De novo synthesis of pentoses via cyanohydrins as key intermediates

Article abstract of DOI:10.1016/j.tet.2009.04.048

A de novo synthesis of pentoses is described starting from (Z)-2-buten-1,4-diol (1). The key step is the enzyme catalysed enantioselective HCN-addition to O-protected 4-hydroxybut-2-enal using the hydroxynitrile lyase from Hevea brasiliensis, followed by an asymmetric dihydroxylation. For the cyanohydrin reaction the influence of the configuration of the double bond and of the protecting group was investigated. The dihydroxylation step was found to be influenced by the protecting group on position 4.

Full text of DOI:10.1016/j.tet.2009.04.048

Tetrahedron 65 (2009) 5418–5426
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
De novo synthesis of pentoses via cyanohydrins as key intermediates
,
,b,
*
Manuela Avi a, Richard Gaisberger a b, Sabine Feichtenhofer a, Herfried Griengl a
a Institute of Organic Chemistry, Graz University of Technology, Stremayrgasse 16, 8010 Graz, Austria
b Research Centre Applied Biocatalysis, Petersgasse 14, 8010 Graz, Austria
a r t i c l e i n f o
a b s t r a c t
Article history:
A de novo synthesis of pentoses is described starting from (Z)-2-buten-1,4-diol (1). The key step is the
enzyme catalysed enantioselective HCN-addition to O-protected 4-hydroxybut-2-enal using the hy-
droxynitrile lyase from Hevea brasiliensis, followed by an asymmetric dihydroxylation. For the cyano-
hydrin reaction the influence of the configuration of the double bond and of the protecting group was
investigated. The dihydroxylation step was found to be influenced by the protecting group on position 4.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 7 January 2009
Received in revised form 27 March 2009
Accepted 13 April 2009
Available online 18 April 2009
1. Introduction
from Prunus amygdalus (PaHNL) finds industrial application in the
synthesis of (R)-2-hydroxy-4-phenylbutyronitrile, an important
Recently,
L
-sugars have found increasing application in pharma-
building block for the production of nonsulfhydril angiotensin-
ceuticals and cosmetics.1–3,37 As building blocks of nucleoside ana-
converting enzyme (ACE) inhibitors.19,20
logues they are promising candidates in antiviral and antitumoral
Herein the enzymatic cyanohydrin transformation of different
4-O-protected 4-hydroxybut-2-enals with the (S)-selective HbHNL
and the following synthetic route to pentoses is described.
therapy.
viral activity, in combination with lower cytotoxicity and greater
metabolic stabilityas their
-counterparts.2 Asaresultclinicaltrialsare
reported, for example, for 1-( -2-fluoro-2-deoxyarabinofuranosyl)-
5-methyluracil (
-FMAU) as anti-hepatitis B virus (HBV) agent.2,4
These nucleosides are easily synthesised from -ribose, which
does, however, not occur in nature and is very expensive. In recent
L-nucleosides often exhibit comparable or even greater anti-
D
b-L
L
2. Results and discussion
L
As mentioned above the key steps to introduce the chiral centres
are the HbHNL catalysed cyanohydrin reaction followed by a dihy-
droxylation. The stereocentre introduced by the HCN addition
should direct the dihydroxylation to take place from the less hin-
dered side, affording the desired pentose.
years several syntheses of
available sugars, such as
L
-ribose have been reported from readily
-ribose,5–8 -glucose,9 -galactose,10
-carbohydrates
D
D
D
L-
arabinose11,12 etc. But only few de novo syntheses of
L
have been published.13,14 Herein, a de novo synthesis of pentoses is
reported, where the key step is an enzymatic cyanohydrin reaction
followed by an asymmetric dihydroxylation.
(Z)-But-2-en-1,4-diol was monoprotected prior to oxidation to
(E)- and (Z)-aldehydes according to literature21,22 (Scheme 1). Pro-
tecting groups of different size and polarity were inserted to in-
vestigate their influence on the enzymatic cyanohydrin reaction.
After monoprotection the oxidation with pyridinium chloro-
chromate (PCC)21 afforded (E)-aldehydes 3a–e. Therefore, a more
Cyanohydrins are valuable building blocks making, for example,
a
-hydroxy acids and b
-amino alcohols easily accessible.15,16 They
can be synthesised enantioselectively through the hydroxynitrile
lyase (HNL) catalysed HCN addition to aldehydes and ketones. Many
HNLs from plants are known, which differ in structure, substrate
acceptance and stereoselectivity.15,17 Thus, it is possible to convert
a broad range of aldehydes and ketones into enantiopure (R)- or (S)-
cyanohydrins depending on the HNL used. For example, the (S)-
selective HNL from Hevea brasiliensis (HbHNL) is used in the large
scale production of (S)-3-phenoxybenzaldehyde cyanohydrin,
which is an intermediate in the synthesis of pyrethroids, a class of
synthetic insecticides.18,19 On the other hand, (R)-selective HNL
22
gentle oxidation with MnO2 had to be applied to obtain the (Z)-
aldehydes 30a–e, suitable for the synthesis of the pentoses of the
desired configuration.
The cyanohydrin reaction was performed in a biphasic system of
tert-butyl methyl ether (tBME)/H2O (1/1 v/v) at pH 5.0 and 4.5 at
0 ꢀC. The (E)-aldehydes were converted with high yields and high
enantiomeric excess (ee 88–99%), except for 3c and 3e (Table 1). The
unfavoured interaction of an additional oxygen atom in case of the
methoxymethyl group in 3c and the bulkiness of the TBDPS-group
in 3e could be an explanation for the lower ee’s. An increase of pH-
value from 4.5 to 5.0 resulted in faster conversion, but also in lower
selectivity.
* Corresponding author. Tel.: þ43 316 873 8240; fax: þ43 316 873 8740.
E-mail address: herfried.griengl@a-b.at (H. Griengl).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.04.048

M. Avi et al. / Tetrahedron 65 (2009) 5418–5426
5419
O
CN
OR'
RO
RO
4, 5a-e
c 79 - 100%
d 69 - 71%
a
3a-e
75%
OH
37 -
b
HO
RO
OH
OR′
CN
63 - 100%
2a - e
1
c, d
c 68 - 100%
d 68 - 89%
RO
RO
19 - 61%
O
a R = allyl
b R = Bn
3'a-e
4', 5'a-e
c R = MOM
d R = TBDMS
e R = TBDPS
4 R' = H
5 R' = TBDPS
Scheme 1. Reagents and conditions: (a) PCC, sodium acetate, Celite 545, CH2Cl2. (b) MnO2, CH2Cl2, 0 ꢀC. (c) HbHNL, HCN, tBME/buffer. (d) tBDPSiCl, imidazole, DMF.
Table 1
reaction in a 1/1 ratio, whereas using a 2/1 organic solvent/aqueous
phase ratio the selectivities achieved are marginally higher (88% ee)
and constant over a wider pH-range. In order to obtain ee’s>90% also
the enzyme amount was optimised. The conversion of 30a was in-
vestigated in tBME/H2O (2/1 v/v) at pH 4.2 varying the enzyme
amount from 150 to 5000 U/mmol substrate. As a result, the ee could
be enhanced to 92.4% applying 700 U/mmol substrate in a biphasic
system of tBME/H2O (2/1 v/v) at pH 4.1–4.3. The achieved optically
purity was satisfactory for the follow-up synthesis.
Subsequently, the hydroxy group of cyanohydrin (S)-40a was
protected as silyl ether prior to the dihydroxylation. Today the
method of choice for an asymmetric cis-dihydroxylation of an alkene
clearly is the Sharpless methodology.38,39 However, attempted
transformation of (Z)-cyanohydrin 50f, the (Z)-stereochemistry is
required for the intended ribo-configuration of the product and
protection of the cyanohydrin is necessary for stability reasons, ap-
plying standard conditions40 failed also after pH-adjustment.41
Therefore, several variants of the OsO4-procedure were investigated.
The bulky TBDPS-group was introduced to maximise the directing
effect of the chiral centre and drive the dihydroxylation to take place
on the less hindered side.23 cis-hydroxylation of 50a with OsO4
and N-methyl morpholine-N-oxide (NMO)24,25 should afford 2-t-
Yields and enantiomeric excess for the conversion of E-aldehydes 3a–e
Substrate
R
Enzyme amount, U/mmol
pH
yield,a
%
ee, %b
3a
Allyl
5680
6910
4650
4670
19,800
7200
6900
19,600
19,200
10,700
14,200
5.0
4.5
5.1
4.6
4.5
5.0
4.6
5.0
4.5
5.0
4.5
104
100
105
113
94
84
79
95
88
98
96
98
97
32
66
99
99
51c
25c
3b
Bn
3c
3d
3e
MOM
TBDMS
TBDPS
87
36c
20c
a
Crude product.
Measured by chiral HPLC after derivatisation.
Measured by chiral HPLC without derivatisation.
b
c
Due to the low selectivity in case of the MOM-protected (E)-
substrate the corresponding (Z)-aldehyde 30c was not used for the
enzymatic HCN-addition. The reaction time for the conversion of
(Z)-aldehydes 30a–e is much longer in comparison to (E)-aldehydes
3a–e, but fortunately no isomerisation to the (E)-aldehydes is ob-
served. Therefore, the reaction temperature was raised to room
temperature (rt). In comparison with the corresponding (E)-alde-
hydes substrates 30a, 30b and 30d were converted with lower yields
and only low to moderate ee’s (10–80%), whereas 30e was not
converted at all (Table 2). Only for 30a HbHNL gave reasonable se-
lectivities, affording the (S)-cyanohydrin 40a in 89% yield and 81% ee
at pH 4.5. Again, raising the pH resulted in a drop of selectivity.
