A new strategy for the synthesis of optically pure β-fluoroalkyl β-amino acid derivatives

Article abstract of DOI:10.1021/ol802733t

(Chemical Equation Presented) The first general approach for the diastereoselective formation of a variety of optically pure anti/β- fluoroalkyl β-amino acid derivatives is described. The process relies on the stereocontrolled reaction, mediated by a remo

Full text of DOI:10.1021/ol802733t

ORGANIC
LETTERS
2009
Vol. 11, No. 3
641-644
A New Strategy for the Synthesis of
Optically Pure ꢀ-Fluoroalkyl ꢀ-Amino
Acid Derivatives
Santos Fustero,*,†,‡ Carlos del Pozo,‡ Silvia Catala´n,‡ Jose´ Alema´n,§
Alejandro Parra,§ Vanesa Marcos,§ and Jose´ Luis Garc´ıa Ruano*,§
Departamento de Qu´ımica Orga´nica, UniVersidad de Valencia, E-46100 Burjassot, Spain,
Laboratorio de Mole´culas Orga´nicas, Centro de InVestigacio´n Pr´ıncipe Felipe, E-46012
Valencia, Spain, and Departamento de Qu´ımica Orga´nica (C-I), UniVersidad Auto´noma de
Madrid, Cantoblanco, 28049-Madrid, Spain
santos.fustero@uV.es; joseluis.garcia.ruano@uam.es
Received November 26, 2008
ABSTRACT
The first general approach for the diastereoselective formation of a variety of optically pure anti-ꢀ-fluoroalkyl ꢀ-amino acid derivatives is
described. The process relies on the stereocontrolled reaction, mediated by a remote sulfoxide, of fluorinated imines with sulfinylated benzyl
carbanions, which are used as synthetic equivalents of chiral ester enolates.
ꢀ-Amino acids (ꢀ-AAs) play a significant role in medicinal
chemistry.1 They are the structural units of ꢀ-peptides,
compounds with better pharmacological profiles than natural
peptides, displaying highly stable secondary structures and
being more resistant to proteolytic degradation.2 Furthermore,
natural products containing ꢀ-amino acid units exhibit
antibiotic, antifungal, cytotoxic, and other pharmacological
properties.3 In contrast to the wide knowledge about these
compounds, very little is known about the chemistry and
biological activity of fluorine-containing ꢀ-amino acids
despite the significant benefits that the substitution of
hydrogen by fluorine imparts in organic compounds.4 Thus,
the search for new methodologies for preparing enantio-
merically pure fluorinated ꢀ-amino acids is of particular
interest nowadays.5
† Universidad de Valencia.
‡ Centro de Investigacio´n Pr´ıncipe Felipe.
§ Universidad Auto´noma de Madrid.
Among the different substitution patterns of fluorinated
(1) (a) Seebach, D.; Hook, D. F.; Gla¨ttli, A. Biopolymers (Peptide
Science) 2006, 84, 23. (b) EnantioselectiVe Synthesis of ꢀ-Amino Acids,
2nd ed.; Juaristi, E. C., Soloshonok, V. A., Eds.; Wiley-VCH Ltd.: New
York, 2005. (c) Lelais, G.; Seebach, D. Biopolymers (Peptide Science) 2004,
76, 206. (d) Liu, M.; Sibi, M. P. Tetrahedron 2002, 58, 7991. (e)
Frackenpohl, J.; Arvidsson, P. I.; Schreiber, J. V.; Seebach, D. ChemBio-
Chem 2001, 2, 445. (f) Borman, S. Chem. Eng. News 1999, 77, 27.
(2) (a) Seebach, D.; Gardiner, J. Acc. Chem. Res. 2008, 41, 1366–1375.
(b) Fu¨lo¨p, F.; Martikek, T. A.; To´th, G. K. Chem. Soc. ReV. 2006, 35, 323.
(c) Cheng, R. P.; Gellman, S. H.; DeGrado, W. F. Chem. ReV. 2001, 101,
3219. (d) Mathad, R. I.; Gessier, F.; Seebach, D.; Jaun, B. HelV. Chim.
