Although several examples of selective reduction of

Although several examples of selective SGC-CBP30 of α-diazoesters to α-hydrazonoesters have been described in the literature, reports on practical and general examples of such a process are scarce. In this context, there was a need to devise a mild and general method for the selective reduction of α-diazoesters to α-hydrazonoesters. To our delight and after examining a host of reducing agents and conditions, we observed that NaBH in THF was able to effect this reduction in excellent yields in all examples under very mild reaction conditions (). At this juncture and with both enantiomers of α-hydrazonoesters in hand, we were prepared to test the base-promoted elimination of N. Of all the bases investigated, the best results were obtained with DBU. When 2equiv of DBU was added to an α-hydrazonoester solution in CHCl elimination of N proceeded efficiently at rt to give esters in excellent yields. Finally, hydrolysis of the ester group with LiOH in THF/HO furnished both enantiomers of the desired acids , whose optical purity was analyzed by capillary electrophoresis giving ee values >97% in all cases. Encouraged by these remarkable results and having established the preferred reaction conditions for each step, deamination of several representative α-aminoesters bearing a variety of functional groups was performed to demonstrate the versatility of this three-step deamination sequence. As shown in , many functional groups tolerated the mild reaction conditions of all three steps, including amides (entry 2), carbamates (entry 3), ureas (entry 4), nitriles (entry 9) and sulfonamides (entry 10). Phenylalanine derivatives (entries 1–4) proved to be excellent substrates for the deamination process with good yields in almost all the steps and examples. Successful deamination of aminoester is also a good example of the potential of the method: Although yields in all three synthetic steps are only moderate, the allylic urea functionality of aminoester probably would be affected by the reaction conditions of many of the deamination methods described in the literature. On the other hand, yields obtained in diazo formation and reduction steps in other aromatic α-aminoesters (entries 5–6) were only moderate. For the reduction step, steric factors seemed to play an important role and contributed to the decreased reactivity of β-substituted-α-diazoesters (entries 12–14) compared with the non-substituted ones. In these examples, not only a large excess of NaBH and longer reaction times (up to three days) were needed in order to obtain significant amounts of the desired β-substituted-α-hydrazonoesters but also higher reaction temperatures did not have a beneficial effect on the reaction. Finally, treatment of α-hydrazonoesters with DBU led to the desired deaminated esters with satisfactory results in all the examples studied. In order to force the reaction to completion, N elimination was carried out under reflux in CHCl in many examples. In summary, we have developed an efficient and practical three-step sequence for the reductive elimination of the amino group in α-aminoesters based on the NaBH-mediated selective reduction of α-diazoesters to α-hydrazonoesters The scope and limitations of this method have been examined with several representative α-aminoesters bearing different functionalities with excellent results in most of the examples. This methodology has also been successfully applied to the synthesis of a series of CysLT1 antagonists.
Introduction Cysteinyl leukotrienes (CysLTs), LTC4, LTD4 and LTE4, potent inflammatory mediators derived from arachidonic acid [1], are known to be very potent bronchoconstrictors and to play an important role in asthma and allergic rhinitis [2], [3]. They have been also implicated in a number of inflammatory conditions including cardiovascular diseases, coronary artery disease, atherosclerosis and stroke [4], [5], [6] or in cardiovascular complications of inflammatory processes [7].