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248 RECENT ADVANCES IN SOLID-PHASE SYNTHESIS OF NATURAL PRODUCTS
breakthrough discoveries in biological and medicinal chemistry. 6,7 This chapter highlights some beautiful syntheses of nonoligomeric natural products on solid phases.
There are several ways to prepare libraries of natural product derivatives on a solid phase. These include (a) total synthesis on the resin; (b) derivation of supported natural products; and (c) syntheses of analogs based on a natural product scaffold. This review will provide examples of all these approaches.
Prostaglandins are complex structures that have a wide range of biological activities. Syntheses of these molecules are challenging because their biological activities are highly dependent upon stereochemistry (and stereochemical impurities) and because the products/intermediates tend to be unstable to many reaction conditions.8 Two main strategies have appeared for solid-phase synthesis of both the E- and F-series prostaglandins. They both are based on solution-phase approaches, and they both feature cy-clopentene synthons generated in solution and then attached to a resin.
8.2.1. PGE2 Methyl Ester and PGF2a
Janda and Chen’s approach to the E- and F-series prostaglandins (Scheme
l)9,l° takes advantage of Noyori’s convergent three-component coupling strategy.11 It features non-cross-linked polystyrene (NCPS) as a support. This soluble support facilitates synthetic operations in solution, extraction into organic phase during work-up procedures, and the direct measurement of nuclear magnetic resonance (NMR) spectra by conventional means.12
Details of the Janda-Chen synthesis were as follows. A tetrahydropyran (THP) linker was attached to the NCPS support enabling attachment of alcohols via THP ether formation.13 The THP-NCPS resin 1 is derivatized with /?-(+)-4-hydroxy-2-cyclopentanone 2, giving the THP ether-based resin 3, followed by coupling of the C13_20 fragment by enone-cuprate addition. The cuprate required was generated from the corresponding E-vinyl stannane 4. The resulting enolate was trapped as the silyl enol ether
5. Then regeneration of the enolate with methyl lithium was followed by alkylation with the C,_7 fragment via the corresponding propargyl triflate
6. Lindlar hydrogenation provides compound 7 having the cis double bond
(i) L-se!ectride >
(ii) LiOH, (iii) HF
8 (X = Y = O; R = Me)
9 (X = H, Y = OH; R = H)
= non-crosslinked polystyrene
250 RECENT ADVANCES IN SOLID-PHASE SYNTHESIS OF NATURAL PRODUCTS
(i) HCOOH P™T PdtPPhA
(iii) Dess-Martin periodinane
ZrCp2HCI,CuCN MeLi, THF
8.3. EPOTHILONE A 251
at C5_6. Cleavage from the resin at this juncture provided the PGE2 methyl ester 8 in 37% overall yield from NCPS chloride resin.9 Alternatively, L-selectride reduction followed by saponification of the methyl ester and cleavage from the resin gave PGF2a 9 in 30% overall yield.10 Only the naturally occurring stereoisomers were observed.
8.2.2. PGE and PGF Analogs
The prostaglandin synthesis developed by Ellman and co-workers (Scheme
2) differs from Janda’s in several respects. Analogs of both E and F series (differing in the C,_7 side chain) were prepared.14 In their approach, 2-bro-mocyclopentene derivatives were synthesized in solution prior to resin attachment. In the first example, the 2-bromocyclopentene 11 was linked to the chlorodibutylsilyl polystyrene resin 10 as the silyl ether 12.15 Deprotection of the trimethoxytrityl alcohol-protecting group (TMT), Suzuki coupling with an alkylborane generated in situ from a monosubstituted alkene, and oxidation16 provided the resin-bound cyclopentenone 13 with the C,_7 side chain in place.17
Hydrozirconation of alkyne 14, followed by cuprate addition, was then used to install the C,3_20 side chain of 15. Reduction of the ketone (L-selec-tride) followed by hydrogen fluoride cleavage provides the F-series derivatives 16, while direct cleavage of 15 gave the E-series compounds 17.
Other derivatives were prepared by modifications of the original Ellman route. Thus, a second cyclopentene precursor 18 containing the C5_6 cis double bond was carried through to give the resin-bound intermediate 19 via a Stille coupling and an oxidation. Subsequent cuprate addition, reduction, and cleavage give 20 and 21 (the F and E series) with the C5_6 double bond intact. This type of approach was used to synthesize 11 more compounds in this series.