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Synthesis of chiral N-protected β-amino alcohols by the use of UNCAs
TermhcdmttLdters. Vol. 35. NO.4, pp. 569571. 1994 Elsevier Science Lti F%inted in Great Britain ‘XW-4039194 S6.00+0.00
OWO-4039(93)Eo310-G
Synthesis of Chiral N-Protected P-Amino Alcohols by the Use of UNCAs
Jean-Akin
Fehrenbl,
Jean-Christophe
Califanol, Muriel Amblardl,
Albert I.&et2 & Jean
MartinezI+
Abstract: A facile synthesis of a wide variety of N-protected p-amino akobol derivatives under mild conditions is described.N-umtbane proceded amino acid N-carboxyanhydrides(UNCAs) were used as startingma&al and reduced into the correspooding akohols with the appropriate hydride, sodium borobydride. The reaction is simple, unexpensive, e&ly scaled up, and pmceeds witbout observablemcemization.
N-protected pamino
are key intermediates
alcohols are of great interest in the synthesis of pcptidc bond surrogates because they
for the obtention
of a-amino
proteases or for the preparation of stereochemically
aldehydes
by oxydationl
which are potent inhibitors of
defined “methylene-oxy”
dipeptides*. They can also be
incorporated at the C-terminal end of hormones like in the case of enkephalins
to achieve receptor selectivity3.
N-protected B-amino alcohols are prcpar+I by reduction of allcyl esters of amino acid#,
and active esters of
amino acids6 with sodium borohydride. Recently we and others described an efficient synthesis of N-protected P-amino-alcohols convenient
via the reduction
of mixed anhydrides
by sodium
borohydride798.
and attractive one-pot synthesis of p-amino alcohols by chemoselective
amino acids N-carboxyanhydtides
(UNCAS) with sodium borohydride.
Scheme 1. Synthesis of P_amino-alcohols
RI
from UNCAs.
R
NaBH, , H,O DME, RT
Rr = Boc, Fmoc. Z
569
We present here a
reduction of N-protected
RI-NH-C-CH2-OH
570
The synthesis of UNCAs and their use in peptide synthesis were described by Fuller et aLo. Mom recently Savrda and Wakselman described another attractive method of synthesis N,N-bis(alkoxycarbony1) crystalline
compounds,
amino acid derivatives
were reduced by sodium borohydride
into N-protected
rapidly {in a few minutes) at room temperature high homogeneity
with the SOCXJDMF
stable when stored in anhydrous
(Scheme
1). Different
conditions;
of UNCAs (2 and Boc) by reacting Vilsmeier
reagentlo.
they are commemi&ly
UNCAs
available.
B-amino alcohols in ~,2-~~e~oxy~~~
am
UNCAs
as solvent.,
in good to high yields with retention of optical purity and with
reaction
conditions
were investigated,
all of them leading
to the
expected @amino alcohols in satisfactory yields (Table 1).
Table 1. Synthesis of Boc-Lphenylalaninol
from Boc-L-Phe-NCA
under different reaction conditions.
Experimental
Ie120D
Yield
conditions
(c = 1, MecXI)
(%)
mp (C? *
81
98-100
A
- 24
B
- 23
87
96
C
- 23
91
96
D
- 26
91
96
* mp = 93-95°C (from reference 8).ComlitionsA : as ctescriw in reference 8; B : solvent THF, H-LiAl(OtBu)34 molar equivaknts added portionwise; C : solvent TEE NaEHQ 1 molar equivalent added portionwise; D : solvent 1.2~~0~~~
NaBHq 1.5
melar equivalent in water aided in one pution.