In order to obtain a product with high enantiomeric purity, suit-
able for the follow-up synthesis, the conversion of 30a was optimised.
The pH-range was varied from 5.0 to 4.0 and the best selectivities
were achieved between pH 4.1–4.3. Lower pH-values seem to affect
the catalyst’s stability, whereas at higher pH-values the chemical
background reaction is more competitive. The organic solvent/aque-
ous phase ratio showed also to have great influence on the enantio-
meric excess. The ee is strongly pH-dependent when performing the
Table 2
Yields and enantiomeric excess for the conversion of Z-aldehydes 30a,b,d,e
Substrate
R
enzyme amount, U/mmol
pH
Yield, %
ee, %a
30a
Allyl
7600
6700
6900
7200
7900
8490
10,000
5.0
4.5
5.0
4.5
5.0
4.5
4.5
65b
89
>99
89
74
81
54
59
9
30b
30d
Bn
TBDMS
TBDPS
99
78
10
n.d.c
30e
n.d.c
a
Measured by chiral HPLC after derivatisation.
Crude substrate.
Measured by chiral HPLC without derivatisation.
b
c
OR'
CN
OR'
OR'
CN
b
50%
c
a
5'a
RO
CN
HO
RO
67%
HO OH
R = TBDMS
R' = TBDPS
5'f
5'd
6d (55% de)
d
66%
OR'
OR'
e
32%
O
RO
RO
CN
O
O
O
O
7d
ribo / arabino 1:1
8d (55% de)
Scheme 2. Reagents and conditions: (a) SeO2, acetic acid, dioxane, reflux. (b) tBuDMSiCl, imidazole, CH2Cl2. (c) OsO4, H2O2, acetone/H2O. (d) 2,2-dimethoxypropane, pyridinium-p-
toluene sulfonate, CH2Cl2. (e) DIBAL-H, pentane, ꢁ78 ꢀC.

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M. Avi et al. / Tetrahedron 65 (2009) 5418–5426
OR'
CN
OR'
OR'
CN
a
b
86%
RO
CN
RO
RO
RO
59%
O
O
HO OH
rac-5'b
rac-6b (26% de)
ribo / arabino 1:1
rac-7b (20% de)
c
33%
OR'
O
O
OR''
OR'
10a-c
OR''
d
RO
+
O
RO
86%
HO
O
O
HO
OR'
9a-c
rac-8b (23% de)
D-arabinose
skeleton
L-ribose
skeleton
a R = Bn, R' = TBDPS, R'' = H
b R = Bn, R' = TBDPS, R'' = Me
c R = Bn, R' = H, R'' = Me
Scheme 3. Reagents and conditions: (a) OsO4, H2O2, acetone/H2O. (b) 2,2-dimethoxypropane, pyridinium-p-toluene sulfonate, CH2Cl2. (c) DIBAL-H, pentane, ꢁ78 ꢀC. (d) Dowex
50 W-X4, MeOH. All compounds are racemic, only one enantiomer is shown.
butyldiphenylsilyloxy-3, 4, 5-trihydroxypentanenitrile because of
the simultaneous cleavage of the allyl ether under these conditions.
However, NMR-spectra of the peracetylated product mixture in-
dicated, that both double bonds were dihydroxylated. Therefore,
cleavage of the protecting group to give compound 50f was performed
according to literature with SeO2 and acetic acid26 prior to the hy-
droxylation step.
Attempts to convert 50f into 2-t-butyldiphenylsilyloxy-3, 4, 5-
trihydroxypentanenitrile with OsO4 and NMO were unsuccessful.
Therefore, the protected cyanohydrins 50b, 50d and 5-acetyl-50f were
investigated under different hydroxylation conditions. The best re-
sults were achieved for asymmetric dihydroxylation of 50b and 50d
with a catalytic amount of OsO4 and H2O2 as reoxidant.23,24 Un-
fortunately, it was not feasible to use the protected cyanohydrins
from the enzymatic cyanohydrin reaction of 30b and 30d, since these
compounds could only be obtained with low enantiomeric excess.
Therefore, the allyl ether of intermediate 50a was cleaved and the
obtained free hydroxy group was protected again to obtain the de-
sired product 6d without loss of enantiomeric purity (Scheme 2).
Conversion with tert-butyldimetylsilyl chloride gave the desired
product 50d in high yields, whereas it was not possible to introduce
the benzyl group.
6b, affording 8d in a 3.5/1 ratio of arabinose/ribose and 8b in a 1.7/1
ratio. Separation by flash chromatography allows to obtain both
sugars in pure form.
3. Conclusion
A de novo synthesis of pentoses is described starting from (Z)-2-
buten-1,4-diol (1). The enantioselective HCN addition to O-pro-
tected 4-hydroxybut-2-enal using the HNL from H. brasiliensis is the
key step, which is followed by an asymmetric dihydroxylation. The
configuration of the double bond and the protecting group strongly
influence the conversion and selectivity of the reaction. In the se-
ries of O-protected (Z)-4-hydroxybut-2-enals, which are adequate
for the purpose of synthesis of pentoses, only the allyl protected
compound 30a was converted in sufficiently high selectivity. The
dihydroxylation step is also influenced by the protecting group at
position 4. Only compounds 50b and 50d were converted, affording
product mixtures with different ratios of
D-arabinose and L-ribose.
4. Experimental
4.1. General
The following hydroxylation of (S)-50d yielded 6d as a mixture of
two stereoisomers in a 3.5/1 ratio. After protection of the diol with
2,2-dimethoxypropane to give 7d and reduction with DIBAL-H, 8d
was obtained in 32% yield in an isomeric ratio of 3.5/1 (Scheme 2).
All solvents and materials not described in this chapter are
commercially available and were appropriately purified, if neces-
sary. The hydroxynitrile lyases were kindly provided by DSM Fine
Chemicals Austria. Reactions were monitored by TLC (Merck silica
gel 60 F254) and the compounds were visualised by UV (254 nm)
and by spraying with Mo-reagent (10% H2SO4, 10%
(NH4)Mo7O24$4H2O and 0.8% Ce(SO4)2$4H2O in water) or vanillin/
H2SO4 solution (1 g vanillin in1000 ml H2SO4 conc). Flash chro-
matography was performed on Silica gel 60 (230–400 mesh,
Merck). 1H and 13C NMR-spectra were recorded on a VARIAN
GEMINI 200 MHz (1H 200 MHz, 13C 50 MHz) and VARIAN INOVA
500 MHz (1H 500 MHz, 13C 125 MHz) spectrometer with TMS as an
internal reference. HPLC enantiomeric separation was performed
using a JASCO 880-PU pump and a JASCO 873 UV/VIS detector
connected to a DAICEL OD-H column (25 cmꢂ0.46 cm) or a DAICEL
AD column (25 cmꢂ0.46 cm). Mass spectra: GCT Premier (Waters).
For analytical data vide infra.
Therefore, besides the desired
obtained.
L-ribose also some D-arabinose was
For structure elucidation racemic 50b was converted to 8b fol-
lowing the same synthetic route (Scheme 3). A mixture of protected
arabinose and ribose is obtained in 17% overall yield and in a ratio of
1.7/1. Cleavage of the protecting groups with a strong acidic ion ex-
changer in methanol gave a mixture of 5-O-benzyl pentoses. Sepa-
ration by flash chromatography, analysis by NMR and comparison
with data from literature27,28 showed that the major products are 5-
O-benzyl arabinose derivatives (10).
Comparison of the NMR-spectra of the product mixtures 6d, 7d
and 8d with 6b, 7b and 8b showed that for the conversion of 50d the
major product is also the D-arabinose derivative. The dihydroxylation
step is thereby influenced by the protecting group at C5. 6d
(R¼TBDMS) is obtained in a ratio of arabinose/ribose of 2/1, whereas
6b (R¼Bn) is formed in a 1/1 ratio. The influence of the already
existing stereocentre seems to have far less influence on directing
the dihydroxylation step. Additionally, ribo-6d and ribo-6b are not
converted at the same rate as compared to arabino-6d and arabino-
4.2. Synthesis of (Z)-4-allyloxybut-2-en-1-ol (2a) with KOH
To a solution of 6.5 ml (79.1 mmol, 1 equiv) of 1 in 150 ml of
DMSO 1.2 equiv allylbromide and 1.8 equiv potassium hydroxide

M. Avi et al. / Tetrahedron 65 (2009) 5418–5426
5421
are added. The mixture is stirred at rt until quantitative conversion.
The solution is diluted with water and extracted three times with
CH2Cl2. The aqueous layer is acidified with 1 M HCl and extracted
again five times with CH2Cl2. The combined organic layers are dried
over Na2SO4 and the solvent is removed under reduced pressure.
