1.2-Prenyl migrations

Scheme 13 Studies on prenyl migration from the indole-3- to the -2-position by the Nakagawa [79] and Ottenheijm [80] groups...

Scheme 39 Biosynthetic origin of paraherquamide A (199) with /ert-prenyl migration according to Williams and co-workers [164]...

The 2-lerl-prenyl group itself stems from the mevalonate pathway and is introduced in a non-stereospecific manner, as shown by isotope labelling studies [164], The order of oxidations, of Diels-Alder reactions and of the tcrt-prenyl migration is still a subject of research on the individual alkaloids. 

Scheme 44 Synthesis of (+)-versicolamide B (231) carrying out the Diels-Alder reaction after the tert-prenyl migration by Williams and co-workers [181]...

Non-brominated indoles also underwent the 2-tert-prenyl migration induced by NBS and methylation of the side chain nitrogen was not necessary. N, Ni,-Dimethyl-2-tert-prenyltryptamine (238) afforded the AAi -dimethylamidinium salt 239, which precipitated from EtOAc (63% yield. Scheme 46). When the side chain was monoformylated, no cyclisation was observed. In the case of AbWb-dimethyl-2-Icrt-prenyltryptamine (240), oxidation with NBS was carried out in acetone for solubility reasons affording 3-bromoindole 242 (21%) via bromoin-dolenine 241, which was observed on NMR control. Loss of the side chain of the 3-bromoindolenine on alkaline work-up can be explained by nucleophilic attack of hydroxide at the imine (3-position. 

In a variation of these reactions, Grieco and Masaki used p-toluenesulfonyl groups to direct alkylation reactions in the formation of carbon chains and then cleaved the sulphones with lithium in ethylamine. This type of synthetic construction involving the use of sulphur-containing molecules has become a typical sequence in organic syntheses. In this case, the reactions formed part of successful syntheses of squalene and sesquifenchene and were carried out without any migration or loss of stereochemical integrity of the double bonds. Similar sequences have been reported by Trost (prenylation reactions) and Marshall (synthesis of a cembranoid precursor). 

One advantage of the small size of a-factor and related pheromones is that they can be directly visualized after metabolic labeling. Few other proteins are so small, thus S. cerevisiae a-factor and related proteins like AFRP, as well as pheromones from other species, are often the only proteins that migrate near the dye front in SDS-PAGE analysis, and are far away from the bulk of larger cellular proteins [91,92]. In addition, radiolabeling is assured, as all prenylated molecules have at least one Cys residue in the CAAX motif that can be radiolabeled by S-Cys. Thus, direct visualization from protein preparations of whole cell extracts or culture supernatants is feasible. 

Fig. 8.3. Inhibition of prenylation in STS-26T cells by GGTI-2Z/lovastatm combination treatment. (A) inhibition of Rapl prenylation, (B) detection of Rab5. Unprenylated GTPases migrate more slowly on SDS-PAGE gels. Adapted from Sane et al. [35]. Copyright 2010 American Society for Pharmacology and Experimental Therapeutics.

The classic example for conversion of allylphenols to propenylphenols is the base-catalyzed rearrangement of eugenol 117 to isoeugenol 118 (eqnation 52) °. Silyl protected phenolic tertiary cinnamyl alcohols 119 undergo a lithinm-ammonia indnced hydrogenol-ysis with concomitant double bond migration. This reaction serves as a nniqne approach to prenyl-snbstimted aromatic componnds 120 (equation 53)" " . ... 

Another chiral synthesis of eldanolide (129) depends on the ready availability of the amide 134 from ethyl (S)-lactate. Carefully controlled reaction gave prenylation at the primary position (20 1 compared with tertiary position). A vinylsilane group was then introduced, and migration of this group was carried... 

The most understandable and well-discussed inhibitory mechanism is the blockade of protein prenylation. Rho GTPase, such as Rho, Rac, and Cdc42, play a key role in the migration signal transduction pathway, and post-translational modification with isoprenoids is necessary for their full activation to anchor to the cell membrane. Famesyl pyrophosphate and geranylgeranyl pyrophosphate are well-known isoprenoids prodncts, and HMG-CoA reductase is also involved in the isoprenoid synthetic pathway. 

Based on this result, these workers speculate the involvement of the reverse prenylated diketopiperazine A, that subsequently undergoes a [1,2]-migration of the prenyl unit to the 3-position giving structure B (Scheme 24) which subsequently suffers cyclization and oxidation to roquefortine. 

To rationalize this data, these workers speculate the intermediacy of the N-prenylated indole derivative A (Scheme 25) an aza-Claisen-type rearrangement would furnish B and a stereorandom [1,2]-migration of the isoprene moiety would result in the loss of the stereochemical integrity of the label in C-26 and C-27. An alternative pathway involving direct alkylation at C-3 of the... 

Grundon et al. examined the possibility that the reverse prenyl unit was introduced via an indolic N-prenylated precursor followed by aza-Claisen rearrangement and 1,2-migration as shown in Scheme 38 [61]. These workers synthesized l-([l- H]-3,3-dimethylallyl)-L-tryptophan and cyclo-L-alanyl-l-([l- H]-3,3-dimethylaUyl)-L-tryptophan and fed these labeled substances to cultures of Aspergillus amstelodami and found that neither compound was incorporated in radiochemically significant amounts into echinulin. 

A similar mechanism was also postulated by Barrow et al. for the incorporation of the reversed isoprene unit at the indolic 3-position of roquefortine (see Schemes 22 and 25) [44] to date there is no experimental support published in the literature for the notion that the reverse prenyl unit at ei er the 2-position, as is found in echinulin, or the 3-position, as is found in roquefortine, is introduced indirectly at the indole nitrogen (or some other position) followed by migration. All evidence, both direct and indirect, points to the direct S attack of the pertinent indole carbons on dimethylallylpyrophosphate. 

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