Stereocontrolled Total Synthesis of (+)-Altohyrtin A/Spongistatin 1 Financial support was provided by the EPSRC (GR/L41646), Cambridge Commonwealth Trust (Scholarship to M.J.C.), EC (Marie Curie Postdoctoral Fellowship to J.L.A.), DFG (Postdoctoral Fellowship to T.T.), NSERC-Canada (Postdoctoral Fellowship to R.M.O.), Churchill College (Research Fellowship to D.J.W.), Kingapos;s College and Sims Fund, Cambridge (Scholarship to D.Y.K.C.). We also thank Merck and AstraZeneca Pharmaceuticals for generous supp

Abstract

As an exceptionally potent antimitotic macrolide, altohyrtin A/spongistatin 1 shows great promise in cancer chemotherapy but its extreme scarcity in the natural sponges has halted its further preclinical development. A highly stereocontrolled total synthesis, which exploits boron‐mediated aldol bond constructions, has been realized to provide, for the first time, a useful amount of synthetic material.

Strategies for the Formation of Tetrahydropyran Rings in the Synthesis of Natural Products

“…The F ring of spongistatin 1 has also been constructed by an oxy‐Michael reaction. In this case, the cyclisation of 41 was promoted under basic conditions and generated the desired isomer 42 in a 95:5 ratio (Scheme ) 23. A similar strategy was also employed by Roush in his synthesis of the C(29)–C(45) segment of spongistatin 1 24…”

Conquering peaks and illuminating depths: developing stereocontrolled organic reactions to unlock nature's macrolide treasure trove

“…33 Falling under its spell, we viewed it as the definitive complex macrolide to showcase the aldol methodology developed in the group. 34 We aimed to devise a flexible and convergent synthesis that was efficient enough to deliver useful quantities and permit further biological studies.…”

“…This was both due to the range of potentially reactive functionalities present and the increased stereochemical complexity relative to the other fragments. 34,38 Given that the planned coupling between the northern and southern hemispheres involved a Wittig reaction with an advanced C1-C28 aldehyde, an efficient construction of phosphonium salt 31 was sought (Scheme 12). The boron-mediated aldol reactions used to assemble this fragment enabled the expedient formation of four key carbon-carbon bonds and six associated stereocentres.…”

Catalytic Asymmetric Synthesis of Geminal-Dicarboxylates

“…1,2 For many years, stereocontrolled access to chiral acetal derivatives relied on derivatisation of chiral starting materials, [3][4][5][6][7][8] metal mediated desymmetrisations, [9][10][11] or kinetic or thermodynamically controlled cyclisation of carbonyl containing chiral-compounds. [12][13][14][15][16][17] A recent approach to bis-heteroatom containing stereogenic centers involves catalysis with very sterically hindered chiral Brønsted acids. Though generally envisaged to occur via oxocarbenium ion or imine intermediates ( Fig.…”