Large-scale synthesis of (R)-2-amino-1-(2-furyl)ethanol via a chemoenzymatic approach

Article abstract of DOI:10.1021/op050264b

A two-step chemoenzymatic synthesis of (R)-2-amino-1-(2-furyl)ethanol for laboratory production was developed followed by successful up-scaling to kilogram scale. The generation of the asymmetric centre was accomplished by a highly enantioselective cyanohydrin reaction of furan-2-carbaldehyde with hydrocyanic acid catalyzed by the hydroxynitrile lyase from Hevea brasiliensis. Subsequent sodium borohydride reduction furnished the desired product with an enantiomeric excess of higher than 99.5%. This procedure can be considered a convenient general route for the stereoselective synthesis of ethanol amine derivatives underlining the role of biocatalysis for the generation of stereogenic centres in the synthesis of chiral intermediates.

Full text of DOI:10.1021/op050264b

Organic Process Research & Development 2006, 10, 618−621
Large-Scale Synthesis of (R)-2-Amino-1-(2-furyl)ethanol via a Chemoenzymatic
Approach
Thomas Purkarthofer,† Thomas Pabst,‡ Cor van den Broek, Herfried Griengl,† Oliver Maurer,§ and Wolfgang Skranc*,§
Research Centre Applied Biocatalysis, Petersgasse 14, A-8010 Graz, Austria, DSM Pharma Chemicals Regensburg
GmbH, RESCOM, Donaustaufer Strasse 378, D-93055 Regensburg, Germany, DSM Research, AdVanced Synthesis
Catalysis & DeVelopment, P.O. Box 18, 6160 MD Geleen, The Netherlands, and DSM Fine Chemicals Austria NfG
GmbH & Co KG, R & D Center Linz, St.-Peter-Strasse 25, A-4021 Linz, Austria
Abstract:
In our development efforts we needed to set up a short
and efficient sequence for the production of 3, possibly
involving the generation of the chiral centre in a single
stereoselective step to avoid the resolution of a racemate. In
general the application of a robust and reliable in-house
technology for the synthesis of newly emerging target
molecules appears to be an appealing strategy for synthetic
planning. In this regard we envisaged the route to vicinal
amino alcohols via the reduction of cyanohydrins, which is
supposed to be especially attractive for the synthesis of amino
alcohols containing a primary amine function.
The synthesis of the desired (R)-cyanohydrin has been
reported in the literature either by dipeptide-catalyzed
hydrocyanation,6 metal-mediated cyanosilylation,7 kinetic
resolution8 or hydroxynitrile lyase-catalyzed hydrocyanation.9
The asymmetric enzymatic large-scale production of cyano-
hydrins catalyzed by both (R)- and (S)-hydroxynitrile lyases
is well established at DSM,10 and the synthesis of a large
number of enantiomerically enriched cynohydrins has been
reported in the literature.11 Hydroxynitrile lyases are versatile
plant enzymes which catalyze the cleavage of R-hydroxy-
nitriles to set free HCN in a vegetal defense mechanism.12
The reversed processsthe stereoselective addition of hydro-
cyanic acid to carbonyl compoundsshas matured to a very
powerful tool in enzymatic asymmetric organic synthesis.13
To date these biocatalysts are available in recombinant form
for the production of enantiomerically enriched cyanohydrins
A two-step chemoenzymatic synthesis of (R)-2-amino-1-(2-
furyl)ethanol for laboratory production was developed followed
by successful up-scaling to kilogram scale. The generation of
the asymmetric centre was accomplished by a highly enantio-
selective cyanohydrin reaction of furan-2-carbaldehyde with
hydrocyanic acid catalyzed by the hydroxynitrile lyase from
HeWea brasiliensis. Subsequent sodium borohydride reduction
furnished the desired product with an enantiomeric excess of
higher than 99.5%. This procedure can be considered a
convenient general route for the stereoselective synthesis of
ethanol amine derivatives underlining the role of biocatalysis
for the generation of stereogenic centres in the synthesis of
chiral intermediates.
