Cyanobacteria have earned a specific place in the production of natural products with significant biological activities. These activities including antibiotic, antifungal, and anticancer properties in addition to the production of potent toxins.1,2 Consequently these compounds have been attracted considerable attention by synthetic and medicinal chemists across the globe. In 2014, Igarashi and co-workers reported the isolation of 14-membered oxylipin-derived cytotoxic macrolide named as sacrolide-A from the cyanobacterium Aphanothece sacrum. Aphanothece sacrum, a luxury ingredient for Japanese cuisine exist as a macroscopic gelatinous floating colony in fresh water discovered in the Kyushu District, Japan.

Absolute configuration of sacrolide-A was confirmed via chiral anisotropy analysis and conformational analysis of different ring-opened derivatives by NOESY and HSQC experiments. Sacrolide-A (1) possesses a wide antimicrobial spectrum, a potent inhibitor for the growth of few species of gram-positive bacteria such as yeast Saccharomyces cerevisiae and fungus Penicillium chrysogenum and cytotoxic against 3Y1 rat fibroblasts with GI50 4.5 μM.5 Sacrolide A (1) embedded with α, β-unsaturated ketone with a cis-configured double bond in the side chain including two chiral centers. Barred from overharvesting and water pollution due to its economical value coupled with increasing urbanization made sacrolide-A, a scarce source which could be procured by its chemical synthesis. Impressive molecular structure with sensitive functionality and modification in structure-activity relationship with biological activation of suitable derivatives in order to enhance biological profile coupled with the limited availability of sacrolide A has prompted us to undertake its chemical synthesis and we have accomplished a simple and straightforward strategy of sacrolide A in 12 steps from the known compound with 9% overall yield.

During the course of our synthesis5 we found the seco-acid 2 was highly fragile towards the base since it was racemized (3a:3b ~1:1) when we subjected for macrolactonization with 4-dimethylamainopyridine (DMAP) at C-13 position, this was confirmed by 1 H NMR, 13CNMR analysis optcal rotations. Consequently at this juncture we envisioned acid catalyzed macrolactonization of seco-acid 2 under Kita’s protocol6 instead basic acylating catalyst DMAP (Scheme 2).

When we switched to acid mediated macrolactonization, accordingly we treated seco-acid 2 with ethoxyacetylene in presence of [RuCl2 (p-cymene)]2 catalyst in toluene followed by addition of camphorsulfonic acid (CSA) gave 14-membered macrolactone 4 as a single isomer in 60% yield. Deprotection of MOM ether was carried out with trifluoroacetic acid (TFA) in CH2 Cl2 at ambient temperature to produce 1 in 82% yield (Scheme 2), thereby end-game of total synthesis of sacrolide A.5 In conclusion, we have developed a simple and efficient synthetic way to sacrolide A in 12 steps from the known compound. Base mediated macrolactonizations of seco-acid 2 resulted recimization at α-hydroxy carobon attached hydrogen. Acid mediated Kita macrolactonization served as ideal reaction condition to accomplish the total synthesis of sacrolide A.

References:

1. R. K. Singh, S. P. Tiwari, A. K. Rai, T. M. Mohapatra, J. Antibiot. 2011, 64, 401–412.

2. L. T. Tan, Phytochemistry 2007, 68, 954–979.

3. N. Oku, M. Matsumoto, K. Yonejima, K. Tansei, Y. Igarashi, Beilstein J. Org. Chem. 2014, 10, 1808–1816.

4. N. Oku, K. Yonejima, T. Sugawa, Y. Igarashi, Biosci., Biotechnol, Biochem. 2014, 78, 1147–1150.

5. B. Thirupathi, B. J. Jena, ChemistrySelect. 2019, 4, 2908-2911

6. a). Y. Kita, H. Maeda, K. Omori, T. Okuno, Y. Tamura, J. Chem. Soc. Perkin Trans. 1 1993, 2999-3005.; b) B. M. Trost, J. D. Chisholm, Org. Lett. 2002, 4, 3743-3745., c) C. H. Kim, H. J. An, Y, W. Shin, S. K Woo, S. K. Jung, E. Lee, Angew. Chem. Int. Ed. 2006, 45, 8019-8021.