Synthesis of structurally diversified α-substituted β-amino acids and derivatives via conjugate radical additions and Heck reactions

Article abstract of DOI:10.1055/s-2001-16781

An efficient short-step synthesis of α-substituted β-amino, β-hydrazino, β-N-hydroxy esters and β-urethane N-carboxyanhydrides is reported: Structural diversity was easily incorporated in good yields at the α position of the carboxylic group via conjugate

Full text of DOI:10.1055/s-2001-16781

LETTER
1467
Synthesis of Structurally Diversified -Substituted -Amino Acids and
Derivatives via Conjugate Radical Additions and Heck Reactions
Jacques Huck, Jean-Marie Receveur,* Marie-Louise Roumestant, Jean Martinez
Laboratoire des Aminoacides, Peptides et Protéines, UMR CNRS 5810, Universités Montpellier I & II, 2 Place E. Bataillon,
34095 Montpellier Cedex 05, France
Fax (33) 04 67 14 48 66; E-mail: recevej@netscape.net
Received 28 June 2001
CO2Me
2, K2CO3
CO2Me
Abstract: An efficient short-step synthesis of -substituted -ami-
no, -hydrazino, -N-hydroxy esters and -urethane N-carboxyan-
hydrides is reported. Structural diversity was easily incorporated in
good yields at the position of the carboxylic group via conjugate
radical additions and Heck reactions performed on the conjugated
double bond of synthons 3, 8 and 9.
Br
R
(Boc)2N
(Boc)2N
CH3CN, RT,18h, 99%
1
3
O
CO2Me
O
Key words: -substituted -amino acids, radical addition, Heck
reaction, -UNCAs
R
4
N
Boc
O
5
Scheme 1
As part of an ongoing project concerning the synthesis
of Urethane N-carboxyanhydrides from -amino acids
( -UNCAs), we have developed a short-step synthesis
of structurally diversified -substituted N-diprotected
-amino esters and derivatives that may be used as precur-
sors for the preparation of -UNCAs. Therefore, we wish
to report herein the synthesis of N-diprotected -methyl-
ene -amino, -hydrazino and -N-hydroxy esters as well
as to describe the radical and Heck reactions performed on
the conjugated double bond of these building blocks.
6, K2CO3
CH3CN, 35 ºC, 5h, 45%
CO2Me
BocHN
CO2Me
N
H
8
Br
7, K2CO3
CH3CN, RT,18h, 95%
1
BocO
CO2Me
N
Boc
9
-Amino acids and their derivatives are attractive targets
for medicinal chemists as they are found as components of
naturally occurring molecules.1 In addition, -amino acids
are useful as precursors for the synthesis of novel biolog-
ically active peptide analogues and non-peptide com-
pounds.2
Scheme 2
reaction of BocNHNH2 6 and BocONHBoc 7 with 1 gave
rise to the corresponding -methylene -hydrazino and
-N-hydroxy esters 85 and 9,6 thus constituting a new class
of -amino esters derivatives (Scheme 2).
We have recently developed a general route for the syn-
thesis of -UNCAs.3 These molecules are of strong inter-
est since, like their -UNCA analogues, they can be easily
and cleanly incorporated into biologically active targets.
Our five-step strategy for the preparation of -UNCAs in-
volved formation of an N-diboc -amino acid followed by
a subsequent cyclisation step via a Vilsmeier reaction. Al-
though successful, some remaining problems in the pro-
cess needed to be solved. Therefore, the investigation was
next extended to improve our strategy with the purpose
of: 1) introducing the N-diboc protecting group in one
step; 2) incorporating a large structural diversity in our
molecules at the latest possible stage of the synthesis;
3) reducing the number of steps. With these three goals in
mind, we envisaged to develop a new route, outlined in
Scheme 1, for the synthesis of a wide variety of -substi-
tuted -UNCAs.
Having synthesised in one step the N-diprotected -amino
ester 3, we next tried to incorporate structural diversity
in our molecules. Attempts to alkylate the position of
-UNCA derived from -alanine failed because of the
lack of stability of such a compound towards strong basic
conditions. Therefore, structural diversity was incorporat-
ed at an earlier stage of the synthesis via 1-4 radical
additions7 and Heck reactions,8 performed on the conju-
gated double bond of building block 3. Our results are
summarised in Tables 1 and 2.
As can be seen from Tables 1 and 2, radical and Heck re-
actions performed on building block 3 gave rise in good
yields to a range of -amino esters 4a-d9 and 10a-b10 bear-
ing alkyl, aryl and functional moieties at the position of
the carboxylic acid group. Thus, use of synthon 3 in radi-
cal and Heck reactions appeared to be a short and efficient
procedure for the synthesis of structurally-diversified
-substituted -amino esters or acids.11
Synthon 34 was easily isolated in high yield via reaction of
HN(Boc)2 2 with methyl 2-bromomethyl acrylate 1 in the
presence of potassium carbonate. It is worth noting that
Synlett 2001, No. 9, 1467–1469 ISSN 0936-5214 © Thieme Stuttgart · New York

