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Spirastrellolide A is an antimitotic polyketide that shows potent and selective inhibition of protein phosphatase 2A (IC50 = 1 nM) and causes premature entry of cells into mitosis (Figure 1). 1 This 38 membered macrocycle contains both 6,6-and 5,6,6spiroketal units, a cis-2,6-disubstituted tetrahydropyran, and a multitude of additional functionality. The acyclic side chain, appended at C38, contains a skipped diene and terminates in an -hydroxy carboxylic acid. The complex architecture and interesting biological profile of this and other spirostrellolides 2 have captured the attention of the organic chemistry community. Total syntheses of spirastrellolide A and F methyl esters have appeared, 3 as have a number of reports describing the preparation of spirastrellolide fragments. 4

The annual incidence of mild traumatic brain injury (MTBI) is 3.8 million in the USA with 10–15% experiencing persistent morbidity beyond one year. Chronic traumatic encephalopathy (CTE), a neurodegenerative disease characterized by accumulation of hyperphosphorylated tau, can occur with repetitive MTBI. Risk factors for CTE are challenging to identify because injury mechanisms of MTBI are heterogeneous, clinical manifestations and management vary, and CTE is a postmortem diagnosis, making prospective studies difficult. There is growing interest in the genetic influence on head trauma and development of CTE. Apolipoprotein epsilon 4 (APOE-ε4) associates with many neurologic diseases, and consensus on the ε4 allele as a risk factor is lacking. This review investigates the influence of APOE-ε4 on MTBI and CTE. A comprehensive PubMed literature search (1966 to 12 June 2018) identified 24 unique reports on the topic (19 MTBI studies: 8 athletic, 5 military, 6 population-based; 5 CTE studies: 4 athletic and military, 1 leucotomy group). APOE-ε4 genotype is found to associate with outcomes in 4/8 athletic reports, 3/5 military reports, and 5/6 population-based reports following MTBI. Evidence on the association between APOE-ε4 and CTE from case series is equivocal. Refining modalities to aid CTE diagnosis in larger samples is needed in MTBI.

The carbonyl ene reaction of 2-methylenetetrahydropyrans provides a rapid, high yielding route for the preparation of β-hydroxydihydropyrans under mild conditions. This process provides a new entry for the synthesis of 2-substituted tetrahydropyrans and for the direct introduction of oxygen heterocycles into molecular frameworks.

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