Appending a Side Chain

Appending a side chain to the core of a complex molecule very often involves a type II olefin (the core) and a type I olefin (the side chain). However, in some cases the side chain can be of type II or III as exemplified in this section. 

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This chapter is divided into six sections. The first three sections loosely reflect the role of alkene cross-metathesis (CM) in the general plan of the synthesis of natural products, which can be the functionaHzation of terminal olefins appending a side chain to the core of a complex compound, or couphng two fragments to build the entire skeleton of the target molecule. Afterwards, tandem processes involving CM will be presented, followed by a few examples ofene-yne and alkyne CM in natural product synthesis [1]. 

The predominance of nuclear methoxylation over competing alkyl side-chain oxidation processes for these systems was largely attributed to an intramolecular attack by the appended side-chain alkoxy radical on the anodically generated aromatic radical cation in the usual EEQCp mechanism [99]. A more recent mechanistic study of anodic oxidation of chiral alkoxynaphthalene derivative (LXXXIX) sheds some additional light on this process [Eq. (46)] [100]. The isolation of a 2 1 mixture of enantiomeric methoxylated products indicated that intramolecular attack by the appended alkoxy radical on the aromatic radical cation (path B) was disfavored at —7S°C (a nearly 1 1 mixture of enantiomers was obtained at 25 C), since the intermediate cyclic ketal resulting from such a process would be a meso form that would lead to a racemic mixture of methoxylated products. Note that the chirality of the appended hydroxyether side-chain disappears upon cycliza-tion to the acetal. 

This result argued for the alternate view of the EEC Cp mechanism sequence, involving initial face-selective attack on the chiral radical-cation intermediate by methoxyl radical (path A), followed by acetal cyclization and proton loss. A rationale for the increased chemical yields observed for the systems studied in Eqs. (44) and (45) was not addressed in this work, although intramolecular solvation and stabilization of the intermediate radical cation by the appended hydroxyether side chain was suggested as one of the possible factors involved in the observed stereodifferentiation [101,102]. 

A latest example features coordination chemistry for supramolecular stitching of HBC nanotubes." By means of vapor diffusion, HBC 6 with pyridine (Py)-appended TEG side chains (Figure 1) is self-assembled properly into nanotubes with a diameter of 18nm (Figure 9a and e). On the other hand, when 6 is allowed to coassemble under heat-cool conditions with fran -[Pt(PhCN)2Cl2] in toluene, a poor solvent for 6, a nanotubular object with a diameter of 28 nm forms (Figure 9b and f) ... 

With the co side chain at C-12 in place, we are now in a position to address the elaboration of the side chain appended to C-8 and the completion of the syntheses. Treatment of lactone 19 with di-isobutylaluminum hydride (Dibal-H) accomplishes partial reduction of the C-6 lactone carbonyl and provides lactol 4. Wittig condensation8 of 4 with nonstabilized phosphorous ylide 5 proceeds smoothly and stereoselectively to give intermediate 20, the bistetra-hydropyranyl ether of ( )-1, in a yield of -80% from 18. The convergent coupling of compounds 4 and 5 is attended by the completely selective formation of the desired cis C5-C6 olefin. 

In place of a Grignard reagent, several homoenolate equivalents have also been employed. Kempt 1 7 reported the titanium-mediated addition of /V-alkylmethylacrylamide dianions to N-protected a-amino aldehydes (Scheme 8). Pyrolytic cyclization affords a 3-methylenetetrahydrofuran-2-one and the side chain of C3 is appended via conjugate addition. The resulting lactone can be converted into the 1-hydroxyethylene dipeptide by hydrolysis. The stereochemistry of the C6 atom is the same as that of the a-amino aldehyde. However, the stereoselectivities of the reactions regarding the C3 and C5 atoms are unsatisfactory. 

Cyclization of side chain nitriles has found extensive use in the synthesis of benzocyclobutenes (70 n = 2),104 the versatile synthons which open on mild thermolysis to give o-quinodimethanes for inter- and intra-molecular [4 + 2] trapping.108 The nitrile group in (70) can be manipulated into a variety of functionalities for appending the dienophile portion. For example, in the synthesis of chelidonine, the nitrile (71) was converted, by hydrolysis followed by Curtius degradation and reaction of the formed isocyanate with benzyl alcohol, to a urethane (72). The latter was then condensed with a benzyl bromide to get the compound (73), which was elaborated further as shown in Scheme 14.109... 

A chromophore such as the quinone, ruthenium complex, C(,o. or viologen is covalently introduced at the terminal of the heme-propionate side chain(s) (94-97). For example, Hamachi et al. (98) appended Ru2+(bpy)3 (bpy = 2,2 -bipyridine) at one of the terminals of the heme-propionate (Fig. 26) and monitored the photoinduced electron transfer from the photoexcited ruthenium complex to the heme-iron in the protein. The reduction of the heme-iron was monitored by the formation of oxyferrous species under aerobic conditions, while the Ru(III) complex was reductively quenched by EDTA as a sacrificial reagent. In addition, when [Co(NH3)5Cl]2+ was added to the system instead of EDTA, the photoexcited ruthenium complex was oxidatively quenched by the cobalt complex, and then one electron is abstracted from the heme-iron(III) to reduce the ruthenium complex (99). As a result, the oxoferryl species was detected due to the deprotonation of the hydroxyiron(III)-porphyrin cation radical species. An extension of this work was the assembly of the Ru2+(bpy)3 complex with a catenane moiety including the cyclic bis(viologen)(100). In the supramolecular system, vectorial electron transfer was achieved with a long-lived charge separation species (f > 2 ms). 

The a-chloroacetamide group has features that are beneficial for undirected ABPP. Its small size does not bias binding elements towards a specific class of enzyme, and it possesses reactivity towards a broad variety of nucleophilic amino acid residues. A library of a-chloroacetamide-based probes were synthesized by Cravatt s group. The binding element in these probes was a dipeptide that was varied with small, large, hydrophobic, and charged side chains, and a biotin or rhodamine tag was appended as a reporter tag. Upon screening of eukaryotic proteomes with this library, many enzymes previously unaddressed by directed ABPP probes were uncovered. These included fatty acid synthase, hydro-xypyruvate reductase, malic enzyme, and the nitrilase superfamily [163, 164]. In contrast to the sulfonate esters, a-chloroacetamides react preferentially with cysteine residues in the proteome. 

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