A novel one-pot reaction involving organocopper-mediated reduction/transmetalation/asymmetric alkylation, leading to the diastereoselective synthesis of functionalized (Z)-fluoroalkene dipeptide isosteres

Article abstract of DOI:10.1039/b608596b

By a novel one-pot reaction sequence involving consecutive organocopper-mediated reduction, transmetalation and asymmetric alkylation, a highly diastereoselective synthesis of functionalized (Z)-fluoroalkene dipeptide isosteres was achieved in good to exc

Full text of DOI:10.1039/b608596b

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A novel one-pot reaction involving organocopper-mediated reduction/
transmetalation/asymmetric alkylation, leading to the
diastereoselective synthesis of functionalized (Z)-fluoroalkene dipeptide
isosteres{
Tetsuo Narumi,a Ayumu Niida,a Kenji Tomita,a Shinya Oishi,a Akira Otaka,ab Hiroaki Ohnoa and
Nobutaka Fujii*a
Received (in Cambridge, UK) 16th June 2006, Accepted 14th September 2006
First published as an Advance Article on the web 28th September 2006
DOI: 10.1039/b608596b
By a novel one-pot reaction sequence involving consecutive
organocopper-mediated reduction, transmetalation and asym-
metric alkylation, a highly diastereoselective synthesis of
functionalized (Z)-fluoroalkene dipeptide isosteres was
achieved in good to excellent yields.
Alkene-based dipeptide isosteres containing (E)-alkene or (Z)-
fluoroalkene units are thought to be potential dipeptide
mimetics.1,2 (Z)-Fluoroalkene dipeptide isosteres are structurally
similar to (E)-alkene dipeptide isosteres (EADIs), but differ in their
electrostatic nature, which plays a significant role in their intra-
and intermolecular interactions. Of note, due to the presence of the
highly electronegative fluorine substituent, (Z)-fluoroalkene dipep-
tide isosteres more faithfully resemble native peptides than do
EADIs. In this regard, there is increasing interest in the
development of efficient methodologies for the stereoselective
Fig. 1 Synthesis of (E)-alkene or (Z)-fluoroalkene dipeptide isosteres by
and divergent synthesis of (Z)-fluoroalkene isosteres.
a reduction/direct alkylation methodology.
The organocopper- or samarium diiodide (SmI2)-mediated
reduction of a,b-enoates, possessing leaving group(s) at the
c-position, is an effective methodology for the stereoselective
synthesis of (E)-olefins and (Z)-fluoroolefins.3,4 The dienolate
intermediates resulting from the reduction can be efficiently
trapped in situ by an appropriate electrophile, such as alkyl
halides, aldehydes and ketones. Recently, we have applied this
reduction/direct alkylation methodology to the synthesis of
a-alkylated (E)-alkene and (Z)-fluoroalkene dipeptide isosteres
(Fig. 1).5,6 Although this reduction/direct alkylation of the
difluoroenoate 1 is extremely useful for the regio- and stereo-
selective formation of the required (Z)-fluoroalkene unit, this
synthetic route has not addressed the stereoselective construction
of a-side chains. Since amino acids have a center of chirality, the
equivalent side chains must be introduced with high stereo-
selectivity into the peptide isosteres. Herein, we report the
diastereoselective synthesis of highly functionalized (Z)-fluoroalk-
ene dipeptide isosteres by a novel one-pot reaction sequence,
involving organocopper-mediated reduction, transmetalation and
asymmetric alkylation as the key steps.
The synthesis of the key intermediates, N-enoyl sultams 8 and 9,
is illustrated in Scheme 1. The a,a-difluoro-b-amino ester 76 was
reduced to an aldehyde and then subjected to Horner–
Wadsworth–Emmons-type coupling with (S)- or (R)-N-
diethoxyphosphonoacetylcamphorsultam7 to give N-enoyl sultam
8 or 9 in an E-selective manner.
Initially, we examined the organocopper- and SmI2-mediated
reduction of 8. Both reactions, using the Gilman reagent
(Me2CuLi?LiI?2LiBr at 278 uC for 30 min) and the cyano
aGraduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-
ku, Kyoto 606-8501, Japan. E-mail: nfujii@pharm.kyoto-u.ac.jp
bGraduate School of Pharmaceutical Sciences, The University of
Tokushima, Tokushima 770-8505, Japan
{ Electronic supplementary information (ESI) available: Experimental
procedures, spectral data and analytical data for 12a, and copies of 1H and
13C NMR spectra for all new compounds. See DOI: 10.1039/b608596b
Scheme 1 Synthesis of the substrate for one-pot organocopper-mediated
reduction/asymmetric alkylation.
4720 | Chem. Commun., 2006, 4720–4722
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Gilman reagent (Me2CuLi?LiCN?2LiBr at 278 uC for 30 min),
proceeded smoothly to yield the desired reduction product in 95
and 74% yields, respectively (Table 1, entries 1 and 2). Although
the electron-donating ability of higher order cuprate
(Me3CuLi2?LiI?3LiBr) is more effective than those of the Gilman
and cyano Gilman reagents,8 the reaction of 8 with higher order
