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Diastereoselective synthesis of α-amino-β-hydroxyacids
Tetrahedron Letters,Vol.25,No.41,pp Printed in Great Britain
DIASTEREOSELECTIVE
Giuseppe
Guanti,
.3*
4693-4696,1984
SYNTHESIS
Luca Banfi,
a
OF
oo40-4039/84 $3.00 + .oo 01984 Pergamon Press Ltd.
a-AMINO-B-HYDROXYACIDS1
a
Enrica Narisano,
and Carlo Scolastico
b
a Istituto di Chimica Organica dell'lhiversità,Centro C.N.R. di Studio sui Diariloidi e loro AppZicazioni, Palazzo delle Scienze, Corso Europa, 16132 Genova, Italy b
Istituto di Chimica Organica detl'lrniversità, Via Venezian 21, 20133 Milano, ItaZy
Summary:
threo-a-Dibensylamino-B-hydroxyesters
ectivity
through
reduction
the NaBH
(2) have been synthesised
of a-dibenzylamino-B-oxoesters
with high diastereosel-
(4) and then tranformed
into
threo-a-amino-B-hydroxyac?ds.
a-Amino-B-hydroxyacids
are derivatives
of primary
importance
both 3
hibitors,* selective
and as starting syntheses
mers still appears
for
of these compounds
B-lactam
antibiotics
have been described,
now prepared
reduction
a series
of ca-amino-B-hydroxyacids
of
the
resulting
E-oxoesters
(4)
(2) and
appeared
(3) in good
to be much
Stereochemical
(1) (LDA, THF, -6OOC)
EtOH'
(see Scheme
methyl-
or t-butyl-
of lithium
of the same enolates
enolates
followed
by
However,
1).
affording
threo
the acylation-reduction
compounds
(2) with
procedure
d.e. up to
298%.
are listed in the Table.7
In a typical
aqueous
yield
more stereoselective
results
oxoesters
using
(method B), gave o-dibenzylamino-E-hydroxy6
esters
some stereo-
of the thren5 iso-
the preparation
from (la,b) with aldehydes (method A) and the acylation
derived
Although
synthesis.
(la,b) as starting material. Both the condensation
-N,N-dibensylglycinate
afford
294
in-
to be troublesome.
We have
NaBH4
material
as enzymatic
procedure
was added
(4) in yields
for method
B a solution
to a THF solution ranging
of the appropriate
from 60 to 90%. The reduction
with an excess of NH4C1,
buffered
of the lithium enolate
by addition
derived
acyl chloride
(-6C)OC) to
was thence carried
of an excess
of NaBH4.
from
out in
It is in-
10 teresting
to note that in the absence of NH4Cl the reaction While for methyl esters
(4b) could be reduced
only
In these cases, probably decomposition
became
did not occur.
(4a) the reaction was in every case complete,
in part, and, for B2 = t-Bu, the reaction
because
of steric inhibition,
t-butyl
esters
did not take place at all.
the rate of reduction
was lower and NaBH4
competitive.
The stereochemical
course of the reaction
4693
is in agreement either with a Felkin model
4694
(figure
1) or with
bonyl and carboxyl
a Cram cyclic oxygens
model
in which
an electrophile
(X)"
is chelated
by the car-
(figure II).
$&"Y
;k& -
HH Ix3 = PhCH2
1
The relative by their conversion
II
configuration
into d,Z-threonine
of
(2) for H2 = Me and Ph was unambiguously
and,d,Z-phenylserine
products were correlated to these by t.1.c. comparisons 1 13 H and C n.m.r. spectra. a-Dibenzylamino-B-hydroxyesters acids
(5) by
(0.5 N KOH,
acid
hydrolysis
isation detected
Finally genation
easily
methodology
ether) and by means of
(2) and (3) were then transformed OOC,
70%)
for
(2b) and
into corresponding
(3b), and mild
saponification
to be used for a wide range of compounds.
the deprotection
of the amino moiety was easily obtained
(H Pd/C, 95% EtOH, 7O"C, 90%) to give a-amino-6-hydroxyacids 2'
for achieving accessible
the acylation-reduction
90-100% diastereomerically
substrates.
and enantioselective developed
(n-hexane-diethyl
The other
7:3,
In summary, pathway
(vide infra).
