)-5-[N-(tert-Butoxycarbonyl)amino]-8-[N-
(tert-butoxycarbonyl)-N-(2-nitrophenylsulfonyl)amino]-2-{3-
[N-(tert-butoxycarbonyl)-N-(2-nitrophenylsulfonyl)-
amino]propyl}-4-fluorooct-3-enoyl (S)-sultam (35)
To a solution of the bis-TBS ether 32 (259.7 mg,
0.335 mmol) in CH3CNeH2O (1:1, 6.7 mL) at 0 ꢁC under ar-
gon was added aqueous H2SiF6 (3.28 N, 104 mL), and the mix-
ture was stirred at room temperature for 1 h. After diluted with
AcOEt (100 mL), the reaction mixture was washed with aque-
ous 5% K2CO3 and dried over MgSO4. Concentration under
reduced pressure gave the corresponding diol, which was
used in the next step without purification. To a solution of
the diol, PPh3 (529.3 mg, 2.02 mmol) and NsNHBoc
(606.8 mg, 2.01 mmol) in THF (6.7 mL), and a solution of
DEAD in toluene (2.2 M, 913 mL, 2.01 mmol) were succes-
sively added at 0 ꢁC under argon. After being stirred at
room temperature overnight, concentration under reduced
pressure followed by flash chromatography over silica gel
gave the title compound 35 (320 mg, 85%) as a semisolid:
[a]2D5 ꢀ35.9 (c 1.00, CHCl3); IR (ATR): 3394 (NHCO),
1728 (CO), 1336 (NSO2), 1152 (NSO2); 1H NMR
(500 MHz, CDCl3) d 0.96 (s, 3H), 1.18 (s, 3H), 1.30e1.48
(m, 30H), 1.61e1.93 (m, 10H), 2.04e2.11 (m, 2H), 3.42e
3.50 (m, 2H), 3.73e3.79 (m, 4H), 3.90e3.91 (m, 1H),
4.11e4.13 (m, 1H), 4.19e4.29 (m, 1H), 4.76 (d, J¼9.0 Hz,
1H), 5.03 (dd, J¼36.1, 9.2 Hz, 1H), 7.72e7.73 (m, 6H),
8.26e8.29 (m, 2H); 13C NMR (125 MHz, CDCl3) d 19.7,
20.7, 26.2, 26.3, 27.1, 27.6 (3C), 27.6 (3C), 28.1 (3C), 29.4,
31.0, 32.5, 38.2, 40.7, 44.4, 47.3, 47.3, 47.5, 48.2, 51.3 (d,
J¼28.8 Hz), 52.7, 64.9, 79.5, 84.7, 84.9, 103.7, 103.7, 124.1,
124.2, 131.6, 131.6, 132.7, 132.8, 133.2, 134.0, 134.1, 147.4
(2C), 150.1 (2C), 154.7, 158.5 (d, J¼262.7 Hz), 172.2; 19F
NMR (470 MHz, CDCl3) d ꢀ119.1 to ꢀ119.0 (m); HRMS
(FAB), m/z calcd for C48H66FN6O17S3 ([MꢀH]ꢀ)
1113.3636, found 1113.3624.
1
(NSO2); H NMR (400 MHz, CDCl3) d 0.04 (s, 6H), 0.88 (s,
9H), 0.97 (s, 3H), 1.15 (s, 3H), 1.25e1.66 (m, 15H), 1.85e
2.04 (m, 5H), 2.38e2.32 (m, 1H), 2.52e2.59 (m, 1H),
3.39e3.53 (m, 2H), 3.57e3.63 (m, 2H), 3.84e3.90 (m, 1H),
4.09e4.25 (m, 2H), 4.76 (d, J¼9.0 Hz, 1H), 4.93e5.10 (m,
3H), 5.69e5.81 (m, 1H); 13C NMR (100 MHz, CDCl3)
d ꢀ5.4 (2C), 18.2, 19.8, 20.7, 25.6, 25.9 (3C), 26.4, 28.2
(3C), 28.6 (m), 32.8, 38.3, 38.4, 40.7, 44.6, 47.6, 48.2, 51.5
(d, J¼27.3 Hz), 53.0, 62.4, 65.1, 79.4, 103.3 (d, J¼11.6 Hz),
117.7, 134.0, 154.8, 158.6 (d, J¼263.2 Hz), 172.2; 19F NMR
(376 MHz, CDCl3) d ꢀ119.6 (dd, J¼35.2, 20.7 Hz); HRMS
(FAB), m/z calcd for C32H54FN2O6SSi ([MꢀH]ꢀ) 641.3461,
found 641.3469.
