New methodology for the stereoselective synthesis of a-furfurylamines from sugars: Application to the synthesis of furyl amino acids and 3-Furylisoserines

Article abstract of DOI:10.1002/ejoc.201000183

The synthesis of two new furyl amino acids as rigid isosteres of the dipeptides (D)-H-Ser-(D, L)-Thr-OH and (L)-H-Ser-(D, L)Thr-OH is presented. The developed synthetic methodology starts from D-xylose and D-arabinose and makes use of trihydroxypropylfura

Full text of DOI:10.1002/ejoc.201000183

FULL PAPER
DOI: 10.1002/ejoc.201000183
New Methodology for the Stereoselective Synthesis of α-Furfurylamines from
Sugars: Application to the Synthesis of Furyl Amino Acids and
3-Furylisoserines
Lidia Molina,[a] Elena Moreno-Clavijo,[a] Antonio J. Moreno-Vargas,*[a] Ana T. Carmona,[a]
and Inmaculada Robina*[a]
Keywords: Heterocycles / Carbohydrates / Peptidomimetics / Amino acids
The synthesis of two new furyl amino acids as rigid isosteres
of the dipeptides ( )-H-Ser-( )-Thr-OH and ( )-H-Ser-( )-
Thr-OH is presented. The developed synthetic methodology
starts from -xylose and -arabinose and makes use of trihy-
strategy is the introduction of an amino function at the α-
position of the adequate trihydroxypropylfuran derivative.
This methodology was also applied to the synthesis of two
new (2R,3R)-3-furylisoserines as analogues of the C-13
Taxol/Taxotere side chain.
D
D,L
L
D,L
D
D
droxypropylfurans as intermediates. The key step of the
kaloids, indolizidines, and quinolizidines through the aza-
Achmatowicz rearrangement[6,7] (Figure 1). Other types of
α-furfurylamines are the 3-furylisoserines. These com-
pounds have gained a lot of interest since the discovery of
Milataxel (1),[8] a taxane of a new generation that has a 3-
furylisoserine moiety in the C-13 side chain of the baccatin
skeleton. This taxane has shown better pharmacological
properties than those of known antitumor agents such as
Taxol (2, paclitaxel) and Taxotere (3, docetaxel) that incor-
porate 3-phenylisoserines as C-13 side chains.[8b] This fact
makes the synthesis of (2R,3R)-furylisoserine derivatives an
interesting goal to be achieved.
Introduction
The area of peptidomimetics is of interest in the field of
molecular diversity and drug discovery. The rational design
of drugs based on peptides requires improving their sta-
bility against enzymatic hydrolysis by proteases and con-
trolling the flexibility of the peptide chain towards the
active conformation of a given receptor.[1] In this regard,
the use of unnatural amino acids is of special interest for
the generation of different molecular entities able to interact
with biological targets, thus providing useful information
about the corresponding biologically active protein confor-
mation in structure–activity relationship studies. As an ex-
ample, δ-amino acids that have structural analogy with di-
peptides have been constructed to mimic dipeptide se-
quences with added structural constraints.[2] In recent years,
unnatural amino acids incorporating heterocyclic moieties
derived from thiazole, oxazole, imidazole, and furan have
been assembled into peptidomimetics for the purpose of
drug discovery.[3] These heterocyclic amino acids are also of
importance, as they are part of biologically active products,
both natural and synthetic.[4] Recently, they have also been
used in macrocyclic peptides to create conformationally
preorganized scaffolds.[5]
Figure 1. General structures for heterocyclic-based amino acids, α-
furfurylamines, and 3-arylisoserines.
Among heterocyclic amino acids, furyl amino acids are
of particular interest because they can also be considered
as α-furfurylamines,[6] which are versatile intermediates for
the synthesis of azasugar derivatives such as piperidine al-
The synthesis of thiazole-, oxazole-, and imidazole-based
amino acids is usually carried out through aromatization of
the corresponding peptide derivative under different condi-
tions (Scheme 1).[5] However, the syntheses of furyl-based
amino acids are scarce.[9]
As part of our continuing interest in the synthesis and
biological applications of chiral furan amino acids,[3c,10] we
present a new strategy for the synthesis of constrained furyl
amino acids 4 and ent-4 starting from -sugars (Scheme 2).
The key step of the strategy is based on the stereoselective
[a] Department of Organic Chemistry, Faculty of Chemistry, Uni-
versity of Seville
Prof. García González 1, 41012 Seville, Spain
Fax: +34-954-624960
E-mail: ajmoreno@us.es
robina@us.es
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000183.
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Stereoselective Synthesis of α-Furfurylamines from Sugars
Results and Discussion
Stereoselective Synthesis of Furyl Amino Acids from
Sugars
D-
Recently, it has been described that condensation be-
tween hexoses and ethyl acetoacetate catalyzed by CeCl3/
NaI/SiO2 under solvent-free conditions at 50 °C affords tet-
rahydroxybutylfurans in good yields.[13] This method is an
efficient alternative to the classical García–González reac-
tion, where this condensation is catalyzed by ZnCl2 in
EtOH as solvent.[14] We have successfully applied this meth-
odology to the condensation of pentoses, -xylose, and -
arabinose with benzyl acetoacetate for the synthesis of tri-
hydroxypropylfurans 7 and 8 (Scheme 3). These compounds
were obtained in moderate-to-good yields without epi-
merization at C-1 of the polyolic chain. A slight epimeri-
zation was observed when the experiment was carried out
with the use of ZnCl2 as catalyst.
Scheme 1. General strategy for the synthesis of thiazole-, oxazole-,
and imidazole-based amino acids.
introduction of an amino function at the α-position of a
polyhydroxyalkylfuran moiety. These compounds can be
envisaged as rigid isosteres of dipeptides ()-H-Ser-(,)-
Thr-OH and ()-H-Ser-(,)-Thr-OH. These dipeptides are
involved in the highly conserved peptide sequence of several
serine/threonine protein kinases[11] found in many human
malignancies and so have potential for the development of
inhibitors. We also present the synthesis of new N,O-pro-
tected (2R,3R)-3-furylisoserines 5 and 6 by applying a sim-
ilar methodology. These compounds are ready for the cou-
pling to the baccatin skeleton for the preparation of new
heteroaromatic taxoids, according to established methodol-
ogies.[12] New compounds 5 and 6 bear COOEt/CH2O-
TrOMe groups that will allow further derivatization.
Scheme 3. Synthesis of trihydroxypropylfuran intermediates.
Protection of the primary alcohol in compound 7 af-
forded silyl derivative 9. In order to introduce an azide
function at C-1 of the polyolic chain, we carried out the
reaction of 9 with thionyl chloride and triethylamine to ob-
tain the corresponding cyclic sulfite 10 in 92% yield
(Scheme 4). This compound was stable and could be puri-
fied by column chromatography and isolated as a diastereo-
isomeric mixture (1:1, epimers at sulfur). Although nucleo-
philic displacements are commonly performed on key sul-
fate intermediates,[15] the activated pseudo-benzylic position
C-1 in sulfite 10 is thought to be reactive enough for nucleo-
philic ring opening. Treatment of sulfite 10 with NaN3/
DMF at 60 °C gave a mixture of azido derivatives 11, epi-
mers at C-1 (anti/syn = 4), indicating that SN2 and SN1-like
mechanisms participated in the displacement. With the
hope to avoid this epimerization, we decided to use the mix-
ture TMSN3/TBAF in THF as a source of azide anion with
increased nucleophilicity. Thus, reaction under these condi-
tions and at room temperature gave diastereomerically pure
azido derivative 12 in 77% yield with concomitant removal
of the protecting group.
Scheme 2. Structure of the new furyl amino acids and furylisoser-
ines.
The synthesis of diastereoisomeric azido derivative 15
was tried in a similar way but starting from trihydroxyprop-
Some of the results of this work have already been com- ylfuran 8 (Scheme 4). Regioselective protection of 8, fol-
municated in a preliminary form.[10c] We report herein de- lowed by sulfite formation afforded compound 14, which
tails of the extended study.
could be purified by column chromatography; it was iso-
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Scheme 4.
lated as a diastereoisomeric mixture (1:1, sulfur epimers) in
1
51% yield (two steps). H NMR experiments showed that
the initial ratio of sulfite epimers in 14 changed to a 10:1
ratio after 5 d in a CDCl3 solution (Scheme 5). This epi-
merization was not observed in the diastereoisomeric mix-
ture of cyclic sulfites 10 under a similar experiment. This
indicates that the initial epimer ratio (syn/anti = 14a/14b =
1) in sulfites 14 obtained under kinetic control changes as
a result of the sulfur epimerization to give anti isomer 14b,
which is thermodynamically more stable. In the case of cy-
clic sulfites 10, both stereoisomers, 10a and 10b, should
have similar thermodynamic stability, explaining that no ep-
imerization is observed in this case. Reaction of cyclic sul-
fites 14 with TMSN3/TBAF in THF at room temperature
afforded azido derivative 15 after 48 h (57%, Scheme 4).
The displacement–deprotection step for compound 14
proved to be slower than for its isomer 10. Besides, partial
Scheme 5.
