Brefeldin synthesis step

Three novel stereo- and regioselective schemes for the total synthesis of (+ )-brefeldin A 440 have been accomplished. Each of them exploit intermolec-ular nitrile oxide cycloaddition for constructing the open chain and introducing substituents, but differ in subsequent stages. The first (480) and the second (481) use intramolecular cycloaddition for the macrocycle closure. However, in the second scheme INOC is followed by C=C bond cis-trans-isomerization. In the third scheme (481) intermolecular cycloaddition is followed by ring closing metathesis as the key step. 

The key step in the formal total synthesis of ( )-brefeldin A utilized the acid catalyzed ring opening of (289) to (290) 99>. 

Asymmetric epoxidation is applied to the synthesis of the novel ferroelectric liquid crystals 99 that have the chiral trans-2, >-e, o y hexyl group as a core moiety (Scheme 31). The (25, 35 )-epoxy alcohol 98, conveniently obtained in 86% ee, is transformed into the desired material in two steps [99]. A formal synthesis of Brefeldin A (102), which shows a variety of biological activity represented by antitumor, antifungal, and antiviral activity, is accomplished via a highly enantioselective intramolecular hydroacylation of racemic pentanal 100 with 0.9 % of cationic Rh[(S)-binap] BF4. A 1 1 mixture of trans- and cis-cyclopentanones 101 is obtained with a high enantiomeric excess of 96% for each (Scheme 32). In the following step, the undesired cw-isomer is converted into the thermodynamically favored tran -isomer for further transformation [100]. 

The key step in D. Kim s total synthesis of (-)-brefeldin A was an intramoiecuiar nitriie-oxide cycioaddition. In order to prepare the substrate for this cycioaddition, a doubie Finkeistein reaction was performed first an alkyl tosylate was replaced with iodide then the iodide was exchanged with a nitrite ion to afford the desired alkyl nitro compound. 

Our kinetic studies of mutant PrPs synthesized in CHO cells suggest that individual steps in formation of PrP may take place in at least two different cellular locations (Fig. 5). Because mutant PrPs become PIPLC-resistant within minutes of synthesis in pulse-labeling experiments, this early step must take place in the ER. Consistent with this conclusion, acquisition of PIPLC resistance is not affected by treatment of cells with brefeldin A or by incubation at 18°C, manipulations that block exit of proteins beyond the Golgi (Daude et al, 1997). In contrast, detergent insolubility and protease resistance, which do not develop until later times of chase, and are reduced by brefeldin A and 18°C incubation, are likely to be acquired after arrival of the protein at the cell surface, either on the plasma membrane itself or in endocytic compartments. Raft domains may be involved in these changes (unpublished data). 

As an alternative to baker s yeast, the use of plant tissues (e.g., from apple, carrot, cucumber, onion, or potato) has been suggested [112,113]. It remains unclear, however, whether endophytic microorganisms are involved in these reductions [114]. Heterocyclic ketones [111, 115-117] as well as many a-hydroxy ketones [96,118-121] have been the subject of yeast-mediated reductions. For the latter compounds very high ee values have been obtained, albeit the yields were moderate. Monobenylated (S)-l,n-diols have been prepared using highly diluted yeast suspensions, and ee values up to 95% could be achieved [122]. Yeast-mediated reductions of acyclic ketones were key steps in the total synthesis of the pheromone sulcatol [123], brefeldin A [124], and endo-brevicomin [125]. 

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