Asymmetric synthesis of fluorinated cyclic β-amino acid derivatives through cross metathesis

Article abstract of DOI:10.1021/ol061892w

The asymmetric synthesis of several fluorinated cis-2-aminocycloalkane carboxylic acids (cis-2-ACACs) with a cross metathesis (CM) reaction as the key step has been carried out, constituting the first time a metathesis protocol has been undertaken with fl

Full text of DOI:10.1021/ol061892w

ORGANIC
LETTERS
2006
Vol. 8, No. 20
4633-4636
Asymmetric Synthesis of Fluorinated
Cyclic -Amino Acid Derivatives
â
through Cross Metathesis
Santos Fustero,*,†,‡ Mar´ıa Sa´nchez-Rosello´,† Juan F. Sanz-Cervera,†,‡
Jose´ Luis Acen˜a,‡ Carlos del Pozo,† Begon˜a Ferna´ndez,† Ana Bartolome´,† and
Amparo Asensio†
Departamento de Qu´ımica Orga´nica, UniVersidad de Valencia,
E-46100 Burjassot, Spain, and Laboratorio de Mole´culas Orga´nicas,
Centro de InVestigacio´n Pr´ıncipe Felipe, E-46013 Valencia, Spain
santos.fustero@uV.es
Received July 31, 2006
ABSTRACT
The asymmetric synthesis of several fluorinated cis-2-aminocycloalkane carboxylic acids (cis-2-ACACs) with a cross metathesis (CM) reaction
as the key step has been carried out, constituting the first time a metathesis protocol has been undertaken with fluorinated imidoyl chlorides.
Subsequent chemoselective hydrogenation of the olefin moiety, Dieckmann condensation, and stereoselective reduction of the iminic double
bond afforded the corresponding
â-amino esters with several ring sizes. The asymmetric version of the process was achieved by using
(
−)-8-phenylmenthol as a chiral auxiliary.
The synthesis of â-amino acid derivatives1 has generated
much attention not only due to their presence in a wide
number of natural products but also because compounds
bearing this structural motif have shown interesting biological
properties, including antibiotic characteristics and inhibitory
effects against cholesterol and fat absorption.2 They have
thus been used as important building blocks in drug research,
comprising, for example, the monomeric units of â-peptides,1
which in turn display secondary structures that are signifi-
cantly more stable than their parent R-peptides. Among
â-amino acid derivatives, work on 2-aminocycloalkane
carboxylic acids (2-ACACs) has witnessed a surge since the
pioneering research done by the Gellman and Seebach
research groups.3 Their innovation involved folding oli-
gopeptidic chains bearing 2-ACAC moieties into helical
structures to confer rigidity to the final backbone, thus giving
rise to conformationally restricted peptidomimetics that have
proved to be stable against metabolic degradation.4
Olefin metathesis is now widely considered to be one of
the most powerful synthetic tools in organic chemistry for
the creation of carbon-carbon double bonds.5 The ongoing
development of robust ruthenium catalysts has had a
tremendous impact on the use of the cross metathesis reaction
† Universidad de Valencia.
‡ Centro de Investigacio´n Pr´ıncipe Felipe.
(1) (a) EnantioselectiVe Synthesis of â-Amino Acids, 2nd ed.; Juaristi,
E. C., Soloshonok, V. A., Eds.: Wiley-VCH Ltd.: New York, 2005. (b)
Frackenpohl, J.; Arvidsson, P. I.; Schreiber, J. V.; Seebach, D. ChemBio-
Chem 2001, 2, 445-455. (c) Borman, S. Chem. Eng. News 1999, 77, 27.
(d) Liu, M.; Sibi, M. P. Tetrahedron 2002, 58, 7991-8035. (e) Lelais, G.;
Seebach, D. Biopolymers (Pept. Sci.) 2004, 76, 206-243. (f) Seebach, D.;
Hook, D. F.; Gla¨ttli, A. Biopolymers (Pept. Sci.) 2006, 84, 23-37.
(2) (a) Werder, M.; Hauser, H.; Abele, S.; Seebach, D. HelV. Chim. Acta
1999, 82, 1774-1783. (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, 7553-7559. (d) Hamuro, Y.; Schneider, J. P.;
DeGrado, W. F. J. Am. Chem. Soc. 1999, 121, 12200-12205.
(3) (a) Fu¨lo¨p, F. Chem. ReV. 2001, 101, 2181-2204. (b) Seebach, D.;
Kimmerlin, R. S.; Sebesta, R.; Campo, M. A.; Beck, A. K. Tetrahedron
2004, 60, 7405-7506. (c) Cheng, R. P.; Gellman, S. H.; DeGrado, W. F.
Chem. ReV. 2001, 101, 3219-3232.
(4) (a) Spatola, A. F. In Chemistry and Biochemistry of Amino Acids,
Peptides and Proteins; Weinstein, B., Ed.; Marcel Dekker: New York, 1983.
(b) Hawkins, J. M.; Lewis, T. A. J. Org. Chem. 1994, 59, 649-652.
10.1021/ol061892w CCC: $33.50
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Published on Web 08/29/2006