Introduction
The demand for chiral enantiopure advanced intermediates
for the pharmaceutical industry is constantly increasing.1 As
a consequence, the development of convenient protocols for
the production of single enantiomers of chiral materials has
become a very important issue.2
A recent research project at DSM was dealing with the
synthesis of (R)-2-amino-1-(2-furyl)ethanol (3) on kilogram
scale.
The 1,2-amino alcohol moiety is a widespread structural
motif in natural and synthetic biologically active molecules.
Therefore, these intermediates are important building blocks
for fine chemical synthesis owing to the biological signifi-
cance of these substances.3 To date a wealth of synthetic
procedures for the production of vicinal amino alcohols has
been developed.4 Obvious synthetic strategies to obtain 3
comprisesamong otherssthe opening of the corresponding
enantiopure epoxide and the stereoselective reduction of a
corresponding ketone.5
(5) (a) Merten, J.; Fro¨hlich, R.; Metz, P. Angew. Chem. 2004, 116, 6117-
6120; Angew. Chem., Int. Ed. 2004, 43, 5991-5994. (b) Hamada, T.; Torii,
T.; Izawa, K.; Ikariya, T. Tetrahedron 2004, 60, 7411-7417.
(6) Kogut, E. F.; Thoen, J. C.; Lipton, M. A. J. Org. Chem. 1998, 63, 4604-
4610.
(7) Li, Y.; He, B.; Qin, B.; Feng, X.; Zhang, G. J. Org. Chem. 2004, 69, 7910-
7913.
(8) Waldmann, H. Tetrahedron Lett. 1989, 30, 3057-3058.
(9) (a) Schmidt, M.; Herve´, S.; Klempier, N.; Griengl, H. Tetrahedron 1996,
52, 7833-7840. (b) Effenberger, F.; Eichhorn, J. Tetrahedron: Asymmetry
1997, 8, 469-476. (c) Griengl, H.; Klempier, N.; Po¨chlauer, P.; Schmidt,
M.; Shi, N.; Zabelinskaja-Mackova, A. A. Tetrahedron 1998, 54, 14477-
14486. (d) Solis, A.; Luna, H.; Pe´rez, H. I.; Manjarrez, N. Tetrahedron:
Asymmetry 2003, 14, 2351-2353. (e) Veum, L.; Hanefeld, U.; Pierre, A.
Tetrahedron 2004, 60, 10419-10425.
* Corresponding author: E-mail: Wolfgang.Skranc@dsm.com. Telephone:
+43(0)732-6916-4058. Fax: +43(0)732-6916-64058.
† Research Centre Applied Biocatalysis, Graz, Austria.
‡ DSM Pharma Chemicals Regensburg, Germany.
DSM Research, Advanced Synthesis Catalysis & Development, Geleen, The
Netherlands.
(10) (a) Po¨chlauer, P. Chim. Oggi 1998, 16, 15-19. (b) Glieder, A.; Weis, R.;
Skranc, W.; Poechlauer, P.; Dreveny, I.; Majer, S.; Wubbolts, M.; Schwab,
H.; Gruber, K. Angew. Chem. 2003, 115, 4963-4966; Angew. Chem., Int.
Ed. 2003, 42, 4815-4818. (c) Weis, R.; Gaisberger, R.; Skranc, W.; Gruber,
K.; Glieder, A. Angew. Chem. 2005, 117, 4778-4782; Angew. Chem., Int.
Ed. 2005, 44, 4700-4704.
§ DSM Fine Chemicals Austria NfG GmbH & Co KG, Linz, Austria.
(1) Breuer, M.; Ditrich, K.; Habicher, T.; Hauer, B.; Kesseler, M.; Stu¨rmer,
R.; Zelinski, T. Angew. Chem. 2004, 116, 806-843; Angew. Chem., Int.
Ed. 2004, 43, 788-824.
(2) Patel, R. N. Food Technol. Biotechnol. 2004, 42, 305-325.
(3) Kleemann, A.; Engel, J. Pharmaceutical Substances: Syntheses, Patents,
Applications; 3rd ed.; Thieme: Stuttgart, New York, 1999.
(4) Bergmeier, S. C. Tetrahedron 2000, 56, 2561-2576.
