Stereoselective construction of functionalized (Z)-fluoroalkenes directed to depsipeptide isosteres

Article abstract of DOI:10.1016/S0040-4039(02)01169-3

Cu(I)-mediated alkyl-transfer reaction of trialkylaluminum (R₃Al) with (E)- or (Z)-4,4-difluoro-5-hydroxyallylic alcohol derivatives proceeded in an SN′-type manner to give the corresponding 2-alkylated (Z)-4-fluoro-5-hydroxyhomoallylic alcohol

Full text of DOI:10.1016/S0040-4039(02)01169-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 5845–5847
Stereoselective construction of functionalized (Z)-fluoroalkenes
directed to depsipeptide isosteres
Midori Okada,a Yuko Nakamura,a Akio Saito,b Azusa Sato,a Hiroaki Horikawaa and
Takeo Taguchib,*
aTokyo Women’s Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
bTokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
Received 10 May 2002; revised 10 June 2002; accepted 14 June 2002
Abstract—Cu(I)-mediated alkyl-transfer reaction of trialkylaluminum (R3Al) with (E)- or (Z)-4,4-difluoro-5-hydroxyallylic
alcohol derivatives proceeded in an SN%-type manner to give the corresponding 2-alkylated (Z)-4-fluoro-5-hydroxyhomoallylic
alcohol derivatives with 2,5-syn- or 2,5-anti selectivity, respectively. Oxidation of the primary hydroxyl group of the product to
carboxylic acid was easily achieved without epimerization at the chiral centers. © 2002 Elsevier Science Ltd. All rights reserved.
Fluoroolefins (ꢀCFꢁCHꢀ) are considered to be ideal
mimics for amide bonds (ꢀCOꢀNHꢀ) due to the close
similarity of the steric and electronic properties.1 Con-
trary to these similarities, fluoroolefins should be non-
hydrolyzable bonds both chemically and enzymatically,
and the lack of rotational freedom of this bond is also
a different property from that of the amide bond. On
the basis of these unique properties, utilization of (Z)-
fluoroalkene dipeptide or depsipeptide isosteres as non-
hydrolyzable and/or conformationally restricted
replacements for the parent amide bonds has attracted
much attention in the field of medicinal chemistry (Fig.
1).2–5 For the synthesis of fluoroalkene dipeptide or
depsipeptide isosteres,2–5 there remains several prob-
lems to be solved with respect to the stereochemical
control of the Z-configuration of the fluoroolefin part
and the relative stereochemistry of the two chiral cen-
ters (2- and 5-positions), as well as the use of readily
obtainable starting material.
Recently, we have reported that a-alkylated (Z)-g-
fluoro-b,g-enoates 2 can be prepared from g,g-difluoro-
a,b-enoates 1 upon treatment with trialkylaluminum
(R3Al) and Cu(I) or through Me2CuLi-mediated reduc-
tive defluorination followed by a-alkylation with alkyl
halide (Scheme 1, a or b).6 As an alternative method for
the synthesis of 2 from 1, Otaka demonstrated the
utilization of organocopper reagents under reduction–
oxidative alkylation conditions (Scheme 1, c).7
Although these reactions proceed with complete Z
selectivity, low diastereoselectivity in each reaction is a
severe problem to be solved.
Further efforts were made to develop a highly stereose-
lective preparation of these compounds, and we found
that Cu(I)-mediated alkyl-transfer reaction of trialkyl-
aluminum (R3Al) with (E)-4,4-difluoro-5-hydroxyallylic
alcohol derivatives 3 provides the corresponding 2-alkyl-
ated 4-fluorohomoallylic alcohol derivatives 4 in a com-
pletely Z and 2,5-syn selective manner (Scheme 2). In
this paper, we report these promising results for the
preparation of (Z)-fluoroalkene depsipeptide isosteres
5.
Y
O
Y
O
a or b or c
R1
OEt
R1
OEt
F
F
R2
Figure 1. Displacement of amide bond by Z-fluoroolefin
F
2
1 Y= OH, NHAr, NHBoc, H
Z selective
non-diastereoselective
Keywords: fluoroolefin; difluoroallyl alcohol; trialkylaluminum;
cuprous iodide; depsipeptide.
