A new chiral auxiliary derived from (2S)-phenylglycinol: An access to enantiomerically pure β-amino acids

Article abstract of DOI:10.1055/s-1999-2704

A new bicyclic heterocycle 3, which is potentially useful for the synthesis of β-amino acids, has been obtained from a reaction between (S)- phenylglycinol and cyanogen bromide followed by a condensation with methyl propiolate. Conjugate additions of different organocuprate reagents to this chiral Michael acceptor occurred with complete diastereoselectivity. An optically pure β amino acid was obtained in excellent yield from the masked chiral derivative 4a.

Full text of DOI:10.1055/s-1999-2704

LETTER
727
A New Chiral Auxiliary Derived from (2S)-Phenylglycinol: an Access to
Enantiomerically Pure b-Amino Acids
Claude Agami, Sandrine Cheramy, Luc Dechoux,* Catherine Kadouri-Puchot
Laboratoire de Synthèse Asymétrique associé au CNRS, Université Pierre et Marie Curie, 4 place Jussieu, 75005 Paris, France
Fax +33 (1) 44272620; E-mail: dechoux@ccr.jussieu.fr
Received 5 February 1999
The bicyclic compound 3 was used in Michael reactions
with three different organocuprate reagents.13 In all cases,
this reaction afforded compounds 4a-c as pure diastere-
omers in high yields (Scheme 2).
Abstract: A new bicyclic heterocycle 3, which is potentially useful
for the synthesis of b-amino acids, has been obtained from a reac-
tion between (S)-phenylglycinol and cyanogen bromide followed
by a condensation with methyl propiolate. Conjugate additions of
different organocuprate reagents to this chiral Michael acceptor oc-
curred with complete diastereoselectivity. An optically pure b ami-
no acid was obtained in excellent yield from the masked chiral
derivative 4a.
O
O
b
a
Ph
N
NH
3
N
N
Ph
Key words: b-amino acids, chiral auxiliary, asymmetric synthesis,
organocuprates.
O
R
O
5
4
4a R=Me 86% (de>95%)
4b R=n-Bu 93% (de>95%)
The asymmetric synthesis of b-amino acids has attracted
much attention in recent years.1 Actually, although less
abundant than their a-analogs, b-amino acids are crucial
structural features of numerous biologically active natural
products2 and were often used as building blocks for the
synthesis of b-lactam antibiotics.3 Racemic b-amino acids
have been prepared by using several methods but their
enantioselective syntheses have been described only re-
cently.4 In this paper, we report a highly diastereoselective
conjugate addition of organocuprate reagents to a new bi-
cyclic chiral building block 3. Chiral auxiliaries have al-
ready been used in the synthesis of substituted b-amino
acids. Some of them are especially noteworthy: (i) 6-sub-
stituted perhydropyrimidin-4-one and dihydropyrimidi-
nones, respectively used by Cardillo et al5 and by Chu and
Konopelski,6 (ii) chiral derivatives of 3-aminopropionic
acid which allowed Seebach and Juaristi7 to develop many
syntheses, (iii) lithiated hydropyrimidines used by See-
bach et al8 to synthesize a-branched b-amino acids.
4c R=Ph
81% (de>95%)
Scheme 2 a) R2CuLi, TMSCl, Et2O/THF, -78 °C to rt. b) Me2CuLi,
THF, 91%.
The observed stereoselectivity corresponds to an attack of
the nucleophile in an anti orientation with respect to the
phenyl group. It is interesting to note that the efficiency of
the reaction was highly improved when it was performed
in the presence of TMSCl, whose utility, in similar cases,
is well-established.14 Thus, in the absence of TMSCl,
product 5 was formed via a b-elimination process involv-
ing the abstraction of the benzylic hydrogen (Scheme 2).
In order to liberate the corresponding b-amino acid and to
determine the absolute configuration of the new chiral
center, we synthesized b-amino acid 8 derived from com-
pound 4a. Some difficulties were encountered when it
came to hydrogenolyze the benzylic C-N bond. Surpris-
ingly, it appears that the reacting bond was the C-O one.
Reaction with hydrogen in presence of palladium on car-
bon, platinum oxide or palladium hydroxide in acidic, ba-
sic or neutral medium gave the reduced product 6.
Nevertheless, dihydrouracil 6 was hydrolyzed by the ac-
tion of sodium hydroxide.15 Finally, after purification on
an acidic cation exchanger, the amino acid 7 was submit-
ted to the action of hydrogen in the presence of palladium
hydroxide to afford optically pure (S)-3-aminobutanoic
acid 8.16
Compound 3 was obtained by the following two-step se-
quence: (i) a reaction between (2S)-phenylglycinol 1 and
cyanogen bromide9 affording compound 210 (ii) a conden-
sation of this product with methyl propiolate11 which af-
forded bicyclic heterocycle 312 (Scheme 1).
O
O
OH
b
a
NH
N
N
N
H
NH2
Ph
Ph
Ph
O
1
In conclusion, we have developed a novel and diastereo-
selective method for the asymmetric synthesis of b-substi-
tuted b-amino acids. Asymmetric syntheses which make
further use of chiral derivative 3 are currently in progress.
2
3
Scheme 1 a) BrCN, EtOH, reflux, 98%; b) methyl propiolate, EtOH,
reflux, 67%.
Synlett 1999, No. 6, 727–728 ISSN 0936-5214 © Thieme Stuttgart · New York

