Cross-metathesis reactions as an efficient tool in the synthesis of fluorinated cyclic β-amino acids

Article abstract of DOI:10.1021/jo900296d

The synthesis of enantiomerically pure, cyclic, γ,γ- difluorinated β-amino acids with various ring sizes has been carried out with a cross-metathesis (CM) reaction being one of the key steps, followed by a Dieckmann-type condensation to bring about the cy

Full text of DOI:10.1021/jo900296d

Cross-Metathesis Reactions as an Efficient Tool in the Synthesis of
Fluorinated Cyclic ꢀ-Amino Acids§
Santos Fustero,*,†,‡ María Sa´nchez-Rosello´,‡ Jose´ Luis Acen˜a,‡ Begon˜a Ferna´ndez,†
Amparo Asensio,† Juan F. Sanz-Cervera,†,‡ and Carlos del Pozo†
Departamento de Química Orga´nica, UniVersidad de Valencia, E-46100 Burjassot, Spain, and Laboratorio
de Mole´culas Orga´nicas, Centro de InVestigacio´n Príncipe Felipe, E-46012 Valencia, Spain
santos.fustero@uV.es
ReceiVed February 12, 2009
The synthesis of enantiomerically pure, cyclic, γ,γ-difluorinated ꢀ-amino acids with various ring sizes
has been carried out with a cross-metathesis (CM) reaction being one of the key steps, followed by a
Dieckmann-type condensation to bring about the cyclization. Subsequent catalytic hydrogenation under
microwave irradiation with (-)-8-phenylmenthol as a chiral auxiliary led to the successful chemo- and
diastereoselective chemical reduction of the resulting cyclic ꢀ-enamino esters. The efficiency and scope
of the CM reaction with different types of fluorinated imidoyl chlorides and unsaturated esters has also
been studied in order to determine the optimal reaction conditions with regard to selectivity and reactivity.
Introduction
these compounds have been reported to be antibiotics and
antifungals4 as well as potential inhibitors of protein-protein
interactions.5
The main drawback with using bioactive peptides as drugs
is their metabolic lability, which results in poor bioavailability.
This problem can be addressed, however, by introducing
nonproteinogenic amino acids, such as ꢀ-amino acids,1 into the
peptidic structure, which enhances the stability of the resulting
compounds by rendering their amide bonds unrecognizable to
proteolytic enzymes.2 Moreover, non-natural oligomers of
ꢀ-amino acids (ꢀ-peptides)3 are able to adopt well-defined
secondary structures (helices, turns, and sheets) and usually
remain stable toward enzymatic attack. In addition, many of
Of particular interest are those amino acids in which both
the ꢀ-amino and the acid functionalities are attached to an
aliphatic ring, e.g., ꢀ2,3-amino acids or 2-aminocycloalkanecar-
boxylic acids (2-ACACs).6 Among these, several five- and six-
membered derivatives have been shown to exhibit antibacterial
activity. Examples include cispentacin,7 a naturally occurring
antifungal agent against Candida albicans infections, its syn-
thetic derivative PLD-118, which is currently in clinical trials,8
and the 2-aminocyclohexenecarboxylic acid BAY 9379 (Chart
* To whom correspondence should be addressed. Tel: +34-963544279. Fax:
+34-963544938.
§ Dedicated to Prof. Josep Font on the occasion of his 70th birthday.
† Universidad de Valencia.
(4) (a) Porter, E. A.; Wang, X.; Lee, H.; Weisblum, B.; Gellman, S. H. Nature
(London) 2000, 404, 565–565. (b) Karlsson, A. J.; Pomerantz, W. C.; Weisblum,
B.; Gellman, S. H.; Palecek, S. P. J. Am. Chem. Soc. 2006, 128, 12630–12631.
(5) Kritzer, J. A.; Stephens, O. M.; Guarracino, D. A.; Reznik, S. K.;
Schepartz, A. Biorg. Med. Chem. 2005, 13, 11–16.
‡ Centro de Investigacio´n Pr´ıncipe Felipe.
(1) (a) Cardillo, G.; Tomasini, C. Chem. Soc. ReV. 1996, 25, 117–128. (b)
Ojima, I.; Lin, S.; Wang, T. Curr. Med. Chem. 1999, 6, 927–954.
(2) Adessi, C.; Soto, C. Curr. Med. Chem. 2002, 9, 963–978.
(3) (a) Cheng, R. P.; Gellman, S. H.; DeGrado, W. F. Chem. ReV. 2001,
101, 3219–3232. (b) Seebach, D.; Beck, A. K.; Bierbaum, D. J. Chem.
BiodiVersity 2004, 1, 1111–1239. (c) Seebach, D.; Hook, D. F.; Gla¨ttli, A.
Biopolymers (Pept. Sci.) 2006, 84, 23–37. (d) Wu, Y. D.; Han, W.; Wang, D. P.;
Zhao, Y. L. Acc. Chem. Res. 2008, 41, 1418–1427. (e) Seebach, D.; Gardiner,
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Hashimoto, S. J. Antibiot. 1990, 43, 513–518. (c) Benedek, G.; Palko´, M.; We´ber,
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3414 J. Org. Chem. 2009, 74, 3414–3423
10.1021/jo900296d CCC: $40.75 2009 American Chemical Society
Published on Web 04/06/2009

Synthesis of Fluorinated Cyclic ꢀ-Amino Acids
CHART 1. Biologically Active Cyclic ꢀ-Amino Acids
SCHEME 1. Two Synthetic Strategies for the Preparation
of Cyclic Fluorinated ꢀ-Amino Acid Derivatives
CHART 2. Structures of Ruthenium Catalysts I-III
1). However, in contrast to linear ꢀ-amino acids,9 the synthesis
of cyclic ꢀ-amino acids has been explored to a much lesser
extent.10
The chemistry of fluorinated analogues of ꢀ-amino acids is
receiving more and more attention as the benefits conferred to
organic molecules when fluorine is substituted for hydrogen
become clearer.11 So far, however, most of the reported
examples focus on the synthesis of acyclic compounds.12 In fact,
the only examples of cyclic derivatives that have been described
to date are a racemic difluorinated analogue of cispentacin13
and a fluoropyranose containing a ꢀ2,2-amino acid unit.14 The
lack of a general synthetic strategy, coupled with our current
interest in obtaining various types of fluorinated nitrogen-
containing heterocycles with the aid of metathesis reactions,15
led us to embark on the development of two complementary
synthetic routes for the preparation of five- to seven-membered
difluoro ꢀ2,3-amino acid derivatives with a CF2 group next to
the amino group. To this end, we used unsaturated fluorinated
imidoyl chlorides and esters as starting materials.16 In a first
approach, a ring-closing metathesis (RCM)-based protocol (path
A) efficiently led to the preparation of seven-membered rings.17
A second strategy employing a cross-metathesis (CM) reaction
(path B) followed by chemoselective hydrogenation and a
Dieckmann-type cyclization proved to be more flexible in
accessing different ring sizes (Scheme 1).18
Cross-metathesis (CM) reactions are currently witnessing a
tremendous rise in popularity since new and more reactive
catalysts such as I-III (Chart 2) have become available.19 This
reaction, however, has two main drawbacks, namely the lack
of control in product selectivity when using two different olefins
and the low stereoselectivity associated with the newly formed
double bond. Recently, a general model for predicting product
selectivity has been proposed by Grubbs and co-workers based
on the ability of the olefins to homodimerize as well as on the
reactivity of the corresponding homodimers under metathesis
conditions.20 According to this model, olefins can be classified
into four types (I-IV), each with decreasing reactivity toward
CM reactions.
(9) (a) Liu, M.; Sibi, M. P. Tetrahedron 2002, 58, 7991–8035. (b) Cole,
D. C. Tetrahedron 1994, 50, 9517–9582. (c) EnantioselectiVe Synthesis of
ꢀ-Amino Acids; 2nd ed.; Juaristi, E. C., Soloshonok, V. A., Eds.; Wiley-VCH
Ltd.: New York, 2005.
(10) (a) Kuhl, A.; Hahn, M. G.; Dumie´, M.; Mittendorf, J. Amino Acids 2005,
29, 89–100. (b) Fu¨lo¨p, F.; Martinek, T. A.; To´th, G. K. Chem. Soc. ReV. 2006,
35, 323–334. (c) Miller, J. A.; Nguyen, S. B. T. Mini-ReV. Org. Chem. 2005, 2,
39–45.
(11) See, for example: (a) O’Hagan, D. Chem. Soc. ReV. 2008, 37, 308–
319. (b) Mu¨ller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881–1886.
(12) (a) Soloshonok, V. A.; Soloshonok, I. V.; Kukhar, V. P.; Svedas, V. K.