1
epimerization was detected (syn/anti = 18, measured by H
Oxidative cleavage of diol 12 followed by reduction of
NMR spectroscopic analysis of the crude mixture), which the resulting aldehyde afforded alcohol 19 in 83% yield.
is presumably due to the participation of an SN1-like Mosher’s ester of alcohol 19 confirmed that no epimeri-
mechanism. Alternatively, treatment of 14 with an excess zation at C-1Ј occurred in the oxidative cleavage–reduction
amount (3 equiv.) of tetrabutylammonium azide in THF af- steps (Scheme 6). Hydrogenation of 19 with the use of Pd/
forded 16 in a shorter reaction and without epimerization C (10%) as catalyst afforded furyl amino acid 4 in good
at C-1Ј. Further treatment of 16 with TBAF/THF afforded yield. Compound 15 was transformed into furyl amino acid
15 in 56% overall yield. To confirm the configuration of C- ent-4 by following the same way. Amino acid 4 and its en-
1Ј in azido derivatives 12 and 15, corresponding precursors antiomer ent-4 were transformed into activated protected
11 and 16 were transformed into their oxazolidine-2-thione amino acid derivatives 21 and ent-21, as suitable building
derivatives 17 and 18, respectively. These rigid structures blocks for their incorporation into peptides following both
showed unequivocal NOEs that confirmed the proposed solid- and solution-phase peptide syntheses. Therefore, 4
structures (Scheme 4).
and ent-4 were N-protected following the procedure of
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Stereoselective Synthesis of α-Furfurylamines from Sugars
Koole.[16] The resulting Fmoc-amino acids were directly 28 was carried out by using Dess–Martin reagent followed
treated with PyBOP/DIPEA [(benzotriazol-1-yloxy)tri- by treatment of the resulting aldehyde with NaClO2 and 2-
pyrrolidinophosphonium hexafluorophosphate/N,N-diiso- methyl-2-butene in a buffered medium to afford 29 and 30
propylethylamine] to afford the corresponding activated in moderate-to-good yields. Compounds 29 and 30 are
Fmoc-amino acids 21 and ent-21 that could be isolated and ready to be coupled to baccatin under standard methods.[12]
purified by column chromatography.
Scheme 6.
The special stability of these benzotriazole-activated es-
ters is due to the aromatic character of the furan-3-carbox-
ylic acid moiety. This particular property makes these com-
pounds attractive building blocks for peptide synthesis, es-
pecially in the solid phase where a high excess of activated
amino acid is used for each coupling and the use of reco-
vered amino acid needs further reactivation in situ.
Scheme 7.
Synthesis of (2R,3R)-3-Furylisoserines
The synthetic pathway for the preparation of new 3-fury-
lisoserine derivatives involves the use of azido derivative 24
Conclusions
as the key intermediate. This compound was prepared in
The synthesis of two new chiral furyl amino acids was
diastereoisomerically pure form[17] following the same carried out by a stereoselective route starting from -aldo-
methodology described for the synthesis of 16 but starting pentoses. These compounds are dipeptide isosteres and use-
from -arabinose and ethyl acetoacetate (Scheme 7).[18] Hy- ful building blocks for the construction of peptidomimetics.
drogenation of compound 24 in the presence of Boc2O af- They were transformed into stable activated Fmoc deriva-
forded 25 in 84% yield. Cyclic N,O-acetalization of 25 with tives ready for peptide synthesis. Additionally, -arabinose
p-anisaldehyde dimethylacetal gave the corresponding 1,3- was effectively transformed into two different N,O-pro-
oxazolidine 27 as a mixture of diastereoisomers[19] in 72% tected 3-furylisoserines, which are useful building blocks for
yield, after standard removal of the silyl protecting group. coupling to baccatin. To the best of our knowledge, this is
Alternatively, reduction of the ethoxycarbonyl group in ox- the first synthesis of 3-heteroarylisoserines that uses a sugar
azolidine 26 with LiAlH4 in THF at 0 °C followed by pro- as starting material. The new compounds incorporate a
tection of the resulting alcohol with p-methoxytrityl chlo- substituent on the furan ring, which can improve the solu-
ride and desilylation under standard conditions gave bility of the targeted final taxoid and adds a new element
alcohol 28 in 53% overall yield as a mixture of diastereoiso- of structural diversity to the previously described 3-furyliso-
mers. Oxidation of the free hydroxymethyl group on 27 and serines.
Eur. J. Org. Chem. 2010, 3110–3119
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[α]2D0 = –4 (c = 2.45, CH Cl ). IR: ν = 3442 (OH), 3070, 2930, 2857,
˜
2
2
Experimental Section
1715 (CO), 1427, 1112, 702 cm–1. 1H NMR (300 MHz, CD3OD,
General Remarks: Optical rotations were measured in a 1.0-cm or
1.0-dm tube with a Perkin–Elmer 241MC spectropolarimeter. 1H
and 13C NMR spectra were obtained for solutions in CDCl3 and
CD3OD. All the assignments were confirmed by 2D NMR experi-
ments. The NMR spectra for all compounds were performed in
CITIUS (Research general service for the University of Seville).
The FAB mass spectra were obtained by using glycerol or 3-ni-
trobenzyl alcohol as the matrix. TLC was performed on silica gel
HF254 (Merck); detection was achieved by UV light and charring
with H2SO4 or with Pancaldi reagent [(NH4)6MoO4, Ce(SO4)2,
H2SO4, H2O]. Silica gel 60 (Merck, 230 mesh) was used for prepar-
ative chromatography.
25 °C): δ = 1.01 [s, 9 H, (CH3)3C], 2.49 (s, 3 H, CH3), 3.54 (dd,
J3Јb,2Ј = 4.9 Hz, 1 H, 3Јb-H), 3.72 (dd, J3Јa,3Јb = 10.5 Hz, J3Јa,2Ј
=
5.3 Hz, 1 H, 3Јa-H), 3.90 (m, 1 H, 2Ј-H), 4.74 (d, J1Ј,2Ј = 5.8 Hz, 1
H, 1Ј-H), 5.24 (d, 1 H, CH2Ph), 5.29 (d, 1 H, CH2Ph), 6.55 (s, 1
H, 4-H), 7.68–7.28 (m, 15 H, Ar-H) ppm. 13C NMR (75.4 MHz,
CD3OD, 25 °C): δ = 165.3 (COOBn), 160.1 (C-2), 154.7 (C-5),
137.8, 136.7, 136.6, 134.5, 134.4, 130.8, 129.6, 129.2, 128.7 (18 C,
C-aromat.), 115.0 (C-3), 109.0 (C-4), 74.8 (C-2Ј), 68.7 (C-1Ј), 67.0
(CH2Ph), 66.0 (C-3Ј), 27.3 [(CH3)3C], 20.0 [(CH3)3C], 13.9 (CH3)
ppm. MS (FAB): m/z = 567.2186 [M + Na]+.
Benzyl
5-(3-O-tert-Butyldiphenylsilyl-1,2-di-O-sulfinyl-D-threo-
1,2,3-trihydroxyprop-1-yl)-2-methylfuran-3-carboxylate (10): To a
solution of 9 (4.66 g, 8.5 mmol) and triethylamine (5.24 mL,
37.4 mmol) in dry CH2Cl2 (15 mL) cooled to 0 °C was dropwise
added a solution of thionyl chloride (1.56 mL, 21.3 mmol) in dry
CH2Cl2 (2 mL). The mixture was stirred at 0 °C for 30 min, then
diluted with cooled ether (400 mL) and washed with water and
brine. The organic phase was dried (Na2SO4), filtered, and concen-
trated. The resulting residue was purified by column chromatog-
raphy (diethyl ether/petroleum ether, 1:3) to give 10 (4.61 g, 92%,
Benzyl 2-Methyl-5-(D-threo-1,2,3-trihydroxyprop-1-yl)furan-3-car-
boxylate (7): Silica gel (2 g) was added to a mixture of CeCl3·7H2O
(0.452 g, 1.2 mmol) and NaI (56 mg, 1.2 mmol) in acetonitrile
(28 mL), and the mixture was stirred overnight. Then, -xylose
(720 mg, 4 mmol) was added to the mixture, and the suspension
was stirred for 1 h. The solvent was evaporated, benzyl acetoacetate
(0.9 mL, 5.2 mmol) was added to the mixture, and the free solvent
mixture was stirred for 24 h at 50 °C. After this period, MeOH was
added to the mixture, the resulting suspension was filtered through
Celite, and the solid residue was washed several times with MeOH.
