Enantioselective synthesis of β-fluoroamines from β-amino alcohols: Application to the synthesis of LY503430

Article abstract of DOI:10.1021/ol1019579

N,N-Dialkyl-β-amino alcohols were enantiospecifically and regioselectively rearranged by using N,N-diethylaminosulfur trifluoride (DAST) to give optically active β-fluoroamines in excellent yields and enantiomeric excesses. This rearrangement was applied to the enantioselective synthesis of LY503430, a potential therapeutic agent for Parkinson's disease.

Full text of DOI:10.1021/ol1019579

ORGANIC
LETTERS
2010
Vol. 12, No. 20
4620-4623
Enantioselective Synthesis of
ꢀ-Fluoroamines from ꢀ-Amino Alcohols:
Application to the Synthesis of
LY503430
Be´ranger Duthion, Domingo Gomez Pardo,* and Janine Cossy*
Laboratoire de Chimie Organique, ESPCI ParisTech, CNRS, 10 rue Vauquelin,
75231 Paris Cedex 05, France
domingo.gomez-pardo@espci.fr; janine.cossy@espci.fr
Received August 18, 2010
ABSTRACT
N,N-Dialkyl-ꢀ-amino alcohols were enantiospecifically and regioselectively rearranged by using N,N-diethylaminosulfur trifluoride (DAST) to
give optically active ꢀ-fluoroamines in excellent yields and enantiomeric excesses. This rearrangement was applied to the enantioselective
synthesis of LY503430, a potential therapeutic agent for Parkinson’s disease.
The introduction of a fluorine atom in organic molecules can
alter their physical, chemical, and biological properties.1
Because of the great importance of fluorinated compounds
as pharmaceuticals and agrochemicals, the development of
chiral fluorinating agents and enantioselective methods has
been increasing in the last decades.2,3
expansions through anchimeric assistance of an electron-rich
group present in the vicinity of a hydroxyl group.7
Few synthetic methods were developed to prepare linear
ꢀ-fluoroamines.8 Recently, organocatalytic fluorination of
aldehydes was used to access chiral ꢀ-fluoroamines.8c
However, only secondary ꢀ-fluoroamines were obtained with
good enantiomeric excesses. Here, we would like to report
a general enantioselective rearrangement of optically active
linear ꢀ-amino alcohols A to ꢀ-fluoroamines B using DAST
and its application to the synthesis of LY503430, a potential
therapeutic agent for Parkinson’s disease9 (Scheme 1).
Different fluorinating agents, among them, N,N-bis(2-
methoxyethyl)aminosulfur trifluoride (deoxo-fluor)4 and N,N-
diethylaminosulfur trifluoride (DAST)5 revealed powerful
reagents to transform alcohols to the corresponding monof-
luorinated products.6 The fluorination of optically active
alcohols by using these reagents proceeds in general with
inversion of configuration. Furthermore, these reagents can
induce rearrangements such as ring contractions or ring
(7) (a) Ferret, H.; De´champs, I.; Gomez Pardo, D.; Van Hijfte, L.; Cossy,
J. ARKIVOC 2010, Viii, 126–159. (b) Ye, C.; Shreeve, J. M. J. Fluorine
Chem. 2004, 125, 1869–1872. (c) De´champs, I.; Gomez Pardo, D.; Cossy,
J. Eur. J. Org. Chem. 2007, 4224–4234. (d) De´champs, I.; Gomez Pardo,
D.; Cossy, J. Synlett 2007, 263–267.
(1) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc.
ReV. 2008, 37, 320–330.
(8) (a) Verniest, G.; Van Hende, E.; Surmont, R.; De Kimpe, N. Org.
Lett. 2006, 21, 4767–4770. (b) Verniest, G.; Colpaert, F.; Van Hende, E.;
De Kimpe, N. J. Org. Chem. 2007, 72, 8569–8572. (c) Fadeyi, O. O.;
Lindsley, C. W. Org. Lett. 2009, 11, 943–946 and references cited therein.
(9) Murray, T. K.; Whalley, K.; Robinson, C. S.; Ward, M. A.; Hicks,
C. A.; Caroline, A.; Lodge, D.; Vandergriff, J. L.; Baumbarger, P.; Siuda,
E.; Gates, M.; Ogden, A. M. J. Pharmacol. Exp. Ther. 2003, 306, 752–
762.
(2) Cahard, D.; Xu, X.; Couve-Bonnaire, S.; Pannecoucke, X. Chem.
Soc. ReV. 2010, 39, 558–568
.
(3) Ma, J.-A.; Cahard, D. Chem. ReV. 2008, 108, PR1–PR43
.
(4) Lal, G. S.; Pez, G. P.; Pesaresi, R. J.; Prozonic, F. M.; Cheng, H. J.
Org. Chem. 1999, 71, 7048–7054.
(5) Middleton, W. J. J. Org. Chem. 1975, 40, 574–578.
(6) Singh, R. P.; Shreeve, J. M. Synthesis 2002, 17, 2561–2578.
10.1021/ol1019579  2010 American Chemical Society
Published on Web 09/17/2010