(CM);6 in fact, as both the chemo- and stereoselectivity of
this process steadily improve, it is finding increasingly ample
application in the synthesis of natural products.7 However,
examples of this methodology being used for the preparation
of cyclic â-amino acid derivatives are very scarce.8 To date,
only a few reports have been published on the synthesis of
these derivatives, and all of these have involved a ring-
closing metathesis (RCM) protocol.9
involving a cross metathesis reaction (CM), could be used
for the synthesis of these derivatives. In the present paper,
we thus describe a new and efficient method for the racemic
and asymmetric synthesis of fluorinated cis-ACACs with a
CM reaction as the key step. The retrosynthetic analysis is
outlined in Scheme 2.
Moreover, despite the importance of â-amino acid deriva-
tives, very little research has been done on their fluorinated
analogues. In fact, not only have few reports related to these
building blocks been published10 but also, to the best of our
knowledge, only two of these reported on the preparation of
fluorinated 2-ACACs.11 One such preparation method,
developed by our research group,11a afforded racemic flu-
orinated seven-membered â-amino acid derivatives (()-3.
These were prepared through an RCM of the appropriate
â-imino esters 2, which had been previously synthesized by
reacting imidoyl chlorides 1 with unsaturated esters (Scheme
1). This strategy, however, was of little use in the preparation
Scheme 2. Retrosynthetic Analysis
Scheme 1. Previous Preparation of Seven-Membered Cyclic
Fluorinated â-Amino Acids 3 by Means of an RCM
Our strategy starts with a CM reaction of imidoyl chlorides
1 with unsaturated esters 4 to afford the coupling products
5.13 Subsequent chemoselective hydrogenation of the double
bond on 5 and Dieckmann-type condensation lead to the
cyclic â-imino esters 7, which are then selectively reduced
and deprotected to give the desired cis-ACACs 8.
Given the various possible reaction pathways to products
5, ethyl acrylates 4 (m ) 0) and imidoyl chlorides 1 with
several different side chains (n ) 1-3) were chosen as
starting materials for the CM reaction.14 Thus, when com-
pounds 1 and ethyl acrylate (5 equiv) were heated in toluene
at 95 °C in the presence of a second-generation Grubbs
catalyst [(IMesH2)(PCy3)Cl2RudCHPh] 9 (5 mol %) for 15
h, the desired coupling products 5 were obtained in excellent
yields and stereoselectivities (Table 1).
of five- and six-membered rings as access to the correspond-
ing RCM precursors 2 proved impossible with the afore-
mentioned methodology.12
We surmised that to circumvent this problem of forming
differently sized rings an alternative strategy, namely one
(5) Grubbs, R. H. In Handbook of Metathesis; Wiley-VCH Verlag Gmbh
and Co.: KGaA, Weinheim, 2003; Vols. 1-3.
(6) (a) Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H. Angew.
Chem., Int. Ed. Engl. 1995, 34, 2039-2041. (b) Scholl, M.; Ding, S.; Lee,
C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953-956. (c) Jafarpour, L.; Hillier,
A. C.; Nolan, S. P. Organometallics 2002, 21, 442-444.
Starting fluorinated imidoyl chlorides 1 were prepared
from the corresponding carboxylic acids 12 with the meth-
odology developed by Uneyama.15 The synthesis of imidoyl
(7) (a) 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. (b) Connon, J. S.; Blechert, S. Angew Chem., Int. Ed. 2003, 42, 1900-
1923. (c) Vernall, A. V.; Abell, A. D. Aldrichimica Acta 2003, 36, 93-
105.
(8) To date, only one example of the synthesis of δ-amino acids through
the use of a CM protocol has been described. See: Vasbinder, M. M.; Miller,
S. J. J. Org. Chem. 2002, 67, 6240-6242.
(9) (a) Perlmutter, P.; Rose, M.; Vounatsos, F. Eur. J. Org. Chem. 2003,
756-760. (b) Chippindale, A. M.; Davies, S. G.; Iwamoto, K.; Parkin, R.
M.; Smethurst, C. A. P.; Smith, A. D.; Rodriguez-Solla, H. Tetrahedron
2003, 59, 3253-3265. (c) Gardiner, J.; Anderson, K. H.; Downard, A.;
Abell, A. D. J. Org. Chem. 2004, 69, 3375-3382. (d) Abell, A. D.; Gardiner,
J. Org. Lett. 2002, 4, 3663-3666.
(10) (a) Review: Qiu, X.-L.; Meng, W.-D.; Qing, F.-L. Tetrahedron
2004, 60, 6711-6745. (b) Fustero, S.; Pina, B.; Salavert, E.; Navarro, A.;
de Arellano, M. C. R.; Fuentes, A. S. J. Org. Chem. 2002, 67, 4667-4679.
(11) (a) Fustero, S.; Bartolome´, A.; Sanz-Cervera, J. F.; Sa´nchez-Rosello´,
M.; Garc´ıa Soler, J.; Ram´ırez de Arellano, C.; Simo´n Fuentes, A. Org.
Lett. 2003, 5, 2523-2526. (b) Mittendorf, J.; Kunisch, F.; Matzke, M.;
Militzer, H.-C.; Schmidt, A.; Scho¨nfeld, W. Bioorg. Med. Chem. Lett. 2003,
13, 433-436.
(12) When m ) 0 (Scheme 1), competitive side reactions such as
isomerization processes of the starting unsaturated esters were observed in
our attempts to prepare precursors of RCM 2. In the case of five-membered
rings, applying this methodology proved impossible and led mainly to a
complex mixture of products: Bartolome´, A. Ph.D. Dissertation, University
of Valencia (Spain), 2002.
(13) The successful use of fluorinated imidoyl chlorides in CM reactions,
which is reported here for the first time, shows once more the versatility of
ruthenium catalysts as well as their tolerance for a wide range of functional
groups.
(14) We also tested an alternative strategy using various chain lengths
of imidoyl chlorides 1 combined with unsaturated esters 4 other than
acrylates (m ) 1, 2), but the reactions were considerably less efficient in
terms of both yields and selectivities. The presence of the CF2 group may
be responsible for the high selectivity observed, also preventing any further
isomerization of the double bond. See: 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.
(15) (a) Uneyama, K.; Tamura, K.; Mizukami, H.; Maeda, K.; Watanabe,
H. J. Org. Chem. 1993, 58, 32-35. (b) Uneyama, K. J. Fluorine Chem.
1999, 97, 11-25.
4634
Org. Lett., Vol. 8, No. 20, 2006

