Swinholide total synthesis

Swinholide A. The swinholides are a series of complex macrodiolides isolated from the marine sponge Theonella Swinhoei, which display potent cytotoxicity against a range of human tumour cell lines. Swinholide A (71) provided an excellent opportunity to showcase the synthetic utility of a range of aldol reactions. For its total synthesis by our group in 1994 [50] the fully protected preswinholide A 72 was considered to be an essential late-stage intermediate, which appeared accessible via two directed aldol reactions of a suitable butanone equivalent with aldehydes 73 and 74 (Scheme 9-24). 

The second total synthesis of swinholide A was completed by the Nicolaou group [51] and featured a titanium-mediated syn aldol reaction, followed by Tishchenko reduction, to control the C21-C24 stereocenters (Scheme 9-30). The small bias for anri-Felkin addition of the (Z)-titanium enolate derived from ketone 89 to aldehyde 90 presumably arises from the preference for (Z)-enolates to afford anti-Felkin products upon addition to a-chiral aldehydes [52], i.e. substrate control from the aldehyde component. 

Swinholide A is an interesting physiologically highly active marine metabolite with a macrocyclic diolide structure and a polyketide carbon skeleton. Recently the first total synthesis of 161 was reported by I. Paterson et al. (21). We focused on the synthesis of the tetrahydropyran part of the molecule as represented by compound 162. The particular feature of this ring is that it bears the largest substituent (at C-27) in an axial arrangement, as shown by the X-ray crystal structure of 161. 

Based on the amalgamation of such a fascinating mode of biological action, a formidable and unique structure, and a need for additional material supplies, swinholide A (1) issued a clarion caU that had to be answered by the chemical community with a total synthesis. While many would attempt to answer that summons, the first to succeed was Professor Ian Paterson and his group at Cambridge University, who prepared the first laboratory samples of swinholide A (1) in 1994. In this chapter, we shall recount the details of their highly inventive route to this formidable target. 

At this point, with a protected form (85) of preswinholide A in hand, the opportunity existed to examine the final steps envisioned to complete the total synthesis of swinholide A (1). While enticing, the Paterson group elected to pursue two other objectives before tackling these final operations. First, to prove the stereochemical outcome of all the preceding steps, they converted 85 into preswinholide A (3) using the three operations defined in Scheme 16, and, in the process, intersected two synthetic conjugates... 

Scheme 20. Final stages and completion of Paterson s total synthesis of swinholide A (1).

Scheme 4.67 Diisopinocampheylboranes 292 as controllers in Paterson s aldol procedure. Application in a total synthesis of swinholide A.

Swinholide A [75] In 1996, Nicolaou s group reported the total synthesis of swinholide A (69) [75] after several efforts [76]. This 44-membered maaolide, which was isolated from Theonella swinhoei by Carmely et al. [77], exhibits an impressive cytotoxic activity [78] by interacting with the actin cytoskeleton [79]. Due to its interesting C2 symmetry, Nicolaou and coworkers envisioned to build the macrolide core through the dimerization of a monomer after esterification and macrolactonization (Scheme 2.56). The retrosynthetic... 

Nicolaou KC, Patron AP, Ajito K, Richter PK, Khatuya H, Bertinato P, Miller RA, Tomaszewski MJ. Total synthesis of swinholide A, preswinholide A, and hemiswinholide A. Chem. -Eur. J. 1996 2 847-868. 

Mulzer, J., Meyer, F., Buschmann, J., and Luger, P. (1995) Asymmetric synthesis of the C-26-C-32 tetrahydropyran moiety of swinholide A by hetero-Diels—Alder reaction. Tetrahedron Lett., 36, 3503—3506. Paterson, 1., Gumming, J.G., Ward, R.A., and Lamboley, S. (1995) The total synthesis of swinholide A. 1. A stereocontrolled synthesis of a C19-C32 segment. Tetrahedron, 51, 9393-9412. 

Keck, G.E. and Limdquist, G.D. (1999) Synthetic studies toward the total synthesis of swinholide. 1. Stereoselective construction of the C-19-C-35 subunit J. Org. Chem., 64, 4482-4491. 

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