Acta 2005, 88, 266. (e) Mathad, R. I.; Jaun, B.; Flo¨gel, O.; Gardiner, J.;
Lo¨weneck, M.; Code´e, J. D.; Seeberger, P. H.; Seebach, D.; Edmonds,
M. K.; Graichen, F. H.; Abell, A. D. HelV. Chim. Acta 2007, 90, 2251. (f)
Hook, D. F.; Gessier, F.; Noti, Ch.; Kast, P.; Seebach, D. ChemBioChem
2004, 5, 691.
ꢀ-AAs (Figure 1),6 R-functionalized ꢀ-fluoroalkyl derivatives
(3) (a) Werder, M.; Hauser, H.; Abele, S.; Seebach, D. HelV. Chim. Acta
1999, 82, 1774. (b) Porter, E. A.; Wang, X.; Lee, H.; Weisblum, B.;
Gellman, S. H. Nature 2000, 404, 565. (c) Liu, D.; DeGrado, W. F. J. Am.
Chem. Soc. 2001, 123, 7553. (d) Hamuro, Y.; Schneider, J. P.; DeGrado,
W. F. J. Am. Chem. Soc. 1999, 121, 12200. (e) Specker, E.; Bottcher, J.;
Lilie, H.; Heine, A.; Schoop, A.; Muller, G.; Griebenow, N.; Klebe, G.
Angew. Chem., Int. Ed. 2005, 44, 3140. (f) Myers, A. G.; Barbay, J. K.;
Zhong, B. J. Am. Chem. Soc. 2001, 123, 7207. (g) Bialy, L.; Waldmann,
H. Angew. Chem., Int. Ed. 2005, 44, 2. (h) Isanbor, Ch.; O’Hagan, D. J.
Fluorine Chem. 2006, 127, 303.
(4) (a) O’Hagan, D. Chem. Soc. ReV. 2008, 37, 308. (b) Mu¨ller, K.;
Faeh, C.; Diederich, F. Science 2007, 317, 1881.
10.1021/ol802733t CCC: $40.75
Published on Web 01/07/2009
2009 American Chemical Society

preparation of the corresponding anti derivatives still remains
a challenge.
The most direct route to prepare the skeleton of ꢀ-fluo-
roalkyl ꢀ-AAs is the reaction of fluorinated imines with
R-lithiated esters. Previous results from our laboratory
demonstrated that the reaction of 8-phenyl menthol derived
ester enolates with fluorinated imines takes places with poor
chemical yields and diastereoselectivity.10 We envisioned the
possibility of using 2-p-tolylsulfinyl benzyl carbanions as
synthetic chiral equivalents of ester enolates, since they have
been demonstrated to be highly efficient in controlling the
anti-stereoselectivity of their reactions with N-sulfinylimi-
nes12 as well as N-arylimines.13 Thus, the phenyl-p-tolyl-
sulfoxide group would be used both as chiral inducer in its
reaction with fluorinated aldimines and ketimines and also
as precursor of the carboxylic moiety by a two-step desulfi-
nylation/phenyl ring oxidation sequence. In this paper, we
describe a highly efficient stereoselective synthesis of enan-
tiopure anti-ꢀ-fluoroalkyl ꢀ-amino acids by using a chiral
sulfinyl group as inducer. This methodology is also suitable
for the generation of new types of ꢀ-AAs containing a
quaternary stereocenter (Figure 1). The retrosynthetic analysis
is depicted in Scheme 1.
Figure 1. Substitution patterns of acyclic fluorinated ꢀ-AAs.
ꢀ2(R1),ꢀ3(RF,R2)-AAs are worth mentioning. Probably, the
most representative examples of these are isoserines (R1 )
OH, R2 ) H), substructures found in medicinally relevant
molecules such as the antitumoral agents taxol and bestatin.