4.21. (2R,5S,3Z)-5-[N-(tert-Butoxycarbonyl)amino]-8-(tert-
butyldimethylsiloxy)-2-[3-(tert-butyldimethylsiloxy)propyl]-4-
fluorooct-3-enoyl (S)-sultam (32)
To a solution of the (S)-sultam derivative 30 (929 mg,
1.45 mmol) in THF (30 mL) at 0 ꢁC under argon was added
dropwise (Sia)2BH in THF (0.49 M, 8.88 mL, 4.35 mmol),
and the mixture was stirred at room temperature overnight.
After being diluted with THF (60 mL), aqueous 50% H2O2
(1.15 mL) and 20% AcOK (1.45 mL) were added with addi-
tional stirring at room temperature for 2 h. The mixture was
extracted with Et2O and the extract was washed with saturated
Na2S2O3 and dried over MgSO4. Concentration under reduced
pressure followed by flash chromatography over silica gel
gave the corresponding alcohol. To a solution of the alcohol
in CH2Cl2 (20 mL) at room temperature under argon was
added imidazole (120 mg, 1.75 mmol) and TBSCl (240 mg,
1.60 mmol). After stirring for 1 h, the precipitate was filtrated
off and the filtrate was concentrated under reduced pressure,
followed by flash chromatography over silica gel to give the
title compound 32 (930.7 mg, 83%) as a colorless oil: [a]D23
ꢀ57.7 (c 1.32, CHCl3); IR (ATR): 3375 (NHCO), 1702
(CO), 1336 (NSO2), 1165 (NSO2); 1H NMR (500 MHz,
CDCl3) d 0.02 (s, 6H), 0.04 (s, 6H), 0.87 (s, 9H), 0.88
(s, 9H), 0.97 (s, 3H), 1.15 (s, 3H), 1.32e1.72 (m, 18H),
4.23. (2R,5S,3Z)-5-[N-(9-Fluorenylmethoxycarbonyl)amino]-
4-fluoro-8-[N-(2-nitrophenylsulfonyl)amino]-2-{3-[N-(2-
nitrophenylsulfonyl)amino]propyl}oct-3-enoic acid (36)
To a solution of the sultam 35 (376.2 mg, 0.337 mmol) and
aqueous 50% H2O2 (119.6 mL, 1.75 mmol) in THFeH2O (5:1,
6 mL) at 0 ꢁC was added aqueous 1 N LiOH (670 mL,
0.67 mmol), and the mixture was stirred at room temperature

4344
T. Narumi et al. / Tetrahedron 64 (2008) 4332e4346
for 2 h. After being diluted with AcOEt (20 mL), the mixture
was washed with 0.1 N HCl and dried over MgSO4. Concentra-
tion under reduced pressure gave the corresponding acid, which
was used in the next step without purification. To a solution of
the acid in CH2Cl2 (15 mL) at 0 ꢁC was added TFA (4 mL),
and the mixture was stirred at room temperature for 0.5 h. Con-
centration under reduced pressure gave an oily residue, which
was dissolved in MeCNeDMFeH2O (10:9:1, 20 mL).
