Enantioselective synthesis of β-amino-diacids

Article abstract of DOI:10.1016/j.tetlet.2005.09.114

An efficient route to orthogonally protected β-amino-diacids is described: chiral derivative 3 was shown to be a precursor of enantiopure substituted β-amino acids. The key step of the procedure is a diastereoselective reduction of β-enaminolactones 5 by

Full text of DOI:10.1016/j.tetlet.2005.09.114

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 8203–8205
Enantioselective synthesis of b-amino-diacids
Jeanne Alladoum and Luc Dechoux*
`
´ ´
Laboratoire de Synthese Asymetrique (Institut de Chimie Moleculaire FR 2769), Universite Pierre et Marie Curie,
4 place Jussieu, 75005 Paris, France
´
Received 16 July 2005; revised 16 September 2005; accepted 19 September 2005
Available online 10 October 2005
Abstract—An efficient route to orthogonally protected b-amino-diacids is described: chiral derivative 3 was shown to be a precursor
of enantiopure substituted b-amino acids. The key step of the procedure is a diastereoselective reduction of b-enaminolactones 5 by
NaBH3CN in CH2Cl2. A study concerning the regio- and diastereoselectivity of alkylation of b-enaminolactone 3 is also presented.
Ó 2005 Elsevier Ltd. All rights reserved.
MeO2C
b-Amino acids have attracted much attention in recent
years, whether as analogues of a-amino acids to increase
HO
Ph
b)
a)
the resistance of peptides to enzymatic degradation1 or
as building blocks for the synthesis of b-lactam antibiot-
ics.2 In addition, b-amino acids derivatives are crucial
structural components of numerous biologically active
natural products.3 Although many methods for synthe-
sizing enantiomerically pure b-amino acids have been
reported, great effort continues to be devoted towards
more efficient enantioselective methods.4 There are
many approaches for asymmetric synthesis of b-amino
acids including homologation of a-amino acids,5 enzy-
matic resolution,6 addition of enolates to imines,7 cata-
lytic hydrogenations.8 The most obvious strategy
consists of chiral Lewis acid catalyzed conjugate addi-
tion of amines to a,b-unsaturated esters.9 Another strat-
egy is based on stereoselective alkylation en route to
enantiopure b-amino acids using chiral auxiliaries.10
OH
HN
Ph
NH
H2N
O
MeO2C
CO2Me
O
Ph
3
2
1
Scheme 1. Reagents and conditions: (a) acetonedicarboxylate, toluene,
reflux 48 h 100%; (b) (i) NaH, THF, 1 h, (ii) NH4Cl/H2O, 83%.
The condensation of dimethyl acetonedicarboxylate
with (R)-phenylglycinol 1 proceeds in toluene. This con-
densation to form the two Z- and E-diastereoisomers
does not require the removal of water and, after two
days in the refluxing solvent, b-enaminoester 2 was
obtained in nearly quantitative yield by evaporation of
the solvent. The next step involved the formation of
the optically active heterocyclic compound via cycliza-
tion. The crude material was then dissolved in dry
THF and the addition of NaH (1.1 equiv) at room tem-
perature provided after 15 min, classical work-up and
chromatography a good yield of the desired b-enamino-
lactone 3 (83% from starting (R)-phenylglycinol 1) as a
unique regioisomer.13
Herein, we report a novel synthetic strategy for the con-
struction of orthogonally protected b-amino-diacids by
using a new chiral auxiliary 3. While b-amino-diacids
and -diesters have a broad range of synthetic applica-
tions,11 they have been used most extensively as precur-
sors to b-lactams.12
Next, we were interested by the regio- and stereoselectiv-
ity of alkylation of the b-enaminolactone 3, a class of
compounds which has been only scarcely explored to
date.14 The results are reported in Scheme 2.
The synthesis of compound 3 was realized in two steps
(Scheme 1).
Enolates 30 derived from product 2 was generated by
reaction with MeONa, which was liberated during the
cyclization step at 0 °C in THF. The electrophiles
(RX in conditions band d) were added at 0 °C and
the reaction mixtures were stirred for 1 h 30 min at this
Keywords: Asymmetric synthesis; b-Enaminolactone; b-Amino acids;
(R)-Phenylglycinol; b-Amino-diacids.
Corresponding author. Fax: +33 01 44 27 26 20; e-mail:
*
dechoux@ccr.jussieu.fr
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.09.114

