Making Sugars of a Single Chirality

Transfer of stereochemical information from low-optical-purity amino acids to sugars may have set the stage for the single-handedness of tetroses and hexoses in nature. Armando Córdova and coworkers at Stockholm University make this suggestion on the basis of findings that simple amino acids catalyze the formation of tetroses and hexoses in high enantiomeric excess even when the catalyst is not enantiopure (Chem. Commun. 2005, 2047).

With graduate students Magnus Engqvist, Ismail Ibrahem, and Henrik Sundén and postdoc Jesús Casas, Córdova has found that protected 2-hydroxyacetaldehyde condenses to tetrose and hexose in high enantiomeric excess in the presence of a catalytic amount of enantiopure l-proline. Even when the catalyst is only 30% enantiopure, the products still are obtained in enantiomeric excesses of 95–99%. The catalyst's enantiopurity exhibits a significant nonlinear effect on the enantiopurity of the product, the results show.

TWO POINTS are key, according to Córdova: First, hexoses are formed directly and enantioselectively by the amino acid-catalyzed reaction, and second, the reaction significantly amplifies the product's enantiomeric excess.

On the first point, Córdova notes that a previous proline-catalyzed synthesis of sugars from protected 2-hydroxyacetaldehyde makes use of the catalyst only to produce the tetrose. He refers to work by David W. C. MacMillan of California Institute of Technology (C&EN, April 12, 2004, page 34). In that work, MacMillan emphasized the need to obtain a tetrose that is inert to further proline-catalyzed aldol reaction to achieve high stereo- and chemoselectivity in a second step to form the hexose. That second step is a Lewis acid-mediated Mukaiyama aldol addition (C&EN, Aug. 16, 2004, page 6).

Córdova's reaction yields the hexose directly. For practical synthesis, however, the reaction is far from straightforward. "The process is dynamic," Córdova says. After the first condensation forms a tetrose, the product may or may not be available for a second condensation to a hexose or it can revert to the starting hydroxyaldehyde. To favor hexose formation, the team protects the free hydroxyl groups. Even so, after four days the reaction yields 40% hexose and 45% tetrose, but each is at an enantiomeric excess of at least 95%.

On the second point, Córdova notes that the idea that the homochirality of carbohydrates now seen on Earth originated from amino acids is not new, but the nonlinear effect on hexose formation had not been unequivocally demonstrated before. The nonlinear effect shows that amino acids not only transfer their asymmetry to sugars but also amplify the effect, he says. "It is known that amino acids exist in space in enantiomeric excesses of about 15%," he adds. The work shows that even with a catalyst enantiopurity of 10%--similar to that of extraterrestrial amino acids found in the Murchison meteorite--the hexose is formed in 33% enantiomeric excess.

In earlier work, the team showed that -hydroxylated carbonyl compounds such as 2-hydroxyacetaldehyde could be formed by incorporation of singlet molecular oxygen into carbonyl compounds in a reaction also catalyzed by simple amino acids (Angew. Chem. Int. Ed. 2004, 43, 6532; J. Am. Chem. Soc. 2004, 126, 8914). "We envision that sugar-type molecules could have originated from simple carbonyl compounds through a series of amino acid-mediated reactions," Córdova tells C&EN. "Whether that is what happened in the prebiotic world is not known." Nevertheless, he points out, 2-hydroxyacetaldehyde is known to have existed in the prebiotic world and also has been detected in space.

The amino acid-catalyzed reactions are more enantioselective in organic solvents than in water, Córdova emphasizes. This fact jibes with highly selective enzyme-mediated carbohydrate biosynthesis. Reaction conditions in the enzyme's reactive site are more controlled, and that site is usually hydrophobic, he points out. "We're realizing that a long time ago maybe amino acids made sugars but not as highly selectively as proteins eventually could."

The intrinsic ability of amino acids to catalyze sugar-forming reactions may have biological implications for the present, Córdova speculates. "It's possible that it could happen in vivo, and who knows what the consequences of that are?"