Scheme 4. Preparation of Enamino Esters 7a-c
Table 1. Preparation of Disubstituted Olefins 5 by Means of a
CM Reaction
entry
1
n
5
E/Za (ratio)
yield (%)
1
2
3
1a
1b
1c
1
2
3
5a
5b
5c
23:1
46:1
11:1
95
94
93
a The E/Z isomeric ratio was determined by means of 19F NMR
spectroscopy and GC-MS analysis. PMP ) p-methoxyphenyl.
We next undertook the Dieckmann condensation of
substrates 6. The ester enolate necessary for the cyclization
had to be formed with 2 equiv of LDA at -78 °C because
1 equiv is consumed by the final product. After 1 h, cyclic
products 7 were obtained in moderate to good yields.
Although 7a,b were isolated in their enaminic form, com-
pound 7c proved to be a tautomeric mixture in a 3:2 ratio
(Scheme 4).
The next step comprised the chemo- and stereoselective
reduction of the imino-enamino moiety. After several at-
tempts, we were delighted to find that performing a
hydrogenation under microwave irradiation conditions al-
lowed the reduction to take place with complete selectivity.19
Thus, when 7a-c were dissolved in ethanol and then heated
in a microwave during 45 min at 100 °C in the presence of
palladium on charcoal and with ammonium formate as a
hydrogen source, the formation of the corresponding amino
esters 8a-c occurred efficiently, thus affording the corre-
sponding cis diastereomers exclusively and in good yields
(Scheme 5).
chloride 1a from acid 12a (n ) 1)16 was carried out as
previously reported,11a and acids 12b (n ) 2) and 12c (n )
3) were obtained from 4-bromo-1-butene (10b) and 5-bromo-
1-pentene (10c), respectively, as shown in Scheme 2. Thus,
10b,c were first transformed into their corresponding Grig-
nard derivatives, which were then treated with diethyl oxalate
to furnish R-ketoesters 11b,c.17 Reaction with Deoxofluor18
[(MeOCH2CH2)2NSF3] followed by saponification of the
ethyl ester with lithium hydroxide afforded acids 12b,c in
high yields (Scheme 3).
Scheme 3. Preparation of Starting Imidoyl Chlorides 1b,c
Scheme 5. Synthesis of â-Amino Esters 8
With compounds 5 in hand, the next step in our synthetic
strategy was the chemoselective hydrogenation of the olefinic
moiety. Optimal reaction conditions involved treating coup-
ling products 5 with hydrogen under pressure (4 atm) in the
presence of Pd/C (10%) in ethyl acetate as solvent. These
reactions generally required 24 h to proceed to completion
and afforded Dieckmann precursors 6 in good yields while
maintaining the ester and imidoyl chloride functionalities
unaltered (Scheme 4).
The relative cis configuration between the amino and the
acid groups of 8c was determined upon comparing its NMR
spectra with those of another sample of the same compound
previously synthesized by our group, albeit with a different
methodology.20 In contrast, the configuration of compounds
8a,b was established with the aid of NOE experiments.
Once the target molecules had been successfully prepared
in a racemic manner, the next challenge was to prepare them
(16) Lang, R. W.; Greuter, H.; Romann, A. J. Tetrahedron Lett. 1988,
29, 3291-3294.
(17) Macritchie, J. A.; Silcock, A.; Willis, C. L. Tetrahedron: Asymmetry
1997, 8, 3895-3902.
(19) (a) Banik, B. K.; Barakat, K. J.; Wagle, D. R.; Manhas, M. S.; Bose,
A. K. J. Org. Chem. 1999, 64, 5746-5753. (b) Kumar, V.; Sharma, A.;
Sinha, A. K. HelV. Chim. Acta 2006, 89, 483-495.
(18) Lal, G. S.; Pez, G. P.; Pesaresi, R. J.; Prozonic, F. M.; Cheng, H.
J. Org. Chem. 1999, 64, 7048-7054.
(20) See compound 11a in ref 11a.
Org. Lett., Vol. 8, No. 20, 2006
4635