J. Org. Chem. 1998, 63, 1878–1884. (b) Fustero, S.; Pina, B.; García de la Torre,
M.; Navarro, A.; Ramírez de Arellano, C.; Simo´n, A. Org. Lett. 1999, 1, 977–
980. (c) Marcotte, S.; Pannecoucke, X.; Feasson, C.; Quirion, J.-C. J. Org. Chem.
2001, 64, 8461–8464. (d) Fustero, S.; Salavert, E.; Pina, B.; Ramírez de Arellano,
C.; Asensio, A. Tetrahedron 2001, 57, 6475–6486. (e) Crousse, B.; Narizuka,
S.; Bonnet-Delpon, D.; Be´gue´, J.-P. Synlett 2001, 679–681. (f) Ohkura, H.;
Handa, M.; Katagiri, T.; Uneyama, K. J. Org. Chem. 2002, 67, 2692–2695. (g)
Fustero, S.; Pina, B.; Salavert, E.; Navarro, A.; Ramírez de Arellano, M. C.;
Simo´n Fuentes, A. J. Org. Chem. 2002, 67, 4667–4679. (h) Staas, D. D.; Savage,
K. L.; Homnick, C. F.; Tsou, N. N.; Ball, R. G. J. Org. Chem. 2002, 67, 8276–
8279. (i) Soloshonok, V. A.; Ohkura, H.; Sorochinsky, A.; Voloshin, N.;
Markovsky, A.; Belik, M.; Yamazaki, T. Tetrahedron Lett. 2002, 43, 5445–
5448. (j) Vidal, A.; Nefzi, A.; Houghten, R. A. J. Org. Chem. 2002, 67, 8268–
8272. (k) Sorochinsky, A.; Voloshin, N.; Markovsky, A.; Belik, M.; Yasuda,
N.; Uekusa, H.; Ono, T.; Berbasov, D. O.; Soloshonok, V. A. J. Org. Chem.
2003, 68, 7448–7454. (l) Hook, D.; Gessier, F.; Noti, C.; Kast, P.; Seebach, D.
ChemBioChem 2004, 5, 691–706. (m) Chung, W. J.; Omote, M.; Welch, J. T.
J. Org. Chem. 2005, 70, 7784–7787. (n) Fustero, S.; Jime´nez, D.; Sanz-Cervera,
J. F.; Sa´nchez-Rosello´, M.; Esteban, E.; Simo´n-Fuentes, A. Org. Lett. 2005, 7,
3433–3436. (o) Huguenot, F.; Brigaud, T. J. Org. Chem. 2006, 71, 2159–2162.
(p) Shimada, T.; Yoshioka, M.; Konno, T.; Ishihara, T. Chem. Commun. 2006,
3628–3630. (q) Edmonds, M. K.; Graichen, F. H. M.; Gardiner, J.; Abell, A. D.
Org. Lett. 2008, 10, 885–887. (r) Michaut, V.; Metz, F.; Paris, J.-M.; Plaquevent,
J.-C. J. Fluorine Chem. 2007, 128, 500–506. (s) Boyer, N.; Gloanec, P.; De
Nanteuil, D.; Jubault, P.; Quirion, J.-C. Tetrahedron 2007, 63, 12352–12366.
(13) Mittendorf, J.; Kunisch, F.; Matzke, M.; Militzer, H.-C.; Schmidt, A.;
Scho¨nfeld, W. Bioorg. Med. Chem. Lett. 2003, 13, 433–436.
A wide variety of nitrogen-containing olefins has been
employed in CM reactions,19c including protected amines and
amino acids,21 amides,22 ureas,23 nitriles,24 and nitro com-
pounds.25 In contrast, unsaturated imidoyl halides have not been
(16) It should be noted that fluorinated imidoyl halides constitute readily
available building blocks for the synthesis of a variety of fluorine-containing
molecules: (a) Uneyama, K. J. Fluorine Chem. 1999, 97, 11–25. (b) Uneyama,
K.; Amii, H.; Katagiri, T.; Kobayashi, T.; Hosokawa, T. J. Fluorine Chem. 2005,
126, 165–171.
(17) Fustero, S.; Bartolome´, A.; Sanz-Cervera, J. F.; Sa´nchez-Rosello´, M.;
García Soler, J.; Ramírez de Arellano, C.; Simo´n Fuentes, A. Org. Lett. 2003,
5, 2523–2526.
(18) For a preliminary communication, see: Fustero, S.; Sa´nchez-Rosello´,
M.; Sanz-Cervera, J. F.; Acen˜a, J. L.; del Pozo, C.; Ferna´ndez, B.; Bartolome´,
A.; Asensio, A.; Ramírez de Arellano, C. Org. Lett. 2006, 8, 4633–4636.
(19) For reviews, see: (a) Schrodi, Y.; Pederson, R. L. Aldrichimica Acta
2007, 40, 45–52. (b) Connon, S. J.; Blechert, S. Angew. Chem., Int. Ed. 2003,
42, 1900–1923. (c) Vernall, A. J.; Abell, A. D. Aldrichim. Acta 2003, 36, 93–
105. For leading references, see: (d) Crowe, W. E.; Zhang, Z. J. J. Am. Chem.
Soc. 1993, 115, 10998–10999. (e) Blackwell, H. E.; O’Leary, D. J.; Chatterjee,
A. K.; Washenfelder, R. A.; Bussmann, D. A.; Grubbs, R. H. J. Am. Chem. Soc.
2000, 122, 58–71. (f) Chatterjee, A. K.; Morgan, J. P.; Scholl, M.; Grubbs, R. H.
J. Am. Chem. Soc. 2000, 122, 3783–3784.
(14) Vera-Ayoso, Y.; Borrachero, P.; Cabrera-Escribano, F.; Dia´nez, M. J.;
Estrada, M. D.; Go´mez-Guille´n, M.; Lo´pez-Castro, A.; Pe´rez-Garrido, S.
Tetrahedron: Asymmetry 2001, 12, 2031–2041.
(15) (a) Fustero, S.; Sa´nchez-Rosello´, M.; Jime´nez, D.; Sanz-Cervera, J. F.;
del Pozo, C.; Acen˜a, J. L. J. Org. Chem. 2006, 71, 2706–2714. (b) Fustero, S.;
Catala´n, S.; Piera, J.; Sanz-Cervera, J. F.; Ferna´ndez, B.; Acen˜a, J. L. J. Org.
Chem. 2006, 71, 4010–4013. (c) Fustero, S.; Sa´nchez-Rosello´, M.; Rodrigo, V.;
del Pozo, C.; Sanz-Cervera, J. F.; Simo´n, A. Org. Lett. 2006, 8, 4129–4132. (d)
Fustero, S.; Sa´nchez-Rosello´, M.; Rodrigo, V.; Sanz-Cervera, J. F.; Piera, J.;
Simo´n-Fuentes, A.; del Pozo, C. Chem.sEur. J. 2008, 14, 7019–7029.
(20) Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J. Am.
Chem. Soc. 2003, 125, 11360–11370.
(21) Biagini, S. C. G.; Gibson, S. E.; Keen, S. P. J. Chem. Soc., Perkin Trans.
1 1998, 2485–2499.
J. Org. Chem. Vol. 74, No. 9, 2009 3415

Fustero et al.
subjecting the starting R-ketoesters 6a,b29 to difluorination
with Deoxofluor30 and subsequent hydrolysis. Carboxylic
acids 5a-e were then transformed into the corresponding
imidoyl chlorides 1a-e, in accordance with the methodology
described above27 (Scheme 3).
SCHEME 2. Synthetic Strategy for the Preparation of
Cyclic Fluorinated ꢀ-Amino Acids based on the CM
Reaction between Imidoyl Chlorides 1 and Esters 2
We initially tested the cross-metathesis reaction of imidoyl
chloride 1a with unsaturated esters 2 bearing a remote olefin in
the R-, ꢀ-, or γ-position in relation to the ester functionality.
