Stereoselective synthesis of allyl- and homoallylglycines

Article abstract of DOI:10.1016/S0040-4039(01)00459-2

A new method for the synthesis of N-protected allyl- and homoallylglycines was developed from aspartic and glutamic acid derivatives. The carboxylic side-chains of aspartic and glutamic derivatives was first transformed into the Weinreb amide by coupling with N,O-dimethylhydroxylamine and then reduced into the corresponding aldehyde. The latter could react with methyl-triphenylphosphonium bromide to yield the title compounds with 50% total yield.

Full text of DOI:10.1016/S0040-4039(01)00459-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 3319–3321
Stereoselective synthesis of allyl- and homoallylglycines
Ce´line Douat,a Annie Heitz,b Jean Martineza,* and Jean-Alain Fehrentza
aLAPP, associe´ au CNRS-Universite´s Montpellier I & II, Faculte´ de Pharmacie, 15 av. C. Flahault, 34060 Montpellier, France
bCBS, UMR5048 CNRS-UMI, Faculte´ de Pharmacie, Montpellier, France
Received 12 March 2001; revised 19 March 2001; accepted 20 March 2001
Abstract—A new method for the synthesis of N-protected allyl- and homoallylglycines was developed from aspartic and glutamic
acid derivatives. The carboxylic side-chains of aspartic and glutamic derivatives was first transformed into the Weinreb amide by
coupling with N,O-dimethylhydroxylamine and then reduced into the corresponding aldehyde. The latter could react with
methyl-triphenylphosphonium bromide to yield the title compounds with 50% total yield. © 2001 Elsevier Science Ltd. All rights
reserved.
Allyl- and homoallylglycines are of great importance,
particularly with the publication of ring-closing olefin
metathesis on allylglycine containing peptides to con-
struct rigidified peptide systems.1 Furthermore, these
a-amino acids are also used as starting materials for the
syntheses of, e.g. sulfur-containing trifunctional amino
acids2 or 3-amino-5-hydroxymethyl-g-lactones.3 Vari-
ous publications reported the preparation of allyl- and
hydride and that it was possible to synthesize N and
side chain protected aspartyl and glutamyl aldehyde
derivatives in fairly good conditions.12 In this paper, we
want to show that the carboxylic side-chain of aspartyl
and glutamyl residues can also be reduced into alde-
hyde and then reacted with the ylide derived from
CH3PPh3Br to produce enantiomerically pure allyl and
homoallylglycine derivatives with an acceptable yield.
homoallylglycines,
including
the
reactions
of
alkyltrimethylsilanes with nitrones,4 allylsilanes with
glycidyl cation equivalents,5 the direct alkylation of
pseudoephedrine glycinamide,6 the zinc mediated alky-
lation of oximes,7 the enolate alkylation of
diphenyloxazinones8 or alkylation of aldimines and the
ketimine derivatives of glycine esters.9,10 These deriva-
tives are commercially available but expensive. We
decided to develop a new synthesis of allyl- and
homoallylglycine derivatives by a simple route from
easily available aspartic and glutamic acid derivatives.
We recently published that Weinreb amide11 of N-pro-
tected amino acids could be reduced with bulky
hydrides such as tris(tert-butoxy)lithium aluminum
Previous syntheses of side-chain aldehyde function of
C- and N-protected aspartyl or glutamyl derivatives
have been reported. Several proceeded by reduction of
the corresponding acid chloride with tri-n-butyltin
hydride in the presence of tetrakis(triphenyl-
phosphine)palladium(0),13 by reduction of the corre-
sponding oxazolidinone acid chloride with tri-n-
butyltin hydride14 or by hydrogenolysis of the same
oxazolidinone in the presence of palladium barium
sulfate.15 Another paper related the regioselective
reduction of dimethyl N,N-di-Boc-glutamate by
DIBAL for the synthesis of (S)-a-amino arachidonic
acid.16
X-NH COOtBu
X-NH COOtBu
X-NH COOtBu
)n
X-NH COOtBu
c
b
a
(
)n
(
)n
(
(
)n
CO-N(Me)OMe
CHO
COOH
1
2
3
4
X : Boc, Z
n = 1,2
a) HCl, HN(Me)OMe, BOP, DIEA; b) (OtBu)3LiAlH, c) KN(TMS)2, CH3PPh3Br
Scheme 1. Synthetic pathway of allyl- and homoallylglycine.
Keywords: allylglycine; homoallylglycine; Weinreb amide; aspartic acid; glutamic acid.
* Corresponding author. Tel.: 33 4 67 54 86 50; fax: 33 4 67 41 20 17; e-mail: martinez@colombes.pharma.univ-montp1.fr
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00459-2

