Michail Tsakos

The chiral N1-Cbz, N2-H derivative of the piperazic acid monomer is a valuable building block in the total synthesis of natural products, comprising this nonproteinogenic amino acid. In that context, we wish to report an improved synthetic protocol for the synthesis of both (3R)- and (3S)-piperazic acids bearing the carboxybenzyl protecting group (Cbz) selectively at the N1 position. Our method builds on previously reported protocols, circumventing their potential shortcomings, and optimizing the ultimate selective deprotection at the N2 position, thus, offering an efficient and reproducible pathway to suitably modified piperazates in high optical purity.

The human farnesyl pyrophosphate synthase (hFPPS), a key regulatory enzyme in the mevalonate pathway, catalyzes the biosynthesis of the C-15 isoprenoid farnesyl pyrophosphate (FPP). FPP plays a crucial role in the post-translational prenylation of small GTPases that perform a plethora of cellular functions. Although hFPPS is a well-established therapeutic target for lytic bone diseases, the currently available bisphosphonate drugs exhibit poor cellular uptake and distribution into nonskeletal tissues. Recent drug discovery efforts have focused primarily on allosteric inhibition of hFPPS and the discovery of non-bisphosphonate drugs for potentially treating nonskeletal diseases. Hit-to-lead optimization of a new series of thienopyrimidine-based monosphosphonates (ThP-MPs) led to the identification of analogs with nanomolar potency in inhibiting hFPPS. Their interactions with the allosteric pocket of the enzyme were characterized by crystallography, and the results provide further insight into the pharmacophore requirements for allosteric inhibition.

Rakicidin A is a prominent member of a small class of macrocyclic lipodepsipeptide natural products that contain an electrophilic 4-amido-2,4-pentadienoate (APD) functionality. Rakicidin A displays selective growth inhibitory activity against hypoxic cancer cells as well as imatinib-resistant chronic myelogenous leukemia (CML) cells. In this paper we present and discuss the two known synthetic routes to rakicidin A, which provide an instructive comparison of strategies used to address the synthetic challenges inherent to rakicidin A. In addition to the synthetic discussion we provide a status on the ongoing biological investigations and emerging structure–activity relationships of the rakicidin scaffold. 1 Introduction 2 The APD-CLD Class of Natural Products 3 Total Syntheses of Rakicidin A 4 Biological Investigations of Rakicidin A and Analogues 5 Conclusion and Perspectives

We report a concise asymmetric synthesis of rakicidin A, a macrocyclic depsipeptide that selectively inhibits the growth of hypoxic cancer cells and stem‐like leukemia cells. Key transformations include a diastereoselective organocatalytic cross‐aldol reaction to build the polyketide portion of the molecule, a highly hindered ester fragment coupling reaction, an efficient Helquist‐type Horner—Wadsworth—Emmons (HWE) macrocyclization, and a new DSC‐mediated elimination reaction to construct the sensitive APD portion of rakicidin A. We further report the preparation of a simplified structural analogue (WY1) with dramatically enhanced hypoxia‐selective activity.

We report a new and rapid method for side-chain dehydration/dehydrothiolation of serine, threonine, and cysteine building blocks. The method relies on activation with 3-nitro-2-pyridinesulfenyl chloride (Npys-Cl) followed by treatment with base. It is possible to perform the sequence as a one-pot operation and due to the significant functional-group compatibility of Npys-Cl, this method may be compatible with multifunctional and complex substrates.

An Npys-mediated elimination method allows facile construction of the trademark functionality of the rakicidins – a new class of biologically-relevant Michael-acceptors.

In this review we investigate the use of complex ester fragment couplings within natural product total syntheses. Using examples from the literature up to 2014 we illustrate the state-of-the-art as well as the challenges within this area of organic synthesis.