Organic Cumulative Exam February 22, 2018

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1 rganic Cumulative Exam February 22, 2018 Answer only three of the five questions. o more than three question answers will be graded and any work not to be considered must be clearly marked as such. early indicate which questions are to be graded on the front of your answer booklet. 1. (33 points) A formal synthesis of ( )-cephalotaxine was recently published by Zhang and coworkers. The synthesis is shown below. rg. Lett. doi: /acs.orglett.7b LiHMDS, THF A 2. Pd(dba) 2 (5 mol%) ligand (12.5 mol%) THF, rt B ligand: tbu CF 3 P(p-CF 3 -Ph) 2 >85% yield, 93% ee Pd 2, Cu 2 C MeH KH D Pd/C, H 2 MeH E PhI(Ac) 2 KH F DMF, H 2 reflux MeC 2 H MeH C 19 H 23 6 F 3 C CF 3 DMS G DMS 110 C H Me known H H Me H, 80% ee ( )-cephalotaxine Show the mechanism for the transformation of A to B. Give the structure of intermediates C through G. (c) Although B was produced with high ee, the final intermediate H was isolated in only 80% ee. How did this loss in ee occur (show a mechanism). (d) Propose a synthesis of starting material A (Hanaoka s ketone). page 1 of 5

2 2. (33 points) Agostic interactions are weak interactions (less than a full covalent bond) between metal centers and atoms in an organic ligand. While the term is normally considered as an aspect of transition metal chemistry, a recent report of a highly unusual structure for an organolithium compound claimed such an interaction. synthesis: Etienne et al. Angew. Chem, Int. Ed., 2018, 57, The authors note one very rare structural feature for the lithium atom: identify it. (HIT: what is the structure about Li in methyllithium?) The second unusual feature is the close contact between lithium and the β-carbons in the cyclopropyl group; they label this an agostic interaction. n what basis do you think they made this assignment? If there were no such interaction, what would you expect to see? (c) ne significant question is whether this interaction is an artifact of the solid state structure, and if this structure persists in solution. 1 H DSY structure: left: XRD; right, calculated DFT PBE0/def2TZVP. Italicized numbers are computed J CC values in Hz. experiments in C 6 D 6 suggest a formula weight in solution of 470 ± 47 g/mol. What do you conclude? Is this fully definitive of the solution structure? (d) Most agostic interactions are with C-H bonds and can be detected by unusual J CH values. The J CH for the β position is 156 Hz. n the other hand, the computed J CC values differ significantly in the ring. Which atom (C or H) most likely interacts with the lithium? Provide a bonding model to account for your answer. (e) What role (if any) does the TMS goup play in either stabilizing the C-Li bond or in contributing to the agostic interaction? page 2 of 5

3 3. Recently, Merck researchers shed light on the longstanding debate around the absolute configuration of (+)-frondosin B (1). They replicated previous total syntheses and verified that Trauner s group made 1, but showed that the inverted optical rotation is due to a minor impurity (R,R)-10 (~7%). The impurity was isolated and its structure assigned as indicated. Joyce et al. Chem. Sci. 2018, 9, 415. UV, ECD, VCD, and IR spectra were measured and computed for various intermediates of the frondosin B synthesis. Explain briefly each technique and draw example spectra. (12 points) The optical rotation of the Trauner product hinted towards an inversion of the stereogenic center; however, the Merck group shows that the penultimate gemdimethylation step produces an unpredicted minor impurity (~7%) with strong chiroptical properties. Provide reasons why the Trauner group could have missed the impurity. (6 points) (c) ame three experiments you can perform to verify the absolute configuration of 1 or that can confirm inversion. (6 points) (d) Why were MR spectroscopy, optical rotation ([a] D ), and mass spectrometry measurements alone not enough to verify the purity of frondosin B? (4 points) (e) Why was MacMillan s 2010 synthesis crucial to enable the Merck study? (1 point) (f) The impurity (R,R)-10 was isolated by the Merck team using preparative supercritical chromatography on a chiral stationary phase. Its structure was elucidated by various techniques. What differences in MR experiments would you expect between (R)-8 and (R,R)-10? (4 points) page 3 of 5

4 4. Prof. oah Burns gave a seminar at SU on the topic of reagent-controlled interhalogenation of alkenes and derivatization of vicinal dihalides for target synthesis. The bromochlorination reaction shown below is representative of the interhalogenation chemistry developed by Burns et al. (18 points) J. Am. Chem. Soc. 2015, 135, Ph H H Ph = ligand H ligand (20 mol%) BS, Ti(iPr) 3 H hexanes, 20 C %, 90% ee i. Draw all distinct isomeric products that could arise from dihalogenation of trans-2- butene, cyclohexene, and (E)-2-phenyl-2-butene, with 2 and then do the same for. Comment on the isomeric relationship between the products in each case. ii. What aspects of selectivity are involved in the conversion of 1 to 2. iii. Provide a detailed mechanism for the conversion of 1 to 2 that accounts for ALL aspects of selectivity evident in the reaction. Catalytic enantioselective bromochlorination was used in total syntheses of the chamigrene-type sesquiterpenes ( )-dactylone and (+)-aplydactone. (15 points) Burns et al. Angew. Chem., Int. Ed. 2016, 55, H steps? Ac mechanism? H Ac geraniol (3) 4 K 2 C 3, H 2 (F 3 C) 2 CHH 5 3 steps (+)-aplydactone (8) hv (350 nm) 98% structure? ( )-dactylone (7) C 15 H 21 (c) Me 2 Al Mg, Ti 4 THF, CH 2 2 Se 2 ; (d) IBX 6 i. Give reagents and conditions for the multistep conversion of geraniol (3) to 4. ii. Formulate a mechanism for the transformation of 4 to 5 and account for the stereochemical outcome of the reaction. iii. Provide the structure of ( )-dactylone (7). page 4 of 5

5 5. (33 points) The following questions have to do with polyacenes, such as pentacenes. A relevant publication is: Houk et al. J. Am. Chem. Soc., 2007, 129, pentacene (c) (d) You work for industry, and your job is to develop a new organic dye. Your company currently owns several patents regarding substituted pentacenes. The CE of your company wants you to use pentacenes to develop new organic dyes that exhibit a wide range of colors for printing purposes. Can pentacene be used to create different color dyes? Explain your reasoning. ote: This is not an open-ended question there is a clear right answer and reasoning. Larger polyacenes develop diradical characters, which are distinctly unexpected when one compares to the smaller counterparts. Explain what is driving this behavior. Pentacene dimerizes readily under a variety of conditions. What is the structure of the most stable dimer? What is the first step in the mechanism? Explain the origins of regioselectivity of the first step. Long polyacene units are of great interest to the development of molecular electronics. ame the phenomenon that occurs in the limit of infinite polyacenes. Explain why this occurs. page 5 of 5