Asymmetric cyanohydrin synthesis catalyzed by Al(salen)/triphenylphosphane oxide

Article abstract of DOI:10.1002/ejoc.200400721

Various aldehydes undergo asymmetric trimethylsilylcyanation with (CH ₃)₃SiCN (TMSCN) in the presence of a chiral Al(salen) complex and Ph₃PO as the catalyst. This is a double activation where Al(salen) plays the role of Lewis acd and POPh₃ acts as a Lewis base. Various kind of aldehydes were subjected to the enantioselective addition of (CH₃)₃SiCN at temperatures between -40 °C and -50 °C. Hydrolysis of the adducts gave cyanohydrins with over 90 % yield and 80 % ee in most cases. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005.

Full text of DOI:10.1002/ejoc.200400721

FULL PAPER
Asymmetric Cyanohydrin Synthesis Catalyzed by Al(salen)/Triphenylphosphane
Oxide
Sung Soo Kim*[a] and Dae Ho Song[a]
Keywords: Aldehydes / Aluminum / Cyanation / Phosphane oxide
Various aldehydes undergo asymmetric trimethylsilylcyan-
ation with (CH3)3SiCN (TMSCN) in the presence of a chiral
Al(salen) complex and Ph3PO as the catalyst. This is a double
activation where Al(salen) plays the role of Lewis acd and
POPh3 acts as a Lewis base. Various kind of aldehydes were
subjected to the enantioselective addition of (CH3)3SiCN at
temperatures between –40 °C and –50 °C. Hydrolysis of the
adducts gave cyanohydrins with over 90% yield and 80% ee
in most cases.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
Introduction
Chiral cyanohydrins are useful intermediates because the
two functional groups can be easily transformed into vari-
ous homochiral ones, including α-hydroxy acids,[1,2] α-hy-
droxy aldehydes,[3] α-hydroxy ketones,[3] β-hydroxy
amines,[2,3] and α-amino acid derivatives.[4] A number of
catalysts for the asymmetric addition of cyanide to alde-
hydes[5] are known, including synthetic peptides and chiral
transition metal complexes. Belokon,[6] Shibasaki,[7]
Deng,[8] Hoveyda and Snapper,[9] Bu,[10] and Feng[11] have
made considerable contributions to the development of cat-
alysts for chiral silylcyanation, and we have reported achiral
silylcyanation of aldehydes and ketones catalyzed by N-
morpholine N-oxide and various alkali fluorides.[12] The
salen structure has been employed as a base with which
numerous metal ions can be combined to make effective
catalysts. Belokon and North et al.[6] have reported various
The reaction conditions of entry 3 were chosen for the reac-
tion at room temp. because of the shorter reaction time.
Neither Al(salen) nor Ph3PO alone induce any enantio-
selectivity (entries 7 and 8). Molecular sieves (MS) or
tBu3PO were also used as the additive but gave poor ee
(entries 9 and 10). This may indicate a double activation
process occurring through the catalysis of both the chiral
Lewis acid and achiral Lewis base. The Al(salen) complex
functions as a Lewis acid to activate the aldehyde while
Ph3PO acts as a Lewis base for the activation of TMSCN.
The reaction temperature was then varied and found to be
optimal at –50 °C (entry 13). The attack of cyanide should
occur at the si face of the aldehyde carbonyl to afford an
(R)-cyanohydrin because the re face is effectively blocked
by bonding between the carbonyl oxygen and the Al atom
of chiral Al(salen) (Figure 1).
TiIV–salen complexes that are effective for silylcyanation.
[6b]
[Ti(salen)(μ-O)]2
proved to be the best catalyst (52–92%
ee). The same authors[6e] also used VO(salen) as the catalyst
to give 68–95% ee. Bu et al.[10] modified the substituents on
the benzene ring of the salen ligand (tert-pentyl group) and
combined it with Ti(OiPr)4 to give the products in 84–94%
yield and 92–97% ee. We would like to report here the chi-
ral silylcyanation of aldehydes utilizing Al(salen) and
Ph3PO as the catalyst.
Accordingly, structurally different aldehydes were used as
substrates in the reaction under the conditions of entry 13
of Table 1. Benzaldehydes with various electron-donating
