Synthesis of the F-O-G fragment of ristocetin A via ruthenium-promoted intermolecular S N Ar reaction

Using the ruthenium-promoted intermolecular S N Ar reaction, a key building block corresponding to the F-O-G fragment of ristocetin A has been synthesized


Introduction
The vancomycin group of antibiotics has recently generated a significant amount of interest among synthetic chemists, due to both their clinical importance and their challenging molecular architecture.Currently vancomycin and teicoplanin are the only members of this group that are waging a lone battle against methicillin-resistant Staphylococcus aureus infections.However, with rapidly emerging 1 bacterial resistance to these antibiotics, there is a desperate need for stronger antibiotics.Total syntheses of vancomycin 2 and teicoplanin 3 aglycones have already been reported.Ristocetin A 1, a member of the vancomycin group of antibiotics, in addition to having structural features similar to vancomycin, incorporates a 14-membered diaryl ether linkage between amino acid residues F and G.
The construction of the diaryl ether linkage in these types of molecules presents a formidable challenge due to the presence of base-sensitive amino acid residues such as aryl glycine derivatives. 4Studies in our group have focused on the application of a ruthenium-promoted S N Ar reaction to the construction of the diaryl ethers. 5Complexation of ruthenium to the aromatic subunits takes place under very mild conditions and the subsequent etherification occurs without significant epimerization of arylglycines or phenylalanine residues.Demetalation under simple photolytic conditions furnishes the desired diaryl ether, allowing at the same time recycling of the ruthenium complex precursor.We have previously reported synthetic studies toward the BCDF 6 and DEF 7 ring systems of ristocetin A, that employ the ruthenium-promoted S N Ar reaction.In this article, we report the synthesis of the F-O-G acid 2 which will serve as a key building block in our efforts to achieve the total synthesis of ristocetin A.

Results and Discussion
The requisite F and G-ring amino alcohols were synthesized by employing the Sharpless asymmetric aminohydroxylation as a key step.As shown in Scheme 1, 3,5-bis(benzyloxy)-4methylbenzaldehyde 3 8 was converted by Wittig olefination to 3,5-bis(benzyloxy)-4methylstyrene 4 which, when subjected to the Sharpless aminohydroxylation using t-butyl carbamate as a nitrogen source, furnished the desired amino alcohol 5 in 62% yield, with enantioselectivity greater than 99%.The enantiomeric purity was determined by Mosher ester analysis 9 of chromatographically pure 5. Hydrogenolysis under standard conditions gave the desired F-ring phenol 6 in 80% yield.The desired G-ring amino alcohol 8 was synthesized in 63% yield with an enantiomeric purity of 93%, by reacting 3-chloro-4-methoxystyrene 7 10 with t-butyl carbamate under standard Sharpless aminohydroxylation reaction conditions (Scheme 2).The primary alcohol in 7 was protected as a 2-methoxyethoxymethyl (MEM) ether 9 (96%).Treatment of 9 with TFA/CH 2 Cl 2 (1:1) at 0 °C removed the Boc group selectively and subsequent reaction with 2trimethylsilylethyl-p-nitrophenylcarbonate in the presence of triethylamine installed the required amino-protecting group (NHTeoc), orthogonal to the F-ring Boc group, in 88% yield over two steps.It may be noted that direct introduction of NHTeoc group during the aminohydroxylation step was not successful.Refluxing 10 with [CpRu(CH 3 CN) 3 ]PF 6 in 1,2-dichloroethane gave the G-ring ruthenium complex 11 in quantitative yield as a mixture of two diastereomers.The formation of diastereomers is due to introduction of ruthenium on either face of the planar asymmetric molecule and is unimportant because the metal will be removed at a later stage.
As shown in Scheme 3, the F-O-G diaryl ether linkage was installed by the rutheniumpromoted intermolecular S N Ar reaction between the F-ring phenol 6 and G-ring ruthenium complex 11 in the presence of cesium carbonate as base and in DMF solvent.Subsequent photolysis gave the desired F-O-G ether 12 in 33% yield over two steps.Other bases such as sodium hydride and sodium-2,6-di-t-butylphenoxide were also examined but gave similar yields.Further optimization of this reaction is currently being pursued in our laboratory.The phenolic group on the F-ring in 12 was methylated (CH 3 I, n-Bu 4 NI, Cs 2 CO 3 /DMF, 83%) and the resulting alcohol 13 was oxidized in two steps (Dess-Martin oxidation followed by treatment with NaClO 2 /NaH 2 PO 4 , 51%) to give the F-O-G acid 2 as a mixture of diastereomers (>2:1), probably epimeric at the α C-H of the F-ring residue.The epimerization likely occurs at the intermediate aldehyde stage (by nmr), and optimization of this oxidation step is currently in progress.

Conclusions
The ruthenium-mediated intermolecular S N Ar reaction was effectively utilized to synthesize an important building block corresponding to the F-O-G ring system.Future studies involve coupling of the fully functionalized ABCD ring system of ristocetin A with the F-O-G acid 2 and subsequent coupling with the E-ring amino acid, followed by further manipulation to complete the total synthesis of ristocetin A.

Experimental Section
General Procedures.Analytical TLC was performed with aluminium plates precoated with silica gel F 254 (EMerck) and visualized by UV light and/or phosphomolybdic acid or Verghn′s reagent.Flash chromatography was carried out on silica gel (170-400 µ).Melting points were determined using a Thomas Hoover capillary melting point apparatus and are uncorrected.NMR spectra were recorded on a Varian Gemini XL200 (200 MHz, 1 H frequency), Varian Gemini XL300 (300 MHz, 1 H frequency), or Varian INOVA 600 (600 MHz, 1 H frequency) spectrometer at 25 °C, using CDCl 3 or acetone-d 6 or CD 3 CN and referenced to the solvent.Infrared spectra were recorded on a Nicolet Impact 400 FTIR spectrometer.Mass spectra were recorded on a Kratos MS25A instrument.