For this we used second-generation Grubbs catalyst II, obtaining
the corresponding cross-coupled products 3 with a varied degree
of efficiency depending on the ester used and the reaction
conditions. These results are summarized in Table 1. When using
CH2Cl2 as solvent, for example, the reaction with an excess (2
equiv) of ethyl 4-pentenoate 2a (m ) 2), benzyl 3-butenoate
2b, or methyl 3-butenoate 2c (m ) 1) (type I olefins, rapid
homodimerization) afforded the homodimers of reactants 7 and
8a-c, therefore decreasing the yield of the desired products
3a-c (entries 1-3).31 A longer reaction time only caused a
slight alteration in the product ratio (entry 4). The E/Z selectivity
was moderate in all cases, as determined with the aid of 19F
NMR. Increasing the reaction temperature and changing the
solvent to toluene likewise failed to improve the results due to
the fact that the ester double bond in 2c (m ) 1) partially
isomerized under the reaction conditions, either before32 or
after15a the metathesis process, thus affording a complex mixture
of products (entry 5). The best results with regard to yield and
selectivity came with the use of less reactive olefins such as
acrylates (type II olefins, with a slower homodimerization than
type I). Thus, the reaction with ethyl acrylate 2d (m ) 0) was
quite slow in refluxing CH2Cl2, affording compound 3d in yields
ranging from 40 to 70% and with almost complete E selectivity
(entries 6-8). In this case (m ) 0), no ester homodimer
formation was observed. Moreover, the use of toluene as a
solvent along with a higher reaction temperature and a greater
amount of acrylate led to the isolation of 3d in excellent yield
(entry 9).33 Under these conditions, the imidoyl chloride
homodimer 7 probably reacted with acrylate 2d through a
secondary metathesis process, thus affording the desired cross-
coupled product 3d. Most importantly, the imidoyl chloride
function withstood the metathesis conditions, thus providing a
route for its further functionalization.
viewed as suitable coupling partners in CM processes up to this
point, mostly due to their instability. Nevertheless, R-fluorinated
imidoyl halides are relatively stable16 and have thus been
employed as starting substrates for the synthesis of different
types of fluorinated molecules.26 We anticipated that, according
to Grubbs’ model,20 these imidoyl halides would behave as
either type I or II olefins in CM reactions, depending on the
catalyst employed. In fact, in a previous communication, we
described the use of unsaturated R,R-difluoroimidoyl chlorides
in selective CM reactions with acrylates and the further
application of the resulting cross-coupled products to the
synthesis of fluorinated cyclic ꢀ-amino acid derivatives.18 This
paper describes in full the scope and limitations of this
methodology for the preparation of enantiomerically pure, cyclic,
fluorinated ꢀ-amino acids.
Results and Discussion
The first step in our strategy to synthesize cyclic fluorinated
ꢀ-amino acids was the cross-metathesis (CM) reaction between
imidoyl chlorides 1 and unsaturated esters 2 to afford cross-
coupling products 3 (Scheme 2).
Given the various possible reaction pathways (due to the use
of chains with different lengths in both imidoyl chloride and
ester starting materials), we first decided to examine the CM
reaction between imidoyl chlorides and esters in order to find
the best route to products 3 in terms of selectivity and reactivity.
A number of unsaturated fluorinated imidoyl chlorides 1
was prepared from the corresponding carboxylic acids 5
through treatment with a primary amine and PPh3/CCl4/
Et3N.27 The synthesis of carboxylic acids 5a-c by means of
a sigmatropic rearrangement of allyl chlorodifluoroacetates
4a-c was carried out as previously reported,28 whereas the
preparation of the longer analogues 5d,e was achieved by
A two-step procedure, namely the self-dimerization of imidoyl
chloride 1a followed by a CM with unsaturated esters, was also
evaluated. In this way, homodimer 7 was prepared in good yield
(75%) and with 9:1 E/Z selectivity under the initially tested
conditions (catalyst II, CH2Cl2, reflux).34 A small amount of
compound 9 was also obtained, resulting from the phenyl group
being incorporated from the catalyst. Next, compound 7 reacted
with methyl 3-butenoate 2c in the presence of catalyst II and
refluxing toluene to give the coupled product 3c in moderate
yield and with moderate selectivity. In contrast, the reaction
with ethyl acrylate 2d afforded enoate 3d in the same way as
(22) Choi, T. L.; Chatterjee, A. K.; Grubbs, R. H. Angew. Chem., Int. Ed.
2001, 40, 1277–1279.
(23) Forment´ın, P.; Gimeno, N.; Steinke, J. H. G.; Vilar, R. J. Org. Chem.
2005, 70, 8235–8238.
(24) Hoveyda, H. R.; Ve´zina, M. Org. Lett. 2005, 7, 2113–2116.
(25) Marsh, G. P.; Parsons, P. J.; McCarthy, C.; Corniquet, X. G. Org. Lett.
2007, 9, 2613–2616.
(29) Macritchie, J. A.; Silcock, A.; Willis, C. L. Tetrahedron: Asymmetry
1997, 8, 3895–3902.
(30) Lal, G. S.; Pez, G. P.; Pesaresi, R. J.; Prozonic, F. M.; Cheng, H. J.
Org. Chem. 1999, 64, 7048–7054.
(26) See, for example: (a) Fustero, S.; Salavert, E.; Pina, B.; Ram´ırez de
Arellano, C.; Asensio, A. Tetrahedron 2001, 57, 6475–6486. (b) Fustero, S.;
Pina, B.; Salavert, E.; Navarro, A.; Ram´ırez de Arellano, M. C.; Simo´n Fuentes,
A. J. Org. Chem. 2002, 67, 4667–4679. (c) Fustero, S.; García Soler, J.;
Bartolome´, A.; Sa´nchez-Rosello´, M. Org. Lett. 2003, 5, 2707–2710.
(27) Uneyama, K.; Tamura, K.; Mizukami, H.; Maeda, K.; Watanabe, H. J.
Org. Chem. 1993, 58, 32–35.
(31) Purification of cross-coupled products 3a-c by means of column
chromatography was hampered by the difficult separation of ester homodimers
8.
(32) For a review, see: Schmidt, B. Eur. J. Org. Chem. 2004, 1865–1880.
(33) The isomerization of the double bond in the reaction of 1a with acrylates
was thwarted by an electronic effect of the CF2 group. For a mechanistic
explanation, see ref 15a.
(28) Greuter, H.; Lang, R. W.; Romann, A. J. Tetrahedron Lett. 1988, 29,
3291–3294.
(34) The same reaction in the presence of first-generation Grubbs catalyst I
afforded only 20% of homodimer 7 after 48 h.
3416 J. Org. Chem. Vol. 74, No. 9, 2009

Synthesis of Fluorinated Cyclic ꢀ-Amino Acids
SCHEME 3. Synthesis of Fluorinated Imidoyl Chlorides 1a-e
TABLE 1. CM of Imidoyl Chloride 1a with Unsaturated Esters 2
SCHEME 5. CM of 1a with Ethyl Methacrylate
TABLE 2. CM of Imidoyl Chlorides 1b,c with Unsaturated Esters
2
solvent/ time
2 (equiv) T (°C)
E/Z
7
8
entry
m
R
(h) 3a (%) ratiob (%) (%)
1
2
3
4
5
6
7
8
9
2
1
1
1
1
0
0
0
0
Et
2a (2)
2b (2)
2c (2)
2c (2)
2c (2)
2d (2)
2d (2)
2d (3)
2d (5)
CH2Cl2/∆
CH2Cl2/∆
CH2Cl2/∆
CH2Cl2/ ∆ 15 3c (70)
PhMe/∆
3
4
4
3a (70)
3b (60)
3c (60)
3:1 13 8a (10)
10:1 10 8b (13)
10:1 10 8c (25)
7:1 14 8c (19)
Bn
Me
Me
Me
Et
Et
Et
Et
15
5
c
CH2Cl2/∆
3d (40)d >20:1 16
CH2Cl2/∆ 15 3d (60)d >20:1
CH2Cl2/∆ 48 3d (70) >20:1
8
6
8d (4)e
2
solvent/ time
3b
(%)
3f (75)d
3g (40)
3g (50)
3h (40)e
f
E/Z
PhMe/∆
15 3d (95) >20:1
entry 1a (%)
m
R
(equiv)
T (°C)
(h)
ratioc
a Isolated yields after flash chromatography purification. b Ratio
calculated from signal integration in the 19F NMR spectra and/or with
the aid of GC-MS. c Complex mixture. d Starting material was recov-
ered (30-40%) after purification. e Determined with the aid of GC-MS.
1
2
3
4
5
1b (10)
1b (36)
1b (30)
1c (32)
1c
1
0
0
1
0
Me
Et
Et
Me
Et
2c(2)
2d(3)
2d(5)
2c(2)
2d(3)
CH2Cl2/∆
CH2Cl2/∆
PhMe/∆
CH2Cl2/∆
CH2Cl2/∆
15
48
15
15
48
6:1
>20:1
>20:1
5:1
SCHEME 4. Synthesis and Reactivity of Imidoyl Chloride
Homodimer 7
a Starting imidoyl chloride recovered. b Isolated yields after flash
chromatography purification. c Ratio calculated from integration in the
19F NMR spectra and/or with the aid of GC-MS. d 15% of ester
homodimer 8c was also detected with the aid of GC-MS. e 27% of
ester homodimer 8c was also detected with the aid of GC-MS.
f Complex mixture.
model. However, in refluxing toluene, 1a could be regarded as
a type I olefin because its homodimer 7 is able to react
selectively with other olefins under these conditions.
