SCIENCE
Total Synthetic Route to Complex Monosaccharides Achieved By choosing target molecules suited to synthetic strategy, Yale scientists prepare C& C9, and C11 sugars from simple, nonsugar starting materials Ron Dagani, C&EN Washington
Artisans know that fitting the tool to the task leads to the best results. Likewise, synthetic organic chemists, who are artisans in the molecular realm, make their task easier when they fit the synthetic strategy to the synthetic target. The wisdom of this rule of thumb recently has been demonstrated anew by chemistry professor Samuel J. Danishefsky and coworkers at Yale University. They have developed a new method for the total synthesis of carbohydrates and are using it to make unusual, complex monosaccharides with stereogenic centers galore. Specifically, the monosaccharides are biologically active Cg, C9, and C11 sugars, which are less common than C5 or C 6 sugars such as ribose or glucose. By choosing target molecules especially suited to the synthetic strategy, the Yale group has become the first to prepare complicated sugars with more than six carbon atoms from simple, nonsugar starting materials. In their work, the Yale researchers are following in the grand classical tradition of the late synthetic maestro Robert B. Woodward and others, who taught a generation of chemists that constructing a dissymmetric molecule is like solving an elaborate puzzle. The key challenge was to set all the stereocenters in the proper configuration. Traditionally, this has been accomplished by using the asymmetry of the sub18
January 20, 1986 C&EN
strate to control the stereochemical outcome of the reaction. Although a rival synthetic strategy based on powerful chiral reagents has emerged in recent years, the classical strategy of substrate control still is dominant and is the strategy that underlies Danishefsky's carbohydrate syntheses. The Yale researchers became interested in synthesizing complex sugars as a result of their basic explorations into the cyclocondensation reaction of activated dienes with aldehydes (C&EN, June 24, 1985, page 26). That reaction, which is catalyzed by Lewis acids, yields pyrans and pyrones. Although chemists have been aware of the reaction for decades, it was Danishefsky's group that elucidated its stereochemical course and showed how different Lewis acids could be used to affect its outcome. The first step of Danishefsky's synthetic plan calls for using a highly substituted diene in the cyclocondensation reaction. That leads to a pyran ring brimming with functional groups. Those groups then are manipulated to produce an array of stereogenic centers. The array establishes a "chiral bias" in the molecule. By selecting the appropriate reagents and catalysts, Danishefsky explains, that bias can be relayed to more-distant parts of the molecule via, for example, chelation effects. In this way, the Yale workers can use the dissymmetry of the "homebuilt" ring to control the stereochemical course of reactions that are shaping outlying parts of the molecule. "A particularly fascinating possibility ," Danishefsky says, "is the creation of a new aldehyde on the sugar side chain and the use of this aldehyde in a second cyclocondensation reaction. The dissymmetric
pyran initially constructed through the first cyclocondensation would be used to guide the stereochemical sense of the next cyclocondensation. " Danishefsky and his colleagues indeed have succeeded in using that strategy to build what he calls a carbon-linked disaccharide— for example, a C5 sugar connected to a Ce sugar. Further elaboration of the basic structure capped the total synthesis of two naturally occurring nucleoside antibiotics—tunicaminyluracil and hikosamine. Tunicaminyluracil is the Cn-sugar-containing moiety of the tunicamycins, a class of nucleosides that can affect the biosynthesis of complex polysaccharides and other biological compounds. Hikosamine is the Cn-sugar component of hikizimycin, a compound active against parasitic worms. Derivatives of both sugars previously had been prepared in other laboratories by coupling C 5 and C 6 fragments having the appropriate stereochemistry. Danishefsky wanted to show that those molecular frameworks could be built using successive cyclocondensations to achieve asymmetric induction. Since the method already had been worked out, the synthetic sequence in each case was accomplished by a single coworker. Michael Barbachyn, a postdoctoral research associate at the time, built tunicaminyluracil using a series of three cyclocondensation steps. The product, which contains an intact pentose and hexose ring, was isolated as the heptaacetyl derivative. Hikosamine was synthesized by former graduate student Clarence Maring. The molecule, which contains a six-carbon chain attached to a hexose ring, required two cyclocondensations. The pyran ring arising from the second of these reac-
Multistep synthetic strategy leads to C-n sugars I. Aldehyde, diene cyciocondense to give pyran ring
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Lewis acid
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