Enantioselective synthesis of α-fluorinated β2-amino acids

Article abstract of DOI:10.1021/ol703045z

A methodology for the enantioselective synthesis of α-fluorinated β²-amino acids has been developed from readily available carboxylic acids 3. Conversion to the Evan's oxazolidinone followed by enantioselective fluorination and alkylation gave 7 in high diastereomeric excess (>95%). Subsequent removal of the oxazolidinone and amination at the Bn-protected hydroxyl center gave optically active α-fluorinated β²-amino acids.

Full text of DOI:10.1021/ol703045z

ORGANIC
LETTERS
2008
Vol. 10, No. 5
885-887
Enantioselective Synthesis of
-Fluorinated
2-Amino Acids
r
â
Michael K. Edmonds,† Florian H. M. Graichen,‡ James Gardiner,§ and
|
Andrew D. Abell*,
School of Applied Science, Christchurch Polytechnic Institute of Technology,
Christchurch, New Zealand, Department of Chemistry, UniVersity of Canterbury,
Christchurch, New Zealand, Eidgeno¨ssische Technische Hochschule, Zurich,
Switzerland, and School of Chemistry and Physics, UniVersity of Adelaide, Australia
andrew.abell@adelaide.edu.au
Received December 19, 2007
ABSTRACT
A methodology for the enantioselective synthesis of
3. Conversion to the Evan’s oxazolidinone followed by enantioselective fluorination and alkylation gave 7 in high diastereomeric excess
r-fluorinated â
2-amino acids has been developed from readily available carboxylic acids
(>95%). Subsequent removal of the oxazolidinone and amination at the Bn-protected hydroxyl center gave optically active
amino acids.
r -
-fluorinated â2
The incorporation of fluorine into a peptide or protein is
known to influence its conformation and biological activity.
This can then provide fundamental insights into protein
structure and function.1,2 For example, synthetic analogues
of collagen, which contain a fluorinated proline analogue
(Flp) in place of hydroxyproline, show remarkable stability.3,4
This strongly suggests that the stability of natural collagen
is due to electronic effects rather than hydrogen bonding, as
had been previously thought. In addition, recent reports by
O’Hagan et al.5,6 suggest that a fluorine suitably positioned
in an amide, either R to the carbonyl or â to the N-H bond,
stabilizes anti and gauche geometries, respectively. This
phenomenon has been put to good effect by Seebach et al.2
with the preparation of 2 and its incorporation (in place of
1) into an oligo â-peptide to disrupt an inherent 314 helix
structure (Figure 1).
Figure 1. â-Amino acids.
† Christchurch Polytechnic Institute of Technology.
‡ Postdoctoral Fellow with Prof. Andrew Abell, University of Canterbury.
§ Postdoctoral fellow with Prof. Dr. Dieter Seebach, ETH Zu¨rich, 2004-
2007.
| University of Adelaide.
While much is known about the influence of â amino
acids7 of type 1 (and hence 2) on conformational preferences
of â-peptides,8-10 the alternative â2 amino acids7 have
received less attention, partly due to difficulties in accessing
(1) Ja¨ckel, C.; Koksch, B. Eur. J. Org. Chem. 2005, 4483.
(2) Mathad, R. I.; Gessier, F.; Seebach, D.; Jaun, B. HelV. Chim. Acta
2005, 266.
(3) Barth, D; Milbradt, A. G.; Renner, C.; Moroder, L. ChemBioChem
2004, 5 79.
(4) Hodges, J. A.; Raines, R. T. J. Am. Chem. Soc. 2003, 125, 9262.
(5) Briggs, R. S.; O’Hagan, D.; Howard, J. A. K.; Yufit, D. S. J. Fluorine
Chem. 2003, 119, 9.
(6) Schu¨ler, M.; O’Hagan, D.; Slawin, A. M. Z. Chem. Commun. 2005,
4324.
(7) â3- and â2-amino acids possess an extra carbon between the CdO/
R-C and R-C/N groups of a natural R-amino acid, respectively.
(8) Seebach, D.; Matthews, J. L. J. Chem. Soc., Chem. Commun. 1997,
21, 2105.
10.1021/ol703045z CCC: $40.75
© 2008 American Chemical Society
Published on Web 01/31/2008