Type III olefins (unable to homodimerize) such as ethyl
methacrylate 2e were less effective under the optimized condi-
tions (catalyst II, refluxing toluene), yielding only low conver-
sions (<20%). However, the use of neat methacrylate and
prolonged reaction times (4 days) led to the preparation of the
trisubstituted cross-coupled product 3e as a single isomer
(Scheme 5).
The introduction of methyl groups into imidoyl chlorides 1b,c
decreased their reactivity toward CM reactions in comparison
to that of 1a (Table 2). For instance, 1b, with a methyl group
in allylic position, reacted well with methyl 3-butenoate 2c to
give the corresponding cross-metathesis product 3f (entry 1),
but yields were much lower with ethyl acrylate 2d in both
when starting from 1a (see Table 1, entry 9). It is worth noting
that the identical reaction carried out in refluxing CH2Cl2 only
produced recovered starting material 7 (Scheme 4).
While homodimer 7 of 1a is easily formed in refluxing
dichloromethane (conditions for which olefins were catego-
rized),20 it does not react with other olefins in this solvent. This
means that, in the presence of second generation catalyst II,
imidoyl chloride 1a acts as a type II olefin according to Grubbs’
J. Org. Chem. Vol. 74, No. 9, 2009 3417

Fustero et al.
TABLE 3. Chemical Reduction of ꢀ-Enamino Esters 11
SCHEME 6. CM of Imidoyl Chlorides 1d,e with Ethyl
Acrylate
NaCNBH3
dr yield
Zn(BH4)2
dr yield
HCO2NH4, Pd-C, microwave
dr
yield
(%)
n
(()-12 (cis/trans) (%) (cis:trans) (%)
(cis:trans)
1 (()-12a
2 (()-12b 88:12
3 (()-12c 96:4
52:48
70
70
60
94:6
85:15
97:3
90
80
87
>99:1
>99:1
>99:1
83
87
82
SCHEME 8. Strategies for the Asymmetric Synthesis of
Cyclic Fluorinated ꢀ-Amino Acids
SCHEME 7. Synthesis of Cyclic Enamino Esters 11
the use of NaBH4 in CH2Cl2 in the presence of a Lewis acid
(ZnI2), as we had employed this method successfully in the past
for the reduction of acyclic and cyclic fluorinated ꢀ-enamino
esters.26a,b These reactions took place with good yields and better
selectivities, which reached 94% de for the seven-membered
derivative 12c. Finally, we attempted a catalytic hydrogenation
in order to obtain the corresponding cis-diastereoisomers. After
several attempts, we found that hydrogenation under microwave
irradiation in ethanol with Pd-C and HCO2NH4 as the hydrogen
source reduced cyclic derivatives 11 in good yields to give cis-
ꢀ-amino esters 12 exclusively, a procedure that worked well
with several ring sizes (Table 3).
At this point, the next challenge was to prepare cyclic
fluorinated ꢀ-amino acids in enantiomerically pure form.
The chemo- and stereoselective reduction of chiral nonrace-
mic ꢀ-enamino ester derivatives represents a simple and
attractive route for obtaining enantiopure ꢀ-amino acids. Two
approaches were considered, namely the incorporation of a chiral
auxiliary either on the nitrogen atom of the starting imidoyl
chloride or in the acrylic ester moiety (Scheme 8).36 Thus, the
CM reaction would give optically pure products, which could
then be transformed into N-protected chiral ꢀ-amino esters.
Finally, amine deprotection and ester hydrolysis would lead to
the target compounds.
dichloromethane and toluene (entries 2 and 3). As expected,
1c, with a methyl group on an olefinic carbon, was less reactive,
affording the CM product 3h in moderate yield only after
reaction with methyl 3-butenoate 2c (entry 4). Indeed, reaction
with ethyl acrylate 2d failed to give the CM product (entry 5).
Both substrates 1b and 1c could thus be regarded as type III
olefins, since they did not form the corresponding homodimers
and reacted sluggishly with ethyl acrylate (a type II olefin).
Substrates 1d,e, which contain longer unsaturated chains, were
used to prepare imidoyl chlorides 3i,j in excellent yields through
a CM reaction with ethyl acrylate 2d under the same conditions
that were found to be optimal in the case of 1a (catalyst II,
refluxing toluene) (Scheme 6). These results should be compared
to the more difficult preparation of CM products 3a-c, which
have the same chain length, starting from 1a and esters other
than acrylates (see Table 1, entries 1-5).
Once the cross-metathesis products 3d,i,j had been obtained,
we were able to prepare 5-, 6-, and 7-membered ꢀ-amino acid
derivatives, respectively.18 After undergoing the CM reaction,
olefin hydrogenation and a subsequent Dieckmann-type cy-
clization of these derivatives afforded ꢀ-enamino esters 11
(Scheme 7).
For the crucial stereoselective reduction step, various reducing
agents were tested for their efficiency in affording ꢀ-amino acid
derivatives 12 in racemic form (Table 3). Thus, cyclic com-
pounds 11 were first reduced with NaCNBH335 in THF/TFA at
0 °C, producing moderate yields and variable diastereoselec-
tivities, depending on the ring size. Another attempt involved
In the first approach, we decided to use the methyl ether of
(R)-phenylglycinol because it had proven to be extremely
efficient in the asymmetric synthesis of fluorinated cyclic
R-amino acids.15c,d This chiral auxiliary was introduced through
the preparation of the corresponding imidoyl chloride 1f
(Scheme 9), which was subjected to a CM reaction with ethyl
acrylate under the optimized conditions (catalyst II, refluxing
toluene). Next, olefin hydrogenation occurred chemoselectively
in the presence of PtO2 under H2 pressure (4 atm) to give the
(35) (a) Reduction by the Alumino- and Borohydrides in Organic Synthesis,
2nd ed.; Seyden-Penne, J., Ed.; Wiley-VCH: New York, 1997. (b) See ref
17.
(36) The enantioselective hydrogenation of five-membered enamino ester 11a
with a ruthenium catalyst [Ru(COD)(Methallyl)2] and a chiral ligand [(S)-BINAP]
was also attempted with no success.
3418 J. Org. Chem. Vol. 74, No. 9, 2009

Synthesis of Fluorinated Cyclic ꢀ-Amino Acids
SCHEME 9. Use of (R)-Phenylglycinol Methyl Ether as
Chiral Auxiliary
SCHEME 10. Use of (1R,2S,5R)-8-Phenylmenthol as Chiral
Auxiliary
new imidoyl chloride (-)-10d, which was then cyclized to
afford chiral enamino ester (+)-11d in good yield. Compound
11d was subsequently reduced with the system NaBH4/ZnI2 in
CH2Cl2 (Scheme 9, method A) to give a nonseparable mixture
of the four possible diastereoisomers of 12d in a 20:20:20:40
ratio (GC-MS) and moderate yield (40%). In order to improve
these results, we carried out the reduction with NaCNBH3 in
THF/TFA (method B), but once again, all four diastereoisomers
were detected with the aid of GC-MS (50:25:13:12) in only
30% yield. Finally, we tried the catalytic hydrogenation (method
C), but no reaction took place, regardless of whether PtO2 and
H2 (900 psi) or phase-transfer conditions (HCO2NH4 and Pd-C)
were used.
In view of these poor results in terms of yield and diaste-
reoselectivity, we decided to change the strategy by incorporat-
ing a chiral auxiliary [(+)-8-phenylmenthol] into the ester
moiety (Scheme 10). Thus, the synthetic strategy was repeated
starting from imidoyl chlorides 1a and 1d, which were coupled
with the acrylic ester of (-)-8-phenylmenthol, which was
previously prepared in the laboratory.37 The CM reaction, in
which Grubbs catalyst II in refluxing toluene was used, took
place in good yields and with high E/Z selectivity. The cross-
coupling products (+)-3l,m were then hydrogenated and cy-
clized under the conditions outlined above to afford five- and
six-membered chiral esters 11e,f in good yields (Scheme 10).
While the cyclopentane derivative (+)-11e was isolated exclu-
sively in its enamino form, the six-membered analogue (-)-11f
appeared as a 1:1 mixture of the imino and enamino tautomers,
which were separated by means of flash chromatography.
The next step involved the diastereoselective reduction of
the imino/enamino moiety. Several reducing agents were
tested on the five-membered enamino ester (+)-11e (see
Table 4). The reduction with NaCNBH3 in THF/TFA gave a
TABLE 4. Chemical Reduction of ꢀ-Enamino Ester (+)-11e
dr (cis:cis:
12e overall
entry
[H]
NaCNBH3
Zn(BH4)2
H2 (50 atm), PtO2
trans:trans)a
yieldb (%)
1
2
3
4
48:25:14:13
62:11:15:12
88:12:0:0
60
68
40c
58d
HCO2NH4,
80:20:0:0
Pd-C, microwave
a Diastereomeric ratio determined with the aid of GC-MS. b Isolated
yields after column chromatography. c A partial hydrogenation of the
PMP group took place, making the purification difficult and lowering
the chemical yield. d 77% yield based on recovered starting material.
