Stereoselective synthesis of chiral furan amino acid analogues of D- and L-serine from D-sugars

Article abstract of DOI:10.1055/s-2006-941570

The synthesis of chiral furan amino acid analogues of D- and L-serine is reported. The developed methodology starting from D-xylose affords the corresponding amino acid derivative analogue of D-serine enantiomerically pure. Starting from D-arabinose, the

Full text of DOI:10.1055/s-2006-941570

LETTER
1327
Stereoselective Synthesis of Chiral Furan Amino Acid Analogues of
D- and L-Serine from D-Sugars
S
ynthesisof Ch
i
iral
F
u
d
ra
n
A
minoA
i
cidsfro
a
m
D
-Sugar
s
Molina, Antonio J. Moreno-Vargas,* Ana T. Carmona, Inmaculada Robina*
Department of Organic Chemistry, Faculty of Chemistry, University of Seville, P. O. Box 553, 41071 Seville, Spain
Fax +34(954)624960; E-mail: ajmoreno@us.es; E-mail: robina@us.es
Received 31 January 2006
azasugar derivatives9 such as piperidine alkaloids, in-
dolizidines and quinolizidines through the aza-Achma-
towicz rearrangement.10
Abstract: The synthesis of chiral furan amino acid analogues of D-
and L-serine is reported. The developed methodology starting from
D-xylose affords the corresponding amino acid derivative analogue
of D-serine enantiomerically pure. Starting from D-arabinose, the
corresponding analogue of L-serine was isolated in 92.3% enantio-
meric purity. The analogue of D-serine was transformed into a stable
Fmoc activated derivative ready to be incorporated into peptides.
Here we report a novel stereoselective route for the syn-
thesis of a-furfuryl amines and their transformation into
D- and L-serine analogues. This methodology implies a
nucleophilic displacement by azido anions on the inter-
mediate sulfites that were obtained starting from D-xylose
and D-arabinose, respectively (Scheme 1). Additionally,
our target compounds are analogues of b-hydroxy-a-ami-
no acids, which are constituents of many biologically
active natural products and medicinally important com-
pounds.11
Key words: furan amino acids, cyclic sulfites, serine analogues,
polyhydroxyalkyl furans, a-furfuryl amines
The rational design of new peptide-based drugs requires
compounds with improved stability towards proteolytic
cleavage on physiological systems, and a lessening of the
peptide’s intrinsic flexibility in order to obtain the effec-
tive conformation required for receptor binding. These
requirements have been achieved by insertion of rigid
non-peptide moieties into the appropriate site of the pep-
tide backbone. This is a common approach to restrict the
conformational degrees of freedom or stabilization of sec-
ondary structures that favors the binding to receptors.1 In
this context, many structurally rigid amino acids have
been designed. Among them, heteroaromatic amino acids
have recently attracted much attention,2 and have been
assembled into peptidomimetics for the purpose of drug
discovery.3
OH
O
S
O
COOH
O
COOP1
H2N
O
D-xylose
O
P2O
1
Me
Me
OH
O
S
O
COOH
O
H2N
COOP1
O
D-arabinose
O
ent-1
Me
P2O
Me
As part of our continuing interest in the synthesis and Scheme 1
biological applications of chiral furan amino acids,4 we
present the synthesis of constrained analogues of D- and L-
Thus, the reaction of D-xylose and D-arabinose with
benzyl acetoacetate in the presence of ZnCl2 as catalyst12
afforded trihydroxypropyl furans 2 and 3, respectively, in
moderate to good yield (Scheme 2). The trihydroxypropyl
derivatives were obtained with good stereoselectivities
which implies almost no epimerization at C-1¢ of the
polyolic chain (S/R = 36 for 2 and R/S = 19 for 3). Recent-
ly, it has been reported that the reaction of aldopentoses
and other sugars including disaccharides with b-dicarbon-
yl compounds can be performed using CeCl3 as catalyst.13
In our hands, the condensation of D-xylose and D-arabi-
nose with benzyl acetoacetate and CeCl3 (25%), provoked
the total epimerization at C-1¢ after six hours of reaction,
which is in contradiction with the results reported in the
literature.13
serine (1 and ent-1, Scheme 1) as novel scaffolds for the
synthesis of non-proteinogenic peptides. Given that com-
plex biochemical processes involve molecular recognition
based not only on polar but also on hydrophobic interac-
tions, the structure of our targets is of interest because
they contain an alkyl furan moiety which increases the ri-
gidity and hydrophobicity.5 In addition, constrained serine
analogues incorporated into peptides have been reported
to clarify the conformational role of the hydroxymethyl
group6 and several serine analogues have been reported
with this goal.7
The stereoselective introduction of an amino function into
the a-position of a furan moiety has been widely studied8
due to their interest as building blocks for the synthesis of
Regioselective protection of the primary alcohol function
in 2 afforded silyl derivative 4 after separation of the mi-
nor epimer by flash chromatography (Scheme 3). For the
introduction of an azide function at C-1¢ of the polyolic
SYNLETT 2006, No. 9, pp 1327–1330
Advanced online publication: 22.05.2006
DOI: 10.1055/s-2006-941570; Art ID: G04606ST
© Georg Thieme Verlag Stuttgart · New York
0
1.
