A rapid approach to amino-acid derivatives by [2,3]-stevens rearrangement

Article abstract of DOI:10.1055/s-2000-6494

Allylation of amino-acid esters gives rise to intermediate quaternary ammonium salts, which undergo proton abstraction to give ylides and [2,3]- sigmatropic rearrangement. The resulting α-amino-acid derivatives can be subjected to N-deallylation to provid

Full text of DOI:10.1055/s-2000-6494

236
LETTER
A Rapid Approach to Amino-Acid Derivatives by [2,3]-Stevens
Rearrangement
Amélie P.A. Arboré, Daniel J. Cane-Honeysett, Iain Coldham,* Mark L. Middleton
School of Chemistry, University of Exeter, Stocker Road, Exeter, UK EX4 4QD
Fax +44 1392 263434; E-mail: I.Coldham@exeter.ac.uk
Received 29 November 1999
Me
Bn
Ph
Abstract: Allylation of amino-acid esters gives rise to intermediate
N
MeI
quaternary ammonium salts, which undergo proton abstraction to
Me
N
CO2Me
CO2Me
give ylides and [2,3]-sigmatropic rearrangement. The resulting a-
amino-acid derivatives can be subjected to N-deallylation to pro-
vide a rapid access to a-allyl-a-amino-esters. Using N-benzyl pro-
line methyl ester, chirality transfer from carbon to nitrogen then
back to carbon takes place.
DMF, K2CO3
DBU, 40 °C
Me
1
63%
2
Scheme 1
Key words: amines, amino acids, rearrangements, ylides, chirality
transfer
ylide 3 and rearrangement to give the a-amino-acid deriv-
ative 4. We were pleased to find that the N-allyl groups
could be cleaved selectively using palladium(0)5 to give
the primary amine 5 (Scheme 3). This method therefore
allows a rapid (two step) preparation of allyl glycine me-
thyl ester from the simple glycine methyl ester.6
The preparation of unnatural amino-acids and their deriv-
atives continues to attract considerable research interest.1
This is due in part to their use as sources of ligands for cat-
alytic reactions or their incorporation within peptides or
analogues in order to confer desirable properties such as
conformational restriction. We have reported recently a
new approach to amino-acids by N-alkylation of N-allyl
a-amino-esters.2,3 The resulting quaternary ammonium
salts rearrange, after ammonium ylide formation, by a
[2,3]-Stevens rearrangement. For example, the allyl gly-
cine derivative 2 can be formed using a one pot N-alkyla-
tion-ylide formation-rearrangement protocol from the
amine 1.
NH2
CO2Me
Br
N
N
CO2Me
3
80%
DMF, K2CO3
DBU, 40 °C
CO2Me
3
4
Scheme 2
The [2,3]-Stevens rearrangement of ammonium ylides is
known using a variety of N-allyl quaternary ammonium
salts and basic conditions, although the use of simple N-
allyl a-amino-esters is rare.4 The combined N-alkylation,
ylide formation and rearrangement strategy (e.g. 1 to 2,
Scheme 1) occurs under mild conditions and avoids the
need to isolate the ammonium salt, providing N,N-dialky-
lated a-amino-acid derivatives from N-allyl a-amino-es-
ters in one pot. A drawback of this method, however, is
the necessity to prepare the starting materials from the N-
unsubstituted a-amino-esters and the inability to convert
the product to the a-amino-acid derivatives which are un-
substituted on the nitrogen atom. In this paper we report a
more convenient approach to a-amino-acid derivatives
using this type of chemistry, starting from simple esters of
natural amino acids and leading, after N-deallylation, to
N-unsubstituted a-amino-esters.
N
NH2
CO2Me
Pd(PPh3)4
N,N-dimethyl-
barbituric acid
CO2Me
4
72%
5
Scheme 3
The allylation and in situ rearrangement of various simple
a-amino-esters was investigated as outlined in Table 1.
Allyl iodides, bromides or chlorides could be used suc-
cessfully. Slight improvements to the yields were ob-
tained by adding Bu4NI to the reactions with allyl
bromide. The use of crotyl chloride gave the allyl-trans-
posed product 7c (R" = Me), illustrating that the product
arises from a [2,3]-sigmatropic rearrangement. With the
