[mikeB]

Hi,

Does anyone have experience in reducing and adding organolithium/magnesium reagents to a Weinreb amide in the presence of a γ-lactam group? That is, can this be done without protecting the lactam NH? I was thinking about deprotonating the lactam NH first with NaH and then do business as usual at the Weinreb amide site. Any thoughts or suggestions?

--Mike

[Babcock_Hall]

I don't have experience in the presence of a γ-lactam.  Are you following a published protocol, or has this not been done before?

[mikeB]

No, I have not found examples of this done before. For the reduction I will be using Lithium diisobutyl-tert-butoxyaluminum hydride (LDBBA), which was actually mentioned on this forum in a topic on ester reduction. It's a very mild reducing reagent, but highly reactive toward Weinreb amides. Not sure how much more Weinreb amides are susceptible to nucleophilic additions then regular amides. Based on electronics I expect them to be more reactive, but I wasn't able to find literature to corroborate that.

--Mike

[rolnor]

I would try first just add the RLi, a lactam is very stable.

[mikeB]

I would try first just add the RLi, a lactam is very stable.

I would think the RLi would be quenched by the lactam unless the addition to the Weinreb amide is faster than protonation by the lactam NH.

--Mike

[Babcock_Hall]

When I used one equivalent of LDBBA, the reduction of the Weinreb was unsuccessful.  My tentative interpretation is that the reagent abstracted a proton from a BOC-NH group on another portion of my molecule.  I should have added a second equivalent, but I did not think of it at the time.