Efficient synthesis of β2-amino acid by homologation of α-amino acids involving the reformatsky reaction and Mannich-type imminium electrophile

Article abstract of DOI:10.1021/jo060316a

Development of new methods for the synthesis of β-amino acids is important as polymers of these compounds are promising peptidomimetic candidates in medicinal chemistry. We report here our findings on a new and highly efficient general strategy for the synthesis of β²-amino acids by homologation of α-amino acids, involving the Reformatsky reaction and Mannich-type imminium electrophile.

Full text of DOI:10.1021/jo060316a

Efficient Synthesis of â2-Amino Acid by
Homologation of r-Amino Acids Involving the
Reformatsky Reaction and Mannich-Type
Imminium Electrophile
chain on the 3-aminopropanoic acid skeleton. If most of the
â3-amino acids bearing proteinogenic side chains are easily
obtained by Arndt-Eistert homologation of R-amino acids,6
preparation of â2-amino acids is much more difficult. Several
methodologies have been suggested for this purpose,7 involving,
for instance, the diastereoselective alkylation of a chiral deriva-
tive of â-alanine,8 Curtius rearrangement of a chiral succinate,9
or conjugate addition of nitrogen10 or carbon nucleophile11 to
the appropriate Michael acceptor. One of the most useful
strategies, based on the pioneering work of Evans12 and
Oppolzer,13 is the aminomethylation of a chiral precursor, which
bears the side chain of the amino acid.14 Noticeably, Seebach
et al. have successfully used this methodology for the prepara-
tion of a wide range of â2-amino acids.9b,15 However, the low
reactivity of the used aminomethylating reagent makes this
method inefficient in some cases; in particular, the preparation
of amino acids bearing a functional group on their side chain
required multistep procedures. In some cases, it was necessary
to use an alternative, which consists of the introduction of a
carboxymethyl group followed by Curtius rearrangement.9b
Although good yields and diastereoselectivities are generally
obtained, the multiplication of the number of steps limits the
application of such a method to laboratory scale. Thus, it appears
necessary to us to develop a new scalable strategy for the
synthesis of these compounds, particularly for amino acids
bearing a functional group on their side chain. The aim of this
work is the production of these compounds on an industrial
scale.
Roba Moumne,†,‡ Solange Lavielle,† and Philippe Karoyan*,†
Synthe`ses, Structures et Fonctions des Mole´cules BioactiVes,
CNRS/UMR 7613, UniVersite´ Pierre et Marie Curie, 4,
Place Jussieu, 75252, Paris Cedex 05, France, and
Senn Chemicals AG Industriestrasse, 12 P.O. Box 267,
CH-8157 Dielsdorf, Switzerland
karoyan@ccr.jussieu.fr
ReceiVed February 15, 2006
Development of new methods for the synthesis of â-amino
acids is important as polymers of these compounds are
promising peptidomimetic candidates in medicinal chemistry.
We report here our findings on a new and highly efficient
general strategy for the synthesis of â2-amino acids by
homologation of R-amino acids, involving the Reformatsky
reaction and Mannich-type imminium electrophile.
We report here our findings on a new and highly efficient
general strategy for the synthesis of â2-amino acids starting from
R-amino acids, via the Reformatsky reaction and Mannich-type
iminium electrophile. The classical Reformatsky reaction in-
(6) Ellmerer-Mu¨ller, E. P.; Bro¨ssner, D.; Maslouh, N.; Tako, A. HelV.
Chim. Acta 1998, 81, 59.
(7) Lelais, G.; Seebach, D. Biopolymers (Peptide Sci.) 2004, 76, 206.
(8) (a) Juaristi, E.; Quintana, D.; Lamatsch, B.; Seebach, D. J. Org. Chem.
1991, 56, 2553. Juaristi, E.; Quintana, D.; Balderas, M.; Garcia-Perez, E.
Tetrahedron: Asymmetry 1996, 7, 2233. (b) Seebach, D.; Boog, A.;
Schweizer, W. B. Eur. J. Org. Chem. 1999, 335. (c) Ponsinet, R.; Chassaing,
G.; Vaissermann, J.; Lavielle, S. Eur. J. Org. Chem. 2000, 83. (d) Gutie´rez-
Garcia, V. M.; Reyes-Rangel, G.; Lopez-Ruiz, H.; Juaristi, E. Tetrahedron
2001, 57, 6487. Gutie´rez-Garcia, V. M.; Reyes-Rangel, G.; Munoz-Muniz,
O.; Juaristi, E. HelV. Chim. Acta, 2002, 85, 4189. (e) Nagula, G.; Huber,
V. J.; Lum, C.; Goodman, B. A. Org. Lett. 2000, 2, 3527.
(9) (a) Sibi, M. P.; Deshpande, P. K. J. Chem. Soc., Perkin Trans. 1
2000, 1461. (b) Seebach, D.; Schaeffer, L.; Gessier, F.; Bindscha¨dler, P.;
Ja¨ger, C.; Josien, D.; Kopp, S.; Lelais, G.; Mahayan, Y. R.; Micuch, P.;
Sebesta, R.; Schweiser, B. W. HelV. Chim. Acta 2003, 86, 1852.
