Diastereoselective synthesis of N-protected β-Amino-α-hydroxyacids (norstatines) from urethane N-carboxyanhydrides (UNCAs)

Article abstract of DOI:10.1039/a809421g

β-Amino-α-hydroxyacids (norstatines) are prepared from urethane N- protected carboxyanhydrides (UNCAs); the key step is the diastereoselective reduction of a keto-acetylenic compound, which lead is, with syn diastereoselectivity, to the corresponding prop

Full text of DOI:10.1039/a809421g

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282 J. CHEM. RESEARCH (S), 1999
J. Chem. Research (S),
1999, 282^283y
Diastereoselective Synthesis of N-Protected
b-Amino-a-hydroxyacids (Norstatines) from
Urethane N-Carboxyanhydrides (UNCAs)y
Patrick Audin,*a Catherine Pothion,b Jean-Alain Fehrentz,b
Andre Loffet,c Jean Martinezb and Joelle Parisa
a Laboratoire de Chimie Therapeutique, ISPB, 8 Avenue Rockefeller 69 373 Lyon Cedex 08,
France
b LAPP UMR 5810 CNRS Montpellier 1-Montpellier 2, Faculte de Pharmacie, 15 Avenue Charles
Flahault, 34 060 Montpellier, France
c Senn Chemicals International, 94 250 Gentilly, France
b-Amino-a-hydroxyacids (norstatines) are prepared from urethane N-protected carboxyanhydrides (UNCAs); the key
step is the diastereoselective reduction of a keto-acetylenic compound, which lead is, with syn diastereoselectivity,
to the corresponding propargylic alcohol.
The development of new synthetic routes to unusual amino
acids has attracted considerable recent interest. In particular,
the naturally occurring peptides bestatin and amastatin dis-
covered by Umezawa1 contain a b-amino-a-hydroxyacid
moiety (norstatine). These peptides were shown to be potent
inhibitors of aminopeptidases.2 Furthermore, norstatine-
related compounds have been reported to be HIV protease3
and renin inhibitors.4 b-Amino-a-hydroxyacids are thereby
We studied ¢rst the reactivity of urethane N-protected
carboxyanhydrides 1 towards ethynylmagnesium bromide.
To avoid a possible double addition of the acetylide on
the carbonyl group, the reaction was run at low temperature
( 60 to 40 8C) and we noticed that UNCAs are reactive
enough to yield to the corresponding keto-acetylenics 2 in
acceptable yields (Table 1).
In
a
second approach, we have examined the
interesting synthetic targets since norstatine acts as
transition state mimic of peptide bond hydrolysis.
a
stereoselective reduction of compounds 2 with Luche's
reagent.9 We assumed that reduction under these conditions
led, with non-chelation control, to the syn propargylic
alcohols 3 (Scheme 2).
We have been involved in the study of the reactivity of
urethane N-protected carboxyanhydrides (UNCAs). UNCAs
are very reactive and were used with success for the synthesis
of various amino acid derivatives such as b-amino-alcohols,5
statine derivatives6 and a-amino-aldehydes.7 We have pre-
viously described a general method for the preparation of
norstatines from N-protected aminoaldehydes.8 The key step
was the reaction of ethynylmagnesium bromide with
N-protected aminoaldehydes to a¡ord propargylic alcohols
with syn diastereoselectivity. We propose here an alternative
route to prepare norstatines from UNCAs 1 (Scheme 1).
The interest in this method is to allow the preparation of
both syn or anti diastereomers, according to the reduction
conditions used for the keto-acetylenic derivative.
H –
H
R
H
R
H
O
HO
N
Boc
N
H
Boc
H
Scheme 2
Boc
NH
R
H
To con¢rm the supposed syn diastereoselectivity of the
reduction leading to the (2S, 3S)-norstatines, we have con-
verted the propargylic alcohol 3a into the corresponding
oxazoline derivative 5 after reaction with 2,2-dimethoxy-
propane (Scheme 3).
H
i
O
H
Boc
N
R
O
O
O
1 R = Me, Pri, Bui, Bn
2
ii
Boc
Boc
NH
H
iii–v
H
NH
H
CO2H
R
R
Table
1
Preparation of norstatines
4
from N-protected
N-carboxyanhydride (UNCAs)
OH
OH
4
3
Keto-acetylenic Propargylic
compound 2
(% yield)
alcohol 3
(% yield)
Norstatine 4
(% yield)
UNCA (1)
Scheme 1 i, H CꢀC MgBr, THF, 60 8C; ii, NaBH4,
Boc-Ala-NCA (1a) 72
Boc-Phe-NCA (1b) 41
Boc-Leu-NCA (1c) 62
Boc-Val-NCA (1d) 60
96
58
65
60
^
CeCl3 Á7H2O, MeOH, 78 8C; iii, dihydropyran, PPTS, CH2Cl2; iv,
(syn/anti:
80/20)
95
(syn/anti:
72/28)
97
(syn/anti:
70/30)
^
‡
NalO4, RuCl3, CH3CN/CCl4, H2O; v, H3O .
* To receive any correspondence.
y This is a Short Paper as de¢ned in the Instructions for Authors,
Section 5.0 [see J. Chem. Research (S), 1999, Issue 1]; there is
therefore no corresponding material in J. Chem. Research (M).