FmoceOSu (159.2 mg, 0.472 mmol) and Et3N (94 mL,
0.675 mmol) were added to the mixture at 0 ꢁC, and the mixture
was stirred at room temperature for 12 h. After being diluted
with AcOEt (70 mL), the reaction mixture was washed with
1 N HCl and dried over dried over MgSO4. Concentration under
reduced pressure followed by flash chromatography over silica
gel gave the title compound 36 (267.3 mg, 94% yield) as a semi-
solid: [a]2D3 ꢀ21.1 (c 1.05, CHCl3); IR (ATR): 3347 (OH), 1709
(CO), 1341 (NSO2), 1165 (NSO2); 1H NMR (500 MHz, CDCl3)
d 1.43e1.81 (m, 8H), 3.04e3.10 (m, 4H), 3.38e3.41 (m, 1H),
4.17e4.19 (m, 2H), 4.34e4.43 (m, 2H), 4.86 (dd, J¼35.8,
9.5 Hz, 1H), 5.08 (d, J¼8.4 Hz, 1H), 5.50e5.54 (m, 2H),
7.27e7.39 (m, 4H), 7.56e7.57 (m, 2H), 7.68e7.71 (m, 4H),
7.74 (d, J¼7.4 Hz, 2H), 7.78e7.81 (m, 2H), 8.07e8.10 (m,
2H); 13C NMR (125 MHz, CDCl3) d 25.7, 26.8, 28.7, 28.9,
39.7, 43.0, 43.1, 50.2, 51.7 (d, J¼28.8 Hz), 66.8, 104.7 (d,
J¼13.2 Hz), 119.8 (2C), 124.9, 125.0, 125.1, 125.1, 127.0
(2C), 127.6 (2C), 130.8 (2C), 132.6, 132.7, 133.3, 133.5,
133.5, 141.1 (2C), 143.6, 143.7, 147.8 (2C), 155.8, 158.4 (d,
J¼261.5 Hz), 176.1; 19F NMR (470 MHz, CDCl3) d ꢀ120.8
to ꢀ120.7 (m); HRMS (FAB), m/z calcd for C38H37FN5O12S2
([MꢀH]ꢀ) 838.1870, found 838.1882.
concentrated under reduced pressure to give a crude linear
peptide. To a mixture of the linear peptide and NaHCO3
(57.1 mg, 0.680 mmol) in DMF (41 mL) was added diphenyl-
phosphoryl azide (DPPA, 87.9 mL, 0.408 mmol) at ꢀ40 ꢁC.
The mixture was stirred for 48 h with warming to room tem-
perature and then filtered. The filtrate was concentrated under
reduced pressure, followed by flash chromatography over sil-
ica gel with CHCl3eMeOH (99:1) to give the title cyclic pseu-
dopeptide 41 (68.3 mg, 64% yield) as a white powder: [a]D25
ꢀ45.0 (c 0.565, DMSO); IR (ATR): 3288 (NHCO), 1644
(CO), 1340 (NSO2), 1161 (NSO2); 1H NMR (500 MHz,
DMSO-d6) d 0.80e0.88 (m, 2H), 0.99e1.08 (m, 1H), 1.11e
1.45 (m, 13H), 1.56e1.62 (m, 1H), 2.47e2.56 (m, 2H),
2.67e2.89 (m, 5H), 3.04e3.14 (m, 2H), 3.48 (dd, J¼14.4,
3.9 Hz, 1H), 3.80 (dd, J¼14.5, 6.9 Hz, 1H), 4.01 (br s, 1H),
4.34e4.39 (m, 2H), 4.74 (dd, J¼37.8, 9.8 Hz, 1H), 6.77 (d,
J¼8.4 Hz, 2H), 7.02 (d, J¼8.5 Hz, 2H), 7.30e7.33 (m, 3H),
7.61 (br s, 1H), 7.70e7.97 (m, 16H), 8.48 (d, J¼8.2 Hz,
1H); HRMS (FAB), m/z calcd for C51H56FN8O13S2
([MꢀH]ꢀ) 1071.3398, found 1071.3409.
4.24.3. FCN001: cyclo(eD-TyreArgej[(Z)-CF]CH]e
ArgeNaleGlye)$2TFA (25)
The cyclic pseudopeptide 41 (34.4 mg, 0.0320 mmol) was
treated with aqueous 95% TFA (3 mL) for 3 h. Concentration
under reduced pressure gave an oily residue, which was used
immediately in the next step without purification. To a solution
of the crude mixture in DMF (5 mL) were added 2-mercaptoe-
thanol (22.4 mL, 0.32 mmol) and DBU (193 mL, 1.56 mmol),
and the mixture was stirred at 50 ꢁC for 2.5 h. After concentra-
tion under reduced pressure, the residue was washed three
times with Et2O and treated with Et3N (392 mL, 2.84 mmol)
and 1H-pyrazole-1-carboxamidine hydrochloride (55.8 mg,
0.38 mmol) in DMF (5 mL). After concentration under re-
duced pressure, purification by preparative HPLC gave the di-
trifluoroacetate of the title cyclic pseudopeptide 25 (2.4 mg,
8%) as colorless freeze-dried powder: [a]2D5 ꢀ24.9 (c 0.150,
DMSO); IR (ATR): 3275, 3191, 3071, 2925, 2852, 1651,
4.24. Generalprocedureforsynthesisofprotectedpeptideresin
Protected peptide resin was manually constructed by Fmoc-
based solid-phase synthesis. t-Bu ether for D-Tyr was em-
ployed for side-chain protection. Fmoc deprotection was
achieved by 20% piperidine in DMF (20 min). Fmoc-amino
acids except for FmoceL-Orn(Ns)ej[(Z)-CF]CH]eL-
Orn(Ns)eOH 36 were coupled by treatment with 3 equiv of
reagents [Fmoceamino acid, DIPCI, and HOBt$H2O] to free
amino acids in DMF for 1.5 h (for 39, see the following).