The filtered solution was evaporated to dryness, and the resulting
crude was purified by column chromatography (CH2Cl2/MeOH,
12:1) to afford 7 (0.62 g, 50%) as a colorless oil. [α]2D2 = –11 (c =
1:1 mixture of diastereoisomers) as a yellow oil. IR: ν = 2931, 2858,
˜
1
1719 (CO), 1428, 1218 (SO), 1113, 700 cm–1. H NMR (300 MHz,
CDCl3, 25 °C, mixture of diastereoisomers a and b): δ = 1.04, 1.02
[2 s, 9 H each, (CH3)3C (a, b)], 2.60 [s, 6 H, CH3 (a, b)], 3.87 [dd,
1 H, 3Јb-H (b)], 3.93 [dd, J3Јb,2Ј = 4.3 Hz, 1 H, 3Јb-H (a)], 4.02 [dd,
J3Јa,3Јb = 11.9 Hz, 1 H, 3Јa-H (b)], 4.03 [dd, J3Јa,3Јb = 11.3 Hz, J3Јa,2Ј
= 5.5 Hz, 1 H, 3Јa-H (a)], 4.67 [m, 1 H, 2Ј-H (a)], 5.17 [dt, J2Ј,3Јa
= J2Ј,3Јb = 3.5 Hz, 1 H, 2Ј-H (b)], 5.28 [d, 1 H, CH2Ph (a or b)],
5.29 [s, 2 H, CH2Ph (a or b)], 5.32 [d, 2JH,H = 12.6 Hz, 1 H, CH2Ph
0.85, MeOH). IR: ν = 3430 (OH), 1697 (CO), 1429, 1227, 1090,
˜
1
777 cm–1. H NMR (300 MHz, CD3OD, 25 °C): δ = 2.53 (s, 3 H,
CH3), 3.46 (dd, J3Јb,2Ј = 6.2 Hz, 1 H, 3Јb-H), 3.59 (dd, J3Јa,3Јb
=
11.3 Hz, J3Јa,2Ј = 4.8 Hz, 1 H, 3Јa-H), 3.84 (m, 1 H, 2Ј-H), 4.60 (d,
J1Ј,2Ј = 5.3 Hz, 1 H, 1Ј-H), 5.26 (s, 2 H, CH2Ph), 6.59 (s, 1 H, 4-
H), 7.40–7.31 (m, 5 H, Ar-H) ppm. 13C NMR (7.4 MHz, CD3OD,
25 °C): δ = 165.3 (COOBn), 160.2 (C-2), 154.7 (C-5), 137.7, 129.6,
129.2, 129.1 (6 C, C-aromat.), 114.9 (C-3), 108.9 (C-4), 74.7 (C-2Ј),
68.6 (C-1Ј), 67.0 (CH2Ph), 63.9 (C-3Ј), 13.8 (CH3) ppm. MS (CI):
m/z (%) = 306.1116 [M]+, 288 (10) [M – H2O]+.
(a or b)], 5.47 [d, J1Ј,2Ј = 8.7 Hz, 1 H, 1Ј-H (b)], 5.88 [d, J1Ј,2Ј
=
8.7 Hz, 1 H, 1Ј-H (a)], 6.79, 6.78 [2 s, 1 H each, 4-H (a, b)], 7.63–
7.32 [m, 30 H, Ar-H (a, b)] ppm. 13C NMR (75.4 MHz, CDCl3,
25 °C): δ = 163.2, 163.1 [COOBn (a, b)], 161.6, 161.5 [C-2 (a, b)],
145.3, 144.2 [C-5 (a, b)], 136.1, 135.7, 135.6, 132.7, 132.6, 132.5,
132.4, 130.2, 130.1, 128.8, 128.5, 128.4, 128.1, 128.0 [18 C, C-aro-
mat. (a, b)], 114.8 [2 C, C-3 (a, b)], 113.3, 112.9 [C-4 (a, b)], 84.0
[C-2Ј (a)], 80.9 [C-2Ј (b)], 78.1 [C-1Ј (a)], 75.9 [C-1Ј (b)], 66.4, 66.3
[CH2Ph (a, b)], 62.8 [C-3Ј (a)], 61.2 [C-3Ј (b)], 26.8, 26.7 [(CH3)3C
(a, b)], 19.4, 19.3 [(CH3)3C (a, b)], 14.2, 14.1 [CH3 (a, b)] ppm. MS
(FAB): m/z = 549.2054 [M – SO2 + Na]+.
Benzyl
2-Methyl-5-(D-erythro-1,2,3-trihydroxyprop-1-yl)furan-3-
carboxylate (8): This compound was prepared in a manner similar
to that described for 7 except that -arabinose was used as the
starting material. Yield: 55%, colorless oil. [α]2D2 = +5 (c = 1.0,
MeOH). IR: ν = 3421 (OH), 1713 (CO), 1427, 1227, 1085,
˜
1
698 cm–1. H NMR (300 MHz, CD3OD, 25 °C): δ = 2.55 (s, 3 H,
Benzyl 5-(1-Azido-1-deoxy-D-erythro-1,2,3-trihydroxyprop-1-yl)-2-
CH3), 3.64 (dd, J3Јb,2Ј = 6.1 Hz, 1 H, 3Јb-H), 3.74 (dd, J3Јa,3Јb
=
methylfuran-3-carboxylate (12): To
a
solution of 10 (4.61 g,
11.4 Hz, J3Јa,2Ј = 3.6 Hz, 1 H, 3Јa-H), 3.85 (m, 1 H, 2Ј-H), 4.53 (d,
J1Ј,2Ј = 7.3 Hz, 1 H, 1Ј-H), 5.26 (s, 2 H, CH2Ph), 6.58 (s, 1 H, 4-
H), 7.40–7.31 (m, 5 H, Ar-H) ppm. 13C NMR (7.4 MHz, CD3OD,
25 °C): δ = 165.4 (COOBn), 160.2 (C-2), 154.9 (C-5), 137.8, 129.6,
129.5, 129.3, 129.2, 129.2 (6 C, C-aromat.), 114.8 (C-3), 109.2 (C-
4), 74.5 (C-2Ј), 69.1 (C-1Ј), 67.0 (CH2Ph), 64.4 (C-3Ј), 13.9 (CH3)
ppm. MS (CI): m/z (%) = 306.1093 [M]+, 307 (7) [M + H]+, 289
(49) [M – OH]+.
7.8 mmol) in THF (15 mL) was added TMSN3 (3.24 mL,
23.4 mmol) and TBAF (1  in THF, 1.6 mL), and the mixture was
stirred 24 h at room temperature. Then, the solution was concen-
trated, and the resulting residue was purified by chromatography
column (diethyl ether/petroleum ether, 5:1) to give 12 (1.98 g, 77%)
as a colorless oil. [α]2D0 = +99 (c = 0.87, CH Cl ). IR: ν = 3449
˜
2
2
(OH), 2924, 2104 (N3), 1715 (CO), 1225 (N3) cm–1. 1H NMR
(300 MHz, CDCl3, 25 °C): δ = 2.60 (s, 3 H, CH3); 3.72 (dd, J3Јb,2Ј
= 5.2 Hz, 1 H, 3Јb-H), 3.76 (dd, J3Јa,3Јb = 11.5 Hz, J3Јa,2Ј = 3.4 Hz,
1 H, 3Јa-H), 4.02 (m, 1 H, 2Ј-H), 4.56 (d, J1Ј,2Ј = 7.3 Hz, 1 H, 1Ј-
H), 5.29 (s, 2 H, CH2Ph), 6.75 (s, 1 H, 4-H), 7.40–7.28 (m, 5 H,
Ar-H) ppm. 13C NMR (75.4 MHz, CDCl3, 25 °C): δ = 163.5 (CO-
OBn), 160.4 (C-2), 147.5 (C-5), 135.9, 128.6, 128.3, 128.2 (6 C, C-
aromat.), 114.2 (C-3), 110.9 (C-4), 71.9 (C-2Ј), 66.2 (CH2Ph), 62.9
(C-3Ј), 59.9 (C-1Ј), 14.3 (CH3) ppm. MS (CI): m/z = 332.1236 [M
+ H]+.
Benzyl 5-(3-O-tert-Butyldiphenylsilyl-D-threo-1,2,3-trihydroxyprop-
1-yl)-2-methylfuran-3-carboxylate (9): To a solution of 7 (4.75 g,
15.5 mmol) in dry DMF (15 mL) at 0 °C was added tert-butyldi-
phenylchlorosilane (TBDPSCl, 4.1 mL, 34.1 mmol) and imidazole
(2.12 g, 31 mmol). The reaction mixture was stirred at 0 °C for 2 h,
then water (0.1 mL) was added, and the mixture was stirred for
30 min. The solution was concentrated in vacuo, and the residue
was dissolved in CH2Cl2 (100 mL) and washed with NH4Cl, water,
and brine. The organic layer was concentrated, and the resulting
residue was purified by column chromatography (diethyl ether/pe-
troleum ether, 1:3Ǟ2:1) to give 9 (5.18 g, 60%) as a colorless oil.
Benzyl
5-(3-O-tert-Butyldiphenylsilyl-D-erythro-1,2,3-trihydroxy-
prop-1-yl)-2-methylfuran-3-carboxylate (13): This compound was
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 3110–3119

Stereoselective Synthesis of α-Furfurylamines from Sugars
prepared in a manner similar to that described for 9 except that
H) ppm. 13C NMR (75.4 MHz, CDCl3, 25 °C): δ = 163.5 (CO-
OBn), 160.2 (C-2), 147.9 (C-5), 136.2, 135.7, 135.6, 132.8, 132.7,
130.1, 128.8, 128.4, 128.0, 128.0 (12 C, C-aromat.), 114.2 (C-3),
110.4 (C-4), 72.9 (C-2Ј), 66.2 (CH2Ph), 64.4 (C-3Ј), 60.3 (C-1Ј),
27.0 [(CH3)3C], 19.4 [(CH3)3C], 14.0 (CH3) ppm. MS (FAB): m/z
compound
C32H36O6Si (544.22): calcd. C 70.56, H 6.66; found C 70.37, H
6.74. [α]2D0 = +1 (c = 0.71, CH Cl ). IR: ν = 3464 (OH), 3070, 2931,
8 was initially used. Yield: 59%, colorless oil.