(10) Lee, H. S.; Park, J. S.; Kim, B. M.; Gellman, S. H. J. Org. Chem.
2003, 68, 1575. Bedow, J. E.; Davies, S. G.; Smith, A. D.; Russel, A. J. J.
Chem. Soc., Chem. Commun. 2004, 2778.
The control of both stability and three-dimensional structure
of peptides and proteins by chemical modifications of protei-
nogenic amino acids has been the keystone of peptide chemistry
for the past decades. The aim of these studies is the development
of compounds with improved selectivity, bioavailability, stabil-
ity, and permeability.1 Such goals may be successfully reached
with â-peptides. Indeed, Gellman2 and Seebach3 have shown
that short polymers made of â-amino acids can fold to form
predictable secondary structures in solution. Moreover, these
compounds are stable to cleavage by peptidases4 and can mimic
R-peptides in biological interactions.3,5
Apart from polysubstituted derivatives, â2- and â3-amino
acids can be distinguished regarding the position of the side
(11) Rimkus, A.; Sewald, N. Org. Lett. 2003, 5, 79. Eilitz, U.; Lessmann,
F.; Seidelmann, O.; Wendisch, V. Tetrahedron: Asymmetry 2003, 14, 189.
Dursma, A.; Minard, A. J.; Feringa, B. L. J. Am. Chem. Soc. 2003, 125,
3700.
† Universite´ Pierre et Marie Curie.
‡ Senn Chemicals AG Industriestrasse.
(1) Karoyan, P.; Sagan, S.; Lequin, O.; Quancard, J.; Lavielle, S.;
Chassaing, G. Targets Heterocycl. Syst. 2004, 8, 216.
(2) Cheng, P. R.; Gellman, S. H.; DeGrado, W. F. Chem. ReV. 2001,
101, 3219.
(3) Seebach, D.; Beck, A. K.; Bierbaum, D. J. Chem. BiodiV. 2004, 1,
1111.
(4) (a) Frakenpohl, J.; Arvidsson, P. I.; Schreiber, J. V.; Seebach, D.
ChemBioChem 2001, 2, 445. (b) Sagan, S.; Milcent, T.; Ponsinet, R.;
Convert, O.; Tasseau, O.; Chassaing, G.; Lavielle, S.; Lequin, O. Eur. J.
Biochem. 2003, 270, 939.
(5) Kritzer, J. A.; Stephens, O. M.; Guarracino, D. A.; Reznik, S. K.;
Schepartz, A. Bioorg. Med. Chem. 2005, 13, 11.
(12) Evans, D. A.; Urpi, F.; Somers, T. C.; Clark, J. S.; Bilodeau, M. T.
J. Am. Chem. Soc. 1990, 112, 8215.
(13) Oppolzer, W.; Moretti, R.; Thomi, S. Tetrahedron Lett. 1989, 30,
5603.
(14) Hintermann, T.; Seebach, D. Synlett 1997, 437. Arvanatis, T. E.;
Ernst, H.; Ludwig, A. A.; Robinson, A. J.; Wyatt, P. B. J. Chem. Soc.,
Perkin Trans. 1 1998, 521.
(15) Hintermann, T.; Seebach, D. HelV. Chim. Acta 1998, 81, 2093.
Sebesta, R.; Seebach, D. HelV. Chim. Acta 2003, 86, 4061. Gademann, K.;
Kimmerlin, T.; Hoyer, D.; Seebach, D. J. Med. Chem. 2001, 44, 2460.
Seebach, D.; Namoto, K.; Mahajan, Y. R.; Bindscha¨dler, P. Chem.
BiodiVersity 2004, 1, 65.
10.1021/jo060316a CCC: $33.50 © 2006 American Chemical Society
Published on Web 03/21/2006
3332
J. Org. Chem. 2006, 71, 3332-3334

SCHEME 1. Synthesis of r-Bromoacetate Estersa
SCHEME 2. Reformatsky’s Reaction with Imminium
Trifluoroacetate
a Key: (A) NaNO2, NaBr, 2.5 M H2SO4; (B) NaNO2, NaBr, 0.75 M
HBr; (C) MeOH, cat. H2SO4, reflux; (D) CH3COCl, MeOH, rt.