1
1644, 1634, 1537, 1514, 1435, 1367, 1182, 1132; H NMR
(500 MHz, DMSO-d6) d 1.12e1.38 (m, 6H), 1.57e1.67 (m,
2H), 2.68 (dd, J¼13.7, 7.8 Hz, 1H), 2.87 (dd, J¼13.8,
7.2 Hz, 1H), 2.93e3.01 (m, 5H), 3.12e3.22 (m, 2H), 3.55
(dd, J¼14.6, 4.2 Hz, 1H), 3.79 (dd, J¼14.7, 6.7 Hz, 1H),
4.20 (br s, 1H), 4.33e4.41 (m, 2H), 4.92 (dd, J¼38.2,
9.6 Hz, 1H), 6.63 (d, J¼8.5 Hz, 2H), 6.67e7.55 (br m, 4H),
6.97 (d, J¼8.5 Hz, 2H), 7.34e7.36 (m, 2H), 7.43e7.51 (m,
5H), 7.67 (s, 1H), 7.79e7.81 (m, 2H), 7.84e7.87 (m, 2H),
7.94e7.99 (m, 2H), 8.46 (d, J¼8.1 Hz, 1H), 9.18 (br s, 1H);
HRMS (FAB), m/z calcd for C37H48FN10O5 ([MþH]þ)
731.3793, found 731.3754.
4.24.1. HeD-Tyr(t-Bu)eOrn(Ns)ej[(Z)-CF]CH]e
Orn(Ns)eNaleGlye(2-Cl)Trt resin (39)
Nal residue was coupled by general coupling protocol on He
Glye(2-Cl)Trt resin (0.87 mmol/g, 114.9 mg, 0.100 mmol).
FmoceOrn(Ns)ej[(Z)-CF]CH]eOrn(Ns)eOH 36 (92.2 mg,
0.110 mmol) was incorporated by treatment of DIPCI (34 mL,
0.220 mmol) and HOBt$H2O (84.3 mg, 0.550 mmol) for 12 h.
D-Tyr(t-Bu) was coupled by general coupling protocol to afford
the title protected peptide resin 39.
Acknowledgements
4.24.2. cyclo[eD-Tyr(t-Bu)eOrn(Ns)ej[(Z)-CF]CH]e
Orn(Ns)eNaleGlye] (41)
The protected peptide resin 39 (0.100 mmol) was subjected
to HFIPeCH2Cl2 (3:7, 15 mL) treatment at room temperature
for 2 h. After filtration of the residual resin, the filtrate was
This research was supported in part by the 21st Century
COE Program ‘Knowledge Information Infrastructure for Ge-
nome Science’, a Grant-in-Aid for Scientific Research from
the Ministry of Education, Culture, Sports, Science, and

T. Narumi et al. / Tetrahedron 64 (2008) 4332e4346
4345
Springer: Berlin, Germany, 2000; (e) Urban, J. J.; Tillman, B. G.; Cronin,
W. A. J. Phys. Chem. A 2006, 110, 11120e11129.
Technology, Japan, the Japan Society for the Promotion of Sci-
ence (JSPS), and the Japan Health Science Foundation. T.N.
and K.T. are grateful for the JSPS Research Fellowships for
Young Scientists.
11. Dutheuil, G.; Lei, X.; Pannecoucke, X.; Quirion, J.-C. J. Org. Chem. 2005,
70, 1911e1914.
12. Copper- or SmI2-mediated reductive defluorination: (a) Otaka, A.;
Mitsuyama, E.; Watanabe, H.; Oishi, S.; Tamamura, H.; Fujii, N. Chem.