728
C. Agami et al.
LETTER
O
(10) Data for compound 2: 1H NMR (250 MHz, CDCl3): 4.17 (dd,
O
J = 8 and 7.3 Hz, 1H), 4.74 (dd, J = 8 and 9 Hz, 1H), 4.95 (ls,
a
2H), 5.13 (dd, J = 7.3 and 9 Hz, 1H), 7.14-7.30 (m, 5H). 13
NMR (63 MHz, CDCl3): 65.7, 75.6, 126.7, 127.7, 128.8,
142.2, 162.1. mp 114 °C. [a]20D:+11 (c 1, CHCl3).
C
N
NH
N
N
Ph
Ph
Me
Ph
O
Me
O
4a
6
(11) Lin, T.S.; Luo, M.Z.; Liu, M.C. Tetrahedron Lett., 1994, 35,
3477-3480.
b
(12) Selected data for compound 3: 1H NMR (250 MHz, CDCl3):
4.49 (dd, J = 7.8 and 9.2 Hz, 1H), 5.01 (t, J = 9.2 Hz, 1H), 5.23
(dd, J = 7.8 and 9.2 Hz, 1H), 5.95 (d, J = 7.5 Hz, 1H), 6.90 (d,
J = 7.5 Hz, 1H), 7.23-7.31 (m, 5H). 13C NMR (63 MHz,
CDCl3):61.9, 73.9, 109.8, 127.1, 129.7, 130.1, 135.1, 135.8,
160.9, 172.0. mp 186 °C. [a]20D : -18 (c 0.4, MeOH).
(13) General procedure for Michael addition. To a solution of
compound 3 (0.93 mmol) in THF (10 ml) were successively
added, at –78 °C, trimethylsilylchloride (0.93 mmol) and a
solution of alkyl organocuprate (1.4 mmol, 0.15 M in diethyl
ether, prepared by addition, at –10 °C, of a solution of
commercially organolithium (2.8 mmol) to a suspension of
CuI (1.4 mmol) in diethyl ether). The reaction was allowed to
reach room temperature within 1 hour and the mixture was
stirred at rt for 2 hours. An aqueous solution saturated with
ammonium chloride (15 ml) was added and the reaction
mixture was extracted with CH2Cl2 (2 x 20 ml). After
evaporation the residue was chromatographed (EtOAc /
MeOH). Selected data for 4a: 1H NMR (250 MHz, CDCl3):
1.20 (d, J = 6.4 Hz, 3H), 2.35 (dd, J = 15.9 and 6.6 Hz, 1H),
2.59 (dd, J = 15.9 and 6.9 Hz, 1H), 3.39-3.44 (m, 1H), 4.32
(dd, J = 8.9 and 6.3 Hz, 1H), 4.81 (t, J = 8.9 Hz, 1H), 5.03 (dd,
J = 8.6 and 6.2 Hz, 1H), 7.22-7.39 (m, 5H). 13C NMR (63
MHz, CDCl3):17.2, 37.1, 45.5, 60.3, 73.2, 126.9, 128.6, 129.7,
135.5, 167.2, 178.1. [a]20D :+119 (c 1, CHCl3).
c
NH2 OH
NH OH
Me
O
Me
O
8
7
Scheme 3 a) H2, Pd/C, EtOH, 100%; b) NaOH 1M, then Dowex
(50W x 8), 88%; c) H2, Pd(OH)2, EtOH, 100%
References and Notes
(1) Jones J.H.; in Amino Acids and Peptides; Specialist Periodical
Report; The Royal Society of Chemistry, 1992, 23.
(2) See for example: Spatola, A.F. in Chemistry and Biochemistry
of Amino Acids, Peptides and Proteins; Weinstein, B; (Ed.),
New York, 1983, 7; Drey, C.N.C. in Chemistry and
Biochemistry of Amino Acids, Barrett, G.C. (Ed.), London,
1985.
(3) Tamariz, J. In Enantioselective Synthesis of b-Amino Acids;
Juaristi, E., Ed.;.Wiley-VCH, 1997, 45-66.
(4) Juaristi, E. Enantioselective Synthesis of b-Amino Acids,
Wiley-VCH, 1997.
(5) Cardillo, G.; Gentilucci, L.; Tolomelli, A.; Tomasini, C. J.
Org. Chem., 1998, 63, 3458-3462.
(6) Chu, K.S.; Konopelski, J.P. Tetrahedron, 1993, 49, 9183-
9190.
7) (a) Juaristi, E.; Escalante, J.; Lamatsch, B.; Seebach, D. J.
Org. Chem., 1992, 57, 2396-2398. (b) Juaristi, E.; Lopez-
Ruiz, H.; Madrigal, D.; Ramirez-Quiros, Y.; Escalante J. J.
Org. Chem., 1998, 63, 4706-4710.
(14) Corey, E.J.; Boaz, N.W. Tetrahedron Lett., 1985, 26, 6019-
6022; Alexakis, A.; Berlan, J.; Besace, Y. Tetrahedron Lett.,
1986, 27, 1047-1050.
(15) Rachina, V.; Blagoeva, I. Synthesis, 1982, 967-968.
(16) Selected data for the (S)-3-aminobutanoic acid 8: [a]20D :+34
(c 0.6, H2O); [lit.7a: [a]28D :+32.2 (c 0.9, H2O);
lit.17:[a]23D:+37.2 (c 0.3, H2O)].
(17) Keglevic, D.; Ladesic, B. Croat. Chem. Acta, 1959, 31, 57-66.
(8) Seebach, D.; Boog, A.; Schweizer, W.B. Eur. J. Org. Chem.,
1999, 335-360.
(9) Compound 2 was already described in racemic form: Kampe,
K.D. Liebigs Ann. Chem., 1974, 593-607.
Article Identifier:
1437-2096,E;1999,0,06,0727,0728,ftx,en;G06299ST.pdf
Synlett 1999, No. 6, 727–728 ISSN 0936-5214 © Thieme Stuttgart · New York