0
6.
2
0
0
6

1328
L. Molina et al.
LETTER
D
-xylose
2
OH
ZnCl2, EtOH
reflux, 30 min
+
S
1) TBDPSCl, imidazole
DMF, 0 °C
2) flash chromatography
COOBn
COOBn
O
O
HO
60%
67%
OBn
O
OH
2
Me
S/R = 36
OH
COOBn
D-arabinose
PO
OH
ZnCl2, EtOH
reflux, 30 min
R
O
OH
+
P = tert-butyldiphenylsilyl
4
HO
Me
O
O
69%
O
OH
SOCl2
Et3N, CH2Cl2
3
OBn
Me
92%
O
R/S = 19
O
Scheme 2
S
N3
NaN3
O
COOBn
COOBn
chain of a tetrahydroxybutylfuran derivative, we have
recently reported14 on the regioselective chlorination at
C-1¢ followed by nucleophilic displacement with an azido
anion. However, this procedure is poorly stereoselective
giving a mixture of epimers at C-1¢ in a 2:1 ratio.
PO
DMF, 60 °C
44%
O
O
OH
PO
5
Me
Me
6
R/S = 4
TMSN3, TBAF
THF, r.t.
77%
We present in this letter a methodology that improves this
functionalization in order to obtain a-furfuryl amino de-
rivatives with high stereoselectivity and good yield. Reac-
tion of 4 with thionyl chloride and triethylamine afforded
the stable cyclic sulfite 5 in 92% yield, which could be
even purified by column chromatography. Although nu-
cleophilic displacements are commonly performed on key
sulfate intermediates, the activated benzylic position C-1¢
in sulfite 5 is thought to be reactive enough for nucleo-
philic ring-opening. Treatment of 5 with NaN3/DMF at 60
°C gave a mixture of azido derivatives 6,15,16 epimers at C-
1¢, in a ratio R/S = 4, indicating that SN2 and SN1-like
mechanisms participated in the displacement. In order to
avoid epimerization, we decided to use the mixture
TMSN3/TBAF with increased nucleophilicity and solubil-
ity of the azide anion in organic solvents. Thus, the reac-
tion of 5 with TMSN3/TBAF in THF at room temperature
gave the azido derivative 717 as unique compound in 77%
yield with the concomitant removal of the silyl protecting
group. This fact indicates that the reaction occurred
through an SN2 mechanism allowing the total stereoselec-
tive introduction of the azide function. Oxidative cleavage
of diol 7 followed by reduction of the aldehyde function
with NaBH4 afforded alcohol 8 in 83% overall yield. In
order to confirm that no epimerization at C-1¢ occurred in
the reduction, Mosher’s ester of compound 8 was pre-
N3
COOBn
HO
R
O
OH
7
Me
1) NaIO4, MeOH
2) NaBH4
83%
OH
F3C OCH3
Mosher's
O
Ph
acid
chloride
COOBn
O
N3
COOBn
pyridine, r.t.
N3
O
O
quant.
8
Me
9
Me
H2, Pd/C
MeOH
74%
OH
COOH
H2N
O
1
Me
Scheme 3
room temperature gave the azido derivative 11 (57% after
48 h of reaction). The displacement–deprotection step for
compound 10 proved to be slower than for its epimer 5.