Several stereocontrolled methods for their preparation have
been devised.7 However, methods for synthesizing the
R-alkyl analogues (R1 ) alkyl, R2 ) H, alkyl, aryl) are rather
scarce. Regarding ꢀ-AAs containing a quaternary stereo-
center in the ꢀ3 position, their stereoselective synthesis
constitutes an enormous challenge for synthetic chemists,
which explains why fluorinated ꢀ-AAs with this substitution
pattern have not been reported to date.8
Scheme 1. Synthetic Strategy
In this sense, Soloshonok reported a chemoenzymatic
approach to anti- and syn-R-methyl-ꢀ-trifluoromethyl-ꢀ-
alanine derivatives.9 A diastereoselective base-catalyzed
[1,3]-proton shift reaction followed by an enzyme-catalyzed
resolution allowed for the preparation of all four possible
diastereoisomers in enantiomerically pure form. We also
developed a highly diastereoselective route to enantiopure
syn-R-alkyl ꢀ-fluoroalkyl ꢀ-amino acids, based on a chemo-
and diastereoselective reduction of chiral fluorinated ꢀ-e-
namino esters.10 More recently, these compounds were also
obtained by means of an indirect Mannich-type reaction of
fluorinated aldimines with aliphatic aldehydes catalyzed by
proline.11 However, to our knowledge, the diastereoselective
We have recently reported that the deprotonation of sulfo-
xides (S)-2 at the benzylic position with LDA at -78 °C
and subsequent treatment with fluorinated imines 3 [PG )
p-methoxyphenyl (PMP)] led to the formation of fluorinated
indolines in a highly selective fashion after the reaction
mixture was allowed to reach room temperature.14 When the
reactions were hydrolyzed at -78 °C, diastereomeric mix-
tures of fluorinated amines 4 and 5 were obtained, with 4
being formed as the major or exclusive product (Table 1).
Thus, with o-tolyl derived sulfoxides 2a (R1 ) H), separable
diastereoisomeric mixtures of amines 4 and 5 were obtained
(Table 1, entries 1-5). Surprisingly, the best results were
(5) Review: Qiu, X.-L.; Meng, W.-D.; Qing, F.-L. Tetrahedron 2004,
60, 6711.
(6) For the enantioselective synthesis of enantiomerically pure ꢀ2(R),ꢀ3(RF)-
AAs, see: (a) Sani, M.; Bruche´, L.; Chiva, G.; Fustero, S.; Piera, J.;
Volonterio, A.; Zanda, M. Angew. Chem., Int. Ed. 2003, 42, 2060. (b)
Fustero, S.; Chiva, G.; Piera, J.; Volonterio, A.; Zanda, M.; Gonza´lez, J.;
Mora´n, A. Chem. Eur. J. 2007, 13, 8530. (c) Yamauchi, Y.; Kawate, T.;
Itahashi, H.; Katagiri, T.; Uneyama, K. Tetrahedron Lett. 2003, 44, 6319.
For the enantioselective synthesis of enantiomerically pure ꢀ2(F2),ꢀ3(R)-
AAs, see: (d) Edmonds, M. K.; Graichen, F. H. N.; Gardiner, J.; Abell,
A. D. Org. Lett. 2008, 10, 885. (e) Hook, D. F.; Gessier, F.; Noti, C.; Kast,
P.; Seebach, D. ChemBiochem 2004, 5, 691. (f) Sorochinsky, A.; Voloshin,
N.; Markovski, A.; Belik, M.; Yasuda, N.; Uekusa, H.; Ono, T.; Bervasov,
D. O.; Soloshonok, V. A. J. Org. Chem. 2003, 68, 7448. (g) Marcotte, S.;
Pannecoucke, X.; Feasson, C.; Quirion, J.-C. J. Org. Chem. 1999, 64, 8461.
(7) Jiang, Z.-X.; Qing, F.-L. J. Org. Chem. 2004, 69, 5486, and
references therein.
(8) For recent reviews of creation of quaternary stereocenters, see: (a)
Cozzi, P. G.; Hilfrag, R.; Zimmermann, N. Eur. J. Org. Chem. 2007, 5969.
(b) Christoffers, J.; Baro, A. AdV. Synth. Catal. 2005, 347, 1473.
(9) Soloshonok, V. A.; Soloshonok, I. V.; Kukhar, V. P.; Svedas, V. K.
J. Org. Chem. 1998, 63, 1878.
(12) (a) Garc´ıa-Ruano, J. L.; Alema´n, J.; Soriano, J. F. Org. Lett. 2003,
5, 677. (b) Garc´ıa-Ruano, J. L.; Alema´n, J. Org. Lett. 2003, 5, 4513. (c)
Garc´ıa-Ruano, J. L.; Alema´n, J.; Parra, A. J. Am. Chem. Soc. 2005, 127,
13048.