Commun. 2000, 1081e1082; (b) Otaka, A.; Watanabe, H.; Mitsuyama,
E.; Yukimasa, A.; Tamamura, H.; Fujii, N. Tetrahedron Lett. 2001, 42,
285e287; (c) Otaka, A.; Watanabe, H.; Yukimasa, A.; Oishi, S.;
Tamamura, H.; Fujii, N. Tetrahedron Lett. 2001, 42, 5443e5446; (d)
Otaka, A.; Watanabe, J.; Yukimasa, A.; Sasaki, Y.; Watanabe, H.; Kinosh-
ita, T.; Oishi, S.; Tamamura, H.; Fujii, N. J. Org. Chem. 2004, 69, 1634e
1645; (e) Niida, A.; Tomita, K.; Mizumoto, M.; Tanigaki, H.; Terada, T.;
Oishi, S.; Otaka, A.; Inui, K.; Fujii, N. Org. Lett. 2006, 8, 613e616; (f)
Narumi, T.; Niida, A.; Tomita, K.; Oishi, S.; Otaka, A.; Ohno, H.; Fujii,
N. Chem. Commun. 2006, 4720e4722; (g) Tomita, K.; Narumi, T.; Niida,
A.; Oishi, S.; Ohno, H.; Fujii, N. Biopolymers 2007, 88, 272e278.
13. R3Al-copper-mediated alkylative defluorination: (a) Okada, M.; Naka-
mura, Y.; Saito, A.; Sato, A.; Horikawa, H.; Taguchi, T. Chem. Lett.
2002, 28e29; (b) Nakamura, Y.; Okada, M.; Horikawa, H.; Taguchi, T.
J. Fluorine Chem. 2002, 117, 143e148; (c) Okada, M.; Nakamura, Y.;
Saito, A.; Sato, A.; Horikawa, H.; Taguchi, T. Tetrahedron Lett. 2002,
43, 5845e5847; (d) Nakamura, Y.; Okada, M.; Sato, A.; Horikawa, H.;
Koura, M.; Saito, A.; Taguchi, T. Tetrahedron 2005, 61, 5741e5753;
(e) Nakamura, Y.; Okada, M.; Koura, M.; Tojo, M.; Saito, A.; Sato, A.;
Taguchi, T. J. Fluorine Chem. 2006, 127, 627e636.
Supplementary data
1
Copies of H NMR spectra for all new compounds; prepa-
ration and copies of CD spectra of methyl ester derivatives of
15a,b, 16a,b, and 18a,b. Supplementary data associated with
this article can be found in the online version, at
doi:10.1016/j.tet.2008.02.076.
References and notes
1. (a) Peptidomimetics Protocols; Kazmierski, W. M., Ed.; Human: Totowa,
NJ, 1999; (b) Burgess, K. Acc. Chem. Res. 2001, 34, 826e835; (c) Bursa-
vich, M. G.; Rich, D. H. J. Med. Chem. 2002, 45, 541e558; (d) Hruby,
V. J. J. Med. Chem. 2003, 46, 4215e4231.
2. For some recent examples of (E)-Alkene isostere, see: (a) Tamamura, H.;
Hiramatsu, K.; Ueda, S.; Wang, Z.; Kusano, S.; Terakubo, S.; Trent, J. O.;
Peiper, S. C.; Yamamoto, N.; Nakashima, H.; Otaka, A.; Fujii, N. J. Med.
Chem. 2005, 48, 380e391; (b) Badur, N. G.; Harms, K.; Koert, U. Synlett
2005, 773e776; (c) Wiktelius, D.; Luthman, K. Org. Biomol. Chem. 2007,
5, 603e605; (d) Badur, N. G.; Harms, K.; Koert, U. Synlett 2007, 99e102
and references cited therein.
14. Copper-mediated reduction of g-substituted-a,b-enoates: (a) Ibuka, T.;
Aoyagi, T.; Yamamoto, Y. Chem. Pharm. Bull. 1986, 34, 2417e2427;
(b) Fujii, N.; Habashita, H.; Shigemori, N.; Otaka, A.; Ibuka, T.; Tanaka,
M.; Yamamoto, Y. Tetrahedron Lett. 1991, 32, 4969e4972; (c) Ibuka, T.;
Yoshizawa, H.; Habashita, H.; Fujii, N.; Chounan, Y.; Tanaka, M.;
Yamamoto, Y. Tetrahedron Lett. 1992, 33, 3783e3786.
