A concise enantioselective synthesis of marine macrolide-stagonolide E via organocatalysis Soumen Dey, Arumugam Sudalai ⇑ Chemical Engineering and Process Development Division, CSIR-National Chemical Laboratory, Pashan Road, Pune 411 008, India article info Article history: Received 12 January 2015 Accepted 2 March 2015 Available online 20 March 2015 abstract A short and efficient enantioselective synthesis of marine macrolide stagonolide E in high enantiomeric purity (98% ee and 8.5% overall yield) starting from commercially available raw materials has been achieved. The strategy involves proline catalyzed sequential a-aminooxylation and Horner– Wadsworth–Emmons olefination, highly stereoselective Ando’s cis-olefination, and modified Yamaguchi macrolactonization as the key reaction steps. Ó 2015 Elsevier Ltd. All rights reserved. 1. Introduction Stagonolides 1–4 represent a family of novel 10-membered ring lactone natural products (Fig. 1). 1 Among them stagonolide E 1 is a secondary metabolite of Stagonospora cirsii, a fungal pathogen of the weed Cirsium arvense. It has been isolated from the fungus Curvularia sp. PSU-F22. 2 This family of natural products displays a wide range of pharmacologically interesting properties such as antibacterial, antitumoral, and antifungal, and the inhibition of cholesterol biosynthesis. 3 The low availability of these macrolides coupled with their interesting biological profile continued to attract the attention of synthetic organic chemists worldwide. Three syntheses of stagonolide E 1 have been described, which rely upon Jacobsen’s kinetic resolution, enzymatic catalysis, and chiral pool resources, respectively. 4 Nevertheless, they suffer from cer- tain disadvantages, including the use of chiral building blocks, long reaction sequences and low overall yields. Our continued interest in the use of proline and its derivatives as versatile organocatalysts in the total synthesis of bioactive molecules 5 prompted us to take up the synthesis of stagonolide E 1. 2. Results and discussion The retrosynthetic scheme for the target molecule 1 is pre- sented in Scheme 1. We envisioned that stagonolide E 1 could be obtained from hydroxy-a,b-unsaturated ester 5, then Ando’s cis- Wittig olefination followed by intramolecular Yamaguchi cycliza- tion. The key intermediate 5 can in turn be obtained from aldehyde 6 via a-aminooxylation followed by Horner–Wadsworth–Emmons olefination in a sequential manner, while epoxide 7 can be readily obtained from 1,6-hexanediol 8 by standard sequences of reactions of aldehyde, followed by epoxide formation. Accordingly, the synthesis began with commercially available 1,6-hexanediol 8, which was mono protected as its benzyl ether 9 followed by its oxidation with IBX produced aldehyde 10 in 98% yield. The D-proline catalyzed asymmetric a-aminooxylation 6 of aldehyde 10 gave chiral diol 11, which involved two steps: (i) the reaction of aldehyde 10 with nitrosobenzene in the presence of D-proline as a catalyst in CH 3 CN at À20 °C followed by its treat- ment with NaBH 4 in MeOH at 0 °C to give the crude aminooxy alco- hol in situ; (ii) subsequent reduction of this crude aminooxy alcohol with 30% CuSO 4 in EtOH furnished chiral diol 11 in 60% overall yield and with 98% ee (by chiral HPLC analysis). The selective monotosylation of primary alcohol 11 was then achieved to afford the corresponding tosylate 7 in situ, which upon treatment with K 2 CO 3 in MeOH yielded the terminal chiral epoxide 7 in 70% yield and with 98% ee (by chiral HPLC analysis). The chiral epoxide (À)-7 was subsequently subjected to regioselective reduc- tive ring opening with LiAlH 4 in THF at 0 °C to afford the secondary alcohol 12 as the exclusive product in 98% yield. Alcohol 12 was then protected as its TBS ether 13 (TBSCl, imid.) and the benzyl ether in 13 was subsequently deprotected under hydrogenolysis conditions [10% Pd/C, H 2 (1 atm), EtOAc] to give the primary alco- hol 14 in 96% yield. The IBX oxidation of alcohol 14 in DMSO pro- duced the key intermediate aldehyde 6 in 98% yield. The one-pot sequential asymmetric aminooxylation–HWE olefination 8 reaction of aldehyde 6 was readily carried out by using L-proline as the organocatalyst in CH 3 CN at À20 °C, which resulted in the formation of c-hydroxy-a,b-unsaturated ester 5 in 65% yield and 98% de; 9 [a] D 25 = À13.1 (c 1.8, CHCl 3 ). The chiral secondary alco- hol functionality in 5 was protected as its MOM ether 15 (MOMCl, http://dx.doi.org/10.1016/j.tetasy.2015.03.001 0957-4166/Ó 2015 Elsevier Ltd. All rights reserved. ⇑ Corresponding author. Tel.: +91 20 25902565; fax: +91 20 25902676. E-mail address: a.sudalai@ncl.res.in (A. Sudalai). Tetrahedron: Asymmetry 26 (2015) 344–349 Contents lists available at ScienceDirect Tetrahedron: Asymmetry journal homepage: www.elsevier.com/locate/tetasy