Jeremy Robertson

Radical translocation reactions in synthesis

This review highlights synthetically useful transformations of organic free-radicals in which a key step is relocation of the radical site by intramolecular abstraction either of a hydrogen atom or a group (e.g. phenyl, cyano, trialkylsilyl). The material is organised around the nature of the radical that initiates translocation and coverage is largely confined to reports that have appeared within the past decade, reference to earlier work only being made in order to establish a context for more recent results.

Kinetics, safety and tolerability of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate in healthy adult subjects.

Induction of mild states of hyperketonemia may improve physical and cognitive performance. In this study, we determined the kinetic parameters, safety and tolerability of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate, a ketone monoester administered in the form of a meal replacement drink to healthy human volunteers. Plasma levels of β-hydroxybutyrate and acetoacetate were elevated following administration of a single dose of the ketone monoester, whether at 140, 357, or 714 mg/kg body weight, while the intact ester was not detected. Maximum plasma levels of ketones were attained within 1-2h, reaching 3.30 mM and 1.19 mM for β-hydroxybutyrate and acetoacetate, respectively, at the highest dose tested. The elimination half-life ranged from 0.8-3.1h for β-hydroxybutyrate and 8-14 h for acetoacetate. The ketone monoester was also administered at 140, 357, and 714 mg/kg body weight, three times daily, over 5 days (equivalent to 0.42, 1.07, and 2.14 g/kg/d). The ketone ester was generally well-tolerated, although some gastrointestinal effects were reported, when large volumes of milk-based drink were consumed, at the highest ketone monoester dose. Together, these results suggest ingestion of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate is a safe and simple method to elevate blood ketone levels, compared with the inconvenience of preparing and consuming a ketogenic diet.

Carbocyclic ring expansion reactiuon VIA radical chain processes

Abstract A free radical mediated ring expansion of cis - and trans - α-alkylated-β-stannylcyclohexanones to provide efficient routes to cis - and trans -cyclononenones and cyclodecenones is described. The cis-/trans - relationship in the precursor was found to have significant bearing on the alkene geometry of the ring expanded product.

Bistrifluoromethanesulfonimide in the catalytic conjugate allylation of α,β-unsaturated carbonyl compounds

Abstract Bistrifluoromethanesulfonimide may be used directly to initiate the catalytic conjugate allylation of α,β-unsaturated carbonyl compounds with allyltrimethylsilane; high yields of either silyl enol ethers of δ,e-unsaturated ketones and esters may be obtained under mild conditions.

The synthesis of (±)-heliotridane and (6S,7S)-dihydroxyheliotridane via sequential hydrogen atom abstraction and cyclisation

Abstract Treatment of N-(3-bromo-3-butenyl)pyrrolidine derivatives with tributyltin hydride and AIBN leads to hydrogen atom transfer of the intermediate vinyl radicals to give α-amino radicals which then cyclise stereoselectively yielding pyrrolizidines 1 and 13.

Stereospecificity in the Au-catalysed cyclisation of monoallylic diols. Synthesis of (+)-isoaltholactone.

We describe a concise synthesis of (+)-isoaltholactone via a Au-catalysed cyclisation of a monoallylic diol to form the tetrahydrofuranyl ring. Analogous cyclisations show that the stereochemical outcome is dictated by the stereochemistry of the diol substrate.

Novel ketone diet enhances physical and cognitive performance

Ketone bodies are the most energy‐efficient fuel and yield more ATP permole of substrate than pyruvate and increase the free energy released from ATP hydrolysis. Elevation of circulating ketones via high‐fat, low carbohydrate diets has been used for the treatment of drug‐refractory epilepsy and for neuro degenerative diseases, such as Parkinsons disease. Ketones may also be beneficial for muscle and brain in times of stress, such as endurance exercise. The challenge has been to raise circulating ketone levels by using a palatable diet without altering lipid levels. We found that blood ketone levels can be increased and cholesterol and triglycerides decreased by feeding rats a novel ketone ester diet: chow that is supplemented with (R)‐3‐hydroxybutyl (R)‐3‐hydroxybutyrate as 30% of calories. For 5 d, rats on the ketone diet ran 32% further on a tread mill than did control rats that ate an isocaloric diet that was supplemented with either corn starch or palmoil (P < 0.05). Ketone‐fed rats completed an 8‐ arm radial maze test 38% faster than did those on the other diets, making more correct decisions before making a mistake (P < 0.05). Isolated, perfused hearts fromrats that were fed the ketone diet had greater free energy available from ATP hydrolysis during increased work than did hearts from rats on the other diets as shown by using [31P]‐ NMRspectroscopy. The novelketone diet, therefore, improved physical performance and cognitive function in rats, and its energy‐sparing properties suggest that it may help to treat a range of human conditions with metabolic abnormalities.—Murray, A. J., Knight, N. S., Cole, M. A., Cochlin, L. E., Carter, E., Tchabanenko, K., Pichulik, T., Gulston, M.K., Atherton, H. J., Schroeder, M.A., Deacon, R.M. J., Kashiwaya, Y., King, M.T., Pawlosky, R., Rawlins, J. N. P., Tyler, D. J., Griffin, J. L., Robertson, J., Veech, R. L., Clarke, K. Novel ketone diet enhances physical and cognitive performance. FASEB J. 30, 4021–4032 (2016). www.fasebj.org

Oral 28-day and developmental toxicity studies of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate

(R)-3-Hydroxybutyl (R)-3-hydroxybutyrate (ketone monoester) has been developed as an oral source of ketones, which may be utilized for energy. In a 28-day toxicity study, Crl:WI (Wistar) rats received diets containing, as 30% of the calories, ketone monoester (12 and 15 g/kg body weight/day for male and female rats, respectively). Control groups received either carbohydrate- or fat-based diets. Rats in the test group consumed less feed and gained less weight than control animals; similar findings have been documented in studies of ketogenic diets. Between-group differences were noted in selected hematology, coagulation, and serum chemistry parameters; however, values were within normal physiological ranges and/or were not accompanied by other changes indicative of toxicity. Upon gross and microscopic evaluation, there were no findings associated with the ketone monoester. In a developmental toxicity study, pregnant Crl:WI (Han) rats were administered 2g/kg body weight/day ketone monoester or water (control) via gavage on days 6 through 20 of gestation. No Caesarean-sectioning or litter parameters were affected by the test article. The overall incidence of fetal alterations was higher in the test group; however, there were no specific alterations attributable to the test substance. The results of these studies support the safety of ketone monoester.

Synthesis of spiroacetal enol ethers by oxidative activation of furan derivatives.

Activation of furan by electron transfer combines with the radical stabilizing effect of the alkynyl substituent (R = Ph, MeC[triple bond]C-) to achieve site-selective cation formation. A tethered hydroxy group acts as a probe of this site-selectivity to produce the ring system present in spirocyclic natural products found in Artemisia and Chrysanthemum species. cis-Dihydroxylation proceeds with high anti-stereoselectivity with respect to the tetrahydropyranyl ring oxygen.

Structure and reactivity of bicyclic methylene aziridines prepared by intramolecular aziridination of allenes

Unprecedented bicyclic methylene aziridines are prepared by rhodium(II)-catalyzed allene aziridination of buta-2,3-dienyl carbamates. Aspects of their NMR and X-ray data are described and a preliminary reactivity profile is given, including overall S(N)V-mode ring-opening with organometallic reagents.