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• Three protecting group manipulations are performed.
• 3,4-Dimethoxybenzyl (DMPM) groups are cleaved oxidatively.
• TES groups are acid labile.
• Which alcohol is protected as TES ether now?
• Hydroboration is regioselective with alkynes, too.
TESO Î OH
Previous studies had shown that the 3,4-dimethoxybenzyl (DMPM) group was impossible to cleave at a later stage of the synthesis, since it interfered with the diene moiety at C-10-C-13. Therefore it had to be replaced by a more labile protecting group like the TES group. DMPM is a variation of the para-methîxóbenzyI (PMB) group, which is cleaved under oxidative conditions using DDQ or cerium ammonium nitrate (CAN). Therefore it can be cleaved while silyl and benzyl ethers (reductive deprotection) are stable. A protecting group strategy that employs different protecting groups which can each be cleaved selectively by using different conditions is called orthogonal. The TES group is then cleaved by trifluoroacetic acid (TFA). The next step again introduces a TES group using the TES-chloride. Here the sterically less encumbered alcohol is more reactive and therefore can be selectively protected. In a parallel protecting group strategy one uses the same protecting groups and selectively protects and deprotects depending on the reactivity of the substrate.
With the TES protected alcohol at C-19 and the free alcohol at C-15 the subsequent reactions could be performed. Hydroboration of the triple bond and aqueous work-up creates vinylboronic acid 10, which is the other coupling partner with 6.
2 (-)-Bafilomycin Ai
TESO Î OH
• What metal catalyzes this reaction?
• Do you know variations in the Suzuki reaction?
1. 20 mol% [Pd(PPh3)4], aq. TlOH, THF, r. t„ 30 min, 65 %
The diene synthesis using vinyl boranes or vinyl boronic acids with alkene halides catalyzed by palladium(O) has been developed by Suzuki and co-workers.19 This reaction is explained in Chapter 10. The Suzuki coupling has not been as widely used in total synthesis as the Stille reaction, even though tin reagents are much more toxic. One of the drawbacks of the Suzuki reaction is the decreased rate of reaction when substrates of higher molecular weight are used. Kishi found that addition of thallium hydroxide increases the rate of reaction by a factor of 1000.20 Under the modified conditions the reactions now proceed almost instantaneously even at 0 °C and produce less side products, allowing its application to substrates with fragile functional groups and high molecular weight. The only drawback is the high toxicity of thallium compounds.
2 (-)-Bafilomycin A j
1.1N KOH, dioxane,
80 °C, 1.5 h
2.2,4,6-Trichlorobenzoyl-chloride, /Pr2EtN, THF, then DMAP, toluene, reflux, 24 h
52 % (over two steps)
• Hydrolysis of the ester is the first step.
• Acid chlorides and carboxylic acids react with base to anhydrides.
• After change of solvent and addition of DMAP, the mixed anhydride is attacked by the nucleophilic alcohol oxygen.
ci o o
Hydrolysis of the methyl ester is afforded by saponification with KOH in dioxane and the seco-acid was used in the subsequent steps without purification.
Macrocycles are often not easy to form, especially when they include many substituents. The applied procedure to synthesize macrolactones was introduced by Yamaguchi and co-workers and has since been used extensively.21 First the acid is transformed into the mixed anhydride 26. Refluxing the anhydride in toluene will yield the desired macrocycle. The attack of the alcohol at the trichlorobenzoic acid carbonyl moiety is not favored because of steric hindrance by the chlorine substituents ortho to the acid. Therefore the ring is closed selectively. Usually in macrocyclizations high dilution conditions are applied, too, in order to avoid intermolecular reactions.
2 (-)-Bafilomycin À]
• Protecting group operations are performed in the first two steps.
• An alcohol is oxidized to the ketone.
1. TESOTf, 2,6-lutidine, CH2C12, -50 °C, 20 min, 85 %
2. TFA, THF, 5 °C, 6 h, 90 %
3. Dess-Martin periodinane, pyridine, CH2C12, 0 °C, 4 h, 98 %
The triethylsilyltriflate is used to protect the secondary alcohol 12 at C-7 first. Now the alcohols at C-7 and C-19 are both TES protected. Since the secondary alcohol is less hindered having one methyl substituent the authors succeeded in selectively deprotecting only C-
19 with trifluoroacetic acid. This strategy appears to be complicated but proved to be necessary since attempts to use a TBS or TES protected C-7 alcohol in the macrocyclization failed to react probably because of interference of the protecting group with the methyl substituents at C-6 and C-8 in the transition state. The experiment using unprotected C-7, C-15 and C-19 alcohols gave mainly a 20-membered macrolactone. The hydroxy functionality at C-7 also needed to be protected for the following step since the C-19 alcohol could not be selectively oxidized in its presence. The C-19 oxidation was then accomplished using the standard Dess-Martin reagent (see Chapter 1)