FULL PAPER An Efficient Stereoselective Total Synthesis of Bioactive (3R,5R )-1-(4-Hydroxyphenyl)-7- phenylheptane-3,5-diol via Asymmetric Aldol Reaction by Perla Ramesh*, Atla Raju, and Nitin W. Fadnavis Natural Products Chemistry Division, CSIR-IndianInstitute of Chemical Technology, Tarnaka, Hyderabad-500007, India (phone: þ 91-40-27191631; fax: þ 91-40-27160512; e-mail: perlaramesh@yahoo.co.in) An efficient stereoselective total synthesis of (3R,5R)-1-(4-hydroxyphenyl)-7-phenylheptane-3,5-diol (1) is reported based on the Mukaiyama aldol reaction. The total synthesis of compound 1 was accomplished with 30% overall yield in simple eight steps from commercially available trans-cinnamaldehyde. Introduction. – Diarylheptanoids are an important class of biologically active natural products. They have been shown to display promising biological activities including antioxidant, anticancer, and anti-inflammatory activities [1–7]. One such diarylheptanoid is (3R,5R)-1-(4-hy- droxyphenyl)-7-phenylheptane-3,5-diol (1, Fig. 1), isolated from Alpinia officinarum (Zingiberaceae), which exhibits anti-emetic activity [8 – 10] . Recently, Reddy et al. reported the first total synthesis of 1 using Sharpless kinetic resolution and an asymmetric epoxidation as the key steps from commercially available 4-hydroxybenzaldehyde [11]. This synthetic method suffers from a large number of synthetic steps and a low overall yield. We herein report the total synthesis of 1 through Mukaiyama aldol reaction in simple eight steps with 30% overall yield. Results and Discussion. – The retrosynthetic plan of the target molecule 1 is illustrated in Scheme 1. Compound 1 could be obtained by Grignard reaction and acetonide deprotection followed by Pd/C reduction of primary alcohol 7 . The latter could be derived from 4 by a successive implementation of diastereoselective reduction and aceto- nide protection. d-Hydroxy-b-keto ester 4 can be easily prepared via asymmetric Mukaiyama aldol reaction be- tween Chan(s diene 3 and trans-cinnamaldehyde 2. To begin the synthesis, the commercially available trans-cinnamaldehyde 2 was subjected to the stereoselec- tive Mukaiyama aldol reaction with Chan(s diene 3 in the presence of catalytic amounts of Ti( i PrO) 4 /( S )-BINOL complex (2 mol-%) to furnish aldol product 4 [12][13] in 94% yield with > 97% ee as determined by chiral HPLC [14]. anti-Selective reduction of 4 was performed with Me 4 NBH(AcO) 3 to give the desired anti-diol 5 exclusively, isolated in 80% yield (syn/anti 1:19) [15][16]. The diol was protected as acetonide using 2,2-dimethoxypropane (DMP) and a catalytic amount of PPTS. The relative configuration of acetonide anti-6 was confirmed by 13 C-NMR according to Rychnovsky(s method [17][18]. In the 13 C-NMR spectrum of 6, the C-atoms of the acetonide Me groups were observed at 24.6 and 25.2 ppm and that of the quaternary C-atom at 100.6 ppm, confirming the presence of the anti-acetonide 6 [13] ( Fig. 2). Then, the protected anti-diol ester 6 was reduced to the corresponding primary alcohol by treatment with LiAlH 4 in dry THF at 08 for 30 min. The primary OH group of 7 was reacted with TsCl in the presence of Et 3 N and DMAP (cat.) in CH 2 Cl 2 to obtain crude compound 8, which was Helv. Chim. Acta 2016, 99, 70 – 72 70 DOI: 10.1002/hlca.201500189 # 2016 Verlag Helvetica Chimica Acta AG, Zürich Scheme 1. Retrosynthetic Analysis of Compound 1 Fig. 1. Structure of the diarylheptanoid 1 Fig. 2. Key 13 C-NMR data of compound 6