8204
J. Alladoum, L. Dechoux / Tetrahedron Letters 46 (2005) 8203–8205
NaO
CO2Me
HO
R
OMe
a)
b)
4a R=Bn (Yield=72%, de=40%)
4b R=Me (Yield=46%, de=34%)
Ph
NH
HN
HN
O
MeO2C
CO2Me
O
O
Ph
O
Ph
d)
2
3
4
CO2Me
R
CO2Me
R
c)
HN
Ph
HN
O
O
O
O
Ph
5
3
Scheme 2. Reagents and conditions: (a) NaH (1.1 equiv), THF, 0 °C, 15 min; (b) (i) RX (0.95 equiv), 1.5 h at 0 °C, (ii) aqueous NH4Cl; (c) aqueous
NH4Cl; (d) (i) NaH (1.1 equiv), (ii) RX (2.2 equiv) 1.5 h at 0 °C, (iii) aqueous NH4Cl.
CO2Me
CO2Me
H
R
R
6a R=Bn (Yield=47%, de>95%)
6b R=Me (Yield=37%, de>95%)
6c R=H (Yield=53%, de>95%)
a)
HN
HN
O
O
O
O
Ph
Ph
4
6
Scheme 3. Reagents and conditions: (a) (i) AcOH (13 equiv), 0 °C, CH2Cl2, (ii) NaBH3CN (1.1 equiv), CH2Cl2 0 °C to rt, 1 h, (iii) aqueous NH4Cl.
CO2Me
temperature and further hydrolyzed with a saturated
R
CO2Me
H
R
aqueous ammonium chloride solution (conditions c cor-
respond to those reported in Scheme 1 for the formation
of compound 3).
H
a)
7a R=Bn (Yield=82%)
7b R=Me (Yield=84%)
7c R=H (Yield=96%)
HN
H2N
O
CO2H
O
Ph
The results reported show that the electrophile (RX) at-
tack the ambident enolate 30 with total exo-regioselectiv-
ity (conditions b). In all cases, we observed the presence
of the exo-dialkylated products 5 (5a: R = Bn, 5b:
R = Me). These products 5 were exclusively formed
when 1.1 more equivalent of base and RX were used
(conditions d). Unfortunately, the diastereoselectivity
of alkylation was low (conditions b). The major diaste-
reoisomer 4a could be separated by crystallization from
Et2O.15 The R-absolute configuration of the new created
stereocenter in product 4a was established by X-ray
analysis.16 Configuration of compound 4b was deduced
from the stereochemistry of product 4a.
7
6
Scheme 4. Reagents and conditions: (a) H2, Pd(OH)2/C (0.5 equiv),
MeOH, rt, two days.
responding b-enaminoesters 7 in enantiopure forms and
in good yields (Scheme 4).20
In summary, we have developed a novel and diastereo-
selective method for the asymmetric synthesis of ortho-
gonally protected b-amino-diacids in four steps starting
from (R)-phenylglycinol 1. Complete diastereocontrol
in the reduction step allows easy access to b-aminolac-
tones 6. Heterocycles derived from b-enaminolactones
3 are currently used in the asymmetric synthesis of
poly-substituted piperidines and quinolizidines.
The reductions of compounds 4 were carried out with
NaBH3CN (6 equiv) in dichloromethane with acetic acid
(13 equiv) at 0 °C for 1 h to give the saturated amino-
lactones 6 (Scheme 3).17
1
References and notes
In all experiments we observed, in the H NMR spec-
trum of the crude material, compound 6 as almost
pure.18 Some loss of material during the extraction
and chromatography processes could explain the yields,