˜
2
2
2858, 1715 (CO), 1427, 1113, 701 cm–1. 1H NMR (300 MHz,
CD3OD, 25 °C): δ = 1.04 [s, 9 H, (CH3)3C], 2.51 (s, 3 H, CH3), (%) = 570.2441 [M + H]+, 527 (5) [M – N3]+.
3.76 (dd, 1 H, 3Јb-H), 3.80 (dd, J3Јa,3Јb = 10.5 Hz, 1 H, 3Јa-H), 3.99
Benzyl 5-[(4R,5S)-5-(tert-Butyldiphenylsilyloxy)methyl-2-thioxazol-
(dt, J2Ј,3Јa = J2Ј,3Јb = 5.3 Hz, 1 H, 2Ј-H), 4.73 (d, J1Ј,2Ј = 5.9 Hz, 1
H, 1Ј-H), 5.26 (s, 2 H, CH2Ph), 6.56 (s, 1 H, 4-H), 7.65–7.31 (m, 15
H, Ar-H) ppm. 13C NMR (75.4 MHz, CD3OD, 25 °C): δ = 165.4
(COOBn), 160.1 (C-2), 154.7 (C-5), 137.8, 136.7, 136.7, 134.6,
130.8, 129.6, 129.2, 128.8, 128.7 (18 C, C-aromat.), 114.9 (C-3),
109.2 (C-4), 74.9 (C-2Ј), 69.2 (C-1Ј), 66.9 (CH2Ph), 66.2 (C-3Ј),
27.3 [(CH3)3C], 20.0 [(CH3)3C], 13.9 (CH3) ppm. MS (FAB): m/z
= 567.2183 [M + Na]+.
idin-4-yl]-2-methylfuran-3-carboxylate (17): To a solution of 11
(157 mg, 0.47 mmol) in dry DMF (5 mL) at 0 °C was added tert-
butyldiphenylchlorosilane (282 µL, 1.04 mmol) and imidazole
(71 mg, 1.04 mmol). The reaction mixture was stirred at 0 °C for
1.5 h, water (0.1 mL) was then added, and the mixture was stirred
for 30 min. The solution was concentrated in vacuo, and the residue
was dissolved in CH2Cl2 (100 mL) and washed with NH4Cl, water,
and brine. The organic layer was concentrated, and the resulting
residue was purified by column chromatography (diethyl ether/pe-
troleum ether, 1:4Ǟ1:1) to give the corresponding silyl derivative
(218 mg, 85%) as a colorless oil that was not characterized. Silyl
derivative (170 mg, 0.298 mmol) was dissolved in dry THF
(3.5 mL) and Ph3P (96 mg, 0.366 mmol) was added. The mixture
was stirred for 12 h at room temperature. Then, water (0.3 mL) was
added, and the mixture was stirred for 1 h at room temperature.
The mixture was concentrated and coevaporated with toluene. The
resulting crude was dissolved in CH2Cl2 (2 mL), and a solution of
Benzyl
5-(3-O-tert-Butyldiphenylsilyl-1,2-di-O-sulfinyl-D-erythro-
1,2,3-trihydroxyprop-1-yl)-2-methylfuran-3-carboxylate (14): This
compound was prepared in a manner similar to that described for
12 except that compound 13 was initially used. Yield: 86% (1:1
mixture of diastereoisomers that isomerize after 5 d to a major iso-
mer), colorless oil. IR: ν = 2932, 2858, 1718 (CO), 1428, 1218 (SO),
˜
1
1113, 701 cm–1. H NMR (300 MHz, CDCl3, 25 °C, major stereo-
isomer): δ = 0.99 [s, 9 H, (CH3)3C], 2.47 (s, 3 H, CH3), 3.61 (dd,
J3Јb,2Ј = 6.5 Hz, 1 H, 3Јb-H), 3.76 (dd, J3Јa,3Јb = 11.0 Hz, J3Јa,2Ј
=
5.4 Hz, 1 H, 3Јa-H), 5.18 (m, 1 H, 2Ј-H), 5.26 (d, 1 H, CHHPh), 1,1Ј-thiocarbonyldiimidazole (53 mg, 0.298 mmol) in CH2Cl2
2
5.28 (d, JH,H = 12.3 Hz, 1 H, CHHPh), 5.85 (d, J1Ј,2Ј = 6.2 Hz, 1
H, 1Ј-H-), 6.71 (s, 1 H, 4-H), 7.46–7.28 (m, 15 H, Ar-H) ppm. 13C stirred at room temperature for 24 h. Then, the solution was diluted
NMR (75.4 MHz, CDCl3, 25 °C, major stereoisomer): δ = 163.2 with CH2Cl2 and washed with brine. The organic phase was dried
(2 mL) was added under an atmosphere of argon. The mixture was
(COOBn), 160.9 (C-2), 144.7 (C-5), 136.0, 135.6, 135.6, 135.5, (Na2SO4), filtered, and concentrated to dryness. The resulting
132.5, 132.4, 130.2, 130.1, 128.8, 128.5, 128.4, 128.0, 127.9 (18 C, crude was purified by column chromatography (diethyl ether/petro-
C-aromat.), 114.4 (C-3), 112.4 (C-4), 80.5 (C-2Ј), 78.3 (C-1Ј), 66.3 leum ether, 1:2) to give 17 (150 mg, 84%) as a white foam. [α]2D0
=
(CH2Ph), 61.5 (C-3Ј), 26.7 [(CH3)3C], 19.2 [(CH3)3C], 14.0 (CH3) +37 (c = 0.85, CH Cl ). IR: ν = 3304 (NH), 1716 (CO), 1496, 1112
˜
2
2
ppm. MS (FAB): m/z = 549.2073 [M – SO2 + Na]+.
(CS), 702 cm–1. H NMR (300 MHz, CDCl3, 25 °C): δ = 0.97 [s, 9
H, (CH3)3C], 2.44 (s, 3 H, CH3), 3.62 (dd, J1ЈЈb,5Ј = 6.8 Hz, 1 H,
1ЈЈb-H), 3.80 (dd, J1ЈЈa,1ЈЈb = 11.2 Hz, J1ЈЈa,5Ј = 4.8 Hz, 1 H, 1ЈЈa-
H), 5.07 (m, 1 H, 5Ј-H), 5.13 (d, J4Ј,5Ј = 8.6 Hz, 1 H, 4Ј-H-), 5.28
(s, 2 H, CH2Ph), 6.64 (s, 1 H, 4-H), 7.55–7.30 (m, 15 H, Ar-H)
ppm. 13C NMR (75.4 MHz, CDCl3, 25 °C): δ = 189.7 (C-2Ј), 163.2
(COOBn), 161.0 (C-2), 146.0 (C-5), 136.0, 135.6, 132.5, 132.4,
130.2, 130.1, 128.8, 128.5, 128.4, 128.0, 127.9 (18 C, C-aromat.),
114.5 (C-3), 111.1 (C-4), 84.5 (C-5Ј), 66.4 (CH2Ph), 61.3 (C-1ЈЈ),
55.9 (C-4Ј), 26.8 [(CH3)3C], 19.2 [(CH3)3C], 14.0 (CH3) ppm. MS
(FAB): m/z = 608.1928 [M + Na]+.
1
Benzyl 5-(1-Azido-1-deoxy- -threo-1,2,3-trihydroxyprop-1-yl)-2-
D
methylfuran-3-carboxylate (15): This compound was prepared in a
manner similar to that described for 12 except that compound 14
was initially used. Yield: 79% (S/R = 18), colorless oil. [α]2D4 = –95
(c = 0.56, CH Cl ). IR: ν = 3418 (OH), 2104 (N ), 1714 (CO), 1227
˜
2
2
3
1
(N3) cm–1. H NMR (300 MHz, CDCl3, 25 °C): δ = 1.97 (br. s, 1
H, OH), 2.59 (s, 3 H, CH3), 2.67 (br. s, 1 H, OH), 3.49 (dd, J3Јb,2Ј
= 5.4 Hz, 1 H, 3Јb-H), 3.67 (dd, J3Јa,3Јb = 11.6 Hz, J3Јa,2Ј = 3.6 Hz,
1 H, 3Јa-H), 4.02 (m, 1 H, 2Ј-H), 4.57 (d, J1Ј,2Ј = 7.5 Hz, 1 H, 1Ј-
H), 5.28 (s, 2 H, CH2Ph), 6.73 (s, 1 H, 4-H), 7.43–7.34 (m, 5 H,
Ar-H) ppm. 13C NMR (75.4 MHz, CDCl3, 25 °C): δ = 163.4 (CO-
OBn), 160.6 (C-2), 147.2 (C-5), 136.0, 128.8, 128.5, 128.4 (6 C, C-
aromat.), 114.3 (C-3), 110.9 (C-4), 72.5 (C-2Ј), 66.3 (CH2Ph), 63.1
(C-3Ј), 60.8 (C-1Ј), 14.1 (CH3) ppm. MS (FAB): m/z = 354.1083
[M + Na]+.