* Corresponding author. Tel.: +81-426-76-3257; fax: +81-426-76-3257;
e-mail: taguchi@ps.toyaku.ac.jp
Scheme 1. Reagents and conditions: (a) R2 Al, CuI·2LiCl (for
3
Y=OH); (b) (1) Me2CuLi, (2) R2-X; (c) (1) [R2Cu], (2) O2.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01169-3

5846
M. Okada et al. / Tetrahedron Letters 43 (2002) 5845–5847
R23Al
OH
OH
OH
OH
F
a) or b) or c)
2
2
CuI•2LiCl
R1
5
OH
Ph
R1
Ph
5
OH
OH
THF, 0 °C
F
F
R2
R2
F
F
F
OH
4
3
3d
4 Z:E= >100: <1
3a R1=Ph
Z selective
2,5-syn selective
3b R1=PhCH2CH2
3c R1=PhCH2
Scheme 3. Reagents and conditions: (a) Me3Al, CuI·2LiCl, 22
h, 4a-1 53%, syn/anti=1/11; (b) Me2CuLi, 4 h, 4a-1 76%,
syn/anti=1/4.7; (c) i-Bu3Al, CuI·2LiCl, 22 h, 4a-2 30%, anti
only.
OH
O
2
R1
5
OH
R2
F
5
The reactivity and stereochemical outcome of Z-isomer
3d was compared with those of E-isomer 3a. The
results obtained are shown in Scheme 3. Reaction of
Z-isomer 3d under the similar conditions (Me3Al,
CuI·2LiCl, THF, 0°C, 22 h) proceeded more slowly
than that of E-isomer 3a to give the methylated 4-
fluorohomoallylic alcohol 4a-1 in moderate yield (53%)
along with the recovery of 3d (41%). The stereochem-
istry of the product thus obtained indicated that the
reaction proceeds in a highly Z-selective manner (Z/E
>100) and in a relatively high anti-selective manner
(syn/anti=1/11), opposite to that of E-isomer 3a
(Scheme 3). Using i-Bu3Al instead of Me3Al under
similar conditions, 3d gave the allylic substitution
product 4a-2, having Z-configuration and 2,5-anti rela-
tive stereochemistry, in 30% yield along with the recov-
ery of 3d (49%). As in the case of E-isomer 3a, reaction
of Z-isomer 3d with Me2CuLi proceeded with lower
diastereoselectivity (syn/anti=1/4.7) to give 4a-1 in 76%
yield (Scheme 3).
Scheme 2.
As the substrates, we chose both E- and Z-isomers of
4,4-difluoro-5-hydroxyallylic alcohol derivatives (3a–c8
and 3d9) to examine the reactivity and the stereochemi-
cal outcome in organocopper-mediated reactions to
convert to the 2-alkylated 4-fluorohomoallylic alcohol
derivative 4.
In Table 1, preliminary results of reactions of (E)-
difluoroallylic alcohols 3a–c with R2 CuLi (entries 8–
2
10) and R2 Al–CuI·2LiCl (entries 2–7) are shown.
Reaction of3 3a with Me2CuLi proceeded smoothly
(THF, 0°C, 2.5 h) to give the 2-methylated homoallylic
alcohol 4a-1 in high yield (90%) with relatively high Z
selectivity (Z/E=15), but with low diastereoselectivity
(syn/anti=2 for the Z isomer) (entry 8). Similar high Z
selectivity but almost no diastereoselectivity was
observed in the reactions of 3a or 3b with alkyllithium-
based copper reagents (entries 9 and 10). On the other
hand, when the reaction of (E)-difluoroallylic alcohols
3a–c was conducted using a combination of trialkylalu-
minum (R3Al, 5–10 equiv.) and CuI·2LiCl10(2.5 equiv.)
in THF at 0°C for 15–20 h, the desired 4-fluoro-5-
hydroxyhomoallylic alcohols 4a–c were obtained in
good to excellent yield (62–98%) with complete Z-selec-
tivity and 2,5-syn diastereoselectivity (entries 2–7).11 In
the absence of CuI·2LiCl, no reaction occurred upon
treating 3a with Me3Al resulting in the recovery of 3a
(entry 1). Thus, Cu(I) is a crucial additive for the
alkyl-transfer reaction of trialkylaluminum to
proceed.12,13
The results mentioned above indicated that using the E-
or Z-isomer of 4,4-difluoro-5-hydroxyallylic alcohol 3,
both the syn or anti isomers of 2-alkylated (Z)-4-fluoro-
5-hydroxyhomoallylic alcohol 4 are highly selectively
constructed by the reaction with R3Al and CuI·2LiCl,
although the product yield should be improved in the
case of the Z-isomer of 3.
