TBS ether

The C.115 amino group was protected as a trimethylsilylethyl carbamate (Me3SiCH2CH20C0NHR), a group that was stable to the synthesis conditions and cleaved by the conditions used to remove the t-butyldimethylsilyl (TBS) ethers. 

The oxirane ring in 175 is a valuable function because it provides a means for the introduction of the -disposed C-39 methoxy group of rapamycin. Indeed, addition of CSA (0.2 equivalents) to a solution of epoxy benzyl ether 175 in methanol brings about a completely regioselective and stereospecific solvolysis of the oxirane ring, furnishing the desired hydroxy methyl ether 200 in 90 % yield. After protection of the newly formed C-40 hydroxyl in the form of a tert-butyldimethylsilyl (TBS) ether, hydrogenolysis of the benzyl ether provides alcohol 201 in 89 % overall yield. 

With ring G in place, the construction of key intermediate 105 requires only a few functional group manipulations. To this end, benzylation of the free secondary hydroxyl group in 136, followed sequentially by hydroboration/oxidation and benzylation reactions, affords compound 137 in 75% overall yield. Acid-induced solvolysis of the benzylidene acetal in 137 in methanol furnishes a diol (138) the hydroxy groups of which can be easily differentiated. Although the action of 2.5 equivalents of tert-butyldimethylsilyl chloride on compound 138 produces a bis(silyl ether), it was found that the primary TBS ether can be cleaved selectively on treatment with a catalytic amount of CSA in MeOH at 0 °C. Finally, oxidation of the resulting primary alcohol using the Swem procedure furnishes key intermediate 105 (81 % yield from 138). 

Stereoselective cyclization controlled by a substituent remote from the reaction center is often difficult to achieve. However, 1-mediated cyclization of the substrates illustrated in Eq. 9.54 proceeds in a highly stereoselective manner when the hydroxy group is converted to a magnesium alkoxide prior to cyclization [99,100]. The effect of the alkoxide group is much more favorable than that of the corresponding TBS ether. 

As depicted in Fig. 6, syntheses of enantiomerically pure 116 and 117 have been carried out [236]. Lipase AK-catalysed asymmetric acetylation of meso-2,4-dimethyl-1,5-pentanediol A yielded (2R,4S)-5-acetoxy-2,4-dimethylpen-tanol B. Protection of the free hydroxy group as the terf-butyldimethylsilyl (TBS) ether, saponification of the acetate, and oxidation furnished the aldehyde C. Reaction of C with ethylmagnesium bromide gave a diastereomeric mixture of the corresponding secondary alcohols which could be resolved by asym-... 

A synthesis of 149, cucujolide VIII, proceeded via the tert-butyldimethylsi-lyl-(TBS)-ether of methyl (E)-12-hydroxydodec-4-enoate B [293] (Fig. 7). Deprotonation in a-position and reaction with di(4-methoxyphenyl)diselenide furnished C. This was transformed to the macrolide E after saponification of the ester moiety, deprotection of the hydroxy group, and Mitsunobu lactonization. Alternatively, the unsaturated lactone F was synthesized from B following a sequence similar to that from C to D. Oxidative elimination of the arylseleno group... 

Zn, TiCl4, CH2Br2, THF, CH2CI2 methylenation of aldehydes, ketones no reaction with esters, THP-ethers, TBS-ethers, carboxylic acids, alcohols [716,717]... 

The sulfone moiety was reductively removed and the TBS ether was cleaved chemoselectively in the presence of a TPS ether to afford a primary alcohol (Scheme 13). The alcohol was transformed into the corresponding bromide that served as alkylating agent for the deprotonated ethyl 2-(di-ethylphosphono)propionate. Bromination and phosphonate alkylation were performed in a one-pot procedure [33]. The TPS protecting group was removed and the alcohol was then oxidized to afford the aldehyde 68 [42]. An intramolecular HWE reaction under Masamune-Roush conditions provided a macrocycle as a mixture of double bond isomers [43]. The ElZ isomers were separated after the reduction of the a, -unsaturated ester to the allylic alcohol 84. Deprotection of the tertiary alcohol and protection of the prima-... 

Scheme 12). For this purpose, acid 68 was esterified with alcohol 64 to give the linear epothilone precursor 69. After selective deprotection of the primary TBS ether (CSA, CH2Cl2/MeOH) and oxidation, precursor 51 (Fig. 13), suitable for ring-closing chromium-Reformatsky reaction, was obtained. After treatment of 51 with CrCl2 and Lil in THF, the desired 6RJS isomer was obtained exclusively, whereas the diastereomeric precursor with the incorrect stereochemistry at C8 did not cyclize with the same efficiency, rate and selectivity. 

Later work by Hoberg showed that switching from the original protecting groups of a TBS ether at C-7 and acetate at C-5 to a 4,6-<9-dibutylsilylidene protection mode prevented the intramolecular reaction.54,55 Cyclopropanation of... 

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