Farnesyl aldehyde

Isomerization of farnesyl pyrophosphate is believed to involve reversible dephosphorylation with the formation of the corresponding alcohols and may proceed via 6-trans-farnesyl aldehyde. 

Information regarding the substrate activity of Reel was central to the development of substrate-based inhibitors. Investigation with farnesylated cysteine and farnesylated tetrapeptides did, however, result in enzymatic inhibition. The carboxylate terminus of a prenylcysteine modified with an aldehyde was found to be a low micromolar inhibitor [21]. Rando and coworkers also investigated modified farnesylated tetrapeptides. By modifying the substrate to remove the scissile bond, the potent statine-tetrapeptide (Figure 9.1) was discovered and has low nanomolar activity against Reel in crude membrane fractions. 

The synthesis of heme A (Fig. 2) involves the initial addition of the farnesyl moiety to the heme 2-vinyl group by heme O synthase, which generates heme O that only has this modification. In a second step, heme A synthase oxidizes the 8-methyl of heme O to an aldehyde, which generates heme A. An electron transfer mechanism (rather than double hydroxylation) has been proposed for this final biosynthetic step (28). 

The method used by Coates and Robinson" involved the copper-catalysed decomposition of trans,trans-farnesyl diazoacetate (4) to the cyclopropyl-lactone (5) having the stereochemistry shown. This was transformed into the cis-aldehyde-ester (6) by standard methods. Base epimerization gave the more stable transcompound (7). A Wittig reaction between the trans-aldehyde-ester (7) and the phosphorane (8), followed by lithium aluminium hydride reduction, yielded presqualene alcohol (1) as the major product accompanied by the minor isomer (9). 

Synthesis of Phosphoric Acids and their Derivatives. - Among various approaches to phosphate esters the phosphorylation of phenols with dialkyl cyanophosphonate and the synthesis of triaryl phosphates under phase-transfer conditions are worthy of mention. Mixed trialkyl phosphates are also reported to be formed by brief cathodic electrolysis of the reaction of dialkyl phosphonates with aromatic aldehydes and ketones, presumably by rearrangement of the initial a-hydroxy compounds. Further reports have appeared of the generation of metaphosphates by various methods. The synthesis of analogues 1 of famesyl pyrophosphate which incorporate photoactive esters has been reported both compounds are competitive inhibitors of farnesyl transferase. 

A related methodology (ref. 112) was employed in which rather than a C.,5 farnesyl component a compound was reacted with a chroman-2-acetaldehyde derivative. In this scheme the C.,4 aldehyde simultaneously formed at the ozonolysis stage in the previosly described synthesis was used. Thus, 2-carboxymethyl-6-hydroxy-2,5,7,8-tetramethylchroman, [(6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)acetic acid] served as a source by resolution with (S)-a-methylbenzylamine of the two enantiomeric acids. The 2(S)-enantiomer was converted by way of the acid chloride to the aldehyde, a homologue of that employed by the Swiss workers in the foregoing method. The aldehyde was reacted with the triphenylphosphonium salt from the C bromide by the Wittig reaction to afford 2R,4 R,8 R-a-tocopherol. A novel aspect of this approach was that it enabled a synthesis of 2R,3 E,7 E-a-tocotrienol to be achieved from the same carboxymethyl intermediate. 

Scheme 5.28 Cascade process in S. cerevisiae toward the artimisinin precursor artemisinic acid. Pathway engineering yields amorpha-4,n-diene via farnesyl pyrophosphate (FPP), and oxidations of amorphadiene are catalyzed by CYP71AV1 (redox partner protein not shown), alcohol dehydrogenase ADHl, and aldehyde dehydrogenase ALDHl. Artemisinin is synthesized in vitro from the produced artemisinic acid by established Synthetic chemistry. ADS, amorphadiene synthase.

LiAFH4 reduces a,)8-unsaturated aldehydes to the corresponding allylic alcohols in a 1,2-addition mode, as demonstrated with the synthesis of , -[l- H]farnesol (276, R = H), a precursor of ,/i-[l- H]farnesyl pyrophosphate (276, R = On the other... 

---