Enantioselective synthesis of γ-functionalized α-dehydroamino esters

Article abstract of DOI:10.1055/s-2007-983840

Copper-catalyzed asymmetric 1,4-addition of diethylzinc to β,γ-unsaturated α-imino esters 1 using a copper-phosphoramidite complex affords enantiomerically enriched γ-functionalized α-dehydroamino esters 2. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-983840

PRACTICAL SYNTHETIC PROCEDURES
3923
Enantioselective Synthesis of g-Functionalized a-Dehydroamino Esters
E
nantioselecti
r
ve Synth
a
e
sis of
g
-Fu
n
nctionalized
c
a
-Dehydro
i
amino
s
Esters co Palacios,* Javier Vicario
Departamento de Química Orgánica I, Facultad de Farmacia, Universidad del País Vasco,
Apartado 450, 01080 Vitoria-Gasteiz, Spain
Fax +34(945)130756; E-mail: francisco.palacios@ehu.es
PSP
Received 8 May 2007; revised 11 June 2007
No106
Abstract: Copper-catalyzed asymmetric 1,4-addition of diethylzinc to b,g-unsaturated a-imino esters 1 using a copper-phosphoramidite
complex affords enantiomerically enriched g-functionalized a-dehydroamino esters 2.
Key words: amino acids, asymmetric catalysis, imines, Michael addition, organometallics
Ph
Ph
O
O
O
P
N
O
Ph
N
NH
Et
Ph
Et2Zn, Cu(MeCN)4PF6
toluene, –40 °C
EtO2C
EtO2C
NO2
NO2
1a
2a
Scheme 1 Copper-catalyzed asymmetric conjugate addition of Et2Zn to a,b-unsaturated imine 1a derived from a-amino acids
a-Dehydroamino acids represent an important family of imidazolidines7 or aziridines,8 nucleophilic addition to
compounds in organic synthesis, since they are ordinary alkynoates,9 or Horner–Emmons condensation of phos-
synthons of natural and unnatural a-amino acids, most phorylglycine esters and aldehydes.10
commonly through their enantioselective catalytic hydro-
As part of our research in the field of the chemistry of aza-
genation.1 They can also be precursors of oxalamic acid
dienes,11 we have recently developed an efficient synthet-
derivatives if the C=C bond is ozonolyzed2 and have been
ic methodology for the synthesis of a,b-unsaturated
often used as precursors of a-keto acids through the hy-
imines derived from a-amino acids through aza-Wittig re-
drolysis of the imine functional group3 (Scheme 2).
action of b,g-unsaturated a-keto esters and P-trimethyl-
phosphazenes.11b The easy synthetic availability of such
R3
R3
R3
1-azadienes prompted us to examine their reactivity to-
wards nucleophile species. Specifically we thought that
regioselective nucleophilic conjugate addition takes place
with simultaneous formation of a new stereogenic center,
and therefore we conceived the idea of developing a syn-
thetic methodology for the catalytic enantioselective 1,4
addition of organozinc reagents to a,b-unsaturated imines
derived from a-amino acids which would afford chiral
a-dehydroamino acid derivatives12 (Scheme 1).
O3
H2, cat.
NH
NH
NH
R2
O
+
R2
R2
R1O2C
O
R1O2C
H3O+
R1O2C
O
peptides or
depsipeptides
R2
R1O2C
Scheme 2 Synthetic applications of a-dehydroamino acids
In a typical procedure, Et2Zn was added over two hours at
–40 °C to a toluene solution of 1-azadiene 1 and the cop-
per catalyst, which was previously prepared ‘in situ’ from
Cu(MeCN)4PF6 and TADDOL derived phosphoramidite.
This method was successfully applied to the synthesis of
several (S)-a-dehydroamino esters 2, observing very good
enantioselectivities in all the cases (Scheme 3, Table 1).13
As well as being interesting synthetic intermediates, a-de-
hydroamino acids also show intriguing biological
activities4 and have been used to modify the conforma-
tional properties of peptides.5 The most common proce-
dure for the preparation of a-dehydroamino acids is the b-
elimination of a-amino acid derived alcohols or halides,6
although other efficient synthesis of a-dehydroamino ac-
ids have also been reported; for example, ring opening of
Although an increase in enantioselectivity can be
achieved if the temperature is lowered, a rise in the rates
of the double and 1,2 addition products is also observed at
–50 °C or –80 °C, whereas lower enantioselectivity and
no significant decrease in the rates of the double and 1,2-
SYNTHESIS 2007, No. 24, pp 3923–3925
x
x.
x
x
.
2
0
0
7
Advanced online publication: 29.08.2007
DOI: 10.1055/s-2007-983840; Art ID: Z11207SS
© Georg Thieme Verlag Stuttgart · New York

