Synthesis of α-amino acids via a carbolithiation reaction on acyclic ene-carbamates and an internal N→C alkyloxycarbonyl migration

Article abstract of DOI:10.1055/s-2007-984874

A novel and efficient synthesis of precursors of α-amino acids is described. The key step involves a carbolithiation reaction on acyclic ene-carbamates generated from the corresponding vinylphosphates via a palladium cross-coupling reaction followed by a spontaneous internal N→C alkyloxycarbonyl migration. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-984874

LETTER
1925
Synthesis of a-Amino Acids via a Carbolithiation Reaction on Acyclic Ene-
Carbamates and an Internal N→C Alkyloxycarbonyl Migration
Synthesis of
a-Ae
Institut de Chimie Organique et Analytique UMR 6005, Université d’Orléans, Rue de Chartres, BP 6759, 45067 Orléans Cedex 2, France
Fax +33(2)38417281; E-mail: isabelle.gillaizeau@univ-orleans.fr; E-mail: gerard.coudert@univ-orleans.fr
Received 3 April 2007
In connection with our efforts to develop synthetic routes
Abstract: A novel and efficient synthesis of precursors of a-amino
to nitrogen-containing derivatives, we have undertaken a
research program directed towards expanding the range of
acids is described. The key step involves a carbolithiation reaction
on acyclic ene-carbamates generated from the corresponding vi-
lactam-derived vinyl phosphates available to the organist
chemist.6,7 Taking advantage of our previous results, a
synthesis of the original acyclic amide-derived vinylphos-
phates 3 was envisaged. Starting from aromatic primary
amines 1, after protection of the nitrogen, the amide 2 was
treated with LDA (1.2 equiv) at –78 °C in THF providing
the desired lithium enolate that was quenched with diphe-
nylchlorophosphate (1.2 equiv, cf. Table 1). After workup
and purification by silica gel chromatography, the re-
quired acyclic amide-derived vinylphosphates 3a–c were
isolated in good yields. A Pd-catalyzed Suzuki–Miyaura
coupling reaction was then investigated. By using classi-
cal conditions, a range of acyclic ene-carbamates 4a–f,
substituted a to nitrogen by different aryl or heteroaryl
groups, was isolated in fair to good yields (cf. Table 2).8
nylphosphates via a palladium cross-coupling reaction followed by
a spontaneous internal N→C alkyloxycarbonyl migration.
Key words: non-natural amino acids, carbolithiation, ene-carba-
mate, vinyl phosphate, alkyloxycarbonyl migration
The development of new synthetic approaches to nonnat-
ural amino acids is a blossoming field of research since
such compounds find applications in the synthesis of
pharmacologically useful molecules, analogues of bioac-
tive peptides mimetics.1 Our goal was to devise a new
route to a-amino acids based on a vinyl carbolithiation
performed on acyclic ene-carbamates as the original key
synthetic step. Carbolithiation has seen increasing use as
a powerful method for complex ring synthesis.2 However,
very few teams have reported the intermolecular nucleo-
philic addition of organolithium reagents to an alkene, an
addition generally difficult to control since it may lead to
polymerization of the olefin.3 To obtain synthetically use-
ful carbolithiation reactions, the final organometallic ad-
duct must be stabilized4 or must differ markedly from the
starting one.5 In a previous work, we reported a successful
carbolithiation approach on seven-membered ring ene-
carbamates.6 In this paper, we want to explore the scope
of our method and to this purpose, study carbolithiation on
acyclic ene-carbamates in order to develop a process that
would give easy access to a-amino acids bearing a quater-
nary carbon next to the nitrogen (cf. Scheme 1). The first
part of this work concerns the preparation of acyclic ene-
carbamates from the corresponding vinylphosphates via a
palladium cross-coupling reaction. Carbolithiation on the
latter will be investigated in a second stage.
Carbolithiation was then considered, and acyclic ene-car-
bamates 4a–f were submitted to reaction with a small
range of commercially available organolithium reagents.
Treatment of 4a–f in THF at –78 °C with an excess of RLi
followed by warming to 0 °C led to the formation of
unexpected derivatives 79 (cf. Scheme 2 and Table 3). We
can assume that firstly a nucleophilic intermolecular
Table 1 Preparation of Acyclic Amide-Derived Vinylphosphates
3a–c
1) aq HCl, Ac2O, AcONa
Ar
Ar
NH2
N
O
2) Boc2O, DMAP, MeCN
Boc
1
2
O
P
OPh
OPh
1) LDA
Ar
N
O
2) ClP(O)(OPh)2
Boc
3
R4
R3
O
1) R4Li
2) E+
OPh
OPh
R3M
Entry
Ar
Amide 2a Yield
Vinylphos- Yield
R1
R1
R1
P
*
phate 3b
(%)
N
R2
R3
N
N
R2
O
(%)
Pd(0)
E
R2
1
2
3
Ph
2a
2b
2c
82
61
98
3a
83
E = COOR
2-MeC6H4
3-MeOC6H4
3b
82
Scheme 1 Access to a-amino acids
SYNLETT 2007, No. 12, pp 1925–1929
3c
95
a Conditions: i) aq HCl, Ac2O, AcONa; ii) Boc2O, DMAP, MeCN.
b Conditions: i) LDA (1.2 equiv), THF, –78 °C, 1 h; ii) ClP(O)(OPh)2
(1.2 equiv), –78 °C.
2
4
.0
7
.2
0
0
7
Advanced online publication: 27.06.2007
DOI: 10.1055/s-2007-984874; Art ID: D09907ST
© Georg Thieme Verlag Stuttgart · New York