Oxidation of the primary hydroxyl group of 4 to car-
boxylic acid can be achieved by Jones’ oxidation after
protection of the secondary hydroxyl group as its ace-
tate form to give the desired acid 5 (5a-1 in 53% and
Table 1. Reaction of (E)-difluoroallylic alcohol 3a–c with R2 Al-CuI·2LiCl or R2 CuLi
3
2
Entry
1
R1
Ph
Reagent
4
R2
Yield (%)a
Z/Eb
syn:antib,c
1
2
3
4
5
6
7
8
9
3a
Me3Al
4a-1
4a-1
4a-2
4b-1
4b-2
4c-1
4c-2
4a-1
4a-3
4b-1
Me
Me
i-Bu
Me
i-Bu
Me
i-Bu
Me
n-Bu
Me
0d
98
68
65
62
98
78
90
58
90
Me3Al, CuI·2LiCl
i-Bu3Al, CuI·2LiCl
Me3Al, CuI·2LiCl
i-Bu3Al, CuI·2LiCl
Me3Al, CuI·2LiCl
i-Bu3Al, CuI·2LiCl
Me2CuLi
\95
\95
\95
\95
\95
\95
15
\95:1
\95:1
\95:1
\95:1
\95:1
\95:1
2:1
3b
3c
3a
3b
PhCH2CH2
PhCH2
Ph
n-Bu2CuLie
13
11
1.1:1
1:1
10
PhCH2CH2
Me2CuLie
a Isolated yields.
b The ratio was determined by 1H and 19F NMR.
c For the Z-isomer.
d Recovery of 1a.
e Me3Al (2 equiv.) was added.

M. Okada et al. / Tetrahedron Letters 43 (2002) 5845–5847
5847
OH
OH
O
3. (a) Allemendinger, T.; Furet, P.; Hungerbuhler, E. Tetra-
hedron Lett. 1990, 31, 7297–7300; (b) Allemendinger, T.;
Felder, E.; Hungerbuhler, E. Tetrahedron Lett. 1990, 31,
7301–7304.
4. Bartlett, P. A.; Otake, A. J. Org. Chem. 1995, 60, 3107–
3111.
1) - 5)
2
2
R1
5
R1
5
OH
OH
Me
F
Me
5a-1 R1=Ph
F
4a-1 R1=Ph
4c-1 R1=PhCH2
5c-1 R1=PhCH2
5. (a) Welch, J. T.; Lin, J. Tetrahedron 1996, 52, 291–304;
(b) Lin, J.; Toscano, P. J.; Welch, J. T. Proc. Natl. Acad.
Sci. USA 1998, 95, 14020–14024.
Scheme 4. Reagents and conditions: (1) TBDMSCl, imidazole,
DMF; (2) Ac2O, Et3N, THF; (3) TBAF, THF; (4) CrO3,
H2SO4, acetone; (5) KOH, H2O–MeOH, then 10% HCl.
6. Okada, M.; Nakamura, Y.; Sato, A.; Horikawa, H.;
Saito, A.; Taguchi, T. Chem. Lett. 2002, 28–29.
7. (a) Otaka, A.; Watanabe, H.; Yukimasa, A.; Oishi, S.;
Tamamura, H.; Fujii, N. Tetrahedron Lett. 2001, 42,
5443–5446; (b) See also: Otaka, A.; Watanabe, H.; Mit-
suyama, E.; Yukimasa, A.; Tamamura, H.; Fujii, N.
Tetrahedron Lett. 2001, 42, 285–287.
8. (E)-Difluoroallylic alcohols 3a–c were prepared by
DIBAL reduction of the corresponding ester forms 1. See
Refs. 6 and 7.
5c-1 in 52% overall yield, respectively), without
detectable epimerization at the chiral centers (Scheme
4).
In conclusion, we have developed a completely stereose-
lective synthesis of (Z)- and 2,5-syn 2-alkyl-4-fluoro-5-
hydroxy-3-alkenoic acid through the Cu(I)-mediated
allylic substitution reaction of trialkylaluminum with
(E)-4,4-difluoro-5-hydroxyallylic alcohol derivative.