Purification by flash chromatography (elution gradient cyclohex-
ane/ethyl acetate 25/1 to pure ethyl acetate) gives 6.4 g (63%) of 2a
as light yellow oil. Spectroscopic data are comparable with those
reported in literature.21
4.5.2. (E)-4-Benzyloxybut-2-enal (3b)
2.37 g (75%) as light yellow oil. Spectroscopic data are compa-
rable with those in literature.30
4.5.3. (E)-4-Methoxymethoxybut-2-enal (3c)
696 mg (37%) as light yellow oil. 1H NMR (200 MHz, CDCl3)
d:
3.37 (s, 3H, MOM-CH3); 4.33 (dd, 2H, H4; J¼4.0, 1.8); 4.67 (s, 2H,
MOM-CH2); 6.35 (ddd, 1H, H2, J¼15.8, 7.9, 1.3); 6.84 (dtd, 1H, H3,
J¼15.8, 4.0, 1.3); 9.57 (dd, 1H, H1, J¼7.9, 1.3). 13C NMR (50 MHz,
CDCl3) d: 55.72, 66.04, 96.39, 131.85, 153.00, 193.47.
4.3. Synthesis of (Z)-4-Methoxymethoxybut-2-en-1-ol (2c)
4.5.4. (E)-4-t-Butyldimethylsilyloxybut-2-enal (3d)
455 mg (56%) as colourless liquid. Spectroscopic data are com-
parable with those reported in literature.31
To a solution of 1.0 g (11.4 mmol, 1 equiv) of 1 and 1.6 equiv. N-
ethyldiisopropylamine in 25 ml CH2Cl2 1.4 equiv methoxymethyl
chloride are added dropwise under stirring. After quantitative
conversion the solution is extracted with 1 M HCl and saturated
aqueous NaHCO3. The organic layer is dried over Na2SO4 and the
solvent is removed under reduced pressure. After purification by
flash chromatography (cyclohexane/ethyl acetate 10/1) 2b is
obtained in 33% yield (482 mg) as light yellow oil. 1H NMR
4.5.5. (E)-4-t-Butyldiphenylsilyloxybut-2-enal (3e)
685 mg (57%) as colourless oil. Spectroscopic data correspond
with those reported previously.33
4.6. General procedure for the oxidation to (Z)-
(200 MHz, CDCl3)
d: 2.40 (br d, 1H, OH); 3.36 (s, 3H, MOM-CH3);
aldehydes 30a–e27
4.13 (d, 2H, H4, J¼7.5); 4.17 (d, 2H, H1, J¼7.0); 4.62 (s, 2H, MOM-
CH2); 5.60–5.89 (m, 2H, H2, H3). 13C NMR (50 MHz, CDCl3)
58.47, 62.68, 95.57, 127.88, 132.91.
d: 55.50,
The oxidation of 4-O-protected but-2-en-1,4-diol was per-
formed according to literatute27 in CH2Cl2. After purification by
flash chromatography aldehydes 30a–e are obtained and the un-
converted educts are recovered.
4.4. General procedure for the mono O-protection of (Z)-but-
2-en-1,4-diol with NaH29
4.6.1. (Z)-4-Allyloxybut-2-enal (30a)
1.57 g (19%) as light yellow oil. 63% of 2a recovered. 1H NMR
According to literature29 diol 1 is converted using NaH and the
corresponding protecting reagent. Purification by flash chroma-
tography gives the pure 4-O-protected but-2-en-1,4-diols 2b, 2d
and 2e.
(200 MHz, CDCl3)
d
: 4.05 (d, 2H, Allaliph-CH2, J¼4.8); 4.49 (d, 2H, H4,
J¼5.3); 5.20–5.34 (m, 2H, Allolef-CH2); 5.82–5.96 (m, 1H, All-CH);
5.99–6.10 (n.a., 1H, H2); 6.55–6.67 (m, 1H, H3); 10.07 (d, 1H, H1,
J¼7.0). 13C NMR (50 MHz, CDCl3)
d: 67.14, 72.11, 118.07, 129.90,
134.18, 147.79, 191.69.
4.4.1. (Z)-4-Benzyloxybut-2-en-1-ol (2b)
2.45 g (42%) as light yellow oil. Spectroscopic data are slightly
4.6.2. (Z)-4-Benzyloxybut-2-enal (30b)
different from those reported30 1H NMR (200 MHz, CDCl3)
d: 2.11
1.96 g (20%) as light yellow oil. 77% of 2c recovered. Spectro-
(br s, 1H, OH); 4.09 (d, 2H, H4, J¼5.3); 4.16 (d, 2H, H1, J¼5.7); 4.53 (s,
scopic data are comparable with those reported.34
2H, Bn-CH2); 5.67–5.88 (m, 2H, H2, H3); 7.29–7.36 (m, 5H, Bn-Ph).
13C NMR (50 MHz, CDCl3)
d
: 58.89, 65.86, 72.71, 128.05, 128.11,
4.6.3. (Z)-4-t-Butyldimethylsilyloxybut-2-enal (30d)
128.45, 128.71, 132.62, 138.05.
3.74 g (61%) as colourless liquid. Spectroscopic data are slightly
different from those reported.35 1H NMR (200 MHz, CDCl3)
d: 0.10
4.4.2. (Z)-4-(tert-Butyldimethylsilyloxy)-but-2-en-1-ol (2d)
12.4 g (100%) as light yellow oil (crude). Spectroscopic data
correspond with those reported in literature.31
(s, 6H, TBDMS-2CH3); 0.90 (s, 9H, TBDMS-3CH3); 4.67 (d, 2H, H4,
J¼4.8); 5.93–6.03 (n.a., 1H, H2); 6.51–6.62 (m, 1H, H3); 10.15 (d, 1H,
H1, J¼7.0). 13C NMR (50 MHz, CDCl3)
: ꢁ5.10, 18.50, 26.06, 61.42,
d
128.78, 150.89, 192.11.
4.4.3. (Z)-4-(tert-Butyldiphenylsilyloxy)-but-2-en-1-ol (2e)
1.11 g (56%) as colourless oil. Spectroscopic data are comparable
with those in literature.32
4.6.4. (Z)-4-t-Butyldiphenylsilyloxybut-2-enal (30e)
207 mg (54%) as light yellow oil. 1H NMR data correspond with
those in literature.36 13C NMR (50 MHz, CDCl3)
d: 19.36, 26.99,
61.72, 128.14, 129.05, 130.75, 133.00, 135.75, 150.19, 191.68.
4.5. General procedure for the oxidation to (E)-
aldehydes 3a–e21
4.7. Synthesis and safe-handling of anhydrous HCN–CAUTION
To a solution of 4-O-protected but-2-en-1,4-diol in anhydrous
CH2Cl2 1.5 equiv pyridinium chlorochromate, 1.5 equiv sodium ac-
etate and Celite 545 are added. The mixture is stirred at rt until
quantitative conversion and subsequently poured into Et2O under
vigorous stirring. The mixture is filtered over a Florisil bed. Evap-
oration of the solvent and purification by flash chromatography
yields aldehydes 3a–e.
All reaction equipment, in which HCN or cyanides were in-
volved, was placed in a well-ventilated hood. For continuous
warning, an electrochemical sensor for HCN detection was used.
The required amount of HCN was freshly prepared by adding
dropwise a saturated NaCN solution to aqueous sulfuric acid (60%)
at 80 ꢀC. HCN was transferred in a nitrogen stream through a drying
column and collected in a cooling trap at ꢁ12 ꢀC. Waste solutions
containing cyanides were treated with aqueous sodium hypo-
chlorite (10%). Subsequently the pH was adjusted to 7.0 with
aqueous sulfuric acid.
4.5.1. (E)-4-Allyloxybut-2-enal (3a)
2.1 g (46%) as light yellow oil. Spectroscopic data are comparable
with those reported.21

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M. Avi et al. / Tetrahedron 65 (2009) 5418–5426
4.8. General procedure A (GPA): synthesis of racemic
cyanohydrins
4.9.6. (E)-5-t-Butyldimethylsilyloxy-2-hydroxypent-3-
enenitrile (4d)
GPA affords 96 mg (56%) of rac-4d and GPB 504 mg (87%) of
To a cooled (0 ꢀC) solution of aldehyde in anhydrous tert-butyl
methyl ether (tBME) basic ion exchanger (Amberlyst A-21) and 2.0–
5.0 equiv. HCN are added. The resulting mixture is stirred at 0 ꢀC
until quantitative conversion and subsequently filtered over
a Na2SO4 bed. Evaporation of the solvent under reduced pressure
yields the crude cyanohydrins 4a–e and 40a–e as light yellow liq-
uids, which were further converted without purification. For
spectroscopic data see below.
(2S)-4d. 1H NMR (200 MHz, CDCl3)
d: 0.08 (s, 6H, TBDMS-2CH3);
0.91 (s, 9H, TBDMS-3CH3); 3.05 (br s, 1H, OH); 4.24 (d, 2H, H5,
J¼1.8); 5.01 (d, 1H, H2, J¼4.0); 5.87 (ddd, 1H, H3, J¼15.4, 5.3, 1.3);
6.16 (dt, 1H, H4, J¼15.4, 3.5). 13C NMR (50 MHz, CDCl3)
: ꢁ5.16,
d
18.59, 26.10, 61.62, 62.26, 118.58, 123.23, 135.98.