1926
B. Cottineau et al.
LETTER
Table 2 Preparation of Acyclic Ene-Carbamates 4a–f via Suzuki Coupling Reactiona
O
OPh
OPh
Pd(0)
Ar
Ar
P
N
Ar'
N
O
Ar'B(OH)2
Boc
Boc
3
4
Entry
1
Ar
Ph
Boronic acids
PhB(OH)2
Product
4
Yield (%)
Boc
N
Ph
4a
83
67
73
Boc
N
2-MeC6H4
2
3
2-MeC6H4
PhB(OH)2
PhB(OH)2
4b
4c
Boc
N
3-MeOC6H4
3-MeOC6H4
3-MeOC6H4
Boc
N
3-MeOC6H4
4
2-NaphthylB(OH)2
4d
70
Boc
N
3-MeOC6H4
5
6
3-MeOC6H4
3-MeOC6H4
2-Benzo-furylB(OH)2
4e
4f
77
50
O
Boc
N
2-FurylB(OH)2
3-MeOC6H4
O
a Conditions: ArB(OH)2 (1.5 equiv), PdCl2(PPh3)2 (5 mol%), 2 M Na2CO3 (2 equiv), a few drops of EtOH, THF, reflux 1 h.
R
R
addition of organolithium reagent to double bond of the
ene-carbamate gave rise to the organolithium intermedi-
ates 5. Theoretical studies reported by Houk and Bailey10
reveal indeed that the initial step for the intermolecular
carbometalation is an energetically favorable coordina-
tion of the lithium atom with the p-system (in Scheme 2,
with the Ar¢ group in our case). The p-chelation was also
promoted by a complex-induced proximity effect
(CIPE)4b of the carbamate donor. Secondly, by warming
the reaction mixture to 0 °C, the benzylic organolithium-
type intermediate became thermally labile and spontane-
ously underwent an internal Boc-carbonyl migration from
the nitrogen to the benzylic carbon to give 6. Rouden and
Lasne11 also reported the N→C alkyloxycarbonyl migra-
Ar'
Ar'
–78 °C
to 0 °C
Ar
Ar
RLi
Ar
O
N
N
Ar'
N
*
O
Li
–78 °C
Li
Boc
O
O
4
5
6
R
H2O
Ar'
Ar
N
*
O
H
O
7
Scheme 2 Carbolithiation reaction on acyclic ene-carbamates 4
Synlett 2007, No. 12, 1925–1929 © Thieme Stuttgart · New York

LETTER
Synthesis of a-Amino Acids
1927
tion from lithium intermediates. Subsequent hydrolysis addition of lithium amide on the double bond of the
provided in fair to good yields a-amino esters 7a–l, pre- acyclic ene-carbamate was observed, followed by a Boc
cursors of a-amino acids bearing a quaternary carbon next carbonyl transfer. To the best of our knowledge, there is
to the nitrogen.
no literature precedent for such addition.
It is noteworthy that in the case of compounds 7c, 7d, and
7j (entries 3, 4, and 10, Table 3), an unusual nucleophilic
Table 3 Carbolithiation Reaction on Ene-Carbamates 4a–fa
t-BuO
O
1) RLi, –78 °C to 0 °C
H
N
R
N
Ar
Ar
CO2t-Bu
2) H2O, NH4Cl
Ar'
Ar'
4
7
Entry
Substrate
RLi
Product
7
Yield (%)
(75%)
H
N
Me
Ph
CO2t-Bu
1
2
4a
4a
MeLi
7a
H
N
Ph
Ph
CO2t-Bu
PhLi
7b
7c
78
89
i-Pr
H
N
N
i-Pr
CO2
i-Pr
3
4
4a
4a
Ph
t-Bu
N
Li
i-Pr
Ph
H
N
N
Me
Ph
Me
7d
51
Ph
CO2t-Bu
N
Li
H
N
Me
CO2t-Bu
2-MeC6H4
2-MeC6H4
3-MeOC6H4
5
6
7
4b
4b
4c
MeLi
PhLi
MeLi
7e
7f
80
81
68
H
N
Ph
CO2t-Bu
H
N
Me
CO2t-Bu
7g
Synlett 2007, No. 12, 1925–1929 © Thieme Stuttgart · New York

