Glucolipsin A

During the screening of the natural products for their ability to increase the activity of glucokinase by relieving inhibition by long chain fatty acyl CoA esters (FAC), two novel compounds, glucolipsin A (1) and B (2) were isolated from the butanol extracts of Streptomyces purpurogeniscleroticus WC71634 and Nocardia vaccinii WC65712, respectively. The structures of these two compounds were established by spectroscopic methods and chemical degradation. Glucolipsin A (1) and B (2) relieved the inhibition of glucokinase by FAC with RC50 values of 5.4 and 4.6 microM.

The absolute stereochemistry at the site of attachment of the fatty acid residues to the lactide core of the glycolipids cycloviracin B1 (1) and glucolipsin A (13) has been elucidated as (3R,3'R) by comparison of their 13C NMR data with those of the three possible, differently configured core structures 9, 12, and 14. Moreover, a careful analysis of this set of NMR data allows us to conclude that the structures previously proposed for a seemingly closely related class of antivirally active compounds, i.e., the fattiviracin family, need revision. The key step en route to the symmetrical dilactones 9 and 12 consists of a highly efficient cyclodimerization process which exploits the template effect exerted by potassium cations on the hydroxy acid cyclization precursor. The latter is obtained in excellent overall yield by a sequence involving ring-opening Claisen condensation of pentadecanolide to form the functionalized beta-ketoester 4, asymmetric hydrogenation catalyzed by [(BINAP)RuCl2]2.NEt3, and a beta-selective glycosylation reaction using trichloroacetimidate 6. The unsymmetrical dilactone 14, in contrast, is prepared by a stepwise approach based on a Yamaguchi lactonization as the means to close the macrocyclic ring.

The previously unknown stereostructure of glucolipsin A (1), a complex glycolipid endowed with glucokinase-activating properties, was unambiguously elucidated as (2R,2'R,3S,3'S) by comparison of its spectroscopic and analytical data with those of all conceivable C(2)-symmetric stereoisomers. This set of macrodiolides was prepared by a sequence comprising auxiliary guided aldol reactions, glycosidation of the resulting beta-hydroxy acid derivatives with trichloroacetimidate 7, followed by hydrolytic cleavage of the auxiliaries used. The hydroxy acids thus formed were subjected to a macrodilactonization reaction mediated by 2-chloro-1,3-dimethylimidazolinium chloride (22) as the activating agent; this transformation is highly productive only in the presence of admixed potassium cations which likely serve as templates to preorganize two substrate molecules in a favorable head-to-tail arrangement. Glucolipsin and analogues were subjected to enzymatic assays that revealed that glycoconjugates of this type effectively inhibit the activity of the dual specific phosphatase Cdc25A with IC(50) values in the low micromolar range, while being hardly active against the tyrosine phosphatase PTP1B in vitro. This activity profile was compared to that of other glycolipids previously prepared in this laboratory, including cycloviracin B(1) (2), caloporoside (38), woodrosin I (39), sophorolipid lactone (40), and tricolorin G (41).