Diastereomeric fluoroolefins as peptide bond mimics prepared by asymmetric reductive amination of α-fluoroenones

Article abstract of DOI:10.1002/anie.200604246

(Chemical Equation Presented) Fluoropeptidomimetics: An efficient asymmetric reductive amination of fluoroenones has been developed that affords potential precursors of fluoropeptide isosteres. Stereoselective routes with different reductive agents provid

Full text of DOI:10.1002/anie.200604246

Communications
DOI: 10.1002/anie.200604246
Peptide Mimics
Diastereomeric Fluoroolefins as Peptide Bond Mimics Prepared by
Asymmetric Reductive Amination of a-Fluoroenones**
Guillaume Dutheuil, Samuel Couve-Bonnaire, and Xavier Pannecoucke*
Among the numerous peptide bond analogues, monofluori-
nated olefins are considered to be ideal mimics because of
their close steric and electronic similarities.[1] Moreover,
fluoroolefins are not affected by chemical or enzymatic
hydrolysis.[1c,d,2] Another important feature is the lack of
rotational freedom of this peptidic bond isostere:“transoid”
and “cisoid” conformation effects can be estimated sepa-
rately. Since the pioneering work of Allmendinger et al.,[2b]
useful synthetic methods have been developed to prepare
fluoroolefins as peptide bond analogues. These include
classical olefination reactions (aldol,[3] Horner–Wadsworth–
Emmons,[1d,4] and Peterson[5] reactions) and elegant defluori-
nation reactions.[6] Nevertheless, stereochemical control of
the fluoroalkene configuration as well as the chiral centers a
to the double bond are still important issues to be addressed.
In our project we proposed a stereoselective and mild
method to obtain both E and Z isomers of the dipeptide
mimics 3. Our strategy was based on an efficient Negishi-type
reaction with easily accessible bromofluoroalkenes,[7] allow-
ing us access to both Z and E fluoroenones 2 (Scheme 1).[8] At
this stage, we were interested in short sequences to transform
unsaturated ketones 2 into chiral allylic primary amines 3,
which are potential dipeptide mimics. To our knowledge, no
reductive aminations of a-fluoro a,b-unsaturated ketones 2
had been described. Moreover, there are only few examples
of either nonstereoselective[9] or asymmetric[10,11] amination
reactions of enones in the literature. Since our first attempts
as enantioselective reduction studies gave only moderate
results,[12] we turned our attention to diastereoselective
processes. Only two chiral agents have been used for the
diastereoselective reduction of enones : a-methylbenzylami-
ne[11a,b] and Ellmanꢀs sulfinamide.[11c] The facile deprotection
of the latter and the high diastereoselectivity induced by this
auxiliary prompted us to test this method.[11c,13] Herein we
report the first diastereoselective reductive amination of a-
fluoroenones 2 and their transformation into dipeptide
mimics.
Preliminary tests were made with the aromatic compound
2a. A one-pot procedure for sulfinyl imine synthesis[14] and
subsequent reduction was developed, and we obtained
compounds 4 in good yields and high diastereoselectivities
(Scheme 2, Table 1). When the imines were purified and
Scheme 2. Diastereoselective reductive amination of a-fluoro a,b-unsa-
turated ketones 2.
isolated before reduction, no significant change in the
diastereoselectivity was observed, indicating that the pres-
ence of Ti(OEt)4 does not affect the reduction process.
Different metal hydrides were tested for the reductive
amination of compound 2a. Common coordinating reagents
such as NaBH4, BH3, 9-borabicyclo[3.3.1]nonane (9-BBN),
and diisobutylaluminum hydride (DIBAL-H) furnished
amines 4a in yields up to 79% and with excellent diastereo-
selectivities of up to 97% de for the crude mixture (entries 1–
4, Table 1). It should be noted that in each case a single
chromatographic purification on silica gel afforded the almost
diastereomerically pure product (up to 99% de). When the
Ellman (S)-sulfinamide was used as a reagent and DIBAL-H
as the reducing agent, the resulting crystals of 4a displayed
the absolute S configuration at the created stereogenic center
(X-ray analysis).[15]
Scheme 1. Fluoroolefins 3 as amide mimics and the general synthetic
method developed.
[*] Dr. G. Dutheuil, Dr. S. Couve-Bonnaire, Prof. X. Pannecoucke
ECOFH, IRCOF, UMR CNRS 6014, INSA de Rouen
1 rue Tesniere, 76131 Mont Saint-Aignan (France)
Fax: (+33)2-3552-2962
E-mail: xavier.pannecoucke@insa-rouen.fr
[**] This research was supported financially by the Ministry of Education
and Research (doctoral fellowship to G.D.) and the Region Haute-
Normandie (PunchOrga Program).
