Metathesis at an Implausible Site: A Formal Total Synthesis of Rhizoxin D

Abstract

S2General. All reactions were carried out under Ar in glassware dried with a heat gun under vacuum (Schlenk line). The solvents were purified by distillation over the indicated drying agents and were transferred under Ar: THF, Et 2 O (Mg/anthracene), acetone (B 2 O 3 ), toluene (Na/K), CH 2 Cl 2 (CaH 2 ), MeOH (Mg, stored over 3Å MS); DMSO, DMF, CH 3 CN, NEt 3 and pyridine were dried by an adsorption solvent purification system based on molecular sieves. Unless stated otherwise, all commercially available compounds (ABCR, Acros, Aldrich, Strem, TCI) were used as received. [(Cp*RuCl) 4 ] was prepared according to a literature procedure and was stored under Argon. 1 Thin layer chromatography (TLC): Macherey-Nagel precoated plates (POLYGRAM® SIL/UV254); Flash chromatography: Merck silica gel 60 (40-63 μm) with predistilled or HPLC grade solvents; IR: ALPHA spectrometer (Bruker), wavenumbers (ṽ) in cm -1 . MS (EI): Finnigan MAT 8200 (70 eV), ESIMS: ESQ 3000 (Bruker), accurate mass determinations: Bruker APEX III FT-MS (7 T magnet) or MAT 95 (Finnigan); Optical rotations ([ ] ) were measured with a Perkin-Elmer Model 343 polarimeter.NMR: Spectra were recorded on a Bruker AV 400, AV 500 or AV 600 spectrometer in the solvents indicated; chemical shifts (δ) are given in ppm relative to TMS, coupling constants (J) in Hz. The solvent signals were used as references and the chemical shifts converted to the TMS scale (CDCl 3 at 7.26 and 77.16 ppm, CD 3 OD at 3.31 ppm and 49.00 ppm for 1 H and 13 C NMR spectroscopy, respectively).Where indicated, the signal assignments in the NMR spectra are unambiguous; the numbering scheme is arbitrary as shown in the inserts.(R)-Oct-1-en-3-ol (4). Novozyme (300 mg) was added to a solution of (±)-oct-1-en-3-ol (8.0 mL, 6.6 g, 52 mmol) and vinyl acetate (18.0 mL, 194 mmol) in hexane (70 mL) and the resulting suspension was gently stirred (~ 50 rpm) at ambient temperature. The progress of the reaction was monitored by GC-MS. After 42 h the immobilized enzyme was filtered off and rinsed with hexane (4 x 10 mL) and the combined filtrates were concentrated under reduced pressure. Purification of the residue by flash chromatography (hexane/tert-butyl methyl ether, 9:1 → 1:1) yielded the product as colorless liquid with a mushroom-like odor (2.27 g, 34%). The physical properties of the product were in full accordance with the literature; 2 the enantiomeric excess (> 99% ee) was determined by gas chromatography using a chiral stationary phase, cf: 1 P.

Stereoselective Construction of (E,Z)‐1,3‐Dienes and Its Application in Natural Product Synthesis

“…Indeed, either E ‐ene‐yne or Z ‐ene‐yne macrocyclic compounds could be efficiently obtained [207–210] . Moreover, Fürstner developed efficient alkyne hydrofunctionalisation reactions that further expanded the potential of this strategy, primarily for structure−activity relationship studies [211–214] …”

“…[207][208][209][210] Moreover, Fürstner developed efficient alkyne hydrofunctionalisation reactions that further expanded the potential of this strategy, primarily for structureÀ activity relationship studies. [211][212][213][214] RCAM strategies have been used with E,Z-dienes containing natural products, such as latrunculins, [215,216] mandelalide A, [217,218] disorazole C 1 , [219] lactimidomycin. [220,221] and rhizoxin D. [222] To highlight the potential of the RCAM strategy, three complementary approaches are highlighted in scheme 87: E-Eneyne formation and cis semi-reduction (221) in the total synthesis of the originally assigned structure of mandelalide A (eq (a)); Z-ene-yne (222) formation and alkyne trans-reduction (223) in the total synthesis of lactimidomycin (eq (b)); and a head-to-tail homodi-merisation strategy affording 224 in the formal synthesis of disorazole C 1 (eq (c)).…”

Applications of the Horner–Wadsworth–Emmons Olefination in Modern Natural Product Synthesis

“…122 Fürstner and co-workers presented their own synthetic effort in 2019 that extended earlier studies and resulted in a different modern strategy (Scheme 31). 123 The synthesis was based on intermolecular HWE olefination for coupling 254 and 255 followed by macrocyclization to form a 16-membered ring through ring-closing alkyne metathesis.…”

From Target-Oriented to Motif-Oriented: A Case Study on Nannocystin Total Synthesis

“…Discovered by Fürstner et al in 2009, 2D and its benchtop stable precursor represent a latest generation of alkyne metathesis catalysts with outstanding reactivity, functional group compatibility, and operational practicality [ 45 , 46 , 47 , 48 ]. Since the advent of these broadly applicable catalysts, RCAM in alliance with postmetathetic elaborations has become a privileged methodology [ 49 , 50 ] in the total synthesis of stereodefined polyunsaturated macrocycles [ 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 ]. As for the present study, 2A and 2B constitute two versatile intermediates for diversification.…”