Interestingly, when amino alcohol 4 was treated with
DAST (1.1 equiv, THF, 1 h, 0 °C), fluoroamine 5 was
formed in 95% yield with no trace of its regioisomer
(Scheme 3). This result is certainly due to the presence
Scheme 1. General Scheme
Scheme 3. Rearrangement of 4
Our study started with the rearrangement of ꢀ-amino
alcohol 1. When this compound was treated with DAST (1.1
equiv) in THF at 0 °C, two fluoroamines 2 and 3 were formed
in a ratio 70/30 in 72% yield. To prove that an aziridinium
intermediate C was involved in the formation of 2 and 3,
amino alcohol 1′ was treated with DAST. After 1 h at 0 °C,
compounds 2 and 3 were obtained in a similar ratio (2/3 )
70/30) and in a similar yield (70%). These results suggest
that DAST can induce the formation of an aziridinium
intermediate C (Scheme 2).10
of the phenyl group which favored the attack of the
fluorine anion on the benzylic carbon of the aziridinium
intermediate D. This case is closely related to the
regioselective rearrangement of benzylic ester of N,N-
dibenzyl-L-serine induced by DAST.12 The (S)-configu-
ration of the tertiary center was determined after trans-
formation of 5 to 6 (thiosalicylic acid, Pd(dba)2, DPPB,
THF then HCl, 1 M)13 and comparison of the RD of 6
and (R)-6.14
Scheme 2. Rearrangement of 1 and 1′
Similarly, when amino alcohol 715 (ee ) 93%) was treated
with DAST (1.5 equiv, THF, 1 h, 0 °C), fluoroamine 11 was
isolated in 84% yield and with an enantiomeric excess of
91%. We have to point out that the regioisomer 11′ was not
detected. The configuration of the quaternary center was
determined after the transformation of 11 to 16. After
comparison of the RD of 16 and (S)-16′ described in the
literature,16 the (R) configuration was assigned to the
quaternary stereogenic center present in 16 (Scheme 4).
This rearrangement is general as amino alcohols 8-10
were transformed to 12-14 in excellent yields and with good
to excellent enantiomeric excesses17 (Table 1).
This enantioselective rearrangement can be explained by
the activation of the hydroxy group of aminoalcohol A by
DAST to produce intermediate E which is transformed to
aziridinium F by an SNi reaction. After selective attack of
the fluorine atom on the more substituted carbon of the
aziridinium, the fluoroamine B is formed (Scheme 5).
Furthermore, to prove that amines 2 and 3 were not formed
under thermodynamic control, ꢀ-fluoroamine 2 was treated
with DAST (1.1 equiv, 0 °C, 1 h). Under these conditions,
compound 2 was recovered quantitatively without any traces
of 3. This result proves that compounds 2 and 3 are not under
a thermodynamic equilibrium (via aziridinium C). Therefore,
this rearrangement is under kinetic control, and the attack
of the fluorine atom on aziridinium C leads to a mixture of
the rearranged ꢀ-fluoroamine 2 (attack a) and its regioisomer
3 (attack b) as described for the opening of aziridiniums by
fluoride anion.11
(11) (a) D’hooghe, M.; Catak, S.; Stankoviæ, S.; Waroquier, M.; Kim,
Y.; Ha, H.-J.; Van Speybroeck, V.; De Kimpe, N. Eur. J. Org. Chem. 2010,
4920–4931 and references cited therein. (b) Alvernhe, G.; Lacombe, S.;
Laurent, A. Tetrahedron Lett. 1980, 21, 289–292.
(12) Somekh, L.; Shanzer, A. J. Am. Chem. Soc. 1982, 104, 5836–5837.
(13) Lemaire-Audoire, S.; Savignac, M.; Geneˆt, J. P. Tetrahedron Lett.
1995, 36, 1267–1270.
(14) Hamman, S. J. Fluorine Chem. 1989, 45, 377–387.
(15) Smith, N. D.; Wohlrab, A. M.; Goodma, M. Org. Lett. 2005, 7,
255–258.
(16) Avenoza, A.; Busto, J. H.; Corzana, F.; Jime´nez-Ose´s, G.; Peregrina,
J. M. Chem. Commun. 2004, 980–981.
(10) Metro, T.-X.; Duthion, B.; Gomez Pardo, D.; Cossy, J. Chem. Soc.
ReV. 2010, 39, 89–102.
(17) Determined by supercritical fluid chromatography on the chiral
phase.
Org. Lett., Vol. 12, No. 20, 2010
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Scheme 4
.
Rearrangement of 7 and Chemical Correlation
Scheme 5. Mechanism of the Rearrangement
For our part, we have envisaged an enantioselective
synthesis of LY503430 from 4-hydroxy-D-phenylglycine 17
utilizing, as the key step, the enantioselective rearrangement
of amino alcohol 25 induced by DAST to produce the desired
fluoroamine 26 which will be the precursor of LY503430
(Scheme 6).
Table 1. Rearrangement of 8-10
Scheme 6. Retrosynthesis of LY503430
The synthesis of LY503430 started with 4-hydroxy-D-
phenylglycine 17 which was transformed to oxazolidinones
18/18′ in a ratio of 5/1 (ClCO2Me/NaOH, then PhCH(OMe)2,
BF3·OEt2, CH2Cl2, yield ) 68%), Scheme 7).19
After chromatography, 18 was isolated and converted to
the alkylated oxazolidinone 19 (LiHMDS, MeOTf, THF)
with a diastereomeric ratio superior to 95/5. After reduction
with L-Selectride, oxazolidinone 20 was formed in 74%
yield, with an enantiomeric excess of 97%.17 In order to
introduce the biaryl moiety, a Suzuki coupling was envis-
aged. Thus, 20 was transformed to triflate 21 (Tf2O, Py,
96%), and this latter was treated with the boronic acid 23
(2.0 equiv) in the presence of palladium(0) [Pd(OAc)2 (5
mol %), X-Phos (12.5 mol %), K3PO4·H2O (3.0 equiv), THF,
100 °C, 12 h, MW]20 to produce the desired coupling product
22 (80% yield). Compound 22 was then transformed to
a 2.2 equiv of DAST was used.
As the rearrangement of amino alcohols A induced by
DAST is enantioselective and regioselective, its application
to the synthesis of LY503430 was envisaged. LY503430 is
a potential therapeutic agent for Parkinson’s disease9 which
was prepared by Eli Lilly starting from 4-iodoacetophenone
and by using a diastereomeric salt resolution to introduce
the chirality.18
(18) Magnus, N. A.; Aikins, J. A.; Cronin, J. S.; Diseroad, W. D.; Hargis,
A. D.; Letourneau, M. E.; Parker, B. E.; Reutzel-Edens, S. M.; Schafer,
J. P.; Staszak, M. A.; Stephenson, G. A.; Tameze, S. L.; Zollars, L. M. H.
Org. Process Res. DeV. 2005, 9, 621–628.
(19) O’Donnell, M. J.; Fang, Z.; Ma, X.; Huffman, J. C. Heterocycles
1997, 46, 617–630.
(20) Nguyen, H. N.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc.
2003, 125, 11818–11819.
4622
Org. Lett., Vol. 12, No. 20, 2010