Benzyl 5-[(4S,5S)-5-(tert-Butyldiphenylsilyloxy)methyl-2-thioxazol-
idin-4-yl]-2-methylfuran-3-carboxylate (18): This compound was
prepared in a manner similar to that described for 17 except that
compound 16 was initially used. Yield: 86%, colorless oil. IR: ν
˜
= 3408 (NH), 1638 (CO), 1497, 1113 (CS), 701 cm–1. 1H NMR
(300 MHz, CDCl3, 25 °C): δ = 2.56 (s, 3 H, CH3), 1.07 [s, 9 H,
(CH3)3C], 3.82 (dd, J1ЈЈb,5Ј = 3.9 Hz, 1 H, 1ЈЈb-H), 3.99 (dd, J1ЈЈa,1ЈЈb
= 11.7 Hz, J1ЈЈa,5Ј = 4.2 Hz, 1 H, 1ЈЈa-H), 4.86 (m, 1 H, 5Ј-H), 5.04
(d, J4Ј,5Ј = 6.3 Hz, 1 H, 4Ј-H), 5.27 (s, 2 H, CH2Ph), 6.57 (s, 1 H, 4-
H), 7.73–7.36 (m, 15 H, Ar-H) ppm. 13C NMR (75.4 MHz, CDCl3,
25 °C): δ = 189.3 (C-2Ј), 163.2 (COOBn), 161.0 (C-2), 147.6 (C-5),
136.0, 135.8, 135.7, 135.0, 132.8, 132.3, 130.3, 129.8, 128.8, 128.5,
128.3,128.1, 127.9 (18 C, C-aromat.), 114.5 (C-3), 110.0 (C-4), 86.6
(C-5Ј), 66.4 (CH2Ph), 62.9 (C-1ЈЈ), 55.0 (C-4Ј), 26.8 [(CH3)3C], 19.4
[(CH3)3C], 14.0 (CH3) ppm. MS (FAB): m/z = 608.1885 [M +
Na]+.
Benzyl
5-(1-Azido-3-O-tert-butyldiphenylsilyl-1-deoxy-D-threo-
1,2,3-trihydroxyprop-1-yl)-2-methylfuran-3-carboxylate (16): To a
solution of compound 14 (173 mg, 0.29 mmol) in THF (3 mL) was
added Bu4NN3 (247 mg, 0.87 mmol). The mixture was stirred at
room temperature overnight. The solvent was evaporated, and the
resulting residue was purified by column chromatography (diethyl
ether/petroleum ether, 1:5) to give 16 (130 mg, 79%) as a colorless
oil. [α]2D4 = –49 (c = 0.56, CH Cl ). IR: ν = 3440 (OH), 2929, 2103
˜
2
2
(N3), 1717 (CO), 1613, 1427, 1227 (N3), 1113, 1076, 823, 741,
701 cm–1. 1H NMR (300 MHz, CDCl3, 25 °C): δ = 1.06 [s, 9 H,
(CH3)3C], 2.54 (s, 3 H, CH3), 2.56 (s, 1 H, OH), 3.58 (dd, J3Јb,2Ј
=
5.2 Hz, 1 H, 3Јb-H), 3.68 (dd, J3Јa,3Јb = 10.6 Hz, J3Јa,2Ј = 4.7 Hz, 1
Benzyl 5-[(R)-1-Azido-2-hydroxyethyl]-2-methylfuran-3-carboxylate
H, 3Јa-H), 4.04 (m, 1 H, 2Ј-H), 4.59 (d, J1Ј,2Ј = 6.5 Hz, 1 H, 1Ј-H), (19): To a solution of 12 (113 mg, 0.342 mmol) in MeOH (5 mL)
5.29 (s, 2 H, CH2Ph), 6.65 (s, 1 H, 4-H), 7.64–7.31 (m, 10 H, Ar- cooled to 0 °C was dropwise added a solution of NaIO4 (146 mg,
Eur. J. Org. Chem. 2010, 3110–3119
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3115

I. Robina et al.
FULL PAPER
0.68 mmol) in H2O (1 mL), and the mixture was stirred for 1 h.
chloride (46 mg, 0.18 mmol) was added; the mixture was then
Then, the solution was filtered, and NaBH4 (27 mg, 0.68 mmol) stirred for 1.5 h at room temperature. Water (0.1 mL) was added,
was added to the filtrate. After 15 min, the solution was neutralize
with citric acid (pH 7) and concentrated in vacuo. The crude was
dissolved in CH2Cl2 (60 mL) and washed with water (30 mL). The
organic layer was dried (Na2SO4), filtered, and concentrated in
vacuo. The resulting residue was purified by chromatography col-
umn (diethyl ether/petroleum ether, 1:3) to give 19 (84 mg, 83%) as
and the reaction mixture was stirred for 1 h and then evaporated
to give the N-protected amino acid that was used in the next step
without any purification. The crude N-protected amino acid was
dissolved in DMF and DIEA (53 µL, 0.3 mmol) and PyBOP
(88 mg, 0.168 mmol) were then added. The mixture was stirred for
1 h at room temperature, and then the solution was evaporated in
vacuo. The resulting residue was purified by column chromatog-
raphy (AcOEt/petroleum ether, 1:1) to give 21 (57 mg, 78%) as a
a colorless oil. [α]2D0 = +101 (c = 1.96, CH Cl ). IR: ν = 3414 (OH),
˜
2
2
2921, 2104 (N3), 1715 (CO), 1408, 1227 (N3), 1076 cm–1. 1H NMR
(300 MHz, CDCl3, 25 °C): δ = 1.94 (t, JOH,2Ј = 6.5 Hz, 1 H, OH),
white solid. [α]2D0 = +38 (c = 0.84, CH Cl ). IR: ν = 3320 (OH),
˜
2
2
2.59 (s, 3 H, CH3), 3.91–3.87 (m, 2 H, 2Ј-H), 4.58 (t, J1Ј,2Ј = 6.3 Hz, 3065, 2950, 1793 (CO), 1711 (CO), 1266, 960, 740 cm–1. H NMR
1 H, 1Ј-H), 5.28 (s, 2 H, CH2Ph), 6.68 (s, 1 H, 4-H), 7.41–7.36 (m, (300 MHz, CDCl3, 25 °C): δ = 2.60 (s, 3 H, CH3), 4.04–3.91 (m, 2
5 H, Ar-H) ppm. 13C NMR (7.4 MHz, CDCl3, 25 °C): δ = 163.5 H, 2Ј-H), 4.22 (t, 1 H, CH of Fmoc), 4.49 (d, J = 6.5 Hz, 2 H, CH2
(COOBn), 160.3 (C-2), 147.7 (C-5), 136.1, 128.8, 128.4, 128.3 (6 C, of Fmoc), 4.94 (br. s, 1 H, 1Ј-H), 5.75 (d, JNH,1Ј = 7.5 Hz, 1 H,
C-aromat.), 114.3 (C-3), 110.0 (C-4), 66.3 (CH2Ph), 63.5 (C-2Ј), NH), 8.08–7.27 (m, 12 H, Ar-H), 6.76 (s, 1 H, 4-H) ppm. 13C NMR
1
60.4 (C-1Ј), 14.0 (CH3) ppm. MS (CI): m/z (%) = 301.1063 [M]+,
259 (51) [M – N3]+.
(75.4 MHz, CDCl3, 25 °C): δ = 163.6 (COOBt), 159.6 (C-2), 156.3
(CO of Fmoc), 152.4 (C-5), 143.8, 143.6, 141.5, 129.0, 127.9, 127.2,
125.1, 120.6, 120.2, 107.4 (18 C, C-aromat.), 109.0 (C-3), 108.5 (C-
4), 67.2 (CH2 of Fmoc), 63.4 (C-2Ј), 51.0 (C-1Ј), 47.4 (CH of
Fmoc), 14.3 (CH3) ppm. MS (FAB): m/z = 547.1581 [M + Na]+.
Benzyl 5-[(R)-1-Azido-2-hydroxyethyl]-2-methylfuran-3-carboxylate
(ent-19): This compound was prepared in a manner similar to that
described for 19 except that compound 15 was initially used. Yield:
80%, colorless oil. [α]2D7 = –108 (c = 0.93, CH2Cl2).
Benzotriazol-1-yl 5-[(R)-1-(9-Fluorenylmethoxycarbonyl)amino-2-
hydroxyethyl]-2-methylfuran-3-carboxylate (ent-21): This com-
pound was prepared in a manner similar to that described for 21
except that compound ent-4 was initially used. Yield: 60%, color-
less oil. [α]2D5 = –35 (c = 0.79, CH2Cl2).