85%) for (2a) and (3a) (see Scheme 2). In no instance was epimer1 by t.1.c. and H n.m.r.. The mildness of these two complementary ester hydroly-
MeOH-H20
ses enable the present
16
(CF3COOH,
respectively
established
Further
synthesis
method
here reported
represents
pure threo-ca-amino-B-hydroxyacids
application
of
of polyfunctionalised
N,N-dibenzylglycinates compounds
of biological
Scheme 1
0 Method * ,
RJy
II OR’
+
NR;
(la,b)
(3a,b)
(2a,b) Method
0
\ ?
R
R2TOR’ NR; (4a,b)
a:
R’ = Me
b:
R’
R3=
=
t-Bu
PhCH2
hydro-
(6).
in our laboratory.
R;N&OR,
by catalytic
a new synthetic starting
from
to the diastereointerest
are being
4695
Scheme 2
(2a,b) or (3a,b)
R3 =
Table.
Stereoselective
(6)
PhCH2
synthesis
R1
R2
EntI-y
(5)
of a-dibenzyZwnino-fi-hydroxyesters via reduction
of &oxoesters
yieldb
threo : erythroc
(%)
(21 and (31 via aldol condensationa yieldb
threo :erythroc
(%)
Me
81
93: 7
89
57:43
;-8c
50
89:ll
91
60:40
Me
70
299:
1
75
46:54
t-Bu
57
)99:
1
74
18:82
Me
75
96: 4
80
71:29
t-Bu
52
89:ll
86
46:54
95: 5
78
21:79
9O:lO
77
16:84
65
31:69
56
20:80
Me
Ph {
n-C H 6 13
9
Me
83
299:
1
t-Bu 10
t-Bu
aAldehydes -60°C).
were b After
added
at -60°C
to a solution c
chromatography.
Determined
of by
lithium 1 H
n.m.r.
enolate or
derived
standardised
from
(1)
(LDA, THF,
spectrodensitometry
(254 nm).
This Pubblica
research
Istruzione.
was
financially
assisted
by
a grant
from C.N.R.
and Ministero
della
4696
Referentes cmd Notes 1. Dedicated
to Prof. Giuseppe
2. T. Nakatsuka,
T. Miwa, and T. Mukaiyama,
6. Here only one enantiomeric
form is arbitrarily
reaction
(la) and acetaldehyde
shown although
(ref. 8) between
catalysed
by TiCl
configuration
therein.
as that of threonine.
racemates
the trimethylsilyl
or BF
Et20 was tested. 3
ectivities
birthday.
and D. Butina, J. Org. Chem., 1979, 44, 3967.
L. Somekh,
the Mukaiyama
th
1983, 48, 3556 and referentes
5. We name as threo the isomer with the same relative
7. Also
of his 70
Chem. Lett., 1981, 279; 1982, 145.
and M.J. Miller, J. Org. Chem.,
3. P.G. Mattingly 4. A. Shanzer,
Leandri on the occasion
ketene
were obtained. acetal
derived
from
In both cases low stereosel-
were observed.
8. T.H. Chan, T. Aida, P.K.W. Lau, V. Gorys, and D.N. Harpp, Tetrahedron Lett., 1979, 4029. 9. 70% (for Rl = Me) or 95% (for Rl = t-Bu) aqueous EtOH. 10. S.H. Pines, S. Karady,
and M. Sletzinger,
ll. This can be the sodium
ion
(see ref.
J. Org. Chem.,
12) or the ammonium
íL. R.S. Glass, D.R. Deardorff,
and H. Henegar,
13. Although
of reduction
previous
examples
(see ref. 14), they generally a crucial
role
the nitrogen formation
atom. We argued
of the threo
the carboxyl
of a-amino-
isomers
group
i) by a higher
ion
(through
or a-acetylamino-fl-oxoesters isomer.
by the amino group
like dibenzylamino
discrimination
would
between
(Received
have
the amino between
groups on
favoured
the
("large") and
the two sides of
of a Cram cyclic model involving
K. Matsumoto,
and K. Okumura,
Chem. & Ind.,
chelation
1973, 228; W.A. Bolhofer,
J. Amer. Chem. Soc., 1952, 74, 5459; see also ref. 9.
16. L. Velluz,
are known
(see ref. 15).
T. Iwasaki,
15. M. Tramontini,
bonds).
It seemed likely that
by the size of the protective
("medium") groups in 1; ii) by a larger differentiation the effectiveness
two hydrogen
Lett., 1980, 2467.
for the erythro
had to be played
that a bulky
attack in II; iii) by preventing
14. M. Suzuki,
Z’etrahedron
show a preferente
in these reductions
1968, 33, 1758.
