Paul R. Blakemore

Ethyl (benzothiazol-2-ylsulfonyl)acetate: a new reagent for the stereoselective synthesis of α,β-unsaturated esters from aldehydes

The title reagent engaged in the modified Julia olefination with aldehydes under mild reaction conditions (DBU, CH2Cl2, rt or −78 °C) to yield α,β-unsaturated esters; aryl aldehydes and aliphatic aldehydes possessing significant chain branching elements gave trans alkene products with high stereoselectivity (E : Z up to >98 : 2), while straight chain aliphatic aldehydes gave cis products preferentially (Z : E up to 92 : 8).

A synthesis of herboxidiene

The natural herbicide herboxidiene was constructed from two key fragments using a modified Julia olefination based on the benzothiazolyl sulfone activator. Key steps in the synthesis of the C1–C10 oxane fragment were (a) a modified Julia olefination using a 1-phenyl-1H-tetrazolyl sulfone as activator and (b) an intramolecular addition of an alkoxide to an α,β-unsaturated ester. Key steps in the synthesis of the C11–C19 polyketide fragment were (a) a directed aldol reaction using a camphor-10,2-sultam as auxiliary; (b) an Ireland–Claisen rearrangement and (c) a hydroxy-directed epoxidation.

Programmed Synthesis of a Contiguous Stereotriad Motif by Triple Stereospecific Reagent-Controlled Homologation

All distinct diastereoisomers of a contiguous stereotriad motif were separately targeted by a triple chain extension of B-phenethyl boronic esters using four unique presentation sequences of enantiomorphs of 1-[(2)H]-1-chloro-2-(1,3-dioxolan-2-yl)ethyllithium. The (R)- or (S)-configured chloroalkyllithium reagents were generated by sulfoxide-lithium exchange from the appropriate scalemic p-tolyl chloroalkyl sulfoxides using phenyllithium (THF, -78 °C). Stereotriad synthesis was accomplished in a single reaction vessel [7-19% yield, typical dr ≥ 74 (target):26 (∑ all other isomers)] and implemented by a simple algorithm consisting of reagent charging and temperature cycling events.

Iterative Stereospecific Reagent-Controlled Homologation Using a Functionalized α-Chloroalkyllithium: Synthesis of Cyclic Targets Related to Epibatidine

Enantioenriched 1-chloro-2-(1,3-dioxolan-2-yl)ethyllithium was generated by PhLi initiated sulfoxide-ligand exchange and deployed in situ for sequential double stereospecific reagent-controlled homologation (StReCH) of B-(2-chloro-pyrid-5-yl) pinacol boronate. This process afforded highly functionalized contiguous stereodiad motifs (typically, % ee ≥ 98%, dr ≥ 85:15) amenable to subsequent annulative transformations as demonstrated by the concise synthesis (5-7 steps) of cyclic adducts related to the analgesic alkaloid epibatidine.

Investigation of Functionalized α‐Chloroalkyllithiums for a Stereospecific Reagent‐Controlled Homologation Approach to the Analgesic Alkaloid (−)‐Epibatidine

Four putative functionalized α-chloroakyllithiums RCH2CHLiCl, where R=CHCH2(18 a), CCH (18 b), CH2OBn (18 c), and CH[O(CH2)2O] (18 d), were generated in situ by sulfoxide-lithium exchange from α-chlorosulfoxides, and investigated for the stereospecific reagent-controlled homologation (StReCH) of phenethyl and 2-chloropyrid-5-yl (17) pinacol boronic esters. Deuterium labeling experiments revealed that α-chloroalkyllithiums are quenched by proton transfer from their α-chlorosulfoxide precursors and it was established that this effect compromises the yield of StReCH reactions. Use of α-deuterated α-chlorosulfoxides was discovered to ameliorate the problem by retarding the rate of acid-base chemistry between the carbenoid and its precursor. Carbenoids 18 a and 18 b showed poor StReCH efficacy, particularly the propargyl group bearing carbenoid 18 b, the instability of which was attributed to a facile 1,2-hydride shift. By contrast, 18 d, a carbenoid that benefits from a stabilizing interaction between O and Li atoms gave good StReCH yields. Boronate 17 was chain extended by carbenoids 18 a, 18 b, and 18 d in 16, 0, and 68% yield, respectively; α-deuterated isotopomers D-18 a and D-18 d gave yields of 33 and 79% for the same reaction. Double StReCH of 17 was pursued to target contiguous stereodiads appropriate for the total synthesis of (-)-epibatidine (15). One-pot double StReCH of boronate 17 by two exposures to (S)-D-18 a (≤66 % ee), followed by work-up with KOOH, gave the expected stereodiad product in 16% yield (d.r.~67:33). The comparable reaction using two exposures to (S)-D-18 d (≤90% ee) delivered the expected bisacetal containing stereodiad (R,R)-DD-48 in 40% yield (≥98% ee, d.r.=85:15). Double StReCH of 17 using (S)-D-18 d (≤90% ee) followed by (R)-D-18 d (≤90% ee) likewise gave (R,S)-DD-48 in 49% yield (≥97% ee, d.r.=79:21). (R,S)-DD-48 was converted to a dideuterated isotopomer of a synthetic intermediate in Coreys synthesis of 15.