in enantiomerically pure form. Of the several strategies tried,
the one using 8-phenylmenthol as a chiral source proved to
be the most efficient. Thus, (+)-8-phenylmenthol acrylate
was heated with imidoyl chloride 1a in the presence of
catalyst 9 (5 mol %). The resulting cross-coupling product
(+)-5d was then hydrogenated and cyclized under the
conditions outlined above to afford chiral enamino ester (+)-
7d in good yield. The crucial hydrogenation step through
microwave irradiation gave rise to a 4:1 mixture of diaster-
eomers in 52% yield (77% based on recovered starting
material). Longer reaction times and higher temperatures led
to no significant improvement in the conversion; therefore,
we chose to recycle the starting material after separation.
Scheme 6. Asymmetric Version of the Synthesis
The major diastereomer was separated by means of flash
chromatography, and its absolute configuration was deter-
mined with the aid of X-ray analysis of its hydrochloride
derivative (+)-15 (Scheme 6).21 This amino ester was
prepared through successive ester reduction with LiAlH4,
coupling of the newly created alcohol functionality with
4-bromo benzoyl chloride, and PMP deprotection upon
treatment with CAN. Additionally, the relative cis config-
uration of compound 8a was confirmed by means of its
reduction with LiAlH4, which afforded a compound identical
in all respects to 13. It is important to note that compound
(+)-13 constitutes a fluorinated analogue of cis-pentacin,
which is known for its antifungal properties.22
In conclusion, the synthesis of several fluorinated cis-2-
ACACs with a CM reaction as the key step has been
successfully carried out. A second-generation Grubbs catalyst
was found to be compatible with the presence of imidoyl
chlorides, which were used here for the first time in a
metathesis protocol. The described methodology provided
â-amino esters with several ring sizes, thus improving upon
previously described strategies. Initial studies concerning the
asymmetric version of the process were also described;
further studies are currently underway and will be reported
in due course.
Acknowledgment. The authors thank the Ministerio de
Educacio´n y Ciencia (BQU2003-01610) and the Generalitat
Valenciana (GR03-193 and GV05/079) of Spain for financial
support. M.S.R. and B.F. express their thanks for predoctoral
fellowships and C.P. for a Ramo´n y Cajal contract.
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.
(21) Full details of the X-ray structure of cis-(+)-15 will be published
in a full account of this work.
(22) (a) Oki, T.; Hirano, M.; Tomatsu, K.; Numata, K.; Kamei, H. J.
Antibiot. 1989, 42, 1756-1762. (b) Kawabata, K.; Inamoto, Y.; Sakane,
K.; Iwamoto, T.; Hashimoto, S. J. Antibiot. 1990, 43, 513-518.
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Org. Lett., Vol. 8, No. 20, 2006