Total Synthesis of the Marine Phosphomacrolide, (-)-Enigmazole A, Exploiting Multicomponent Type I Anion Relay Chemistry (ARC) in Conjunction with a Late-Stage Petasis-Ferrier Union/Rearrangement.

An effective late-stage large-fragment union/rearrangement exploiting the Petasis-Ferrier protocol, in conjunction with multicomponent Type I Anion Relay Chemistry (ARC) to access advanced intermediates, permits completion of a convergent, stereocontrolled total synthesis of the architecturally complex phosphomacrolide (-)-enigmazole A (1).

Stereocontrolled Synthesis of Left Halves of Halichondrins.

A stereocontrolled synthesis of the left halves of halichondrins was reported. An intramolecular oxy-Michael reaction under basic conditions was used to construct the [6,6]-spiroketal in a stereocontrolled manner. With this approach, the left halves of halichondrins, homohalichondrins, and norhalichondrins were synthesized.

Unified Synthesis of Right Halves of Halichondrins A-C.

The right halves of halichondrins A-C were synthesized by coupling the common C20-C37 building block 9 with the C1-C19 building blocks 10a-c, respectively. Catalytic, asymmetric Ni/Cr-mediated coupling was used for three C-C bond formations. For all cases, the stereochemistry was controlled with the Cr catalyst prepared from the chiral sulfonamide identified via the toolbox approach. For (3 + 4)-, (6 + 7)-, and (9 + 10)-couplings, the stereoselectivity of 28:1, >40:1, and ∼20:1 was achieved by the Cr catalysts prepared from (S)-H, (S)-I, and (R)-L, respectively. Unlike the first and second couplings, the third coupling used the structurally complex nucleophile. It was demonstrated that the coupling efficiency was excellent even with the electrophile/nucleophile molar ratio = 1.0/1.1. In addition, the third coupling was achieved with the substrate bearing a free hydroxyl group. The products obtained in the Ni/Cr-mediated couplings were converted to the right halves of halichondrins A-C in excellent overall yields. The right halves of halichondrins A-C (1a-c) were synthesized in 28, 24, and 24 steps from commercial d-galactal in 13.4%, 21.1%, and 16.7% overall yield, respectively.

Zirconium/Nickel-Mediated One-Pot Ketone Synthesis.

A zirconium/nickel-mediated one-pot synthesis of ketones is reported. In the presence of Zn or Mn, Cp2 ZrCl2 was found to dramatically accelerate the coupling and suppress side product formation via an I→SPy displacement at the same time. Unlike Zn/Pd- and Fe/Cu-mediated one-pot ketone syntheses, the new method is effective for nucleophiles bearing OR or equivalent functional groups at the α-position. A mechanism comprising a nickel catalytic cycle, a zirconium catalytic cycle, and Zr→Ni transmetalation is proposed, and Cp2 ZrCl2 and/or low-valent Zr species are suggested to play crucial dual roles.

Unified, Efficient, and Scalable Synthesis of Halichondrins: Zirconium/Nickel-Mediated One-Pot Ketone Synthesis as the Final Coupling Reaction.

Unified, efficient, and scalable syntheses of the halichondrin natural products are reported. A newly developed Zr/Ni-mediated one-pot ketone synthesis was used to couple the two halves of the final product at a late stage in the synthesis. With the use of a slight excess of the left halves, the desired ketones were isolated in yields of 80-90 %. The halichondrins were obtained from these ketones in two steps, namely desilylation and [5,5]-spiroketal formation. The new synthetic route was effective for the total synthesis of all members in the homohalichondrin subgroup. The scalability of this process was demonstrated with halichondrin B; 150 mg of halichondrin B (68 % overall yield) were obtained from 200 mg of the right-half precursor.

Total Synthesis of (-)-Enigmazole A.

A highly convergent, stereocontrolled total synthesis of the architecturally complex marine sponge metabolite (-)-enigmazole A has been achieved. Highlights include an unprecedented late-stage large-fragment Petasis-Ferrier union/rearrangement, a multicomponent Type I Anion Relay Chemistry (ARC) tactic, and a dithiane-epoxide union in conjunction with an oxazole-directed stereoselective reduction.

Efficacy of extracorporeal shock waves in the treatment of myofascial pain syndrome: a systematic review and meta-analysis of controlled clinical studies.

Background: Myofascial pain syndrome (MPS) is recurrent local myofascial pain with various treatment methods. In recent years, extracorporeal shock wave therapy (ESWT) has attracted much attention, but its role still lacks systematic review. We included controlled clinical studies for meta-analysis to systematically evaluate the application effect of ESWT. Methods: The English literature from PubMed, Embase, Cochrane Central Register of Controlled Trials, and Web of Science to October 2021 was searched by computer. After screening, the quality was evaluated by the PEDro (Physiotherapy Evidence Database) scale and analyzed by RevMan 5.4 software. Results: A total of 571 patients were included in 8 studies. The MPS pain sites of 541 patients were in the neck and upper back, and only 30 patients had pain sites in the waist. Meta-analysis showed that the pain level after ESWT was lower than that after other treatment methods [mean difference (MD) =-1.34, 95% confidential interval (CI): -1.87 to -0.81, P<0.00001], the pain threshold after ESWT was higher than that after other treatment methods (MD =0.90, 95% CI: 0.73 to 1.07, P<0.00001), and the neck disability index after ESWT was lower (MD =-1.79, 95% CI: -2.48 to -1.10, P<0.00001). Discussion: ESWT can avoid the adverse effects of invasive procedures on patient tolerance and compliance; compared with trigger point injection (TPI), dry needling, ultrasound-guided pulsed radiofrequency (US), and other methods, ESWT can more effectively relieve pain in patients with MPS.

LC-MS guided isolation and dereplication of Lycopodium alkaloids from Lycopodium cernuum var. sikkimense of different geographical origins.

Lycopodium alkaloids (LAs) are the characteristic metabolites of club mosses. Chemical differences often exist in different specimens of a single plant species collected from different geographic origins. In this study, a preliminary LC-MS detection and dereplication analyses of alkaloidal constituents of Lycopodium cernuum var. sikkimense (Müll. Hal.) C.B. Clarke (LCVS2) collected from Fujian province led to the isolation and characterization of three undescribed LAs, lycocernuskines A-C, and six known cernuane-type LAs. The known compounds were previously isolated from the same plant species (LCVS1) collected from Chongqing, and so their dereplication in LCVS2 was accomplished based on their retention times (tR) and the quasi-molecular ion peaks in the LC-MS fingerprint. Chemical structures were identified by spectroscopic methods, single-crystal X-ray diffraction analysis, and electronic circular dichroism calculations. Lycocernuskines A and B are the first two examples of C-12 hydroxylated phlegmarane-type LAs bearing a nitrone residue at the quinoline ring. The isolates were evaluated for their anti-AChE and neuroprotective effects.