The stereoselective total synthesis of ()-achaetolide Pallavi Thakur a , Boyapelly Kumaraswamy a,⇑ , Gurram Raji Reddy a , Rakeshwar Bandichhor b,⇑ , Khagga Mukkantii c a Maithili Life Sciences Pvt. Ltd, Plot No. 146 A, Phase-II, IDA, Mallapur, Hyderabad 500 076, India b Innovation Plaza, IPD, R&D, Dr. Reddy’s Laboratories Ltd, Survey Nos. 42, 45, 46, and 54, Bachupally, Qutubullapur, R.R. District 500 073, Andhra Pradesh, India c Institute of Science and Technology, Center for Environmental Science, JNT University, Kukatpally, Hyderabad 500 072, India article info Article history: Received 7 March 2012 Accepted 21 March 2012 Available online 10 May 2012 abstract The stereoselective total synthesis of ()-achaetolide is described in a convergent manner. Grignard addi- tion, Wittig homologation, acetate aldol and ring closing metathesis reactions were the key steps involved. The required olefinic alcohol fragments were synthesized from a single chiral pool material 2-deoxy-D-ribose and olefinic acid fragment was prepared from acetate aldol reaction. Both the olefinic acid and alcohols were prepared in a concise method. Ó 2012 Elsevier Ltd. All rights reserved. 1. Introduction In recent years, 10 membered lactone containing molecules have attracted the attention of both biologists and chemists due to their potent biological activities. 1 These lactones are secondary metabolites mainly biosynthesized by fungi, bacteria (antibiotics) and marine organisms, with only few being produced by plants or insects (pheromones). This family of natural products displays a wide range of biological properties, such as antibacterial and antifungal, phytotoxic activities and the inhibition of cholesterol biosynthesis. 2 A few recently isolated 10-membered macrolides in- clude achaetolide, herbarumins I–III, 3 stagonolides A–I 4 and mod- iolides A and B (Fig. 1). 5 In 1983, Bodo et al. reported the isolation of achaetolide from the culture broth of Achaetomium cri- salliferum. 6 Later on Takada et al. established the stereochemistry of achaetolide from a different species, Ophiobolus sp. 7 Achaetolide is a 10-membered macrolide with four stereocentres (3S,6R,7S,9R), three hydroxyl groups and a trans-olefin functionality. The scarce availability of these natural materials has prompted several syn- thetic chemists to take up their total synthesis for further evalua- tion towards biological screening. 8 Herein we report a practical and stereoselective total synthesis of achaetolide from the chiral precursor 2-deoxy-D-ribose in which C-3 and C-4 stereogenic centres are correlated with the (6S) and (7R) carbon centres of the target molecule. Scheme 1 outlines our retrosynthetic analysis of achaetolide. We envisioned that the target molecule can be obtained from ester 7 with two terminal olefin moieties by a ring closing metathesis followed by deprotection of the acetonide group. Ester 7 in turn can be obtained by the coupling/esterification of acid 8 with dia- stereomeric alcohols 9 and 9a by applying two different protocols. Acid 8 can be obtained from the hydrolysis of compound 10. Imide 10 was prepared by an auxiliary based asymmetric acetate aldol reaction. Alcohols 9 and 9a were synthesized from commercially available deoxy-D-ribose involving a chiral pool approach using selective acetonide protection, a seven-carbon Grignard reaction and a one carbon homologation by selective oxidation and Wittig reactions. 2. Results and discussion We began with the synthesis of compounds 9 and 9a from com- mercially available chiral carbohydrate 2-deoxy-D-ribose. Protec- tion of hydroxyl groups of 2-deoxy-D-ribose 9 with 2,2 dimethoxy propane under PTSA conditions led to product 11. Grignard addi- tion with freshly prepared n-heptyl magnesium bromide gave a diastereomeric mixture 12 and 12a in almost a 1:1 ratio with 92% yield. The diastereomers were separated by flash column chro- matography and used separately in further reactions (Scheme 2). We initially focused on the synthesis of 9 and also the synthesis of C-6 epimer 9a. Compound 12 can be utilized for the synthesis of 9, whereas other isomer 12a can be used for the synthesis of 9a. Thus, 1,5-diol 12 was subjected to oxidative lactonization in the presence of BAIB-EMPO to obtain lactone 13. 10 Reduction of lac- tone 13 to lactol 14 by using DIBAL-H was achieved in 85% yield which upon homologation via 1C-Wittig reaction with methyltri- phenylphosphonium bromide in the presence of potassium tert- butoxide yielded olefin 9 (Scheme 3). After completion of the synthesis of compound 9, we proceeded further with the other diastereomer 12a for the synthesis of 9a, which is the C-6 epimer of 9. Accordingly, compound 12a was sub- jected to a similar sequence of reactions such as 1,5-diol oxidative 0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tetasy.2012.03.010 ⇑ Corresponding authors. Tel.: +91 40 27150243; fax: +91 40 40062330 (B.K.). E-mail addresses: kumarboyapally@gmail.com (B. Kumaraswamy), rakesh- warb@drreddys.com (R. Bandichhor). Tetrahedron: Asymmetry 23 (2012) 547–553 Contents lists available at SciVerse ScienceDirect Tetrahedron: Asymmetry journal homepage: www.elsevier.com/locate/tetasy