SNAP-7941 synthesis

Figure 12 The snapping synthesis of R12 using the donor-acceptor jt-jt interaction template synthetic strategy.

Goss JM, Schaus SE (2008) Enantioselective synthesis of SNAP-7941 chiral dihydropy-rimidone inhibitor of MCHl-R. J Org Chem 73 7651-7656... 

Finally, as shown in Table V, activity of ferrochelatase is also decreased by -NO. This mitochondrial enzyme catalyzes the final step in heme synthesis, the insertion of ferrous iron into porphyrin, and has been shown to contain an Fc2S2 nonheme iron-sulfur cluster which is required for activity (Dailey et aL, 1994). This result suggests that loss of activity may occur by nitrogen oxide-mediated [i.e., -NO in the presence of dioxygen (Wink et aL, 1993a)] destruction of its iron-sulfur cluster. Consistent with this result, while inhibition of ALAS and increase in HO induced by SNAP requires a period of 4-8 hr (consistent with the established effects of heme on these enzymes, as described above), the inhibition of ferrochelatase is virtually complete within 1 hr (Kim et aL, 1995). 

Y. Hou, X. Wu, W. Xie, P. G. Braunschweiger, and P. G. Wang, The synthesis and cytotoxicity of fructose-l-SNAP, a novel fructose eonjugated 5-nitroso nitric oxide donor, Tetrahedron Lett, 42 (2001) 825-829. 

Figure 2.24 Synthesis and activation of enzyme responsive snap-top cap to trigger release from mesoporous silica. Reprinted with permission from K. Patel, S. Angelos, W.R. Dichtel, A. Coskun, Y.W. Yang, J.I. Zink and J.F. Stoddart,/. Am. Chem. Soc., 130, 2382. Copyright (2008) American Chemical Society...

SCHEME 6.43 Two asymmetric routes to the synthesis of MCH inhibitor SNAP-7941 293 [90],... 

Schaus and Goss reported an enantioselective synthesis of SNAP-7941 62, a potent melanin-concentrating hormone receptor antagonist, by using a chiral phosphoric acid-catalyzed Biginelli reaction (Scheme 9.23) [72]. 

SCHEME 9.23 Enantioselective synthesis of the SNAP-7941 62 through a key Biginelli reaction. 

A second method to achieve the synthesis of the enantioenriched dihy-dropyrimidone core of SNAP-7941 was based on the cinchona alkaloid-catalysed Mannich reaction of p-keto esters with acylimines. Therefore, the reaction of a p-keto ester with an a-amido sulfone performed in the presence of cinchonine produced the Mannich product as a mixture of two diastereomers in an excellent yield (Scheme 3.20). This diastereomeric mixture was transformed in high yield into a key intermediate of the synthesis of SNAP-7941, showing a good enantioselectivity. This compound was finally converted into desired SNAP-7941, which is an inhibitor of MCHl-R in a G protein-coupled receptor. 

FIGURE 10.3 Common methods of interlocked structure formation. Cyclization (a) and double cyclization (b) of catenanes. Clipping (c), stoppering (d), and snapping (e) approaches for rotaxane synthesis. 

Goss, J. M., Schaus, S. E. (2008). Enantioselective synthesis of SNAP-7941 chiral dihy-dropyrimidone inhihitor of MCHl-R. Journal of Organic Chemistry, 73, 7651 -7656. 

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