A straightforward route to novel α,α-disubstituted tetrahydrofuran β-amino acids and spirodiketopiperazines from sugar lactones

Article abstract of DOI:10.1055/s-0030-1258572

Indium-mediated Reformatsky reactions of aldonolactones with ethyl α-bromoisobutyrate allowed the synthesis of ulosonic acid esters, which were readily transformed into the corresponding tetrahydrofuran β-azido esters in a stereoselective fashion. This approach provided monomeric components suitable for oligomerization to the carbopeptoid class of foldamers and prompted the total synthesis of the attractive novel spiro diketopiperazine, which can be regarded as a spironucleoside. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0030-1258572

LETTER
2549
A Straightforward Route to Novel a,a-Disubstituted Tetrahydrofuran
b-Amino Acids and Spirodiketopiperazines from Sugar Lactones
Route to
Novel
a
a
,
a
-
Disubstit
q
uted
T
etrahy
u
drofuran
b
-A
e
minoAcid
l
s
G. Soengas*
Departmento de Química Fundamental, Universidad de A Coruña, Campus de A Zapateira, s/n, 15071 A Coruña, Spain
Fax +34(981)167065; E-mail: rsoengas@udc.es
Received 13 August 2010
In memory of Professor Jose M. Concellón
The special folding properties of b-peptides has in recent
times prompted exhaustive studies into the preparation of
conformationally restricted b-amino acids, including type
1 furanoid b-amino acids. In this context, the related b,b-
Abstract: Indium-mediated Reformatsky reactions of aldonolac-
tones with ethyl a-bromoisobutyrate allowed the synthesis of ulo-
sonic acid esters, which were readily transformed into the
corresponding tetrahydrofuran b-azido esters in a stereoselective
fashion. This approach provided monomeric components suitable disubstituted b-amino acids 2 (Figure 1) could be novel,
for oligomerization to the carbopeptoid class of foldamers and
more convenient candidates for the preparation of stabi-
prompted the total synthesis of the attractive novel spiro diketo-
piperazine, which can be regarded as a spironucleoside.
lized peptidomimetic type 1 b-amino acids that are struc-
turally related to a,a-disubstituted a-amino acids, which
Key words: indium, Reformatsky reaction, sugar amino acids
(SAA), b-amino acids, spirodiketopiperazines
have also been used for the preparation of conformation-
ally stabilized peptides.
Furanoid sugar b-amino acids 1 have been synthesized by
a Wittig reaction involving a sugar-derived lactone, fol-
Sugar amino acids (SAA)1 constitute a large family of hy-
lowed by a 1,4-addition of benzylamine.9 However, this
brid carbohydrate derivatives that bear an amino and a
approach is not suitable to give the target amino acids 2 re-
carboxylic acid group and these compounds include natu-
ported here.
rally occurring members such as neuraminic acid and mu-
raminic acid.2 Among them, sugar amino acids arising
R4
O
O
R4
O
from the direct incorporation of the amino acid moiety on
the cyclic carbohydrate scaffold have emerged as a new
class of promising hybrids that have played an important
role in drug design and development. In fact, since the
first reported synthesis of a SAA,3 a vast number of these
amino acids have been prepared for use as glycosidase in-
hibitors and as starting materials of great interest for the
preparation of peptidomimetics.4 The rigid furan or pyran
rings make these systems ideal nonpeptididic scaffolds for
incorporation into peptides in order to induce conforma-
tional restrictions5 and enhance metabolic stability in
pharmacologically active peptides.6 In addition, the pres-
ence of several stereogenic centers on these rings7 can be
exploited to create chemical diversity and, furthermore,
protection or deprotection of the hydroxy substituents
opens opportunities to access hydrophobic or hydrophilic
peptidomimetics.8
CO2Et
OH
n OR1
In, THF
+
R3O
n OR1
R3O
Br
CO2Et
OR2
OR2
3–7
8–12
Scheme 1 Preparation of ulosonic acid esters
As a part of our current studies on the synthetic usefulness
of indium in carbohydrate chemistry,10 we recently report-
ed a highly efficient indium-mediated Reformatsky reac-
tion
between
ethyl
a-bromoisobutyrate
and
aldonolactones.10a This approach allowed us to access 2-
deoxy-2,2¢-dimethyl-3-ulosonates, which should provide
an easy access to the target SAA 2. Thus, diverse 2-deoxy-
2,2¢-dimethyl-3-ulosonates were prepared by indium-
mediated reaction of ethyl a-bromoisobutyrate with D-
manno, D-ribo, L-gulo and D-allo lactones 3–7 (Scheme 1,
Table 1).