(11) (a) Gregory, R. J. H. Chem. ReV. 1999, 99, 3649-3682. (b) North, M.
Tetrahedron: Asymmetry 2003, 14, 147-176.
(12) Gruber, K.; Kratky, C. J. Polym. Sci., Part A: Polym. Chem. 2004, 42,
479-486.
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10.1021/op050264b CCC: $33.50 © 2006 American Chemical Society
Published on Web 03/30/2006

Scheme 1. Chemoenzymatic approach for the production
of (R)-2-amino-1-(2-furyl)ethanol (3)
Table 1. HbHNL-catalyzed synthesis of
(R)-2-(2-furyl)-2-hydroxyacetonitrile (2)
quantity yield ee
quantity yield ee
batch
[g]
[%] [%]
batch
[g]
[%] [%]
1
2
3
4
5
32.4
33.3
33.7
32.0
35.0
88 99.7
90 99.6
91 99.6
87 99.8
95 99.6
6
7
8
9
31.3
30.4
30.8
31.3
85 99.6
82 99.6
83 99.6
85 99.8
with both (R)- and (S)-configuration, rendering this technol-
ogy enantiocomplementary.10,14
Herein we report on the synthesis of (R)-2-amino-1-(2-
furyl)ethanol (3) via (R)-2-(2-furyl)-2-hydroxyacetonitrile (2)
by stereoselective enzyme-catalyzed hydrocyanation of furan-
2-carbaldehyde (1) using the recombinant hydroxynitrile
lyase from HeVea brasiliensis (HbHNL) followed by reduc-
tion of the cyanohydrin 2 with sodium borohydride. This
procedure enables the use of a reliable in-house technology
for the stereoselective generation of the asymmetric centre
in the key step of a straightforward synthesis, applying furan-
2-carbaldehyde (1) as a cheap starting material and avoiding
any protection/deprotection steps (Scheme 1).
spontaneous unselective addition of HCN to the carbonyl
substrate and racemization of the cyanohydrin product are
suppressed. At the same time the enzyme activity is strongly
reduced, or even complete inactivation of the catalyst is
observed. The application of higher pH values (6-7)
provides optimal biocatalyst activity. However, this is usually
accompanied by a decrease of enantiomeric excess of the
product due to nonenzymatic HCN addition. Freshly pro-
duced hydrocyanic acid as the cyanide source was added
dropwise to the reaction mixture over a period of 15 min.
After completion of the reaction (prolonged reaction times
lead to a decrease of enantiomeric excess) and product
isolation, the cyanohydrin was analyzed by chiral GC after
acetylation using racemic material as a reference. Due to
internal laboratory safety regulations limiting the amount of
HCN applied in one transformation, the required quantity
of 2 had to be synthesized in cumulative batches. In every
single reaction the product was obtained in 83-95% yield
with an optical purity exceeding 99%. In total, 290 g of 2
were produced in reproducible constant yield and quality in
nine single batches (Table 1). In general a reuse of the
biocatalyst in successive batches is possible and economically
feasible; however, recycling of the enzyme was not consid-
ered on this production scale.
Results and Discussion
Synthesis of (R)-2-(2-Furyl)-2-hydroxyacetonitrile (2)
on Laboratory Scale. The first task of the project was to
synthesize a 100-g sample of 3 with an enantiomeric excess
greater than 98%. At the same time it was imperative to
choose the reaction conditions in such a way that would allow
up-scaling of the procedure.
To minimize the time for the development of the process
the hydroxynitrile lyase from HeVea brasiliensis (HbHNL)
was the enzyme of choice to be investigated for the
carboligation step to yield the cyanohydrin intermediate 2,
not only because of its stereopreference and substrate range
but also because we were able to rely on a wealth of
experience from prior applications of this enzyme.
