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Intramolecular ketophosphonate-aldehyde condensation25 has been used by Nicolaou and co-workers as a cyclization release strategy to form macrocycles in the muscone series of natural products (Scheme 5).26 A highlight of this work was development of a unique phosphonate resin.
Details of the muscone synthesis were as follows. The resin precursor 40 was prepared by reaction of the low-load chloromethyl polystyrene with 1,4-butanediol followed by capping with CH3P(0)(0CH3)C1 (97% yield overall). This resin is loaded into SMART microreactors for directed-sort-ing-based library synthesis.27 The resins were then treated with n-BuLi and a series of long-chain alkenyl esters 41 to give the corresponding ketophos-phonates 42. Chain extension of these alkenes was affected via alkene metathesis with alkene substrates 43 (using Grubb’s catalyst 29), thereby affording a collection of olefinic alcohols 44. These alcohols 44 were oxidized under Dess-Martin conditions,16 then treated with potassium carbonate to promote condensation with the resulting aldehyde. Keto-macrocycles 45 were thus released from the resin. No dimeric product was obtained, even though it was in analogous solution-based chemistry. Cu-prate addition to the product enones 45 followed by hydrogenation gave the muscone-based products 46, including racemic muscone (46, R1 = R2 = H; R3= CH3).
256 RECENT ADVANCES IN SOLID-PHASE SYNTHESIS OF NATURAL PRODUCTS
Î^Ìã ^ð_ Me MeO
(i) BuLi, THF
Grubb’s cat. 29 benzene , 48h
(i) Dess-Martin periodinane
(i) R 2CuLi,
(ii) H2> Pd-C
8.6. TAXOID LIBRARIES FROM BACCATIN III
This is the first of two syntheses included in this chapter to highlight how natural product-based scaffolds can be attached to a resin for convenient derivatization into libraries. The other example is the synthesis of sarcodic-tyin libraries described in the next section. In both cases, interesting libraries were made with minimal development time by performing scaffold construction in solution or obtaining it from a natural source.
Scheme 6 describes the taxoid library synthesis.28 The supported and highly functionalized intermediate 48 was produced from baccatin III 47 in several steps. These involved elaboration of baccatin III in solution by
8.6. TAXOID LIBRARIES FROM BACCATIN III 257
47 (baccatin III)
(i) several steps
(ii) 2-CI-trityl resin (iii) MeOH
(i) piperidine, DMF (ii) R1C02H , PyBOP
(iii) R2C02H , DIC
(iv) AcOH , CF3CH2OH
connecting the taxol (3-amino acid side chain, then adding an FMOC-pro-tected glutamic acid derivative onto this. That same glutamic acid served as a point of attachment to 2-chlorotrityl resin to give 48. An excess of resin was used to trap this precious intermediate, then the unreacted functional groups were capped with methanol. At this point the resin was loaded into radiofrequency-encoded microcans for efficient construction of the library.27 Removal of the FMOC groups gave a primary alcohol that was acylated in the presence of the secondary alcohol on the Eastern cyclohexyl
258 RECENT ADVANCES IN SOLID-PHASE SYNTHESIS OF NATURAL PRODUCTS
ring. The latter alcohol was then acylated using another batch of carboxylic acids (R2C02H). Resin cleavage gave a library of 400 taxoid analogs 49. Isolated yields varied from 27 to 72% with purities ranging from 55 to 100%.
8.7. SARCODICTYIN LIBRARIES
Sarcodictyin libraries have been prepared from the supported scaffold 50 (Scheme 7). This scaffold was made via an approach developed in a solution-phase synthesis of sarcodictyin A.29 Again, this synthesis is from Nicolaou and co-workers.30 Scaffold 50 was modified for resin attachment by acylation of the secondary alcohol, creation of an aldehyde linker via ketal formation from the tertiary alcohol, then oxidation.16 This sequence gave the aldehyde 51 that was then attached to the resin by reaction with an excess of the phosphorane resin 52 followed by capping with acetaldehyde. The result was the pivotal anchored intermediate 53. This was then deriva-tized via the following steps: (a) deacetylation by methanolysis was followed by coupling of the imidazole acrylate side chain found in the natural product; (b) desilylation and oxidation of alcohol 54 with Dess-Martin periodinane-NaC102 to give the corresponding carboxylic acid 55l6; and (c) various operations on the acid formed, including esterification with methanol. The resulting compounds were cleaved from the resin by ketal hydrolysis to yield the desired library. Sarcodictyin A 61 was formed in 51 % yield from resin 53.