3320
C. Douat et al. / Tetrahedron Letters 42 (2001) 3319–3321
Table 1. Results
1
2: Yield (%)
[h]2D0 (MeOH, c=1)
3: Yield (%)a
4: Yield (%)b
[h]D (MeOH, c=1)
Boc-(
Boc-(
L
L
)Glu-OtBu
)-Asp-OtBu
92
88
89
−21
−11
−22
95
93
95
48
50
58
−19
−3
−15
Z-(
L
)-Glu-OtBu
a Yields of the crude.
b Yields of both steps (2“4) after a flash chromatography on silica gel.
Our synthesis strategy is illustrated in Scheme 1. Start-
ing from N-protected tert-butyloxycarbonyl or benzyl-
oxycarbonyl aspartic or glutamic acid tert-butyl ester,
the side-chain carboxylic function is coupled with N,O-
dimethylhydroxylamine in the presence of an activating
agent. This acylation reaction proceeds in almost quan-
titative yield. The Weinreb amide can then be reduced
with tris(tert-butoxy)lithium aluminum hydride in an
anhydrous solvent at room temperature within 3 h.
After a classical workup, the crude is allowed to react
for 30 min to 1 h with the preformed ylide prepared by
action of KN(TMS)2 with CH3PPh3Br under argon. A
classical workup followed by a flash chromatography
yielded the target compounds with yields of about 50%.
diethylether (2×20 mL), the organic phases washed
twice with water and brine (20 mL), dried over sodium
sulfate, filtered and concentrated. After flash chro-
matography on silica gel with an eluent system AcOEt/
hexane (1/9), the expected compound was obtained as
an oil with a global yield of 48%.
In conclusion, we proposed a simple synthesis of allyl-
and homoallylglycines from easily available aspartic
and glutamic acid derivatives. The stereochemistry of
the obtained allylic compound depends on the stereo-
chemistry of the starting amino acid. No racemization
by enolization can occur with the side-chain aldehyde
function.
The obtained results are summarized in Table 1 and
their physical constants are reported.17 Although Boc
and Z-protection of the primary amine can be used in
these syntheses, Fmoc protection has to be avoided
because it is cleaved in the basic medium containing the
ylide moiety. Benzyl esters of the a carboxylic function
are reduced by the hydride; all attempts to reduce the
Weinreb amide of the side-chain without protecting the
a carboxylic function failed. So the use of bulky esters
such as tert-butyl ester are highly recommended. If
benzyloxycarbonyl group (Z) is used for the amine
protection, the tert-butyl ester of the desired allyl-
glycine derivative can easily and quantitatively be
removed by TFA to generate the carboxylic function in
order to incorporate the new residue in a peptidic
sequence.
References
1. Miller, S. J.; Blackwell, H. E.; Grubbs, R. H. J. Am.
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Glu[N(Me)OMe]-OtBu (0.9 mmol) are dissolved in 10
mL of anhydrous THF. LiAlH(OtBu)3 (2.7 mL, 2.7
mmol, 3 equivalents, 1 M in THF) were added and
allowed to react at room temperature for 3 h under
stirring. The mixture is then hydrolyzed with a solution
of potassium hydrogenosulfate (5% in water). After a
classical workup,18 the aldehyde is obtained with a
crude yield of 95%. To a suspension of methyl-
triphenylphosphonium (617 mg, 1.73 mmol, 2 equiva-
lents) in anhydrous THF (5 mL) and under argon, were
added 3.11 mL of KN(TMS)2 (1.55 mmol, 1.8 equiva-
lents, 0.5 M in toluene). After 30 min, a solution
containing the aldehyde (240 mg, 0.84 mmol) was
added to the yellow colored ylide solution via a can-
nula. The reaction was completed within 30–60 min
(completion is followed on TLC with a AcOEt/hexane
(3/7) eluent system). The reaction mixture was
hydrolyzed with a saturated solution of ammonium
chloride. The desired compound was extracted with
16. Kokotos, G.; Padron, J. M.; Martin, T.; Gibbons, W. A.;
Martin, V. S. J. Org. Chem. 1998, 63, 3741–3744.

C. Douat et al. / Tetrahedron Letters 42 (2001) 3319–3321
3321
17. Boc-homoallyl-Gly-OtBu: M+H+ 286, Rf: 0.59 (AcOEt/
1/9); 1H NMR (360 MHz, DMSO-d6): l (ppm) 1.25 (s,
9H, tBu), 1.64–1.46 (m, 2H, CH2b), 1.95 (m, 2H, CH2g),
3.75 (m, 1H, CHa), 4.84 (m, 2H, CH2o), 4.91 (s, 2H,
CH2-Z), 5.64 (m, 1H, CHd), 7.23 (s, 5H, f-Z), 7.50 (d,
1H, NH).
1
hex: 1/9); H NMR (360 MHz, DMSO-d6): l (ppm) 1.40
(s, 18H, Boc+tBu), 1.7–1.5 (m, 2H, CH2b), 2.00 (m, 2H,
CH2g), 3.72 (m, 1H, CHa), 4.93 (m, 2H, CHo), 5.71 (m,
1H, CHd), 7.05 (d, 1H, NH).
Boc-allyl-Gly-OtBu: M+H+ 272, Rf: 0.4 (AcOEt/hex: 1/
9); 1H NMR (360 MHz, DMSO-d6): l (ppm) 1.30 (s,
18H, Boc+tBu), 2.25 (m, 2H, CH2b), 3.75 (m, 1H, CHa),
4.95 (m, 2H, CH2d), 5.70 (m, 1H, CHg), 7.00 (d, 1H,
NH).
Z-Homoallyl-Gly-OH: M+H+ 264, H NMR (360 MHz,
1
DMSO-d6): l (ppm) 1.65–1.45 (m, 2H, CH2b), 1.90 (m,
2H, CH2g), 3.80 (m, 1H, CHa), 4.83 (m, 2H, CH2o), 4.87
(s, 2H, CH2-Z), 5.63 (m, 1H, CHd), 7.20 (s, 5H, f-Z),
7.45 (d, 1H, NH).
Z-Homoallyl-Gly-OtBu: M+H+ 320, Rf: 0.5 (AcOEt/hex:
18. Fehrentz, J. A.; Castro, B. Synthesis 1983, 676–678.
.
.