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30 min, 89 %
3. nBuLi, THF, -78 °C, 99 %
4. DDQ, CH2CI2, pH 7- buffer, 0 °C, 20 min, 96 %
• Oxidation of the free alcohol is achieved in the first step.
• PPh3 and CBr4 react to form Ph3P=CBr2 which then reacts with the aldehyde.
• Steps 2 and 3 transform an aldehyde into an alkyne.
• Step 4 is an oxidative deprotection reaction.
2 (-)-Bafilomycin À/
Discussion The primary alcohol is oxidized in the standard Swern procedure to
give aldehyde 19.9 This very popular oxidation method creates a reactive intermediate (22) from dimethyl sulfoxide and oxalyl chloride. This intermediate is then attacked in SN2 fashion at the sulfur atom by the substrate alcohol. Upon work-up with triethylamine the desired aldehyde or ketone and dimethylsulfide is formed.
01 + GO + CO2
2 eq. nBuLi followed by H20
The reaction sequence in steps two and three is known as the Corey-Fuchs method to create an alkyne from an aldehyde:10 Reaction of triphenylphosphane with carbontetrabromide gives phenylphosphane-dibromomethylene. This reagent then transforms aldehyde 19 into the corresponding dibromoalkene 20 thereby extending the chain by one carbon. Reaction of the bromo compound with two equivalents of n-butyllithium in THF at -78 °C results in the rapid formation of the acetylenic lithio derivative which forms the terminal acetylene 21 upon aqueous work-up.
The para-methoxybenzyl group belongs to a class of alcohol protecting groups that are stable to basic conditions but can be removed by oxidation. Here DDQ (2,3-dichloro-5,6-dicyano-l,4-benzoquinone) is used to yield the free primary alcohol 3.
2 (-)-Bafilomycin À;
: 1 -
• This reaction is a carbometalation. Hints
• Trimethylaluminum is used. Which other metal is necessary?
• The carboalumination intermediate is treated with iodine.
1. AlMe3, [Cp2ZrCl2], C1(CH2)2C1, 60 °C, 14 h, Solution
then I2, -30 °C, 1 h, 65 %
Negishi and co-workers developed this carbometalation reaction of alkynes with organoalane-zirconocene derivatives, and it has since turned into an often used route to stereo- and regiodefined trisubstituted olefins.11
Applying a methylalane and a zirconocene derivative (E)-2-methyl-l-alkenylalanes can thus be synthesized with stereoselectivity generally greater than 98 %, the regioselectivity observed with terminal alkynes being ca. 95 %. This Zr catalyzed carboalumination reaction most likely involves direct Al-C bond addition assisted by zirconium to yield the carboalane 23. The carboalanes are versatile intermediates, since the aluminum moiety can be easily replaced by hydrogen, iodine and various carbon electrophiles to produce the trisubstituted olefin 4.
: 8+ 5-
\ / + ZrCp2CI2 Me AIMe2 23
Me I 4
1.(COCI)2, DMSO, Et3N, CH2CI2, -78 °C -» 0 °C,
2. Ph3PCH(Me)C02Et, OTBS toluene,60 °C, 15 h,
90 % (over two steps) OH -~
3. DIBAH.THF,-78 °C 3.5 h, 99 %
2 (-)-Bafilomycin À/
• Another Swern reaction is performed.
• An aldehyde reacts with a phosphorus ylide.
• Diisobutylaluminumhydride (DIBAH) is a reducing agent.
The primary alcohol is first oxidized to an aldehyde, which is then the substrate in a Wittig olefination reaction. Here a stabilized ylide is employed and therefore the E double bond is formed exclusively. (For a detailed description of the Wittig reaction see Chapter 13; the selectivity issues are explained in Chapter 9.)
The resulting ester can then be reduced with diisobutylaluminumhydride (DIBAH) to synthesize the primary alcohol 5.
• The first two steps turn an alcohol into an olefin again.
• What reagent oxidizes allylic alcohols to aldehydes?
• What variation in the Wittig methodology is also often used to synthesize E olefins?
• Deprotection of the TBS ether follows.
2 (-)-Bafilomycin A t
1. Mn02, CH2C12, r. t„ 18 h, 99 %
2. KHMDS, THF, (;Pr0)2P(0)CH(0Me)C02Me, crown-6, 0 °C
r. t, 8 h, 85 %
3. TBAF, THF, r. t., 2 h, 82 %
Manganese dioxide is an important reagent, since it can oxidize primary or secondary alcohols to the aldehydes or ketones in neutral media. Oxidation of allylic and benzylic alcohols with Mn02 is faster than that of saturated alcohols. The primary synthetic utility of Mn02 is therefore the selectivity of oxidation of allylic over saturated alcohols. There is rather poor selectivity in the oxidation of primary allylic alcohols over secondary allylic alcohols, though. The mechanism is believed to proceed through radical intermediates. The reactivity of manganese dioxide is strongly influenced by the method of preparation. One of the more common methods involves precipitation of Mn02 from a warm aqueous solution of KMn04 and MnS04. The reagent is then activated by heating it to ca. 200 °C for several hours.
Thus the primary allylic alcohol 5 is transformed into an aldehyde, which can now be used in a Horner-Wadsworth-Emmons reaction. In this reaction the dienoate moiety was obtained in a Z,E\E,E-selectivity of 95:5.