Paterson’s synthesis

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

Scheme 25 Paterson s synthesis of C1-C5, C9-C16 and C17-C24 subunits from common precursor diol...

Scheme 28 Paterson s synthesis of C1-C8 phosphonate and completion of third-generation synthesis...

We have already collected some powerful tools for use in stereocontrolled aldol reactions, but we have not finished. We shall see now in Paterson s synthesis of (+)-discodermolide, how reagent control is used not to enhance the intrinsic substrate selectivity, but to overturn it. The aldol reaction is undoubtedly one of the most powerful ways of making carbon-carbon bonds and nature thinks so too. There are numerous natural products that are replete with 1,3 related oxygen functionality. Many of these are acetate or propionate-derived in nature. The methods detailed above developed from studies into the syntheses of these natural products. The manipulations of chiral ethyl ketones of this kind are of particular interest when it comes to natural products that are polypropionate-derived. 

Paterson s synthesis is based on a short and eflScient asymmetric route to the simplified erythronolide derivative 120 (R=TBS) by using an Evans aldol reaction for the preparation of the C2-C4 and Cg-Cjo fragments. 

A similar reaction was used for preparation of the remote stereocenter in 85, an intermediate in Paterson s synthesis of aurisides A and B. The asymmetric catalysis of the aldol reaction with fluoral has also been investigated by Mikami for highly enantioselective syntheses of fluorine-containing aldols. The reaction of the ketene trimethylsilyl acetal 86 with fluoral (87) in the presence of the BfNOL-catalyst 67 yielded the aldol adduct 88 in moderate yield (56%) and high enantioselectivity (90% ee). 

Paterson s synthesis of oleandolide, the aglycon of the macrolide antibiotic oleandomycin, relied on an analogous use of macrocyclic stereocontrol for the introduction of an epoxide late in the route (Equation 5) [20]. The reaction between ketone 48 and trimethylsulfonium ylide thus furnished epoxide 49 in 83 % yield and dr >97 3. 

Scheme 13.71 shows the most recent version of a synthesis of (-l-)-discodermolide developed by Ian Paterson s group at Cambridge University. The synthesis was based on three major subunits and used boron enolate aldol addition reactions to establish the stereochemistry. 

Since its introduction by Allred and Liebsekind in 1996 [114], copper thiophene-2-carboxylate (CuTC) has emerged as a mild and useful reagent for mediating the cross-coupling of organostannanes with vinyl iodides at room temperature. CuTC is especially effective for substrates that are not stable at high temperature. In Paterson s total synthesis of elaiolide, he enlisted a CuTC-promoted Stille cyclodimerization of vinyl iodide 131 to afford the 16-membered macrocycle 132 under very mild conditions [115]. 

As one might expect, there are very many aldol reactions to be found in Paterson s synthesis46 of dis-codermolide 261. The synthesis involves 23 steps (in the longest linear sequence) and the overall yield is 10.3%. If we naively equate the yield with those 23 steps then we have an average yield in every step of around 90%. Several other groups are interested in the synthesis of discodermolide 47,48... 

Paterson s group exploited a useful aldol reaction for macrolide synthesis by using the chiral boron enolate of diethylketone prepared with (—)- or (-1-)-(Ipc)2BOTf/iPr2EtN. 

Scheme 4. (a) Chiral auxiliaries in the form of a-oxygenated substrates to accomplish 1,2-anf/ aldol stereoselectivity in Paterson s total synthesis of ACRL Toxin IIIB (42) and (b) methods to remove the directing group. (1994) ... 

Scheme 5. Use of three different approaches for aldol stereoselectivity in Paterson s total synthesis of ebelactones A and B (61 and 62). (1990) ...

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

The outstanding diastereoselectivity in these reactions is further demonstrated in Paterson s total synthesis of the potential antiviral agent (+)-... 

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

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