Besides, partial epimerization was detected (ratio on C-1¢,
1
pared. H NMR and 13C NMR experiments showed that
only diastereomer 918 was present and no signals for the
epimerized derivative could be found. Finally, hydro-
genation of 8 using Pd/C (10%) as catalyst afforded the
furan amino acid 1 in good yield.
1
S/R = 13 = 11/7 measured by H NMR in the crude mix-
ture) which is presumably due to the participation of an
SN1-like mechanism. Attempts to improve the stereo-
selectivity of the displacement using DMF as solvent or
lower temperatures were not successful. Oxidative cleav-
age of 11 followed by reduction with NaBH4 afforded al-
cohol ent-8, that was reduced to give the amino acid
derivative ent-1 in good-to-moderate yield (Scheme 4).
The enantiomeric purity (92.3%) of ent-8 was determined
by formation of the corresponding Mosher’s ester.
In a similar way, the synthesis of ent-1 was carried out
starting from trihydroxypropyl furan 3 (C-1¢, R/S = 19)
that was obtained from D-arabinose in 69% yield
(Scheme 4).
tert-Butyldiphenylsilyl protection followed by sulfite for-
mation afforded 10 (C-1¢, R/S = 23) after purification by
column chromatography (Scheme 4). Displacement reac-
tion of 10 using the mixture TMSN3/TBAF in THF at
Synlett 2006, No. 9, 1327–1330 © Thieme Stuttgart · New York

LETTER
Synthesis of Chiral Furan Amino Acids from D-Sugars
1329
3
1
N
1. TMSCl/Py
2. FmocCl
3. H2O
N
Bt =
N
O
N3
S
O
OH
OH
O
R
TMSN3/TBAF
O
COOBn
COOBn
PyBOP
DIEA, DMF
HO
S
THF, r.t.
COOH
COOBt
O
O
FmocHN
FmocHN
OH
PO
57%
O
Me
Me
10
78%
(overall)
11
S/R = 13
15
Me
Me
16
R/S = 23
P = tert-butyldiphenylsilyl
Scheme 6
OH
OH
1) NaIO4, MeOH
2) NaBH4
N3
logue ent-1, the method provides the target compound
with 92.3% of enantiomeric purity. Compound 1 was
easily transformed into the corresponding Fmoc-activated
derivative ready to be incorporated into a peptide or pep-
tidomimetic following the Fmoc strategy for solid-phase
peptide synthesis. Due to the aromatic character of the
furan-3-carboxylic acid, compound 16 is stable which
makes it an attractive building block for solid phase pep-
tide synthesis as compared to most OBt esters21 of Fmoc-
amino acids which are not stable enough and need to be
generated in situ. Work is in progress to prepare peptido-
mimetics with conformational bias by solid phase synthe-
sis using the new scaffold, and to extend this methodology
to other constrained hetaryl amino acids.
H2, Pd/C
MeOH
COOH
COOBn
H2N
O
80%
O
71%
Me
ent-8
ent-1
Me
Mosher's acid
chloride
quant.
F3C OCH3
pyridine
O
Ph
O
COOBn
N3
O
(92.3% enantiomeric purity)
Me
12
Scheme 4
7
11
1. TBDPSCl/Imidazole
CH2Cl2, 0 °C
Acknowledgment
2. a) Ph3P/CH2Cl2; b) H2O
3 (Im)2C=S, CH2Cl2
71%
79%
We thank the Ministerio de Educación y Ciencia of Spain
(CTQ2004-00649/BQU), the European Commission (FP6, TRIoH,
LSHG-CT-2003-503480) and the Junta de Andalucía (FQM-345)
for financial support.
COOBn
NOE
COOBn
Me
NOEs
4
H
4
H
H
H
H
Me
3'
3'
O
O
TBDPSO
TBDPSO
1'
1'
References and Notes
2'
2'
13
O
NH
O
NH
14
(1) (a) Recent Advances in Peptidomimetics; Tetrahedron
Symposia-in-Print, No. 83; Aubé, J., Ed.; Tetrahedron;
2000, 56, 50. (b) Robinson, J. A. Synlett 2000, 429.
