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Synthesis of Garner’s Aldehyde Carmen Cannon, Kristina Truitt, Rachel Andrews, Bette’ Ford and Victoria Geisler Department of Chemistry, University of West Georgia, Carrollton, Georgia 30118 Abstract Studies have implicated sphingosine is a highly bioactive compound that reversibly inhibits protein kinase C; an important regulatory enzyme in cell growth and differentiation. We ultimately would like to examine the role of the 3-hydroxyl group of sphingosine. In order to create the analogs, the synthesis of Garner’s aldehyde must be done. During this process of synthesizing, it is extremely important that the end product is in its most pure state. Introduction Garner’s aldehyde (1,1-dimethylethyl 4- formyl-2, 2-dimethyl-oxazolidine-3- carboxylate) was initially synthesized by Dr. Philip Garner in 1984. 1 Since that time, Garner’s aldehyde has proven to be a useful building block in asymmetric syntheses. The goal of the research was to synthesize Garner’s aldehyde in preparation for future research and development of sphingosine analogs shown below. Sphingosine, a component of sphingolipids within cell membranes, is thought to be involved in certain cell processes such as signaling, cell differentiation, and cell recognition. Future research in the area of sphingosine analogs will hopefully lead to advancements in cancer and tumor treatments. OH NH 2 OH Sphingosine N NH 2 OH Targets N H NH 2 OH Methods Synthesis of Garner’s Aldehyde The formation of Garner’s aldehyde was a four-step literature process described by Dondoni and Perrone in the scientific journal Organic Syntheses and illustrated in Scheme 1. 2 The first step involved the protection of the acidic amine hydrogens on L-serine methyl ester using a Boc group. Step B protected the remaining acidic hydrogen via the creation of an oxazolidine ring using dimethoxypropane. Reduction of the ester to the aldehyde was accomplished in the last two steps. First, reduction of the ester to the alcohol was accomplished using lithium aluminum hydride followed by Swern oxidation to give the desired Garner’s aldehyde. Scheme 1 Synthesis of Garner’s Aldehyde. Figure 1 Comparison between sphingosine and our desired analogs. Results The synthetic approach, which has been adopted for the preparation of Garner’s aldehyde is outlined in Scheme 1. The overall synthesis of the Garner aldehyde is ongoing. Reactions A and B were preformed numerous times. The TLC analysis of reaction B indicated that this product was very impure. Column chromatography was used to purify the product. The 1 H NMR results are shown in Figure 2 and indicate that the product is still slightly impure. This material was used to carry out reaction C and the resulting impure produce was purified by column chromatography. We have obtained approximately 5 grams of alcohol and will proceed with reaction D in the near future. Concerning yields of products obtained thus far, the nature of the data obtained limits the calculation of the percent yields in most cases. Due to the fact that a single reaction was often conducted with combined products from previous reactions of varying sources, the only true yield that can be calculated is that of reaction A, which was determined to be 95%-a percentage that was congruent with that of the literature 2 . References 1.Liang, Xify, and Bols. Garner’s Aldehyde. Journal of the American Chemical Society . 4 June 2001: 1:2136-2157. 2.Dondoni and Perrone. Synthesis of 1, 1-dimethylethyl (S)-4-formyl-2, 2- dimethyl-3oxazolidincarboxylate by Oxidation of the Alcohol . Organic Syntheses , Call. Vol. 10, p.320 (2004) Acknowledgements Dr. Victoria Geisler, Research Advisor National Science Foundation, STEP Grant # DUE-0336571 Chemistry professors at the University of West Georgia. HO NH 3 O O Cl - Boc 2 O ,Et 3 N THF THF O N Boc OH O N Boc O O CH 3 DM SO ,(CO Cl) 2 i-Pr 2 NEt HO HN O O CH 3 O O O N Boc O H OCH 3 H 3 CO "G arner's Aldehyde" LAH BF 3 -O Et 2 L-serine m ethylester A B C D Supported By NSF STEP tiarxn b 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 Chemical Shift (ppm) 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Normalized Intensity 36.19 M02(br.s.) 1.39 Figure 2: NMR of Reaction B O N O O O O b f e d c a a a d f e b,c a
