Stereoselective total synthesis of C2-symmetric natural products pyrenophorol and its derivatives

Abstract A stereoselective total synthesis of 16-membered C2-symmetric macrodiolide Pyrenophorol, Tetrahydropyrenophorol and 4,4-diacetylpyrenophorol have been accomplished. The synthesis started from commercially available L-Aspartic acid and the key reactions involved are regioselective epoxide opening, CBS reduction, Pinnick oxidation and Mitsunobu dilactonization. Graphical Abstract

The broad spectrum of bioactivity and the unique structure has attracted the synthetic chemists and led to its synthesis in different routes (Dommerholl et al. 1991;Machinaga and Kibayashi 1993;Amigoni and Le Floc'h 1997;Yadav et al. 2009;Oh and Kang 2011;Chatterjee et al. 2014;Edukondalu et al. 2015;Risi et al. 2015;Alluraiah et al. 2018;Ashok et al. 2018). As part of our regular research program in synthesis of biologically active molecules (Narsaiah et al. 2015a(Narsaiah et al. , 2015b(Narsaiah et al. , 2016(Narsaiah et al. , 2018, we have carry out the stereoselective total synthesis of Pyrenophorol and its derivatives. The reported methods followed expensive protocols like Grubbs and AD-mix and the resolution protocol involved the loss of one isomer. Our strategy was started from commercially available starting materials and completed with good yield.

Results and discussion
As shown in the retrosynthetic analysis (Scheme 1), the target molecule has been achieved from the monomer of compound 18, which obtained from stereoselective reduction of keto compound 12, and which accomplished from compound 4.
The synthesis started from commercially available of (L)-Aspartic acid (2). Brominative diazotisation of (L)-Aspartic acid using NaNO 2 and KBr followed by reduction of dicarboxylic acid to diol (3) by using BH 3 DMS gave quantitative yield (Shibata et al. 1986;Rabinson and Brimble 2007). Elimination of bromine, one pot intramolecular, base induced epoxide formation insitu, remaining primary alcohol protected as benzyl ether using benzyl bromide NaH to furnish, (R)-epoxide (4) (Frick et al. 1992;Naysmith and Brimble 2013). Regioselective epoxide opening with LiAlH 4 gave secondary alcohol (5) exclusively (Kumar and Reddy 2012), which was protected as TBDPS ether using TBDPS-Cl and TBAI afforded compound (6) 90% in yield. Reductive cleavage of benzyl ether selectively by lithium naphthalene at À40 C led to its primary alcohol (7) in quantitative yield. Free alcohol group converted to tosyl group followed by SN 2 substitution with NaCN in presence of catalytic amount NaI in DMSO at 80 C to furnish cyano compound (9) in 88% yield (Motozaki et al. 2005;Kadam and Sudhakar 2015). Partial reduction of (9) with DIBAL-H at À78 C gave aldehyde (Ishigami et al. 2006), which was subjected to nucleophilic addition with THP protected propargyl alcohol using n-BuLi at À78 C to afford compound (11) in 78% yield (Dagmer and Philip 2010). The obtained secondary hydroxyl group was oxidized with IBX in DMSO and DCM mixture (1:3) gave alkynone in (12) very good yields (Sabitha et al. 2013) (Scheme 2).

Experimental section
See the supplementary material

Conclusion
In conclusion, we have demonstrated a stereoselective total synthesis of Pyrenophorol, Tetrahydropyrenophorol and diacetylpyrenophorols. The starting material used for synthesis is commercially available (L)-Aspartic acid. The important reactions involved are regioselective epoxide opening, CBS reduction, Pinnick oxidation and Mitsunobu macrolactanization. All the reactions were very clean and good yields and the final products were good agreement with naturally isolated products.