The first aminocatalyzed α-alkylation of α-branched aldehydes with benzyl bromides as alkylating agents has been developed. Using a sterically demanding proline derived catalyst, racemic α-branched aldehydes are reacted with alkylating agents in a DYKAT process to give the corresponding α-alkylated aldehydes with quaternary stereogenic centers in good yields and high enantioselectivities.
The synthesis of 3-azabicyclo[3.2.0]heptyl boropinacolates and trifluoroborates via the [2 + 2] photocycloaddition of the corresponding alkenyl boronic derivatives and maleimides or maleic anhydride is described. Optimization of the reaction conditions (i.e., wavelength, concentration of the reagents, photosensitizer) was carried out, and the scope and limitations of the method were studied. Alkenyl boronic acid pinacolates were found to be more suitable for the [2 + 2] cycloaddition, providing better reaction outcomes compared to the trifluoroborates. The utility of this approach was shown by the preparation of bi-and trifunctional building blocks (21 examples), which could be easily synthesized on up to 60 g scale. These cycloadducts provide a convenient entry into the 3-azabicyclo[3.2.0]heptane scaffold through the C−C coupling or oxidative deborylation reactions.
A conformationally restricted monofluorinated α-amino acid, (3-fluorobicyclo[1.1.1]pentyl)glycine (F-Bpg), was designed as a label for the structural analysis of membrane-bound peptides by solid-state F NMR spectroscopy. The compound was synthesized and validated as a F label for replacing natural aliphatic α-amino acids. Calculations suggested that F-Bpg is similar to Leu/Ile in terms of size and lipophilicity. The F NMR label was incorporated into the membrane-active antimicrobial peptide PGLa and provided information on the structure of the peptide in a lipid bilayer.
Difluorocyclopropanation of alkenyl trifluoroborates using TMSCF 3 -NaI system was reported for the first time. The developed method allowed preparation of monocyclic, spiroand fused-bicyclic gem-difluorocyclopropanes bearing addi-groups. [20][21][22][23][24] Nonetheless, the addition of difluorocarbene equivalent derived from TMSCF 3 to alkenylboronic derivatives was unknown until the present study. Scheme 1. Difluorocyclopropanation of alkenylboronic derivatives.In this work, application of TMSCF 3 -NaI system in refluxing THF (66°C) for the synthesis of gem-difluorocyclopropyl boronic derivatives and its effectiveness for multigram scale synthesis is reported (Scheme 1). It is shown that alkenyl trifluoroborates are optimal substrates for the preparation of aliphatic derivatives which facilitate isolation of the target products. The studied reaction scope included substrates bearing secondary N-Boc protected amine, ester, ether, phenyl and cyclopropyl moieties and provided products with spiro-and fused-bicyclic molecular topologies.
Results and DiscussionOur study commenced with testing TMSCF 3 -NaI system in reaction with substrate 5a (Scheme 2), for which the difluorocyclopropanation using XCF 2 CO 2 Na (X = Cl, Br) at 180°C and 150°C, Scheme 2. Attempted difluorocyclopropanation of alkenyl boronic derivatives using the TMSCF 3 -NaI system.
2218Scheme 3. Preparation of trifluoroborate salts 7 from pinacolboronates 9.Scheme 4. Synthesis of pinacolboronates 9e (A) and 9p (B).
Syntheses of bicyclo[1.1.1]pentane‐derived azides and terminal alkynes – interesting substrates for click reactions – are described. With a few exceptions, these compounds were prepared in two or three steps starting from common synthetic intermediates – the corresponding carboxylic acids. The key step in the synthesis of 1‐azidobicyclo[1.1.1]pentanes is a copper‐catalysed diazo‐transfer reaction with imidazole‐1‐sulfonyl azide. The preparation of bicyclo[1.1.1]pentyl‐substituted alkynes relies on a Seyferth–Gilbert homologation with dimethyl 1‐diazo‐2‐oxopropylphosphonate (Ohira–Bestmann reagent). Both types of target compounds were found to be suitable substrates for click reactions, and thus they are promising building blocks for medicinal, combinatorial and bioconjugate chemistry. A practically important side result of this study was a multigram preparation of Boc‐monoprotected 1,3‐diaminobicyclo[1.1.1]pentane – a representative bicyclic conformationally restricted diamine derivative.
A convenient approach to the multigram synthesis of functionalized 1,2‐disubstituted cyclopropyltrifluoroborates was developed, based on Pd(II)‐ or Cu(I)‐catalyzed reaction of vinyltrifluoroborate and diazo compounds. Optimized protocols allowed for the preparation of the target products as pure diastereomers on multigram scale. It was shown that the title compounds were good coupling partners for the Suzuki‐Miyaura and Chan‐Lam reactions, which provide medicinally relevant (het)arylcyclopropanes with high diastereoselectivity.magnified image
The literature on cycloaddition reactions of boron-containing alkenes is surveyed with 132 references. The data are categorized according to the reaction type ([2+1], [2+2], [3+2], [4+2], and [4+3] cycloadditions). The cyclopropanation and the Diels–Alder reactions of alkenylboronic derivatives have been studied more or less comprehensively, and for some substrates, they can be considered as convenient methods for the rapid regio- and stereoselective construction of even complex cyclic systems. Other types of the cycloadditions, as well as mechanistic aspects of the processes, have been addressed less thoroughly in the previous works.1 Introduction2 [2+1] Cycloaddition2.1 Cyclopropanation2.1.1 With Methylene Synthetic Equivalents2.1.2 With Substituted Carbenoids2.2 Epoxidation2.3 Aziridination3 [2+2] Cycloaddition4 [3+2] Cycloaddition4.1 With Nitrile Oxides4.2 With Diazoalkanes4.3 With Nitrones4.4 With Azomethine Ylides5 [4+2] Cycloaddition6 [4+3] Cycloaddition7 Conclusions and Outlook
An approach to the synthesis of oxa‐ and azabicyclo[n.1.0]alkan‐1‐yl trifluoroborates on a multigram scale was developed. Two synthetic strategies were evaluated: the first based on the lithiation–borylation of the corresponding 2‐bromoallyl derivatives, and the other relying on regioselective hydroboration of the appropriate hetera‐substituted enynes. The second method appeared to be more efficient in terms of scalability and substrate scope. Further steps included ring closing‐metathesis, mild palladium‐catalyzed cyclopropanation with diazomethane, and reaction with KHF2 and furnished the title compounds in up to 50 g scale in a single run (10–41 % overall yield, 4–5 steps).
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