1468
J. Huck et al.
Table 1 Radical conjugate additions of alkyl iodides on synthon 3
LETTER
CO2Me
CO2Me
R
RI
(Boc)2N
(Boc)2N
3
10
Reagents and conditions: A mixture of 3 (1 eq.), AIBN (0.1 eq.) and Bu3SnH (1.3 eq.) in ben-
zene was slowly added over the course of 90 min. via a syringe pump to a refluxing solution of
alkyl iodide (2 eq.) in benzene, under an argon atmosphere. After completion, the reaction mix-
ture was refluxed for a further 90 min., quenched by addition of KF and purified by silicagel
chromatography to yield products 4a-d as colourless oils. a Yields of isolated compounds.
Table 2 Heck reactions of aryl iodides on synthon 3
CO2Me
CO2Me
R
RI
(Boc)2N
(Boc)2N
3
4
Reagents and conditions: A mixture of 3 (1 eq.), PPh3 (0.2 eq.), Pd(OAc)2 (0.1 eq.), K2CO3
(2.5 eq.), nBu4Br (1 eq.) and aryl iodide (2 eq.) in acetonitrile was refluxed overnight under an
argon atmosphere. After usual work-up and purification by silicagel chromatography, products
10a,b were isolated as colourless oils. aYields of isolated compounds. bDetermined by 1H NMR;
Z or E structures were assigned by NOE experiment.
4a methyl ester hydrolysis in basic conditions (NaOH, di- ((COCl)2, DMF, C5H5N, CH3CN, -20 °C to r.t., 4 h). 12
oxane/water, r.t., 18 h, 92%) followed by a subsequent cy- was isolated as a white solid in a 65% yield after recrys-
clisation of the acid 1112 into its -UNCA derivative 1213 tallisation (Scheme 3).
was achieved via a previously reported procedure3
Synlett 2001, No. 9, 1467–1469 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Synthesis of Structurally Diversified -Substituted -Amino Acids and Derivatives
1469
(4) 3: 250 MHz 1H NMR/CDCl3 (ppm) : 1.40 (s, 18H), 3.65 (s,
3H), 4.26 (s, 2H), 5.40 (s, 1H), 6.11 (s, 1H). 400 MHz 13
O
CO2H
C
(Boc)2N
(COCl)2, DMF, C5H5N
O
NMR (ppm) : 28.4, 46.6, 52.3, 83.1, 123.9, 125.6, 137.1,
166.7. HRMS (Fab+): m/z (Theo.) 316.1760, m/z (Found)
316.1685.
CH3CN, –20 ºC to RT, 4h,
65%
N
Boc
O
11
12
(5) 8: 250 MHz 1H NMR/CDCl3 (ppm) : 1.45 (s, 9H), 3.67 (s,
2H), 3.79 (s, 3H), 5.75 (s, 1H), 6.10 (bs, 1H), 6.28 (s, 1H). 400
MHz 13C NMR (ppm) 28.7, 52.3, 53.3, 80.9, 128.1, 137.1,
157.1, 167.3. MS (Fab+): (M+H)+ 231, (M+Na)+ 253.
(6) 9: 250 MHz 1H NMR/CDCl3 (ppm) : 1.44 (s, 9H), 1.47 (s,
9H), 3.73 (s, 3H), 4.44 (s, 2H), 5.82 (s, 1H), 6.32 (s, 1H). 400
MHz 13C NMR (ppm) : 27.8, 28.3, 50.9, 52.2, 82.9, 85.1,
127.4, 135.1, 152.4, 154.7, 166.3. HRMS (Fab+): m/z (Theo.)
332.1709, m/z (Found) 332.1636.
Scheme 3
In summary, we have described an efficient and general
two-step synthesis of a wide range of -substituted -ami-
no, -hydrazino and -N-hydroxy esters starting from
commercially available compounds 1, 2, 6 and 7.14 1,4
Radical additions and Heck reactions were performed on
the conjugated double bond of synthons 3, 8 and 9 to give
adducts 4a-d and 10a,b in good yields. -Amino esters
could be fully deprotected to yield the corresponding ra-
cemic free -amino acids in high yields. We are currently
investigating the synthesis of optically pure -substituted
-amino acids via asymmetric conjugate radical addition
performed on synthon 3, the results of which will be pub-
lished elsewhere.
(7) Kessler, H.; Wittmann, V.; Köck, M.; Kottenhahn, M.
Angewandte Chemie. Int. Ed. Eng. 1992, 31, 902
