1.2- Dithiolenes molybdopterin

The metal is chelated by an ene-1,2-dithiolate (dithiolene) of the dihydropyran ring which is fused to a partially reduced pteridine 178. The syntheses of these molybdopterin-related proligands were described as model compounds for verification of the stability in vitro <2001CC 123>. The proligand 179 is a relatively stable compound however, after several weeks, the pyran ring opened and oxidation to the diol derivatives 180 was observed (Scheme 35). 

Figure 18. Synthesis of a molybdenum dithiolene (via a [3 + 2] pathway) and its conversion to a thiophene derivative. Structure of urothione, the oxidative degradation product of a molybdopterin (228).

Relevant to the quest for molybdopterin-related ligands, heterocycle-substituted trithiocarbonates were shown to give modest yields of the CpCo (dithiolene) when treated with CpCo(cod) (cod = 1,5-cyclooctadiene, Eq. 26) (85). 

A. The Dithiolene Unit as Revealed by Degradation Studies of Molybdopterin / 504... 

The particular dithiolene chosen by Nature for catalytic systems may, indeed, appear very strange. The dithiolene within molybdopterin bears substituents that are more complicated than found on other dithiolenes. Figure 2 provides several views of molybdopterin to aid the reader to understand the pieces and shape of this odd ligand. 

Moco (66). The pieces of this degradation puzzle, illustrated in Fig. 5, eventually fit together to implicate a reduced tetrahydropterin substituted at the 6-position by a four-carbon chain including a dithiolene on the a and (3 carbons, a hydroxyl at the y carbon and a terminal phosphate group (62, 65). This novel pterin was named molybdopterin. All the species in Fig. 5 contributed in some way to deducing the nature of molybdopterin, although only a few will receive special comment below. 

Stronger chemical evidence for the presence of a dithiolene in molybdopterin was obtained when the mild alkylation reagent iodoacetamide effectively trapped the dithiolene (65). This reaction yielded a derivative whose characterization by FAB mass spectrometry and nuclear magnetic resonance (NMR) was consistent with the structure shown in Fig. 5. The method appeared to leave the side chain intact and preserved the pterin oxidation state. From this experiment the view persisted that molybdopterin is a disubstituted dithiolene bearing a reduced pterin and a short chain terminated with a phosphate. 

Ultimately, the proposed molybdopterin structure in Fig. 5 was verified by protein crystallography that finally revealed the pyran ring whose signature was lost during the degradation studies (42). Conclusive evidence for a dithiolene chelate at the active site came first from the protein crystal structure of a... 

The indirect chemical evidence described above was masterfully interpreted to suggest the dithiolene chelate and substituents of molybdopterin. Nevertheless, it was protein crystallography that provided definitive proof of the intact dithiolene chelate in the molybdenum and tungsten enzymes. Improvements both in protein crystal growth, diffraction data collection, and in computation... 

The active site of the oxidized form of TMAO is nearly identical to that of DMSOR with two molybdopterin ligands and a coordinated serine —OH group (33). Two oxo ligands to Mo were included in the refinement but, given the low resolution data used in this structure (2.5 A) and what has been learned about variable O-donor ligands in DMSOR, this is unlikely to be correct. Another peculiarity of this structure is the large deviation from planarity within the Mo-dithiolene five-membered chelate ring but this observation also remains in doubt at 2.5-A resolution. 

The structure of AOR was important for several reasons. It showed the first detailed structural information for molybdopterin chelated through its dithiolene group to a metal and it presented two surprises to researchers in the field. The structure revealed the presence of a pyran ring bearing the dithiolene fused to the expected reduced pterin system and the presence of two, not one, molybdopterin ligands chelated to the W atom, which were related by an approximate C2 axis. 

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