Stereoselective α-alkylation of new chiral auxiliaries: An access to enantiomerically pure α- and α,β-substituted β-amino acids

Article abstract of DOI:10.1055/s-1999-2925

New bicyclic heterocycles 5, which are potentially useful for the enantioselective synthesis of substituted β-amino acids, have been synthesized. A study on the α-alkylation of these chiral auxiliaries is presented. An optically pure β-amino acid was obtained in excellent yield from its masked chiral derivative 6a.

Full text of DOI:10.1055/s-1999-2925

1
838
LETTER
Stereoselective a-Alkylation of New Chiral Auxiliaries: An Access to
Enantiomerically Pure a- and a,b-Substituted b-Amino Acids
Claude Agami, Sandrine Cheramy, Luc Dechoux*
Laboratoire de Synthèse Asymétrique associé au CNRS, Université Pierre et Marie Curie, 4 place Jussieu, 75005 Paris, France
Fax (33) 01 44 27 26 20; E-mail: dechoux@ccr.jussieu.fr
Received 8 July 1999
On the other hand, chiral bicyclic auxiliaries 5b and 5d
were obtained by diastereoselective alkylation of 1 with
organocuprate reagents in the same way as reported in
Abstract: New bicyclic heterocycles 5, which are potentially useful
for the enantioselective synthesis of substituted b-amino acids, have
been synthesized. A study on the a-alkylation of these chiral auxil-
4
iaries is presented. An optically pure b-amino acid was obtained in Scheme 1.
excellent yield from its masked chiral derivative 6a.
Enolates derived from products 5 were generated by treat-
ment with LiHMDS for 15 min at -10°C in THF. The elec-
trophile was added at -10°C or at –50°C and the reaction
Key words: b-amino acids, chiral auxiliary, asymmetric synthesis
mixture was stirred for 2 h at this temperature and further
1
7
The asymmetric synthesis of b-amino acids has attracted hydrolyzed with a saturated NH
Cl aqueous solution (Ta-
4
2
much attention in recent years owing especially to their ble 1).
use as building blocks for the synthesis of b-lactam anti-
3
4
biotics. We recently published the synthesis of a new
chiral auxiliary 1 derived from (2S)-phenylglycinol which
provides an enantioselective access to b-substituted b-
amino acids 3 via intermediates 2 (Scheme 1).
Scheme 1
These intermediates result from a diastereoselective alky-
lation of the bicyclic enone 1 and we wish to present here
the outcome of a further alkylation involving these inter-
mediates 2.
Chiral intermediates 5a and 5b were synthesized by the
following two-step sequence: (i) reaction between (2S)-
phenylglycinol and cyanogen bromide affording com-
The overall yields of alkylation range from 88% to 96%
when the reactions were performed at –10°C. At –50°C,
the yield drops due to incomplete conversion. The major
isomer obtained in every case resulted from the alkylation
of the apparently most hindered b side of the enolate inter-
mediate. The S absolute configuration of the a center in
5
pound 4, (ii) condensation of this product with ethyl
6
acrylate or ethyl crotonate to form adducts 5a and 5b re-
spectively (Scheme 2).
1
adducts 6 was established by NOE H NMR experiments
in the case of a,b-dialkylated 6b-d compounds. Adduct 6a
8
led to the known (S)-3-amino-2-methylpropanoic acid 8
by using the chemical sequence described in Scheme 3.9
Hydrogenation (Pd/C catalyst) of adduct 6a gave the re-
duced product 7.10 The experimental conditions of base-
a) methyl acrylate, EtOH, reflux, 97%. b) ethyl crotonate, EtOH,
reflux, 25%.
11
catalysed hydrolysis which were used in the synthesis of
4
b-amino acids, gave rise, in the present case, to epimeri-
Scheme 2
sation of the created stereocenter which is now a to a car-
bonyl group. However, strong acidic conditions afforded
Synlett 1999, No. 11, 1838–1840 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
An Access to Enantiomerically Pure b-Amino Acids
1839
References and Notes
(
1) Juaristi, E. Enantioselective Synthesis of b-Amino Acids, Ed.
Wiley-VCH, 1997.
(
2) See for recent examples: Seebach, D.; Boog, A.; Schweizer,
W.B. Eur. J. Org. Chem., 1999, 335-360. Ohtake, H.; Imada,
Y.; Murahashi, S.I. J. Org. Chem., 1999, 64, 3790-3791. Jew,
S.; Cha, K.; Kang, S.; Woo, Y.; Kim, H.; Park, H.
Heterocycles 1999, 50, 677-680. Cardillo, G.; Gentilucci, L.;
Tolomelli, A.; Tomasini, C. J. Org. Chem., 1998, 63, 3458-
a) H , Pd/C, EtOH, 12h, 100%; b) HCl 8M, reflux, 96h, then Dowex
2
(
50W x 8), 68%.
3
462.
Scheme 3
(
(
(
(
3) Tamariz, J. In Enantioselective Synthesis of b-Amino Acids;
Juaristi, E., Ed.Wiley-VCH, 1997, 45-66.
4) Agami, C.; Cheramy, S.; Dechoux, L.; Kadouri-Puchot, C.
Synlett, 1999, 727-728.