At that stage, we postulated that modulations in the steric
bulk and in the electronic properties of the metal hydride
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
1290
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2007, 46, 1290 –1292

Angewandte
Chemie
Table 1: Diastereoselective reduction of fluoroenones 2.
We then tried to extend the method to aliphatic com-
Entry Fluoroenone 2[a]
Reducing
agent
4, Yield[b]
de[c,d]
pounds using DIBAL-H and L-Selectride as the reducing
agents. The phenylethyl derivative (Z)-2b and compound
=
(À788C)
NaBH4
(Z)-2c, a precursor of the Ala-Y[(Z)CF CH]-Gly dipeptide
mimic, gave good yields and excellent diastereoselectivities
(entries 8–11, Table 1). Very good results were also obtained
with compound (Z)-2d, a precursor of the Phe-Y[(Z)CF
1
2
3
4
5
6
7
(S,S,Z)-4a, 67
(S,S,Z)-4a, 48
(S,S,Z)-4a, 77
(S,S,Z)-4a, 79
(S,R,Z)-4a, 64 96 (70)
(S,R,Z)-4a, 72 97 (95)
(S,R,Z)-4a, 63 94 (79)
94 (89)
96 (93)
91 (89)
99 (97)
BH3
9-BBN[e]
DIBAL-H
LiBHEt3
L-Selectride
K-Selectride
=
CH]-Gly derivative, showing that an increase in the steric
hindrance of the ketimine moiety does not affect the
reduction (entries 12 and 13, Table 1)). The reduction process
applied to the cisoid peptide mimic precursor (E)-2c was not
affected by the double-bond geometry and led to excellent
results (entries 14 and 15, Table 1)). Lastly, we tested the
chiral precursor (Z)-2e and observed no mismatch effects for
the reduction process. Indeed, results were still good in terms
of yield (> 60%) and excellent in terms of diastereoselectivity
(up to 99% de). It should be noted that for all these
substrates, the reversal of stereoselectivity depending on the
reducing reagent was effective (see Table 1).
8
9
DIBAL-H
L-Selectride
(S,S,Z)-4b, 57 98 (96)
(S,R,Z)-4b, 46 99 (94)
10
11
DIBAL-H
L-Selectride
(S,S,Z)-4c, 65
(S,R,Z)-4c, 67
98 (95)
96 (95)
12
13
DIBAL-H
L-Selectride
(S,S,Z)-4d, 58 99 (98)
(S,R,Z)-4d, 57 99 (98)
In our ongoing project aimed to develop a general route to
peptidomimetics bearing the fluoroolefin isostere Y[CF
=
CH], we performed a three-step procedure—a double
deprotection step, protection of the amine group with an 9-
fluorenylmethyloxycarbonyl (Fmoc) moiety, and oxidation of
the alcohol to the carboxylic acid—to prepare dipeptide
mimics ready for automated synthesis (Scheme 3). Ala-Gly
14
15
DIBAL-H
L-Selectride
(S,S,E)-4c, 60
(S,R,E)-4c, 86
99 (96)
99 (98)
16
17
DIBAL-H
L-Selectride
(R,S,S,Z)-4e, 61 99 (96)
(R,S,R,Z)-4e,
99 (91)
62
[a] TBDPS=tert-butyldiphenylsilyl.[b] Yield of isolated product. [c] The de
values were determined from the 19F NMR spectra of isolated products.
[d] The de value of the crude product is given in brackets. [e] The reaction
was conducted at 08C and yielded an inseparable mixture of 9-BBN
derivative and 4. The yield of 4 given (77%) is estimated.
Scheme 3. Synthesis of dipeptide analogues. Fmoc-OSu =9-fluorenyl-
methyloxycarbonyl-N-hydroxysuccinimide.
could lead to a reversal of the diastereofacial selectivity, like
that described by Ellman and Kochi.[16] Such variations in the
stereochemical outcome of the addition of carbon nucleo-
philes to sulfinyl imines[17] and reduction of tert-butanesulfinyl
imine bearing a hydroxy group in b position[18] have already
been reported. Indeed, with poorly coordinating and bulky
reagents such as LiBHEt3, L-Selectride, and K-Selectride, the
opposite (R) stereomer could be obtained in yields of up to
72% and diastereoselectivities of up to 95% de for crude
mixtures and up to 97% de for purified products (entries 5–7,
Table 1). In the course of our study a similar reversal of
diastereofacial selectivity was described by Andersen et al.
