Total Synthesis of Mycinolide IV and Path‐Scouting for Aldgamycin N

Abstract Proof‐of‐concept is provided that a large estate of 16‐membered macrolide antibiotics can be reached by a “unified” approach. The key building block was formed on scale by an asymmetric vinylogous Mukaiyama aldol reaction; its alkene terminus was then converted either into the corresponding methyl ketone by Wacker oxidation or into a chain‐extended aldehyde by catalyst‐controlled branch‐selective asymmetric hydroformylation. These transformations ultimately opened access to two structurally distinct series of macrolide targets. Notable late‐stage maneuvers comprise a rare example of a ruthenium‐catalyzed redox isomerization of an 1,3‐enyne‐5‐ol into a 1,3‐diene‐5‐one derivative, as well as the elaboration of a tertiary propargylic alcohol into an acyloin by trans‐hydrostannation/Chan‐Lam‐type coupling. Moreover, this case study illustrates the underutilized possibility of forging complex macrolactone rings by transesterification under essentially neutral conditions.


General.
Unless otherwise stated, all reactions were performed in oven-dried (80 °C) or flame-dried glassware in anhydrous solvents under argon, applying standard Schlenk techniques. Dry argon (>99.5%) was purchased from Air Liquide.
The following solvents were purified by distillation over the indicated drying agents and transferred under argon: tetrahydrofuran and diethyl ether (Mg/anthracene), dichloromethane (CaH2), hexanes and toluene (Na/K), methanol (Mg, stored over 3 Å molecular sieves). Acetonitrile, dimethyl sulfoxide, dimethylformamide, pyridine and triethylamine were dried using an adsorption (molecular sieves) solvent purification system. Solvents were removed under reduced pressure below 40 °C using a rotary evaporator.
Commercial technical-grade cumene hydroperoxide (Aldrich, 80 % w/w) was used as received. Commercial titanium(IV) isopropoxide was distilled under reduced pressure and stored under argon at −20 °C.
Trimethylsilylacetylene and hexafluorobenzene were distilled under argon before use. Commercial anhydrous dimethoxymethane was stored over activated 4 Å molecular sieves under argon. Chlorobenzene was dried and stored over activated 4 Å molecular sieves, and degassed by bubbling argon through it.
Thin layer chromatography (TLC) was performed on Macherey-Nagel precoated plates (POLYGRAM ® SIL/UV254); the compounds were detected by UV light (254 nm) or heating of the plate with a heat gun after treatment with stain solutions comprising either potassium permanganate or phosphomolybdic acid. Flash chromatography was performed with VWR silica gel 60 (40 -63 µm).
Automated column chromatography was conducted on a Biotage ® Isolera TM or a Biotage ® Selekt instrument, using the chromatography cartridges indicated in the respective procedure. Diastereomeric ratios (d.r.) of intermediates were determined by 1 H NMR spectroscopy from the relative integrals of sufficiently separated, characteristic signals of the respective intermediate.
NMR spectra were recorded on Bruker AV 400, AV 500 or AVIII 600 spectrometers in the solvents indicated. The solvent signals were used as references, chemical shifts were converted to the TMS scale and reported as follows: chemical shift in ppm (multiplicity, coupling constant J in Hz, number of protons).
Multiplets are designated by the following abbreviations: s for singlet, d for doublet, t for triplet, q for quartet, quint for quintet, m for complex pattern (multiplet); the abbreviation br indicates a broad signal. 13 C NMR spectra were recorded in { 1 H}-decoupled mode. Melting points were determined using a Büchi B-540 apparatus. IR spectra were recorded on a Bruker Alpha Platinum ATR spectrometer at room S2 temperature. Mass spectra were recorded using the following instruments: MS (EI):
Cumene hydroperoxide (80% technical grade, 27 mL, 146 mmol) was added and the resulting mixture stirred for 30 min before a mixture of 12a (6.04 g, 83.8 mmol) and powdered 4 Å molecular sieves (~1.5 g) in dichloromethane (40 mL) was introduced. Stirring was continued for another 14 h at −20 °C. After the addition of citric acid monohydrate (3.56 g) in diethyl ether/acetone (225 mL/25 mL), the mixture was warmed to room temperature and stirred for 30 min before the orange suspension was filtered through a short pad of Celite ® , which was rinsed with dichloromethane (5 × 10 mL). The combined filtrates were concentrated under reduced pressure (150 mbar, 38 °C) and the residue was purified by flash chromatography (pentane/diethyl ether, 1:1) to give the title compound as a colorless liquid (3.