(Longer reaction times and higher temperatures led to no significant
improvement in the conversion.)
mixture of the four possible diastereoisomers in a 48:25:14:
13 ratio (as determined with the aid of GC-MS) and 60%
yield (entry 1). With the reducing system NaBH4/ZnI2 in
CH2Cl2, the result was similar in terms of chemical yield
and stereoselectivity (entry 2), while catalytic hydrogenation
under high pressure (50 atm) in the presence of PtO2 took
place with good diastereoselectivity, but only moderate yield
(entry 3). The best conditions were again those involving a
phase-transfer catalysis hydrogenation under microwave
irradiation. Thus, compound (+)-11e was reduced after 45
min at 100 °C in the presence of Pd-C and HCO2NH4 to
(37) Whitesell, J. K.; Bhattacharya, A.; Buchanan, C. M.; Chen, H. H.; Deyo,
D.; James, D.; Liu, C.-L.; Minton, M. A. Tetrahedron 1986, 42, 2993–3001.
J. Org. Chem. Vol. 74, No. 9, 2009 3419

Fustero et al.
SCHEME 13. Epimerization of Five-Membered Amino
SCHEME 11. Diastereoselective Reduction of Compound
(-)-11f
Ester (+)-19
again with satisfactory yields for both ring sizes.40 Oxidation
of optically pure compounds 15 was accomplished through
treatment with NaIO4 and RuCl3 in a mixture of MeCN, CCl4,
and H2O. Finally, elimination of the N-Boc protecting group
on cyclic amino acids (+)-16a and (-)-16b in acidic conditions
(HCl in Et2O) led to the desired cyclic fluorinated ꢀ2,3-amino
acids 17a and 17b in enantiomerically pure form. Amine
deprotection on compound (+)-16a in MeOH as the solvent
gave the corresponding methyl ester hydrochloride (+)-18
(Scheme 12). Monoprotected amino acids 16 and 18 can be
regarded as monomeric units for the further construction of
fluorinated ꢀ-peptides.41 It is worth noting that compound (+)-
17a is a fluorinated analogue of the antifungal ent-cispentacin.7
Finally, we demonstrated that the cis ꢀ-amino acid (+)-16a
can be converted into the corresponding trans diastereoisomer.
Thus, N-Boc ꢀ-amino ester (+)-19 was treated with sodium
methoxide42 in MeOH to yield its trans epimer (-)-20 in
excellent yield (Scheme 13).
SCHEME 12. Final Deprotection of Chiral Amino Esters
12e,f
Conclusions
In conclusion, we have shown that fluorinated imidoyl
chlorides are useful compounds in cross-metathesis reactions
with unsaturated esters, providing an efficient starting point for
the preparation of nitrogen-containing organofluorine com-
pounds. In particular, the reaction between imidoyl chlorides 1
with various unsaturated chain lengths and an excess of ethyl
acrylate in the presence of second-generation Grubbs catalyst
II takes place in excellent yields and with high selectivities when
toluene is used as the solvent. Thus, the compatibility of the
imidoyl chloride functionality with the ruthenium catalyst once
again demonstrated the versatility of these complexes. This
methodology was then successfully used to synthesize cyclic
fluorinated ꢀ-amino acids in enantiomerically pure form by using
8-phenylmenthol-derived acrylates as chiral auxiliaries.
afford an 80:20 mixture of the cis-diastereoisomers 12e in
58% yield (entry 4). These conditions were also applied to
the cyclohexene derivative (-)-11f to afford the correspond-
ing chiral amino ester (-)-12f as the major product (Sch-
eme 11).38
In all cases, the major diastereoisomer was separated by
means of flash chromatography, and upon X-ray analysis of a
p-bromobenzoate derivative (+)-13, its absolute configuration
was found to be (1S,2S).39
To complete the synthesis, we undertook the removal of the
amino acid protecting groups on compounds (+)-12e and (-)-
12f (Scheme 12). To achieve this goal, we first changed the
nitrogen protecting group from PMP to Boc in order to avoid
PMP oxidation in subsequent steps. Thus, treatment of chiral
amino esters 12e and 12f with CAN and subsequent acylation
led to N-Boc chiral amino esters 14a and 14b in good yields.
The removal of the chiral auxiliary was achieved through
reduction with LiAlH4 to give alcohols (+)-15a and (-)-15b,
Experimental Section
General Procedure for the Synthesis of Fluorinated
Imidoyl Chlorides 1. PPh3 (3.0 equiv) and Et3N (1.2 equiv) were
(39) For the X-ray structure of (+)-13, see ref 18.
(40) In this manner, the chiral auxiliary 8-phenylmenthol was also recovered
(70-80%).
(41) (a) Hook, D. F.; Gessier, F.; Noti, C.; Kast, P.; Seebach, D. ChemBio-
Chem 2004, 5, 691–706. (b) See ref 3.
(38) In this reaction, an 86:14 mixture of the cis diastereoisomers was
obtained.
(42) Tang, W.; Wu, S.; Zhang, X. J. Am. Chem. Soc. 2003, 125, 9570–9571.
3420 J. Org. Chem. Vol. 74, No. 9, 2009

Synthesis of Fluorinated Cyclic ꢀ-Amino Acids
added to a cold (0 °C) solution of the corresponding carboxylic
acid 5 (1.0 equiv) in CCl4 (1 M). After the solution was stirred for
10 min, p-anisidine (1.2 equiv) was added, and the mixture was
stirred under reflux for 3 h. The solvents were then removed under
reduced pressure, and the residue was extracted with hexane and
filtered. The filtrate was concentrated and purified through distil-
lation under reduced pressure. Compounds 1a,43 1d,18 1e,18 and
(-)-1f15c were previously described.
from 760 mg (1.43 mmol) of (+)-3m as a colorless oil (85% yield):
Rf ) 0.40 (hexane/ethyl acetate, 10:1); [R]25 ) +7.2 (c 1.1,
D
CHCl3); 1H NMR (300 MHz, CDCl3) δ 0.77 (d, J ) 6.6 Hz, 3H),
0.80-1.06 (m, 3H), 1.10 (s, 3H), 1.21 (s, 3H), 1.38-1.40 (m, 4H),
1.53-1.60 (m, 2H), 1.64-1.72 (m, 3H), 1.91-1.99 (m, 1H),
2.05-2.19 (m, 2H), 3.73 (s, 3H), 4.73 (dt, J ) 10.7, 4.3 Hz, 1H),
6.85 (d, J ) 9.1 Hz, 2H), 7.06 (d, J ) 9.1 Hz, 2H), 7.02-7.07 (m,
1H), 7.15-7.19 (m, 5H); 13C NMR (75.5 MHz, CDCl3) δ 21.3 (t,
3JCF ) 3.8 Hz), 21.7, 22.6, 24.0, 26.4, 28.6, 31.2, 31.5, 33.7, 34.5
1-Chloro-2,2-difluoro-3-methyl-N-(4-methoxyphenyl)-4-penten-
1-imine (1b). By means of the general procedure described above,
1.27 g of 1b was obtained from 1.00 g (6.67 mmol) of 2,2-difluoro-
3-methyl-4-pentenoic acid (5b) as a yellow oil (70% yield): bp
2
(t, JCF ) 23.6 Hz), 39.5, 41.7, 50.2, 55.3, 73.9, 114.1, 118.1 (t,
1JCF ) 246.6 Hz), 123.1, 124.9, 125.3, 127.8, 137.0, 137.3 (t, 2JCF
) 37.1 Hz), 151.8, 158.5, 172.3; 19F NMR (282.4 MHz, CDCl3) δ
-109.24 (t, JFH ) 16.4 Hz, 2F); HRMS (EI) calcd for
C30H38ClF2NO3 (M+) 533.2508, found 533.2504.
