Total Synthesis of Lyngbouilloside and Analogs

Lyngbouillosidei (1, Figure 1) is a glycosidic macrolide isolated from a sample of the cyanobacterium Lyngbya bouillonii, a species that quickly emerged as an outstanding source of new compounds. Lyngbouilloside was found to be cytotoxic to neuroblastoma cells (IC 50 = 17M). The proposed relative stereochemistry of 1 was elucidated by Gerwick et al. using extensive spectroscopic analysis and chemical derivatization.i However, based on the proposed stereochemistry on a closely related product, there is an uncertainty regarding this stereochemical assignment all the more since no total synthesis has been reported so far.ii Synthesis is the only means by which reasonable quantities can be accessed and the relative and absolute configuration can be confirmed. In addition, we want to access several derivatives for biological tests and elucidate the pharmacophore via a flexible and convergent route. With this project we want to apply the double conjugate addition of dithiols to propargylic carbonyl systems developed by Ley et aliii to the total synthesis of lyngbouilloside (1). There are two strategies towards the synthesis of 1. The crucial steps in the first strategy consist of ring closing metathesis to construct the C-8 - C-9 bond and of the generation of the cyclic 6-membered hemiacetal by a Meinwald type addition. Late stage glycosylation with the according L-rhamnopyranoside derivative and Wittig olefination reveals the protected aglycon core. The stereogenic center at C-13 is generated using Jacobson kinetic resolution. Asymmetric crotylation employing the Brown protocol sets the adjacent stereogenic centers at C-10 and C-11. For the construction of the pyran moiety (C-3 - C-8) we want to utilize Ley`s method for the formation of ß- keto-1,3-dithianes, followed by tandem cyclization. C-7 is derived from glycidol, the masked ketone at C-5 shall be stereoselectively reduced under substrate control. A second strategy towards the total synthesis of lyngbouilloside (1) employs Schmidt glycosylation to attach the pyranose moiety to the aglycon. For completion of the core fragment, a macrolactonization strategy is envisaged. C-8 - C-9 bond formation shall be accomplished by a Julia-Kocienski-olefination followed by reduction and parallel deprotection of the tertiary alcohol for the macrocyclization. Building block C-12 - C16 is obtained from 4-pentyn-1-ol, fragment C-9 - C-11 can be synthesized from Roche ester and the pyran C-1 - C-8 goes back to oxaloacetic acid and 2-deoxy-D-erythro- pentose. i L. T. Tan, B. L. Marquez, W. H. Gerwick, Lyngbouilloside, a novel glycosidic macrolide from the marine cyanobacterium Lyngbya bouillonii, J. Nat. Prod. 2002, 65, 925. ii H. Luesch, W. Y. Yoshida, G. C. Harrigan, J. P. Doom, R. E. Moore, V. J. Paul, Lyngbyaloside B, a new glycoside macrolide from a Palauan marine cyanobacterium Lyngbya sp., J. Nat. Prod. 2002, 65, 1945. iii H. F. Sneddon, A. van den Heuvel, A. K. H. Hirsch, R. A. Booth, D. M. Shaw, M. J. Gaunt, S. V. Ley, Double conjugate addition of dithiols to propargylic carbonyl systems to generate protected 1,3-dicarbonyl compounds, J. Org. Chem., 2006, 71, 2715.