Furthermore, the enzyme is produced by overexpression
and is purified at DSM, thus providing sufficient quantities
of biocatalyst for development and production. The HbHNL-
catalyzed addition of HCN to furan-2-carbaldehyde (1) was
carried out in an aqueous buffer/tert-butyl methyl ether
(TBME) emulsion at pH 5.2 and 0 °C. In previous compre-
hensive studies ethers such as diisopropyl ether and TBME
proved to be the most suitable solvents for this purpose. The
choice of pH for enzymatic cyanohydrin reactions is of
utmost importance. At low pH (<5) the
It is important to note that the orientation of asymmetric
induction of the (S)-selective HbHNL is maintained with
furan-2-carbaldehyde as the substrate. The (R)-configuration
of 3 has to be assigned according to the Cahn-Ingold-
Prelog rules.
Reduction of (R)-2-(2-Furyl)-2-hydroxyacetonitrile (2).
The reduction of R-hydroxynitriles to yield vicinal amino
alcohols is conveniently accomplished with complex metal
hydrides, e.g., lithium aluminium hydride (LAH) or sodium
borohydride. This particular transformation is reported to
proceed without racemization which was a fundamental
prerequisite for our purposes.15 Owing to the hazardous
nature of LAHsespecially with regard to large-scale
applicationsand its elevated price compared to NaBH4, we
considered the latter the reagent of choice for the reduction
of 2. Hence, we elaborated this transformation by applying
NaBH4 in THF in combination with a carboxylic acid (to
generate the borane-THF complex) followed by aqueous
quench of the reaction. After acidifying the aqueous layer
and extraction with an organic solvent, 3 was purified by
crystallization.
(13) (a) Effenberger, F. Angew. Chem. 1994, 106, 1609-1619; Angew. Chem.,
Int. Ed. Engl. 1994, 33, 1555-1564. (b) Griengl, H.; Hickel, A.; Johnson,
D. V.; Kratky, C.; Schmidt, M.; Schwab, H. Chem. Commun. 1997, 1933-
1940. (c) Effenberger, F.; Fo¨rster, S.; Wajant, H. Curr. Opin. Biotechnol.
2000, 11, 532-539. (d) Johnson, D. V.; Zabelinskaja-Mackova, A. A.;
Griengl, H. Curr. Opin. Chem. Biol. 2000, 4, 103-109. (e) Griengl, H.;
Schwab, H.; Fechter, H. Trends Biotechnol. 2000, 18, 252-256. (f) Fechter,
M. H.; Griengl, H. Enzymatic synthesis of cyanohydrins. In Enzyme
Catalysis in Organic Synthesis; Drauz, K., Waldmann, H., Eds.; Wiley-
VCH: Weinheim, 2002; pp 974-989. (g) Fechter, M. H.; Griengl, H. Food
Technol. Biotechnol. 2004, 42, 287-294. (h) Sharma, M.; Sharma, N. N.;
Bhalla, T. C. Enzyme Microb. Technol. 2005, 37, 279-294.
(14) (a) Hasslacher, M.; Schall, M.; Hayn, M.; Griengl, H.; Kohlwein, S. D.;
Schwab, H. J. Biol. Chem. 1996, 271, 5884-5891. (b) Weis, R.; Poechlauer,
P.; Bona, R.; Skranc, W.; Luiten, R.; Wubbolts, M.; Schwab, H.; Glieder,
A. J. Mol. Catal. B: Enzym. 2004, 29, 211-218. (c) Poechlauer, P.; Skranc,
W.; Wubbolts, M. The Large-Scale Biocatalytic Synthesis of Enantiopure
Cyanohydrins. In Asymmetric Catalysis on Industrial Scale; Blaser, H. U.,
Schmidt, E., Eds.; Wiley-VCH: Weinheim, 2004; pp 151-164.
(15) (a) Ziegler, T.; Ho¨rsch, B.; Effenberger, F. Synthesis 1990, 575-578. (b)
Monterde, M. I.; Nazabadioko, S.; Robolledo, F.; Brieva, R.; Gotor, V.
Tetrahedron: Asymmetry 1999, 10, 3449-3455.