(13) Garc´ıa-Ruano, J. L.; Alema´n, J.; Alonso, I.; Parra, A.; Marcos, V.;
Aguirre, J. Chem. Eur. J. 2007, 13, 6169.
(10) Fustero, S.; Pina, B.; Salavert, E.; Navarro, A.; de Arellano,
M. C. R.; Fuentes, A. S. J. Org. Chem. 2002, 67, 4667.
(14) García-Ruano, J. L.; Alema´n, J.; Catala´n, S.; Marcos, V.; Mon-
teagudo, S.; Parra, A.; del Pozo, C.; Fustero, S. Angew. Chem., Int. Ed.
2008, 47, 7941.
(11) Fustero, S.; Jime´nez, D.; Sanz-Cervera, J. F.; Sa´nchez-Rosello´, M.;
Esteban, E.; Simo´n-Fuentes, A. Org. Lett. 2005, 7, 3433.
642
Org. Lett., Vol. 11, No. 3, 2009

the hydrogen occupying the flagpoles.17 As the metal blocks
the upper face, the approach of the electrophile can only take
place at the lower face (Figure 2), thus justifying that all
compounds obtained in these reactions have the S configu-
ration at the benzylic carbon.18 Two possible approaches of
the electrophile can be postulated, respectively yielding the
anti and syn (1,5-like vs 1,5-unlike addition) isomers (Figure
2). Both of them arrange the CdN bond antiperiplanar with
respect to the C-R1 bond, thus maintaining the electrostatic
stabilization derived from the interaction of the N (negatively
charged in the transition state) with the S (positively
charged).19 This assumption, along with the minimization
of steric interactions of RF with R1 and the sulfinylated aryl
groups, could justify the complete anti-selectivity observed
in reactions from (S)-2b as well as the predominance of the
anti isomers in reactions from (S)-2a (Table 1).
Table 1. Reaction of Sulfoxides 2 with Imines 3
entry
3
R1
R2
RF
CF3
CF2Cl
CF2CF3
4, 5 (% yield)b ratio 4:5c
1a
2a
3
3a
3b
3c
3d
3e
3a Me
3b Me
3c
H
H
H
H
H
H
H
H
4a, 5a (74)
4b, 5b (80)
4c, 5c (75)
4d, 5d (77)
4e, 5e (45)
4f (69)
4g (71)
4 h, 5 h (60)
4i (86)
69:31
70:30
67:33
96:4
>99:1
>99:1
>99:1
4:1
4a
5
Me CF3
Me CF2CF3
H
H
H
6a
7a
8
CF3
CF2Cl
CF2CF3
Addition products 4 were then subjected to the desulfu-
ration/oxidation sequence that gave rise to the corresponding
fluorinated ꢀ-amino acid derivatives 1. Removal of the
sulfoxide group was achieved by treatment with Raney-Ni,
which afforded the desulfurated products 6 in nearly
quantitative yields after 12 h at room temperature.
Me
9a
10
3d Me Me CF3
3e Me Me CF2CF3
>99:1
>99:1
4j (55)
a See ref 14. b Combined yields of 4 + 5. c Diastereoisomeric ratios
were determined by 19F NMR.
The transformation of the phenyl ring into the carboxylic
acid required the previous conversion of the PMP group into
other nitrogen protecting groups compatible with the phenyl
ring oxidation. With this purpose, compounds 6 were treated
with CAN (cerium ammonium nitrate) at 0 °C for 1 h, which
provoked the PMP removal. Resulting amines were then
N-acetylated with acetic anhydride under standard conditions,
yielding the fluorinated amides 7 in good to excellent yields
(Table 2).
achieved when the reaction was carried out with ketimines
(R2 * H), reaching diastereoisomeric ratios of up to 99%
(Table 1, entries 4 and 5). We were delighted to find that,
using of sulfoxides 2b with R1 ) Me, the process evolved
in a completely stereoselective way, yielding mainly com-
pounds 4 as single diastereoisomers with both fluorinated
aldimines and ketimines15,16 (Table 1, entries 6-10).