1
88-91 °C (2 × 10-2 Torr); H NMR (300 MHz, CDCl3) δ 1.08
(d, J ) 7.0 Hz, 3H), 3.00-3.10 (m, 1H), 3.61 (s, 3H), 5.02-5.09
(m, 2H), 5.61-5.73 (m, 1H), 6.72 (d, J ) 9.0 Hz, 2H), 6.90 (d, J
) 9.0 Hz, 2H); 13C NMR (75.5 MHz, CDCl3) δ 13.0 (t, 3JCF ) 4.0
General Procedure for the Dieckmann-Type Cyclization: Syn-
thesis of Imino/Enamino Esters 11. N-Butyllithium (2.5 M in
hexane, 2.1 equiv) was added dropwise to a cold (-30 °C) solution
of diisopropylamine (2.1 equiv) in THF (0.25 M). After being stirred
for 30 min, the mixture was cooled to -78 °C and a solution of
the corresponding imidoyl chloride 10 (1.0 equiv) in THF (0.12
M) was added slowly. The reaction mixture was stirred for 1 h at
-78 °C, and then it was quenched with satd aq NH4Cl. The aqueous
layer was extracted with CH2Cl2, and the combined organic layers
were washed with brine and dried over anhydrous Na2SO4. The
filtrate was concentrated and purified by means of flash chroma-
tography on silica gel with the appropriate solvents. Compounds
11a, 11b, 11c, and (+)-11e were previously described.18
2
1
Hz), 43.0 (t, JCF ) 23.3 Hz), 55.4, 114.1, 118.0 (t, JCF ) 251.6
Hz), 118.8, 122.8, 124.2, 134.5 (t, 3JCF ) 4.3 Hz), 134.5, 137.2 (t,
2JCF ) 17.5 Hz), 158.4; 19F NMR (282.4 MHz, CDCl3) δ -104.96
(dd, JFF ) 254.1 Hz, JFH ) 12.9 Hz, 1F), -106.79 (dd, JFF ) 254.1
Hz, JFH ) 16.0 Hz, 1F); HRMS (EI) calcd for C13H14ClF2NO (M+)
273.0575, found 273.0580.
General Procedure for the Cross-Metathesis Reaction: Synthe-
sis of Imidoyl Chlorides 3, 7, and 9. Unsaturated ester 2 (2.0 or
5.0 equiv) and second-generation ruthenium alkylidene catalyst II
(5-10 mol %) were added successively to a solution of fluorinated
imidoyl chloride 1 (1.0 equiv) in CH2Cl2 or PhMe (0.25 M). The
mixture was stirred at 95 °C under argon atmosphere overnight.
The solvent was then removed under reduced pressure, and the
crude reaction mixture was purified by means of flash column
chromatography on silica gel with the appropriate solvents.
Compounds 3d, 3i, 3j, and (+)-3l were previously described.18
(+)-(E)-(1′R,2′S,5′R)-8′-Phenylmenthyl 7-chloro-6,6-difluoro-7-
(4-methoxyphenylimino)-2-heptenoate [(+)-3m]. By means of the
general procedure described above, 825 mg of 3m was obtained
from 540 mg (1.97 mmol) of 1d and 1.10 g (3.94 mmol) of (+)-
8-phenylmenthyl acrylate37 as a yellow oil (80% yield) with an
E/Z isomer ratio of 19:1, as determined by means of signal
integration in the 19F NMR. Data for the E isomer: Rf) 0.40
(hexane/ethyl acetate, 10:1); [R]25D) +4.9 (c 1.4, CHCl3); 1H NMR
(300 MHz, CDCl3) δ 0.78 (d, J ) 6.4 Hz, 3H), 0.85-1.07 (m,
3H), 1.11 (s, 3H), 1.21 (s, 3H), 1.38-1.42 (m, 1H), 1.55-1.70
(m, 2H), 1.80 (br d, J ) 12.2 Hz, 1H), 1.98-2.03 (m, 1H),
2.21-2.34 (m, 4H), 3.74 (s, 3H), 4.75 (dt, J ) 10.7, 4.3 Hz, 1H),
5.19 (d, J ) 15.6 Hz, 1H), 6.35 (d, J ) 15.8 Hz, 1H), 6.86 (d, J )
9.0 Hz, 2H), 6.99-7.18 (m, 7H); 13C NMR (75.5 MHz, CDCl3) δ
(-)-(1′R,2′S,5′R)-3,3-difluoro-1-(8′-phenylmenthyloxycarbonyl)-
2-(4-methoxyphenylamino)-1-cyclohexene [(-)-11f]. By means of
the general procedure described above, from 560 mg (1.05 mmol)
of (+)-10f, (-)-11f was obtained as a mixture of enamino (229
mg, 43% yield) and imino forms (234 mg, 44% yield), both as a
yellow oils. Data for the enamino form: Rf) 0.40 (hexane/ethyl
acetate, 10:1). [R]25D) -252.3 (c 1.0, CHCl3). 1H NMR (300 MHz,
CDCl3) δ 0.81 (d, J ) 6.6 Hz, 3H), 0.88-1.08 (m, 3H), 1.16 (s,
3H), 1.29 (s, 3H), 1.56-1.66 (m, 6H), 1.80-1.84 (m, 1H),
1.99-2.11 (m, 4H), 3.71 (s, 3H), 4.92 (dd, J ) 10.6, 4.5 Hz, 1H),
6.73-6.78 (m, 2H), 7.06-7.20 (m, 7H), 8.66 (br s, 1H). 13C NMR
3
(75.5 MHz, CDCl3) δ 21.8, 22.0 (t, JCF) 10.3 Hz), 25.3, 26.7,
2
27.8, 31.4, 33.2 (t, JCF) 24.4 Hz), 33.3, 34.5, 39.8, 42.2, 50.5,
3
4
55.4, 73.4, 101.9 (t, JCF) 7.5 Hz), 113.9, 124.9, 125.1 (t, JCF
)
1
2
2.9 Hz), 125.4, 128.9 (t, JCF) 248.7 Hz), 131.9, 148.9 (t, JCF
)
23.3 Hz), 151.6, 156.9, 166.9, 172.1. 19F NMR (282.4 MHz, CDCl3)
δ -97.66 (br, 2F). HRMS (EI) calcd for C30H37F2NO3 (M+):
497.2742, found: 497.2755. Data for the imino form: Rf) 0.20
(hexane/ethyl acetate, 10:1). [R]25D) -242.95 (c 0.9, CHCl3). H
1
21.7, 24.2, 24.4 (t, 3JCF ) 4.6 Hz), 26.4, 28.5, 31.2, 33.1 (t, 2JCF
)
)
NMR (300 MHz, CDCl3) δ 0.83 (d, J ) 6.6 Hz, 3H), 0.87-0.95
(m, 3H), 1.08 (s, 3H), 1.18 (s, 3H), 1.28-1.47 (m, 4H), 1.60-1.84
(m, 5H), 1.96-2.05 (m, 1H), 2.24-2.33 (m, 1H), 3.15 (br s, 1H),
3.79 (s, 3H), 4.82 (dt, J ) 10.8, 4.4 Hz, 1H), 6.85-6.90 (m, 7H),
24.2 Hz), 34.5, 39.5, 41.6, 50.4, 55.4, 74.1, 114.1, 117.6 (t, 1JCF
2
246.7 Hz), 122.5, 123.3, 124.7, 125.3, 127.9, 136.6, 136.7 (t, JCF
) 37.4 Hz), 145.1, 151.8, 158.7, 165.2. 19F NMR (282.4 MHz,
CDCl3) δ -107.70 (t, JFH) 15.5 Hz, 2F). HRMS (EI) calcd for
C30H36ClF2NO3 (M+): 531.2352, found: 531.2361.
7.01-7.05 (m, 2H). 13C NMR (75.5 MHz, CDCl3) δ 19.0 (t, 3JCF
)
)
2
9.2 Hz), 21.8, 23.0, 26.4, 27.0, 29.2, 31.3, 34.5, 36.2 (dd, JCF
General Procedure for the Chemoselective Hydrogenation of
Olefins: Synthesis of Imidoyl Chlorides 10. Palladium on active
carbon (10 wt %, 0.2 equiv) or platinum dioxide (0.2 equiv) was
added to a solution of the enoate (1.0 equiv) in EtOAc (0.05 M).
The resulting suspension was stirred in a medium pressure reactor
with hydrogen (4 atm) for 24 h. The reaction mixture was then
filtered through Celite. The filtrate was concentrated and purified
by means of flash chromatography on silica gel with the appropriate
solvents. Compounds 10a, 10b, 10c, and (+)-10e were previously
described.18
25.9, 21.9 Hz), 39.3, 41.3, 45.3, 50.3, 55.5, 75.7, 114.2, 117.9 (dd,
1JCF) 255.9, 237.5 Hz), 120.6, 124.8, 125.0, 127.8, 141.4, 152.0,
2
157.2, 160.4 (dd, JCF) 27.9, 16.4 Hz), 167.3. 19F NMR (282.4
MHz, CDCl3) δ -110.57 (ddd, JFF) 246.7 Hz, JFH) 34.9, 10.8
Hz, 1F), -118.23 (d, JFF) 246.6 Hz, 1F). HRMS (EI) calcd for
C30H37F2NO3 (M+): 497.2742, found: 497.2732.
