Macrophomate synthase

A review cataloging intramolecular Diels-Alder reactions as key steps in the total synthesis of natural products has been published.78 A key step in the total synthesis (g) of (+)-dihydrocompactin (66) is the intramolecular ionic Diels-Alder reaction of the trienone (63) to yield the (+)-compactin core compound (65) via the intermediate cyclic vinyloxocarbenium ion (64) (Scheme 17).79 The intramolecular Diels-Alder reaction of the Asp-Thr tethered compound (67) produced the cycloadduct (68) with high regio- and stereo-selectivity (Scheme 18).80 Mixed quantum and molec- (g) ular mechanics (QM/MM) combined with Monte Carlo simulations and free-energy perturbation (FEP) calculations have been used to show that macrophomate synthase... 

Guimaraes CRW, M Udier-Blagovic, WL Jorgensen (2005) Macrophomate synthase QM/MM simulations address the Diels-Alder versus Michael-Aldol reaction mechanism. J. Am. Chem. Soc. 127 (10) 3577-3588... 

Table 2. Inhibition of Macrophomate Synthase Activity with Bridged Bicyclic Intermediates...

To investigate the substrate diversity of macrophomate synthase, 40 analogs of 2-pyrone were prepared and their relative efficiency was examined in the enzymatic conversions [75]. Though structurally simple 2-pyrone and 4-pyrone were not transformed, various pyrones with different substituents at C-6 (96,98), C-4 (100) and C-4, C-5... 

Alderase, to which presumably growing polyketide chain is binding. It is noteworthy that this enzyme catalizes also the Diels-Alder reaction after preceding polyketide synthesis similar to other two Diels-Alderases, solanapyrone synthase and macrophomate synthase. 

Since we reported the enzymatic activity of SPS in 1995 as the first Diels-Alderase, two additional Diels-Alderases, lovastatin nonaketide synthase (LNKS) and macrophomate synthase (MPS), have been purified and characterized. Two of these catalyze intramolecular Diels-Alder reactions while the third catalyzes an intermolecular Diels-Alder reaction. We have recently reported the detailed reaction pathway ° ° of MPS and its catalytic mechanism based on the crystal structure. " In this section, we describe three natural Diels-Alderases and discuss the mechanism of their catalysis. 

The first determined structure of a Diels-Alderase was that of the macrophomate-synthase of the phytopathogenic fungus Macrophoma commelinae (Fig. 5.158). 

By complexation of diene and dienophile on the macrophomate-synthase, the [4 + 2]-cycloaddition is both electronically and sterically favoured. 

Macrophomate synthase enzyme (MPHS), isolated from the fungus Macrophoma com-melinae, catalyzes the Diels-Alder cycloaddition between 2-pyrones 42 and decarboxylated oxalacetic acid 43 in aqueous buffered medium at pH 7.0, giving the benzoates 44 (Scheme 5.11). These types of aromatic compounds are commonlybiosynthesized by either a shiki-mate or polyketide pathway and therefore the reaction depicted in Scheme 5.11 supports the fact that the Diels-Alder reaction takes place in biosynthesis. 

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