Asymmetric total synthesis of antiviral agents (+)-sattazolin and (+)-sattabacin

The concise enantioselective total synthesis of antiviral agents (+)-sattazolin and (+)-sattabacin are described in six steps. This synthetic strategy started from commercially available isovaleraldehyde and the key reactions involved in this synthesis are Sharpless epoxidation, phenyl Grignard, Eu(III) catalyzed ring opening of chiral epoxide with indole.


Introduction
The potent antiviral (herpes simplex virus) acyloin natural products namely sattazolin and sattabacin were isolated from soil bacteria Bacillus sp., by Satta et al. with ID 50 values of 1.5 µg/mL and 3 µg/mL respectively 1 .The sattazolin selectively inhibits protein synthesis in Herpes virus-infected cells.The antiviral activity of sattabacin against VZV infections in human fibroblast cells, the median inhibitory concentrations (ID 50 ) of both acyclovir and penciclovir have showed to 3 and 4 µg/mL respectively.The ID 50 value of sattabacin 12 µg/mL against VZV infections 2 indicates the sattabacin is more effective than other antiviral compounds.

Figure 1
Miller et al. reported the first asymmetric total synthesis of the sattabacin and sattazolin in three and seven overall steps respectively. 3,4Their structural similarity, no complexity and interesting biological activity of both the natural products drove us to their total synthesis.

Results and Discussion
Retrosynthetic analysis is shown in scheme 1, the sattazolin (1) and sattabacin (2) could be obtained from common intermediate 7 via Eu (III) catalyzed ring opening with indole and regioselective ring opening with phenyl Grignard.The common intermediate 7 could be derived from compound 5 through oxidation followed by keto protection, compound 5 could be constructed from compound 3 by using vinyl Grignard and Sharpless epoxidation.
Total synthesis of sattazolin and sattabacin started from commercially available isovaleraldehyde (3), which was treated with vinyl magnesium bromide to give racemic allylic alcohol 4 in 88% yield. 10 The Sharpless epoxidation of allylic alcohol 4 was conducted at -20 o C in CH 2 Cl 2 using Ti(O i Pr) 4 , t-butyl hydroperoxide (TBHP) and diisopropyl-D-tartrate.After 4h, the chiral epoxide 5 with the desired epoxide configuration could be isolated in good yield 11,12 after separation from the remaining (S)-4 alcohol resulting from the kinetic resolution which occurred.
The hydroxy group in compound 5 was oxidized with Dess-Martin periodinane (DMP) and NaHCO 3 in CH 2 Cl 2 to afford compound 6 in 70% yield. 13,14The keto group in compound 6 was protected as an acetal by the use of trimethylorthoformate 15 in benzene at reflux for 5 h to afford compound 7 in 73% yield.This protected compound 7 was used as common intermediate for both the target compounds.It has already been reported 4 that the direct opening of epoxy ketone 6 with indole in presence of Lewis acid (Yb(OTf) 3 ) did not allow to furnish compound 1.To overcome this we have protected the epoxy ketone as dimethylacetal 7.Then, 7 was reacted with indole in refluxing DCE and in the presence of Eu(OTf) 3 as catalyst for 3h.We were then pleased to isolate the target compound sattazolin (1) in 74% yield.
Further we have synthesized sattabacin (2), from the common intermediate acetal 7. The latter was treated with freshly prepared phenyl magnesium bromide 16,17 and CuI in THF at -78 o C to -30 o C for 1 h.The acetal deprotection was achieved after treatment with 4N HCl in THF at room temperature for 30 min to give sattabacin (2) in good yields 18,19 as shown in the Scheme 2. Compared to the earlier reports, we synthesized our target molecules in fewer steps with appreciable yields and resolved the difficulties in the synthesis of sattazolin to our best.We also confirmed the enantiomeric excess of sattabacin and sattazolin as 84.5% by performing chiral HPLC.The spectral data of our target compounds sattazolin and sattabacin were matched with spectral data and optical rotation of the natural products.
In summary, we have accomplished the enantioselective total synthesis of the antiviral agents sattazolin and sattabacin in 6 overall steps.The key features of the developed synthetic strategy are Sharpless epoxidation for fixing the chiral center via kinetic resolution of allylic alcohol, and the target compounds 1 and 2 were obtained from common intermediate 7 respectively by Eu(III) catalyzed ring opening with indole, regioselective ring opening with phenyl Grignard in high yields.

Experimental Section
General.All reagents were purchased from commercial sources and were used without additional purification.All reactions were performed under an inert atmosphere unless otherwise noted.THF was freshly distilled over Na/benzophenone ketyl.Hexane refers to the fraction boiling in the 60-80 °C range.Column chromatography was performed on silica gel (Acme grade 60-120 mesh).All reactions were monitored by TLC to completion; TLC plates (Merck precoated silica gel 60 F 254 plates) were made visible with UV light, in an I 2 chamber or with phosphomolybdic acid spray.Melting points were recorded using a Buchi M-560 melting point apparatus and are uncorrected.IR spectra were recorded on a Perkin-Elmer FT-IR 240-c spectrophotometer. 1 H NMR spectra were recorded on Bruker-400 MHz, spectrometer in CDCl 3 and using TMS as internal standard, 13 C NMR spectras were recorded on Bruker-100 MHz.Mass spectra were recorded on a Finnigan MAT 1020 mass spectrometer operating at 70 eV.Optical rotations were measured on Rudolph Autopol IV polarimeter at 25 °C.