General Procedure for the Hydrogenation of Enamino/imino
Esters 11: Synthesis of Amino Esters 12. Palladium on active carbon
(10 wt %, 0.2 equiv) and NH4CO2H (10.0 equiv) were added to a
solution of the corresponding enamino/imino ester 11 (1.0 equiv)
in EtOH (0.1 M). The mixture was stirred in a sealed tube in a
microwave reactor at 100 °C for 45 min. The reaction was then
filtered. The filtrate was concentrated and purified by means of flash
chromatography on silica gel with the appropriate solvents.
Compounds 12a, 12b, 12c, and (+)-12e were previously de-
scribed.18
(+)-(E)-(1′R,2′S,5′R)-8′-Phenylmenthyl 7-chloro-6, 6-difluoro-
7-(4-methoxyphenylimino)- heptanoate [(+)-10f]. By means of the
general procedure described above, 650 mg of 10f was obtained
(43) Fustero, S.; Navarro, A.; Pina, B.; García-Soler, J.; Bartolome´, A.;
Asensio, A.; Simo´n, A.; Bravo, P.; Fronza, G.; Volonterio, A.; Zanda, M. Org.
Lett. 2001, 3, 2621–2624.
J. Org. Chem. Vol. 74, No. 9, 2009 3421

Fustero et al.
(-)-(1S,2S,1′R,2′S,5′R)-3,3-Difluoro- 2-(4-methoxyphenylamino)-
1-(8′-phenylmenthyloxycarbonyl)cyclohexane [(-)-12f]. By means
of the general procedure described above, from 100 mg (0.20 mmol)
of (-)-11f was obtained 50 mg of 12f as a white solid (50% yield),
together with 8 mg of its diastereoisomer (8% yield) and 25 mg of
recovered (-)-11f (25% yield): Rf ) 0.25 (hexane/ethyl acetate,
10:1); [R]25D ) -28.6 (c 0.9, CHCl3); 1H NMR (300 MHz, CDCl3)
δ 0.80 (d, J ) 6.6 Hz, 3H), 0.85-0.99 (m, 2H), 1.03 (s, 3H), 1.10
(s, 3H), 1.13 (d, J ) 2.9 Hz, 1H), 1.23 (d, J ) 3.4 Hz, 1H),
1.55-1.65 (m, 4H), 1.76-1.80 (m, 2H), 1.91-2.08 (m, 4H), 2.46
(q, J ) 6.9 Hz, 1H), 3.67 (s, 3H), 3.78 (quint, J ) 9.3 Hz, 1H),
4.73 (dt, J ) 10.7, 4.3 Hz, 1H), 4.42 (d, J ) 8.9 Hz, 1H), 6.61 (d,
J ) 8.9 Hz, 2H), 6.71 (d, J ) 8.9 Hz, 2H), 7.02-7.22 (m, 5H);
13C NMR (75.5 MHz, CDCl3) δ 20.2 (t, 3JCF ) 5.2 Hz), 21.7, 21.9,
1H), 3.50-3.52 (m, 2H), 4.17-4.22 (m, 1H), 4.87 (d, J ) 6.2 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 22.1 (t, 3JCF ) 4.0 Hz), 28.2,
32.5 (t, JCF ) 24.3 Hz), 42.5, 56.8 (dd, JCF ) 25.3, 18.5 Hz),
61.8, 80.7, 129.3 (t, 1JCF ) 254.4 Hz), 156.6; 19F NMR (282.4 MHz,
CDCl3) δ -98.2 (dq, JFH ) 14.4 Hz, JFF ) 234.6 Hz, 1F), -108.2
(dm, JFF ) 233.2 Hz, 1F); HRMS (FAB) calcd for C11H19F2NO3
(M+ + 1) 252.1411, found 252.1416.
2
2
General Procedure for the Synthesis of N-Boc-Protected Chiral
Amino Acids 16. N-Boc-protected amino alcohols 15 (1 equiv) were
dissolved in CCl4/CH3CN/H2O (1:2:1.5) under brisk stirring. Then,
NaIO4 (10 equiv) and RuCl3 ·3H2O (0.05 equiv) were added. After
the mixture was stirred at room temperature for 2 h, the reaction
salts were filtered off and washed with CCl4. The organic layer
was extracted with EtOAc, washed with brine, and dried over
anhydrous Na2SO4, and the solvents were removed under reduced
pressure. The crude reaction mixture was purified by means of
column chromatography on silica gel with the appropriate solvents.
(+)-(1S,2S)-3,3-Difluoro-2-(N-tert-butoxycarbonylamino)cyclo-
pentanecarboxylic Acid [(+)-16a]. By means of the general
procedure described above, 70 mg of 16a was obtained from 100
mg (0.40 mmol) of (+)-15a as a colorless oil (66% yield) as a 1:1
2
24.5, 26.5, 28.2, 29.8 (t, JCF ) 23.3 Hz), 31.2, 34.5, 39.5, 41.7,
3
2
43.9 (t, JCF ) 2.9 Hz), 50.0, 55.7, 57.0 (t, JCF ) 26.7 Hz), 75.2,
114.6, 115.6, 123.4 (t, 1JCF) 247.2 Hz), 125.1, 125.3, 127.9, 141.6,
151.7, 152.8, 171.3; 19F NMR (282.4 MHz, CDCl3) δ -115.49 (dt
d, JFF ) 230.2 Hz, JFH ) 15.5, 9.9 Hz 1F), -106.75 (dt d, JFF
)
230.2 Hz, JFH) 16.1, 10.8 Hz 1F); HRMS (EI) calcd for
C30H39F2NO3 (M+) 499.2898, found 499.2892.
mixture of rotamers: Rf ) 0.50 (hexane/ethyl acetate, 1:1); [R]25
General Procedure for the Synthesis of N-Boc-Protected Chiral
Amino Esters 14. A solution of CAN (3.0 equiv) in H2O (0.6 M)
was added dropwise to a cold (0 °C) solution of 12 (1.0 equiv) in
MeCN (0.1 M). After being stirred for 4 h at room temperature,
the reaction was quenched with 5% aq NaHCO3 until pH 7, and
20% aq Na2S2O3 was added. The aqueous layer was extracted with
EtOAc. The combined organic layers were washed with brine and
dried over anhydrous Na2SO4, and the solvents were removed under
reduced pressure. Then the resulting brown residue was dissolved
in dry CH2Cl2, and (Boc)2O (5.0 equiv) and K2CO3 (3.0 equiv)
were added at room temperature. After being stirred for 4 h at room
temperature, the reaction was quenched with H2O and the aqueous
layer was extracted with EtOAc. The combined organic layers were
washed with brine and dried over anhydrous Na2SO4, and the
solvents were removed under reduced pressure. The crude reaction
mixture was purified by means of column chromatography on silica
gel with the appropriate solvents.
D
1
) +32.5 (c 1.0, CHCl3); H NMR (300 MHz, CDCl3) δ 1.40 (s,
9H), 1.85-1.95 (m, 2H), 2.04-2.21 (m, 2H), 3.15-3.22 (m, 1H),
4.22-4.45 (m, 1H), 5.37 (d, J ) 8.9 Hz, 0.5H), 6.75 (d, J ) 9.3
Hz, 0.5H), 11.38 (br s, 1H); 13C NMR (75.5 MHz, CDCl3) δ 21.7,
22.3, 28.0, 31.9 (t, 2JCF ) 24.0 Hz), 32.0 (t, 2JCF ) 23.3 Hz), 43.8,
2
2
44.1, 56.4 (dd, JCF ) 29.7, 20.0 Hz), 57.4 (dd, JCF ) 33.1, 20.2
Hz), 80.6, 82.3, 127.5 (t, 1JCF ) 252.5 Hz), 128.1 (t, 1JCF ) 254.7
Hz), 155.4, 157.6, 175.1, 177.4; 19F NMR (282.4 MHz, CDCl3) δ
-99.96 (dd, JFH) 11.1 Hz, JFF ) 231.5 Hz, 0.5F), -101.26 (dq,
JFH ) 12.0 Hz, JFF ) 232.4 Hz, 0.5F), -104.52 (dq, JFH ) 15.5
Hz, JFF ) 230.7 Hz, 0.5F), -109.42 (dd, JFH ) 7.8 Hz, JFF ) 231.5
Hz, 0.5F); HRMS (FAB) calcd for C11H17F2NO4 (M+ + 1)
266.1204, found 266.1204.
General Procedure for the Synthesis of Chiral Cyclic ꢀ-Amino
Acids 17. N-Boc-protected amino acids 16 (1 equiv) were dissolved
in diethyl ether, and anhydrous HCl (1 M in diethyl ether) was
added. The mixture was stirred at room temperature for 6 h and
concentrated under reduced pressure to obtain free chiral amino
acids 17, which were purified by washing the solid residue with
diethyl ether.
