An expedient synthesis of spiroketals: model studies for the calyculin C16–C25 fragment
Abstract A new short strategy to prepare the spiroketal fragment of calyculins is presented. A novel Seyferth–Gilbert type homologation of hindered lactols to the corresponding alkynes has been achieved for the first time. The spirocyclization was achieved efficiently via a DIHMA (double intramolecular hetero-Michael addition) process of this hindered ynone. The spirocyclization rate is not dependent on the stereochemistry of the alkoxy substituent in the oxolane ring.
The Binding Mode of Calyculin A to Protein Phosphatase-1
The catalytic subunits of serine/threonine protein phosphatases 1 and 2A are subject to inhibition by various toxins such as the microcystins, the nodularins, okadaic acid, tautomycin, and the calyculins. A recent paper (Bagu, J. R., Sykes, B. D, Craig, M. M., and Holmes, C. F. B. (1997)J. Biol. Chem. 272, 5087–5097) reported the successful docking of the crystal structure of calyculin A to the crystal structure of protein phosphatase-1. Unfortunately, the model presented there is based on the structure of the unnaturalenantiomer of calyculin A and must therefore be incorrect. We have developed a spiroketal vector model which appears to account for the spatial orientation of the hydrophobic and basic chains extending from the spiroketal-phosphate core of calyculin A. The model also clearly demonstrates why the unnatural enantiomer of calyculin A does not fit properly into the pocket of the active site. Based on our model, we present a possible open binding mode for calyculin A in the enzyme. This open structure is conceptually similar to the predicted binding mode of the peptide inhibitor DARPP-32 to the enzyme; the hydrophobic, metal-binding, and electrostatic interactions are all retained in this model.
Promoters for the (alkyne) hexacarbonyldicobalt-based cyclopentenone synthesis
Dimethyl sulfoxide and a variety of other highly polar solvents are shown to promote both inter- and intramolecular cyclopentenone formation from alkenes and (alkyne)hexacarbonyldicobalt complexes. Their use leads to significant changes in both regio- and stereoselectivity when compared to other reaction conditions. 12 refs., 5 tabs.