more hindered a-substituted amino-esters, the yields of
the rearranged products (7d, 7e) were poor, in many cases
the major product being the diallylated amine. In all cases,
the N-allyl groups could be cleaved to give the primary a-
amino-acid derivatives 5 or 8a-d (Scheme 4).
Taking the simple glycine methyl ester as the starting ma-
terial, allylation with excess allyl bromide under the con-
ditions described above, resulted in the formation of the
[2,3]-Stevens product 4 (Scheme 2). Tri-allylation on the
nitrogen atom generates the intermediate quaternary am-
monium salt, which undergoes proton abstraction to the
Synlett 2000, No. 2, 236–238 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
A Rapid Approach to Amino-Acid Derivatives by [2,3]-Stevens Rearrangement
237
NH2
R"
N
R"
X
R"
Pd(PPh3)4
NDMBA
H2N
CO2R'
CO2R'
DMF, K2CO3, DBU
CO2R'
R
R
R
R"
40 °C, 16-48 h
R"
5 or 8
6
4 or 7
Scheme 4
Table 1 Allylation and rearrangement of a-amino-esters 6a
that the allylation of 9 does indeed occur predominantly
cis to the methyl ester group and that the product (-)-12
can be formed with high optical purity at low temperature.
X
CO2Me
CO2Me
N
N
DMF, K2CO3
DBU
Ph
Ph
9
12
The alkylation of the tertiary amine 1 with iodomethane
must generate an intermediate chiral (racemic) ammoni-
um salt. We therefore considered the possibility of effect-
ing asymmetric ammonium salt formation using a chiral
a-amino-ester. Transfer of chirality from carbon to nitro-
gen and then back to carbon is possible by a type of self-
regeneration of chirality.7 A few examples of this process
have been reported recently for the [2,3]-Stevens rear-
rangement.8 Preparation of N-benzyl proline methyl ester
CO2Me
X
CO2Me
N
N
Ph
Ph
10
11
Scheme 5
9 from proline and allylation with allyl bromide or allyl Table 2 Allylation and rearrangement of a-amino-ester 9
iodide gave the rearranged product 12 (Scheme 5). Recent
related work by Glaeske and West8b suggests that allyla-
tion on the nitrogen atom would be expected to take place
predominantly from the same face as the ester group, due
to the trans arrangement of the benzyl and ester groups.9
This gives the salt 10, in which the chirality has been
transferred to the nitrogen atom. Loss of the original chiral
centre by proton abstraction gives the ylide 11. Regenera-
tion of this chiral centre by [2,3]-Stevens rearrrangement
leads to the product 12. The product was found to have op-
tical activity, the level of which depended upon the reac-
PhCH2Br
tion conditions (Table 2). Performing the allylation in the
N
H
N
MeCN, K2CO3
absence of solvent or base at room temperature allowed
the formation of the intermediate quaternary ammonium
salt 10 (X = Br) with a diastereomeric ratio of 4:1 (by 1H
NMR). This suggests that the stereoselectivity arises from
the extent of N-allylation cis or trans to the ester group,
followed by a rearrangement which is stereospecific.
These results are in agreement with work by Glaeske and
West,8b who showed that a similar rearrangement was ste-
reospecific. Lowering the temperature enhances the ste-
reoselectivity in the allylation/rearrangement. An authen-
tic sample of the product (+)-12 was prepared by N-ben-
zylation of the N-unsubstituted proline derivative 1310 of
known absolute stereochemistry (Scheme 6). The specific
rotation of (+)-12, [a]+54.0 (c 0.75, CHCl3),11 indicates
CO2Me
CO2Me
HCl
Ph
13
(+)-12
Scheme 6
In summary, we have shown that allyl glycine esters can
be prepared by a two step sequence from simple a-amino-
esters involving a combined N-allylation-rearrangement,
followed by N-deallylation. Using N-benzyl proline meth-
yl ester as the starting material, the allylation-rearrange-
ment is stereoselective, giving the a-allylated proline
derivative with high optical purity.
Synlett 2000, No. 2, 236–238 ISSN 0936-5214 © Thieme Stuttgart · New York