Vol. 10, No. 3, 2006 / Organic Process Research & Development
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Table 2. Synthesis of (R)-2-(2-furyl)-2-hydroxyacetonitrile
(2) on kilogram scale
However, the reduction step required more optimization
work than the HCN addition. Trifluoroacetic acid turned out
to be the appropriate acid component to give product 3 in
64% yield. Replacing trifluoroacetic acid with trichloroacetic
acid (mainly for cost reasons) furnished 3 in only 37% yield,
although the conversion was virtually identical in both cases,
implying that trichloroacetic acid was not compatible with
the workup procedure (vide infra). After the addition of water
to decompose excess NaBH4 the reaction mixture was
filtrated, THF was removed, and the remaining aqueous
phase was acidified. At this stage careful control of the pH
is mandatory since product degradation was observed at pH
1. The formation of a precipitate during the decomposition
of the NaBH4 excess can be avoided by adding 1 M sulphuric
acid instead of water to the reaction. Stirring in alkaline
solution by addition of a 5 N sodium hydroxide solution at
elevated temperature (60 °C) after quench of the reaction
mixture turned out to be another possibility to circumvent
the filtration step. Furthermore, under these conditions amino
alcohol 3 is liberated from its adduct with the reducing agent.
Unfortunately, using these alternative procedures the content
of the amino alcohol in the crude product decreased
dramatically thereby outweighing the advantages mentioned
above. In addition, the extraction of the amino alcohol from
the aqueous phase during workup had to be investigated as
well. 3 was found to be sufficiently soluble in ethyl acetate.
However, by using this solvent, byproducts of the reaction,
which were not analyzed, were also extracted, leading to
lower product purity and lower yield after crystallization.
TBME extraction was examined, but problems with phase
separation were encountered. This might be due to the
presence of trichloro ethanol which is formed by reduction
of trichloro acetic acidsthe acid component applied in this
particular case. By using trifluoroacetic acid the correspond-
ing alcohol does not interfere with the workup procedure,
and the desired product is obtained in higher yield. The
reason for this observation was not investigated in detail.
The best results in terms of both yield and product purity
could be achieved by extraction of 3 with dichloromethane
or chloroform although long extraction times were needed
due to the reduced solubility of the product as compared to,
for example, solubility in ethyl acetate.
quantity yield ee
quantity yield ee
batch
[kg]
[%] [%]
batch
[kg]
[%] [%]
1
2
3
0.69
1.03
1.11
56 99.1
84 98.8
90 99.3
4
5
6
1.10
1.13
1.16
90 99.3
92 99.0
95 99.4
[diluted with K2HPO4 buffer (pH 5.2) and adjusted to pH
4.9 with a 10% citric acid solution] was added. The mixture
was stirred for 10 min at 0 °C. During 45 min of HCN dosage
the temperature was kept below 3 °C. The remaining HCN
from the pump vessel was fed into a HCN-killing drum
containing a NaOH solution. The reaction was stirred at 0°C
and monitored by GC. When the conversion of the aldehyde
exceeded 99%, a filter aid and TBME were added to the
reactor; after 5 min the reaction mixture was pressed over a
precoated filter with N2 pressure. After phase separation the
organic phase was stabilized with citric acid. The aqueous
phase was washed twice with TBME (also used for pre-
coating of the filter and washing of the filter cake), and the
combined organic solvents and residual water were removed
in a film evaporator yielding pure (R)-2-(2-furyl)-2-hydroxy-
acetonitrile (2). Unreacted HCN in the water phase was
destroyed with a NaOH solution and iron sulphate. The
required amount of 2 was produced in six consecutive
batches in a fully reproducible way (Table 2. The reduced
yield in the first batch was due to bad phase separation. This
problem could be overcome by addition of larger amounts
of filter aid to minimize the solvent interphase).
The combined cyanohydrins 2 were subjected to reduction
in two batches. Sodium borohydride was added to a reactor
containing THF. Subsequently, trifluoroacetic acid was added
slowly over a period of 60 min. After an additional 15 min
of stirring, a solution of 2 in THF is added dropwise over a
period of 90 min. Both the addition of trifluoroacetic acid
and 2 are exothermic and cause hydrogen formation. The
reaction was finished after approximately 2 h. The resulting
suspension was dropped slowly into water, again conceivably
an exothermic step. From the start the temperature was kept
between 15 and 25 °C. Stirring was continued until the gas
development had ceased. After the addition of a filter aid
and filtration and washing of the precipitate with THF, the
latter was removed from the filtrate in vacuo. The residual
water phase was adjusted to pH 2 with 6 M HCl and was
stirred overnight and washed with dichloromethane. In the
following step the pH was shifted to 13-14, and the product
was extracted with dichloromethane in a continuous fashion.
