Modular total synthesis of rhizopodin: a highly potent G-actin dimerizing macrolide.

A highly convergent total synthesis of the potent polyketide macrolide rhizopodin has been achieved in 29 steps by employing a concise strategy that exploits the molecule's C2 symmetry. Notable features of this convergent approach include a rapid assembly of the macrocycle through a site-directed sequential cross-coupling strategy and the bidirectional attachment of the side chains by means of Horner-Wadsworth-Emmons (HWE) coupling reactions. During the course of this endeavor, scalable routes for synthesis of three main building blocks of similar complexity were developed that allowed for their stereocontrolled construction. This modular route will be amenable to the development of syntheses of other analogues of rhizopodin.

Concise synthesis of the macrocyclic core of rhizopodin by a Heck macrocyclization strategy.

A highly convergent synthesis of the central dimeric core of the potent antibiotic macrolide rhizopodin is reported. Notable features of the highly concise route include an effective preparation of the key C8-C22 building block based on an iridium-catalyzed Krische allylation and a chemoselective cross-coupling approach toward the macrocycle involving a highly advantageous Heck reaction for macrocyclization.

Archazolid A binds to the equatorial region of the c-ring of the vacuolar H+-ATPase.

The macrolactone archazolid is a novel, highly specific V-ATPase inhibitor with an IC(50) value in the low nanomolar range. The binding site of archazolid is presumed to overlap with the binding site of the established plecomacrolide V-ATPase inhibitors bafilomycin and concanamycin in subunit c of the membrane-integral V(O) complex. Using a semi-synthetic derivative of archazolid for photoaffinity labeling of the V(1)V(O) holoenzyme we confirmed binding of archazolid to the V(O) subunit c. For the plecomacrolide binding site a model has been published based on mutagenesis studies of the c subunit of Neurospora crassa, revealing 11 amino acids that are part of the binding pocket at the interface of two adjacent c subunits (Bowman, B. J., McCall, M. E., Baertsch, R., and Bowman, E. J. (2006) J. Biol. Chem. 281, 31885-31893). To investigate the contribution of these amino acids to the binding of archazolid, we established in Saccharomyces cerevisiae mutations that in N. crassa had changed the IC(50) value for bafilomycin 10-fold or more and showed that out of the amino acids forming the plecomacrolide binding pocket only one amino acid (tyrosine 142) contributes to the binding of archazolid. Using a fluorescent derivative of N,N'-dicyclohexylcarbodiimide, we found that the binding site for archazolid comprises the essential glutamate within helix 4 of subunit c. In conclusion the archazolid binding site resides within the equatorial region of the V(O) rotor subunit c. This hypothesis was supported by an additional subset of mutations within helix 4 that revealed that leucine 144 plays a role in archazolid binding.

Modular total synthesis of archazolid A and B.

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.

Directed reductive amination of beta-hydroxy-ketones: convergent assembly of the ritonavir/lopinavir core.

An efficient procedure for the directed reductive amination of beta-hydroxy-ketones (3) for the stereoselective preparation of 1,3-syn-amino alcohols (6) is reported. The operationally simple protocol uses Ti(iOPr)4 for coordination of the intermediate imino alcohol (5) and PMHS as the reducing agent. The method was expanded to an asymmetric aldol reductive amination sequence to allow a highly convergent synthesis of the hydroxy-amine core of the HIV-protease inhibitors ritonavir and lopinavir. [reaction: see text].

Hydrogen bond catalyzed direct reductive amination of ketones.

[reaction: see text] A novel, biomimetic concept for the direct reductive amination of ketones is described that relies on selective imine activation by hydrogen bond formation. The mild, acid- and metal-free process requires only catalytic amounts of thiourea as hydrogen bond donor and utilizes the Hantzsch ester for transfer hydrogenation. The method allows the efficient synthesis of structurally diverse amines.

Efficient one-pot synthesis of biologically active polysubstituted aromatic amines.

An efficient and modular one-pot synthesis of polysubstituted aromatic amines by a mild reductive amination procedure is described and the biological potential of these nitrogen-centered compounds is demonstrated by growth inhibition of murine connective tissue cells and microscopy-based morphological studies.