S3
The racemic sample was obtained by epoxidation of (Z)-2-buten-1-ol with 3-chloroperbenzoic acid. The analytical data are in agreement with those reported in the literature. 5
After the suspension had been cooled to −20 °C, titanium(IV) isopropoxide (

Preparation of the Common Eastern Fragment (S)-2-Methylpent-4-en-1-yl acetate (4).
Purification of this concentrated solution by flash chromatography (pentane/diethylether  Once the addition was complete, the mixture was warmed to room temperature and stirring was continued for another 3 h. The reaction was quenched by the addition of water and the mixture was extracted twice with diethylether. The combined organic phases were washed with brine and evaporated, and the residue was purified by flash chromatography (pentane/diethyl ether, 5:1) to afford the title compound as a colorless liquid (6.40 g, 75% yield  After complete addition, the mixture was stirred for an additional hour at this temperature before the reaction was quenched with saturated aqueous sodium bicarbonate solution (50 mL). The resulting mixture was warmed to room temperature, the aqueous phase was extracted thrice with dichloromethane, and the S14 combined organic layers were stirred vigorously with aqueous HCl (2 M, 400 mL) for 1 h. The resulting aqueous phase was extracted thrice with dichloromethane and the combined organic layers were washed with brine and dried over anhydrous magnesium sulfate. The drying agent was filtered off and the solution was concentrated under reduced pressure. The residue was purified by flash chromatography (hexanes/EtOAc, 9:1) to afford the title compound admixed with the C-6 epimer as a colorless oil (

Stereochemical Analysis of Product 7 formed by the Vinylogous Mukaiyama Aldol Reaction
(1) The identity of the minor diastereoisomer (C-6 epimer) was established by comparison of the crude mixture obtained under the reaction conditions described above to the reaction outcome when racemic aldehyde 6 was used under otherwise identical conditions. Since no other diastereomers were observed by NMR analysis of the crude product mixture, the aldol reaction itself seems to proceed with a dr > 98:2.
(2) The relative configuration at C-5 was determined by Mosher ester analysis of alcohol 7.

Stereochemical Analysis of the Hydroformylation Product
The analogous reaction using the enantiomeric ligand ent-32 gave 8-epi-27 as the major product (see below); 27 and 8-epi-27 were then transformed into the corresponding lactones 33 and 8-epi-33; the NMR data of these samples could be compared with those of authentic 33 reported in the literature. 10 As shown in Table S2, an excellent match with the reported 1 H NMR data was found for the lactone obtained from aldehyde 27, which was formed with the aid of (Rax,R,R)-BOBPhos (32) as the chiral ligand.
[ ] = 75.0 (c 0.13, MeOH 2.36 mmol) in THF (7 mL) was added, and the resulting mixture was stirred at 78 °C for 1.5 h. Pentane (40 mL) was added, the reaction was quenched with water (20 mL) and the mixture allowed to warm to room temperature. Saturated aqueous NaCl (10 mL) was introduced, the layers were separated and the aqueous phase was extracted with pentane (3 × 10 mL). The combined organic layers were washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate and the drying agent was removed by filtration. The filtrate was evaporated to dryness, giving a pale yellow oil. Purification by automated column chromatography (for each half of the crude product using a Biotage ® 50 g SNAP Ultra HP-Sphere TM 25µm cartridge, loading as a solution in The layers were separated and the aqueous phase was extracted with ethyl acetate (4 × 4 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (5 mL) and filtered through a pad of anhydrous sodium sulfate. The solvent was removed under reduced pressure to give a colourless solid, which was purified by automated column chromatography (Biotage ® 10 g SNAP Ultra HP-Sphere TM 25µm

S34
Comparison of the NMR spectra of mycinolide IV (2) prepared by total synthesis with those of the authentic sample obtained by hydrolysis of mycinamicin IV 11,12 Figure S1 shows a visual comparison of the recorded 13 C NMR spectrum (CDCl3) of synthetic 2 (in black) and a simulated spectrum created in MestReNova based on the 13 C NMR shifts of authentic mycinolide IV in CDCl3 reported in the literature (in red). The comparison of the numeric 13 C NMR shifts confirms the excellent agreement (≤ 0.1 ppm). Since the latter spectrum was only graphically depicted, and no tabulation of chemical shifts and coupling constants was reported, the comparison is limited to this purely graphical and qualitative assessment.
The frequency of the spectrum reported in the literature was not specified; it is assumed to be 100 MHz based on spectra of several mycinamicins reported by the same groups two years later. 13 Since no NMR spectrometer was available to us to record a 1 H NMR spectrum of the synthesized material at 100 MHz, the spectrum was recorded at 600 MHz and all proton chemical shifts were assigned and coupling constants were extracted. This information was then used for a simulation of a 100 MHz 1 H NMR spectrum, using the DAISY module in TOPSPIN. Additionally, OH signals of the recorded spectrum and their couplings to neighbouring protons were removed to account for their invisibility in the literature spectrum due to the presence of an undefined amount of D2O.
S35 Figure S2. 1 H NMR shifts (ppm) of synthetic 2 (in red) and authentic mycinolide IV obtained from the hydrolysis of mycinamicin