Further Applications of Lactone Syntheses on Glyceraldehyde Acetonide, and Attempts at a Safer Process for the Synthesis of Trimethylsilylketene

During this semester, ten reactions were carried out. The first was the synthesis of D-glyceraldehyde acetonide from D-mannitol. The next six reactions were involved with the synthesis of the corresponding γ-lactone of glyceraldehyde acetonide. The final three reactions were attempted syntheses of ethyl ethynyl ether, the key starting material in the synthesis of TMS ketene. Introduction In the area of lactone research, there are several key questions that need answered, and several key reactions that need run. One of the biggest questions involves the mechanism by which a β-lactone expands to a γ-lactone. It has been speculated that the dyotropic rearrangement that is responsible for the expansion is a concerted process. To shed more light on this, ring expansion reactions on optically active molecules is of interest. This is the one of the goals behind the glyceraldehyde acetonide γ-lactone project. Here, the optically active aldehyde would be converted to its corresponding γlactone using Black’s γ-lactone synthesis, and enantiomeric purity of that γ-lactone would be tested on a polarimeter, as well as with perhaps a series of NMR experiments like nOe. If a concerted process were to take place, then the optical purity of the product would remain intact. However, with glyceraldehyde acetonide, one of three therorized products will be obtained (Figure 2), each with intriguing possibilities for further lactone research. The glyceraldehyde acetonide molecule may produce as many as three chiral centers upon expansion to a γ-lactone. Another hot area of lactone research involves not the products of various lactone synthetic protocols, but the reagents used to carry out those reactions. One of the most interesting of these developments is the reagent trimethylsilylketene (TMS-ketene) (Figure 4). This reagent reacts with ketone or aldehyde functions in a [2+2] cycloaddition reaction to yield β-lactones without the need for β-hydroxy acid intermediates. This is a much simplified approach to lactone synthesis, except for the acquisition of the TMSketene itself. TMS-ketene can be purchased commercially, but at an extravagant price, and current reported syntheses involve the use of liquid ammonia and a very cold apparatus. However, our group is finding a solution to this problem. The key to the synthesis of TMS-ketene is the synthesis of ethyl ethynyl ether from chloroacetaldehyde diethylacetal. If this step were to be simplified, then the process as a whole would be much easier; thus making synthesis of lactones from TMS-ketene much more applicable. This reaction (Figure 3) involves use of three equivalents of a strong base to facilitate an E2 reaction of chloroacetaldehyde diethylacetal , a reaction in which a double elimination takes place, affording the alkyne-ether product. Results and Discussion The synthesis of D-glyceraldehyde acetonide (Figure 1) was accomplished from 50 g of D-mannitol in two steps, to yield 31.2 g of the aldehyde, giving an overall percent yield of 44 %. The first step of this reaction was the formation of the bis-acetonide on the two far left and far right alcohols using 2,2-dimethoxypropane. The reaction was carried out in 1,2-dimethoxyethane as the solvent, with tin II) chloride as the catalyst. The product obtained from this reaction was characterized by IR spectroscopy, which showed an alcohol stretch at 3314cm, and a series of C-O stretches in between 1000cm and 1300cm. However, there were two unexplained stretches at 2360cm and 1610cm, which were probably due to impurities, since it was not necessary to purify this product according to the publication used. The second step of this reaction was the cleavage of the bond between the two hydroxyl substituted carbons to yield two equivalents of aldehyde. This was accomplished with sodium metaperiodate, with sodium bicarbonate as a catalyst.