TABLE 2. Yields for the Reformatsky Reaction with Imminium
Trifluoroacetate
TABLE 1. Reaction Conditions (RC) for the Synthesis of
entry
R
4 (yield, %)
r-Bromoacetate Esters
a
b
c
d
e
CH3 (3a)
iBu (3b)
CH2Ph (3c)
4a (43)
4b (66)
4c (74)
4d (73)
4e (72)
yield (RC) (%)
L-amino acids
entry
R
2
3
CH2-(3-indolyl-N-Boc) (3d)
CH2CO2-t-Bu (3e)
Ala
Leu
Phe
Trp(N-Boc)
Asp (O-t-Bu)
a
b
c
d
e
CH3
iBu
caa
70 (A)
90 (A)
67 (B)
86 (B)
79 (C)
94 (C)
59 (D)
51 (D)
CH2Ph
CH2-(3-indolyl-N-Boc)
CH2CO2tBu
SCHEME 3. Deprotection
a ca: commercially available.
volved nucleophilic species resulting from zinc insertion into
carbon-halogen bonds of R-haloacetate esters.16 Such esters,
bearing proteinogenic side chains, when not commercially
available, are easily obtained starting from R-amino acids as
originally reported by Izumiya and others17 (Scheme 1). The
amine moiety can be diazotized and converted to the R-bromo
acid, which is subsequently esterified under conditions suitable
for classical protective groups for peptide synthesis, as described
in Table 1.
SCHEME 4. Asymmetric Aminomethylation
In the classical Reformatsky reaction, the nucleophilic zinc
enolate intermediate is reacted with aldehydes or ketones,
leading to â-hydroxyalkanoates. The scope of the reaction has
been extended to various electrophiles.16 Gilman and Speeter
have first reported the addition of the zinc enolate on benza-
laniline-type Schiff bases in refluxing toluene.18 In that case,
the intermediately formed zinc complex cyclized to give the
â-lactam. In a more detailed study of this reaction, Dardoize et
al.19 have reported that cyclization might be avoided and â3- or
Starting from the R-bromoesters 3a-e, the zinc intermediate
was generated, as reported by Dardoize et al,19a in formaldehyde-
dimethyl acetal at room temperature and reacted with diben-
zylidene iminium trifluoroacetate, leading to compounds 4a-e
with good yields (Table 2).
Subsequent debenzylation with ammonium formate over
palladium charcoal22 was performed for the derivatives 4a-c.
This debenzylation was followed by ester saponification and
N-Boc protection leading to racemic â2-amino acids 5a-c
suitably protected for peptide synthesis (Scheme 3).
The ease of this reaction led us to explore the asymmetric
version of this aminomethylation of the Reformatsky reagent
for the synthesis of â2-homoleucine (Scheme 4), which was
needed for our structure-activity relationship studies of biologi-
cally active peptides. In the classical Reformatsky reaction, the
attachment of chiral auxiliaries (derived from menthol, oxazo-
lidines, or oxazinanes) to halo precursors led to some diaste-
reoselectivity and enantiofacial differentiation.16 We have chosen
Oppolzer’s sultam,23 since good to excellent diastereoselectivi-
ties were usually observed with this chiral auxiliary (Scheme
4).
â
2,3-amino esters could be obtained with aldimine Schiff bases,
depending on the Schiff base, temperature, and solvent used
for the reaction. The addition of the zinc enolate on nonsub-
stituted Schiff bases (i.e., formylimine derivatives that would
lead to â2-amino esters) was not reported due to the inacces-
sibility of reactive formylimine equivalent. Interestingly, Man-
nich-type iminium ions are very reactive aminomethylating
agents,20 but no example of the Reformatsky reaction involving
this type of ion and zinc enolate of esters was described.
Recently, Millot et al. have reported the aminomethylation of
organozinc and Grignard reagents using iminium trifluoroac-
etates.21
We have thus explored the scope of these iminium trifluo-
roacetates regarding the Reformatsky reaction (Scheme 2).
(16) Fu¨rstner, A. Synthesis 1989, 571. Ocampo, R.; Dolbier, W. R., Jr.
Tetrahedron 2004, 60, 9325.
The sodium salt of (+)-10,2-camphorsultam was introduced
after activation of the carboxylic function of 2b with isobutyl
chloroformate leading to compound 6. The aminomethylation
was performed in THF, as described above for the racemate,
leading to a single stereoisomer according to NMR analysis.
The stereochemistry of compound 7 obtained through the
(17) (a) Izumiya, N.; Nagamtsu, A. Bull. Chem. Soc. Jpn. 1952, 52, 265.
(b) Souers, A. J.; Schu¨rer, S.; Kwack, H.; Virgilio, A. A.; Ellman, J. A.
Synthesis 1999, 4, 583. (c) Shin, I.; Lee, M.; Lee, J.; Jung, M.; Lee, W.;
Yoon, J. J. Org. Chem. 2000, 65, 7667.
(18) Gilman, H.; Speeter, M. J. Am. Chem. Soc. 1943, 65, 2255.