Synthesis,
G. Amiard,
1982, 605.
and R. Heymés, BuZletin Soc. Chim. France, 1955, 201.
in UK 24 July
1984)
DIASTEREOSELECTIVE
Giuseppe
Guanti,
.3*
4693-4696,1984
SYNTHESIS
Luca Banfi,
a
OF
oo40-4039/84 $3.00 + .oo 01984 Pergamon Press Ltd.
a-AMINO-B-HYDROXYACIDS1
a
Enrica Narisano,
and Carlo Scolastico
b
a Istituto di Chimica Organica dell'lhiversità,Centro C.N.R. di Studio sui Diariloidi e loro AppZicazioni, Palazzo delle Scienze, Corso Europa, 16132 Genova, Italy b
Istituto di Chimica Organica detl'lrniversità, Via Venezian 21, 20133 Milano, ItaZy
Summary:
threo-a-Dibensylamino-B-hydroxyesters
ectivity
through
reduction
the NaBH
(2) have been synthesised
of a-dibenzylamino-B-oxoesters
with high diastereosel-
(4) and then tranformed
into
threo-a-amino-B-hydroxyac?ds.
a-Amino-B-hydroxyacids
are derivatives
of primary
importance
both 3
hibitors,* selective
and as starting syntheses
mers still appears
for
of these compounds
B-lactam
antibiotics
have been described,
now prepared
reduction
a series
of ca-amino-B-hydroxyacids
of
the
resulting
E-oxoesters
(4)
(2) and
appeared
(3) in good
to be much
Stereochemical
(1) (LDA, THF, -6OOC)
EtOH'
(see Scheme
methyl-
or t-butyl-
of lithium
of the same enolates
enolates
followed
by
However,
1).
affording
threo
the acylation-reduction
compounds
(2) with
procedure
d.e. up to
298%.
are listed in the Table.7
In a typical
aqueous
yield
more stereoselective
results
oxoesters
using
(method B), gave o-dibenzylamino-E-hydroxy6
esters
some stereo-
of the thren5 iso-
the preparation
from (la,b) with aldehydes (method A) and the acylation
derived
Although
synthesis.
(la,b) as starting material. Both the condensation
-N,N-dibensylglycinate
afford
294
in-
to be troublesome.
We have
NaBH4
material
as enzymatic
procedure
was added
(4) in yields
for method
B a solution
to a THF solution ranging
of the appropriate
from 60 to 90%. The reduction
with an excess of NH4C1,
buffered
of the lithium enolate
by addition
derived
acyl chloride
(-6C)OC) to
was thence carried
of an excess
of NaBH4.
from
out in
It is in-
10 teresting
to note that in the absence of NH4Cl the reaction While for methyl esters
(4b) could be reduced
only
In these cases, probably decomposition
became
did not occur.
(4a) the reaction was in every case complete,
in part, and, for B2 = t-Bu, the reaction
because
of steric inhibition,
t-butyl
esters
did not take place at all.
the rate of reduction
was lower and NaBH4
competitive.
The stereochemical
course of the reaction
4693
is in agreement either with a Felkin model
4694
(figure
1) or with
bonyl and carboxyl
a Cram cyclic oxygens
model
in which
an electrophile
(X)"
is chelated
by the car-
(figure II).
$&"Y
;k& -
HH Ix3 = PhCH2
1
The relative by their conversion
II
configuration
into d,Z-threonine
of
(2) for H2 = Me and Ph was unambiguously
and,d,Z-phenylserine
products were correlated to these by t.1.c. comparisons 1 13 H and C n.m.r. spectra. a-Dibenzylamino-B-hydroxyesters acids
(5) by
(0.5 N KOH,
acid
hydrolysis
isation detected
Finally genation
easily
methodology
ether) and by means of
(2) and (3) were then transformed OOC,
70%)
for
(2b) and
into corresponding
(3b), and mild
saponification
to be used for a wide range of compounds.
the deprotection
of the amino moiety was easily obtained
(H Pd/C, 95% EtOH, 7O"C, 90%) to give a-amino-6-hydroxyacids 2'
for achieving accessible
the acylation-reduction
90-100% diastereomerically
substrates.
and enantioselective developed
(n-hexane-diethyl
The other
7:3,
In summary, pathway
(vide infra).
85%) for (2a) and (3a) (see Scheme 2). In no instance was epimer1 by t.1.c. and H n.m.r.. The mildness of these two complementary ester hydroly-
MeOH-H20
ses enable the present
16
(CF3COOH,
respectively
established
Further
synthesis
method
here reported
represents
pure threo-ca-amino-B-hydroxyacids
application
of
of polyfunctionalised
N,N-dibenzylglycinates compounds
of biological
Scheme 1
0 Method * ,
RJy
II OR’
+
NR;
(la,b)
(3a,b)
(2a,b) Method
0
\ ?
