Synthesis of swinholide

Scheme 22 Vinylogous aldol reaction used in Paterson s synthesis of swinholide A...

Another demanding oxidative cyclisation to a p-methoxybenzylidene acetal taken from a synthesis of Swinholide A by Paterson and co-workers1 2 is shown in Scheme 3.83. Note the preservation of the labile di-fer/-butylsilylene group (see section 3,4). Other applications of the reaction to complex natural product synthesis include Oleandolide,88 Discodermolide153 and the Denticulatins.154... 

Given this problem, the attachment of the butanone synthon to aldehyde 74 prior to the methyl ketone aldol reaction was then addressed. To ovenide the unexpected. vTface preference of aldehyde 74, a chiral reagent was required and an asymmetric. syn crotylboration followed by Wacker oxidation proved effective for generating methyl ketone 87. Based on the previous results, it was considered unlikely that a boron enolate would now add selectively to aldehyde 73. However, a Mukaiyama aldol reaction should favour the desired isomer based on induction from the aldehyde partner. In practice, reaction of the silyl enol ether derived from 87 with aldehyde 73, in the presence of BF3-OEt2, afforded the required Felkin adduct 88 with >97%ds (Scheme 9-29). This provides an excellent example of a stereoselective Mukaiyama aldol reaction uniting a complex ketone and aldehyde, and this key step then enabled the successful first synthesis of swinholide A. 

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. 

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... 

Having accomplished one merger, only a final macrolactoni-zation now stood in the way of a completed synthesis of swinholide A (1). Before that step could be executed, however, the protecting groups guarding oxygen functions at C-1 and C-21 in 138 had to be removed. Although such operations are usually cursory events, the complexity of swinholide A (1)... 

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... 

An ample evidence that the earlier described models that are based on the full consideration of a- and p-substituents on the aldehyde are oversimplified can be evidenced by the reported synthesis of swinholide by Paterson et al. [6]. In their synthesis, a simple alteration in the configuration at Y-position changes completely the facial selectivity of the enol nucleophile. As shown in Scheme 2.104, equation A, FeUcin control minimization of yn-pentane interactions and application of the Comforth-Evans transition state lead to a reinforced FeUdn attack. On the other side, just changing the aforementioned configuration (B) leads to yn-pentane interactions between the methyl groups at C4 and C2 and ultimately to a non-FeUdn transition state (Scheme 2.104). 

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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