Open-chain building blocks from chiral lactams. Enantioselective synthesis of macrocyclic nitrogen-containing natural products

Abstract

1. (R)-Phenylglycinol-derived oxazolopiperidone lactams can be converted to enantiopure open-chain amino ester scaffolds by alkaline hydrolysis of the N-Boc 2-piperidones resulting from the reductive cleavage of the oxazolidine ring.

2. Lithium amidotrihydroborate (LiNH2BH3) reduction of diversely substituted (R)-phenylglycinol-derived oxazolopiperidone lactams brought about the reductive opening of both the oxazolidine and lactam rings, providing general access to structurally diverse enantiopure amino diols A bearing a variety of substitution patterns, substituents (alkyl, benzyl, aryl, protected hydroxy), and stereochemistries.

3. Reductive removal of the phenylethanol moiety present in the amino diols prepared by the above procedure, followed by treatment of the resulting primary amines with (Boc)2O provides a general synthetic entry to enantiopure N-Boc 5-aminopentanols bearing substitutents at the 2-, 3-, 4-, 2,2-, 2,3-, 2,4-, and 3,4- positions.

4. The oxidative removal of the phenylglycinol moiety of amino diols A (previously O-silylated) using the I2/aq NH3 system constitutes an excellent procedure for the straightforward preparation of enantiopure substituted 5-hydroxypentanenitrile derivatives.

5. The m-CPBA-promoted oxidative removal of the phenylglycinol moiety of amino diols A (previously O-silylated) constitutes an excellent procedure for the straightforward preparation of enantiopure substituted 5-hydroxypentanoic acid derivatives.

6. As both enantiomers of phenylglycinol are commercially available, both enantiomers of a target 5-aminopentanol, 5-hydroxypentanoic acid, and 5-hydroxypentanenitrile are accessible through the above methodology.

7. The synthetic value of the open-chain amino diols A has been demonstrated with their use as key scaffolds for the enantioselective synthesis of the Haliclona alkaloids haliclorensin C (first total synthesis), haliclorensin (total), halitulin (formal), and isohaliclorensin (formal).

8. The synthetic value of the open-chain amino diols 5-hydroxypentanoic acids, and 5-hydroxypentanenitriles prepared from (S)-phenylglycinol-derived lactams has been demonstrated with their use as key scaffolds for the synthesis of the natural macrolactam fluvirucinin B1.

9. The approach we have developed significantly expands the potential of phenylglycinol-derived d-lactams, which have been converted for the first time to enantiopure open-chain building blocks.