238
A. P. A. Arboré et al.
LETTER
quenched with NaHCO3 (5 cm3), extracted with Et2O (3 x 5
cm3) and washed with brine (2 x 5 cm3). The organic layer was
dried (Na2SO4), evaporated and purified by chromatography,
eluting with light petroleum (bp 40-60 °C)-EtOAc (5:1) to
give the amine 4 (133 mg, 80%) as an oil, Rf [light petroleum
(bp 40-60 °C)-EtOAc (5:1)] 0.40; nmax (neat)/cm-1 1745
(C=O), 1640 (C=C); dH (400 MHz, CDCl3) 5.85-5.71 (3H, m,
3 x CH=), 5.40-5.02 (6H, m, 3 x =CH2), 3.69 (3H, s, OMe),
3.55 (1H, t, J 7, CHCO), 3.35 (2H, ddt, J 15, 7 and 2,
CHAHBNCHAHB), 3.07 (2H, ddt, J 15, 7 and 2,
Acknowledgement
We thank the EPSRC for a studentship and ICI Paints Ltd for an in-
dustrial CASE award (to M.L.M.) and for partial support from the
ERASMUS scheme (to A.P.A.A.). We thank Dr P.L. Taylor for
helpful discussions and N.J. Ashweek for preparation of the Mosher
esters. We acknowledge the use of the EPSRC mass spectrometry
service at the University of Wales Swansea.
References and Notes
CHAHBNCHAHB), 2.52-2.35 (2H, m, CH2CHN); dC (100
MHz, CDCl3) 173.15, 136.41, 134.92, 117.03, 116.78, 62.09,
53.50, 51.00, 34.09 (Found: M+, 209.1421. C12H19NO2
requires M, 209.1416); m/z 209 (1%, M), 168 (70, M - C3H5),
150 (100, M - CO2Me) (Found: C, 68.71; H, 8.99; N, 6.41.
C12H19NO2 requires C, 68.91; H, 9.16; N, 6.99%).
(7) Seebach, D.; Boes, M.; Naef, R.; Schweizer, W.B. J. Am.
Chem. Soc. 1983, 105, 5390.
(8) (a) Gawley, R.E.; Zhang, Q.; Campagna, S. J. Am. Chem. Soc.
1995, 117, 11817; (b) Glaeske, K.W.; West, F.G. Org. Lett.
1999, 1, 31.
(9) Vedejs, E.; Arco, M.J.; Powell, D.W.; Renga, J.M.; Singer,
S.P. J. Org. Chem. 1978, 43, 4831.
(1) (a) R.M. Williams Synthesis of Optically Active a-Amino
Acids, Pergamon, 1989; (b) Duthaler, R.O. Tetrahedron 1994,
50, 1539; (c) Cativiela, C.; Díaz-de-Villegas, M.D.
Tetrahedron: Asymmetry 1998, 9, 3517.
(2) Coldham, I.; Middleton, M.L.; Taylor, P.L. J. Chem. Soc.,
Perkin Trans. 1 1997, 2951.
(3) Coldham, I.; Middleton, M.L.; Taylor, P.L. J. Chem. Soc.,
Perkin Trans. 1 1998, 2817.
(4) For examples of the [2,3]-Stevens rearrangement, see (a) I.E.
Markó Comprehensive Organic Synthesis, B.M. Trost, I.
Fleming, Eds., Pergamon, 1991; vol. 3, ch. 3.10; (b) R.
Brückner Comprehensive Organic Synthesis, B.M. Trost, I.
Fleming, Eds., Pergamon, 1991, vol. 6, ch. 4.6; (c) Honda, K.;
Inoue, S.; Sato, K. J. Am. Chem. Soc. 1990, 112, 1999; (d)
Clark, J.S.; Hodgson, P.B. Tetrahedron Lett. 1995, 36, 2519;
(e) Wright, D.L.; Weekly, R.M.; Groff, R.; McMills, M.C.
Tetrahedron Lett. 1996, 37, 2165; (f) Gulea-Purcarescu, M.;
About-Jaudet, E.; Collignon, N.; Saquet, M.; Masson, S.
Tetrahedron 1996, 52, 2075; (g) Honda, K.; Igarashi, D.;
Asami, M.; Inoue, S. Synlett 1998, 685.
(10) Wang, H.; Germanas, J.P. Synlett 1999, 33.
(11) The product (+)-12 was assumed to be enantiomerically-pure,
based on comparison of the precursors with those reported by
Wang and Germanas.10 Verification of the enantiomeric
excess of the product 12, formed by allylation-rearrangement
of 9, was achieved by formation [reduction of the ester 12
(LiAlH4) and addition of (R)-a-methoxy-a-
(trifluoromethyl)phenylacetyl chloride12] and analysis (1H
NMR in C6D6) of the Mosher ester derivatives.
(5) Garro-Helion, F.; Merzouk, A.; Guibé, F. J. Org. Chem. 1993,
58, 6109.
(12) Dale, J.A.; Dull, D.L.; Mosher, H.S. J. Org. Chem. 1969, 34,
2543.
(6) General procedure for allylation-rearrangement: Allyl
bromide (0.42 cm3, 4.85 mmol) was added to the glycine
methyl ester hydrochloride salt (100 mg, 0.80 mmol) in DMF
(1 cm3), K2CO3 (330 mg, 2.39 mmol) and Bu4NI (25 mg, 0.07
mmol). The mixture was warmed to 40 °C and DBU (0.24
cm3, 1.59 mmol) was added. After 48 h, the mixture was
Article Identifier:
1437-2096,E;2000,0,02,0236,0238,ftx,en;L17199ST.pdf
Synlett 2000, No. 2, 236–238 ISSN 0936-5214 © Thieme Stuttgart · New York