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

Abstract

General. 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

Catalytic Alkyne and Diyne Metathesis with Mixed Fluoroalkoxy-Siloxy Molybdenum Alkylidyne Complexes

“…29 Siloxide-supported alkylidyne complexes are another important class of alkyne metathesis catalysts, 30 and the triphenylsiloxy molybdenum complex I is probably the most frequently used species, 31,32 in particular for natural product synthesis through ring-closing alkyne metathesis (RCAM). [33][34][35][36][37][38][39][40][41][42][43] Recently, molybdenum alkylidyne complexes with arene-bridged tripodal siloxide ligands were introduced and employed as alkyne metathesis catalysts with improved functional group tolerance. [44][45][46][47] This design strategy is somewhat reminiscent of molybdenum alkylidyne complexes with tripodal tris(aryloxide) ligands, 48 which were used extensively in polymer and supramolecular chemistry, [49][50][51][52][53] and more recently, for alkyne metathesis operating under open air conditions.…”

Ring-Closing Metathesis Approaches towards the Total Synthesis of Rhizoxins

“…At the point where our numerous attempts at synthesizing the macrocyclic portion of rhizoxin F ( 2 ) by means of RCM/RRCM had all met with failure, we felt that a radical change in strategy was necessary. Triggered by Fürstner’s groundbreaking work on RCAM in the field of natural product synthesis (for early examples, see in [ 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 ]; for more recent examples, see in [ 23 , 79 , 80 , 81 ], we reasoned that this method would be a promising alternative to RCM. (For a review on the use of RCAM in natural product synthesis, see in [ 82 ].)…”

“…Most recently, Fürstner and co-workers have described an intriguing formal total synthesis of rhizoxin D ( 3 ) that included ring-closure by RCAM between C(11) and C(12) (!) [ 23 ]. The resulting triple bond was then efficiently transformed into the required trisubstituted trans double bond by trans -stannylation and subsequent C-methylation with excellent selectivity.…”

Iron‐Catalyzed Highly Enantioselective cis‐Dihydroxylation of Trisubstituted Alkenes with Aqueous H2O2

“…In all these previously reported iron-catalyzed AD reactions, [6] the substrates were confined to terminal alkenes and internal disubstituted alkenes.T oe xplore the feasibility of the Fe(N 4 )/H 2 O 2 method as ag reen alternative to OsO 4based reagents,w ew ondered whether the scope of the ironcatalyzed AD reactions could be extended to highly substituted alkenes such as trisubstituted alkenes. [8] Tr isubstituted alkenes,i np rochiral forms,a re ubiquitous structures in natural products, [9] and the optically active cisdiols from AD reactions of this class of alkenes possess aq uaternary stereogenic center and are valuable building blocks in synthetic organic chemistry.S uch diol groups are present in many bioactive molecules and pharmaceuticals. [10] To date,t he AD reactions of trisubstituted alkenes,w hich feature steric congestion and encounter increased difficulty in entering the active centers of catalysts,m ainly rely on the Sharpless asymmetric dihydroxylation reaction [1a,b] using osmium catalysts such as AD-mix-a or AD-mix-b [11] (Scheme 1b).…”