(c) Smith, A. B. III; Favor, D. A.; Sprengeler, P. A.;
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Bioorg. Med. Chem. 1999, 7, 9. (d) Hanessian, S.;
McNaughton-Smith, G.; Lombart, H.-G.; Lubell, W. D.
Tetrahedron 1997, 53, 12789. (e) Giannis, A.; Kolter, T.
Angew. Chem., Int. Ed. Engl. 1993, 32, 1244.
S
S
(arrows indicate NOE enhancements)
Scheme 5
The absolute configuration of C-1¢ in 1 and ent-1 was con-
firmed in the corresponding precursors 7 and 11 by trans-
formation into their corresponding oxazolidine-2-thione
derivatives 13 and 14 (Scheme 5). Appropriate NOEs
confirmed the proposed structures.
(f) Kinshenbaum, K.; Zuckerman, R. N.; Dill, K. A. Curr.
Opin. Struct. Biol. 1999, 9, 530. (g) Gellman, S. H. Acc.
Chem. Res. 1998, 31, 173.
(2) (a) Singh, R. K.; Sinha, N.; Jain, S.; Salman, M.; Nazqui, F.;
Anand, N. Tetrahedron 2005, 61, 8868. (b) You, S.-L.;
Razavi, H.; Kelly, J. W. Angew. Chem. Int. Ed. 2003, 42, 83.
(c) You, S.-L.; Kelly, J. W. J. Org. Chem. 2003, 68, 9506.
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(e) Davidson, B. S. Chem. Rev. 1993, 93, 1771. (f) Wipf, P.
Chem. Rev. 1993, 95, 2115. (g) Phillips, A. J.; Uto, Y.;
Wipf, P.; Reno, M. J.; Williams, D. R. Org. Lett. 2000, 2,
1165.
Amino acid derivative 1 is a suitable scaffold for its in-
corporation into peptides through the Fmoc solid-phase
methodology. For this purpose, Fmoc derivative 15 was
prepared starting from
1
following Koole’s
methodology19 (Scheme 6). Moreover, reaction of 15 with
PyBOP/DIEA afforded the activated ester 1620 that could
be isolated by chromatography column.
(3) (a) Bertran, A.; Pattendem, G. Heterocycles 2002, 58, 521.
(b) Wang, W.; Nan, F. J. Org. Chem. 2003, 68, 1636.
(c) You, S.-L. i.; Deechongkit, S.; Kelly, J. W. Org. Lett.
2004, 6, 2627. (d) Pattenden, G.; Thompson, T. Tetrahedron
Lett. 2002, 43, 2459. (e) Deeley, J.; Pattenden, G. Chem.
Commun. 2005, 797.
In summary, the synthesis of new chiral furan amino acid
analogues of D- and L-serine is described starting from D-
aldopentoses. In the case of the D-serine analogue 1 the
method proved to be very efficient as the final product
was obtained enantiomerically pure. For the L-serine ana-
Synlett 2006, No. 9, 1327–1330 © Thieme Stuttgart · New York

1330
L. Molina et al.
LETTER
(4) (a) Moreno-Vargas, A. J.; Fernández-Bolaños, J. G.;
Fuentes, J.; Robina, I. Tetrahedron Lett. 2001, 42, 1283.
(b) Moreno-Vargas, A. J.; Jiménez-Barbero, J.; Robina, I. J.
Org. Chem. 2003, 68, 4138.
(5) (a) Silverman, D. N.; Lindskog, S. Acc. Chem. Res. 1988, 21,
30. (b) Greener, B.; Rose, J. Chem. Commun. 1999, 2361.
(c) Lehn, J. M. Supramolecular Chemistry: Concepts and
Perspectives; VCH: Weinheim, 1995.
1 H, J1¢,2¢ = 7.3 Hz, H-1¢), 4.02 (m, 1 H, H-2¢), 3.76 (dd, 1 H,
J
3¢a,3¢b = 11.5 Hz, J3¢a,2¢= 3.4 Hz, H-3¢a), 3.72 (dd, 1 H,
J
3¢b,2¢ = 5.2 Hz, H-3¢b), 2.60 (s, 3 H, CH3) ppm. 13C NMR
(75.4 MHz, CDCl3, 298 K): d = 163.5 (CO), 160.4, 147.5 (C-
2, C-5), 135.9, 128.6, 128.3, 128.2 (6 C-arom.), 114.2 (C-3),
110.9 (C-4), 71.9 (C-2¢), 66.2 (CH2Ph), 62.9 (C-3¢), 59.9 (C-
1¢), 14.3 (CH3) ppm. HRMS (CI): m/z calcd for C16H18N3O5
+ H+: 332.1246; found: 332.1236.