3924
F. Palacios, J. Vicario
PRACTICAL SYNTHETIC PROCEDURES
NMR spectra were recorded on a Varian VXR 300 MHz spectro-
meter using CDCl3 solutions with TMS as an internal reference
(d = 0.00). Low-resolution mass spectra (MS) were obtained at 50–
70 eV by electron impact (EIMS) on a Hewlett Packard 5973 spec-
trometer and by chemical ionization (CI, N2) on a Hewlett Packard
1100MSD. IR spectra were taken on a Nicolet IRFT Magna 550
spectrometer, and were obtained in KBr for solids or neat for oils.
Elemental analyses were performed in a LECO CHNS-932 appara-
tus. Determination of the enantiomeric ratios was carried out by
HPLC analysis (Chiracel OD-H, hexane–EtOH, 99:1, 0.5 mL/min).
TADDOL derived phoshoramidite ligand is commercially available
and a,b-unsaturated imines 1 derived from a-amino acids were pre-
pared following a literature procedure.11b
Ph
O
Ph
O
P
N
O
O
R2
R2
Ph
Ph
N
NH
Et
Et2Zn, Cu(MeCN)4PF6
toluene, –40 °C
EtO2C
R1
EtO2C
R1
1
2
Scheme 3 Copper-catalyzed asymmetric conjugate addition of
Et2Zn to several a,b-unsaturated imines 1 derived from a-amino acids
Table 1 Enantiomeric Ratio for the Conjugate Addition of Et2Zn to
Several b,g-Unsaturated a-Imino Esters
Asymmetric Conjugate Addition of Et2Zn to a,b-Unsaturated
Imine 1a Derived from a-Amino Acids; Chiral a-Dehydroami-
no Ester 2a; Typical Procedure
Product
2a
R1
R2
Yield (%)a er (%)
A solution of Cu(MeCN)4PF6 (1.86 mg, 5 mmol) and TADDOL de-
rived phosphoramidite ligand (5.40 mg, 10 mmol) in toluene (500
mL) was stirred at r.t. for 1 h. The resulting copper-phosphoramidite
complex solution was cooled to –40 °C and a,b-unsaturated imine
1a (100 mmol) was then added. The resulting solution was stirred at
–40 °C for 15 min and a 1.5 M solution of Et2Zn in toluene (100 mL,
150 mmol) was then added over a period of 2 h. The resulting dark
solution was quenched with sat. aq NH4Cl (1 mL) and stirred vigor-
ously until a clear mixture was obtained. The resulting mixture was
warmed to r.t and extracted with Et2O (3 mL), which was dried
(MgSO4), and concentrated under vacuum. The crude residue was
purified by chromatography (SiO2, Et2O–pentane, 1:3) to afford
33.6 mg (89%) of a-dehydroamino ester 2a as a pale yellow oil;
4-MeC6H4
4-MeOC6H4
4-MeC6H4
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
4-MeC6H4
4-MeC6H4
89
87
85
83
94:6
2b
89:11
88:12
91:9
2cb
2db
a After chromatography.
b Methyl ester instead of ethyl ester.
addition products are observed when the temperature is er = 94:6.
1H NMR (400 MHz, CDCl3): d = 0.81 (t, 3JH,H = 7.7 Hz, 3 H, CH3),
1.27 (t, 3JH,H = 7.2 Hz, 3 H, CH3), 1.74 (m, 2 H, CH2), 2.26 (s, 3 H,
CH3), 3.53 (m, 1 H, CH), 4.22 (q, 3JH,H = 7.2 Hz, 2 H, CH2O), 5.34
(s, 1 H, NH), 6.46 (d, 3JH,H = 9.9 Hz, 1 H, CH=), 6.53 (d, 3JH,H = 7.2
raised to –30 °C, 0 °C or 25 °C. A dramatic drop in the
enantioselectivity as well as increased rates of 1,2- or/and
double addition is also obtained when other noncoordinat-
ing solvents (CH2Cl2, CHCl3), weakly coordinating sol-
vents (Et2O, t-BuOMe), or stronger coordinating solvents
(THF) are used. Both Cu(I) and Cu(II) salts can be used
with success as catalysts for enantioselective Michael ad-
dition of organozinc to b,b-unsaturated a-imino esters 1,
but slightly better enantioselectivities are obtained if
Cu(MeCN)4PF6 is used.
3
3
Hz, 2 Harom), 6.94 (d, JH,H = 7.5 Hz, 2 Harom), 7.20 (d, JH,H = 7.5
Hz, 2 Harom), 8.10 (d, 3JH,H = 7.5 Hz, 2 Harom).
13C NMR (75 MHz, CDCl3): d = 11.8 (CH3), 14.1 (CH3), 20.5
(CH3), 29.8 (CH2), 45.3 (CH), 61.5 (CH2O), 116.9 (2 × CHarom),
123.5 (2 × CHarom), 123.8 (Cquat), 128.5 (2 × CHarom), 129.4
(2 × CHarom), 129.9 (=CH), 130.8 (Cquat), 141.3 (Cquat), 146.4 (Cquat),
150.9 (Cquat), 165.7 (C=O).
MS (CIMS): m/z (%) = 369 (100, [M+ + 1]), 295 (76, [M+
CO2Et]).
–
When the conventional procedure for the addition of orga-
nozinc to conjugated systems is followed,14 double addi-
tion product and the starting 1-azadiene 1 are mostly
recovered. This is probably due to the concomitance of the
resulting enamine with an excess of the very reactive or-
ganometallic species, which can undergo a second cata-
lyzed or non-catalyzed nucleophilic 1,2-addition. Several
attempts to extend this methodology to the regioselective
asymmetric addition of dimethylzinc were unsuccessful,
due to the massive presence of 1,2- and double addition
products.
Anal. Calcd for C21H24N2O4: C, 68.46; H, 6.57; N, 7.60. Found: C,
68.54; H, 6.60; N, 7.57.
Acknowledgment
The present work was supported by the Dirección General de Inve-
stigación del Ministerio de Ciencia y Tecnología (MCYT, Madrid
DGI, CTQ2006-09323) and by the Universidad del País Vasco
(UPV, GIU 06/51). J. V. thanks the Departamento de Educación,
Universidades e Investigación del Gobierno Vasco, for a postdocto-
In conclusion, the synthesis of chiral g-functionalized ral fellowship.
a-dehydroamino acid derivatives is achieved through
asymmetric conjugate addition of diethylzinc to b,g-un-
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1
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Synthesis 2007, No. 24, 3923–3925 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES Enantioselective Synthesis of g-Functionalized a-Dehydroamino Esters3925
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Synthesis 2007, No. 24, 3923–3925 © Thieme Stuttgart · New York