General Access to Modified α‐Amino Acids by Bioinspired Stereoselective γ‐C−H Bond Lactonization

Abstract

α‐Amino acids represent a valuable class of natural products employed as building blocks in biological and chemical synthesis. Because of the limited number of natural amino acids available, and of their widespread application in proteomics, diagnosis, drug delivery and catalysis, there is an increasing demand for the development of procedures for the preparation of modified analogues. Herein, we show that the use of bioinspired manganese catalysts and H2O2 under mild conditions, provides access to modified α‐amino acids via γ‐C−H bond lactonization. The system can efficiently target 1°, 2° and 3° γ‐C−H bonds of α‐substituted and achiral α,α‐disubstituted α‐amino acids with outstanding site‐selectivity, good to excellent diastereoselectivity and (where applicable) enantioselectivity. This methodology may be considered alternative to well‐established organometallic procedures.

C–H Bonds as Functional Groups: Simultaneous Generation of Multiple Stereocenters by Enantioselective Hydroxylation at Unactivated Tertiary C–H Bonds

“…Of interest, 8b is obtained in high enantioselectivity (85% ee), which contrasts with the racemate obtained for 8c . On the other hand, complete recovery of the starting material was observed in 9a bearing cis -diphenyls in the cyclohexane ring, reasonably due to competitive aromatic oxidation that deactivates the catalytic system. , …”

“…The current reaction relies on a catalytic system composed of a chiral manganese complex and a phthalimido-protected amino acid coligand that activates hydrogen peroxide under mild reaction conditions. 36 Asymmetric hydroxylation occurs in short reaction times and results in desymmetrization, generating up to four stable chiral centers in a single step, which are then susceptible to orthogonal chemical manipulation. 37−39 Enantioselectivity is governed by the precise fitting of the cyclohexane scaffold into the active catalytic site, through a network of weak non-covalent interactions that define a lock and key interaction reminiscent of the highly ordered structures of substrate-bound enzymatic sites involved in chiral C−H hydroxylation.…”

“…On the other hand, complete recovery of the starting material was observed in 9a bearing cis-diphenyls in the cyclohexane ring, reasonably due to competitive aromatic oxidation that deactivates the catalytic system. 36,66 Amide substrates (11a−14a) are also hydroxylated in high isolated yields (up to 91%) and enantioselectivies (83−97% ee). As for the ester derivatives, replacement of acetyl by bulkier acyl groups leads to improvements in reaction yield, while retaining high enantioselectivity.…”

“…We take advantage of the known ability of iron and manganese complexes to hydroxylate tertiary C–H bonds via powerful high-valent metal-oxo oxidants. − The reaction constitutes a rather unique case of non-directed chiral functionalization of strong C–H bonds, preceded by carbene C–H insertions catalyzed by rhodium paddlewheel complexes and ketonization of monosubstituted cyclohexanes with manganese catalysts (Figure B). − In the latter case, overoxidation of the first formed alcohol cannot be prevented, eliminating the corresponding hydroxylated stereocenter. The current reaction relies on a catalytic system composed of a chiral manganese complex and a phthalimido-protected amino acid coligand that activates hydrogen peroxide under mild reaction conditions . Asymmetric hydroxylation occurs in short reaction times and results in desymmetrization, generating up to four stable chiral centers in a single step, which are then susceptible to orthogonal chemical manipulation. − Enantioselectivity is governed by the precise fitting of the cyclohexane scaffold into the active catalytic site, through a network of weak non-covalent interactions that define a lock and key interaction reminiscent of the highly ordered structures of substrate-bound enzymatic sites involved in chiral C–H hydroxylation.…”