Seco acid precursor

In retrospect, our design for a seco acid precursor to the aglycon core... 

Next, we investigated whether it might be possible to forge the macrocyclic skeleton of 1 via a macrolactonization, by taking advantage of intrinsic conformational bias of a seco acid precursor (Scheme 10). The alcohol 45... 

A more complex hydroxy acid is lactonized in a synthesis of (9S)-9-dihydroerythronolide A, albeit in low yield (equation 128). By acid treatment (356) is deprotected to give the desired target molecule. The presence of jp -centers in the seco-acid obviously facilitates lactonization, as shown by the preparation of the mycinolide V precursor (357 equation 129). A mixed carbonate is used in the synthesis of the tylonolide precursor (358 equation 130). ° In general, DMAP catalysis is helpful in the ring closing step in most cases. 

The required chain extension of 12 was accomplished via deprotonation with NaH and condensation with aldehyde 7 to afford the Diels-Alder precursor 13 in 50% yield. Thermolysis of triene 13 and lactam 3 in xylene at 170 C for four days resulted in the desired cycloaddition to 14. Chromatographic purification permitted isolation of pure 14 in addition to a small amount of an exo isomer (>4 1 ratio). Acid treatment induced cleavage of both the silyl ether and acetonide. Reprotection of the diol and selective epoxidation of the A olefin produced 15 in 64% yield from 12. Epoxide 12 was then transformed to the isomeric allylic alcohol 16 by conversion of the alcohol to the bromide followed by reductive elimination. Protecting-group manipulation and subsequent oxidation the gave aldehyde 17, which was homologated and hydrolyzed to give seco acid 18 in 32% overall yield from 16. 

Gerlach has also prepared pyrenophorin (9) and its meso diastereomer, as shown in Scheme 4.3,The activated thioester 13 was condensed with Grignard reagent 14, affording a 65% yield of ketone 15. After protection of the ketone carbonyl, introduction of the double bond via a selenylation-oxidation sequence produced 16 (36%). Seco acid 17 was obtained in 79% yield by desilylation followed by basic hydrolysis of the ester. Cyclization to the dimer, again under Mitsunobu conditions, afforded a 24% yield of a 1 1 mixture of the protected precursor of 9 and the corresponding meso diastereomer, which were then converted to 9 and 18 by hydrolysis. 

Isobe et al. at Nagoya made a retro synthesis of the maytansine framework by disconnecting between N19-C1, C2-C3 and Cn-Ci2 so that the ansa-ring was planned to be cyclized from the seco acid-like precursor. An aldol reaction and a... 

Other approaches to make macrocyclic ring systems exist as well. Smith and Ott prepared the central framework of (-)-macrolactin A by using a Mitsunobu reaction to prepare a linear precursor for the final ring closure reaction with a Stille reaction. The Mitsunobu reaction proceeded in 74% yield the Stille reaction, in contrast, took seven days and provided the desired macrocyclic intermediate 60 in 42% yield. In an inverse approach, Williams and Meyer prepared (+)-amphidinolide K by preparing a seco-acid macrolactonisation precursor via Stille reaction and then using the Mitsunobu reaction to close the ring to form 61. ... 

The lactonization of erythronolide A seco acid to form a 14 membered lactone has a cumbersome and instructive history. The Woodward group tested a plethora of protecting group patterns at the seco acid stage until cyclization was finally realized [13] with 38. The success has been traced to the 9(S) configuration of the cyclization precursor 38. 

Synthesizing the chain-extended multiply unsaturated co-bromo- or (D-iodo-fi-ketoamide seco-tetramic acid precursors 42-44a, b, c, etc. depicted in Fig. 8 and utilizing them for polyenoyltetramic acid synthesis. 

The synthesis of the CG525155 (a neutral endopeptidase inhibitor) required a Pd catalyzed Tsuji-Trost reaction as the key step following the strategy described by Johnson. Starting from the optically active allenyl amino acid methylester 91 (synthesized in several steps from 90), the seco-derivative 92 as the crucial precursor was generated in several steps in high yield. The Pd (0)... 

Sol-gel chemistry can be catalyzed by acids or bases, the former being the most common case. In acidic media, the starting point ofthe preparation is the hydrolysis of a mixture of alkoxide precursors, with water, in solvent such as ethanol (EtOH), or other alcohols. This is followed by condensation (polymerization) and sol formation. This colloidal solution is then aged and the evaporation ofthe solvent and water may occur slowly, leading to a bulk gel, or rapidly, by deposition methods such as spin or dip-coating. The porous bulk or thin film gel thus obtained may be further dried and sintered (densified), with simultaneous elimination of porosity and residual OH groups (Seco et al., 2000). For more details on the preparation of sol-gel materials, the reader is referred to Vol. 1 of this series of books, or to a general treatise like that by Brinker and Scherrer (1990). 

There have been many total syntheses of the depsipeptide HDAC inhibitors by academic groups. In the first, by Simon, macrolactonization of the linear seco-hydroxy acid 41 (Scheme 4.3) to the FK228 precursor 43 proved to be challenging under the usual conditions of carboxylic acid activation due to competing elimination of the allylic alcohol. Instead, the cyclization was accomplished by alcohol inversion under Mitsunobu conditions using large... 

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