Benzyl
5-{(R)-1-Azido-2-[(S)-3,3,3-trifluoro-2-methoxy-2-phenyl-
propanoyloxy]ethyl}-2-methylfuran-3-carboxylate (20): To a solu-
tion of 19 (20 mg, 0.066 mmol) in dry pyridine (1.5 mL) cooled to
0 °C was added Mosher’s acid chloride (12.3 µL, 0.066 mmol). The
reaction was stirred at room temperature for 4 h, and then the sol-
vent was evaporated to give pure 20 (34 mg, quant.). [α]2D0 = +25 (c
Ethyl 2-Methyl-5-(L-erythro-1,2,3-trihydroxyprop-1-yl)furan-3-carb-
oxylate (22): Compound 22 was obtained according to the general
procedure described for 7 and 8 except that -arabinose (2 g,
13.3 mmol) was used as the starting sugar. Purification by flash
chromatography on silica gel (CH2Cl2/MeOH, 15:1Ǟ5:1) afforded
22 (2.4 g, 74%) as a white solid. [α]2D1 = –13 (c = 0.97, CH2Cl2). 1H
NMR (300 MHz, CD3OD, 25 °C): δ = 6.56 (s, 1 H, 4-H), 4.53 (d,
J = 7.3 Hz, 1 H, 3Ј-H), 4.27 (q, J = 7.1 Hz, 2 H, CH2CH3), 3.86
(ddd, 1 H, 2Ј-H), 3.75 (dd, J = 11.4 Hz, J = 3.7 Hz, 1 H, 1Јa-H),
3.65 (dd, J = 6.1 Hz, 1 H, 1Јb-H), 2.55 (s, 3 H, CH3), 1.33 (t, 3 H,
CH2CH3) ppm. 13C NMR (75.4 MHz, CD3OD, 25 °C): δ = 165.7
(COOEt), 159.9, 154.8 (C-2, C-5), 115.1 (C-3), 109.2 (C-4), 74.6
(C-2Ј), 69.2 (C-3Ј), 64.4 (C-1Ј), 61.3 (CH2CH3), 14.7 (CH2CH3),
13.9 (CH3) ppm. MS (CI): m/z = 245.1013 [M + H]+.
= 2.62, CH Cl ). IR: ν = 2953, 2107 (N ), 1756 (CO), 1717 (CO),
˜
2
2
3
1227 (N3), 1171, 721, 698 cm–1. 1H NMR (300 MHz, CDCl3,
25 °C): δ = 2.59 (s, 3 H, CH3), 3.53 (q, JCH,F = 1.2 Hz, 3 H, OCH3),
4.53 (dd, 1 H, 2Јb-H), 4.57 (dd, J2Јa,2Јb = 11.4 Hz, 1 H, 2Јa-H), 4.73
(t, J1Ј,2aЈ = J1Ј,2Јb = 6.5 Hz, 1 H, 1Ј-H), 5.28 (s, 2 H, CH2Ph), 6.65
(s, 1 H, 4-H), 7.42–7.33 (m, 10 H, Ar-H) ppm. 13C NMR
(75.4 MHz, CDCl3, 25 °C): δ = 166.4 (CO), 163.3 (COOBn), 160.7
1
(C-2), 146.1 (C-5), 136.1–127.3 (12 C, C-aromat.), 123.1 (q, JC,F
2
= 288 Hz, CF3), 114.4 (C-3), 110.7 (C-4), 84.7 [q, JC,F = 28.2 Hz,
C(OCH3)(CF3)Ph], 66.3 (CH2Ph), 65.2 (C-2Ј), 56.7 (C-1Ј), 55.7
(OCH3), 14.0 (CH3) ppm. MS (CI): m/z (%) = 517.1445 [M]+, 475
(6) [M – N3]+.
5-[(R)-1-Amino-2-hydroxyethyl]-2-methylfuran-3-carboxylic
Acid
Ethyl 5-(1-Azido-3-O-tert-butyldiphenylsilyl-1-deoxy-L-threo-1,2,3-
(4): A solution of 19 (65 mg, 0.216 mmol) in MeOH (3 mL) was
hydrogenated under atmospheric pressure for 3 h by using Pd/C
(10%) as catalyst. Then, the solution was filtered through Celite,
and the catalyst was washed with MeOH. The filtered solution was
concentrated in vacuo to give pure 4 (30 mg, 74%) as a colorless
syrup. 1H NMR (300 MHz, CD3OD, 25 °C): δ = 2.52 (s, 3 H, CH3),
3.82 (dd, 1 H, 2Јb-H), 3.90 (dd, J2Јa,2Јb = 11.5 Hz, 1 H, 2Јa-H), 4.27
(dd, J1Ј,2Јa = 8.0 Hz, J1Ј,2Јb = 4.7 Hz, 1 H, 1Ј-H), 6.61 (s, 1 H, 4-H)
ppm. 13C NMR (75.4 MHz, D2O, 25 °C): δ = 161.5 (COOH), 158.3
(C-2), 144.4 (C-5), 119.7 (C-3), 111.9 (C-4), 60.7 (C-2Ј), 50.4 (C-
1Ј), 13.3 (CH3) ppm.
trihydroxyprop-1-yl)-2-methylfuran-3-carboxylate (24): To a solu-
tion of compound 22 (1.12 g, 4.6 mmol) in dry DMF (8 mL) cooled
to 0 °C was added imidazole (377 mg, 5.52 mmol) and TBDPSCl
(0.66 mL, 5.52 mmol), and the mixture was stirred at 0 °C for 2 h.
Then, water was added (0.5 mL), and the mixture was stirred for
15 min. The mixture was evaporated to dryness, and the resulting
crude was diluted with CH2Cl2 and washed with a saturated aque-
ous solution of NH4Cl, water, and brine. The organic layer was
dried with Na2SO4 and filtered, and the solvent was evaporated to
give 23, which was employed in the following step without purifica-
tion. To a cooled solution of crude 23 (≈4.6 mmol) in dry CH2Cl2
(10 mL) was added Et3N (2.6 mL, 18.4 mmol) and a solution of
SOCl2 (0.68 mL, 9.2 mmol) in CH2Cl2 (10 mL). After 30 min at
0 °C, cold Et2O was added, and the mixture was washed with water
and brine. The organic phase was then dried (Na2SO4), filtered,
and concentrated. The mixture of epimeric cyclic sulfites
(≈4.6 mmol) thus obtained was dissolved in THF (25 mL) and
Bu4NN3 (3.92 g, 13.8 mmol) was added. After 24 h at room tem-
perature, the solvent was evaporated, and the residue was purified
by flash chromatography on silica gel (Et2O/petroleum ether,
1:4Ǟ1:2) to afford 24 (1.05 g, 45%) as a colorless oil. [α]2D4 = +57
5-[(S)-1-Amino-2-hydroxyethyl]-2-methylfuran-3-carboxylic
Acid
(ent-4): This compound was prepared in a manner similar to that
described for 4 except that compound ent-19 was initially used.
Yield: 71%, colorless oil.
Benzotriazol-1-yl 5-[(R)-1-(9-Fluorenylmethoxycarbonyl)amino-2-
hydroxyethyl]-2-methylfuran-3-carboxylate (21): To a stirred mix-
ture of 4 (26 mg, 0.138 mmol) in dry pyridine (2 mL) at 0 °C was
added trimethylsilyl chloride (54 µL, 0.414 mmol), and the reaction
mixture was stirred for 45 min at room temperature. Then, the reac-
tion mixture was cooled to 0 °C and 9-fluorenylmethoxycarbonyl
3116
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Eur. J. Org. Chem. 2010, 3110–3119

Stereoselective Synthesis of α-Furfurylamines from Sugars
(c = 0.86, CH2Cl2). 1H NMR (300 MHz, CDCl3, 25 °C): δ = 7.65–
7.36 (m, 10 H, Ar-H), 6.64 (s, 1 H, 4-H), 4.59 (d, J = 6.3 Hz, 1 H,
3Ј-H), 4.29 (q, J = 7.1 Hz, 2 H, CH2CH3), 4.09–4.01 (m, 1 H, 2Ј-
[s, 9 H, (CH3)3C (a)] ppm. 13C NMR (75.4 MHz, CDCl3, 25 °C,
mixture of diastereoisomers a and b): δ = 164.1 (COOEt), 160.5,
160.0, 159.1, 153.9, 151.9, 149.9 [6 C, CO of Boc (a, b), C-2Ј (a,
H), 3.68 (dd, J = 10.5 Hz, J = 4.7 Hz, 1 H, 1Јa-H), 3.59 (dd, J = b), C-5Ј (a, b)], 131.6, 128.5, 128.2, 114.1, 113.7 [12 C, C-aromat.
5.2 Hz, 1 H, 1Јb-H), 2.57 (d, J = 5.7 Hz, 1 H, OH), 2.54 (s, 3 H,
CH3), 1.35 (t, 3 H, CH2CH3), 1.06 [s, 9 H, C(CH3)3] ppm. 13C
NMR (75.4 MHz, CDCl3, 25 °C): δ = 163.8 (COOEt), 159.8, 147.8
(C-2, C-5), 135.7, 135.6, 132.8, 132.8, 130.1, 128.0, 128.0 (12 C-
(a, b)], 114.6 [C-4Ј (a, b)], 109.5 [C-3Ј (a)], 109.2 [C-3Ј (b)], 91.1 [C-
2 (a)], 90.3 [C-2 (b)], 82.3 [C-5 (a or b)], 81.4 [(CH3)3C (a or b)],
81.2 [C-5 (a or b)], 80.7 [(CH3)3C (a or b)], 60.9 [2 C, CH2OH (a,
b)], 60.3 [2 C, CH2CH3(a, b)], 55.5 [2 C, OCH3 (a, b)], 55.4 [C-4
aromat.), 114.5 (C-3), 110.4 (C-4), 72.9 (C-2Ј), 64.4 (C-1Ј), 66.4 (a)], 55.2 [C-4 (b)], 28.4 [(CH3)3C (b)], 28.0 [(CH3)3C (a)], 14.5 [2
(CH2CH3), 60.3 (C-3Ј), 27.0 [(CH3)3C], 19.4 [(CH3)3C], 14.5 C, CH2CH3 (a, b)], 14.0 [2 C, CH3 (a, b)] ppm. MS (CI): m/z =
(CH2CH3), 13.9 (CH3) ppm. MS (CI): m/z = 465.2088 [M – N3]+.