for the reduction of ketone-derived sulfinyl imines.[19] To
explain their results, they postulated different transition states
depending on the nature of the reducing agent. The same
approach can be applied to our compounds:a six-membered-
ring transition state should be favored by chelation of the
metal hydride to the sulfoxyde moiety, allowing the hydride
delivery to occur at the Si face. When bulkier and non-
coordinating reagents are employed, steric control and the
classical Cramꢀs rule could explain the generation of the
opposite stereomer.[17–19]
and Phe-Gly peptidomimetics were obtained in 71% and
43% overall yields, respectively. The Ala-Ala peptide mimic
was generated in a lower 22% overall yield as a result of less
effective deprotection and Fmoc protection steps. Finally,
three dipeptide mimics were synthesized in a chiral manner:
=
=
Fmoc-Ala-Y[(Z)CF CH]-Gly,
Fmoc-Ala-Y[(Z)CF CH]-
=
Ala, and Fmoc-Phe-Y[(Z)CF CH]-Gly.
In summary, we have reported the first efficient asym-
metric reductive amination of fluoroenones to give potential
fluoropeptide isosteres precursors. Using different reducing
agents, we developed stereoselective routes to both diaste-
reomers from the same chiral nonracemic sulfinyl imine. The
method could be applied to aromatic as well as aliphatic
compounds without erosion of yields and stereoselectivities.
Moreover, neither the fluoroolefin geometry nor the presence
of chiral center on the C-terminal moiety affected the
reduction selectivity. Finally, we applied this methodology
to the synthesis of three chiral dipeptide analogues:Fmoc-
Angew. Chem. Int. Ed. 2007, 46, 1290 –1292
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
1291

Communications
=
=
Gen, Eur. J. Org. Chem. 2001, 911 – 918; c) S. Sano, R. Teranishi,
Y. Nagao, Tetrahedron Lett. 2002, 43, 9183 – 9186.
[5] a) J. T. Welch, J. Lin, Tetrahedron 1996, 52, 291 – 304, and
references therein; b) N. Asakura, Y. Usuki, H. Lio, J. Fluorine
Chem. 2003, 124, 81.
Ala-Y[(Z)CF CH]-Gly, Fmoc-Ala-Y[(Z)CF CH]-Ala, and
=
Fmoc-Phe-Y[(Z)CF CH]-Gly.
Experimental Section
[6] For recent papers see:a) T. Narumi, K. Tomita, A. Otaka, H.
General procedure for the conversion of fluoroenones 2 into fluoro-
tert-butylsulfinamides 4:A solution of 0.5 m Ti(OEt)4 (2 equiv), (S)-
tert-butylsulfinylamine (2 equiv), and fluoroenone 2 (1 equiv) in dry
THF was prepared under argon and heated to reflux for 2 h. The
mixture was allowed to cool to room temperature and then cooled to
À788C. DIBAL-H (1m in toluene, 4 equiv) was then added dropwise,
and the mixture was stirred for 1 h. After the reaction was complete
(19F NMR spectrum of the reaction mixture was monitored), MeOH
was added at À788C. The mixture was then allowed to warm to room
temperature. The resulting solution was then poured into an equal
volume of brine with rapid stirring. The resulting suspension was then
filtered through a plug of Celite, and the filter cake was washed with
EtOAc. The filtrate was washed with brine, the organic layer was
separated, and the aqueous layer was extracted twice with EtOAc.
The combined organic portions were dried, filtered, and concentrated
under reduced pressure. The residue was then purified by chroma-
tography on silica gel (EtOAc/cyclohexane 1:1), affording the desired
tert-butylsulfinamide 4.
Ohno, N. Fujii, Chem. Commun. 2006, 4720 – 4722
, and
references therein; b) Y. Nakamura, M. Okada, M. Koura, M.
Tojo, A Saito, A. Sato, T. Taguchi, J. Fluorine Chem. 2006, 127,
627 – 636, and references therein.
[7] a) X. Lei, G. Dutheuil, X. Pannecoucke, J.-C. Quirion, Org. Lett.
2004, 6, 2101 – 2104; b) G. Dutheuil, X. Lei, X. Pannecoucke, J.-
C. Quirion, J. Org. Chem. 2005, 70, 1911 – 1914.
[8] G. Dutheuil, C. Paturel, X. Lei, S. Couve-Bonnaire, X. Panne-
coucke, J. Org. Chem. 2006, 71, 4316 – 4319.
[9] a) H. G. Brünker, W. Adam, J. Am. Chem. Soc. 1995, 117, 3976 –
3982; b) A. F. Abdel-Magrid, K. G. Carson, B. D. Harris, C. A.