3. For the synthesis of 3,6-dihydropyridine-2-one, see: (a) Niida, A.; Tani-
gaki, H.; Inokuchi, E.; Sasaki, Y.; Oishi, S.; Ohno, H.; Tamamura, H.;
Wang, Z. X.; Peiper, S. C.; Kitaura, K.; Otaka, A.; Fujii, N. J. Org.
Chem. 2006, 71, 3942e3951; (b) Niida, A.; Mizumoto, M.; Narumi, T.;
Inokuchi, E.; Oishi, S.; Ohno, H.; Otaka, A.; Kitaura, K.; Fujii, N.
J. Org. Chem. 2006, 71, 4118e4129 and references cited therein.
4. For some recent examples of tri- or tetrasubstituted alkene isosteres, see:
(a) Oishi, S.; Kamano, T.; Niida, A.; Odagaki, Y.; Hamanaka, N.; Yama-
moto, M.; Ajito, K.; Tamamura, H.; Otaka, A.; Fujii, N. J. Org. Chem.
2002, 67, 6162e6173; (b) Oishi, S.; Miyamoto, K.; Niida, A.; Yamamoto,
M.; Ajito, K.; Tamamura, H.; Otaka, A.; Kuroda, Y.; Asai, A.; Fujii, N.
Tetrahedron 2006, 62, 1416e1424.
15. (a) Ibuka, T.; Aoyagi, T.; Kitada, K.; Yoneda, F.; Yamamoto, Y. J. Organo-
met. Chem. 1985, 287, C18eC22; (b) Chounan, Y.; Ibuka, T.; Yamamoto,
Y. J. Chem. Soc., Chem. Commun. 1994, 2003e2004; (c) Chounan, Y.;
Horino, H.; Ibuka, T.; Yamamoto, Y. Bull. Chem. Soc. Jpn. 1997, 70,
1953e1959.
16. Honda, T.; Wakabayashi, H.; Kanai, K. Chem. Pharm. Bull. 2002, 50,
307e308.
17. Oppolzer, W.; Dupuis, D.; Poli, G.; Raynham, T. M.; Bernardinelli, G.
Tetrahedron Lett. 1988, 29, 5885e5888.
18. Relatively lower yield observed in the reaction with the higher order cup-
rate can be partly due to cleavage of chiral auxiliary by a small amount of
MeLi remaining in the reaction media.
5. Vasbinder, M. M.; Jarvo, E. R.; Miller, S. J. Angew. Chem., Int. Ed. 2001,
40, 2824e2827.
6. XaaePro type isosteres: (a) Sasaki, Y.; Niida, A.; Tsuji, T.; Shigenaga, A.;
Fujii, N.; Otaka, A. J. Org. Chem. 2006, 71, 4969e4979 and references
cited therein.
19. Although the exact mechanism of the described reductive defluorination is
unclear at this stage, single electron transfer from an organocopper to the
substrate is responsible for the observed results.12d,14,15
7. Fluoroalkene isosteres: (a) Abraham, R. J.; Ellison, S. L. R.; Schonholzer,
P.; Thomas, W. A. Tetrahedron 1986, 42, 2101e2110; (b) Allmendinger,
20. (a) Tardella, P. A. Tetrahedron Lett. 1969, 10, 1117e1120; (b) Nishiyama,
H.; Sakuta, K.; Itoh, K. Tetrahedron Lett. 1984, 25, 223e226; (c)
Nishiyama, H.; Sakuta, K.; Itoh, K. Tetrahedron Lett. 1984, 25, 2487e
2488; (d) Suzuki, M.; Yanagisawa, A.; Noyori, R. J. Am. Chem. Soc.
1985, 107, 3348e3349; (e) Suzuki, M.; Yanagisawa, A.; Noyori, R.
