Swinholide synthesis

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

An excellent simple and induced selectivity could be obtained by Mulzer and his group [92] in the cycloaddition of 2-trimethylsilyl-oxy-l,3-pentadiene 2-31 and (lR,2S,5R)-8-phenylmenthyl glyoxylate 2-32 [93] in the presence of 0.2 equivalents of anhydrous MgBr2 in THF at 0 °C. After acidic workup the ketone 2-33 was isolated as a single diastereomer (>98%), which was then used for synthesis of the C-26-C-32 tetrahydropyran moiety of swinholide. In contrast,... 

This methodology which bases on Oppolzer s sultams has also been employed in the synthesis of 2,6-N,N-diacetyl-D-purpurosamidine C [475,476]. Hetero Diels-Alder reactions of carbonyl dienophiles are furthermore involved in the preparation of ( )-ketoheptulosic acid [477] and in the already mentioned asymmetric approach to the C-26-C-32 tetrahydropyran subunit of swinholide A [92]. 

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... 

Further examples of the application of di-fcrf-butylsilylene derivatives to the protection of 1,3-diols in complex natural product synthesis include Salinomy-dn,219 Swinholide,220 Scytophycin C,221 and Muamvatin.222... 

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). 

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. 

These conditions gave excellent selectivity for an external methyl dienoate in the presence of a more hindered internal dienoate during a synthesis of the complex macrolide swinholide. These conditions are also mild enough to prevent retroaldol condensation during ester hydrolysis. In general, the barium salts may also be removed by precipitation with CO2 to form BaCO, which is readily filtered off, a method that is especially useful for water-soluble substrates. 

Ester 58 is a key intermediate in a synthesis concerned with swinholide A.15 We can see that two of the stereocentres could be controlled through the use of a yvn-selectivc aldol. 

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. 

This reaction has certain applications in organic synthesis, such as the preparation of hydrindan," glycoside, and natural product swinholide... 

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... 

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).

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