Catalytic asymmetric hydrogenation of N-Boc-protected pyrroles proceeded with high enantioselectivity by using a ruthenium catalyst modified with a trans-chelating chiral bisphosphine PhTRAP. The ruthenium catalyst prepared from Ru(eta3-methallyl)2(cod) and (S,S)-(R,R)-PhTRAP in the presence of triethylamine was the most enantioselective for the asymmetric hydrogenation of methyl pyrrole-2-carboxylate, giving the desired (S)-proline derivative with 79% ee in 92% yield. Moreover, 2,3,5-trisubstituted pyrroles bearing a large substituent at the 5-position were hydrogenated with 93-99.7% ee. The asymmetric reduction of 4,5-dimethylpyrrole-2-carboxylate gave only all-cis isomer and created three chiral centers with high degree of stereocontrol in a single process. This is the first highly enantioselective reduction of pyrroles.
Benzyl protection of phenols under neutral conditions was achieved by using a Pd(eta3-C3H5)Cp-DPEphos catalyst. The palladium catalyst efficiently converted aryl benzyl carbonates into benzyl-protected phenols through the decarboxylative etherification. Alternatively, the nucleophilic substitution of benzyl methyl carbonates with phenols proceeded in the presence of the catalyst, yielding aryl benzyl ethers.
Approval of avibactam
by the FDA has led to the recognition of
1,6-diazabicyclo[3.2.1]octane (DBO) derivatives as attractive compounds
for β-lactamase inhibition. We achieved a concise and collective
synthesis of 2-thio-substituted DBO derivatives. The synthesis involves
diastereoselective photo-induced Barton decarboxylative thiolation,
which can be applied to large-scale synthesis. The DBO analogues exhibited
strong inhibitory activities against serine β-lactamases and
acceptable solution stabilities for clinical development.
The nucleophilic substitution of diarylmethyl carbonates with malonate carbanions proceeded in the presence of [Pd(π-C3H5)(cod)]BF4–Cy-Xantphos, giving the desired (diarylmethyl)malonates in up to 90% yield. The yield was extremely affected by choice of the phosphine ligand.
Coadministration
of β-lactam and β-lactamase inhibitor
(BLI) is one of the well-established therapeutic measures for bacterial
infections caused by β-lactam-resistant Gram-negative bacteria,
whereas we have only two options for orally active BLI, clavulanic
acid and sulbactam. Furthermore, these BLIs are losing their clinical
usefulness because of the spread of new β-lactamases, including
extended-spectrum β-lactamases (ESBLs) belonging to class A
β-lactamases, class C and D β-lactamases, and carbapenemases,
which are hardly or not inhibited by these classical BLIs. From the
viewpoints of medical cost and burden of healthcare personnel, oral
therapy offers many advantages. In our search for novel diazabicyclooctane
(DBO) BLIs possessing a thio-functional group at the C2 position,
we discovered a 2-sulfinyl-DBO derivative (2), which
restores the antibacterial activities of an orally available third-generation
cephalosporin, ceftibuten (CTB), against various serine β-lactamase-producing
strains including carbapenem-resistant Enterobacteriaceae (CRE). It
can be orally absorbed via the ester prodrug modification and exhibits
in vivo efficacy in a combination with CTB.
The
current worldwide emergence of carbapenem-resistant enterobacterales
(CREs) constitutes an important growing clinical and public health
threat. Acquired carbapenemases are the most important determinants
of resistance to carbapenems. In the development of the previously
reported tricyclic β-lactam skeleton which exhibits potent antibacterial
activities against several problematic β-lactamase-producing
CREs without a β-lactamase inhibitor, we found that these activities
were reduced against clinical isolates with resistance mechanisms
other than β-lactamase production. These mechanisms were the
reduction of outer membrane permeability with the production of β-lactamases
and the insertion of four amino acids into penicillin-binding protein
3. Here, we report the discovery of a potent compound that overcomes
these resistance mechanisms by the conversion of the alkoxyimino moiety
of the aminothiazole side chain in which a hydrophilic functional
group is introduced and the carboxylic acid of the alkoxyimino moiety
is converted to reduce the negative charge of the whole molecule from
2 to 1. This potent tricyclic β-lactam is a promising drug candidate
for infectious diseases caused by CREs due to its potent therapeutic
efficacy in the neutropenic mouse lung infection model and low frequency
of producing spontaneously resistant mutants.
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