Enantioselective synthesis of both enantiomers of 2-amino-2-(2-furyl)ethan-1-ol as a flexible building block for the preparation of serine and azasugars

Article abstract of DOI:10.1016/S0957-4166(03)00158-7

The selective conversion of 1-(2-furyl)-2-hydroxyethan-1-one and ethyl 2-(2-furyl)-2-oxo acetate into (E)- and (Z)-oximes and oxime ethers followed by oxazaborolidine-catalyzed enantioselective reduction using different amino alcohols furnished both enantiomers of the important chiral building block 2-amino-2-(2-furyl)ethan-1-ol with an ee of up to 96%.

Full text of DOI:10.1016/S0957-4166(03)00158-7

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 1335–1340
Enantioselective synthesis of both enantiomers of
2-amino-2-(2-furyl)ethan-1-ol as a flexible building block for the
preparation of serine and azasugars
8
Ayhan S. Demir,* Ozge Sesenoglu, Hilal Aksoy-Cam, Handan Kaya and Kenan Aydogan
Department of Chemistry, Middle East Technical University, 06531 Ankara, Turkey
Received 24 January 2003; revised 10 February 2003; accepted 12 February 2003
Abstract—The selective conversion of 1-(2-furyl)-2-hydroxyethan-1-one and ethyl 2-(2-furyl)-2-oxo acetate into (E)- and (Z)-
oximes and oxime ethers followed by oxazaborolidine-catalyzed enantioselective reduction using different amino alcohols
furnished both enantiomers of the important chiral building block 2-amino-2-(2-furyl)ethan-1-ol with an ee of up to 96%. © 2003
Elsevier Science Ltd. All rights reserved.
1. Introduction
lic reagent to a-furfuryl imine, in low yield. The same
authors reported the asymmetric synthesis of 1 in 5
steps employing a Sharpless asymmetric dihydroxyla-
tion starting from a-furyl ethylene.5a,8 Altenbach et al.
used furyl glycine and obtained the furylamine 1 via the
reduction of the carboxyl group.5b
Optically active a-furylamine derivatives have received
much attention due to their importance as useful build-
ing blocks for the synthesis of a considerable number of
nitrogen-containing natural products, such as a-amino
acids,1 b-lactams,2 indolizidines,3 quinolizidines4 and
piperidine alkaloids.5 Among these, chiral 2-amino-2-
(2-furyl)ethan-1-ol 1 is a very useful starting material
for the synthesis of polyhydroxylated piperidines (aza-
sugars) via chiral dihydropyridones (Scheme 1).5a Poly-
hydroxylated piperidines have attracted considerable
attention due to their importance as glycosidase
inhibitors.6 Zhou5c,d and Altenbach5b have applied this
building block to the total synthesis of 1-deoxyazasug-
ars and desoxoprosophylline.7
As we reported earlier, furyl alkyl ketones can be used
as starting materials for the enantioselective synthesis
of both enantiomers of a-amino acids. Oxime ether
formation and oxazaborolidine-catalyzed enantioselec-
tive reduction followed by oxidation of the furan ring
furnished a-amino acids in good yields and high enan-
tiomeric purities.9,10
In connection with our preliminary results reported
previously, we describe herein the enantioselective syn-
thesis of both enantiomers of 2-amino-2-(2-furyl)ethan-
1-ol 1 starting from 1-(2-furyl)-2-hydroxyethan-1-one 2,
and ethyl 2-(2-furyl)-2-oxo acetate 3, respectively.
Zhou et al. obtained non-racemic 2-amino-2-(2-
furyl)ethan-1-ol 1 from the kinetic resolution of rac-1,
which was prepared by the addition of an organometal-
2. Results and discussion
As illustrated in Scheme 2, 1-(2-furyl)-2-hydroxyethan-
1-one 2 was converted to oxime 4 using H2NOH·HCl/
NaOAc in EtOH. Oxime 4 was obtained in 97% yield
as a mixture of diastereomers ((E)/(Z):ratio:77:23). The
chromatographic separation of these gave pure the
(E)-isomer (mp 132–133oC, 73%) and the (Z)-isomer
(mp 126–127oC, 21%) as colorless solids. The reaction
Scheme 1.