The usefulness of this method was demonstrated (Z, Boc. Fmoc) flable
2). The tort-butyl-ester
by the synthesis of various N-protected g-amino alcohols
or the benxyl ether used for the protection of carboxylic acid side
chain of glutamic acid and of the phenol of tyrosine remains unaffected under the doscribed reaction conditions. IJI a typical experiment, dimethoxyethane
the UNCA derivative
(2, Boc or Fmoc) (10 mmoles)
was dissolved
in 1.2-
(20 ml) and stirred at room temperature. A solution of sodium borohydride (15 mmol) in water
(5ml) was added in one portion. A strong evolution of gas was produced and after 5 to 10 minutes the reaction was quenched by addition of water (200 ml). In some cases, the expected alcohol precipitated
(entries 3,5,7.
and 8, Table 2); it was collected by filtration, washed with water and hexane_ When the expected compound did not precipitate as a solid, the reaction mixture was extracted with ethyl acetate (entries 1.2.4 and 6). and the organic layer washed with water, dried over sodium sulfate and concentrated AlI N-protected
p-amino alcohols that were synthesized
HPLC on a Clg analytical
column.
detected as indicated by comparaison
They were identified
in vacuu.
were homogeneous
by mass suborner.
by TLC and reversed phase No racemixation
of their [ff]B with those reported in the literature.
could be
571
The use of UNCAs and their reduction
allowed us to obtain in a one step synthesis
alcohols in good yields (80 to 96%). The reaction proceeds without racemization procedure (room temperature,
no need to prepare the anhydride.
seems to be valuable for the preparation compatible derivatives
with various
side-chain
of Fmoc-Glu(OtBu)
Table 2. Preparation
easy recovery of the compound).
groups
as revealed
by the syntheses
Yield
of g-amino
and is alcohol
mp
tulzoD (c=l,
amino N-carboxyanhydrides
RfA
Rfg
(96)
(“C)
1 z-Leu
80
oil
-21
0.57
0.64
2 Z-Be
96
64
-14
0.57
0.60
3
90
130
-17
0.52
0.59
Fmoc-Leu
This method
8 (Table 2).
of p-amino alcohols from urethane-protected
g-amino alcohols
and with a very simplified
of 8-amino alcohols from Boc, Z or Fmoc N-carboxyanhydrides protecting
4 and Boc-Tyr(Bxl)
N-protected
the desired f&amino
MeOH)
4 Fmoc-Cilu(OtBu)
83
55-57
-10
0.42
0.59
5 Fmoc-De
89
108-110
-12
0.50
0.70
6 Fmoc-Trp
80
86-90
-26
0.21
0.44
7 Boc-Fhe
91
96
-26
0.48
0.58
8 Boc-Tyr(Bz1)
87
108
-17
0.34
0.60
(A)Ethyl acetatdbexane1:l; (B) dicbtoromethanelmet1955.
In conclusion,
the present
synthesis
of N-protected
h-amino
alcohols
from UNCAs
is a rapid and
convenient
method which can be applied to Z, Boc and Fmoc amino acids. This method permits a selective
conversion
of their carboxyl group into a hydroxymethyl
protecting groups under mild conditions
group in the presence of other functional
side chain
and without racemization.
REFERENCES 1. 2. 3. 4. 5. 6. 7.
a. 9.
10.
Stanfield, C. F.; Parker,J. E. & Kaneliii, P. J. Org. Chea, 1981.46,4797-4798. TenBrink. R. E. J. Org. Chem, 1987.52.418422. Handa, B. K.; Lane, A. C.; Unn, J. A. H.; Morgan, B, A.; Rance. M. J. & Smith, C. F. C. Eur. 1. Phurtnacol., 1981, 70. 531-540. Soai, K.; Oyarnada,H. & Takase, M. Bull. Chem Sot. Jpn., 1984,57,2327-2328. Hamada, Y.; Shibata M.; Sugiura,T.; Kate. S. & Shioii T. 1. Org. Cbem.. 1987,52. 1252-1255. Nitakawa, J.& Shiba, T. C/wn Lctt.. 1979. 981-982. Kokotos, G. Synrhesis, 1990. 299-301. Rodriguez,M.; Lliis. M.; Doulut, S.; Heitz, A. & Mart&z, J. Tetrahedron 2.u.. 1991,32,923-926. Fuller, W. D.; Cohen, M. P.; Shabankareh, M.: Blair, R. K.: MiRer. T. A.: Go&man. M.; & Naider. F. R. J. Am. Chem. Sot.. 1990. 112. 7414-7416. All UNCAs are available from Propeptide, BP 12. 91710 Vert-Le Petit,Fiance. Savrda,J. & Waksebnan, M. IlI&t.? Forum Peptides and Proteins, Biarritz.France,1993, Abstrxt Cl8
(Received in France
15 October 1993; accepted 16 November 1993)
OWO-4039(93)Eo310-G
Synthesis of Chiral N-Protected P-Amino Alcohols by the Use of UNCAs
Jean-Akin
Fehrenbl,
Jean-Christophe
Califanol, Muriel Amblardl,
Albert I.&et2 & Jean
MartinezI+
Abstract: A facile synthesis of a wide variety of N-protected p-amino akobol derivatives under mild conditions is described.N-umtbane proceded amino acid N-carboxyanhydrides(UNCAs) were used as startingma&al and reduced into the correspooding akohols with the appropriate hydride, sodium borobydride. The reaction is simple, unexpensive, e&ly scaled up, and pmceeds witbout observablemcemization.
