Asymmetric Total Synthesis of Stagonolide F

Abstract A highly convergent stereoselective total synthesis of stagonolide F is described starting from commercially available 5-hexen 1-ol using asymmetric dihydroxylation, Jacobsen's hydrolytic kinetic resolution (HKR), regioselective epoxide ring opening with vinyl Grignard reaction, esterification, and ring-closing metathesis (RCM) as key steps. GRAPHICAL ABSTRACT


INTRODUCTION
Naturally occurring macrolides have shown to possess significant biological activities. [1,2] Because of their scarcity, synthetic chemists are attracted to their total synthesis. Stagonolide F (1) is a 10-membered macrolide isolated from Stagonospora cirsii, a fungal pathogen obained from Cirsium arvense, which exhibited potent antifungal, antibacterial, and cytotoxic activities. [3] The structural features combined with interesting biological profiles attracted us to carry out the total synthesis of 1 (Fig. 1). Herein, we report the total synthesis of stagonolide F. To the best of our knowledge, there are two reports in the literature on the synthesis of stagonolid F. [3] Considering the structure as well as its activity and in continuation of our interest on the synthesis of biologically active natural products, [4][5][6] we herewith report an efficient alternative approach for the stereoselective synthesis of 1 from commercially available 5-hexen 1-ol 3 using Sharpless asymmetric dihydroxylation, Jacobsen's hydrolytic kinetic resolution (HKR), regioselective epoxide ring opening, and ring-closing metathesis (RCM) as key steps.
The retrosynthetic analysis of stagonolide F (1) is outlined in Scheme 1. The target molecule 1 can be obtained by RCM and esterfication reactions (Scheme 2), which are used widely in the synthesis of macrolides. The esterfication can be performed by coupling of acid 10 and alcohol 11. The intermediate 10 can be easily prepared from commercially available 5-hexen 1-ol (3). In the present strategy, two stereogenic centers are constructed, one by Sharpless asymmetric dihydroxylation for (5S)-hydroxy, and the second (9S)-hydroxy is introduced by a vinyl Grignard reaction.

RESULTS AND DISCUSSION
As outlined in Scheme 3, intermediate 10 was prepared from 5-hexen 1-ol (3), which was protected with TBSCl to give compound 4 in 93% yield and the asymmetric dihydroxylation of the terminal olefine in 4 with AD-mix-a at 0 C Scheme 1. Retrosynthetic analysis.

SYNTHESIS OF STAGONOLIDE F 2887
furnished compound 5, in 89% yield. [7] The latter was subjected to mono-tosylation in the presence of a catalytic amount of Bu 2 SnO to give the mono-tosylated compound followed by subsequent exposure to K 2 CO 3 to afford epoxide 6 in 92% yield. [7c] Regioselective opening of epoxide 6 with trimethylsulfonium iodide in the presence of n-BuLi as a base in tetrahydrofuran (THF) at À20 C yielded the alcohol 7 in 81% yield. [8] The secondary alcohol obtained, which was protected with methoxy methyl chloride (MOM-Cl) using N,N-diisopropylethylamine (DIPEA) to obtain compound 8 in 91% yield followed by the deprotection of tert-butyl dimethylsilyl group in 8 to afford primary alcohol 9 in 94% yield, which was oxidized with [bis (acetoxy)-iodo] benzene (BAIB) to give an acid 10 in 88% yield. [9] The synthesis of olefinic chiral alcohol 12 was prepared from propylene oxide, following the reported procedure. [10] The intermediate acid 10 was esterified with chiral alcohol 12 in the presence of N,N 0 -dicyclohexylcarbodiimide (DCC) and dimethylaminopyridine (DMAP) at 0 C to obtain the bis-olefine ester 13 in 80% yield. The ester was subjected to ring-closure metathesis (RCM) by using Grubbs's first-generation catalyst, but we could not get the required product. [11] Gratifyingly, the desired product 14 was obtained by using Grubbs's second-generation catalyst (Fig. 2) in 65% yield.
The deprotection of the MOM group under the different condition using CF 3 COOH=CH 2 Cl 2 , 3 N HCl=CH 2 Cl 2 , and pyridinium p-toluenesulfonate (PPTS) in refluxing n-BuOH led to mixture of products; however, the reaction was carried out with success in dimethyl sulfide using Et 2 O=BF 3 Á OEt 2 [12] at À10 C to provide the natural product stagonolide F (1) in 52% yield, and the spectral data of synthetic stagonolide F (1) are identical with those of the natural product. [2b] CONCLUSION In summary, we have described a new stereoselective total synthesis of stagonolide F. Key features of the synthesis are an asymmetric dihydroxylation, regioselective epoxide ring opening, Jacobsen's hydrolytic kinetic resolution (HKR), and Grubbs-catalyzed ring-closing metathesis. The synthesis of stagonolide F was achieved with a short linear sequence in 10 steps with overall yield of 11.29%.

EXPERIMENTAL
All solvents and reagents were of reagent grade and used without further purification unless otherwise stated. Crude products were purified by column chromatography using silica gel (60-120 mesh). Technical-grade EtOAc and hexane used for column chromatography were distilled before use. FTIR spectra were recorded on Thermo Nicolet Nexus 670 spectrometer, neat or as thin film in KBr optics, in cm À1 . Optical rotations measured on Horiba high-sensitivity polarimeter, in 10-mm cell. 1 H and 13 C NMR spectra were recorded in CDCl 3 solvent on a Varian Gemini 500 and Brucker Avance 300 instruments at 300 and 75 MHz, respectively. Chemical shifts were reported in parts per million (d) with respect to TMS as internal standard. Coupling constants (J) are quoted in hertz. Mass spectra were acquired on a Micro mass Quattro micro TM API (Waters) and high-resolution mass spectra were acquired on a QSTARXL Hybrid MS=MS system (applied Biosystems US) mass spectrometer in m=z.