substituents were transformed into chiral cyanohydrins in
over 90% yield and 80% ee (Table 2, entry 1–6). However,
p-NO2C6H4CHO shows very poor reactivity towards the
silylcyanation and was isolated in low yield (40%) along
with numerous other products. trans-Cinnamaldehyde
underwent silylcyanation at relatively high temperature
Results and Discussion
The quantity of Al(salen) and Ph3PO was varied at room
temp. to determine the optimal yield and ee. Entries 3–6 in
Table 1 show similar outcomes with different reaction times.
[a] Department of Chemistry, Inha University,
Incheon 402-751, South Korea
Eur. J. Org. Chem. 2005, 1777–1780
DOI: 10.1002/ejoc.200400721
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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S. S. Kim, D. H. Song
FULL PAPER
Table 1. Silylcyanation of benzaldehyde catalyzed by Al(salen) under various conditions in CH2Cl2.
[a] Yield of isolated product. [b] Conversion.
direction of approach of both groups to give the (R)-form
of the cyanohydrin.
Experimental Section
General Remarks: All aldehydes and Al(salen) were purchased from
Sigma–Aldrich. 1H and 13C NMR spectra were recorded with a
Varian Jemini 2000 (200 MHz) or a Varian Unity Inova 400
(400 MHz) NMR spectrometer. Hewlett–Packard 5890A Gas
Chromatograph/Jeol JMS-DX303 Mass Spectrometer was used to
collect HRMS data.
Figure 1. Transition state involved in the enantioselective cyanosi-
lylation of aldehydes by double-activation catalysis.
(–40 °C) with 91% yield and 78% ee. Furaldehyde (entry 8)
requires a shorter reaction time. 3-Phenylpropanal (entry 9)
reacts smoothly with (CH3)3SiCN to give the chiral cya-
nohydrin. The reaction of trimethylsilyl cyanide with citral
requires a longer reaction time and occurs with 72% ee
(Table 2).
Silylcyanation of the Aldehydes: The aldehyde (2 mmol) was added
to a stirred CH2Cl2 solution of the catalyst [1 mol-% Al(salen),
10 mol-% Ph3PO] and the mixture stirred for 30 min at between–
40 °C and –50 °C. TMSCN (2.4 mmol) was then added with a sy-
ringe pump and the mixture was stirred at the same temperature
for 18–20h. The solvent was then evaporated, 2 n HCl (10 mL) was
added, and the mixture was stirred vigorously at room temp. for
1 h to hydrolyze the trimethylsilyl ether. After addition of ethyl
acetate (30 ml), the mixture was stirred for 30 min. The organic
layer was separated and washed with H2O. The aqueous layer was
extracted with ethyl acetate (2×20 mL), and the combined organic
layers were washed with brine and dried with Na2SO4. The crude
product was further purified by flash chromatography (hexane/
ethyl acetate, 9:1) to give the cyanohydrin in more than 90% yield.
The enantiomeric excess of the products was determined after con-
version to acetyl ester, ethyl carbonate, or tert-butyl dimethylsilyl
Conclusions
A highly efficient double activation catalysis has been de-
veloped for the enantioselective silylcyanation of various al-
dehydes. The Al atom of chiral Al(salen) activates the car-
bonyl oxygen for the formation of Si–O bond. Ph3PO func-
tions as a base for transfer of the NϵC group to the carbon
atom of the carbonyl. The chirality of Al(salen) controls the ether by known methods. The sample was identified by 1H and 13
C
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Asymmetric Cyanohydrin Synthesis
FULL PAPER
Table 2. Trimethylsilylcyanation of aldehydes with Al(salen) and Ph3PO.
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NMR spectroscopy and HRMS, and the ee was determined on a
chiral HPLC column (DAICEL CHIRALCEL OD and DAICEL
CHIRALCEL AS). All data was in accordance with literature val-
[4]
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Acknowledgments
[6]
The authors warmly thank the Korea Science and Engineering
Foundation for financial support (R01-2001-00057).
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Received: October 12, 2004
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