N-protected pamino
are key intermediates
alcohols are of great interest in the synthesis of pcptidc bond surrogates because they
for the obtention
of a-amino
proteases or for the preparation of stereochemically
aldehydes
by oxydationl
which are potent inhibitors of
defined “methylene-oxy”
dipeptides*. They can also be
incorporated at the C-terminal end of hormones like in the case of enkephalins
to achieve receptor selectivity3.
N-protected B-amino alcohols are prcpar+I by reduction of allcyl esters of amino acid#,
and active esters of
amino acids6 with sodium borohydride. Recently we and others described an efficient synthesis of N-protected P-amino-alcohols convenient
via the reduction
of mixed anhydrides
by sodium
borohydride798.
and attractive one-pot synthesis of p-amino alcohols by chemoselective
amino acids N-carboxyanhydtides
(UNCAS) with sodium borohydride.
Scheme 1. Synthesis of P_amino-alcohols
RI
from UNCAs.
R
NaBH, , H,O DME, RT
Rr = Boc, Fmoc. Z
569
We present here a
reduction of N-protected
RI-NH-C-CH2-OH
570
The synthesis of UNCAs and their use in peptide synthesis were described by Fuller et aLo. Mom recently Savrda and Wakselman described another attractive method of synthesis N,N-bis(alkoxycarbony1) crystalline
compounds,
amino acid derivatives
were reduced by sodium borohydride
into N-protected
rapidly {in a few minutes) at room temperature high homogeneity
with the SOCXJDMF
stable when stored in anhydrous
(Scheme
1). Different
conditions;
of UNCAs (2 and Boc) by reacting Vilsmeier
reagentlo.
they are commemi&ly
UNCAs
available.
B-amino alcohols in ~,2-~~e~oxy~~~
am
UNCAs
as solvent.,
in good to high yields with retention of optical purity and with
reaction
conditions
were investigated,
all of them leading
to the
expected @amino alcohols in satisfactory yields (Table 1).
Table 1. Synthesis of Boc-Lphenylalaninol
from Boc-L-Phe-NCA
under different reaction conditions.
Experimental
Ie120D
Yield
conditions
(c = 1, MecXI)
(%)
mp (C? *
81
98-100
A
- 24
B
- 23
87
96
C
- 23
91
96
D
- 26
91
96
* mp = 93-95°C (from reference 8).ComlitionsA : as ctescriw in reference 8; B : solvent THF, H-LiAl(OtBu)34 molar equivaknts added portionwise; C : solvent TEE NaEHQ 1 molar equivalent added portionwise; D : solvent 1.2~~0~~~
NaBHq 1.5
melar equivalent in water aided in one pution.
The usefulness of this method was demonstrated (Z, Boc. Fmoc) flable
2). The tort-butyl-ester
by the synthesis of various N-protected g-amino alcohols
or the benxyl ether used for the protection of carboxylic acid side
chain of glutamic acid and of the phenol of tyrosine remains unaffected under the doscribed reaction conditions. IJI a typical experiment, dimethoxyethane
the UNCA derivative
(2, Boc or Fmoc) (10 mmoles)
was dissolved
in 1.2-
(20 ml) and stirred at room temperature. A solution of sodium borohydride (15 mmol) in water
(5ml) was added in one portion. A strong evolution of gas was produced and after 5 to 10 minutes the reaction was quenched by addition of water (200 ml). In some cases, the expected alcohol precipitated
(entries 3,5,7.