J. Am. Chem. Soc. 1988, 110, 4718e4726.
T.; Felder, E.; Hungerbuhler, E. Tetrahedron Lett. 1990, 31, 7301e7304;
¨
(c) Boros, L. G.; De Corte, B.; Gimi, R. H.; Welch, J. T.; Wu, Y.; Hand-
schumacher, R. E. Tetrahedron Lett. 1994, 35, 6033e6036; (d) Bartlett,
P. A.; Otake, A. J. Org. Chem. 1995, 60, 3107e3111; (e) Welch, J. T.;
Lin, J. Tetrahedron 1996, 52, 291e304; (f) Van der Veken, P.; Senten,
21. A trace amount of g-alkylated regioisomer was observed by RP-HPLC.
22. Fluoroalkene compounds obtained in this study have coupling constants in
a range of JHF¼35.2e37.8 Hz. These values are consistent with those of
`
´
K.; Kertesz, I.; Meester, I. D.; Lambeir, A.-M.; Maes, M.-B.; Scharpe,
S.; Haemers, A.; Augustyns, K. J. Med. Chem. 2005, 48, 1768e1780;
(g) Dutheuil, G.; Couve-Bonnaire, S.; Pannecoucke, X. Angew. Chem.,
Int. Ed. 2007, 46, 1290e1292; (h) Narumi, T.; Tomita, K.; Inokuchi, E.;
Kobayashi, K.; Oishi, S.; Ohno, H.; Fujii, N. Org. Lett. 2007, 9, 3465e
3468.
compounds possessing (Z)-fluoroolefin units. See: Waschusch, R.; Carran,
¨
J.; Savignac, P. Tetrahedron 1969, 52, 14199e14216.
23. See supplementary data, and Ibuka, T.; Habashita, H.; Funakoshi, S.; Fujii,
N.; Baba, K.; Kozawa, M.; Oguchi, Y.; Uyehara, T.; Yamamoto, Y. Tetra-
hedron: Asymmetry 1990, 1, 389e394.
8. Wipf, P.; Henninger, T. C.; Geib, S. J. J. Org. Chem. 1998, 63, 6088e
6089.
24. Fujii, N.; Oishi, S.; Hiramatsu, K.; Araki, T.; Ueda, S.; Tamamura, H.;
Otaka, A.; Kusano, S.; Terakubo, S.; Nakashima, H.; Broach, J. A.; Trent,
J. O.; Wang, Z.; Peiper, S. C. Angew. Chem., Int. Ed. 2003, 42, 3251e3253.
25. Cavelier, F.; Enjalbal, C. Tetrahedron Lett. 1996, 37, 5131e5134.
26. Williams, R. M.; Cao, J.; Tsujishima, H. Angew. Chem., Int. Ed. 2000, 39,
2540e2544.
9. Bondi, A. J. Phys. Chem. 1964, 68, 441e451.
10. (a) Howard, J. A. K.; Hoy, V. J.; O’Hagan, D.; Smith, G. T. Tetrahedron
1996, 52, 12613e12622; (b) O’Hagan, D.; Rzepa, H. S. Chem. Commun.
1997, 645e652; (c) Plenio, H. Chem. Rev. 1997, 97, 3363e3384; (d)
Hiyama, T.; Kanie, K.; Kusumoto, T.; Morizawa, Y.; Shimizu, M. Organo-
fluorine Compounds, Chemistry and Applications; Yamamoto, H., Ed.;
27. Fukuyama, T.; Cheung, M.; Kan, T. Synlett 1999, 1301e1303.

4346
T. Narumi et al. / Tetrahedron 64 (2008) 4332e4346
28. (a) Barlos, K.; Gatos, D.; Kallitsis, J.; Papaphotiu, G.; Sotiriu, P.; Wenqing,
Y.; Schafer, W. Tetrahedron Lett. 1989, 30, 3943e3946; (b) Barlos, K.; Ga-
29. (a) Shioiri, T.; Yamada, S. Chem. Pharm. Bull. 1974, 22, 849e854; (b)
Shioiri, T.; Yamada, S. Chem. Pharm. Bull. 1974, 22, 854e858; (c)
Shioiri, T.; Yamada, S. Chem. Pharm. Bull. 1974, 22, 859e863.
30. Miller, S. C.; Scanlan, T. S. J. Am. Chem. Soc. 1997, 119, 2301e
2302.
¨
tos, D.; Kapolos, S.; Papaphotiu, G.; Schafer, W.; Wenqing, Y. Tetrahedron
¨
Lett. 1989, 30, 3947e3950; (c) Barlos, K.; Gatos, D.; Kapolos, S.; Poulos,
C.; Schafer, W.; Wenqing, Y. Int. J. Pept. Protein Res. 1991, 38, 555e561.
¨