4.9.7. (Z)-5-t-Butyldimethylsilyloxy-2-hydroxypent-3-
enenitrile (40d)
155 mg (88%) of crude rac-40d are obtained as colourless oil
4.9. General procedure B (GPB): synthesis of (S)-cyanohydrins
with HbHNL
following GPA. 222 mg (78%) of crude (2S)-40d are given by GPB. 1H
NMR (200 MHz, CDCl3) d: 0.08 (s, 6H, TBDMS-2CH3); 0.91 (s, 9H,
TBDMS-3CH3); 4.37 (d, 2H, H5, J¼3.1); 4.59 (br s, 1H, OH); 5.24 (d,
To a solution of aldehyde in tBME an aqueous enzyme solution
(1/1 or 2/1 v/v) of HbHNL is added and the resulting mixture is
stirred at 0 ꢀC until an emulsion is formed. The pH of the enzyme
solution is previously adjusted with a diluted citric acid solution.
After addition of freshly prepared prussic acid (2.0 to 5.0 equiv), the
mixture is stirred at 0 ꢀC or rt until quantitative conversion. The
emulsion is diluted with tBME and broken with Celite 545, filtered
and dried over Na2SO4. Evaporation of the solvent under reduced
pressure yields the crude cyanohydrins 4a–e and 40a–e as light
yellow liquids. They are further converted without purification.
1H, H2, J¼5.3); 5.68–5.89 (n.a., 2H, H3, H4). 13C NMR (50 MHz,
CDCl3)
d: ꢁ5.16, 18.57, 26.09, 57.81, 61.05, 118.68, 125.78, 134.43.
4.9.8. (E)-5-t-Butyldiphenylsilyloxy-2-hydroxypent-3-
enenitrile (4e)
GPA gives 111 mg (103%) of crude rac-4e and GPB yields 655 mg
(102%) of crude (2S)-4e. 1H NMR (200 MHz, CDCl3)
d: 1.09 (s, 9H,
TBDPS-3CH3); 2.63 (br s, 1H, OH); 4.28 (dd, 2H, H5, J¼3.2, 1.3); 5.00
(br s, 1H, H2); 5.96 (ddd, 1H, H3, J¼15.4, 5.3); 6.15 (dt, 1H, H4,
J¼15.4, 3.1); 7.41–7.69 (m, 10H, TBDPS-2Ph). 13C NMR (50 MHz,
CDCl3) d: 19.46, 27.03, 61.66, 62.99, 118.48, 123.21, 128.05, 130.13,
4.9.1. (E)-5-Allyloxy-2-hydroxypent-3-enenitrile (4a)
133.36, 135.74. (2S)-4e: 51% ee (n-heptane/i-propanol¼99.75/0.25,
Diacel OD-H, 254 nm, flow¼0.6 mL/min, T¼25 ꢀC, tR,S¼8.7,
tR,R¼8.0).
540 mg (89%) of rac-4a are given according to GPA and 357 mg
(99%) of crude (2S)-4a are obtained using GPB. 1H NMR (200 MHz,
CDCl3) d: 3.79 (br s,1H, OH); 4.02 (n.a., 4H, Allaliph-CH2, H4); 4.99 (br
s, 1H, H2); 5.19–5.34 (m, 2H, Allolef-CH2); 5.91 (n.a., 2H, H3, All-CH);
4.9.9. (Z)-5-t-Butyldiphenylsilyloxy-2-hydroxypent-3-
enenitrile (40e)
6.14 (dt, 1H, H4, J¼15.4, 4.0). 13C NMR (50 MHz, CDCl3)
d: 61.37,
68.96, 71.90, 118.07, 118.83, 125.93, 132.53, 134.19.
105 mg (103%) of crude rac-40e are given following GPA. 1H NMR
(200 MHz, CDCl3)
2H, H5, J¼4.8); 5.22 (d, 1H, H2, J¼7.0); 5.65–5.91 (n.a., 2H, H3, H4);
7.42–7.71 (m, 10H, TBDPS-2Ph). 13C NMR (50 MHz, CDCl3)
: 19.28,
26.95, 57.85, 61.25, 118.96, 125.73, 128.20, 130.71, 132.60, 134.58,
135.78.
d: 1.08 (TBDPS-3CH3); 3.22 (s, 1H, OH); 4.31 (d,
4.9.2. (Z)-5-Allyloxy-2-hydroxypent-3-enenitrile (40a)
GPA gives 100 mg (68%) of rac-40a, whereas GPB affords 2.74 g
d
(76%) of crude (2S)-40a. 1H NMR (200 MHz, CDCl3)
d: 3.97 (br d, 1H,
OH); 4.06 (d, 2H, Allaliph-CH2, J¼5.3); 4.17 (d, 2H, H5, J¼4.4); 5.17–
5.36 (n.a., 3H, H2, Allolef-CH2); 5.88 (m, 3H, H3, H4, All-CH). 13C NMR
(50 MHz, CDCl3)
133.63.
d: 57.64, 66.69, 72.28, 117.63, 118.81, 127.11, 132.49,
4.10. General procedure for the acetylation of cyanohydrins
4b and 40b
4.9.3. (E)-5-Benzyloxy-2-hydroxypent-3-enenitrile (4b)
Cyanohydrins 4b and 40b are acetylated according to standard
procedures with 2.0 equiv acetic anhydride in a pyridine/CH2Cl2
mixture (1/1 v/v).
Following GPA 111 mg (80%) rac-4c are obtained. GPB gives
650 mg (113%) of crude (2S)-4c. 1H NMR (200 MHz, CDCl3)
d: 3.20
(br s, 1H, OH); 4.09 (dd, 2H, H5; J¼4.8, 1.3); 4.55 (s, 2H, Bn-CH2);
4.95 (d, 1H, H2, J¼5.3); 5.88 (ddd, 1H, H3, J¼15.4, 5.3, 1.3); 6.16 (dtd,
1H, H4, J¼15.4, 4.8, 1.3); 7.35–7.50 (m, 5H, Bn-Ph). 13C NMR
4.10.1. (E)-Acetic acid-4-benzyloxy-1-cyanobut-2-
enyl ester (Ac-4b)
(50 MHz, CDCl3)
d
: 61.44, 69.04, 73.07, 118.39, 125.84, 128.10, 128.19,
61%. 1H NMR (200 MHz, CDCl3)
d
: 2.17 (s, 3H, Ac-CH3); 4.12 (d,
2H, H5, J¼4.4); 4.58 (s, 2H, Bn-CH2); 5.90 (n.a., 2H, H2, H3); 6.26
(n.a., 1H, H4); 7.28–7.43 (Bn-Ph). 13C NMR (50 MHz, CDCl3)
: 20.62,
128.77, 132.81, 137.79.
d
4.9.4. (Z)-5-Benzyloxy-2-hydroxypent-3-enenitrile (40b)
61.08, 68.76, 73.08, 115.59, 121.27, 127.98, 128.14, 128.76, 135.84,
137.84, 169.06. HRMS (El) m/z calcd for C14H15NO2 (Mþ) 245, 1052,
found 245.1055. (2S)-Ac-4b: 99% ee (n-heptane/i-propanol¼99/1,
Diacel AD, 210 nm, flow¼0.7 mL/min, T¼25 ꢀC, tR,S¼39.3 min,
tR,R¼45.6 min).
GPA yields 169 mg (93%) of crude rac-40c as colourless liquid.
GPB affords 266 mg (89%) of crude (2S)-40c. 1H NMR (200 MHz,
CDCl3)
CH2); 5.15 (d, 1H, H2, J¼7.0); 5.75–5.97 (m, 2H, H3, H4); 7.32–7.43
(m, 5H, Bn-Ph). 13C NMR (50 MHz, CDCl3)
: 57.58, 66.66, 73.47,
d: 4.03 (br s, 1H, OH); 4.20 (d, 2H, H5, J¼4.4); 4.59 (s, 2H, Bn-
d
118.98, 127.15, 128.39, 128.50, 128.84, 132.54, 136.91.
4.10.2. (Z)-Acetic acid-4-benzyloxy-1-cyanobut-2-
enyl ester (Ac-40b)
4.9.5. (E)-2-Hydroxy-5-methoxymethoxypent-3-enenitrile (4c)
109 mg (82%) of crude rac-4b are given by GPA and 236 mg
(79%) of crude (2S)-4b are obtained following GPB. 1H NMR
92%. 1H NMR (200 MHz, CDCl3)
d: 2.12 (s, 3H, Ac-CH3); 4.19 (dd,
2H, H5, J¼3.5, 1.8); 4.55 (s, 2H, Bn-CH2); 5.66 (n.a., 1H, H3); 5.97 (m,
1H, H4); 6.28 (d, 1H, H2, J¼8.4); 7.30–7.36 (m, 5H, Bn-Ph). 13C NMR
(200 MHz, CDCl3)
d
: 3.37 (s, 3H, MOM-CH3); 4.13 (d, 2H, H5, J¼4.8);
(50 MHz, CDCl3) d: 20.61, 57.82, 66.53, 73.25, 116.16, 122.44, 128.07,
4.65 (s, 2H, MOM-CH2); 4.98 (d, 1H, H2, J¼4.4); 5.86 (ddd, 1H, H3,
128.18, 128.75, 134.89, 137.53, 168.94. (2S)-Ac-40b: 59% ee (n-hep-
tane/i-propanol¼99.75/0.25, Diacel AD, 210 nm, flow¼1.2 mL/min,
T¼25 ꢀC, tR,S¼36.8 min, tR,R¼42.3 min).
J¼15.4, 5.3, 1.3); 6.14 (dtd, H4, J¼15.4, 4.8, 1.3). 13C NMR (50 MHz,
CDCl3) d: 55.66, 61.35, 66.41, 96.15, 118.46, 125.86, 132.44.