* Corresponding author. Fax: +90-312-210-1280; e-mail: asdemir@
metu.edu.tr
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00158-7

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A. S. Demir et al. / Tetrahedron: Asymmetry 14 (2003) 1335–1340
Scheme 2. Reagents and conditions: (a) H2NOH·HCl, NaOAc, EtOH; (b) HCl/Et2O; (c) NaH, BnBr, DMF; (d) BH3·THF, cat.;
(e) O3, DCM, −78°C; (f) BH3·SMe2·THF.
ture of (E)-6 was determined by X-ray crystallographic
analysis.11 Since the two geometric isomers give oppo-
site enantiomers,9,10 in other words the configuration of
the product is fully controlled by the appropriate choice
of the geometric isomer of the oxime, it is essential to
have pure oximes. Oximes were converted to oxime
ethers (E)-7 and (Z)-7 using NaH and benzyl bromide
in 88–92% yields. The O-benzyl oximes were purified by
flash column chromatography and isolated as viscous
oils.
of 4 ((E)/(Z) mixture) with hydrogen chloride in ether
furnished oxime 4 with an (E)/(Z) ratio of 1:6, which
was purified by recrystallization [75% (Z)-4]). The (E)-
and (Z)-isomers were identified by their 1H and 13C
NMR spectra. (The (E)-isomer displays a multiplet for
C-3H of furan at 6.64 ppm, whereas the same proton
appears at 7.34 ppm in the (Z)-isomer. A similar obser-
vation can be seen in 13C NMR shifts: C-3 of the
(E)-isomer appears at 112.7 ppm, and at 119.8 ppm for
the (Z)-isomer. Oximes were converted to O-benzyl
oximes (E)-5 and (Z)-5 using NaH and benzyl bromide
in DMF in 94–96% yields. No isomerization was
observed during this conversion. The O-benzyl oximes
were purified by flash column chromatography and
isolated as viscous oils.
Oxime ethers are a class of readily available compounds
for the conversion of carbonyl groups to amines. Some
of the most important work in this area was reported
by Itsuno et al.,12 who showed that acetophenone
oxime ethers can be converted into amines with high
ee’s using BH3–oxazaborolidine complexes. The enan-
tioselective reduction of (E)-5 and (Z)-5 was carried
out with BH3 in the presence of oxazaborolidine
complexes13 prepared from different chiral amino alco-
hols using the following procedure: A solution of
borane in THF was added under argon dropwise to a
The second approach starts from ethyl 2-(2-furyl)-2-oxo
acetate 3; it is converted selectively to its (E)- and
(Z)-oximes, which are separated carefully either by
chromatography
or
recrystallization
(71–74%
yields).9,10a The (E)- and (Z)-isomers were identified by
1
their H and 13C NMR spectra. Additionally the struc-

A. S. Demir et al. / Tetrahedron: Asymmetry 14 (2003) 1335–1340
1337
solution of (1R,2S)-norephedrine in THF at −20°C.
The resulting mixture was allowed to warm to −5°C
and stirring was continued at this temperature for 16 h.
A solution of oxime ether (E)-5 in THF was added
dropwise. The resulting solution was stirred at 30°C for
48 h (monitored by TLC) and was decomposed by the
slow addition of 2 M aqueous HCl. The product amine
(R)-1 was obtained in 80% yield and 76% ee after
purification of the crude product. Under similar condi-
tions using oxime ether (Z)-5 furnished amine (S)-1 in
75% yield and 73% ee. Different amino alcohols were
used in the reduction reaction and, as shown in Table 1,
the (R)- and (S)-amine are obtained in 73–80% yields
and 73–87% ee. The highest ee was found with amino
alcohol 11. These results are in accordance with our
previous results.9,10
91–93% yields. The absolute configurations of (S)-1
and (R)-1 were found by comparison of the specific
rotation values with known serine data. It is also
possible to predict the absolute configuration of 1 by
converting it to oxazolidinone or its carbamic acid ethyl
ester by known procedures (Scheme 3).14 The amino
alcohols used for the preparation of oxazaborolidines
were recovered in 93–95% yields during the work-up
procedure as their HCl salts.
The reduction of oxime ether (Z)-7 under similar condi-
tions with catalytic amounts of oxazaborolidine com-
plexes prepared with amino alcohols (0.1–0.2 equiv.)
afforded products with ee’s of 16–20%. The effect of the
O-protecting group on the reduction of oxime ethers
was investigated. The reduction was carried out on a
(Z)-O-methyl oxime and determination of the ee’s of
the product amines showed low selectivity (21% ee).
The highest enantiomeric purity was obtained when the
ratio of borane:amino alcohol:oxime ether was ca.