Finally, the raw material was recovered after drying of the
combined organic extracts by azeotropic distillation, polish
filtration, and complete removal of the solvent. Recrystal-
lization from ethyl acetate furnished amino alcohol 3 with a
yield of 57%.
Crystallization experiments for final purification of 3
revealed ethyl acetate to be slightly superior to TBME.
By applying the optimized procedure (R)-2-amino-1-(2-
furyl)ethanol (3) was obtained in 64% yield with a purity
greater than 99% and an enantiomeric excess over 99.5%. 3
was analyzed by GC after transformation of the amino
alcohol into the corresponding acetonide with acetone/
sulphuric acid and by GC/MS after silylation with N,O-
bis(trimethylsilyl)trifluoroacetamide.
Production of (R)-2-Amino-1-(2-furyl)ethanol (3) on
Kilogram Scale. For up-scaling of the procedure no sig-
nificant changes of the laboratory process were necessary.
For the HbHNL-catalyzed cyanohydrin reaction (synthesis
of 2) a cooled reactor, operated atmospherically under N2
purging, was charged with TBME and freshly distilled furan-
2-carbaldehyde (1). After cooling to 0°C the enzyme solution
In summary, we provided a synthetic route for the
production of (R)-2-amino-1-(2-furyl)ethanol (3) via bio-
catalytic hydrocyanation of furan-2-carbaldehyde (1) and
subsequent reduction of (R)-2-(2-furyl)-2-hydroxyacetonitrile
(2) with sodium borohydride. 3 was obtained with higher
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Vol. 10, No. 3, 2006 / Organic Process Research & Development

than 99.5% enantiomeric excess and with a purity greater
than 98%, completely meeting the required specifications.
The described procedure constitutes an efficient method for
the stereoselective chemoenzymatic large-scale production
of chiral 1-substituted ethanol amines. Furthermore, it also
grants access to products bearing substitution patterns other
than the furyl moiety and presumably with both (R)- and
(S)-configuration.
consistent with literature data.9a,17 Chirasil-DEX CB, 130 °C,
74 kPa H2; retention times: 1.46 min 1, 2.92 min S-2 acetate,
3.36 min R-2 acetate.
(R)-2-Amino-1-(2-furyl)ethanol (3): Laboratory Pro-
cedure. THF (900 mL) was placed in the reactor under a
nitrogen atmosphere at 20 °C. NaBH4 (55.3 g, 1.46 mol)
was added slowly, and the temperature of the stirred slurry
was adjusted to 15 °C. Subsequently, 166.6 g (1.46 mol) of
trifluoroacetic acid was added slowly (H2-development) over
a period of 60 min, while the temperature was kept between
15 and 22 °C. After stirring for an additional 15 min 90.0 g
(0.73 mol) of 2 dissolved in 100 mL of THF was added over
a period of 90 min, keeping the temperature below 25 °C.
The reaction mixture was stirred overnight. For workup 500
mL of water were added at 18 °C (H2-development), and
the reaction mixture was stirred until the gas development
had ceased. After filtration of the white precipitate over Celite
and washing with 100 mL of THF, the combined liquids
were subjected to a distillation to remove THF. The residual
aqueous solution was acidified with HCl (pH 2), stirred
overnight, and extracted with CH2Cl2 (2 × 250 mL). By
adding a 50% NaOH solution the aqueous phase was adjusted
to pH 13-14 and extracted with CH2Cl2 in a continuous
fashion. Drying of the combined organic phases with Na2SO4,
filtration, and removal of the solvent under reduced pressure
yielded 59.27 g of 3 as a yellow solid, yield 64%, ee >99.5%.