M. Avi et al. / Tetrahedron 65 (2009) 5418–5426
5423
4.11. General procedure for the protection of cyanohydrins 4
a–d and 40a–d with TBDPS
(2S)-5d: 99% ee (n-heptane/i-propanol¼99/1, Diacel OD-H, 254 nm,
flow¼0.5 mL/min, T¼10 ꢀC, tR,S¼9.8 min, tR,R¼9.3 min). HRMS (El)
m/z calcd for C27H39NO2Si2 (Mþ) 465.2519, found 465.2517.
To a solution of cyanohydrin in N,N-dimethylformamide 1.1 equiv
t-butyldiphenylsilyl chloride and 1.4 equiv imidazole are added and
the reaction mixture is stirred at rt until quantitative conversion. The
DMF is removed under reduced pressure and the residue is trans-
ferred with CH2Cl2 in a separatory funnel. The solution is extracted
with 1 M HCl and water and the organic layer is dried over Na2SO4.
Evaporation of the solvent under reduced pressure and purification
by flash chromatography yields the protected cyanoyhydrins 5a–e
and 50a–e.
4.11.6. (Z)-5-(t-Butyldimethylsilyloxy)-2-(t-butyldiphenylsilyloxy)-
pent-3-enenitrile (50d)
50%. 1H NMR (200 MHz, CDCl3)
d: 0.07 (s, 6H, TBDMS-2CH3);
0.77 (s, 9H, TBDMS-3CH3); 1.09 (s, 9H, TBDPS-3CH3); 3.93 (n.a., 2H,
H5); 5.35 (d, 1H, H2, J¼5.3); 5.56–5.71 (n.a., 2H, H3, H4); 7.35–7.74
(m, 10H, TBDPS-2Ph). 13C NMR (50 MHz, CDCl3)
d
: ꢁ5.39, 18.38,
19.46, 26.00, 26.82, 59.57, 60.43, 118.95, 125.93, 128.14, 128.25,
130.48, 130.61, 131.93, 132.24, 134.04, 135.92, 135.99. (2S)-50d: 10%
ee (n-heptane/i-propanol¼99.75/0.25, Diacel OD-H, 254 nm,
flow¼0.6 mL/min, T¼25 ꢀC, tR,S¼10.1 min, tR,R¼8.1 min).
4.11.1. (E)-5-Allyloxy-2-t-butyldiphenylsilyloxypent-3-
enenitrile (5a)
69%.1H NMR (200 MHz, CDCl3)
d: 1.11 (s, 9H, TBDPS-3CH3); 3.68
4.12. (Z)-(S)-2-(t-Butyldiphenylsilyloxy)-5-hydroxypent-3-
(d, 2H, Allaliph-CH2, J¼3.1); 3.98 (d, 2H, H5, J¼3.1); 4.85 (d, 1H, H2,
J¼5.3); 5.18–5.32 (m, 2H, Allolef-CH2); 5.61–6.00 (n.a., 3H, H3, H4,
All-CH); 7.40–7.74 (m, 10H, TBDPS-2Ph). 13C NMR (50 MHz, CDCl3)
enenitrile (50f)26
To a solution of 630 mg of 50a (1.62 mmol, 1 equiv) in 800
dioxane 180 mg of SeO2 (1.78 mmol, 1.1 equiv) and 140 L of glacial
mL of
d: 19.51, 26.89, 63.10, 69.01, 71.57, 117.45, 118.30, 126.33, 128.17,
m
128.25, 130.59, 130.62, 130.71, 131.59, 132.07, 134.04, 135.95, 136.01.
(2S)-5a: 98% ee (n-heptane/i-propanol¼99.75/0.25, Diacel OD-H,
254 nm, flow¼0.7 mL/min, T¼25 ꢀC, tR,S¼17.5 min, tR,R¼15.8 min).
acetic acid(2.43 mmol,1.5 equiv)areaddedandthemixtureisstirred
under reflux for 1 h. After cooling to rt the orange solution is filtered
through a pad of Celite and washed with CH2Cl2. Evaporation of the
solvent under reduced pressure and purification by flash chroma-
tography (cyclohexane/ethyl acetate 10/1) affords 50f (0.387 g, 68%)
4.11.2. (Z)-5-Allyloxy-2-t-butyldiphenylsilyloxypent-3-
enenitrile (50a)
as a yellow oil. 1H NMR (CDCl3)
d
: 1.09 (s, 9H, TBDPS-3CH3); 3.82 (d,
2H, H5); 5.21 (m, 1H, H2); 5.69 (m, 2H, H3, H4); 7.44–7.75 (m, 10H
TBDPS-2Ph). 13C NMR (CDCl3)
: 19.45, 26.80, 59.08, 62.7, 118.80,
84%. 1H NMR (200 MHz, CDCl3)
d
: 1.09 (s, 9H, TBDPS-3CH3);
3.67–3.74 (n.a., 4H, H5, Allaliph-CH2); 5.06–5.24 (n.a., 3H, H2, Allolef
CH2); 5.79 (m, 3H, H3, H4, All-CH); 7.36–7.74 (m, 10H, TBDPS-2Ph).
13C NMR (50 MHz, CDCl3)
: 19.45, 26.82, 59.52, 66.15, 71.65, 117.60,
-
d
126.71, 128.15, 128.32, 130.75, 131.69, 132.18, 133.74, 135.98, 136.03.
d
118.72, 127.48, 128.16, 128.62, 130.52, 130.64, 131.58, 131.81, 132.12,
134.23, 135.94, 136.01. (2S)-50a: 93% ee (n-heptane/i-prop-
anol¼99.75/0.25, Diacel OD-H, 254 nm, flow¼0.7 mL/min, T¼25 ꢀC,
tR,S¼17.8 min, tR,R¼14.9 min). HRMS (El) m/z calcd for C24H29NO2Si
(Mþ) 391.1967, found 391.1961.
4.13. (Z)-(S)-5-(t-Butyldimethylsilyloxy)-2-(t-butyldiphenyl-
silyloxy)-pent-3-enenitrile (50d), alternative procedure
To a solution 390 mg of 50f (1.11 mmol,1 equiv) in 3 mL of CH2Cl2
are added 185 mg of tert-butyldimethylsilyl chloride (1.1 equiv) and
105 mg of imidazole (1.4 equiv) and the mixture is stirred overnight.
The solution is washed with 1 M HCl and saturated aqueous NaHCO3
and the organic layer is dried over Na2SO4. Evaporation of the sol-
vent under reduced pressure yields 462 mg (89%) of 50d as colour-
less oil, which is used without further purification. For spectroscopic
data see above.
4.11.3. (Z)-5-Benzyloxy-2-t-butyldiphenylsilyloxypent-3-
enenitrile (50b)
75%.1H NMR (200 MHz, CDCl3)
d: 1.10 (s, 9H, TBDPS-3CH3); 3.67–
3.74 (m, 2H, CH2-Bn); 4.24 (d, 1H, H5, J¼11.77); 4.31 (d, 1H, H50,
J¼11.76); 5.24 (m, 1H, H2); 5.75 (m, 2H, H3, H4); 7.16–7.19 (m, 2H,
Ph); 7.26–7.32 (m, 3H, Ph); 7.37–7.51 (m, 6H, Ph); 7.62–7.65 (m, 2H,
Ph); 7.69–7.73 (m, 2H, Ph). 13C NMR (50 MHz, CDCl3)
d
: 19.41, 26.78,
4.14. (2R)-5-(t-Butyldimethylsilyloxy)-2-(t-butyldiphenyl-
59.46, 66.18, 72.79, 118.68, 127.51, 127.84, 127.93, 128.08, 128.21,
128.60, 130.46, 130.59, 131.50, 131.71, 132.07, 135.88, 135.93, 137.63.
silyloxy)-3,4-dihydroxypentanenitrile (6d)
To 1 mL of a solvent mixture of acetone/H2O (4:1) in a 2-necked
4.11.4. (E)-2-t-Butyldiphenylsilyloxy-5-methoxymethoxypent-3-
round bottom flask with septum 15.7
mL of an aqueous OsO4 solution
enenitrile (5c)
(4%, 0.002 mmol, 0.05 equiv) and 14.3
solution (0.14 mmol, 1.3 equiv) are added and stirred for 4–5 min.
Afterwards 1 mL of a solution of 50 mg of 50d (0.107 mmol, 1 equiv)
m
L of a 30% aqueous H2O2
71%. 1H NMR (200 MHz, CDCl3)
d
: 1.10 (s, 9H, TBDPS-3CH3); 3.36
(s, 3H, MOM-CH3); 4.05 (d, 2H, H5, J¼3.5); 4.61 (s, 2H, MOM-CH2);
4.85 (d, 1H, H2, J¼4.8); 5.72–5.97 (n.a., 2H, H3, H4); 7.39–7.73 (m,
in acetone/H2O (4:1) is added. Additional 28.6 mL of aqueous H2O2
10H, TBDPS-2Ph). 13C NMR (50 MHz, CDCl3)
d
: 19.52, 26.90, 55.59,
solution (30%) are added slowly over a period of 4–5 h. The reaction
mixture is stirred for 14 h until quantitative conversion. A few
crystals of Na2SO3 are added and after stirring for another 30 min,
the mixture is filtered over a bed of silica gel and Na2SO4 and the
silica/Na2SO4 bed is washed with ethyl acetate. Evaporation of the
solvent under reduced pressure and purification by flash chroma-
tography (cyclohexane/ethyl acetate 20:1 v/v) affords 36 mg (67%) of
63.10, 66.23, 96.07, 126.34, 128.17, 128.25, 130.60, 130.71, 131.67,
131.78, 132.10, 135.97, 136.06. (2S)-5b: 66% ee (n-heptane/i-prop-
anol¼99.75/0.25, Diacel OD-H, 254 nm, flow¼0.7 mL/min, T¼25 ꢀC,
tR,S¼27.4 min, tR,R¼23.5 min). HRMS (El) m/z calcd for C23H29NO3Si
(Mþ) 395.1917, found 395.1921.