(6) Cleland, W. W.; Kreevoy, M. M. Science 1994, 264, 1887.
(7) (a) Clerici, F.; Gelmi, M. L.; Gambini, A. J. Org. Chem.
1999, 64, 5764. (b) Clerici, F.; Gelmi, M. L.; Gambini, A. J.
Org. Chem. 2000, 65, 6138. (c) Clerici, F.; Gelmi, M. L.;
Gambini, A.; Nava, D. Tetrahedron 2001, 57, 6429.
(d) Avenoza, A.; Busto, J. H.; Canal, N.; Peregrina, J. M. J.
Org. Chem. 2005, 70, 330. (e) Avenoza, A.; Busto, J. H.;
Canal, N.; Peregrina, J. M.; Pérez-Fernández, M. Org. Lett.
2005, 7, 3597.
(8) (a) Sun, X.-L.; Kai, T.; Takayanagi, H.; Furuhata, K. Synlett
1999, 1399. (b) Bushey, M. L.; Haukaas, M. H.; O’Doherty,
G. A. J. Org. Chem. 1999, 64, 2984. (c) Saaby, S.; Bayón,
P.; Aburel, P. S.; Jørgensen, K. A. J. Org. Chem. 2002, 67,
4352. (d) Miyata, O.; Iba, R.; Hashimoto, J.; Naito, T. Org.
Biomol. Chem. 2003, 1, 772.
(18) Selected data for compound 9: [a]D20 +25 (c 2.62, CH2Cl2).
1H NMR (300 MHz, CDCl3, 298 K): d = 7.42–7.36 (m, 10
H, H-arom.), 6.67 (s, 1 H, H-4), 5.30 (s, 2 H, CH2Ph), 4.75
(t, 1 H, J1¢,2¢a = J1¢,2¢b = 6.5 Hz, H-1¢), 4.56 (d, 2 H, H-2¢a and
H-2¢b), 3.55 (q, 3 H, JCH,F = 1.2 Hz, CH3O), 2.58 (s, 3 H,
CH3) ppm. 13C NMR (75.4 MHz, CDCl3, 298 K): d = 166.2
(CO), 163.1 (CO), 160.5, 146.0 (C-2, C-5), 131.8–127.2 (12
C, C-arom.), 123.1 (q, 1 C, 1JC,F = 288, CF3), 114.2 (C-3),
110.5 (C-4), 84.7 [q, 1 C, 2JC,F = 28.2 Hz, (C(OMe)(CF3)Ph],
66.2 (CH2Ph), 65.0 (C-2¢), 56.5 (C-1¢), 55.5 (OCH3), 13.9
(CH3) ppm.
(19) Koole, L. H.; Moody, H. M.; Broeders, N. L. H. L.;
Quaedflieg, P. J. L. M.; Kuijpers, W. H. A.; van Genderen,
M. H. P.; Coenen, A. J. J. M.; van der Wal, S.; Buck, H. M.
J. Org. Chem. 1989, 54, 1657.
(9) For a review on a-furfuryl amine derivatives, see: Zhou,
W.-S.; Lu, Z.-H.; Xu, Y.-M.; Liao, L.-X.; Wang, Z.-M.
Tetrahedron 1999, 55, 11959.
(20) Experimental Procedure for the Preparation of Fmoc-
Activated Amino Acid Derivative 16 from 1.
To a stirred mixture of 1 (26 mg, 0.138 mmol) in dry
pyridine (2 mL) at 0 °C, TMSCl (54 mL, 0.414 mmol) was
dropped and the reaction mixture stirred for 45 min at r.t.
