Total synthesis protecting groups

Total Synthesis of Palytoxin Carboxylic Ad An Example of the Selection, Introduction, and Removal of Protective Groups... 

And so the skillful selection, introduction, and removal of a total of 12 different protective groups have played a major role in the successful total synthesis of paly toxin carboxylic acid (Figure 1,2). 

A 2-methoxyethoxymethyl ether was used to protect one phenol group during a total synthesis of gibberellic acid. 

The completion of the total synthesis only requires a few deprotection steps. It was gratifying to find that the final deprotections could be conducted smoothly and without compromising the newly introduced and potentially labile trisulfide residue. In particular, exposure of intermediate 101 to the action of HF pyridine results in the cleavage of all five triethylsilyl ethers, providing 102 in 90% yield (Scheme 23). Finally, hydrolytic cleavage of the ethylene ketal with aqueous para-toluenesulfonic acid in THF, followed by removal of the FMOC protecting group with diethylamine furnishes calicheamicin y (1) (see Scheme 24). Synthetic calicheami-cin y, produced in this manner, exhibited physical and spectroscopic properties identical to those of an authentic sample. 

A highlight in the application of RCM methodology in natural product synthesis is Hirama s total synthesis of ciguatoxin CTX3C (183) [90], including the more recent improved protective group strategy, as depicted in Scheme 34 [90b]. The structure of 183 spans more than 3 nm and is characterized by 12 six- to nine-membered trans-fused cyclic ethers and a spiroannulated terminal tetra-... 

The nature of the nitrogen protecting group also played a significant role in the chemoenzymatic total synthesis ofepibatidine, which shall be outlined as an example for the synthetic elaboration of the regioselective biooxidation product of a nonnatural precursor. B. bassiana mediated hydroxylation of the aza-norbornane system enabled functionalization for the subsequent introduction of the pyridine system (Scheme 9.10) [82,83]. 

Alkylation of cyanohydrin acetonide 79 with the iodide 78 proceeded smoothly to give pentaacetonide 80 in 70% yield (Scheme 10). This represents the entire polyol framework of roflamycoin. An eight-step sequence involving installation of the polyene, macrocyclization via Horner-Emmons reaction, and protecting group machinations, completed the first total synthesis of roflamycoin. 

At this point, completion of the total synthesis required removal of the three acetonides and the two silyl protecting groups (Scheme 18). Removal of the silyl groups with TBAF and subsequent treatment to acidic deprotection conditions led to complete deprotection of 110, but failed to provide filipin III. It was sus-... 

The aqueous Barbier-Grignard-type reaction has also been used in the synthesis of natural products. Chan and Li used the zinc mediated allylation as a key step in a total synthesis of (+)-muscarine (Scheme 8.5).72 The strategy was based on the observation that the diastereoselectivity of the allylation reaction in water can be reversed through the protection of the a-hydroxyl group. 

In addition to the methodological advances noted above, the Et3SiH variant was utilized in the total synthesis of three members of the allopumil-iotoxin family [ 15,16]. In one of the more complex examples, ynal substrate 1 was converted to product 2 in 93% isolated yield as a single diastereomer (Scheme 4). Simple removal of the protecting groups allowed completion of... 

While in the uncatalyzed reaction of l-ethyleneimino-2-hydroxy-3-butene in THF, refluxing for four hours was necessary to produce 70% of the ester, in the presence of NaNH2 a 90% yield was achieved at room temperature after only five minutes.[13 14] An especially interesting example of the use of the imidazolide method for ester synthesis is illustrated by the total synthesis of actinomycin C3.[15],[16] Working with N-protected L-TV-methylvaline and CDI, esterification of the hydroxyl group on the threonine residue proved successful whereas this could not be accomplished by any of the conventional methods. 

Overall, the racemic synthesis was accomplished in a 15-step sequence with only a single protecting group manipulation and marked the second total synthesis of ( )-nominine (1) (Scheme 1.20) [59], the first having been completed by Muratake and Natsume in 2004 [19]. The asymmetric synthesis of nominine was accomplished in a 16-step sequence in a similar fashion [60]. 

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