which were obtained as indicated in Scheme 3. The ob-
served total diastereoselectivity corresponds to an attack
of the reducing agent in an anti orientation with respect
to the phenyl group.19
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13. Spectral data for compound 3: IR m (cmÀ1): 3293, 1743,
1715, 1655, 1610, 1560. 1H NMR (CDCl3, 250 MHz): 3.17
(s, 2H), 3.68 (s, 3H), 4.23 (d, 1H, J = 12.75 Hz), 4.44 (dd,
1H, J = 6.75 Hz, J = 12.75 Hz), 4.58 (s, 1H), 4.67 (d, 1H,
J = 6.75 Hz), 6.05 (broad s, 1H), 7.28–7.34 (m, 5H). 13C
NMR (CDCl3, 62.9 MHz): 41.8, 52.8, 61.8, 70.2, 88.4,
126.8, 129.0, 129.5, 137.9, 148.4, 169.8, 170.2.
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15. Spectral data for compound 4a: Mp: 202 °C. Anal. Calcd
for C21H21NO4: C, 71.78; H, 6.02; N, 3.99. Found: C,
20
67.34; H, 6.01; N, 3.87. ½aꢀD À38 (c 1, CHCl3). IR m
(cmÀ1): 3261–1736–1638–1580–1549. 1H NMR (CDCl3,
250 MHz): 3.05 (dd, 1H, J = 7.5 Hz, J = 13.25 Hz), 3.18
(dd, 1H, J = 7.75 Hz), 3.29 (t, 1H, J = 7.75 Hz), 3.68
(s, 3H), 4.20 (d, 1H, J = 12.5 Hz), 4.36 (dd, 1H,
J = 6.75 Hz, J = 12.5 Hz), 4.69 (d, 1H, J = 7 Hz), 4.73
(s, 1H), 7.05–7.37 (m, 10H). 13C NMR (CDCl3,
62.9 MHz): 39.8, 53.1, 55.2, 62.1, 70.3, 87.7, 126.9,
127.6, 129.1, 129.2, 129.8, 137.4, 138.0, 152.0, 170.1,
172.7.
16. Atomic coordinates, bond lengths and angles have been
deposited at the Cambridge Crystallographical Data
Center with the deposition number CCDC283799.
17. Reductions were realized on diastereomerically- and
enantiomerically pure compounds 4a,c and on a mixture
of diastereoisomers of compound 4b.
18. The stereochemistry of compounds 6a,c was established by
1H NMR spectroscopy (NOE experiments).
20
19. Spectral data for compound 6a: Mp: 142 °C. ½aꢀD À45 (c
1
1.2, CHCl3). IR m (cmÀ1): 3414–1717. H NMR (CDCl3,
250 MHz): 2.71–2.85 (m, 2H), 2.95–3.05 (m, 3H), 3.21 (dd,
1H, J = 3.5 Hz, J = 9.75 Hz), 3.60 (s, 3H), 4.01 (d, 1H,
J = 7.5 Hz), 4.11 (d, 1H, J = 12.5 Hz), 4.25 (dd, 1H,
J = 7.5 Hz, J = 12.5 Hz), 7.08–7.32 (m, 10H). 13C NMR
(CDCl3, 62.9 MHz): 34.8, 42.9, 52.3, 53.8, 54.3, 63.5, 75.4,
127.1, 127.2, 128.7, 129.0, 129.3, 129.4, 138.9, 140.2, 173.5,
174.1.
20
20. Spectral data for compound 7a: Mp: 186 °C. ½aꢀD À35
(c 0.8, HCl (1 M)). IR m (cmÀ1): 3515–1716. Anal.
Calcd for C13H17NO4: C, 62.14; H, 6.82; N, 5.57.
Found: 60.96; H, 6.80; N, 5.34. 1H NMR (CD3OD,
250 MHz): 2.46 (dd, 1H, J = 9 Hz, J = 17 Hz), 2.63
(dd, 1H, J = 4.5 Hz, J = 17 Hz), 2.98–3.12 (m, 3H),
3.59 (s, 3H), 3.64 (dd, 1H, J = 4.75 Hz, J = 9.25 Hz),
7.18–7.32 (m, 5H). 13C NMR (CD3OD, 62.9 MHz): 36.4,
37.8, 51.1, 51.9, 52.9, 128.4, 130.1, 130.3, 139.1, 174.5,
176.
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