them.11-14 However, the comparatively few reports available
do reveal that oligomers derived from â2 amino acids produce
important and unusual structural motifs.15,16 Given this, and
Seebach’s work on fluorinated â3 amino acids, we now report
the first synthesis of R-fluorinated â2 amino acids for use in
defining the conformation of â-peptides containing them.17
Our methodology has been used to prepare 13a and 13b in
high enantiomeric excess, with 13a being converted to the
N-protected free acids 14a and 15a for use in peptide
synthesis.
Scheme 1. Establishing a Fluorinated Chiral Center
The incorporation of fluorine at the 2 position of â2 amino
acids provided a significant synthetic challenge. Direct
fluorination of â2 amino acids was problematic due to the
steric constraints involved in fluorinating an already crowded
tertiary substituted C-2 center. Consequently, it was decided
that fluorination of suitable 3-substituted propanoic acids
(where the 3-substituent becomes the side chain of the amino
acid), followed by introduction of a CH2NH2 group at the
2-position, would be the best approach. 3-Phenylpropanoic
acid 3a and 3-cyclohexylpropanoic acid 3b were selected
as starting materials for the development of this methodology
to prepare â2 amino acids with both “natural” (phenyl) and
“unnatural” (CH2-cyclohexyl) side chains (Schemes 1 and
2) and to access important examples for use in defining
â-peptide structure.17
The phenyl 3-substituted propanoic acid 3a (Scheme 1)
was converted to the corresponding acid chloride, and this
was reacted with the anion of (4S)-4-benzyl-2-oxazolidinone
to give oxazolidinone 4a in high yield. Subsequent fluorina-
tion by reaction with LDA and N-fluorobenzenesulfonimide
approach was necessary. To this end, alkylation of the sample
of 5a with TiCl4, Pr2Et, and benzyl chloromethyl ether as
the alkylating agent gave 7a in 70% yield and >95% de (as
determined by 1H and 19F NMR), where the benzyl-protected
hydroxylmethyl group is suitable for subsequent conversion
into the desired amine functionality (Scheme 2).
i
1
(NFBS) gave 5a in >90% de (determined by H and 19F
NMR) and in a yield of 79%. Separation of 5a from the
small amount of diastereomer 6a was not necessary given
the next step involved formation and alkylation of a prochiral
enolate intermediate.
Scheme 2. Synthesis of R-Fluorinated â2-Amino Acids
The direct addition of a CH2NHZ group to nonfluorinated
analogues of 5a has been reported using MeOCH2NHZ as
an alkylating reagent.14 However, this approach was unsuc-
cessful in our system, perhaps due to deactivation of the
intermediate enolate by the electronegative fluorine atom.
In support, other alkylating reagents including CH3I and CH3-
OCH2I were also unreactive toward the anion derived from
5, a result consistent with literature reports.18 Hence, a new
(9) Seebach, D.; Beck, A. K.; Bierbaum, D. J. Chem. BiodiVers. 2004,
1, 1111.
(10) Cheng, R. P.; Gellman, S. H.; DeGrado, W. F. Chem. ReV. 2001,
101, 3219.
(11) Moumne, R.; Lelais, G.; Seebach, D. Biopolymers 2004, 76, 206.
(12) Chi, Y. G.; Denise, B.; Guitot, K.; Rudler, H.; Lavielle, S.; Karoyan.
P. Eur. J. Org. Chem. 2007, 12, 1912.
(13) Gellman, S. H. J. Am. Chem. Soc. 2006, 128, 6804.
(14) Seebach, D.; Schaeffer, L.; Gessier, F.; Bindscha¨dler, P.; Ja¨ger, C.;
Josien, D.; Lelais, G.; Kopp, S.; Mahajan, Y. R.; Micuch, P.; Sebesta, R.;
Schweizer, B. W. HelV. Chim. Acta 2003, 86, 1852.
(15) Gessier, F.; Noti, C.; Rueping, M.; Seebach, D. HelV. Chim. Acta
2003, 86, 1862.
(16) Takeuchi, Y.; Nabetani, M.; Takagi, K.; Hagi, T.; Koizumi, T. J.
Chem. Soc., Perkin Trans. 1 1991, 49.
(17) Mathad, R. I.; Jaun, B.; Flo¨gel, O.; Lo¨weneck, M.; Gardiner, J.;
Seebach, D.; Graichen, F. H. M; Edmonds, M. K.; Abell, A.D. HelV. Chim.
Acta 2007, 90, 2251.
(18) Less, S. L.; Handa, S.; Millburn, K.; Leadlay, P. F.; Dutton, C. J.;
Staunton, J. Tetrahedron Lett. 1996, 37, 3515.
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Org. Lett., Vol. 10, No. 5, 2008

Treatment of 7a with LiOOH (generated in situ) removed
the bulky oxazolidinone chiral auxiliary to give the free acid
8a.19 Esterification of this acid, using TMSCl in MeOH, then
gave methyl ester 9a. The benzyl group of 9a was removed
by hydrogenation (Scheme 2) to give the free alcohol 10a,
which was converted to tosylate 11a in good yield on
treatment with tosyl chloride, Et3N, and DMAP. Reaction
of the tosylate 11a with NaN3 gave the azide 12a. Hydro-
genation then gave the free amine, which was N-Boc-
protected by in situ reaction with the (Boc)2O to give 13a,
an R-fluorinated â2-analogue of phenylalanine. The cyclo-
hexyl-substituted â2 amino acid 13b was similarly prepared
in high enantiomeric excess (>95%) from 3b (see Schemes
1 and 2).
phase synthesis. The incorporation of 15a into a â-heptapep-
tide and its effect on molecular conformation is discussed
elsewhere.17
In conclusion, we present the first synthesis of R-fluori-
nated â2-amino acids suitable for incorporation into â-pep-
tides by either solution or solid-phase chemistry. Ongoing
work is directed at applying this methodology to a wide range
of natural and unnaturally substituted R-fluorinated â2-amino
acids as well as investigating the structure and properties of
â-peptides containing these units.17
Acknowledgment. This research was supported, in part,
by the New Zealand Marsden Fund, the New Zealand
Foundation for Research, Science and Technology, and the
Australian Research Council. J.G. was supported by the New
Zealand Foundation for Research, Science & Technology,
Project No. SWSS0401.
Hydrolysis of the methyl ester of 13a with LiOH gave
the Boc-protected free acid 14a. Treatment with TFA
followed by N-(9H-fluoren-2-ylmethoxycarbonyloxy)suc-
cinimide (FmocOSu) gave the Fmoc-protected R-fluorinated
â2-analogue of phenylalanine 15a, which is suitable for solid-
Supporting Information Available: Experimental details
1
for all new compounds and copies of the H and 13C NMR
spectra for key new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
(19) Attempts to convert ozazolidinone protected 7a directly into the
desired amino acid were unsuccessful. As such, the large oxazolidinone
group was replaced with a smaller methyl ester to minimize unfavorable
steric interactions.
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