Described here are the full details of the preparation of a synthetic intermediate representing carbons 1-14 (C1-C14) of the marine natural product okadaic acid (1), the coupling of this fragment with the previously prepared C15-C38 domain, and the completion of an efficient total synthesis of 1. The C1-C14 intermediate was prepared in 11 steps and ∼20% overall yield from a functionalized δ-valerolactone derivative representing C3-C8 of 1. This featured a classic spiroketalization strategy to construct the highly substituted 1,7-dioxaspiro-[5.5]undec-4-ene system, followed by incorporation of the intact C1-C2 R-hydroxyl, R-methyl carboxylate moiety using cis-(S)-lactate pivalidene enolate. The complete C1-C14 intermediate was converted into 1 in five additional steps. Coupling of the C1-C14 fragment with the C15-C38 domain of 1 via C14 aldehyde and C15 -keto phosphonate moieties provided the complete carbon skeleton of 1 bearing a ketone at C16 and a mixed-methyl acetal at C19. Reduction of the C16 ketone using Corey's (S)-CBS/BH 3 system and subsequent acid-triggered spiroketalization formed the central 1,6-dioxaspiro[4.5]decane ring system. Saponification of the C1-C2 pivalidene group and final reductive cleavage of the three benzyl ethers using lithium di-tertbutylbiphenylide in THF provided 1 in 48% yield from the C1-C14 aldehyde, and in 26 steps and ∼2% overall yield in the longest linear sequence from the C22-C27 synthon methyl 3-O-benzyl-R-D-altropyranoside.

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The cytosolic portion of CD45, a major transmembrane glycoprotein found on nucleated hematopoietic cells, contains protein tyrosine phosphatase activity and is critical for T-cell receptor-mediated T-cell activation. CD45 inhibitors could have utility in the treatment of autoimmune disorders and organ graft rejection. A number of 9,10-phenanthrenediones were identified that reversibly inhibited CD45-mediated p-nitrophenyl phosphate (pNPP) hydrolysis. Chemistry efforts around the 9,10-phenanthrenedione core led to the most potent inhibitors known to date. In a functional assay, the compounds were also potent inhibitors of T-cell receptor-mediated proliferation, with activities in the low micromolar range paralleling their enzyme inhibition. It was also discovered that the nature of modification to the phenanthrenedione pharmacophore could affect selectivity for CD45 over PTP1B (protein tyrosine phosphatase 1B) or vice versa.

A convergent synthesis of the C15−C38 domain of the marine natural product okadaic acid is reported. This involved the preparation of intermediates representing the C16−C27 and C28−C38 portions of okadaic acid, their direct coupling, and elaboration to the complete C15−C38 intermediate. A C16−C27 intermediate bearing an aldehyde at C27 was constructed in 14-steps from methyl 3-O-benzyl-α-d-altropyranoside. A C28−C38 intermediate with a primary alkyl bromide at C28 was prepared in 10 steps from methyl (S)-3-hydroxy-2-methylpropionate. These fragments were then joined in ∼55% yield by conversion of the bromide into an alkylcerium reagent then addition to a sensitive β,γ-unsaturated C27 aldehyde to give a mixture of C27 carbinols (27R:27S = 2.5:1). The configuration at C27 of the major coupling product was inverted by a simple oxidation−reduction sequence to establish the 27S-configuration of okadaic acid. Elaboration into a C15 β-keto phosphonate completed the synthesis of the fully functionalized C15−C38 portion of okadaic acid in 19 linear steps and ∼3% overall yield from methyl 3-O-benzyl-α-d-altropyranoside.