# Asymmetric Total Synthesis of Ieodomycin B
## 2 Results  
On the basis of the above considerations, we utilized the 1,3-asymmetrically inductive Mukaiyama aldol reaction in the total synthesis of ieodomycin B. Therefore, we performed our retrosynthetic analysis based on this strategy, as depicted in Scheme 2. We envisioned retrosynthetically that the target molecule ieodomycin B could be prepared from the intermediate **1**, which is suitable for disconnection from the protected aldehyde **3** and silyl enol ether **2** via the 1,3-inductive Mukaiyama aldol reaction. We noticed that **1** has _trans_ configuration. Considering that the chelation-controlled step and deprotection are simple, we decided to protect the hydroxyl in **1** using PMB, in accordance with the studies of [PERSON] et al. [12; 13]. The total synthesis was mainly focused on the formation of the precursor **3**. We propose that **3** can be obtained through a few conversion steps from **4**, which can be prepared by a Crimmins-modified Evans aldol reaction of aldehyde **5**. Compound **5** could be easily prepared from geraniol. The detailed synthetic route for **5** starting from commercially available geraniol followed procedures described in our previous report [10]. As shown in Scheme 3, geraniol underwent Swern oxidation, regioselective epoxidation of the isolated double bond using \(m\)-CPBA, and subsequent Wittig olefination with Ph\({}_{3}\)P=CH\({}_{2}\) to the stable epoxide **8**. Using HIO\({}_{4}\), we cleaved the resulting epoxide to afford the low-boiling-point **5**, which we then immediately subjected to the Crimmins-modified Evans aldol reaction after aborative manipulation. With **5** in hand, secondary alcohol **4** could be obtained by using a Crimmins-modified Evans aldol addition with the acetylthiazolidine thione **9**. In the presence of TiCl4 and (i-Pr)2 NET (DIPEA), titanium enolate generated from **9** reacted with **5**, forming the predominant desired isomer **4** in excellent yield [8]. As described above, we initially attempted to protect the hydroxyl in **4** using the PMB group under certain conditions, but we could not obtain the desired compound **10**. Therefore, we proceeded to convert **4** to a Weinreb amide and then protected it. Direct amidation of **4** with MoCNHMe*HCl catalyzed by imidazole yielded Weinreb amide **11**. Subsequent treatment of the latter with PMBBr in the presence of NaH afforded the PMB ether **12** in a 67% yield (Scheme 4). Subsequently, **12** was reduced with DIBAL-H at \(-78\)\({}^{\circ}\)C for 1 h to produce the Mukaiyama aldol precursor aldehyde fragment **3** in about a 61% yield. With aldehyde **3** in hand, our next objective was to construct the 1,3-_trans_ diol unit. We retrosynthetically devised a Mukaiyama aldol reaction induced by a chiral PMB ether in C-5 to selectively construct the C-3 chiral hydroxyl. In our previous study, we found that the mixed titanium species Ti(O\({}^{\prime}\)Pr)2 Cl2 can effectively induce a chelation-controlled Mukaiyama aldol reaction between the \(\beta\)-alkoxy aldehyde and silyl enol ether, affording the 1,3-_trans_ diol in high yield and with high diastereoselectivity. Meanwhile, common Lewis acids such as BF3\(\bullet\)OEt2, SnCl4, TiCl4, and MgBr2\(\bullet\)OEt2 afforded 1,3-_trans_ diol in a low to moderate yield. Thus, we used Ti(O\({}^{\prime}\)Pr)2 Cl2 in the key Mukaiyama aldol condensation. Considering the possibility of obtaining leodomycin A and the simplicity of the lactonization, we first attempted to use the ((1-methoxyvinyl)oxy)trimethylsilane **2a** as the nucleophilic reagent for reaction with **3**, but failed. We could hardly obtain the related silyl enol ether of methyl acetate upon treatment of methyl acetate with lithium diisopropylamide (LDA) and trimethyl chlorosilane (TMSCl). Believing that the ester group effects the reaction, we switched the methyl to the benzyl group and thus obtained the desired silyl enol ether **2b**[14].