2.5:1.25:1.0. An excess of borane relative to amino
alcohol led to low enantiomeric excesses. Better results
were obtained starting from the reduction of oxime
ethers of ethyl 2-(2-furyl)-2-oxo acetate 3. Enantioselec-
tive reductions of (Z)-7 were carried out using the
conditions described above. Different amounts of
reduction reagents were used and the best enantiomeric
purity was obtained when the ratio of borane:amino
alcohol:oxime ether was ca. 1:6:3. The amino alcohol
(R)-1 was obtained in 94–96% ee and 82–86% chemical
yield. Under similar conditions (E)-7 furnished amine
(S)-1 in 77–81% yield and 71–91% ee (Table 1).
Scheme 3.
Amines were characterized by NMR and IR. The enan-
tiomeric purity of the products was determined via
analysis of the N-acetyl derivative by HPLC on a chiral
stationary phase column comparing with a racemic
product, which was synthesized from (Z)-7 using
BH3·SMe2. As shown in Scheme 2, amines (S)- and
(R)-1 are converted into (S)- and (R)-serine ((S)-8, and
(R)-8) by oxidation of the furan ring with ozone in
Scheme 4.
Table 1. Enantioselective synthesis of (S)-1 and (R)-1 using different amino alcohols

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A. S. Demir et al. / Tetrahedron: Asymmetry 14 (2003) 1335–1340
The suggested mechanism outlined in Scheme 4 shows
that the formation of low energy cis-pentalane is
favored because b-binding of BH3·THF to oxazaboro-
lidine forms very strained trans-pentalane, which is
disfavored. As shown in Table 1, the geometry of oxime
becomes a dominant factor in the stereoselectivity by
the formation of amines. It looks like that the prochiral
nitrogen moiety is responsible for the high selectivity
but not the prochiral carbon.
ethanol (50 mL) and stirred under reflux for 12 h. The
reaction was monitored by TLC. After 12 h the hot
solution was filtered and the ethanol was evaporated.
The remaining solid was dissolved in water and
extracted with diethyl ether. The ether layer was
washed with water and brine and dried over anhydrous
MgSO4. Evaporation of the solvent afforded the crude
product as a mixture of isomers. Separation of the
isomers was achieved by flash column chromatography
(1:5 ether:toluene) to give the following products.
3. Conclusion
4.3.1. (E)-1-(2-Furyl)-2-hydroxyethan-1-one oxime, (E)-
4.15 1H NMR (CDCl3): l 3.34 (br.s, 1H), 4.81 (m, 2H),
6.34 (m, 1H), 6.64 (d, J=3.5,1H), 7.55 (m, 1H), 11.26
(br.s, 1H); 13C NMR (CDCl3): l 61.8, 111.8, 112.7,
140.2, 143.3, 164.2.
1-(2-Furyl)-2-hydroxyethan-1-one and ethyl 2-(2-furyl)-
2-oxo acetate were converted into their (E)- and (Z)-
oximes selectively in good yields, and oxaza-
borolidine-catalyzed enantioselective reduction of the
corresponding O-benzyl oxime ethers afforded both
enantiomers of 1-(2-furyl)ethylamine in good yields
with an ee of up to 96%. Both enantiomers of serine
were then obtained in high yields by the oxidation of
the furan ring with ozone. The configuration of the
amine products is controlled by the appropriate choice
of geometrical isomer of the O-benzyloxime.
4.3.2. (Z)-1-(2-Furyl)-2-hydroxyethan-1-one oxime, (Z)-
4.15 1H NMR (CDCl3): l 3.37 (br.s, 1H), 4.71 (m, 2H),
6.48 (m, 1H), 7.34 (d, J=3.5,1H), 7.64 (m,1H), 10.14
(br.s,1H); 13C NMR (CDCl3): l 61.3, 112.1, 119.8,
140.4, 143.6, 164.7.
4.3.3. (E)-Ethyl 2-(2-furyl)-2-(hydroxyimino)acetate,
(E)-6. Mp 72–73°C; 1H NMR (CDCl3): l 1.42 (t,
J=7.1, 3H), 4.40 (q, J=7.1, 2H), 6.55 (dd, J=1.7, 3.5,
1H), 7.41 (d, J=3.5, 1H), 7.55 (s, 1H), 10.76 (br.s, 1H);
13C NMR (CDCl3): l 13.9, 61.9, 111.6, 119.5, 139.5,
142.4, 143.7, 161.4. Anal. calcd for C8H9NO4 (183.1):
C, 52.46; H, 4.95; N, 7.65. Found: C, 52.65; H, 4.86.