Rationalization of the stereochemical results can be made
by assuming for the nucleophilic carbanion the structure
indicated in Figure 2. The sulfinyl oxygen stabilizes the
Table 2. Preparation of Fluorinated N-Acetyl Amides 7
entry
substrate
R1
R2
RF
7 (% yield)a
1
2
3
4
5
6
4a
4d
4f
4g
4i
H
H
Me
Me
Me
H
H
Me
H
H
Me
CF3
CF3
CF3
CF2Cl
CF3
H
7a (90)
7b (70)
7c (79)
7d (72)
7e (65)
7f (86)
5a
CF3
a Isolated yield after three steps, from 4 to 7.
Figure 2. Diastereoselectivity control in the formation of amines
4 and 5.
The final conversion to the amino ester functionality was
then carried out by phenyl ring oxidation with ruthenium
(17) The assumption of this structure as the most stable one for the
benzyllithium derived from 2b is supported by theoretical calculations. See
ref 13.
(18) Starting from (R)-sulfoxides, resulting compounds would exhibit
an (R)-configuration at this position.
benzyllithium by forming a chelated species, which adopts
a quasi-boat conformation, with the lone electron pair and
(15) Only one exception to this general behavior has been observed;
see Table 1, entry 8.
(16) The absolute configuration of the major diastereoisomers was
established by X-ray analysis. See ref 14.
(19) Similar approaches were used for explaining the stereochemical
results obtained in reactions of sulfinylated thiomethylcarbanions with
ketones. See: Arroyo, Y.; Meana, A.; Sanz-Tejedor, M. A.; Garc´ıa-Ruano,
J. L. Org. Lett. 2008, 10, 2151.
Org. Lett., Vol. 11, No. 3, 2009
643

tetraoxide.20 The isolation of the N-acetylamino acids proved
to be difficult, and we decided to perform an in situ
esterification of the carboxylic acid group by treatment with
trimethylsilyl diazomethane. After chromatographic purifica-
tion, final N-acetyl ꢀ-amino esters 1 were obtained in good
yields (Table 3).
was transformed into the corresponding N-Boc derivative 7g
by reaction of the free amine with di-tert-butyl dicarbonate
after sulfoxide elimination and PMP release. Following the
previously mentioned methodology, 7g was converted into
the N-Boc amino ester 1g in good overall yield (Scheme 2).
Scheme 2. Preparation of N-Boc Derivative 1g
Table 3. Preparation of anti-ꢀ-Amino Esters 1 from Amides 7
In conclusion, the stereocontrolled preparation of ꢀ-fluo-
roalkyl ꢀ-amino acid derivatives has been described. It
involves the highly selective addition of 2-(p-tolylsulfinyl)-
benzylic carbanions to fluorinated imines followed by a
desulfuration/oxidation sequence, which allows the synthesis
of the final amino acid derivatives 1 in good yields. A
combination of steric and electrostatic factors has been
invoked to explain the high selectivity found in the addition
of benzyllithiums to fluorinated aldimines and ketimines. It
is noteworthy that this is one of the first methods described
in the literature for the stereoselective preparation of enan-
tiomerically pure anti-ꢀ-fluoroalkyl-R-alkyl ꢀ-amino esters
and the first one for compounds containing quaternary
centers.
a Isolated yields.
Acknowledgment. Financial support of this work by the
Ministerio de Educacio´n y Ciencia (grants CTQ2006-06741/
BQU and CTQ2007-61462) is gratefully acknowledged.
A.P., V.M., S.C., and S.M. express their thanks for predoc-
toral fellowships. C.P. thanks the same institution for a
Ramo´n y Cajal contract.
It is noteworthy that the use of this methodology allowed
for the selective creation of one stereocenter (Table 3, entries
1, 2, and 6) and two vicinal stereocenters, with an anti
disposition between R1 and the nitrogen-containing substitu-
ent (Table 3, entries 3-5). The generation of quaternary
stereocenters was also achieved in an efficient manner (Table
3, entries 2 and 5).
Supporting Information Available: Experimental pro-
cedures and NMR spectra for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
This sequence is also compatible with the presence of other
nitrogen protecting groups. To illustrate this possibility, 4a
(20) Plietker, B. Synthesis 2005, 2453.
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Org. Lett., Vol. 11, No. 3, 2009