5) Compound 4 was already described in racemic form: Kampe,
K.D. Liebigs Ann. Chem., 1974, 593-607.
optically pure (S)-3-amino-2-methylpropanoic acid 8 in
good yields, after chromatography on an acidic cation ex-
changer.
6) Lin, T.S.; Luo, M.Z.; Liu, M.C. Tetrahedron Lett., 1994, 35,
3477-3480.
The results reported in the Table show that electrophiles
attack the chiral enolates derived from compounds 5 from
the b face, i.e. with a syn relationship with respect to the
phenyl group. This stereochemical course is surprising
since it appears that what could look like the more hin-
dered face is in fact the more accessible one. It should be
noted that a very similar effect was observed by Husson
(7) General procedure for a-alkylation: To a solution of
compound 5 (1 mmol) in THF (10 ml) was added, at –10°C,
LiHMDS (1.1 ml of a 1M solution in THF, 1.1 mmol) and
after 15 min, at –10°C, methyl iodide (0.09 ml, 1.5 mmol) was
added. The reaction mixture was stirred 2 h at –10°C and
further quenched by a saturated NH Cl aqueous solution and
4
extracted with CH Cl (2 x 20 ml). After evaporation, the
2
2
residue was chromatographed (EtOAc / MeOH). Selected data
1
2
1
and al. in the alkylation of hydrazinolactams.
for 6a: H NMR (250 MHz, CDCl
.84 (m, 1H), 2.88 (dd, J=9.2 and 11.7 Hz, 1H), 3.36 (dd,
J=6.8 and 11.7 Hz, 1H), 4.46 (m, 1H), 4.85-4.95 (m, 2H),
3
): 1.23 (d, J=6.9 Hz, 3H),
2
The presence of a methyl substituent on the a face of the
enolate derived from 5b produces an enhancement of the
stereoselectivity (compare entries 2 and 3 in the Table).
This effect is even more pronounced when a butyl group
hinders the a side of the enolate derived from 5d (compare
entries 2,3 and 5).
13
7
.27-7.48 (m, 5H). C NMR (63 MHz, CDCl ): 14.6, 33.5,
3
45.5, 62.9, 73.5, 127.0, 129.6, 129.7, 135.3, 167.2, 181.4.
2
0
1
[a]
(
: +60 (c 0.6, CHCl ). Selected data for ent-6a: H NMR
D
3
250 MHz, CDCl ): 1.14 (d, J=6.9 Hz, 3H), 2.59 (m, 1H), 2.95
3
(
1
t, J=11.5 Hz, 1H), 3.19 (dd, J=7.4 and 11.5 Hz, 1H), 4.27 (m,
H), 4.81-4.94 (m, 2H), 7.29-7.41 (m, 5H). C NMR (63
1
3
Protonation of the enolate derived from 6d (under the
same experimental conditions as above) afforded com-
pound 9 as a enriched diastereoisomer (de = 90%). This
result shows that protonation as well as alkylation occurs
on the same b side of enolates derived from all chiral aux-
iliaries 5 (Scheme 4).
MHz, CDCl ): 13.5, 33.7, 46.0, 63.3, 73.5, 126.7, 129.6,
3
2
0
129.8, 135.0, 168.8, 180.9. [a]
: +196 (c 0.8, CHCl
HRMS calc. for C H O N +H m / z 231.1134, obs m / z
).
D
+
3
13 12
2
2
231.1128.
(
8) General procedure for the hydrolysis of the alkylated
pyrimidinone. A suspension of adduct 7 (180 mg, 0.870
mmol) in 10 ml of 8N HCl was heated at reflux for 96 h. The
aqueous phase was concentrated at reduced pressure and the
amino acid hydrochloride was adsorbed to acidic ion
exchange resin Dowex 50W X8. The resin was washed with
distilled water until the washing came out neutral, and then the
free amino acid was recovered with 3% ammonium
hydroxide. Evaporation afforded (S)-3-amino-2-
methylpropanoic acid 8 (61 mg, 0.59 mmol, 68%). Selected
2
5
13
29
data for 8: [a] : +11 (c 0.3, 1N HCl); [lit. : [a] : +11.6 (c
D
D
1
1
, 1 N HCl). H NMR (250 MHz, D O): 1.15 (d, J=7.3 Hz,
2
3
H), 2.57 (m, 1H), 2.98 (dd, J=12.8 and 5.3 Hz, 1H), 3.08 (dd,
1
3
a) 1) LiHMDS, THF, -10°C, 15min; 2) aq NH Cl, 65%
J=12.8 and 8.4 Hz, 1H). C NMR (63 MHz, D O): 14.0, 38.1,
4
2
4
1.3, 180.3.
Scheme 4
(
9) (R)-3-amino-2-methylpropanoic acid ent-8 was obtained
under the same conditions from diastereoisomer (S,S) of 7.
2
5
13
Selected data for ent-8: [a] : -10 (c 0.35, 1N HCl); [lit. :
D
In conclusion, we have developed a novel and diastereo-
selective method for the asymmetric synthesis of a- and
a,b-substituted b-amino acids. We are currently studying
the access to other classes of compounds by taking advan-
tage of the reactivity of the double bond of chiral auxiliary
2
9
14
29
[
a] : -11.8 (c 1,1, 1N HCl), [lit. : [a] :-14.7 (c 2.60,
D
D
H O).
2
25
1
(
10) Selected data for compound 7: [a] : +90 (c 0.3, CHCl ); H
D
3
NMR (250 MHz, CDCl ): 0.96 (d, J=6.7 Hz, 3H), 1.50 (d,
3
J=7.1 Hz 3H), 2.51-2.61 (m, 2H), 3.13 (m, 1H), 5.78 (q, J=7.1
Hz, 1H) 7.25 (m, 1H), 8.35 (bs, 1H). C NMR (63 MHz,
CDCl ): 12.6, 15.4, 35.2, 43.1, 51.3, 127.1, 127.8, 128.7,
1
3
1
as precursors of other functions.
3
+
139.0, 152.8, 172.5. HRMS calc. for C H O N +H m / z
1
3
14
2
2
2
33.1287, obs m / z 233.1290. Selected data for
2
5
diastereoisomer (S,S) of compound 7 : [a] : +56 (c 0.5,
D
Synlett 1999, No. 11, 1838–1840 ISSN 0936-5214 © Thieme Stuttgart · New York