4.11.5. (E)-5-t-Butyldimethylsilyloxy-2-t-butyldiphenyl-
6d as colourless oil. Isomeric ratio 1/2. 1H NMR (CDCl3)
d: arabino
silyloxypent-3-enenitrile (5d)
(500 MHz): 0.12 (s, 6H, 2CH3-Si); 0.92 (s, 9H, TBDMS-3CH3); 1.17 (s,
9H, TBDPS-3CH3); 2.52 (d, 1H, OH(C4), J¼6.05); 2.91 (d, 1H, OH(C3),
J¼7.65); 3.69–3.77 (m, 2H, H3, H5, J¼10.25, 2.84); 3.85–3.91 (dq, 2H,
H4, H50, J¼10.30, 6.05); 4.77 (d, 1H, H2, J¼2.78); 7.44–7.55 (m, 6H,
TBDPS-Ph); 7.72–7.77 (m, 4H, TBDPS-Ph). ribo (200 MHz): 0.08 (s, 6H,
CH3-Si); 0.85 (s, 9H TBDMS-3CH3); 1.10 (s, 9H TBDPS-3CH3); 3.62–
3.80 (m, 2H, H3, H5); 3.82–3.91 (m, 2H, H4, H50); 4.76 (m, 1H, H2);
71%. 1H NMR (200 MHz, CDCl3)
d: 0.06 (s, 6H, TBDMS-2CH3);
0.91 (s, 9H, TBDMS-3CH3); 1.10 (s, 9H, TBDPS-3CH3); 4.16 (dd, 2H,
H5, J¼3.1; J3¼1.3); 4.85 (d, 1H, H2, J¼4.8); 5.75 (ddd, 1H, H3, J¼15.4,
5.3, 1.3); 5.91 (dt, 1H, H4, J¼15.4, 3.1); 7.35–7.73 (m, 10H, TBDPS-
2Ph). 13C NMR (50 MHz, CDCl3)
d
: ꢁ5.12, 18.58, 19.52, 26.11, 26.90,
62.29, 63.20, 122.58, 123.91, 128.16, 128.32, 130.66, 134.89, 136.07.

5424
M. Avi et al. / Tetrahedron 65 (2009) 5418–5426
7.37–7.55 (m, 6H, TBDPS-Ph); 7.60–7.80 (m, 4H, TBDPS-Ph). 13C NMR
are added and the resulting mixture is stirred for 4–5 min. A so-
d
: arabino (125 MHz): ꢁ5.30, ꢁ5.25, 18.45, 19.68, 26.03, 27.04, 64.0,
lution of 1.033 g of rac-50b (2.34 mmol, 1 equiv) in 19 mL of an
70.09, 74.01, 77.45, 118.38, 128.17, 128.29, 130.80, 130.82, 131.12,
131.32, 136.09, 136.20. ribo (50 MHz): ꢁ5.30, ꢁ5.25, 18.44, 19.52,
25.85, 26.89, 63.35, 70.75, 73.57, 77.72,117.94,128.34, 128.44,130.81,
130.86, 131.15, 131.37, 135.82, 136.02.
acetone/H2O (5:1) mixture is added. Additional 620 mL of the
aqueous H2O2 (30%, 3.08 mmol, 2.6 equiv) solution are added
slowly over a period of 4–5 h and the reaction mixture is stirred for
14 h until quantitative conversion. A few crystals of Na2SO3 are
added and after stirring for 30 min the mixture is filtered over a bed
of silica gel and Na2SO4. The silica/Na2SO4 bed was washed with
ethyl acetate and the combined organic layers are concentrated
under reduced pressure. After purification by flash chromatography
(cyclohexane/ethyl acetate 20:1 v/v) 655 mg (59%) of 6b are
4.15. (2R)-[5-(t-Butyldimethylsilyloxymethyl)-2,2-dimethyl-
[1,3]dioxolan-4-yl]-(t-butyldiphenylsilyloxy)-acetonitrile (7d)
To a solution of 90 mg of 6d (0.18 mmol, 1 equiv) in 5 mL of
CH2Cl2 2,2-dimethoxypropane (445
mL, 3.6 mmol, 20 equiv) and
obtained as colourless oil. Isomeric ratio 1/1. 1H NMR (CDCl3)
d:
a catalytic amount of pyridinium para-toluene sulfonate are added.
The mixture is stirred at rt until quantitative conversion. After
evaporation of the solvent under reduced pressure and purification
by flash chromatography (cyclohexane/ethyl acetate 10:1 v/v)
64 mg (66%) of 7d are obtained as colourless oil. Isomeric ratio 1/1.
arabinoþribo: 1.13 (s, 18H, TBDMS-3CH3, arabino, ribo); 3.58–3.63
(dd, 1H, H5, J¼5.01, 9.7); 3.66–3.70 (dd, 1H, H50, J¼3.1, 9.72); 3.72–
3.87 (m, 8H, H3, H4 arabino, H3, H4 ribo, H5, H50); 4.52 (s, 2H, CH2-
Bn) 4.55, 4.56 (2s, 2H, CH2-Bn); 4.72 (d, 1H, H2, J¼3.30); 4.74 (d, 1H,
H2, J¼3.17); 7.27–7.52 (m, 22H, 6H TBDPS-Ph, 5H Bn arabino, 6H
TBDPS-Ph, 5H Bn ribo); 7.64–7.75 (m, 8H, 4H TBDPS-Ph arabi-
1H NMR (CDCl3)
d
: arabinoþribo: ꢁ0.06 (s, 3H, CH3-Si); ꢁ0.05 (s, 3H,
CH3-Si); 0.01 (s, 3H, CH3-Si); 0.03 (s, 6H, CH3-Si); 0.76 (s, 9H,
TBDMS-3CH3); 0.83 (s, 9H, TBDMS-3CH3); 1.12 (s, 18H, TBDPS-
3CH3); 1.35 (s, 3H, CH3,isoprop); 1.37 (s, 3H, CH3,isoprop); 1.45 (s, 3H,
CH3,isoprop); 1.55 (s, 3H, CH3,isoprop); 3.63–3.68 (dd, 1H, H5 ribo,
J¼10.71, 5.34); 3.80–3.86 (dd, 1H, H50 ribo, J¼10.72, 7.59), 3.92–3.98
(dd, 1H, H5 arabino, J¼4.25, 11.17); 3.98–4.04 (dd, 1H, H50 arabino,
J¼11.32, 5.27); 4.09–4.15 (dt, 1H, H4 ribo, J¼7.11, 5.58); 4.23–4.27
(dd, 1H, H3 ribo, J¼6.82, 2.99); 4.28–4.35 (m, 2H, H3, H4 arabino,
J¼6.18); 4.52 (d, 1H, H2 arabino, J¼6.04); 4.79 (d, 1H, H2 ribo,
J¼3.06); 7.38–7.50 (m, 12H, 6H, TBDPS-Ph ribo, 6H, TBDPS-Ph ara-
bino); 7.68–7.74 (m, 8H, 4H, TBDPS-Ph ribo, 4H, TBDPS-Ph arabino).
noþribo). 13C NMR
d arabino: 19.68, 27.03, 63.92, 69.35, 71.18, 73.85,
74.06, 118.31, 127.99, 128.11, 128.21, 128.33, 128.87, 130.85, 130.86,
131.09, 131.33, 136.08, 136.21, 137.55. ribo: 19.51, 27.01, 65.96, 70.05,
70.76, 73.74, 73.80, 117.20, 127.99, 128.27, 128.29, 128.35, 128.74,
130.81, 130.85, 131.17, 131.72, 135.88, 136.08, 137.72.
4.16. (5-Benzyloxymethyl-2,2-dimethyl-[1,3]dioxolan-4-yl)-
(tert-butyldiphenylsilyloxy)-acetonitrile (7b)
To a solution of 6b (2 g, 4.205 mmol,1 equiv) in 120 mL of CH2Cl2
2,2-dimethoxypropane (10.3 mL, 84.1 mmol, 20 equiv) and a cata-
lytic amount of pyridinium para-toluene sulfonate are added. The
mixture is stirred at rt until quantitative conversion. Evaporation of
the solvent under reduced pressure and purification by flash chro-
matography (cyclohexane/ethyl acetate 10:1 v/v) yields 7b (1.87 g,
13C NMR
d
: arabinoþribo: ꢁ5.35, ꢁ5.18, ꢁ5.15, 18.39, 18.62, 19.54,
19.61, 25.26, 25.27, 26.02, 26.11, 26.97, 26.99, 27.26, 27.33, 61.35,
61.59, 63.17, 63.27, 76.66, 77.93, 78.09, 79.27, 109.66, 109.95, 117.93,
118.45, 128.07, 128.15, 128.20, 130.53, 130.58, 130.64, 130.66, 131.54,
131.56, 131.88, 132.22, 135.97, 136.11, 136.15, 136.20.