R
R
CO2H
CO2H
O
O
R
In order to explore the transformation of sugar-based b-
hydroxyesters 8–12 into the corresponding b-amino acid
esters, we first attempted the N-glycosylation of D-manno
configured ulosonate 8 by acetylation of the free anomeric
hydroxy group followed by treatment of the crude acetate
with trimethylsilyl azide in the presence of trimethylsilyl
triflate.11
R
NH2
OR
NH2
OR
RO
RO
1
2
Figure 1 Sugar b-amino acids
The reaction proceeds stereoselectively to give the corre-
sponding azido ester 14 in good yield (Scheme 2).
SYNLETT 2010, No. 17, pp 2549–2552
Advanced online publication: 23.09.2010
x
x
.x
x
.2
0
1
0
DOI: 10.1055/s-0030-1258572; Art ID: D22010ST
© Georg Thieme Verlag Stuttgart · New York

2550
R. G. Soengas
LETTER
The configuration of the anomeric center was firmly es-
tablished by X-ray diffraction analysis (Figure 2).
Table 1 Indium-Mediated Reformatsky-Type Reaction between
Aldonolactones and Ethyl a-Bromoisobutyrate
Lactone
Uronate
Yield (%)
O
O
O
O
O
O
O
CO2Et
OH
87
O
O
O
O
3
8
O
O
O
CO2Et
BnO
BnO
OH
80
78
O
O
O
O
4
9
O
O
O
CO2Et
OH
OTBS
O
OTBS
O
O
O
Ph
Ph
5
Figure 2 ORTEP diagram for 14
10
O
O
O
O
O
O
This N-glycosylation protocol was next applied to ulo-
sonates 9–12 (Scheme 3, Table 2). As expected, com-
pounds 9, 11, and 12 afforded the corresponding azido
esters 15, 17, and 18 in good yields and with excellent dia-
stereoselectivities. However, derivative 10 afforded the
O-acetyl derivative 16, which remained unaltered under
the N-glycosylation conditions. This lack of reactivity
was related to the bulky protecting group present at the
C-4 position.
O
CO2Et
OH
O
82
85
O
O
O
6
11
O
O
O
O
O
O
O
CO2Et
OH
O
O
O
O
R4
O
R4
O
CO2Et
OH
n OR1
CO2Et
7
12
i, ii
N3
n OR1
R3O
R3O
OR2
OR2
O
O
O
O
O
9–12
15–18
CO2Et
CO2Et
O
i
OH
OAc
Scheme 3 Reagents and conditions: (i) Ac2O, Et3N, CH2Cl2, r.t., 14
O
O
O
O
h; (ii) TMSN3, TMSOTf, powdered MS, CH2Cl2, r.t., 14 h.
8
13
ii
The configuration of 17 at the anomeric center was unam-
biguously established by X-ray crystallographic analysis
(Figure 3), while the absolute configuration of 15 and 18
was deduced from the strong NOE observed between one
of the methyl groups at C-2 and a methyl group of the iso-
propylidene protecting group (Figure 4).
O
O
O
CO2Et
N3
Catalytic hydrogenation of the azido esters 14–18 to give
the corresponding amines led to loss of stereogenic integ-
rity at the anomeric center; the epimeric amino esters
equilibrate even in nonpolar solutions and all attempts to
isolate deprotected equivalents of the amino esters were
unsuccessful.12 However, treatment of the amines with
isocyanates should give anomeric ureas, which are likely
O
O
14
Scheme 2 Reagents and conditions: (i) Ac2O, Et3N, CH2Cl2, r.t., 14
h; (ii) TMSN3, TMSOTf, powdered MS, CH2Cl2, r.t., 14 h, (71% over
two steps).