Then the reaction mixture was cooled to 0 °C, 9-fluorenyl-
methoxycarbonyl chloride (46 mg, 0.18 mmol) was added
and the mixture stirred for 1.5 h at r.t. Afterwards, H2O (0.1
mL) was added, the mixture stirred for 1 h at r.t., and then
evaporated to give 15 that was used in the next step without
any purification. Crude 15 was dissolved in DMF, then
DIEA (53 mL, 0.3 mmol) and PyBOP (88 mg, 0.168 mmol)
were added. The mixture was stirred for 1 h at r.t., then the
solution was evaporated in vacuo. The resulting residue was
purified by column chromatography (EtOAc–PE, 1:1) to
(10) (a) Ciufolini, M. A.; Wood, C. W. Tetrahedron Lett. 1986,
27, 5085. (b) Ciufolini, M. A.; Hermann, C. Y. W.; Dong,
Q.; Shimizu, T.; Swaminathan, S.; Xi, N. Synlett 1998, 105.
(11) (a) McMillan, J. B.; Molinski, T. F. Org. Lett. 2002, 4, 1883.
(b) Willis, M. C.; Cutting, G. A.; Piccio, V. J.-D.; Durbin, M.
J.; John, M. P. Angew. Chem. Int. Ed. 2005, 44, 1543.
(c) Amino Acids, Peptides and Proteins, Vol.1-28; Special
Periodical Reports, Chemistry Society: London, 1968-1995.
(12) For similar condensations between aldohexoses and
ketohexoses with b-dicarbonyl compounds see: García-
González, F. Adv. Carbohydr. Chem. 1956, 11, 97.
(13) Misra, A. K.; Agnihotri, G. Carbohydr. Res. 2004, 339,
1381.
20
give 16 (57 mg, 0.108 mmol, 78%) as a white solid. [a]D
(14) (a) Moreno-Vargas, A. J.; Robina, I.; Demange, R.; Vogel,
P. Helv. Chim. Acta 2003, 86, 1894. (b) Robina, I.; Moreno-
Vargas, A. J.; Fernández-Bolaños, J. G.; Fuentes, J.;
Demange, R.; Vogel, P. Bioorg. Med. Chem. Lett. 2001, 11,
2555.
(15) (a) For the same reaction on a similar but unstable cyclic
sulfite giving only one diasteroisomer, see ref. 8d. (b) Seki,
M.; Mori, K. Eur. J. Org. Chem. 1999, 2965.
+38 (c 0.84, CH2Cl2). 1H NMR (300 MHz, CDCl3, 298 K):
d = 7.57–7.27 (m, 12 H, H-arom.), 6.74 (s, 1 H, H-4), 5.56
(d, 1 H, JNH,1¢ = 7.5 Hz, NHFmoc) 4.90 (br s, 1 H, H-1¢), 4.51
(d, 2 H, J = 6.5 Hz, CH2 of Fmoc), 4.22 (t, 1 H, CH of Fmoc),
3.94 (br m, 2 H, H-2¢a and H-2¢b), 2.62 (CH3) ppm.
13C NMR (75.4 MHz, CDCl3, 298 K): d = 163.4 (CO), 159.5
(C-2), 156.1 (CO of Fmoc), 152.3 (C-5), 143.7, 143.4, 141.4,
128.8, 127.8, 127.1, 124.9, 120.4, 120.0, 107.3 (18 C, C-
arom.), 108.8 (C-3), 108.4 (C-4), 67.0 (CH2 of Fmoc), 63.3
(C-2¢), 50.9 (C-1¢), 47.2 (CH of Fmoc), 14.2 (CH3).
(21) The OBt esters of protected amino acids are not isolable and
must be generated in situ. Only less reactive OPfp esters are
commercially available, see: Novabiochem,® 2004/5
catalogue.
(16) For reviews on cyclic sulfite reactivity, see: (a) Lohray, B.
B. Synthesis 1992, 1035. (b) Byun, H.-S.; He, L.; Bittman,
R. Tetrahedron 2000, 56, 7051.
(17) Selected data for compound 7: [a]D20 +99 (c 0.98, CH2Cl2).
1H NMR (300 MHz, CDCl3, 298 K): d = 7.40–7.28 (m, 5 H,
H-arom.), 6.75 (s, 1 H, H-4), 5.29 (s, 2 H, CH2Ph), 4.56 (d,
Synlett 2006, No. 9, 1327–1330 © Thieme Stuttgart · New York