(8) Tuyet, J. Tetrahedron 1996, 52, 10113
(9) 4a 400 MHz 1H NMR/CDCl3 (ppm) : 0.90 (m, 6H), 1.19 (m,
1H), 1.52 (s, 18H), 1.50 1.68 (m, 2H), 2.82 (m, 1H), 3.60
(dd, 1H, J = 5.5, J = 14), 3.66 (s, 3H), 3.87 (dd, 1H, J = 8.6,
J = 14). 400 MHz 13C NMR (ppm) : 22.2, 23.6, 26.4, 28.4,
39.5, 43.8, 48.9, 52.0, 82.8, 152.8, 175.3. HRMS (Fab+): m/z
(Theo.) 360.2386, m/z (Found) 360.2339.
(10) Cis 10a 400 MHz 1H NMR/CDCl3 (ppm) : 1.45 (s, 18H),
3.59 (s, 3H), 4.50 (s, 2H), 6.69 (s, 1H), 7.20 (m, 5H). 400 MHz
13C NMR (ppm) : 28.4, 49.2, 52.2, 83.2, 128.5, 128.6, 130.5,
135.7, 140.2, 152.5, 168.9, 171.6. MS (Fab+): (M+Na)+ 414,
(2M+Na)+ 805. Trans 10a 400 MHz 1H NMR/CDCl3 (ppm)
: 1.45 (s, 18H), 3.70 (s, 3H), 4.73 (s, 2H), 7.25 (m, 5H), 7.62
(s, 1H). 400 MHz 13C NMR (ppm) : 28.3, 43.4, 52.5, 82.8,
128.8, 129.0, 130.0, 130.3, 135.2, 140.2, 152.8, 168.0. HRMS
(Fab+): m/z (Theo.) 392.2073, m/z (Found) 392.2051.
(11) Removal of the tert-butyloxycarbonyl N-protecting groups
and hydrolysis of the methyl ester moiety of compounds 4a-d
and 10a-b in acidic conditions (6 N HCl, reflux, 90 min.)
afforded the corresponding -substituted -amino acid
hydrochlorides in high yields (90 95%).
Starting from 1, -UNCA 12 was quickly isolated in a
four-step synthesis with an overall yield of 40%. Applica-
tion of this improved strategy to solution phase parallel
synthesis should allow the rapid synthesis of a wide vari-
ety of -substituted -UNCAs that may be of use within
the medicinal and combinatorial chemistry areas.
References and Notes
(1) a) Nicolau, K.C.; Sorensen, E.J. Classics in Total Synthesis,
VCH: Weinheim 1996, 655. b) Crews, P.; Manes, L.V.;
Boehler, M. Tetrahedron Letters. 1986, 27, 2797. c) Juaristi,
E.; Lopez-Ruiz, H. Current Medicinal Chemistry 1999, 6, 983
(2) a) Porter, E.A.; Wang, X.; Lee, H.S.; Weisblum, B.; Gellman,
S.H. Nature 2000, 565. b) North, M. Journal of Peptide
Science 2000, 301. c) Casiraghi, G.; Colombo, L.; Rassu, G.;
Spanu, P. Journal of Organic Chemistry 1991, 56, 6523.
d) Page, M.I. The Chemistry of -Lactams, Ed., Chapman and
Hall: London 1992. e) Lukacs, G. In Recent Progress in the
Chemical Synthesis of Antibiotics and Related Microbial
Products, Ed., Springer Verlag: Berlin 1993, 2, 621
(3) Mc Kiernan, M.; Huck, J.; Fehrentz, J.A.; Roumestant, M.L.;
Viallefont, P. and Martinez, J. Journal of Organic Chemistry
2001, in press
(12) 11: 400 MHz 1H NMR/CDCl3 (ppm) : 0.85 (m, 6H), 1.12 (m,
1H), 1.40 (s, 18H), 1.50 1.63 (m, 2H), 2.75 (m, 1H), 3.55
(dd, 1H, J = 5.6, J = 14.1), 3.80 (dd, 1H, J = 8.4, J = 14.1),
10.50 (m, 1H). 400 MHz 13C NMR (ppm) : 22.8, 23.7, 26.3,
28.4, 39.4, 48.3, 48.6, 83.0, 152.7, 181.1. HRMS (Fab+): m/z
(Theo.) 346.2230, m/z (Found) 346.2229.
(13) 12: 400 MHz 1H NMR/CDCl3 (ppm) : 1.00 (m, 6H), 1.43 (m,
1H), 1.60 (s, 9H), 1.72 1.90 (m, 2H), 2.85 (m, 1H), 3.55 (dd,
1H, J = 9.6, J = 13.3), 4.05 (dd, 1H, J = 5.3, J = 13.3). 400
MHz 13C NMR (ppm) : 22.3, 23.0, 25.8, 28.3, 36.7, 38.2,
44.3, 86.1, 144.9, 151.1, 167.0. HRMS (Fab+): m/z (Theo.)
272.1499, m/z (Found) 272.1498. mp 81-82 °C.
(14) Purchased from Sigma-Aldrich.
Article Identifier:
1437-2096,E;2001,0,09,1467,1469,ftx,en;D13501ST.pdf
Synlett 2001, No. 9, 1467–1469 ISSN 0936-5214 © Thieme Stuttgart · New York