Synlett 2010, No. 17, 2549–2552 © Thieme Stuttgart · New York

LETTER
Route to Novel a,a-Disubstituted Tetrahydrofuran b-Amino Acids
2551
which in turn could easily be transformed into novel and
conformationally stable spiro diketopiperazine deriva-
tives. The anomeric mixture of amino esters 19, obtained
from azido ester 14 by catalytic hydrogenation, was used
as a model and thus reacted with phenyl isocyanate to af-
ford derivative 20 as a single anomer (Scheme 4).
Table 2 Transformation of the Uronates in b-Azido Esters
Ulosonic ester
Azido ester
Yield
(%)
O
O
CO2Et
CO2Et
BnO
BnO
OH
N3
58
92
O
O
O
O
O
N3
O
N3
O
BnO
CO2Et
NOE
O
CO2Et
NOE
9
15
O
O
O
O
O
CO2Et
O
CO2Et
OAc
OH
OTBS
OTBS
O
O
O
15
18
O
Figure 4 NOE experiments on 15 and 18
Ph
Ph
10
16
O
O
O
O
O
O
O
O
O
O
O
CO2Et
CO2Et
CO2Et
CO2Et
O
i
N3
O
OH
O
61
62
N3
NH2
O
O
O
O
O
O
11
17
14
19
O
O
O
O
O
O
ii
CO2Et
CO2Et
OH
O
N3
O
O
O
O
O
O
O
O
Ph
O
N
CO2Et
O
O
iii
12
18
N
H
NH
O
O
O
NHPh
O
O
21
20
Scheme 4 Reagents and conditions: (i) Pd/C, MeOH, r.t., 14 h; (ii)
PhCON, toluene, r.t., 3 h; (iii) NaOMe, r.t., 14 h.
NOE measurements confirmed the proximity between the
anomeric N–H of the urea and H-4 of the sugar ring, thus
establishing the a configuration of urea 20 (Figure 5). The
formation of the a urea from the anomeric mixture 19 is
explained by a faster reaction of phenyl isocyanate with
the less hindered – but less stable – a-anomer as compared
to the b one, thus displacing the anomeric equilibrium to-
ward the a-anomer and giving 20 in 85% yield.13 Basic
treatment of urea 20 easily gave the corresponding dike-
topiperazine 21 without any equilibration of anomers tak-
ing place. The absolute configuration of this spiro
derivative was determined by NMR experiments, which
showed an NOE between the N–H and the H-4 of the sug-
ar ring (Figure 5).
Figure 3 ORTEP diagram for 17
In summary, the generation of THF b-carboxylates from
carbohydrate lactones reported here has proven to be a
short and efficient process. The process involves an easy
and clean N-glycosylation of ulosonic acid esters, easily
obtained by an indium-mediated Reformatsky reaction of
aldonolactones with a-bromoisobutyrate, and provides
to be much more stable as electron-withdrawing groups
stabilize tetrahedral adducts relative to trigonal C=X sys-
tems. Accordingly, we decided to investigate the transfor-
mation of azido esters 14–18 into the corresponding ureas,
Synlett 2010, No. 17, 2549–2552 © Thieme Stuttgart · New York

2552
R. G. Soengas
LETTER
Graf von Roedern, E.; Wermuth, J. Lett. Pept. Sci. 1995, 2,
155. (c) Graf von Roedern, E.; Lohof, E.; Hessler, G.;
Hoffmann, M.; Kessler, H. J. Am. Chem. Soc. 1996, 118,
10156.
O
CO2Et
O
O
O
O
Ph
O
NHPh
N
H
O
O
N
O
N
(5) (a) Perlow, D. S.; Paleveda, W. J.; Colton, C. D.; Zacchei, A.
