Total Synthesis of (R)-Sarkomycin via Asymmetric Rhodium-Catalyzed Conjugate Addition

Abstract

(R)-Sarkomycin was prepared using a five-step total synthesis. Key steps in the enantioselective construction of the targeted scaffold were a rhodium-catalyzed asymmetric conjugate alkenyl addition with subsequent silyl trapping and a Mukaiyama aldol reaction with aqueous formaldehyde. Protection of the hydroxy group as a THP acetal and oxidative cleavage of the C,C-double bond provided a stable direct precursor to the natural product. The final liberation was carried out under slightly acidic conditions in a microwave-assisted reaction, resulting in a high yield of the "deceptive" sarkomycin. This represents the shortest enantioselective synthesis of this rather unstable compound to date and the first to employ asymmetric catalysis to introduce the stereogenic center.

Efficient Mukaiyama–Aldol Reaction with Aqueous Formaldehyde on a Hydrophobic Mesoporous Lewis Acid Polymer

“…In addition, this Yb(OTf) 2 ‐MP‐catalyzed Mukaiyama–aldol process was scalable under mild reaction conditions (Figure ). We were able to perform a 10 mmol‐scale (1.82 g) reaction by using 3‐ethenyl‐1‐trimethylsiloxycyclopent‐1‐ene as the substrate with 10 mol % Yb(OTf) 2 ‐MP and 20 equivalents of aqueous formaldehyde at 20 °C for 24 h in water to give the corresponding 2‐(hydroxymethyl)‐3‐vinylcyclopentanone (65 % yield, diastereomeric ratio dr 7:3) for the first time, which is the important intermediate for the synthesis of the natural product sarkomycin, which has antibiotic and anticancer activity . The scalability and robustness of this environmentally friendly heterogeneous transformation illustrated its potential application in the manufacture of medicinally useful chemicals on an industrial scale.…”

Asymmetric Conjugate Additions and Allylic Alkylations Using Nucleophiles Generated by Hydro‐ or Carbometallation

“…[56] and hasa ppliedt his method to the synthesis of the spiro-unit of vannusal A(Scheme 19). [58] 3. [57] Treatment of the zirconium enolatei nitially produced in the reaction with an excesso fM eLi at À78 8Cg ives al ithiume nolate which can be trapped as as ilane.…”

Strategy of total synthesis based on the use of Rh-catalyzed stereoselective 1,4-addition

“…19 This natural product has shown antibiotic activity but also strong anticancer activity against various cell lines. 19 This natural product has shown antibiotic activity but also strong anticancer activity against various cell lines.…”