Total Synthesis of the Antimitotic Marine Macrolide (−)-Leiodermatolide

Leiodermatolide is an antimitotic macrolide isolated from the marine sponge Leiodermatium sp. whose potentially novel tubulin-targeting mechanism of action makes it an exciting lead for anticancer drug discovery. In pursuit of a sustainable supply, we report a highly stereocontrolled total synthesis (3.2 % yield) based on a convergent sequence of palladium-mediated fragment assembly and macrolactonization. Boron-mediated aldol reactions were used to configure the three key fragments 2, 5, and 6 by employing the appropriate enantiomer of the lactate-derived ketone 7.


II.
Detailed experimental procedures a.

Synthesis of western fragment 2
Ketone 8a To a suspension of magnesium turnings (1.10 g, 45.0 mmol) in THF (20 mL) was added iodine (2 crystals, approx. 20 mg) and 1,2-dibromoethane (50 μL) and the reaction stirred until it became colourless. A solution of TBSO(CH 2 ) 4 Br [4] (11.5 g, 42.9 mmol) in THF (10 mL) was then added dropwise over 2 h and the reaction heated to reflux for 1 h to give a clear grey solution of the Grignard reagent.

SI-17
Benzoate 16c Lithium aluminium hydride (237 mg, 6.25 mmol) was added to a solution of TBS protected aldol adduct 16b (1.62 g, 3.13 mmol) in Et 2 O (5 mL) at −78 °C. After stirring at −78 °C for 30 min, the reaction was quenched by the addition of acetone (5 mL) followed by NH 4 Cl solution (5 mL). Upon warming up to rt, the layers were separated and the aqueous portion extracted with Et 2 O (3 × 50 mL). The combined organic extracts were dried (Na 2 SO 4 ) and concentrated in vacuo to give benzoate 16c as a colourless liquid (1.60 g, 3.08 mmol, crude 98%, >20:1 dr at C13) to be used without further purification.
Alternatively, the reaction was carried out with crude aldol adduct 18f in THF (9.0 mL) and MeOH (6.0 mL) under the same conditions and the crude product was used in the subsequent step without further purification. X-ray crystallographic analysis confirmed the relative configuration of lactone 20 as shown in Figure 2. [11] Figure 2 ORTEP drawing of lactone 20 with thermal ellipsoids shown at 50% probability level.
Hydrogen atoms are omitted for clarity.

Alcohol 22b
A stock solution of HF·Py and pyridine was prepared by adding HF·Py (approx. 70% HF, 1 μL) to a solution of pyridine (3 μL) in THF (1 mL) at °C and the mixture stirred at rt for 30 min. TBS ether 22 (33.3 mg, 36.9 μmol) was dissolved in THF ( mL) cooled to 0 °C and an aliquot of the stock solution (8 μL) was added. The reaction was stirred at rt for 3.5 h before cooling to 0 °C and quenched by careful addition of NaHCO 3 solution. The layers were separated and the aqueous portion It was found to be possible to reverse the order of acetonide deprotection and macrolactonisation albeit in lower yield for the deprotection step. These compounds are described below.