The first organocatalytic cross aldol reaction of ketones and diethyl formylphosphonate

The first organocatalytic cross aldol reaction of ketones and diethyl formylphosphonate hydrate continues to be realized through the use of easily available L-prolinamide as the catalyst. supplementary α-hydroxyphosphonates seem even more significant as all chiral organic amino acids are secondary amines. The optically enriched forms of secondary α-hydroxyphosphonates are mainly obtained through enzymatic methods 6 such as kinetic resolution of racemic combination by bacteria fungi or lipases8 or through asymmetric reduction of α-ketophosphonate with baker’s yeast or fungi.6a 9 Only a few chemical methods are available 6 c which include the asymmetric reduction of α-ketophosphonates 10 asymmetric oxidation of benzylphosphonates11 and diastereoselective addition of dialkyl phosphites to aldehydes (phosphoaldol reaction).12a b These methods are either not catalytic use special reagents that are hard to handle or have very limited substrate scope. A catalytic method based on the phosphoaldol reaction was also reported 12 but the enantioselectivities obtained were dependent on the substrates. Most recently Chen and co-workers reoported a vanadium-catalyzed oxidative kinetic resolution for the high enantioselective synthesis of secondary α-hydroxyhosphonates;13 nonetheless the disadvantage of this method is the sacrifice of 50% of the starting material.13 Thus the development of a catalytic highly enantioselective method for the synthesis of secondary α-hydroxyphosphonates is warranted. Herein we wish to statement our preliminary outcomes of an extremely Rabbit polyclonal to JNK1. enantioselective synthesis of supplementary α-hydroxyphosphonates with a prolinamide-catalyzed asymmetric aldol response.14 Synthesizing extra α-hydroxyphosphonates through the use of our reported protocol7 would need formylphosphonate as the beginning materials (Eq 1 R1 = H). Nevertheless although diethyl formylphosphonate is normally a known substance 15 it really is unstable and everything XR9576 our tries to react it with acetone failed. After that we transformed XR9576 our attentions to its hydrate (4) since it was reported to become more steady and in equilibrium using its formyl type.16 Through the use of acetone (5a) as the model substance we screened some easily available L-proline-derivatives (Amount 1) as the catalyst for the mix aldol result of diethyl formylphosphonate hydrate (4). The full total email address details are summarized in Table 1. Amount 1 Catalysts screened for the combination aldol response. Desk 1 Catalyst Testing and Response Condition Optimizationsa As proven in Desk 1 although L-proline is an excellent catalyst for the mix aldol reaction of α-ketophosphonates 7 it failed to catalyze the aldol reaction of 4 (access 1) presumably because 4 is definitely incompatible with its acidity. In contrast less acidic L-proline tetrazole (2) and L-prolinamide (3) proved to be good catalysts for the desired reaction. At 10 mol % catalyst loading and room heat the aldol product 6a was acquired in 72% (access 2) and 84% ee (access 3) respectively. The reaction conditions were further optimized for 3 as it is definitely more reactive and enantioselective. Catalyst 3 is definitely slightly less reactive in CH2Cl2 (access 4) but the enantioselectivity XR9576 maintains at XR9576 the same level as with acetone. Additional common solvents utilized for aldol reactions such as DMSO (access 5) and DMF (access 6) proved to be less effective than excessive acetone XR9576 (access 3). Nevertheless decreasing the reaction heat XR9576 to 0 °C resulted in an increase of the enantioselectivity (to 92% ee access 7). It is interesting to note the catalyst loading can be further reduced to 5 mol % without influencing the enantioselectivity even though reaction is definitely a little bit slower (access 8). Further shedding of the reaction heat to -20 °C did not improve the enantioselectivity instead has an adverse effect on the reactivity of the catalyst (access 9). Similar reaction with D-prolinamide (product and the ee value for this diastereomer is definitely 99% (access 2). Similarly the reaction 5c and 4 yielded these two products in about 12:1 percentage having a 97% ee for the major kinetic product (6c) and a single diastereomer for the small item (6c’) in high enantioselectivity (99% ee entrance 3). Nevertheless 3 reacts extremely slowly and network marketing leads towards the decomposition of 4 (data not really shown). Substituted ketones can be utilized within this reaction also. Including the aldol result of α-chloroacetone (5d) creates just the kinetic regioisomer in 65% produce and 90% ee (entrance 4). On the other hand acetol (5e) generates inadequate enantioselectivity (43% ee) of the merchandise (entrance 5) presumably because of the interference of.