The present reaction should provide an efficient method
for the preparation of functionalized Z-fluoroolefins,
which, in particular, are applicable to the preparation
of depsipeptide isosteres. Investigation on the mecha-
nistic details of the present reaction is currently in
progress.
9. (Z)-Difluoroallylic alcohol 3d was prepared by a three-
step procedure: (1) indium-mediated reaction of 4-bromo-
4,4-difuoro-2-butyn-1-ol
TBDPS
ether
with
benzaldehyde; (2) hydrogenation (Pd–BaSO4, quinoline);
(3) TBAF, THF. For examples of indium-mediated
difluoropropargylation of aldehydes, see: (a) Wang, Z.;
Hammond, G. B. Tetrahedron Lett. 2000, 41, 2339–2342;
(b) Wang, Z.; Hammond, G. B. J. Org. Chem. 2000, 65,
6547–6552.
10. Lipshutz, B. H.; Segi, M. Tetrahedron 1995, 51, 4407–
4420.
Acknowledgements
11. Typical procedure (Table 1, entry 2): Under an argon
atmosphere, to a solution of 3a (1 mmol) in THF at 0°C
was added trimethylaluminum (5 mmol, 1 M hexane
solution). After stirring for 10 min, a 0.5 M THF solution
of CuI·2LiCl (2.5 mmol)10 was added and the reaction
mixture was stirred for 20 h at 0°C. Addition of 5% HCl
and extractive work-up gave the crude product, which
was purified by column chromatography (silica gel, hex-
ane–AcOEt 1:1) to give 4a-1 in 98% yield.
The authors thank Dr. Motoo Shiro of the Rigaku
Corporation for X-ray analysis of 4a-2 and 4c-2. This
work was partly supported by a Grant-in-Aid for Scien-
tific Research from the Ministry of Education, Culture,
Sports, Science and Technology of Japan.
References
12. Copper-catalyzed SN% substitution of allylic phosphates
and chlorides with trialkylaluminum was reported, see:
Fleming, S.; Kabbara, J.; Nickish, K.; Westermann, J.;
Mohr, J. Synlett 1995, 183–185.
1. (a) Abraham, R. J.; Ellison, S. L. R.; Schonholzer, P.;
Thomas, W. A. Tetrahedron 1986, 42, 2101; (b) Cieplak,
P.; Kollman, P. A. J. Comput. Aided Mol. Des. 1993, 7,
291–304; (c) Hann, M. M.; Sammes, P. G.; Kennewell, P.
D.; Taylor, J. B. J. Chem. Soc., Perkin Trans. 1 1982,
307.
2. (a) Allemendinger, T.; Felder, E.; Hungerbuhler, E. In
Selective Fluorination in Organic and Bioorganic Chem-
istry; Welch, J. T., Ed.; ACS Symposium Series 456;
ACS: Washington, DC, 1991; pp. 186–195; (b) Welch, J.
T.; Lin, J.; Boros, L. G.; DeCorte, B.; Bergmann, K.;
Gimi, R. In Biomedical Frontiers of Fluorine Chemistry;
Ojima, I.; McCarthy, J. R.; Welch, J. T., Eds.; ACS
Symposium Series 639; ACS: Washington, DC, 1996; pp.
129–142.
13. Copper-mediated conjugate additions of trialkylalu-
minum with enones were reported. See: (a) Kabbara, J.;
Fleming, S.; Nickisch, K.; Neh, H.; Westermann, J. Tet-
rahedron 1995, 51, 743–754; (b) Takemoto, Y.; Kuraoka,
S.; Hamaue, N.; Aoe, K.; Hiramatsu, H.; Iwata, C.
Tetrahedron 1996, 52, 14177–14188; (c) Benett, S. M. W.;
Brown, S. M.; Muxworthy, J. P.; Woodward, S. Tetra-
hedron Lett. 1999, 40, 1767–1770; (d) Pamies, O.; Net, G.;
Ruiz, A.; Claver, C.; Woodward, S. Tetrahedron: Asym-
metry 2000, 11, 871–877; (e) Kraus, N.; Hoffmann-
Ro¨der, A. Synthesis 2001, 171–196.