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Solid-phase organik syntheses - Burdges K.

Burdges K. Solid-phase organik syntheses - John Wiley & Sons, 2000. - 283 p.
ISBN 0-471-22824-9
Download (direct link): phaseorganicsynthesis2000.pdf
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8.3. EPOTHILONE A
This total synthesis is the first of three preparations of macrocycles that will be described (epothilone A, zearalenone, and muscone). All feature cyclization/release strategies that involve carbon-carbon bond formation.18 These efforts illustrate how the research on supported syntheses of highly complex structures has inspired the use of creative linker strategies for attachment to a solid phase.
252
RECENT ADVANCES IN SOLID-PHASE SYNTHESIS OF NATURAL PRODUCTS
(i) NaHMDS
(ii) THF ||

j () 1,4-butanediol
Cl (ii) l2,PPh3*" '
(iii) PPh3
0/-^PPh3+|-
OTBS
22
(iii) HF/pyridine
(iv) (COCI)2, DMSO NEt3
CI2Ru(PCy3)2CHPh 29
CH2CI2, 25 eC 48h
(i) separate Isomers
(ii) TFA, CH2CI2 (iii) MeCN
K,
8.4. (S)-ZEARALENONE 253
The specific strategy used by Nicolaou and co-workers in their synthesis of the anticancer agent epothilone A19 was alkene metathesis20 (Scheme 3). This gave cyclization to 16-membered ring compounds while simultaneously cleaving the product from the resin. The alkene functionality formed in this key step was ultimately transformed into the epoxide group of the natural product.
The linker synthesis began by etherification of chloromethyl polystyrene with 1,4-butanediol (Scheme 3). Iodide formation and displacement with triphenylphosphine provided the resin-bound phosphonium salt 22. Wittig olefination of this support with aldehyde 23 gave a supported Z-alkene. Desilylation and Swern oxidation give resin-bound aldehyde 24, ready for introduction of the second sizable organic fragment by aldol condensation of the zinc di-enolate of 25 [formed by treatment with lithium diisopropy-lamide (LDA) and ZnCl2]. The resulting resin-bound alcohol 26 was generated with modest stereoselectivty, and the isomers were not separated until later in the synthesis.
Nicolaous group attached the final fragment in their synthesis by esteri-fication of the resin acid 26 with the heterocycle containing alcohol 27. The product ester 28 set the stage for the key step of the synthesis: metathesis mediated by Grubbs catalyst 29. This proceeded smoothly causing cyclization to the desired 16-membered ring compounds 30 with concomitant liberation of the products into solution. Four isomers of 30 were produced from each of these reactions, that is, both E- and Z-alkenes (E-Z ratio = 6 : 4) from the metathesis, and three isomer configurations (ratio 3:1:6) from the aldol condensation of 24 with 25. The isomers were separated and the appropriate compound (isolated in 16% yield from the mixture) was desilylated, then epoxidized with methyl(trifluoromethyl) dioxirane to yield epothilone A 31 contaminated with a small amount of the a-epoxide isomer. This methodology was used by the same group to create a library of over 100 epothilone analogs for study in the effectiveness of inhibition of tubulin assembly and cytotoxic effects in taxol-resistant tumor cells.21
8.4. (S)-ZEARALENONE
Coupling of aryl halides with alkenyl stannanes promoted through palladium metal catalysis, otherwise known as the Stille coupling, has many applications,22 including solid-phase variants (see Chapter 2).3-5 One of these is featured in Nicolaou and co-workers solid-phase synthesis of (S)-zearalenone wherein a resin-bound alkenylstannane undergoes a Stille cycli-
254 RECENT ADVANCES IN SOLID-PHASE SYNTHESIS OF NATURAL PRODUCTS
zation/cleavage process (Scheme 4).23 This was adopted from an earlier solution phase strategy but required development of a novel tin-based linker.24
The synthesis of (S)-zearalenone began with creation of the chlo-rodibutylstannyl polystyrene resin 32, which ultimately would serve as a Stille coupling partner. Oxidation of chloromethyl polystyrene resin fol-
.
SriT
(i> THF
33
32
Cl () TBAF, THF ^
(iii) NCS, Me2S, NEt3 W
34
MgBr
(ii) NCS, Me2S, NEt3 Q)
36
(i) TBAF , THF ()
MEMO
MEMO
37
DEAD , PPh3
X02H
MEMO
MEMO'
38
(i) Pd(PPh3)4 HO 0 MePh, 48h
(ii)THF/HcT Hcr ^ ^ v v .-0
39 (S-zearalenone) Scheme 4.
8.5. dl-MUSCONE 255
lowed by reaction of the resulting aldehyde with methyltriphenylphos-phorane gave vinyl polystyrene. Reaction of this with dibutyldichlorostan-nane (Bu2SnCl2) in the presence of a radical initiator gave the required resin 32 in 90% yield for the three steps (Scheme 4). Coupling of the vinyl lithium species 33 to the tin polymer 32 occurred upon direct treatment to form the ?-vinylstannane-functionalized polymer exclusively. Desilylation and Corey-Kim oxidation then gave the corresponding ?-stannyl aldehyde 34. Attachment of the second key fragment occurred by treatment with Grig-nard reagent 35 followed by Corey-Kim oxidation to give the ?-stannylke-tone 36. The final piece 37 was connected through Mitsunobu coupling of the alcohol obtained by desilylation of 36. In the featured cleavage step, treatment of the resin-bound stannyl/aryl-iodide 38 with palladium catalyst induced cyclization/release (54% yield for the cyclization) and formed (S)-zearalenone 39 upon acid-induced deprotection of the methoxy ethoxy methyl (MEM) protecting groups.
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