462.2122 [M + H]+.
Ethyl 5-[1-(tert-Butoxycarbonylamino)-3-O-tert-butyldiphenylsilyl- (4R,5R)-N-(tert-Butoxycarbonyl)-5-hydroxymethyl-2-(p-methoxy-
1-deoxy-L-threo-1,2,3-trihydroxyprop-1-yl]-2-methylfuran-3-carb- phenyl)-4-(4-p-methoxytrityloxymethyl-5-methylfuran-2-yl)oxazol-
oxylate (25): A solution of 24 (1.9 g, 3.74 mmol) and (Boc)2O
(978 mg, 4.5 mmol) in MeOH (60 mL) was hydrogenated under at-
mospheric pressure for 1.5 h by using Pd/C (10%) as catalyst. Then,
the solution was filtered through Celite, and the catalyst was
idine (28):[20] To a solution of crude compound 26 (≈2.58 mmol) in
dry THF (14 mL) cooled to 0 °C was slowly added (over 5 min)
LiAlH4 (2  in THF, 2.58 mL, 5.16 mmol), and the reaction mix-
ture was stirred for 30 min at 0 °C. Then, the mixture was diluted
washed with MeOH. Pd/C (10%) and Et3N (0.6 mL) were added, with Et2O and a saturated aqueous solution of Na2SO4 was added
and the mixture was hydrogenated again for 2 h. Then, the solution
was filtered through Celite, and the catalyst was washed with
EtOH. The filtered solution was evaporated to dryness, and the
resulting residue was purified by flash chromatography to give pure
25 (1.78 g, 84%) as a colorless oil. [α]2D2 = +22 (c = 0.45, CH2Cl2).
in small portions. The reaction mixture was filtered through Celite,
the filtrate was washed with water, the organic phase was dried
(Na2SO4), and the solvents were evaporated to dryness. The crude
product thus obtained was dissolved in dry pyridine (20 mL) and
MeOTrCl (1.19 g, 3.87 mmol) was added. The reaction mixture was
IR: ν = 3437 (OH), 2931, 1717 (CO), 1585 (NH), 1497, 1428, 1366, stirred overnight at room temperature. Then, MeOH (2 mL) was
˜
1229, 1168, 1113, 824, 779, 741, 704 cm–1. 1H NMR (300 MHz,
CDCl3, 25 °C): δ = 7.66–7.36 (m, 10 H, Ar-H), 6.49 (s, 1 H, 4-H), was evaporated to dryness, and the resulting crude was dissolved
5.23 (br. s, 1 H, NH), 4.80 (dd, J3Ј,NH = 8.5 Hz, J2Ј,3Ј = 2.5 Hz, 1 in THF (20 mL); TBAF (1  in THF, 5.16 mL, 5.16 mmol) was
added, and the reaction mixture was stirred for 30 min. The solvent
3
H, 3Ј-H), 4.27 (q, JH,H = 7.2 Hz, 2 H, CH2CH3), 4.11–4.05 (m, 1 added in one portion. The mixture was stirred for 2 h at room
H, 2Ј-H), 3.72 (dd, J1Јa,1Јb = 10.3 Hz, J1Јa,2Ј = 4.9 Hz, 1 H, 1Јa-H), temperature. The solvent was evaporated, and the resulting residue
3.60 (dd, J1Јb,2Ј = 7.0 Hz, 1 H, 1Јb-H), 2.64 (br. s, 1 H, OH), 2.53 was purified by flash chromatography (AcOEt/petroleum ether, 1:3)
(s, 3 H, CH3), 1.41 [s, 9 H, (CH3)3C], 1.33 (t, 3 H, CH2CH3), 1.07 to give compound 28 (0.94 g, 53% from 25, mixture of diastereoiso-
[s, 9 H, (CH3)3C] ppm. 13C NMR (75.4 MHz, CDCl3, 25 °C): δ = mers 4.4:1) as a yellow oil. 1H NMR (300 MHz, CDCl3, 25 °C,
164.1 (COOEt), 158.8, 155.7 (C-2, C-5), 151.4 (CO of Boc), 135.7,
133.0, 130.1, 128.0 (12 C, C-aromat.), 114.4 (C-3), 107.9 (C-4), 80.2
major diastereoisomer): δ = 7.37–6.83 (m, 18 H, Ar-H), 6.34 (s, 1
H, 2-H), 6.25 (s, 1 H, 3Ј-H), 4.90 (d, J = 6.9, 1 H, 4-H), 4.40 (m,
[(CH3)3C], 72.4 (C-2Ј), 64.8 (C-1Ј), 60.2 (CH2CH3), 50.0 (C-3Ј), 1 H, 5-H), 3.91–3.71 (m, 10 H, CH2OAr, CH2OTrOMe, CH3OPh,
28.5 [(CH3)3C], 27.0 [(CH3)3C], 19.4 [(CH3)3C], 14.5 (CH2CH3),
CH3OTr), 2.10 (s, 3 H, CH3), 1.41 [s, 9 H, C(CH3)3] ppm. 13C
NMR (75.4 MHz, CDCl3, 25 °C, major diastereoisomer): δ =
159.9, 158.7, 153.9, 149.4, 148.6, 144.8, 136.0, 131.9 (CO of Boc,
C-2Ј, C-5Ј, 6 Cq-aromat.), 130.5, 128.6, 128.4, 127.9 (14 C-aromat.),
117.8 (C-4Ј) 113.7, 113.2 (4 C-aromat.), 110.2 (C-3Ј), 90.3 (C-2),
86.6 [C(CH3)3], 81.3, 81.0 (C-5, rotamers), 61.6 (CH2OH), 58.0
(CH2TrOMe), 55.5 (C-4), 55.4, 55.4 (CH3OPh, CH3OTr), 28.4
[(CH3)3C], 12.0 (CH3 of furan) ppm. MS (ESI): m/z = 714 [M +
Na]+.
13.9 (CH3) ppm. MS (FAB): m/z = 604.2733 [M + Na]+.
(4R,5R)-N-(tert-Butoxycarbonyl)-4-(4-ethoxycarbonyl-5-methyl-
furan-2-yl)-5-hydroxymethyl-2-(p-methoxyphenyl)oxazolidine
(27):[20] To a solution of compound 25 (193 mg, 0.33 mmol) in dry
toluene (6 mL) containing 4 Å MS was added a catalytic amount of
p-toluenesulfonic acid (PTSA; 5 mol-%, 4 mg) and p-anisaldehyde
dimethylacetal (63 µL, 0.36 mmol). The reaction mixture was
stirred for 2 h at room temperature. Then, the mixture was diluted
with AcOEt and washed with a saturated aqueous solution of
NaHCO3 and brine. The organic phase was dried (Na2SO4) and
filtered, and the solvents were evaporated to dryness to give crude
compound 26. The resulting residue was dissolved in THF (4 mL)
and TBAF (1  in THF, 561 µL, 0.561 mmol) was added. The mix-
ture was stirred for 1 h at room temperature. The solvent was evap-
orated, and the crude product was purified by flash chromatog-
raphy on silica gel (Et2O/petroleum ether, 1:1) to give compound
(4R,5R)-N-(tert-Butoxycarbonyl)-5-carboxy-4-(4-ethoxycarbonyl-
5-methylfuran-2-yl)-2-(p-methoxyphenyl)oxazolidine (29):[20] To a
solution of alcohol 27 (260 mg, 0.56 mmol) in CH2Cl2 (9 mL) was
added Dess Martin periodinane (367 mg, 0.84 mmol), and the reac-
tion mixture was stirred for 1.5 h at room temperature. The mixture
was diluted with CH2Cl2 (60 mL), and a saturated aqueous solu-
tion of NaHCO3 and Na2S2O3·5H2O was added; the mixture was
stirred for 5 min. The organic phase was separated, washed with a
27 (109 mg, 72%, 1.1:1 mixture of diastereoisomers) as a colorless saturated aqueous solution of NaHCO3 and brine, and dried with
oil. 1H NMR (300 MHz, CDCl3, 25 °C, mixture of diastereoiso-
mers a and b): δ = 7.43 [d, J = 8.6 Hz, 2 H, Ar-H (b)], 7.36 [d, J
= 8.6 Hz, 2 H, Ar-H (a)], 6.91 [d, 2 H, Ar-H (a)], 6.90 [d, 2 H, Ar-
Na2SO4, and the solvents were evaporated to dryness. The resulting
residue was dissolved in tBuOH (8 mL), and then 2-methyl-2-but-
ene (0.4 mL) and an aqueous solution (4 mL) of NaClO2 (640 mg,
H (b)], 6.61 [s, 1 H, 3Ј-H (a)], 6.49 [s, 1 H, 3Ј-H (b)], 6.33 [s, 1 H, 5.64 mmol) and NaH2PO4 (880 mg, 5.64 mmol) were added. The
2-H (b)], 6.08 [s, 1 H, 2-H (a)], 4.95 [d, J4,5 = 7.8 Hz, 1 H, 4-H (a)],
4.89 [d, J4,5 = 7.2 Hz, 1 H, 4-H (b)], 4.35–4.23 [m, 6 H, 5-H (a), 5-
H (b), CH2CH3 (a, b)], 3.91–3.85 [m, 2 H, CHHOH (a, b)], 3.82
[s, 6 H, OCH3 (a, b)], 3.76–3.63 [m, 2 H, CHHOH (a, b)], 2.58 [s,
3 H, CH3 (a)], 2.51 [s, 3 H, CH3 (b)], 1.92 [br. s, 2 H, OH (a, b)],
reaction mixture was stirred for 2 h at room temperature. The resi-
due was diluted with AcOEt and washed with water. The organic
phase was dried with Na2SO4, filtered, and concentrated. The re-
sulting residue was purified by flash chromatography on silica gel
(CH2Cl2/MeOH, 15:1) to give acid 29 (254 mg, 95%, 1.2:1 mixture
1.39 [s, 9 H, (CH3)3C (b)], 1.36–1.30 [m, 6 H, CH2CH3 (a, b)], 1.07 of diastereoisomers) as a colorless oil. 1H NMR (300 MHz, CDCl3,
Eur. J. Org. Chem. 2010, 3110–3119
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3117

