Recent ring distortion reactions for diversifying complex natural products.

Asymmetric (Transfer) Hydrogenation of Substituted Ketones Through Dynamic Kinetic Resolution

Aldol addition of α-triisopropylsilyl-α-diazoacetone (TIPS-diazoacetone), promoted by excess lithium diisopropylamide (LDA), was developed and applied to the synthesis of original C-TIPS diazoaldols, C-TIPS diazoketols, and a related Mannich-type product. An unprecedented mechanistic pathway has been proposed, involving a lithiated triazene intermediate resulting from the nucleophilic addition of LDA on the diazo moiety, supported by experimental results and DFT calculations.

TIPS-Diazoacetone Aldol Addition: Mechanistic Aspects and Contribution to the Synthesis

&lt;p&gt;&lt;b&gt;Peloruside A (10) is a marine natural product isolated from the sponge Mycale hentscheli originally found in Pelorus Sound, New Zealand. It has the potential to be used as a new anti-cancer agent as it is active against various cancerous cell lines at nanomolar concentrations though stabilisation of microtubules. Development of peloruside A as a drug has been hindered due to a lack of viable sources of the compound, from either large-scale isolation attempts from the sponge or though total synthesis efforts. Therefore, an alternative was proposed though guided analogue synthesis to simplify the structure in a way that still retains the pharmacophores, identified as the side chain (highlighted in blue) and the pyran (highlighted in yellow) while being more synthetically accessible.&lt;/b&gt;&lt;/p&gt; &lt;p&gt;Simple, robust reactions were chosen for the major connections (e.g. forming triazole, ester and amide functional groups) and scaffolding elements (amino acid, 49) were proposed for connection of the pharmacophores to form analogue 47. The unique shape and stereochemistry of the side chain (48) has limited possible new approaches with its synthesis. Instead the proposed synthesis was quite conserved following methodology from previous attempts, namely work undertaken by Taylor.1 The proposed pyran motif differs from that in peloruside A, as it does not have to meet strictly defined binding interactions with the microtubule as much needed for the side chain. As such, a wide variety of synthetic methodology could be considered.&lt;/p&gt; &lt;p&gt;The synthesis of the side chain fragment proved to be quite challenging in both the alkylation that established the stereochemistry of C-18 and the allylation that established the stereochemistry of C 15. Future work will need to focus on overcoming these issues if peloruside A analogues will be produced with this design and at scale. The pyran also had issues in its formation and issues with stereoselectivity, but was generally successful, producing several unique structures. While there were few positive results for hydroxyl-containing pyrans due to unexpected side reactions giving rise to 2,6 dioxabicyclo[3.2.1]octane 261, results with chloride-containing pyrans along with their dehydro chlorinated products (235, 236, 280, 282) led to a deep investigation into the mechanism of Prins pyran cyclisation in this system.&lt;/p&gt; 

/pdf/designing-new-agents-for-the-peloruside-binding-site-1bgwlx6a.pdf

Designing new agents for the peloruside binding site

A computational study was performed to explore the possible mechanisms of β-isocinchonine-catalyzed asymmetric C(sp2)-H allylation of trisubstituted allenoates using Morita-Baylis-Hillman (MBH) carbonates for synthesis of axially chiral tetrasubstituted allenoates. The calculated results indicate that the most energetically favorable pathway includes (1) nucleophilic attack on MBH carbonate by β-isocinchonine, (2) BocO- dissociation, (3) stereoselective formation of the C-C bond, and (4) regeneration of the catalyst. By tracking the orbital overlap/interaction changes, the half shoulder-to-head orbital overlap mode can be smoothly switched to a head-to-head orbital overlap mode for the key C-C σ bond formation, which is also identified as the stereoselectivity-determining process. Further distortion/interaction, noncovalent interaction (NCI), and atom-in-molecule (AIM) analyses demonstrate that C-H···O and C-H···π interactions should be key for controlling the axial and central chirality. This work would be useful for rational design of organocatalytic allylic alkylation reactions for synthesis of axially chiral compounds in the future.

Insights into Organoamine-Catalyzed Asymmetric Synthesis of Axially Chiral Allenoates Using Morita-Baylis-Hillman Carbonates and Trisubstituted Allenoates: Mechanism and Origin of Stereoselectivity.

Function-Oriented Synthesis toward Peloruside A Analogues

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Function-Oriented Synthesis toward Peloruside A Analogues

TIPS-Diazoacetone Aldol Addition: Mechanistic Aspects and Contribution to the Synthesis