1928
B. Cottineau et al.
LETTER
Table 3 Carbolithiation Reaction on Ene-Carbamates 4a–fa (continued)
t-BuO
O
1) RLi, –78 °C to 0 °C
H
N
R
N
Ar
Ar
CO2t-Bu
2) H2O, NH4Cl
Ar'
Ar'
4
7
Entry
Substrate
RLi
Product
7
Yield (%)
H
N
Me
CO2t-Bu
3-MeOC6H4
8
4d
MeLi
7h
56
H
N
n-Bu
CO2t-Bu
3-MeOC6H4
9
4c
4c
n-BuLi
7i
7j
89
86
i-Pr
H
N
N
i-Pr
i-Pr
10
3-MeOC6H4
CO2t-Bu
N
i-Pr
Li
H
N
n-Bu
3-MeOC6H4
CO2t-Bu
11
12
4e
4f
n-BuLi
n-BuLi
7k
7l
26
14
O
H
N
n-Bu
3-MeOC6H4
CO2t-Bu
O
a Conditions: i) RLi, –78 °C, then warming to 0 °C; ii) aq sat. NH4Cl.
The structure of the a-amino esters obtained was unam- The low yields of derivatives 7k and 7l could be attributed
biguously determined by treating derivative 7a, chosen as to the fact that during the carbolithiation step a less-stabi-
a model, by lithium aluminum hydride in THF at 0 °C. In lized carbanion would be generated leading to further side
this case, the expected formation of primary alcohol 812 reactions due to furan ring opening.
was observed (cf. Scheme 3).
To summarize, we have extended the scope of the inter-
molecular carbolithiation reaction to acyclic ene-carba-
mates. The lithium intermediate underwent an unexpected
CH3
Ph
CH3
internal N→C alkyloxycarbonyl migration. The strategy
involved gives easy access to precursors of non-natural a-
amino acids and offers the potential advantage of directly
introducing further molecular diversity onto the mole-
cules as a result of the original choice of the starting pri-
mary amine, the organolithium reagent, and the boronic
acid. Experiments designed to explore first the stereose-
lectivity of the process and then the chemical behavior of
the lithium intermediate according to the carbamate group
used are in progress and will be described in due course.
Ph
O
LiAlH4
Ph
Ph
N
N
*
*
THF, 0 °C
H
H
O
OH
7a
8
Scheme 3 Reduction of the tert-butyloxycarbonyl group of
a-amino ester 7a
Synlett 2007, No. 12, 1925–1929 © Thieme Stuttgart · New York