I. Robina et al.
FULL PAPER
25 °C, mixture of diastereoisomers a and b): δ =7.40 [d, J = 8.6, 2
H, Ar-H (b)], 7.36 [d, J = 8.6, 2 H, Ar-H (a)], 6.91 [d, 2 H, Ar-H
(a)], 6.88 [d, 2 H, Ar-H (b)], 6.66 [s, 1 H, 3Ј-H (a)], 6.57 [s, 1 H,
4Ј-H (b)], 6.34 [s, 1 H, 2-H (b)], 6.19 [s, 1 H, 2-H (a)], 5.41 [d, J4,5
= 4.0, 1 H, 4-H (a)], 5.32 [br. s, 1 H, 4-H (b)], 4.94 [d, J4,5 = 3.4,
1 H, 5-H (b)], 4.74 [d, 1 H, 5-H (a)], 4.32–4.24 [m, 4 H, CH2CH3
(a and b)], 3.81 [s, 6 H, OCH3 (a and b)], 2.60 [s, 3 H, CH3 (a)],
2.56 [s, 3 H, CH3 (b)], 1.35–1.31 [m, 15 H, (CH3)3C (b), CH2CH3
(a and b)], 1.16 [s, 9 H, (CH3)3C (a)] ppm. 13C NMR (75.4 MHz,
CDCl3, 25 °C mixture of diastereoisomers a and b): δ = 171.3
(COOH), 164.0 (COOEt), 160.7, 160.3, 159.2, 151.7, 150.6, 149.6
[6 C, CO of Boc (a and b), C-2Ј (a and b), C-5Ј (a and b)], 130.4,
128.8, 128.6, 114.2, 113.7 [12 C, C-aromat. (a and b)], 114.7 [C-4Ј
(a, b)], 109.6 [C-3Ј (b)], 109.5 [C-3Ј (a)], 92.0 [C-2 (a)], 91.4 [C-2
(b)], 81.9 [(CH3)3C (a or b)], 81.6[(CH3)3C (a or b)], 79.2 [C-5 (a
or b)], 78.4 [C-5 (a or b)], 60.3 [2 C, CH2CH3 (a and b)], 57.4 [C-
4 (a)], 57.2 [C-4 (b)], 55.5 [2 C, OCH3 (a and b)], 28.4 [(CH3)3C
(b)], 28.0 [(CH3)3C (a)], 14.5 [2 C, CH2CH3 (a and b)], 14.0 [2 C,
CH3 (a and b)] ppm. MS (CI): m/z = 476.1941 [M + H]+.
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[3]
[4]
(4R,5R)-N-(tert-Butoxycarbonyl)-5-carboxy-2-(p-methoxyphenyl)-4-
(4-p-methoxytrityloxymethyl-5-methylfuran-2-yl)oxazolidine (30):[20]
To a solution of alcohol 28 (280 mg, 0.41 mmol) in CH2Cl2 (5 mL)
was added Dess Martin periodinane (259 mg, 0.61 mmol), and the
reaction mixture was stirred for 2 h at room temperature. The mix-
ture was diluted with CH2Cl2 (40 mL), a saturated aqueous solu-
tion of NaHCO3 and Na2S2O3·5H2O was added; the mixture was
stirred for 5 min. The organic phase was separated, washed with a
saturated aqueous solution of NaHCO3 and brine, dried with
Na2SO4, and concentrated. The resulting residue was dissolved in
tert-butyl alcohol (6 mL) and 2-methyl-2-butene (0.3 mL) was
added, followed by an aqueous solution (3 mL) of NaClO2
(369 mg, 4.0 mmol) and NaH2PO4 (554 mg, 4.0 mmol). The reac-
tion mixture was stirred for 2 h at room temperature. The residue
was diluted with AcOEt and washed with water. The organic phase
was dried with Na2SO4, filtered, and concentrated. The resulting
residue was purified by flash chromatography (CH2Cl2/MeOH,
50:1Ǟ10:1, 1% of Et3N) to give the triethylammonium salt of acid
30 (225 mg, 70%, 4:1 mixture of diastereoisomers) as a colorless
[5]
1
oil. H NMR (300 MHz, CDCl3, 25 °C, major diastereoisomer): δ
= 7.47–6.79 (m, 18 H, H-aromat.), 6.32 (s, 1 H, H-3Ј), 6.27 (s, 1 H,
H-2), 5.32 (br. s, 1 H, H-5), 4.85 (d, J4,5 = 2.9, 1 H, H-4), 3.83 (s,
2 H, CH2OTrOMe), 3.76, 3.69 (2 s, 3 H each, MeOTr, MeOPh),
3.06 [q, J = 7.3, 6 H, HN(CH2CH3)3], 2.09 (s, 3 H, CH3 of furan),
2.02 [s, 9 H, (CH3)3C], 1.23 [t, 9 H, HN(CH2CH3)3] ppm. 13C
NMR (75.4 MHz, CDCl3, 25 °C, major diastereoisomer): δ = 174.9
(COO), 159.7, 158.5, 153.4, 150.9, 148.2, 144.7, 136.0, 131.7, 130.3,
129.1, 128.5, 127.8, 127.7, 126.8, 117.5, 113.4, 113.2, 113.1 (27 C,
C-aromat. of MeOTr and MeOPh, C-2Ј, C-4Ј, C-5Ј), 109.6 (C-3Ј),
90.5 (C-2), 86.4 [(CH3)C], 80.5, 80.2 (mixture of rotamers, C-4),
58.0 (C-5), 57.9 (CH2OTrOMe), 55.2, 55.1 (CH3OPh, CH3OTr),
45.3 [N(CH2CH3)3] 28.3 [(CH3)3C], 11.9 (CH3 of furan), 8.6
[N(CH2CH3)3] ppm. MS (FAB): m/z = 750 [M – Et3NH + 2Na]+,
728.2859 [M – Et3N + Na]+.
[6]
[7]
[8]
For a review on α-furfurylamine derivatives, see: W.-S. Zhou,
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1999, 55, 11959–11983.
a) M. A. Ciufolini, C. W. Wood, Tetrahedron Lett. 1986, 27,
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T. V. Raju, J. Annapurna, H. Singh, Synlett 2004, 2484–2488.
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[9]
Supporting Information (see footnote on the first page of this arti-
cle): NMR spectra for all new compounds.
[10]
Acknowledgments
[11]
[12]
K. J. Kayser, M. P. Glenn, S. M. Sebti, J. Q. Cheng, A. D.
Hamilton, Bioorg. Med. Chem. Lett. 2007, 17, 2068–2073 and
references cited therein.
According to Greene and Commerçon, the isoserine side chain
in a cyclic oxazolidine form is effectively protected and experi-
We thank the Ministerio de Ciencia e Innovación of Spain
(CTQ2008-01565/BQU) and the Junta de Andalucía (FQM-345)
for financial support. E.M.C. thanks the Ministerio de Educación
for a FPU fellowship.
3118
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 3110–3119

Stereoselective Synthesis of α-Furfurylamines from Sugars
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When the nucleophilic displacement was performed with only
1.5 equiv. of Bu4NN3, compound 24 could be isolated slightly
epimerized (S/R = 16:1) at C-1Ј.
[17]
[18]
Alternatively, compound 24 could be obtained from 22 without
purification of intermediates 22 and 23 in 45% overall yield.
[19] The mixture of diastereoisomeric oxazolidines could not be
separated either by crystallization or flash chromatography.
[20] The nomenclature used for compounds 27–30 is different to
the rest of the compounds due to the presence of the oxazolid-
ine ring and do not correspond with that normally employed
for (2R,3R)-3-arylisoserines.
Received: February 10, 2010
Published Online: April 28, 2010
[16] L. H. Koole, H. M. Moody, N. L. H. L. Broeders, P. J. L. M.
Quaedflieg, W. H. A. Kuijpers, W. M. H. P. van Genderen,
Eur. J. Org. Chem. 2010, 3110–3119
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3119