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J. CHEM. RESEARCH (S), 1999 283
Alcohol 3a.öMajor diastereomer (80%): dH (300 MHz, CDCl3)
1.22 (d, 3 H, J ˆ 7 Hz), 1.45 (s, 9 H), 2.47 (d, 1 H, J ˆ 2:1 Hz), 3.55
(s large, 1 H), 3.75^4.05 (m, 1 H) 4.40 (dxd, 1 H, J ˆ 2:4 Hz,
J0 ˆ 2:1 Hz), 4.77 (s large, 1 H). Minor diastereomer (20%): distinct
signals d 4.35 (dxd, 1 H, J ˆ 5:5 Hz, J0 ˆ 2:1 Hz).
Boc
Boc
NH
N
O
H
H4
H3C
H5
H
i
S
R
Oxazoline Derivative 5.öOn the basis of the 1H NMR coupling
constant (5.4 Hz) and molecular modelling study using the program
SYBYL v. 5.1 (Tripos Associates, St Louis, MO) (torsion between
H4 and H5 ˆ 298) we suggest for the main diastereomer a syn
stereochemistry and a 4S, 5R relative stereochemistry at C4 and
C5, assuming that the chiral centre of the UNCA was ¢xed. For
the minor diastereomer, the measured coupling constant (3.3 Hz)
and the torsion between H4 and H5 (1008) suggest an anti
stereochemistry.
H3C
OH
H
H
3a
5
Scheme 3
The relative con¢guration of 5 was assigned on the basis of
the 1H NMR coupling constant between H4 and H5. The
mixture of stereoisomers was quanti¢ed by the distinguish-
able signals.
The N-protected b-amino-a-hydroxyalkanoic acids 4 were
synthesized as shown in Scheme 1. Alcohols 3 were then
protected by tetrahydropyranylation in quantitative yields
before oxidative cleavage. Oxidation of these intermediates
into acids (norstatines) was achieved using the RuCl3/NaIO4
method10 in 58^65% yields.
Received, 2nd December 1998; Accepted, 4th January 1999
Paper E/8/09421G
References
1
H. Umezawa, T. Aayagi, H. Morishima, M. Matzuzaki, M.
Hamada and T. Takeuchi, J. Antibiot., 1970, 23, 259.
A. Willey and D. H. Rich, Med. Res. Rev., 1993, 13, 327.
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Shibata, E. Itoh and S. Terashima, Chem. Pharm. Bull., 1998,
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In summary, we have demonstrated
a
convenient
2
3
diastereoselective synthesis of norstatines from UNCAs.
The procedure described in this paper allows the preparation
of (2S, 3S)-norstatines. The interest in this methodology is to
allow the preparation of both (2S, 3S)- and (2R, 3S)-
norstatines with the reducing agent used here.
4
5
6
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Experimental
The following procedure is representative. To a stirred solution of
ethynylmagnesium bromide in THF (6.0 mmol) was added under
nitrogen atmosphere at 60 8C, a solution of UNCA (5 mmol) in
THF (10 ml). The reaction mixture was stirred for 4 h between 60
and 40 8C and then quenched with NH4Cl (10 ml). The product was
extracted with ethyl acetate. The combined organic layers were dried
over Na2SO4 and concentrated in vacuo to give an oil which was
puri¢ed by chromatography on silica gel. The keto-acetylenic com-
pound 2a was obtained in 72% yield; mp 66^67 8C, [a]2D0 35:7 (c,
7
8
9
S. Kourtal and J. Paris, Lett. Peptide Sci., 1996, 3, 73.
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1
1.0, methanol); n=cm (KBr) 3398, 3213, 2084, 1690, 1378, 1166;
dH (200 MHz, CDCl3) 1.42 (d, 3 H, J ˆ 7 Hz), 1.45 (s, 9 H), 3.37
10 P. H. Carlsen, T. Katsuki, V. S. Martin and K. B. Sharpless, J.
Org. Chem., 1981, 46, 3936.
(s, 1 H), 4.42 (qxd, 1 H, J ˆ J0 ˆ 7 Hz), 5.12 (s large, 1 H).