Maryanoff, R. D. Shah, J. Org. Chem. 1996, 61, 3849 – 3862;
c) B. C. Ranu, A. Majee, A. Sarkar, J. Org. Chem. 1998, 63, 370 –
373; d) F. Palacios, D. Aparicio, J. Garcia, E. Rodriguez, Eur. J.
Org. Chem. 1998, 1413 – 1423.
[10] For enantioselective processes:a) R. O. Hutchins, S. J. Rao, J.
Adams, M. K. Hutchins, J. Org. Chem. 1998, 63, 8077 – 8080;
b) M. C. Hansen, S. L. Buchwald, Org. Lett. 2000, 2, 713 – 715;
c) K. A. Nolin, R. W. Ahn, D. Toste, J. Am. Chem. Soc. 2005, 127,
12462 – 12463.
[11] For diastereoselective processes:a) G. Bringmann, J.-P. Geisler,
Synthesis 1989, 608; b) C. Cimarelli, G. Palmieri, Tetrahedron:
Asymmetry 2000, 11, 2555 – 2563; c) J. A. Ellman, T. D. Owens,
T. P. Tang, Acc. Chem. Res. 2002, 35, 984.
[12] G. Dutheuil, L. Bailly, S. Couve-Bonnaire, X. Pannecoucke, J.
Fluorine Chem. 2007, 128, 34 – 39.
[13] G. Borg, D. A. Cogan, J. A. Ellman, Tetrahedron Lett. 1999, 40,
6709 – 6712.
[14] G. Liu, D. A. Cogan, T. D. Owens, T. P. Tang, J. A. Ellman, J.
Org. Chem. 1999, 64, 1278 – 1284.
[15] CCDC-623383 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.ca-
m.ac.uk/data_request/cif.
[16] T. Kochi, J. A. Ellman, J. Am. Chem. Soc. 2004, 126, 15652 –
15653.
[17] a) N. Plobeck, D. Powell, Tetrahedron: Asymmetry 2002, 13,
303 – 310; b) B. Z. Lu, C. Senanayake, N. Li, Z. Han, R. P.
Bakale, S. A. Wald, Org. Lett. 2005, 7, 2599 – 2602.
[18] a) T. Kochi, T. P. Tang, J. A. Ellman, J. Am. Chem. Soc. 2002, 124,
6518 – 6519; b) T. Kochi, T. P. Tang, J. A. Ellman, J. Am. Chem.
Soc. 2003, 125, 11276 – 11282.
Received:October 17, 2006
Published online:January 5, 2007
Keywords: asymmetric synthesis · fluoroenones · fluoroolefins ·
.
peptidomimetics · reductive amination
[1] a) J. J. Urban, B. G. Tillman, W. A. Cronin, J. Phys. Chem. A
2006, 110, 11120 – 11129, and references therein; b) N. Asakura,
Y. Usuki, H. Iio, T. Tanaka, J. Fluorine Chem. 2006, 127, 800 –
808; c) K. Zhao, D. S. Lim, T. Funaki, J. T. Welch, Bioorg. Med.
Chem. 2003, 11, 207 – 215; d) P. van der Veken, K. Senten, I.
Kert›sz, I. De Meester, A.-M. Lambeir, M.-B. Maes, S. ScharpØ,
A. Haemers, K. Augustyns, J. Med. Chem. 2005, 48, 1768 – 1780.
[2] a) T. Allmendinger, P. Furet, E. Hungerbühler, Tetrahedron Lett.
1990, 31, 7297 – 7300; b) T. Allmendinger, E. Felder, E. Hunger-
bühler, Tetrahedron Lett. 1990, 31, 7301 – 7304; c) L. G. Boros, B.
De Corte, R. H. Gimi, J. T. Welch, Y. Wu, R. E. Handschu-
macher, Tetrahedron Lett. 1994, 35, 6033 – 6036.
[3] P. A. Bartlett, A. Otake, J. Org. Chem. 1995, 60, 3107 – 3111.
[4] For examples:a) J. R. McCarthy, D. P. Matthews, D. M. Stemer-
ick, E. W. Huber, P. Bey, B. J. Lippert, R. D. Snyder, P. S.
Sunkara, J. Am. Chem. Soc. 1991, 113, 7439 – 7440; b) J. H.
Van Steenis, P. W. S. Boer, H. A. van der Hoeven, A. van der
[19] J. T. Colyer, N. G. Andersen, J. S. Tedrow, T. S. Soukup, M. M.
Faul, J. Org. Chem. 2006, 71, 6859 – 6862.
1292
www.angewandte.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2007, 46, 1290 –1292