G.; Tocco, D. J.; Hoff, D. R.; Vandlen, R. L.; Gerich, J. E.;
Hall, L.; Mandarino, L.; Cordes, E. H.; Anderson, P. S.;
Hirschmann, R. Life Sci. 1984, 34, 1371. (b) Veber, D. F.;
Freidinger, R. M. Trends Neurosci. 1985, 392. (c) Stein,
W. D. The Movement of Molecules Across Cell Membranes;
Academic Press: New York, 1967, 65. (d) Diamond, J. M.;
Wright, E. M. Proc. R. Soc. London, Ser. B 1969, 172, 273.
(6) (a) Creighton, T. E. Proteins: Structures and Molecular
Properties, 2nd ed.; Freeman: New York, 1993.
H
H
H
O
O
O
O
NOE
NOE
20
21
Figure 5 NOE experiments on 20 and 21
access to a,a-disusbstituted THF b-amino acid deriva-
tives. This approach provided monomeric components
suitable for oligomerization to the carbopeptoid class of
foldamers and prompted the total synthesis of the attrac-
tive novel spiro diketopiperazine, which can be regarded
as a spironucleoside,14 a type of C-nucleoside that has
been of great interest12,15 since the discovery of the herbi-
cidal spironucleoside analogue hydantocidine.16
(b) Spatola, A. F. In Chemistry and Biochemistry of Amino
Acids, Peptides and Proteins, Vol. 7; Weinstein, B., Ed.;
Marcel Dekker: New York, 1983, 267. (c) Latham, P. W.
Nat. Biotechnol. 1999, 17, 755.
(7) (a) Patch, J. A.; Barron, A. E. Curr. Opin. Chem. Biol. 2002,
6, 872. (b) Cheng, R. P.; Gellman, S. H.; DeGrado, W. F.
Chem. Rev. 2001, 101, 3219. (c) Seebach, D.; Hook, D. F.;
Glattli, A. Biopolymers 2006, 84, 23. (d) Goodman, C. M.;
Choi, S.; Shandler, S.; DeGrado, W. F. Nat. Chem. Biol.
2007, 3, 252.
Work is in progress on the preparation and structural char-
acterization of homopolymers based on these novel,
promising b-amino acids. Further studies are also under
way on the chemistry and biological activity of the novel
type of sugar-derived spironucleosides reported here.
(8) Kummeter, M.; Kazmaier, U. Eur. J. Org. Chem. 2003,
3325.
(9) Taillefumier, C.; Lakhrissi, Y.; Lakhirissi, M.; Chapleur, Y.
Tetrahedron: Asymmetry 2002, 13, 1707.
(10) (a) Soengas, R. G. Tetrahedron Lett. 2010, 51, 105.
(b) Soengas, R. G.; Estévez, A. M. Eur. J. Org. Chem. 2010,
DOI: 10.1002/ejoc.201000662.
(11) Azido ester 14; mp 88–90 °C (Et2O–hexane).
(12) Estévez, J. C.; Burton, J. W.; Estévez, R. J.; Ardron, H.;
Wormald, M. R.; Dwek, R. A.; Brown, D.; Fleet, G. W. J.
Tetrahedron: Asymmetry 1998, 9, 2137.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
(13) Taillefumier, C.; Lakhrissi, Y.; Lakhirissi, M.; Chapleur, Y.
J. Org. Chem. 2009, 74, 8388.
(14) Taillefumier, C.; Thielges, S.; Chapleur, Y. Tetrahedron
2004, 60, 2213; and references cited therein.
This work was supported by the Spanish Ministry of Science and In-
novation (CTQ2008-06493). R.G.S. thanks the Xunta de Galicia for
financial support (Isidro Parga Pondal program). I would like to
thank Professors Ramón J. Estévez and Juan C. Estévez for helpful
discussions.
(15) (a) Estévez, J. C.; Ardron, H.; Wormald, M. R.; Brown, D.;
Fleet, G. W. J. Tetrahedron Lett. 1994, 35, 8889.
(b) Gimisis, T.; Castellari, C. Chem. Commun. 1997, 2089.
