Anhydrides regioselective reductions

Regioselective reductions of the maleic anhydride derivatives (387) and (389) with lithium aluminum hydride yielded (388) and (390). Metallation of the O-methyltetronic acid (388) with lithium N- cyclohexyl-A- isopropylamide followed by treatment with, for example, p-anisaldehyde led to pulvinones such as (391) (79JCS(P1)70). 

The opposite regioselectivity observed for the addition of methylbutenyltin to similar allyl substrates (equations 241 and 242),137>139 caused by the presence of maleic anhydride in the latter case (equation 242), may be viewed as support for a change in mechanism when the electron deficient alkene ligand is present. Conversely, both reactions could proceed by metal addition, with the regiocontrol exercised by the maleic anhydride acting in the addition-reductive elimination sequence. 

Gribble and Saulnier (79) have extended their ellipticine synthesis 43) to the synthesis of 9-methoxyellipticine (2) (Scheme 24). One of the key features of this approach is the regioselective nucleophilic addition to the C-4 carbonyl group of pyridine anhydride 28. The other noteworthy transformation is the conversion of keto lactam 142 to the diol 143 with methyllithium, a process that presumably involves cleavage of the initial adduct to a methyl ketone which undergoes cyclization at the C-3 position of the indolyl anion. Reduction of 143 with sodium borohydride completes the synthesis of 2, in 47% overall yield from 5-methoxyindole (139). Gribble and students 80) have also used this method to synthesize 8-methoxyellipticine (134), 9-fluoroellipticine (144), and the previously unknown 7,8,9,10-tetrafluorellipticine (145), each from the appropriate indole. 

The reduction of unsymmetiical anhydrides is regioselective Hydride attack takes place on the carbonyl group that is vicinal to the most substituted carbon, as... 

Reduction of the anhydride gave 103 with complete regioselectivity in favour of the carbonyl next to the acetate but without stereoselectivity. This doesn t matter as treatment with acid initiated a rearrangement - cyclisation sequence giving a the alcohol 104 after hydrolysis of its formate. This time there is complete stereoselectivity in the creation of three new chiral centres. 

Nakane and Hutchinson have further shown that the aldol step in this cyclization is stereoselective as well as regioselective. Treatment of (39) with Hunig s base, acetic anhydride and 4-(A, A -dimethyl-amino)pyridine (DMAP), followed by sodium borohydride reduction of the intermediate P-hydroxy aldehyde, gives diol (40) in 48% yield no diastereomeric diols were detected (equation 102). 2i... 

It was known in the early 70 s that unsymmetrically substituted anhydrides and im-ides can undergo highly regioselective transformations, e.g. to lactones and lactams, respectively (see Scheme 6.23) [166]. The growing importance of such products as synthetic intermediates raised the issue of control of regioselectivity, and several authors attempted to identify the factors at play [167-169]. The emphasis was on metal hydride reductions of succinic anhydrides to y-lactones, and succinimides to hydroxypyrrolidinones. Suess [167], Rosenfield and Dunitz [47], and independently Kayser and Morand [169], proposed that the approach of a nucleophile to the less substituted carbonyl group can actually be more hindered if there is indeed a strong preference for rearside attack. The two pathways are compared in Scheme 6.24. 

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