and 8, Table 2); it was collected by filtration, washed with water and hexane_ When the expected compound did not precipitate as a solid, the reaction mixture was extracted with ethyl acetate (entries 1.2.4 and 6). and the organic layer washed with water, dried over sodium sulfate and concentrated AlI N-protected
p-amino alcohols that were synthesized
HPLC on a Clg analytical
column.
detected as indicated by comparaison
They were identified
in vacuu.
were homogeneous
by mass suborner.
by TLC and reversed phase No racemixation
of their [ff]B with those reported in the literature.
could be
571
The use of UNCAs and their reduction
allowed us to obtain in a one step synthesis
alcohols in good yields (80 to 96%). The reaction proceeds without racemization procedure (room temperature,
no need to prepare the anhydride.
seems to be valuable for the preparation compatible derivatives
with various
side-chain
of Fmoc-Glu(OtBu)
Table 2. Preparation
easy recovery of the compound).
groups
as revealed
by the syntheses
Yield
of g-amino
and is alcohol
mp
tulzoD (c=l,
amino N-carboxyanhydrides
RfA
Rfg
(96)
(“C)
1 z-Leu
80
oil
-21
0.57
0.64
2 Z-Be
96
64
-14
0.57
0.60
3
90
130
-17
0.52
0.59
Fmoc-Leu
This method
8 (Table 2).
of p-amino alcohols from urethane-protected
g-amino alcohols
and with a very simplified
of 8-amino alcohols from Boc, Z or Fmoc N-carboxyanhydrides protecting
4 and Boc-Tyr(Bxl)
N-protected
the desired f&amino
MeOH)
4 Fmoc-Cilu(OtBu)
83
55-57
-10
0.42
0.59
5 Fmoc-De
89
108-110
-12
0.50
0.70
6 Fmoc-Trp
80
86-90
-26
0.21
0.44
7 Boc-Fhe
91
96
-26
0.48
0.58
8 Boc-Tyr(Bz1)
87
108
-17
0.34
0.60
(A)Ethyl acetatdbexane1:l; (B) dicbtoromethanelmet1955.
In conclusion,
the present
synthesis
of N-protected
h-amino
alcohols
from UNCAs
is a rapid and
convenient
method which can be applied to Z, Boc and Fmoc amino acids. This method permits a selective
conversion
of their carboxyl group into a hydroxymethyl
protecting groups under mild conditions
group in the presence of other functional
side chain
and without racemization.
REFERENCES 1. 2. 3. 4. 5. 6. 7.
a. 9.
10.
Stanfield, C. F.; Parker,J. E. & Kaneliii, P. J. Org. Chea, 1981.46,4797-4798. TenBrink. R. E. J. Org. Chem, 1987.52.418422. Handa, B. K.; Lane, A. C.; Unn, J. A. H.; Morgan, B, A.; Rance. M. J. & Smith, C. F. C. Eur. 1. Phurtnacol., 1981, 70. 531-540. Soai, K.; Oyarnada,H. & Takase, M. Bull. Chem Sot. Jpn., 1984,57,2327-2328. Hamada, Y.; Shibata M.; Sugiura,T.; Kate. S. & Shioii T. 1. Org. Cbem.. 1987,52. 1252-1255. Nitakawa, J.& Shiba, T. C/wn Lctt.. 1979. 981-982. Kokotos, G. Synrhesis, 1990. 299-301. Rodriguez,M.; Lliis. M.; Doulut, S.; Heitz, A. & Mart&z, J. Tetrahedron 2.u.. 1991,32,923-926. Fuller, W. D.; Cohen, M. P.; Shabankareh, M.: Blair, R. K.: MiRer. T. A.: Go&man. M.; & Naider. F. R. J. Am. Chem. Sot.. 1990. 112. 7414-7416. All UNCAs are available from Propeptide, BP 12. 91710 Vert-Le Petit,Fiance. Savrda,J. & Waksebnan, M. IlI&t.? Forum Peptides and Proteins, Biarritz.France,1993, Abstrxt Cl8
(Received in France
15 October 1993; accepted 16 November 1993)