cuprate (Me3CuLi2?LiI?3LiBr at 278 uC for 30 min) afforded the
reduction product in only a moderate yield (Table 1, entry 3). On
the other hand, reaction with SmI2,9 which is well-recognized as a
powerful one-electron reducing reagent,10 afforded only a mixture
of unidentified compounds (Table 1, entry 4). Based on these
results, we chose the Gilman reagent as our reducing reagent.
Next, we carefully examined trapping of the dienolate
intermediate with alkyl halides to construct the stereogenic center
at the a-position. Initial attempts to trap the Cu or Li dienolates of
intermediate 11a, derived from 8 by organocopper-mediated
reduction, with methyl iodide only furnished complex mixtures
(Scheme 2). This prompted us to use the more reactive tin
dienolate, which could be generated by the organocopper-
mediated reduction of 8, followed by treatment with triphenyltin
chloride and HMPA.11 Sequential reaction of 8 with Gilman
reagent, triphenyltin chloride/HMPA and methyl iodide selectively
afforded the a-methyl fluoroalkene isostere derivative (L-Val–
y[(Z)-CFLCH]–L-Ala) (12a) in 93% isolated yield with exclusive
Z-selectivity.{ The diastereoselectivity of this reaction proved to be
80%, which was confirmed by RP-HPLC analysis.
12c and 12d, respectively, in excellent yields (Table 2, entries 2 to 4).
The reaction with methyl 3-bromopropionate gave the reduction
product 10 with no alkylated product (Table 2, entry 5). Next, we
attempted to synthesize epimeric (L,D)-type isosteres in a similar
manner using (R)-sultam derivatives 9. The reaction with Gilman
reagent, followed by asymmetric alkylation via transmetalation,
proceeded smoothly to afford the corresponding (L,D)-
type a-substituted fluoroalkene isosteres 13a–13d in high
yields and with good to excellent diastereoselectivities (Table 2,
entries 6 to 9).
Finally, the chiral auxiliary of 12b was removed by hydrolysis
under basic conditions to give the Boc–L-Val–y[(Z)-CFLCH]–L-
Phe–OH isostere (14) in 75% yield with 96% de (Scheme 3). We
observed neither epimerization of the a-alkyl groups nor
isomerization of the double bond during cleavage of the chiral
auxiliary.§
In conclusion, we have developed
a novel and highly
diastereoselective one-pot synthesis of functionalized (Z)-fluor-
oalkene dipeptide isosteres. The utility of the newly developed
methodology can be found in the high-to-excellent regio- and
stereoselectivities upon construction of the (Z)-fluoroalkene unit
and a-side chain. Further studies using the developed methodology
on the synthesis and evaluation of bioactive peptides with
fluoroalkene isosteres are now in progress.
Table 2 Diastereoselective synthesis of functionalized (Z)-fluoroalk-
ene dipeptide isosteres by one-pot reduction/transmetalation/asym-
metric alkylation
In a similar manner, the use of benzyl bromide, tert-butyl
bromoacetate and allyl bromide stereoselectively gave the
corresponding a-substituted fluoroalkene dipeptide isosteres 12b,
Table 1 Organocopper- and SmI2-mediated reduction of N-enoyl
sultam 8
Entry
Reagent (equivalents)
Conditions
Yieldb (%)
Entry
Electrophiles
Substrate Productsa (%) deb (%)
1
2
3
4
Me2CuLi?LiIa (4)
Me2CuLi?LiCNa (4)
Me3CuLi2?LiIa (4)
SmI2 (6)
278 uC, 30 min
278 uC, 30 min
278 uC, 30 min
0 uC, 30 min
b
95
74
52
1
2
3
4
5
6
7
8
9
MeI
Bn–Br
8
8
8
8
8
12a (93)c
12b (93)c
12c (80)c
12d (99)c
10 (91)
80
95
.95
.95
—
c
—
t
BrCH2CO2 Bu
a
c
Allyl–Br
BrCH2CH2CO2Me
MeI
In the presence of Li salts (LiCl and/or LiBr). Isolated yield.
mixture of unidentified compounds was obtained.
A
10
10
10
10
13a (69)c
13b (77)c
13c (71)c
13d (79)c
91
90
94
92
Bn–Br
BrCH2CO2 Bu
Allyl–Br
t
a
c
b
Isolated yield. Determined by RP-HPLC of the purified products.
A trace amount of c-alkylated products was detected by RP-
HPLC.
Scheme 2 Diastereoselective synthesis of a L-Val-L-Ala-type (Z)-fluor-
oalkene isostere.
Scheme 3 Cleavage of the chiral auxiliary.
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We thank Dr Terrence R. Burke Jr., NCI, NIH, USA for
proofreading this manuscript. This research was supported in part
by 21st Century COE Program ‘Knowledge Information
Infrastructure for Genome Science’, a Grant-in-Aid for Scientific
Research from the Ministry of Education, Culture, Sports, Science
and Technology, Japan, the Japan Society for the Promotion of
Science (JSPS) and the Japan Health Science Foundation.
Notes and references
{ Fluoroalkene compounds obtained in this study have coupling constants
in the range JHF = 35.6–37.8 Hz. These values are consistent with those of
compounds possessing (Z)-fluoroolefin units.12
§ The absolute configurations of the alkyl groups at the a-position were
determined by circular dichroism measurements using an empirical rule
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4722 | Chem. Commun., 2006, 4720–4722
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