(+)-(1S,2S)-3,3-Difluorocyclopentanecarboxylic Acid Hydro-
chloride [(+)-17a]. By means of the general procedure described
above, 27 mg of 17a were obtained from 45 mg (0.17 mmol) of
(+)-(1S,2S,1′R,2′S,5′R)-3,3-Difluoro-2-(N-tert-butoxycarbony-
lamino)-1-(8′-phenylmenthyloxycarbonyl)cyclopentane [(+)-14a].
By means of the general procedure described above, 206 mg of
14a was obtained from 300 mg (0.62 mmol) of (+)-12e as a
colorless oil (80% yield): Rf ) 0.30 (hexane/ethyl acetate, 15:1);
1
[R]25 ) +46.9 (c 1.0, CHCl3); H NMR (400 MHz, CDCl3) δ
D
0.81 (d, J ) 6.5 Hz, 3H), 0.84-1.06 (m, 2H), 1.12 (s, 3H), 1.22
(s, 3H), 1.37 (s, 9H), 1.41-1.46 (m, 1H), 1.56-1.65 (m, 2H),
1.70-1.75 (m, 2H), 1-87-2.13 (m, 6H), 4.04-4.17 (m, 1H), 4.67
(d, J ) 9.2 Hz, 1H), 4.74 (dt, J ) 10.7, 4.4 Hz, 1H), 7.03-7.08
(m, 1H), 7.18-7.20 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 21.9,
(+)-16a as a white solid (79% yield): mp 227-228 °C; [R]25
)
D
1
+36.2 (c 1.0, H2O); H NMR (300 MHz, D2O) δ 2.07-2.20 (m,
4H), 3.29-3.31 (m, 1H), 3.95-4.00 (m, 1H); 13C NMR (75.5 MHz,
3
2
D2O) δ 23.6 (t, JCF ) 3.0 Hz), 32.0 (t, JCF ) 17.7 Hz), 42.7 (t,
2
3JCF ) 3.9 Hz), 55.3 (dd, JCF ) 23.5, 15.5 Hz), 128.1 (t, JCF
)
2
1
23.7, 26.3, 28.3, 29.0, 31.3, 31.8 (t, JCF ) 22.9 Hz), 34.4, 39.5,
41.5, 43.4, 50.0, 56.1 (dd, 2JCF ) 31.3, 20.3 Hz), 74.7, 80.0, 125.0,
189.3 Hz), 176.1; 19F NMR (282.4 MHz, D2O) δ -97.90 (br d,
JFH) 236.2 Hz, 1F), -103.79 (br d, JFF) 235.5 Hz, 1F); HRMS
(FAB) calcd for C6H10ClF2NO2 (M+ - HCl) 166.0679, found
166.0680.
1
125.3, 127.9, 128.1 (t, JCF ) 254.2 Hz), 151.6, 154.8, 171.0; 19F
NMR (282.4 MHz, CDCl3) δ -107.25 (dq, JFF ) 230.9 Hz, JFH
)
14.4 Hz, 1F), -101.02 (dq, JFF ) 230.9 Hz, JFH ) 12.4 Hz, 1F);
HRMS (EI) calcd for C27H39F2NO4 (M+) 479.2847, found 479.2831.
General Procedure for the Synthesis of N-Boc-Protected Chiral
Amino Alcohols 15. LiAlH4 (5 equiv) was added to a cold (0 °C)
solution of 14 (1 equiv) in THF (0.1 M). After being stirred at
room temperature for 6 h, the reaction was quenched with
Na2SO4 ·10H2O. The organic layer was filtered and concentrated.
The crude reaction mixture was purified by means of column
chromatography on silica gel with the appropriate solvents.
(+)-(1S,5S)-2, 2-Difluoro-1-(N-tert-butoxycarbonylamino)-5-(hy-
droxymethyl)cyclopentane [(+)-15a]. By means of the general
procedure described above, 135 mg of 15a was obtained from 320
mg (0.72 mmol) of (+)-14a as a white solid (75% yield): mp 69-70
Synthesis of (+)-(1S,2S)-Methyl 2-(N-tert-Butoxycarbonylamino)-
3,3-difluorocyclopentanecarboxylate [(+)-19]. N-Boc-protected amino
acid (+)-16a (67 mg, 0.26 mmol) was dissolved in MeOH (4 mL),
and trimethylsilyldiazomethane (2 M in hexane, 0.5 mL) was added
dropwise. The mixture was stirred at room temperature for 10 min
and then concentrated under reduced pressure. The crude reaction
mixture was purified by means of column chromatography on silica
gel (hexane/EtOAc, 4:1) to obtain 40 mg of (+)-19 as a colorless
oil (60% yield): [R]25D +58.0 (c 1.0, CHCl3); 1H NMR (300 MHz,
CDCl3) δ 1.38 (s, 9H), 1.87-1.97 (m, 1H), 2.04-2.12 (m, 3H),
3.18 (dt, J ) 8.4, 4.5 Hz, 1H), 3.64 (s, 3H), 4.39 (quint, J ) 10.5
Hz, 1H), 5.18 (d, J ) 8.9, 1H). 13C NMR (75.5 MHz, CDCl3) δ
21.5 (t, 3JCF ) 4.2 Hz), 27.2, 31.2 (t, 2JCF ) 24.1 Hz), 43.0 (d, 3JCF
) 6.7 Hz), 51.1, 55.3 (dd, 2JCF ) 29.5, 20.0 Hz), 79.2, 114.3, 126.7
°C; Rf ) 0.50 (hexane/ethyl acetate, 1:1); [R]25 ) +28.8 (c 1.0,
D
1
CHCl3); H NMR (400 MHz, CDCl3) δ 1.41 (s, 9H), 1.75-1.81
(m, 1H), 2.03-2.14 (m, 2H), 2.40-2.46 (m, 1H), 2.70-2.73 (m,
1
(t, JCF ) 251.5 Hz), 128.5, 154.2, 171.5; 19F NMR (282.4 MHz,
3422 J. Org. Chem. Vol. 74, No. 9, 2009

Synthesis of Fluorinated Cyclic ꢀ-Amino Acids
CDCl3) δ -101.85 (ddt, JFH ) 11.8, 23.6 Hz, JFF ) 230.9 Hz, 1F),
-106.01 (ddt, JFH ) 16.8, 30.4 Hz, JFF ) 231.5 Hz, 1F); HRMS
(EI) calcd for C12H19F2NO4 (M+) 279.1345, found 279.1332.
1JCF ) 250.8 Hz), 158.7, 181.8; 19F NMR (282.4 MHz, CDCl3) δ
-113.76 (ddt, JFH ) 10.7, 21.1 Hz, JFF ) 227.4 Hz, 1F), -116.54
(ddt, JFH ) 17.2, 34.4 Hz, JFF ) 239.1 Hz, 1F); HRMS (FAB)
calcd for C12H20F2NO4 (M+ + 1) 280.1360, found 280.1355.
Synthesis of (-)-(1R,2S)-Methyl 2-(N-tert-Butoxycarbonylamino)-
3,3-difluorocyclopentanecarboxylate [(-)-20]. Sodium methoxide
(0.5 M in MeOH, 0.9 mL) was added to a solution of (+)-19 (30
mg, 0.1 mmol) in dry MeOH (1.5 mL). The mixture was stirred at
room temperature for 24 h and then concentrated under reduced
pressure. The crude reaction mixture was purified by means of
column chromatography on silica gel (hexane/EtOAc, 5:1) to obtain
Acknowledgment. We would like to thank the Ministerio
de Educacio´n y Ciencia of Spain for financial support (CTQ2007-
61462). B.F. expresses her thanks for a predoctoral fellowship,
M.S.-R. for a postdoctoral contract, and J.L.A. and C.P. for
Ramo´n y Cajal contracts.
29 mg of (-)-20 as a white solid (97% yield): mp 86-87 °C; [R]25
D
-14.0 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3) δ 1.39 (s, 9H),
1.94-2.22 (m, 4H), 2.63 (q, J ) 9.3 Hz, 1H), 3.66 (s, 3H),
4.29-4.34 (m, 1H), 4.72-4.80 (m, 1H); 13C NMR (75.5 MHz,
CDCl3) 25.1 (t, 3JCF ) 4.7 Hz), 29.6, 34.5 (t, 2JCF ) 24.2 Hz), 51.7
(t, 3JCF ) 5.4 Hz), 60.9 (dd, 2JCF ) 26.7, 19.8 Hz), 81.2, 130.2 (t,
Supporting Information Available: Experimental proce-
dures and NMR spectra for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
JO900296D
J. Org. Chem. Vol. 74, No. 9, 2009 3423