1
840
C. Agami et al.
LETTER
(13) Juaristi, E.; Quintana, D.; Balderas, M. Garcia-Perez, E.
1
CHCl ); H NMR (250 MHz, CDCl ): 1.07 (d, J=6.9 Hz, 3H),
3
3
1
.50 (d, J=7.1 Hz 3H), 2.37 (m, 1H), 2.89-2.93 (m, 2H), 5.73
Tetrahedron Asymmetry., 1996, 7, 2233-2246.
(14) Rej, R.; Nguyen, D.; Go, B.; Fortin, S.; Lavallée, J.F. J. Org.
Chem., 1996, 61, 6289-6295.
1
3
(q, J=7.1 Hz, 1H) 7.28 (m, 1H), 7.79 (bs, 1H). C NMR (63
MHz, CDCl ): 12.5, 15.4, 35.2, 43.0, 51.3, 127.1, 127.8,
3
128.7, 139.6, 152.8, 172.5.
(
(
11) Rachina, V.; Blagoeva, I. Synthesis, 1982, 967-968.
12) Roussi, F.; Bonin, M.; Chiaroni, A; Micouin, L.; Riche, C.;
Husson, H.P. Tetrahedron Lett., 1998, 39, 8081-8084.
Article Identifier:
1437-2096,E;1999,0,11,1838,1840,ftx,en;G18399ST.pdf
Synlett 1999, No. 11, 1838–1840 ISSN 0936-5214 © Thieme Stuttgart · New York