LETTER
Synthesis of a-Amino Acids
1929
(9) Representative Procedure for the Preparation of 7a–l
A solution of acyclic ene-carbamate 4a (0.100 g, 0.34 mmol)
in THF (10 mL) was cooled to –78 °C under argon. Sub-
sequently, MeLi (0.450 mL, 1.4 M in hexane, 0.71 mmol)
was added dropwise. After stirring for 30 min at –78 °C, the
reaction mixture was warmed up to 0 °C. After 1 h at 0 °C,
the reaction was quenched by slow addition of H2O. The
aqueous phase was then extracted with EtOAc and the
organic phase was washed with brine. The organic phase
was dried over anhyd MgSO4 and concentrated. Flash
chromatography (PE–EtOAc, 98:2) afforded 7a (75%) as a
white solid; mp 109–110 °C. IR (KBr): 3419, 2980, 1720,
1599, 1504, 1158 cm–1. 1H NMR (250 MHz, CDCl3):
d = 7.56 (d, J = 7.6 Hz, 2 H), 7.20–7.32 (m, 3 H), 6.95 (t,
J = 7.8 Hz, 2 H), 6.57 (t, J = 7.6 Hz, 1 H), 6.35 (d, J = 7.8
Hz, 2 H), 5.35 (br s, 1 H), 2.51 (m, 2 H), 1.30 (s, 9 H), 0.84
(t, J = 7.2 Hz, 3 H). 13C NMR (62.9 MHz, CDCl3): d = 173.0
(s), 144.8 (s), 141.6 (s), 129.0 (d), 128.6 (d), 127.4 (d), 127.2
(d), 117.2 (d), 115.1 (d), 82.5 (s), 67.1 (s), 27.9 (q), 25.8 (t),
8.6 (q). MS (IS): m/z = 312 [M + 1]+.
References and Notes
(1) (a) Williams, R. H. The Synthesis of Optically Active a-
Amino Acids; Pergamon: New York, 1989. (b) Giannis, A.;
Kolter, T. Angew. Chem., Int. Ed. Engl. 1993, 32, 1244.
(c) Duthaler, R. O. Tetrahedron 1994, 50, 1539.
(d) Moutevelis-Minakakis, P.; Sinanoglou, C.; Loukas, V.;
Kokotos, G. Synthesis 2005, 933.
(2) (a) Clayden, J. Organolithiums: Selectivity for Synthesis;
Pergamon: Oxford, UK, 2002, 273. (b) Review: Mealy, M.
J.; Bailey, W. F. J. Organomet. Chem. 2002, 646, 59.
(c) Cottineau, B.; O’Shea, D. F. Tetrahedron Lett. 2005, 46,
1935.
(3) (a) Peters, J. G.; Seppi, M.; Fröhlich, R.; Wibbeling, B.;
Hoppe, D. Synthesis 2002, 381. (b) Norsikian, S.; Marek, I.;
Poisson, J.-F.; Normant, J. F. J. Org. Chem. 1997, 62, 4898.
(c) Superchi, S.; Sotomayor, N.; Miao, G.; Joseph, B.;
Campbell, M. G.; Snieckus, V. Tetrahedron Lett. 1996, 37,
6061.
(4) (a) Klumpp, G. W. Recl. Trav. Chim. Pays-Bas 1986, 105,
1. (b) Klein, S.; Mareck, I.; Normant, J.-F. J. Org. Chem.
1994, 59, 2925. (c) Mück-Lichtenfeld, C.; Ahlbrecht, H.
Tetrahedron 1996, 52, 10025.
(5) (a) Marek, I.; Normant, J. F. Chem. Rev. 1996, 96, 3241.
(b) Beak, P.; Meyers, A. I. Acc. Chem. Res. 1986, 19, 356.
(6) Lepifre, F.; Cottineau, B.; Mousset, D.; Bouyssou, P.;
Coudert, G. Tetrahedron Lett. 2004, 483.
(7) (a) Mousset, D.; Gillaizeau, I.; Hassan, J.; Lepifre, F.;
Bouyssou, P.; Coudert, G. Tetrahedron Lett. 2005, 21,
3703. (b) Mousset, D.; Gillaizeau, I.; Bouyssou, P.; Coudert,
G. J. Org. Chem. 2006, 71, 5993. (c) Claveau, E.;
Gillaizeau, I.; Blu, J.; Bruel, A.; Coudert, G. J. Org. Chem.
2007, accepted.
(10) (a) Houk, K. N.; Rondan, N. G.; Schleyer, P. V. R.;
Kaufman, E.; Clark, T. J. Am. Chem. Soc. 1985, 107, 2821.
(b) Bailey, W. F.; Khnaolkar, A. D.; Gavaskar, K.; Ovaska,
T. V.; Rossi, K.; Thiel, Y.; Wiberg, K. B. J. Am. Chem. Soc.
1991, 113, 5720.
(11) N→C Acyl migration: Rouden, J.; Ragot, A.; Gouault, S.;
Cahard, D.; Plaquevent, J.-C.; Lasne, M.-C. Tetrahedron:
Asymmetry 2002, 13, 1299.
(12) Analytical Data for 8
Brown solid; mp 72–73 °C. IR (KBr): 3404, 2967, 2933,
1600, 1498, 1491, 1446 cm–1. 1H NMR (250 MHz, CDCl3):
d = 7.24–7.29 (m, 5 H), 6.97–7.04 (m, 2 H), 6.59–6.66 (m, 1
H), 6.36–6.40 (m, 2 H), 4.00 (d, J = 11.0 Hz, 1 H), 3.91 (d,
J = 11.0 Hz, 1 H), 2.05–2.16 (m, 1 H), 1.90–2.01 (m, 1 H),
0.79 (t, J = 7.6 Hz, 3 H). 13C NMR (62.9 MHz, CDCl3):
d = 145.2 (s), 142.8 (s), 129.0 (d), 128.7 (d), 127.0 (d), 126.7
(d), 117.7 (d), 115.4 (d), 65.3 (s), 62.5 (s), 30.5 (s), 8.1 (q).
MS (IS): m/z = 242 [M + 1]+.
(8) Other strategy for the preparation of similar derivatives (N-
acyl-a-arylvinylamines), see: Hansen, A. L.; Skrydstrup, T.
J. Org. Chem. 2005, 70, 5997; and references cited therein.
Synlett 2007, No. 12, 1925–1929 © Thieme Stuttgart · New York

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