Scheme 7. Synthesis of LY503430
amino alcohol 25 in five steps. The first step was the
conversion of 22 into amino alcohol 24 (LiOH, EtOH/H2O
then SOCl2, MeOH, 74%) followed by its N,N-bis-allylation
(AllylBr, K2CO3, n-Bu4NI, MeCN, reflux), saponification of
the ester group (NaOH, 1 M, THF 1/1), and amidification
of the resulting carboxylic acid. Amino alcohol 25 was
obtained in 65% overall yield. The key transformation was
then realized by treating 25 with DAST (1.1 equiv) in THF
(0 °C, 1 h), and under these conditions, the fluoroamine 26
was isolated (87% yield) with an enantiomeric excess of
94%.17 In order to obtain LY503430, the amino group was
deprotected (thiosalicylic acid, Pd(dba)2, DPPB, THF,
88%),13 and then the sulfonylation of the resulting primary
amine 27 was achieved (i-PrSO2Cl, Et3N, DMAP, CH2Cl2,
τC ) 30%, corrected yield ) 73%). The spectroscopic data
as well as the RD [RD ) +27.7 (c 0.1, MeOH)] were in
perfect agreement with those previously reported in the
literature [RD ) +31.0 (c 1.0, MeOH)],18 demonstrating once
again that the rearrangement of ꢀ-amino alcohols induced
by DAST is highly enantioselective and regioselective
whatever the substituents on the quaternary carbon.
In conclusion, we have developed an enantioselective and
regioselective rearrangement of linear ꢀ-amino alcohols to
ꢀ-fluoroamines induced by DAST, and this rearrangement
can be used to synthesize biologically active compounds such
as LY503430.
Acknowledgment. Sanofi-Aventis is acknowledged for
financial support (grant to B.D.).
Supporting Information Available: General experimental
procedure and characterization data of compounds 2-27.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL1019579
Org. Lett., Vol. 12, No. 20, 2010
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