4. Experimental
4.1. General methods
NMR spectra were recorded on a Bruker DPX 400.
Column chromatography was conducted on silica gel
60 (mesh size 40–63 mm). Enantiomeric excesses were
determined by HPLC analysis using a Thermo Quest
(TSP) GC–LC–MS equipped with an appropriate opti-
cally active column, as described in the footnote to
Table 1. Optical rotations were measured with a
Bellingham & Stanley P20 polarimeter.
4.3.4. (Z)-Ethyl 2-(2-furyl)-2-(hydroxyimino)acetate,
(Z)-6. Mp 90–92°C; 1H NMR (CDCl3): l 1.31 (t,
J=6.7, 3H), 4.33 (q, J=6.7, 2H), 6.35 (dd, J=1.8, 3.4,
1H), 6.56 (d, J=3.4, 1H), 7.41 (s, 1H), 9.97 (br.s, 1H);
13C NMR (CDCl3): l 14.4, 62.5, 111.9, 112.9, 143.1,
144.9, 145.6, 161.8. Anal. calcd for C8H9NO4 (183.1):
C, 52.46; H, 4.95; N, 7.65. Found: C, 52.32; H, 4.78.
4.2. Synthesis of ethyl 2-(2-furyl)-2-oxo acetate, 3
4.4. Isomerization of oximes
To 1.8 g furyl glyoxalic acid (13 mmol) dissolved in 50
mL CHCl3 was added EtOH (20 mmol) and H2SO4.
The mixture was refluxed for 10 h, cooled to room
temperature and sat. NaHCO3 was added. After sepa-
ration of the layers the organic phase was washed with
brine, dried over MgSO4 and concentrated under
reduced pressure to give the crude product. Further
purification of the crude product by flash column chro-
matography (1:6 EtOAc:hexane) afforded furylglyoxalic
acid ethyl ester in 93% yield. 3: colorless solid, mp
34–35°C; 1H NMR (CDCl3): l 1.40 (t, J=7.2, 3H), 4.39
(q, J=7.2, 2H), 6.61 (dd, J=1.7, 3.6, 1H), 7.63 (d,
J=3.6, 1H), 7.75 (s, 1H); 13C NMR (CDCl3): l 14.4,
62.9, 113.3, 124.8, 149.7, 150.2, 161.4, 171.4. Anal.
calcd for C8H8O4 (168.1): C, 57.14; H, 4.80. Found: C,
57.32; H, 4.66.
Oxime (10 mmol) ((E)/(Z) mixture) was suspended in
dry ether (50 mL) and HCl gas was bubbled through
the solution at 0°C. The reaction was monitored by
TLC. Initially a clear solution was observed and then a
white precipitate formed. Evaporation of the solvent
gave oxime with an (E)/(Z) ratio of 6:1. Separation of
the isomers was achieved by flash column
chromatography.
4.5. General procedure for oxime ethers
To the suspension of NaH (washed from oil with
hexane, 5.4 mmol) in DMF (20 mL) under argon
atmosphere at 0°C was slowly added oxime (5.4 mmol)
over 30 min. Benzyl bromide (5.4 mmol) was added and
the mixture was stirred for 10 h at rt. After the addition
of water (5 mL) the mixture was extracted with ethyl
acetate. The organic layer was washed with water and
brine and dried over MgSO4. The crude product was
purified by flash column chromatography (1:3
EtOAc:hexane).
4.3. General procedure for oximes
Ethyl 2-(2-furyl)-2-oxo acetate 3 (or 2a) (1.5 g, 9
mmol), and NH2OH·HCl (0.8 g, 12 mmol) and
CH3CO2Na (0.9 g, 12 mmol) were mixed in absolute

A. S. Demir et al. / Tetrahedron: Asymmetry 14 (2003) 1335–1340
1339
4.5.1. (E)-1-(2-Furyl)-2-hydroxyethan-1-one O-benzy-
4.7. Ozonolysis
1
loxime, (E)-5. Viscous oil, H NMR (CDCl3): l 3.51
(br.s, 1H), 4.92 (br.s, 2H), 5.43 (s, 2H), 6.52 (m, 1H),
7.25–7.77 (m,7H); 13C NMR (CDCl3): l 61.9, 76.4,
110.3, 112.5, 127.3, 127.4, 128.7, 140.9, 143.4, 144.6,
164.6. Anal. calcd for C13H13NO3 (231.3): C, 67.52; H,
5.67; N, 6.06. Found: C, 67.21; H, 5.43.
