Michael North,* Paola Carta,

Department of Chemistry, King`s College London, Strand, London, WC2R 2LS, U.K

Introduction Using a Sacrificial Aldehyde

Enantiomerically pure cyanohydrins have considerable synthetic potential as chiral building The trend of graph 1 shows the ee increasing with time during the first few hours which indicates the
blocks in organic synthesis due to the fact that the two functional groups (OH and CN) can be complex catalyst 1 is a pre-catalyst. Once this pre-catalyst has been activated, the highest ee is found,
staying constant until completion of reaction. To prove this hypothesis we used a sacrificial aldehyde at the
easily converted into a variety of important products.
beginning of the reaction to activate the catalyst and then added the `real` aldehyde. We expected that the ee
Example: synthesis of -amino-acids1 of the `real` aldehyde would remain constant during the reaction. The following graph shows our hypothesis
1
OR NH2 NH2 was correct:
H H H
R R R
CN CN CO2H
R= aromatic/aliphatic
N O o O N T h e r e a c t i o n i s s t a r t e d a t -9 0 o C u s i n g b e n z a l d e h y d e , t h e n a f t e r 6 h o u r s me t a -t o l u a l d e h y d e wa s a d d e d .
R1= protective group
T h e r e a c t i o n wa s t h e n wa r me d u p t o -4 0 o C a n d l e f t a t t h i s t e mp e r a t u r e f o r 4 8 h o u r s .
Ti Ti
ee% 95

O 90
N O o N
85
met a- t olualdehyde

Project 80
75
PhCHO

70
We have developed an efficient procedure to prepare enantiomerically enriched O-protected 65
addi t i on of met a- t ol ual dehy de
cyanohydrins by the reaction of aldehydes with KCN as the cyanide source and propionic 60
55
anhydride as the protecting group, catalysed by the chiral complex 12: 50
0 4 8 12 16 20 24 28 32 36 40
t i me / h
Chiral Complex 1
Scheme 1 O
(R,R)
O O O O Et
1 (1mol%)/
t
BuOH/H2O
+ KCN +
R H Et O Et -90 to -40oC R
H
CN
CH2Cl2
(S) Using a Variety of Aldehydes and Anhydrides
40% to 95% ee
A range of different O-propionyl cyanohydrins were synthesised, promoted by complex 1, under the optimal
The reaction occurs under heterogeneous conditions and requires additives such as water and tert- conditions found for the reaction using benzaldehyde. As can be seen from Table 1, aromatic aldehydes
butanol for optimal enantioselectivity. The standard conditions require a vigorous stirring of all proved to be much better substrates than aliphatic aldehydes. Table 2 shows the effect that the structure of the
reactants at -90 oC and then a warming of the mixture to -40 oC. ORIGIN OF THE ASYMMETRIC anhydride has on the enantioselectivity of the reaction. This indicates that the anhydride is involved in a key
INDUCTION enantioselectivity determining step in the mechanism.
t
Bu

Table 1
Variation of Enantiomeric Excess with Time ALDEHYDE TIME/h EE% *
t
Bu
A study of the enantioselectivity of the O-propionyl derivative as a function of time was Benzaldehyde 48 92
Table 2
conducted. Aliquots of the reaction, taken at different times, were analysed by chiral gas N Ortho-toluenaldehyde 28 81
N O
chromatography. The ee was found to increase for all the aldehydes during the period of reaction Meta-toluenaldehyde 48 95 ENANTIOMERIC EXCESS (%)
Ti ANHYDRIDE
Para-toluenaldehyde 36 90 OF CYANOHYDRIN ESTERS
as shown in graph 1. t
Bu O
N Meta-metoxyaldehyde 48 90
C
Para-metoxyaldehyde 48 89 Acetic anhydride 90
t
Bu O
t Para Cl-benzaldehyde 16 90
Bu Propionic anhydride 92
Graph 1 (using benzaldehyde) O Trans-cynnamaldehyde 48 95
O
t Ti CF3-benzaldehyde 48 87
Bu Pivalic anhydride 87
H
o N N Cyclohexane 54 41
Reaction at -90 to -40 C Pivalic acetaldehyde 48 78 Benzoic anhydride 56
100
Nonale 48 82
95
90 *Determined by gas chromatography of the O-protected cyanohydrins. Chiral gas was carried out on a -CD Butyryl, fused silica capillary column (30m x
ee% 85 0.25mm) using hydrogen as the carrier gas.

80
75
70 Conclusions
0 10 20 30 40 50 The chiral complex 1 has been shown to be an exceptionally active catalyst in preparing enantiomerically
Tim e enriched O-protected cyanohydrins with very good yields and ee’s whilst also using inexpensive and non-
volatile starting materials. The studies using different anhydrides also show that the enantioselective
It can be seen that the ee increases in the first 4 hours and then stays constant until the reaction conversion of aldehydes into cyanohydrin esters can be optimised by appropriate choice of the anhydride
goes to completion. component.

1North M., Tetrahedron: Asymmetry, 2003, 147-176; 2Belokon Y.N., North M. et al., Tetrahedron, 2001, 771-779. Acknowledgement: The authors thank the EPSRC for financial support