R
R2TOR’ NR; (4a,b)
a:
R’ = Me
b:
R’
R3=
=
t-Bu
PhCH2
hydro-
(6).
in our laboratory.
R;N&OR,
by catalytic
a new synthetic starting
from
to the diastereointerest
are being
4695
Scheme 2
(2a,b) or (3a,b)
R3 =
Table.
Stereoselective
(6)
PhCH2
synthesis
R1
R2
EntI-y
(5)
of a-dibenzyZwnino-fi-hydroxyesters via reduction
of &oxoesters
yieldb
threo : erythroc
(%)
(21 and (31 via aldol condensationa yieldb
threo :erythroc
(%)
Me
81
93: 7
89
57:43
;-8c
50
89:ll
91
60:40
Me
70
299:
1
75
46:54
t-Bu
57
)99:
1
74
18:82
Me
75
96: 4
80
71:29
t-Bu
52
89:ll
86
46:54
95: 5
78
21:79
9O:lO
77
16:84
65
31:69
56
20:80
Me
Ph {
n-C H 6 13
9
Me
83
299:
1
t-Bu 10
t-Bu
aAldehydes -60°C).
were b After
added
at -60°C
to a solution c
chromatography.
Determined
of by
lithium 1 H
n.m.r.
enolate or
derived
standardised
from
(1)
(LDA, THF,
spectrodensitometry
(254 nm).
This Pubblica
research
Istruzione.
was
financially
assisted
by
a grant
from C.N.R.
and Ministero
della
4696
Referentes cmd Notes 1. Dedicated
to Prof. Giuseppe
2. T. Nakatsuka,
T. Miwa, and T. Mukaiyama,
6. Here only one enantiomeric
form is arbitrarily
reaction
(la) and acetaldehyde
shown although
(ref. 8) between
catalysed
by TiCl
configuration
therein.
as that of threonine.
racemates
the trimethylsilyl
or BF
Et20 was tested. 3
ectivities
birthday.
and D. Butina, J. Org. Chem., 1979, 44, 3967.
L. Somekh,
the Mukaiyama
th
1983, 48, 3556 and referentes
5. We name as threo the isomer with the same relative
7. Also
of his 70
Chem. Lett., 1981, 279; 1982, 145.
and M.J. Miller, J. Org. Chem.,
3. P.G. Mattingly 4. A. Shanzer,
Leandri on the occasion
ketene
were obtained. acetal
derived
from
In both cases low stereosel-
were observed.
8. T.H. Chan, T. Aida, P.K.W. Lau, V. Gorys, and D.N. Harpp, Tetrahedron Lett., 1979, 4029. 9. 70% (for Rl = Me) or 95% (for Rl = t-Bu) aqueous EtOH. 10. S.H. Pines, S. Karady,
and M. Sletzinger,
ll. This can be the sodium
ion
(see ref.
J. Org. Chem.,
12) or the ammonium
íL. R.S. Glass, D.R. Deardorff,
and H. Henegar,
13. Although
of reduction
previous
examples
(see ref. 14), they generally a crucial
role
the nitrogen formation
atom. We argued
of the threo
the carboxyl
of a-amino-
isomers
group
i) by a higher
ion
(through
or a-acetylamino-fl-oxoesters isomer.
by the amino group
like dibenzylamino
discrimination
would
between
(Received
have
the amino between
groups on
favoured
the
("large") and
the two sides of
of a Cram cyclic model involving
K. Matsumoto,
and K. Okumura,
Chem. & Ind.,
chelation
1973, 228; W.A. Bolhofer,
J. Amer. Chem. Soc., 1952, 74, 5459; see also ref. 9.
16. L. Velluz,
are known
(see ref. 15).
T. Iwasaki,
15. M. Tramontini,
bonds).
It seemed likely that
by the size of the protective
("medium") groups in 1; ii) by a larger differentiation the effectiveness
two hydrogen
Lett., 1980, 2467.
for the erythro
had to be played
that a bulky
attack in II; iii) by preventing
14. M. Suzuki,
Z’etrahedron
show a preferente
in these reductions
1968, 33, 1758.
Synthesis,
G. Amiard,
1982, 605.
and R. Heymés, BuZletin Soc. Chim. France, 1955, 201.
in UK 24 July
1984)