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10 Myxalamide A
The resulting molecule bears a primary and a secondary alcohol function. The primary alcohol can be selectively protected by using ÒÂ SCI. This silyl protecting group provides excellent stability towards base, but is relatively sensitive to acid. Lastly the secondary alcohol is acylated using propionyl chloride in a standard procedure to give ester 8.
1. LDA, THF, -78 °C, 11 min
2. TBSCI, HMPA, THF,
-78 °C, 45 min
3. -78 °C -> r. t., 3.5 h then CH2N2
86 % (over three steps)
• A silyl enol ether is generated.
• This silyl enol ether undergoes a [3,3]-sigmatropic rearrangement.
Treatment of ester 8 with LDA followed by TBSCI produces an ?-silyl ketene acetal 34, which undergoes a [3,3]-sigmatropic rearrangement upon warming up to room temperature. This [3,3]-rearrangement is one version of the Claisen-rearrangement also called Claisen-Ireland-rearrangement.16 The classical Claisen protocol is the rearrangement of an allyl vinyl ether 28 at high temperature under formation of a ^^unsaturated aldehyde 29.17 However, the product of
10 Myxalamide À
the Claisen-Ireland rearrangement is an or-allylated silylether 31, whose carbonyl double bond is stabilized by mesomeric structure 32 (-14 kcal/mol). This stabilization is an additional driving force compared to the classical reaction whose products cannot be stabilized by resonance structures. The resulting silylester is not stable under hydrolytic conditions and yields the corresponding acid after aqueous work-up.
Enolization of 8 with LDA can proceed via the two different transition states 33 and 37. The steric interactions between the methyl group and the isopropyl group of LDA disfavor transition state 37. Thus the stereochemistry of the enolization proceeds via 33 yielding the Z:-enolate, which is subsequently trapped by TBSC1 to give the corresponding ?-silyl ketene acetal 34. During warm-up to room temperature this acetal undergoes the described rearrangement via the chair-like transition state 35. After acidic work-up and treatment with etheral diazomethane, methyl ester 9 could be isolated.
H3C ©uS Q|-|3 35
,°TBS 2 ÑÍãì2
10 Myxalamide A
• During the first two steps the ester is transformed into a leaving Hints group.
• After reduction, the resulting alcohol is treated with tosyl chloride.
• For the nucleophilic substitution a higher-order cyanocuprate is used.
1. LiAlH4, Et20, 0 °C, 30 min, r. t., 2 h, 99 % Solution
2. TsCl, DMAP, NEt3, CH2C12, r. t„ 21 h, 94 %
3. CuCN, MeLi, Et20, 0 °C, 3.5 h, 94 %
These three reactions extend the carbon framework. First methyl ester
9 is reduced with LiAlH4 to the corresponding alcohol 39, which is then treated with tosyl chloride to yield 40. The use of cyanocuprates for the following reaction is necessary because they are only a little basic and so nucleophilic that they substitute the tosylate. The addition of two equivalents of methyllithium to CuCN forms cuprate 41. This compound is called higher-order cyanocuprate.18 Generation of the reagent at -78 °C followed by warming of the reaction mixture up to room temperature and addition of tosylate 40 yields 76 % of the desired product along with significant amounts of alcohol 39 presumably resulting from attack on the sulfur of the tosylate. When the cuprate is formed at a higher temperature (0 °C) the yield increases to 94 % with little or no formation of alcohol 39.
2 MeLi + CuCN
10 Myxalamide À
© 0 [(CH30)3P0R] sr
1. MCPBA, CH2CI2, -78 °C,
2. P(OMe)3, MeOH, 55 °C,
8 h, 80 % (over two steps)
3.TIPSOTf, NEt3, CH2CI2,
0 °C, 20 min, 94 %
4. 5 % H2S04, THF, r. t.,
, 7.5 h, 94%
• The thioether is oxidized to the sulfoxide.
• The sulfoxide forms an equilibrium with an other compound, that is trapped with the phosphorus reagent.
Oxidizing reagents like MCPBA can attack the molecule at two different positions: at the double bond and at the thioether functionality. The oxidation of the thioether is faster than the epoxidation of the double bond; therefore oxidation of 10 with one equivalent of MCPBA afforded a mixture of diastereomeric sulfoxides 44. These allylic sulfoxides tend to undergo a [2,3]-sigmatropic rearrangement, also called the Evans-Mislow rearrangement.19 The allylic sulfoxide structure 45 is strongly favored at equilibrium; therefore the S-0 bond has to be cleaved to shift the equilibrium in favor of the sulfenate. Trivalent phosphorus reagents react with the sulfenate to cleave the S-0 bond. Presumably they form phosphonium salt 43 via the pentacoordinated phophorane 42. Finally aqueous work-up yields the allylic alcohol 46.
10 Myxalamide À
Next the generated secondary alcohol is protected as triisopropylsilylether using TIPSOTf. The greater bulk of the TIPS group makes it more stable than the TBS group towards acidic hydrolysis; therefore reaction with 5 % H2S04 cleaves the TBS ether selectively to yield 11.