C 13 -C 14 C CHO. CrCl 2, Ni(COD) 2 4Å mol sieves. NHK reaction. nbuli HN(TMS) 2. aldol reaction

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1 Introduction to Synthesis: Design (E 66) Spring 2015 Problem Set #2 KEY 1. The Evans synthesis of (+)-discodermolide appears in the Ph.D. thesis of David alstead (arvard, 1999). copy of this work is posted on lackboard for your convenience. Key disconnections are shown below a. Draw the key intermediates that are used to prepare sections - then indicate how these intermediates are joined (e.g. how are the -, -, and - 22 bonds formed; one step each). You may abbreviate the structure, but be sure to include all necessary functionality and reaction conditions. If a name reaction is used, include the name. Include relevant carbon numbers throughout. key intermediates n 1 TES TES TES - bond I TES rl 2, i(d) 2 4Å mol sieves K reaction TES - bond TES nuli (TMS) 2 aldol reaction TES

2 - 22 bond TES TES SePh KMDS Wittig reaction TES TES SePh b. Explain how stereochemistry was set for each of the Z olefins (there are 3). e specific. e sure to explain why the process used gives the desired stereochemistry. For the - 22 olefin, also explain why the adjacent double bond was not present in the initial coupling reaction used to form the - 22 bond. - 9 stereochemistry: The olefin stereochemistry is set by partial hydrogenation of the alkyne; the Z olefin results due to the syn addition of hydrogen across the triple bond. - stereochemistry: The olefin stereochemistry is controlled by subjecting the individual diastereomers formed in the aldol reaction to one of two different elimination processes. Though the stereochemistry of each diastereomer is unknown, the required olefin geometry can be obtained by first separating the diastereomers and then subjecting each to the two sets of reaction conditions. The outcome, Z versus E olefin, can be determined by M. In one case, a syn elimination (urgess reagent) will give the desired olefin; in the other an anti elimination (Sl 2 /pyridine) will give the desired olefin. For example, if we assume that the stereochemistry of the two diastereomers is as below it is easy to see how each diastereomer can be converted to the desired olefin geometry. ote that in this intermediate, the desired olefin geometry is E. ' ' urgess reagent Sl 2 pyridine urgess reagent Sl 2 pyridine ' ' ' ' syn elim anti elim syn elim anti elim

3 - 22 stereochemistry: The olefin stereochemistry is set by using the Wittig reaction which is selective for the cis olefin when unstabilized ylides are used. E olefin ' vs. ' Z olefin no terminal alkene when setting - 22 stereochemistry: onjugated Wittig reagents are moderately stabilized. In these cases, Wittig reaction gives poor stereoselectivity. y using a phosphonium salt that constains a gamma selinide, these workers were able to maintain Wittig selectivity while at the same time incorporating functionality that would allow later introduction of the terminal olefin. c. Synthesis of the key fragments relies heavily on the Evans' asymmetric aldol methodology. In an interesting twist, formation of fragment and utilize the β-ketoimide 1 to give the anti-anti (1) and anti-syn (4) products respectively. Syn-syn product (3) are also accessible. While the basis for selectivity using the boron enolate is not well understtod, a clear rationale has been established for the other two. s such, draw transition states that account for the stereoselectivity observed in the formation of compounds 3 and 4. Sn(Tf) 2 Et 3 ; 1 n 4 n anti-syn y 2 l Et 3 ; Til 4 ipr 2 Et; 2 n anti-anti 3 n syn-syn see: Evans J. m. hem. Soc. 1990, 112, 66. syn-syn (3)

4 anti-syn (4) 2. Devise an efficient retrosynthetic sequence for the following compounds. Starting material are provided, but you will need to show key intermediates. Keep selectivity issues in mind. ver each retrosynthetic arrow, please indicate what general transformation(s) e.g. oxidation, reduction, aldol, etc. would be required to carry out the reactions in the forward sense. You do not need to show the forward sequence; you do not need to identify specific reaction conditions. a. 3 Grignard imine formation b. 4 electrophilic aromatic substitution etherification

5 c. 5 intramolecular aldol alkylation; oxidation epoxidation