In this review we investigate the use of complex ester fragment couplings within natural product total synthesis campaigns. We first outline the different biosynthetic and chemical strategies for performing complex ester couplings and on this mechanistic background we then present and discuss a collection of successful examples from the literature.
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.
Among the class of primary amine-thioureas based on tert-butyl esters of a-amino acids, the most efficient organocatalyst for "difficult" Michael reactions was identified. The derivative based on (S)-di-tert-butyl aspartate and (1R,2R)-diphenyl-A C H T U N G T R E N N U N G ethylenediamine provided the products of the reaction between aryl methyl ketones and nitroolefins in excellent yields and enantioselectivities. In addition, this new catalyst can be used at low catalyst loading (5 mol%). The utility of this methodology was highlighted by the efficient synthesis of (S)-baclofen, (R)-baclofen and (S)-phenibut.
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.
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