(19) (a) Dardoize, F.; Moreau, J.-L.; Gaudemar, M. Bull. Soc. Chim.
Fr. 1973, 5, 1668 and references therein. (b) Hart, D. J.; Deok-Chang, H.
Chem. ReV. 1989, 89, 1447.
(20) Holy, N.; Fowler, R.; Burnett, E.; Lorenz, R. Tetrahedron 1979,
35, 613.
(22) Anwer, M. K.; Spatola, A. F. Synthesis 1980, 929.
(23) Oppolzer, W.; Moretti, R.; Thomi, S. Tetrahedron Lett. 1989, 30,
6009.
(21) Millot, N.; Piazza, C.; Avolio, S.; Knochel, P. Synthesis 2000, 7,
941.
J. Org. Chem, Vol. 71, No. 8, 2006 3333

SCHEME 5. Enantiomeric Excess
few minutes. A solution of the R-bromo acid (1 equiv) in methylal
(1 mL/mmol) was added dropwise. The reaction was stirred at room
temperature for 15 min, and the solution of imminium trifluoro-
acetate was added. The reaction mixture was stirred at room
temperature for 1.5 h, quenched with saturated solution of NH4Cl,
and extracted with Et2O. The combined organic layers were washed
with saturated aqueous NaHCO3, 5% aqueous Na2S2O3, and
saturated aqueous NH4Cl and dried (MgSO4). After evaporation
of the solvents, the crude product was purified by flash column
chromatography.
aminomethylation reaction was deduced from comparison of
compound 8 optical rotation with an authentic sample8c and
confirmed by NMR analysis following the methodology reported
by Bo¨hm et al (Scheme 5).24 It should be noted that the
stereochemical course of this aminomethylation reaction is
identical to that usually observed with Oppolzer’s sultam for
glycinate-derived enolate.23
(R)-N-(2-Dibenzylaminomethyl-4-methylpentanoyl)camphor-
sultam 7. Compound 7 was obtained by precipitation from
methanol-chloroform as a single diastereoisomer (7.2 g; 64%).
1
Mp ) 108 °C. [R]20D: +69.9 (c 1, CHCl3). H NMR (400 MHz,
CDCl3) δ: 7.18-7.33 (m, 10H); 3.87 (dd, J ) 5 Hz, 7.6 Hz, 1H);
3.68 (d, J ) 13,9 Hz, 2H); 3.41-3.52 (m, 5H); 2.76 (dd, J ) 6.3
Hz, 12.4 Hz, 1H); 2.50 (dd, J ) 12.4 Hz, 7.3 Hz, 1H); 2.00-2.11
(m, 2H); 1.86-1.92 (m, 4H); 1.46-1.56 (m, 3H); 1.31-1.42 (m,
2H); 1.22 (s, 3H); 0.97 (s, 3H); 0.87 (d, J ) 5.8 Hz, 6H). 13C NMR
(100 MHz, CDCl3) δ: 174.9; 139.1; 129.1; 128.0; 126.8; 65.5; 58.1;
56.5; 53.2; 48.2; 47.8; 44.6; 42.6; 38.8; 38.6; 32.9; 26.5; 26.0; 23.0;
22.7; 21.0; 19.9. Anal. Calcd for C31H42N2O3S: C, 71.23; H, 8.10;
N, 5.36. Found: C, 71.05; H, 8.30; N, 5.11.
In conclusion, it has been shown that â2-amino acids can be
prepared by homologation of R-amino acids in few steps. The
strategy reported here involved iminium trifluoroacetate that
appeared to be an efficient aminomethylating agent in the
Reformatsky reaction. The asymmetric synthesis has been
successfully tested. We believe that this strategy is of great value
for rapid generation of â2-amino acids. Moreover, the possibility
of preparation of â2-amino acids bearing a functionalized side
chain in few steps is particularly attractive, since the procedures
described for this purpose are generally long and tedious.
Finally, this methodology can be easily scaled up for the
industrial production of these compounds, and we are currently
working toward this goal.
Acknowledgment. The authors thank Dr. Albert Loffet
(Senn Chemicals International) and Dr. Fabrice Cornille (Sfm)
for their help. Dr. Philippe Karoyan thanks Dr. Franc¸ois
Dardoize for helpful discussions on the Reformatsky reaction.
Experimental Section
Supporting Information Available: Experimental procedures
for all compounds and NMR data for all new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
General Procedure for the Reformatsky Reaction. To a
suspension of zinc dust (1.5 equiv) in methylal (0.5 mL/mmol) was
added dibromoethane (20 µL/mmol). The mixture was refluxed for
(24) Bo¨hm, A.; Seebach, D. HelV. Chim. Acta 2000, 83, 3262.
JO060316A
3334 J. Org. Chem., Vol. 71, No. 8, 2006