A 35 g sample of raw 3 was recrystallized from ethyl acetate
Experimental Section
General. All reagents and solvents were obtained from
commercial sources and appropriately purified if necessary.
Due to the limited stability of cyanohydrin 2, prolonged
1
storage should be avoided. H and 13C NMR spectra were
recorded on a Bruker DPX 300 Avance Series. For GC and
GC/MS analyses see below.
HCN: Safe Handling. Hydrocyanic acid was produced
in the HCN plant at DSM. It is important to avoid
contamination either by base, which could lead to violent
polymerization, or by strong acids, which results in formation
of gaseous products.16 Residual hydrocyanic acid from the
HCN dosage line and unreacted HCN in the aqueous phase
of the reaction mixture were destroyed in a diluted NaOH
solution.
(R)-2-(2-Furyl)-2-hydroxyacetonitrile (2): Laboratory
Procedure. 1 (28.8 g, 0.30 mol) was dissolved in 85 mL of
TBME and cooled to 0 °C. HbHNL solution (7.0 mL, 6500
iU/mL, determined for cleavage of mandelonitrile) was
diluted with 128 mL of phospate buffer pH 5.2 (50 mM),
and the pH was adjusted to 4.9 with a 10% citric acid
solution. The phases were combined in the reactor and stirred
at 0 °C until an emulsion was formed. HCN (29.3 mL, 0.76
mol) was added over a period of 15 min. After 2.5 h the
reaction mixture was diluted with 100 mL of TBME and
was filtrated over Celite. The Celite was washed with 50
mL of TBME. After phase separation the aqueous phase was
extracted with TBME (2 × 60 mL), and the combined
organic phases were dried with Na2SO4. Removal of the
solvent furnished 2 as a slightly yellow oil in 83-95% yield
and an ee > 99.5%. GC analysis: derivatization: 30 µL of
cyanohydrin, 1 mL of CH2Cl2, 40 µL of pyridine, 47 µL of
acetic anhydride, 3 drops of DMAP (10% solution in
CH2Cl2), allowed to stand for 10 min. The 1H- and 13C NMR
spectra of the racemic 2-acetate used as a reference were
1
to yield 28 g of pure product (>99% purity). H NMR
(CD3CN): δ ) 2.43 (br s, 3H), 2.82 (dd, J ) 13 Hz, J ) 7
Hz, 1H), 2.91 (dd, J ) 13 Hz, J ) 5 Hz, 1H), 4.49 (dd, J )
7 Hz, J ) 5 Hz, 1H), 6.25 (d, J ) 3 Hz, 1H), 6.35 (dd, J )
3 Hz, J ) 2 Hz, 1H), 7.42 (d, J ) 2 Hz, 1H). 13C NMR
(CD3CN): δ ) 46.8, 68.9, 106.4 110.6, 142.3, 157.0. GC
analysis: derivatization: 50 mg of 3, 1 mL of acetone, 10
µL of H2SO4, allowed to stand for 15 min; Chirasil-DEX
CB, 90 °C, 74 kPa H2; retention times: 1.65 min S-3
acetonide, 1.85 min R-3 acetonide. GC/MS analysis: de-
rivatization: 100 mg of 3, 100 µL of N,O-bis(trimethylsilyl)-
trifluoroacetamide in CH2Cl2; HP-5 column, 50 °C/2 min -
10 °C/min to 320 °C - 5 min, 66 kPa He; retention times:
10.92 min bis-silyl-3, 13.78 min trisilyl-3.
Received for review December 29, 2005.
OP050264B
(17) (a) Lin, G.; Han, S.; Li, Z. Tetrahedron 1999, 55, 3531-3540. (b) Ooi, T.;
Miura, T.; Takaya, K.; Ichikawa, H.; Maruoka, K. Tetrahedron 2001, 57,
867-873. (c) Hamashima, Y.; Sawada, D.; Nogami, H.; Kanai, M.;
Shibasaki, M. Tetrahedron 2001, 57, 805-814.
(16) Banavali, R.; Chang, M. Y.; Fitzwater, S. J.; Mukkamala, R. Ind. Eng. Chem.
Res. 2002, 41, 145-152.
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