Ozone gas was passed through a solution of amine (5
mmol) in DCM (50 mL) at −78°C. After 30 min the
reaction was stopped and N2 was passed through the
mixture to remove the excess ozone. Evaporation of the
solvent gave the product as a white powder.
4.7.1. (R)-Serine. [h]2D0=+1.4 (c 1, 1N HCl) (commer-
cially available compound), mp 217–219°C.
4.5.2. (Z)-1-(2-Furyl)-2-hydroxyethan-1-one O-benzy-
1
loxime, (Z)-5. Viscous oil, H NMR (CDCl3): l 3.55
(br.s, 1H), 4.97 (br.s, 2H), 5.47 (s, 2H), 6.49 (m, 1H),
7.47–7.81 (m, 7H); 13C NMR (CDCl3): l 62.3, 76.3,
112.4, 116.2, 127.5, 128.6, 130.1, 140.5, 142.9, 144.7,
165.4. Anal. calcd for C13H13NO3 (231.3): C, 67.52; H,
5.67; N, 6.06. Found: C, 67.31; H, 5.37.
4.7.2. (S)-Serine. [h]2D0=−1.3 (c 1, 1N HCl) (commer-
cially available compound), mp 221–223°C.
4.8. Synthesis of rac-1
To a solution of oxime ether (5 mmol) in abs. THF (25
mL) was added BH3·SMe2 (12 mmol) dropwise over 1
h. Then the mixture was stirred for 36 h at rt and
hydrolyzed with 2N aqueous HCl. After separation of
the layers the organic phase was washed with brine,
dried over MgSO4 and concentrated to give the crude
amine. Further purification of the crude product was
achieved by flash column chromatography (1:1:1
EtOAc:hexane:MeOH) to give the racemic amine.
4.5.3. (E)-Ethyl 2-[(benzyloxy)imino]-2-(2-furyl)acetate,
1
(E)-7. Viscous oil, H NMR (CDCl3): l 1.43 (t, J=7.1,
3H), 4.43 (q, J=7.1, 2H), 5.37 (s, 2H), 6.50 (dd, J=1.6,
3.3, 1H), 7.29 (d, J=3.3, 1H), 7.32–7.43 (m, 5H), 7.51
(s, 1H); 13C NMR (CDCl3): l 14.6, 62.3, 78.6, 112.2,
119.8, 128.3, 128.6, 128.7, 128.9, 136.7, 140.8, 143.8,
162.5. Anal. calcd for C15H15NO4 (273.2): C, 65.92; H,
5.53; N, 5.13. Found: C, 65.72; H, 5.66.
4.5.4. (Z)-Ethyl 2-[(benzyloxy)imino]-2-(2-furyl)acetate,
1
(Z)-7. Viscous oil, H NMR (CDCl3): l 1.25 (t, J=7.1,
Acknowledgements
3H), 4.30 (q, J=7.1, 2H), 5.16 (s, 2H), 6.34 (dd, J=1.6,
3.1, 1H), 6.53 (d, J=3.1, 1H), 7.18–7.29 (m, 5H), 7.38
(s, 1H); 13C NMR (CDCl3): l 14.5, 62.2, 77.6, 112.1,
112.7, 128.2, 128.3, 128.4, 128.7, 137.4, 144.9, 145.6,
161.8. Anal. calcd for C15H15NO4 (273.2): C, 65.92; H,
5.53; N, 5.13. Found: C, 66.18; H, 5.69.
Financial support from the Middle East Technical Uni-
versity (BAP-2002), the Scientific and Technical
Research Council of Turkey (TUBITAK), the Turkish
Academy of Science (TUBA), and the Turkish State
Planning
Organization
(DPT)
is
gratefully
acknowledged.
4.6. Reduction of oxime ethers
A solution of borane (20 mmol) in THF (20 ml) was
added under argon dropwise to a solution of amine (10
mmol) in THF (10 ml) at −20°C. The resulting mixture
was allowed to warm to −5°C and stirring was contin-
ued at this temperature for 16 h. A solution of the
oxime ether (8 mmol) in THF (10 mL) was added
dropwise. The resulting solution was stirred at 30°C for
48 h (monitored by TLC) and was decomposed by the
slow addition of 2 M aqueous HCl. After separation of
the layers the organic phase was washed with brine,
dried over MgSO4 and concentrated to give the crude
amine. Further purification of the crude product was
achieved by flash column chromatography (1:1:1
EtOAc:hexane:MeOH) to give the desired compounds
as follows.
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