86%) as colourless oil. Isomeric ratio 1.5/11H NMR (CDCl3)
d: arabino:
1.05 (s, 9H TBDPS-3CH3); 1.36 (s, 3H, CH3,isoprop); 1.50 (s, 3H,
CH3,isoprop); 3.93–4.01 (m, 2H, H5, H50 J¼4.02); 4.20 (t, 1H, H3,
J¼6.18); 4.42 (d, 1H, H2, J¼5.64); 4.49 (d, 1H, CH2-Bn, J¼12.19); 4.52–
4.57 (dt, 1H, H4, J¼6.63, 4.03); 4.69 (d, 1H, CH2-Bn, J¼12.19); 7.26–
7.51 (m, 6H, TBDPS-Ph); 7.60–7.69 (m, 4H, TBDPS-Ph). ribo: 1.08 (s,
9H TBDPS-3CH3); 1.38 (s, 3H, CH3,isoprop); 1.53 (s, 3H, CH3,isoprop);
3.47–3.52 (dd,1H, H5, J¼10.04, 5.81); 3.61–3.66 (dd,1H, H50, J¼10.05,
5.95); 4.24–4.28 (dd, 1H, H3, J¼6.57, 4.18); 4.32–4.35 (m, 1H, H4,
J¼6.20); 4.36 (s, 1H, CH2-Bn); 4.37 (s, 1H, CH2-Bn), 4.64 (d, 1H, H2,
J¼4.18), 7.26–7.51 (m, 6H, TBDPS-Ph); 7.60–7.69 (m, 4H, TBDPS-Ph).
4.15.1. (2R)-[5-(t-Butyldimethylsilanyloxymethyl)-2,2-dimethyl-
[1,3]dioxolan-4-yl]-(t-butyldiphenylsilanyloxy)-acetaldehyde (8d)
50 mg of cyanohydrin 7d (0.093 mmol, 1 equiv) are dissolved
in 6 mL of dry pentane and cooled to ꢁ78 ꢀC. A 1.5 M DIBAL-H
(1.5 equiv) solution in toluene is added under argon atmosphere.
Afterstirringfor3 h atꢁ78 ꢀC 2.5 mLofMeOHareaddedviaa syringe
and the mixture is allowed to warm to 0 ꢀC. After stirring for addi-
tionally 2.5 h,1 mL of 0.5 M H2SO4 is added and the resulting mixture
is stirred further for 1 h at 0 ꢀC. The mixture is diluted with 2 mL H2O
and extracted three times with 10 mL of Et2O each. The combined
organiclayersare driedoverNa2SO4 andconcentratedunderreduced
pressure. Purification by flash chromatography (cyclohexane/ethyl
acetate 20:1 v/v) affords 8d (16 mg, 32%) as colourless oil. Isomeric
13C NMR
d: arabino: 19.44, 25.23, 26.92, 27.06, 63.19, 67.68, 73.81,
76.70, 77.22, 110.24, 118.38, 127.95, 128.14, 128.22, 128.68, 130.68,
130.77, 131.15, 131.64, 135.99, 136.14, 137.89. ribo: 19.50, 25.28, 26.97,
27.36, 63.23, 68.04, 73.81, 75.42, 78.72, 110.17, 117.87, 127.95, 128.17,
128.18, 128.63, 130.62, 130.70, 131.30, 131.90, 136.02, 136.17, 137.66.
ratio 3.5/1.1H NMR (CDCl3)
d: arabino: ꢁ0.08 (s, 3H, CH3-Si); ꢁ0.05 (s,
3H, CH3-Si); 0.77 (s, 9H TBDMS-3CH3); 1.09 (s, 9H TBDPS-3CH3); 1.29
(s, 3H, CH3,isoprop); 1.37 (s, 3H, CH3,isoprop); 3.53–3.57 (dd, 1H, H5,
J¼10.77, 5.41); 3.63–3.67 (dd,1H, H50, J¼10.69, 6.86); 4.22 (dt,1H, H4,
J¼6.86, 5.58); 4.31 (d,1H, H2, J¼6.88); 4.39 (dd,1H, H3, J¼6.87, 5.86);
7.31–7.44 (m, 6H, TBDPS-Ph); 7.67–7.71 (m, 4H, TBDPS-Ph); 9.51 (s,
1H, CHO). ribo: ꢁ0.02 (s, 6H 2CH3-Si); 0.81 (s, 9H TBDMS-3CH3); 1.11
(s, 9H TBDPS-3CH3); 1.30 (s, 3H, CH3,isoprop); 1.43 (s, 3H, CH3,isoprop);
3.66–3.70 (dd,1H, H5, J¼10.37, 5.67); 3.91–3.94 (dd,1H, H50, J¼10.60,
6.85); 4.11 (dt, 1H, H4, J¼6.76, 5.79); 4.39 (dd, 1H, H3, J¼6.87, 3.36),
4.48 (dd, 1H, H2, J¼3.33, 1.07); 7.31–7.44 (m, 6H, TBDPS-Ph); 7.62–
7.65 (m, 4H, TBDPS-Ph); 9.44 (d, 1H, CHO, J¼1.08).
4.17. (5-Benzyloxymethyl-2,2-dimethyl-[1,3]dioxolan-4-yl)-
(tert-butyldiphenylsilyloxy)-acetaldehyde (8b)
To a solution of 1.0 g of 7b (1.94 mmol,1.0 equiv) in 100 mL of dry
pentane at ꢁ78 ꢀC a 1.5 M DIBAL-H (2.61 mL, 2 equiv) solution in
toluene is added under argon atmosphere. After stirring for 2 h at
ꢁ78 ꢀC 50 mL of MeOH are added via a syringe and the mixture is
allowed to warm to 0 ꢀC. After stirring for additionally 2 h, 20 ml of
0.5 M H2SO4 are added and the resulting mixture is stirred for 1 h at
0 ꢀC. Afterwards the mixture is diluted with 20 mL H2O and extrac-
ted three times with 100 mL of Et2O each. The combined organic
layers are dried over Na2SO4 and concentrated under reduced
pressure. Purification by flash chromatography (cyclohexane/ethyl
acetate 10:1 v/v) affords 330 mg (33%) of 8b as colourless oil. Iso-
4.15.2. 5-Benzyloxy-2-(t-butyldiphenylsilyloxy)-3,4-
dihydroxypentanenitrile (6b)
To 5 mL of an acetone/H2O (5:1) mixture in a 2-necked round
bottom flask with septum 350
mL of an aqueous OsO4 (4%) solution
meric ratio 1.6/1. 1H NMR (CDCl3)
3CH3, arabino); 1.07 (s, 9H, TBDPS-3CH3, ribo); 1.30 (s, 3H, CH3,isoprop
d
arabinoþribo: 1.06 (s, 9H, TBDPS-
and 310 L of an aqueous H2O2 (30%, 3.04 mmol, 1.3 equiv) solution
m
,

M. Avi et al. / Tetrahedron 65 (2009) 5418–5426
5425
arabino); 1.31 (s, 3H, CH3,isoprop, ribo); 1.42 (s, 3H, CH3,isoprop, arabino);
1.43 (s, 3H, CH3,isoprop, ribo); 3.45–3.49 (dd, 1H, H5 arabino, J¼10.18,
6.56); 3.50–3.54 (dd,1H, H5 ribo, J¼9.87, 6.76); 3.56–3.61 (dd,1H, H50
arabino, J¼10.19, 4.90); 3.61–3.65 (dd,1H, H50 ribo, J¼9.89, 5.39); 4.18
(d, 1H, H2 arabino, J¼6.14); 4.29 (d, 1H, CH2-Bn arabino, J¼12.06);
4.30–4.35 (m, 3H, H3 arabino, H2, H3 ribo); 4.37–4.45 (m, 4H, H4
arabino, H4, CH2-Bn ribo); 4.45 (d, 1H, CH2-Bn, arabino, J¼12.08);
7.18–7.44 (m,12H, 6H TBDPS-Ph, 5H Bn arabino, 6H TBDPS-Ph, 5H Bn
ribo); 7.57–7.67 (m, 8H, 4H TBDPS-Ph arabino, 6H TBDPS-Ph ribo);
stirred for 5 d. Filtration and evaporation of the solventunder reduced
pressure affords a mixture of six products. Products can be separated
by flash chromatography (cyclohexane/ethyl acetate 10:1 v/v).
4.19.1. Methyl 5-O-benzyl-2-O-(t-butyldiphenylsilyl)-
ribofuranoside ( -9b)
5.6 mg (2.9%) as colourless oil. 1H NMR (CDCl3)
a-L-
a
d
1.1 (s, 9H,
TBDPS-3CH3); 3.22 (d, 1H, OH); 3.33 (s, 3H, OMe), 3.48 (dd, 2H, H5,
H50, J¼3.9); 3.9 (t, 1H, H3, J¼4.8); 4.13 (m, 1H, H2); 4.22 (m, 1H, H4,
J¼3.9); 4.37 (d, 1H, H1, J¼4.4); 4.44 (dd, 2H, H6, H60, J¼12.2); 7.15–
9.40 (d, 1H, CHO ribo, J¼1.45); 9.53 (s, 1H, CHO arabino). 13C NMR
d:
arabino: 19.64, 25.19, 27.14, 27.17, 68.55, 73.45, 76.29, 77.17, 77.36,
109.18, 127.87, 127.88, 127.92, 128.00, 128.58, 130.20, 130.24, 132.98,
136.19, 136.21, 137.84, 200.12. ribo: 19.56, 24.92, 27.09, 27.13, 69.30,
73.45, 75.76, 77.20, 78.37, 109.05, 127.84, 127.90, 127.94, 128.03,
128.56, 130.24, 130.32, 132.93, 136.07, 136.21, 137.96, 201.13.