Spontaneous symmetry breaking during interrupted crystallization of an axially chiral amino acid derivative

High net enantiomeric excess was observed for crystal collections obtained by crystallization of the TFA salt of a configurationally stable yet racemic axially chiral amidoamine in EtOH solution with or without stirring (up to >99% ee at < or = 15% crystallization).

Asymmetric synthesis of (+)-loline

The first asymmetric synthesis of (+)-loline has been achieved in 20 steps from (−)-malic acid by a route incorporating intramolecular hetero-Diels–Alder cycloaddition of an acylnitrosodiene.

Formation of Olefins by Eliminative Dimerization and Eliminative Cross-Coupling of Carbenoids: A Stereochemical Exercise

Two carbenoids combine to generate an olefin by a mechanism involving formation of an ate complex, 1,2-metalate rearrangement, and β-elimination. As each stage of this eliminative coupling is stereospecific, the overall stereochemical outcome can be understood and, in principle fully controlled, providing that the absolute stereochemical configurations of the reacting carbenoid species are defined. In contrast to traditional alkene syntheses, the eliminative cross-coupling of carbenoids offers a connective approach to olefins capable of precisely targeting a given isomer regardless of the nature of the features distinguishing the isomers. The formation of olefins by the eliminative dimerization and eliminative cross-coupling of carbenoids is reviewed with a range of illustrative examples, including the reactions of α-lithiated haloalkanes, epoxides, and carbamates. An emphasis is placed on stereochemical analysis and methods to generate sp3 -hybridized carbenoids in stereodefined form are surveyed.

Non-estrogenic Xanthohumol Derivatives Mitigate Insulin Resistance and Cognitive Impairment in High-Fat Diet-induced Obese Mice

Xanthohumol (XN), a prenylated flavonoid from hops, improves dysfunctional glucose and lipid metabolism in animal models of metabolic syndrome (MetS). However, its metabolic transformation into the estrogenic metabolite, 8-prenylnaringenin (8-PN), poses a potential health concern for its use in humans. To address this concern, we evaluated two hydrogenated derivatives, α,β-dihydro-XN (DXN) and tetrahydro-XN (TXN), which showed negligible affinity for estrogen receptors α and β, and which cannot be metabolically converted into 8-PN. We compared their effects to those of XN by feeding C57BL/6J mice a high-fat diet (HFD) containing XN, DXN, or TXN for 13 weeks. DXN and TXN were present at higher concentrations than XN in plasma, liver and muscle. Mice administered XN, DXN or TXN showed improvements of impaired glucose tolerance compared to the controls. DXN and TXN treatment resulted in a decrease of HOMA-IR and plasma leptin. C2C12 embryonic muscle cells treated with DXN or TXN exhibited higher rates of uncoupled mitochondrial respiration compared to XN and the control. Finally, XN, DXN, or TXN treatment ameliorated HFD-induced deficits in spatial learning and memory. Taken together, DXN and TXN could ameliorate the neurocognitive-metabolic impairments associated with HFD-induced obesity without risk of liver injury and adverse estrogenic effects.

Chapter 6 The synthesis of polycavernoside A. An example of conformationally guided macrolactonization

Publisher Summary Two substances, polycavernosides A and B, have been isolated from the algal extract. The lethal metabolite polycavernoside A has been revealed to be a glycosidic macrolide possessing an unusual tricyclic aglycon, formally derived from a partially dehydrated and unsaturated 3,5,7,13,15-pentahydroxy-9,10-dioxotricosanoic acid. The aglycon is linked at C5 to a disaccharide moiety composed of heavily methylated xylose and fucose sugar units. Yasumoto had garnered enough structural detail of polycavernoside A to make its recreation by purely synthetic means a definite possibility. In this context, it has been recognized that total synthesis would not only help to map out the relative and absolute stereochemical configuration for the natural product, but might also serve to re-establish a supply of the toxin, vital for an understanding of its threat to human health. Polycavernoside synthesis has also presented various issues; one of those issues has been the challenge of orchestrating macrolactonization of a seco carboxylic acid so that it could lead only to a 14-membered ring and no other. An after-the-fact conformational study of the seco acid precursor to lactonization using a molecular mechanics computation provides a plausible rationale for the outcome.