Selective
functionalization of inactive C(sp3)–F
bonds to prepare medicinally interesting aryldifluoromethylated compounds
remains challenging. One promising route is the transition-metal-catalyzed
cross-coupling through oxidative addition of the C(sp3)–F
bond in trifluoromethylarenes (ArCF3), which are ideal
precursors for this process due to their ready availability and low
cost. Here, we report an unprecedented excited-state palladium catalysis
strategy for selective defluoroarylation of trifluoromethylarenes
with arylboronic acids. This visible-light-induced palladium-catalyzed
cross-coupling proceeds under mild reaction conditions and allows
transformation of a variety of arylboronic acids and ArCF3. Preliminary mechanistic studies reveal that the oxidative addition
of the C(sp3)–F bond in ArCF3 to excited-state
palladium(0) via a single electron transfer pathway is responsible
for the C(sp3)–F bond activation.
Asymmetric dearomative [3 + 2] cycloaddition reactions of 3-nitroindoles with vinyl aziridine and vinyl cyclopropanes have been respectively successfully developed in the presence of a chiral box/Pd(0) complex. A series of enantiomerically enriched 3a-nitro-hexahydropyrrolo[2,3-b]indole and 8b-nitrohexahydrocyclopenta[b]indole derivatives containing three contiguous chiral centers are smoothly obtained in high yields with satisfactory regio-, chemo-, and enantioselectivity. Remarkably, the synthetic utility of this process was demonstrated through direct reductive amination and functionalization of the carbon-carbon double bond of the desired products.
Efficient construction of optically pure molecules from readily available starting materials in a simple manner is an ongoing goal in asymmetric synthesis. As a straightforward route, transition-metal-catalyzed enantioconvergent coupling between widely available secondary alkyl electrophiles and organometallic nucleophiles has emerged as a powerful strategy to construct chiral center(s). However, the scope of racemic secondary alkylmetallic nucleophiles for this coupling remains limited in specific substrates because of the difficulties in stereoselective formation of the key alkylmetal intermediates. Here, we report an enantiodivergent strategy to efficiently achieve an array of synthetically useful chiral cyclopropanes, including chiral fluoroalkylated cyclopropanes and enantiomerically enriched cyclopropanes with chiral side chains, from racemic cyclopropylzinc reagents. This strategy relies on a one-pot, two-step enantiodivergent relay coupling process of the racemic cis-cyclopropylzinc reagents with two different electrophiles, which involves kinetic resolution of racemic cis-cyclopropylzinc reagents through a nickel-catalyzed enantioselective coupling with alkyl electrophiles, followed by a stereospecific relay coupling of the remaining enantiomeric cyclopropylzinc reagent with various electrophiles, to produce two types of functionalized chiral cyclopropanes with opposite configurations on the cyclopropane ring. These chiral cyclopropanes are versatile synthons for diverse transformations, rendering this strategy effective for obtaining structurally diversified molecules of medicinal interest.
Propargylic alcohols
and amines are versatile building blocks in
organic synthesis. We demonstrate a straightforward enzymatic cascade
to synthesize enantiomerically pure propargylic alcohols and amines
from readily available racemic starting materials. In the first step,
the peroxygenase from
Agrocybe aegerita
converted
the racemic propargylic alcohols into the corresponding ketones, which
then were converted into the enantiomerically pure alcohols using
the (
R
)-selective alcohol dehydrogenase from
Lactobacillus kefir
or the (
S
)-selective
alcohol dehydrogenase from
Thermoanaerobacter brokii
. Moreover, an enzymatic Mitsunobu-type conversion of the racemic
alcohols into enantiomerically enriched propargylic amines using (
R
)-selective amine transaminase from
Aspergillus
terreus
or (
S
)-selective amine transaminase
from
Chromobacterium violaceum
was established. The
one-pot two-step cascade reaction yielded a broad range of enantioenriched
alcohol and amine products in 70–99% yield.
Chiral amino alcohols are prevalent synthons in pharmaceuticals and synthetic bioactive compounds. The efficient synthesis of chiral amino alcohols using ammonia as the sole amino donor under mild conditions is highly desired and challenging in organic chemistry and biotechnology. Our previous work explored a panel of engineered amine dehydrogenases (AmDHs) derived from amino acid dehydrogenase (AADH), enabling the one-step synthesis of chiral amino alcohols via the asymmetric reductive amination of α-hydroxy ketones. Although the AmDH-directed asymmetric reduction is in a high stereoselective manner, the activity is yet fully excavated. Herein, an engineered AmDH derived from a leucine dehydrogenase from Sporosarcina psychrophila (SpAmDH) was recruited as the starting enzyme, and the combinatorial active-site saturation test/iterative saturation mutagenesis (CAST/ISM) strategy was applied to improve the activity. After three rounds of mutagenesis in an iterative fashion, the best variant wh84 was obtained and proved to be effective in the asymmetric reductive amination of 1-hydroxy-2-butanone with 4-fold improvements in kcat/Km and total turnover number (TTN) values compared to those of the starting enzyme, while maintaining high enantioselectivity (ee >99%) and thermostability (T5015 >53°C). In preparative-scale reaction, the conversion of 100 and 200 mM 1-hydroxy-2-butanone catalyzed by wh84 was up to 91–99%. Insights into the source of an enhanced activity were gained by the computational analysis. Our work expands the catalytic repertoire and toolbox of AmDHs.
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