7.74 (m, 15H, Bn-Ph, TBDPS-2Ph). 13C NMR
d 55.52, 70.55, 71.60,
73.26, 73.59, 84.81, 103.42, 127.80–138.42 (Ph-C). HRMS (El) m/z
calcd for C29H36O5Si (Mþ) 492.2332, found 492.2335.
4.19.2. Methyl 5-O-benzyl-2-O-(t-butyldiphenylsilyl)-
ribofuranoside ( -9b)
20 mg (10.5%) as colourless oil. 1H NMR (CDCl3)
b-L-
b
4.18. Deprotection of 8b to 5-O-benzylfuranoses
d 1.12 (s, 9H,
TBDPS-3CH3); 2.58 (d, 1H, OH); 3.04 (s, 3H, OMe); 3.52 (dd, 1H, H5,
J¼10.5); 3.68 (dd, 1H, H50); 4.04 (m, 1H, H3); 4.13 (d, 1H, H2); 4.18
(m, 1H, H4, J¼6.8); 4.52 (s, 1H, H1); 4.59 (s, 2H, H6, H60); 7.25–7.75
To a solution of 8b (100 mg, 0.193 mol) in 2.5 mL of MeOH Dowex
50 W-X4 (washed with MeOH) is added at rt and the suspension is
stirred for 9 h. Filtration and evaporation of the solvent under re-
duced pressure affords a mixture of four products. Separation is done
by flash chromatography (cyclohexane/ethyl acetate 10:1 v/v).
(m, 15H, Bn-Ph, TBDPS-2Ph). 13C NMR
d 19.57, 27.22, 55.24, 72.19,
72.75, 73.62, 76.92, 83.36, 108.06, 127.79, 127.91, 128.13, 128.20,
128.57, 130.42, 132.50, 133.11, 135.95, 136.06, 138.44. HRMS (El) m/z
calcd for C26H36O5Si (Mþ), 492.2332, found 492.2328.
4.18.1. 5-O-Benzyl-2-O-(t-butyldiphenylsilyl)-
-9a)
5 mg (5.4%) as colourless oil 1H NMR (CDCl3)
a-L-ribofuranose
(a
4.19.3. Methyl 5-O-benzyl-2-O-(t-butyldiphenylsilyl)-
arabinofuranoside ( -10b)
10 mg (5.3%) as colourless oil. 1H NMR (CDCl3)
a
-
L
-
d
1.15 (s, 9H,
a
TBDPS-3CH3), 3.6 (dd, 1H, H5), 3.61 (m, 1H, C1-OH), 3.69 (dd, 1H,
H50, J¼10.25); 3.94 (d, 1H, H3); 4.2 (m, 1H, H4); 4.23 (m, 1H, H2,
J¼5.4); 4.45 (dd, 2H, H6, H60, J¼11.7); 4.94 (dd, 1H, H1, J¼4.4); 7.1–
d
1.05 (s, 9H,
TBDPS-3CH3); 2.25 (d, 1H, OH); 3.22 (s, 3H, OMe); 3.65 (dd, 1H, H5,
J¼9.7); 3.72 (dd, 1H, H50); 3.87 (d, 1H, H3, J¼5.3); 4.09 (s, 1H, H2);
4.2 (m,1H, H4); 4.58–4.68 (dd, 2H, H6, H60, J¼12.2); 4.76 (s, 1H, H1);
7.7 (m, 15H, Bn-Ph, TBDPS-2Ph). 13C NMR
d 70.40, 72.08, 73.61,
73.92, 84.41, 97.30, 127.68–137.29 (Ph-C). HRMS (El) m/z calcd for
7.25–7.65 (m, 15H, Bn-Ph, TBDPS-2Ph). 13C NMR
d55.04, 71.18,
C28H34O5Si4 (Mþ) 478.2176, found 478.2170.
73.68, 79.26, 81.95, 85.62, 109.27, 127.93, 128.03, 128.07, 128.14,
128.65, 130.26, 130.32, 133.11, 133.34, 135.96, 138.28.
4.18.2. 5-O-Benzyl-2-O-(t-butyldiphenylsilyl)-
-9a)
5 mg (5.4%) as colourless oil. 1H NMR (CDCl3)
b
-
L
-ribofuranose
1.15 (s, 9H, TBDPS-
(b
4.19.4. Methyl 5-O-benzyl-2-O-(t-butyldiphenylsilyl)-
arabinofuranoside ( -10b)
11.3 mg (6%) as colourless oil. 1H NMR (CDCl3)
b-L-
d
b
3CH3); 2.76 (d, 1H, C3-OH); 3.22 (d, 1H, C1-OH); 3.46 (dd, 2H, H5,
H50); 4.13 (dd,1H, H2); 4.2 (m,1H, H3); 4.3 (m, 1H, H4); 4.41 (dd, 2H,
H6, H60 J¼12.2); 5.03 (d,1H, H1), 7.1–7.7 (m,15H, Bn-Ph, TBDPS-2Ph).
d 1.10 (s, 9H,
TBDPS-3CH3); 1.85 (br s, 1H, OH); 3.25 (s, 3H, OMe); 3.56 (dd, 1H,
H5, J¼9.3); 3.60 (dd, 1H, H50); 3.86 (q, 1H, H4, J¼6.3); 4.1 (m, 1H,
H2); 4.2 (d, 1H, H1, J¼4.4 Hz); 4.27 (t, 1H, H3); 4.58 (dd, 2H, H6, H60,
13C NMR
d 70.27, 72.64, 73.42, 78.96, 82.76, 102.35, 127.82–138.06
(Ph-C). HRMS (El) m/z calcd for C28H34O5Si (Mþ) 478.2176, found
J¼12.2); 7.15–7.75 (m, 15H, Bn-Ph, TBDPS-2Ph). 13C NMR
d 55.19,
478.2168.
73.08, 73.64, 78.10, 79.15, 79.89, 102.72, 127.74–138.31 (Ph-C).
4.18.3. 5-O-Benzyl-2-O-(t-butyldiphenylsilyl)-
-10a)
15 mg (16.3%) as colourless oil. 1H NMR (CDCl3)
a
-
L
-arabinofuranose
4.19.5. Methyl 5-O-benzyl-a-L-arabinofuranoside (a-10c)
(a
21 mg (21.4%) as colourless oil. Spectroscopic data correspond
d
1.09 (s, 9H,
with those in literature.27
TBDPS-3CH3); 2.35 (br s, 1H, C3-OH); 3.15 (br s, 1H, C1-OH); 3.66
(dd, 1H, H5, J¼10.25); 3.69 (dd, 1H, H50); 3.95 (d, 1H, H3); 4.06 (d,
1H, H2); 4.34 (m, 1H, H4, J¼6.8); 4.6 (dd, 2H, H6, H60, J¼12.2); 5.26
4.19.6. Methyl 5-O-benzyl-b-L-arabinofuranoside (b-10c)
5 mg (5.09%) as colourless oil. Spectroscopic data correspond
(d, 1H, H1), 7.3–7.8 (m, 15H, Bn-Ph, TBDPS-2Ph). 13C NMR
73.72, 79.03, 82.29, 85.75, 103.35, 128.07–138.14 (Ph-C).
d 71.16,
with those reported earlier.27
4.20. Methyl 5-O-benzyl-b-ribofuranoside (b-9c)
4.18.4. 5-O-Benzyl-2-O-(t-butyldiphenylsilyl)-
-10a)
8 mg (8.7%) as colourless oil. 1H NMR (CDCl3)
b-L-arabinofuranose
(b
To a solution
and the mixture is stirred for 7d at rt. Filtration and evaporation of
the solvent affords -9b as colourless oil in 7.8% yield. The
unreacted starting material can be recovered. Spectroscopic data
correspond with those in literature.28
b-9c in 2 mL of MeOH Amberlite IR-120 is added
d
1.13 (s, 9H,
TBDPS-3CH3); 3.60 (dd, 1H, H5, J¼10.0); 3.63 (dd,1H, H50); 3.78 (dd,
1H, H4, J¼5.4); 3.87 (br s, 1H, C1-OH); 4.07 (m, 1H, H3), 4.1 (dd, 1H,
H2); 4.6 (dd, 2H, H6, H60, J¼11.7); 5.12 (d, 1H, H1, J¼4.4); 7.3–7.8 (m,
b
15H, Bn-Ph, TBDPS-2Ph). 13C NMR
80.58, 96.98, 128.01–138.04 (Ph-C).
d 70.98, 73.85, 78.12, 79.89,
Acknowledgements
4.19. Deprotection of 8b to methyl-5-O-benzylfuranosides
The authors want to thank C. Illaszewicz for measurement of
NMR spectra as well as Prof. Dax for his help concerning in-
terpretation of NMR spectra. For providing the enzymes DSM Fine
Chemicals Austria is gratefully acknowledged.
To a solution of 8b (200 mg, 0.39 mmol) in 5 mL MeOH Dowex
50 W-X4 (washed with MeOH) is added at rt and the suspension

5426
M. Avi et al. / Tetrahedron 65 (2009) 5418–5426
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