Studies toward the total synthesis of ristocetin A aglycone using arene-ruthenium complexes as S_NAr substrates: Construction of an advanced tricyclic intermediate

Abstract

Ruthenium-mediated S_NAr reactions are used to construct the diaryl ether linkages in two key intermediates for a projected total synthesis of the aglycone of ristocetin A.

Introduction

Vancomycin (1)¹ has captured the interest of synthetic chemists for a number of years, as a result of its molecular complexity and, perhaps more importantly, the recent emergence of vancomycin resistant strains of infectious bacteria.² Recent increased activity in searching for new antibacterials is expected to lead to solutions to this problem.³

Ristocetin A (2) is structurally related to vancomycin, but possesses different glycoside units, as well as different F and G amino acid residues and an additional ring that is formed by aryl ether bridging between them. Ristocetin, teicoplanin (not shown, but structurally related to ristocetin), and vancomycin are the three most important members of this class of antibiotics, and therefore prime targets for total synthesis efforts. Several total syntheses of vancomycin aglycone have been reported,⁴ and Nicolaou has completed the synthesis of vancomycin itself.⁵ Two independent total syntheses of the teicoplanin aglycone have been reported,⁶ and Boger has completed a total synthesis of ristocetin A aglycone.⁷ While ristocetin A exhibits antibiotic activity similar to vancomycin, its clinical use was discontinued owing to fatalities⁸ that were likely the result of platelet aggregation caused by the antibiotic.⁹ The aglycone of ristocetin has been shown to be a useful lead compound for development of new antibiotics that exhibit activity against vancomycin resistant bacteria.¹⁰

Our approach to the total synthesis of these compounds rests on the ability of a transition metal, coordinated η⁶ to an aromatic ring, to induce nucleophilic attack on the arene. When the aromatic ligand is a halobenzene derivative, most commonly a chloroarene (and therefore readily prepared), the result is nucleophilic substitution. Ruthenium is especially useful for such applications, since it is strongly activating, can be attached to the aromatic moiety without detriment to a wide range of functional side chains (in the present case amino acids), is stable to numerous chemical transformations, and can be removed in a reusable form by non-invasive photochemical methods. This overall process is illustrated schematically in Fig. 1.

Figure 1.

Schematic representation of ruthenium-mediated S_NAr chemistry

Results and Discussion

Following successful model studies,¹¹ we have focused on developing a total synthesis of ristocetin aglycone (3, Scheme 1) that illustrates the compatibility of arene-ruthenium chemistry with complex molecular synthesis. Our strategy was to construct the left hand portion first, as intermediate 4, which would then be coupled to the E-F-O-G intermediate 5, or a similar building block. The coupling product would then be subjected to S_NAr cyclization, demetallation, and further conversion to the target molecule. A previous report has detailed our synthesis of intermediate 4, which also used arene-ruthenium chemistry to construct the aryl ether macrocycle connecting rings C and D.¹²

Scheme 1.

Scheme 2 summarizes our approach to the F-O-G building block 13, which has now been further optimized.¹³ Amine protection as Teoc on the F-ring residue was to be utilized for intermediate 9, to ensure orthogonality with the remaining units. While we have successfully carried out Sharpless aminohydroxylation of the styrene derivative 6 using TeocNH₂ as the carbamate partner, which directly affords the N-Teoc protected amino alcohol,¹⁴ this approach was actually less satisfactory in terms of yield, enantiomeric purity and ease of purification of the product, than the indirect method shown in Scheme 2. Removal of the Boc protecting group (7), followed by Teoc re-protection and chromatographic purification afforded the required material 8 with high e.e. (99%). Hydrogenolysis of the benzyl ethers to give 9, followed by intermolecular etherification using complex 12, then methylation of the remaining phenolic OH afforded the F-O-G building block 13.

Scheme 2.

The S_NAr reaction between 9 and 12 was rather capricious, so we investigated the alternate approach outlined in Scheme 3.¹⁴ The known⁷ benzyloxycarbonyl derivative 17 (95% e.e., prepared as shown) was converted to 18 by hydrogenolysis followed by Teoc protection of the amine. Reaction of 18 with 12 also proved somewhat troublesome, which we tentatively attribute to the sterically congested nature of the chloroareneRuCp complex. After some experimentation, it was found that treatment of 18 with NaH in THF, followed by addition of complex 12 in small portions, then photolytic demetallation, reproducibly afforded 13 in 66% yield over two steps.

Scheme 3.

Building block 13 was used in two approaches to the target molecule (Scheme 5¹⁵), of which the more convergent required coupling of 14, from Teoc deprotection of 13, with complex 19, prepared as described previously.11(a) This coupling afforded 20 in 42% yield (Scheme 4). Jones oxidation of 20 was somewhat problematic, affording the carboxylic acid 5 in variable yield. Direct coupling between 4 and 5afforded intermediate 22 in 33% yield.

Scheme 5.

Scheme 4.

The alternate approach involved coupling of 4 with 15, to afford 21, which was then deprotected and coupled with complex 19 to afford intermediate 22. Given the problematic steps in the construction of 5 and the low yield for its coupling with 4, the less convergent route to 22 via 21 is the preferred one. Cycloetherification of 22, followed by demetallation and TBS protection of the C-ring secondary alcohol afforded the advanced intermediate 23.

In conclusion, we have demonstrated that chloroarene-ruthenium complexes are versatile intermediates for the construction of aryl ether linkages in complex molecular environments. They are easy to prepare, have excellent shelf life, and the organometallic moiety is stable to numerous organic reaction conditions and can be attached to, and disengaged from the arene substrate without detriment to sensitive functionality. Further transformations of 23 are required to afford the aglycone of ristocetin A, and these will be the subject of future work in our laboratory.

Supplementary Data

Experimental procedures and spectroscopic data for all new compounds. The supplementary data is available online with the paper in ScienceDirect, filename: TL XXXXX Supplementary Data.