(c) Kittaka, A.; Asakura, T.; Kuze, T.; Tanaka, H.; Yamada,
N.; Nakamura, K. T.; Miyasaka, T. J. Org. Chem. 1999, 64,
7081. (d) Alvarez, R.; Jimeno, M.-L.; Gago, F.; Balzarini, J.;
Perez-Perez, M.-J.; Camarasa, M.-J. Antiviral Chem.
Chemother. 1998, 9, 333. (e) Chatgilialoglu, C.; Gimisis,
T.; Spada, G. P. Chem. Eur. J. 1999, 5, 2866. (f) Gasch, C.;
Pradera, M. A.; Salameh, B. A. B.; Molina, J. L.; Fuentes, J.
Tetrahedron: Asymmetry 2001, 12, 1267. (g) Renard, A.;
Lhomme, J.; Kotera, M. J. Org. Chem. 2002, 67, 1302.
(h) Babu, B. R.; Keinicke, L.; Petersen, M.; Nielsen, C.;
Wengel, J. Org. Biomol. Chem. 2003, 1, 3514. (i) Bleriot,
Y.; Simone, M. I.; Wormald, M. R.; Dwek, R. A.; Watkin,
D. J.; Fleet, G. W. J. Tetrahedron: Asymmetry 2006, 17,
2276. (j) Sano, H.; Mio, S.; Kitagawa, J.; Sugai, S.
Tetrahedron: Asymmetry 1994, 5, 2233. (k) Dong, S.;
Paquette, L. A. J. Org. Chem. 2006, 71, 1647. (l) Tripathi,
S.; Roy, B. G.; Drew, M. G. B.; Achari, B.; Mandal, S. B.
J. Org. Chem. 2007, 72, 7427.
References
(1) (a) Carbohydrate Mimics; Chapleur, Y., Ed.; Wiley-VCH:
New York, 1998, 87. (b) Gruner, S. A. W.; Lorcardi, E.;
Lohof, E.; Kessler, H. Chem. Rev. 2002, 102, 491.
(c) Chakraborty, T. K.; Jayaprakash, S.; Ghosh, S. Comb.
Chem. High Throughput Screening 2002, 5, 373.
(d) Chakraborty, K.; Jayaprakash, S. Curr. Med. Chem.
2002, 9, 421. (e) Schweizer, F. Angew. Chem. Int. Ed. 2002,
41, 231. (f) Chakraborty, K.; Srinivasu, P.; Tapadar, S.;
Mohan, B. K. J. Chem. Sci. 2004, 116, 187.
(2) (a) Fox, J. J.; Kuwada, Y.; Watanabe, K. A. Tetrahedron
Lett. 1968, 2, 6029. (b) Isono, K.; Asahi, K.; Suzuki, S.
J. Am. Chem. Soc. 1969, 91, 7490. (c) Lichtenthaler, F. W.;
Morino, T.; Menzel, H. M. Tetrahedron Lett. 1975, 9, 665.
(d) Waltho, J. P.; Williams, D. H.; Selva, E.; Ferrari, P.
J. Chem. Soc., Perkin Trans. 1 1987, 2103.
(3) Heyns, K.; Paulsen, H. Chem. Ber. 1955, 88, 188.
(4) (a) Graf von Roedern, E.; Kessler, H. Angew. Chem., Int. Ed.
Engl. 1994, 33, 670. (b) Kessler, H.; Diefenbach, B.;
Finsinger, D.; Geyer, A.; Gurrath, M.; Goodman, S. L.;
Hölzemann, G.; Haubner, R.; Jonczyk, A.; Müller, G.;
(16) (a) Nakajima, M.; Itoi, K.; Takamatsu, Y.; Kinoshita, T.;
Okazaki, T.; Kawakubo, K.; Shindo, M.; Honma, T.;
Tohjigamori, M.; Haneishi, T. J. Antibiot. 1991, 44, 293.
(b) Pham, T. Q.; Pyne, S. G.; Skelton, B. W.; White, A. H.
J. Org. Chem. 2005, 70, 6369.
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