Modular Total Synthesis of Archazolid A and B
ABSTRACT A modular total synthesis of the potent V-ATPase inhibitors archazolid A and B is reported. The convergent preparation was accomplished by late-stage diversification of joint intermediates. Key synthetic steps involve asymmetric boron-mediated aldol reactions, two consecutive Still-Gennari olefinations to set the characteristic (Z,Z)-diene system, a Brown crotyboration, and a diastereoselective aldol condensation of highly elaborate intermediates. For macrocyclization, both an HWE reaction and a Heck coupling were successfully employed to close the 24-membered macrolactone. During the synthetic campaign, a generally useful protocol for an E-selective Heck reaction of nonactivated alkenes and a method for the direct nucleophilic displacement of the Abiko-Masamune auxiliary with sterically hindered nucleophiles were developed. The expedient and flexible strategy will enable further SAR studies of the archazolids and more detailed evaluations of target-inhibitor interactions.
- SourceAvailable from: Thomas RonsonTetrahedron 02/2015; 71(7):989–1009. DOI:10.1016/j.tet.2014.11.009 · 2.82 Impact Factor
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ABSTRACT: It was by way of total synthesis that the issues concerning the stereostructure of leiodermatolide (1) have recently been solved; with the target now being unambiguously defined, the mission of synthesis changes as to secure a meaningful supply of this exceedingly scarce natural product derived from a deep-sea sponge. To this end, a scalable route of 19 steps (longest linear sequence) has been developed, which features a catalytic asymmetric propargylation of a highly enolizable β-keto-lactone, a ring closing alkyne metathesis and a modified Stille coupling as the key transformations. Deliberate digression from this robust blueprint brought a first set of analogues into reach, which allowed the lead qualities of 1 to be assessed. The acquired biodata show that 1 is a potent cytotoxin in human tumor cell proliferation assays, distinguished by GI50 values in the ≤3 nM range even for cell lines expressing the Pgp efflux transporter. Studies with human U2OS cells revealed that 1 causes mitotic arrest, micronucleus induction, centrosome amplification and tubulin disruption, even though no evidence for direct tubulin binding has been found in cell-free assays; moreover, the compound does not seem to act through kinase inhibition. Indirect evidence points at centrosome declustering as a possible mechanism of action, which provides a potentially rewarding outlook in that centrosome declustering agents hold promise of being inherently selective for malignant over healthy human tissue.Journal of the American Chemical Society 10/2014; 136(44). DOI:10.1021/ja508846g · 11.44 Impact Factor
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ABSTRACT: Diastereomeric macrolactones 41 and 48, which are epimeric at C-7, were both prepared by a synthesis based on our previously developed route to the macrolactone core of pladienolide B. Both compounds contain all the functionality of the macrolactone core plus the vinyl iodide unit in the side chain. The key step to construct the seco acid for the macrolactonization was a Horner-Wadsworth-Emmons (HWE) reaction to produce acyclic enone 17. The required keto phosphonate for the HWE reaction was originally obtained from (R)-(-)-linalool. The derived macrolactone underwent a reduction of the enone function to give 7-epi-alcohol 20, and its acetylation, either under Mitsunobu or classical acylation conditions, produced allylic acetate 40. This represents a rare case in which a Mitsunobu reaction occurred with retention of configuration. The complete side chain that contains all the functionality was attached by a Stille cross-coupling reaction to lead to 7-epi-pladienolide B (42). To obtain pladienolide B (1), the reduction of acyclic enone 17 under chelation-controlled conditions [Zn(BH4)(2), Et2O] gave allylic alcohol 43 with the correct configuration at C-7 with regard to the natural product. Conversion of this allylic alcohol to seco acid 46 followed by a Shiina macrolactonization afforded vinyl iodide 48. Its Stille coupling with vinylstannane 39 provided pladienolide B (1). Preliminary testing for cytotoxicity against the L929 cell line showed 7-epi-pladienolide B (42) to be completely inactive, which is in contrast to pladienolide B (1) that displayed an IC50 (half maximal inhibitory concentration) value of 7.5 nM. These results point to the importance of the correct configuration of the OAc functional group at C-7 of pladienolide B.European Journal of Organic Chemistry 02/2014; 2014(5). DOI:10.1002/ejoc.201301468 · 3.15 Impact Factor