Organic Cumulative Exam October 13, 2016

Transcription

1 rganic Cumulative Exam ctober 3, 206 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. Clearly indicate which questions are to be graded on the front of your answer booklet.. (33 points) The following problems are based on the previously distributed article: "Quantification of the Electrophilicity of Benzyne and Related Intermediates" Garg et al. J. Am. Chem. Soc. 206, 38, (a) What are reactivity parameters E, S, and? Explain the terms and their practical impact. (b) How do the authors go about determining E for arynes? What is the "diffusion-clock method"? (c) Why are arynes more reactive than benzene, alkenes, or alkynes? Explain. (d) What were the ranges of reactivity calculated for arynes? (e) Explain the electrophilicity trend observed in the Figure below. (f) Evaluate the quality of the manuscript. What was(were) the scientific outcome(s) of the publication? How much data was presented? Comment on its timeliness? Context? Do you think this paper "deserves" to be published in JACS? page of

2 2. (33 points) Chemical weapons have been used in conflict over much of the past century, unfortunately. ne of the deadliest is the nerve agent VX, which acts as a potent suicide inhibitor that irreversibly binds covalently to a serine in the active site of the acetylcholine esterase enzyme. Chemical means of decomposing VX and related agents are thus desirable targets of research. Accordingly, Schneider et al. reported a pair of reagents ( and 2) designed to deactivate VX. Et P S Me VX nerve agent Angew. Chem., Int. Ed. 202, 55, R = H a R = Me R H 2 H H a 3 S a 3 S H S 3 a a 3 S a 3 S H S 3 a H H H H H H H H (a) Suggest syntheses for and 2 starting with commercially-available reagents. (b) Explain the H MR spectral behavior of VX in the presence of a (the -methylated derivative of ) as illustrated in the following spectra: Spectrum b (top): VX in the presence of a two-fold excess of a Spectrum a (bottom): pure VX in D 2 /phosphate buffer (c) Mass spectrometric monitoring of VX deactivation mediated by calixarene provides several lines of evidence for intermediate b (although no direct observation was made). Suggest a mechanism for how b arises and what its generation implies about the chemical mechanism of VX deactivation. (d) Given the known biochemistry of VX, explain the likely function of the various structural elements of and 2. a 3 S a 3 S H S 3 a H H (e) Explain the safety precautions you would expect to impose before engaging in this work. Consider all aspects of handling VX: storage, handling, collecting analytical data, and waste disposal. b H H C page 2 of

3 3. Burns and coworkers recently reported an enantioselective synthesis of the brominated sesquiterpene (+)-aplydactone. Angew. Chem., Int. Ed. 206, 55, Ac H Ph H Ph H t-bu 2 t-bu (20 mol%) (-i-pr) 3 TiCl (. eq) BS (. eq), hexanes, 20 C Ac 3 Ac 4 Cl 66%, 4% ee dr > : H steps? K 2 C 3, H 2 (F 3 C) 2 CHH, rt, 2 d 4% ee Cl 7, 64%, dr = 4: DBU, PhMe 70 C, then isoprene (20 eq) Me 2 AlCl (3.5 eq) 78 C to 0 C Ac steps? 6 H Ac 5, 54%, 0% ee dr > : steps? (+)-aplydactone (a) Formulate mechanisms for each of the following transformations that account for all relevant aspects of selectivity (e.g. chemo-, regio-, diastereo-, enantio-selectivity): i. omochlorination of allylic alcohol. ii. Solvolysis of dihaloalkene 4. iii. Formation of spirocycle 7 from β-acetoxyketone 6 and isoprene. (6 points each) (b) Suggest reagents and conditions to achieve the (multistep) conversions of: i. Chlorohydrin 3 to alkyl chloride 4. (3 points) ii. Tertiary alcohol 5 to ketone 6. (3 points) iii. Diels-Alder adduct 7 to (+)-aplydactone. (6 points) (c) Comment on the 'ideality' of the synthesis of (+)-aplydactone. (3 points) page 3 of

4 4. (33 points) Lautens and coworkers recently reported an improvement to the so-called Rautenstrauch rearrangement using Au(I) catalysis. rg. Lett. 206, ASAP, doi: 0.02/acs.orglett.6b005 (a) Propose a mechanism of the Rautenstrauch Rearrangement shown in eq.. (b) Two classic methods for cyclopentenone synthesis are the Pauson Khand reaction (eq. 2) and the azarov cyclization (eq. 3). Show the mechanism for these transformations. Considering that the Pauson Khand and azarov are reliable reactions that have been known for several decades, one may wonder why new methods for cyclopentenone synthesis are being created. (c) Give two general limitations for the Pauson Khand reaction and two general limitations of the azarov reaction. (d) Could the limitations you listed be circumvented by this new Rautenstrauch rearrangement? Why or why not? Rautenstrauch rearrangement: tbu PPh 3 AuTf 2 ( mol%) CH 2 Cl 2, AcH, h () Pauson-Khand reaction: R 2 R + R3 R 2 Co 2 (C) R 8 R 4 (2) R 3 R 4 azarov rearrangement: R R 2 Lewis Acid (3) then H 3 + R R 2 page 4 of

5 5. Recently, Yu et al. isolated a new antifungal macrolide () from an endophytic Streptomyces sp., together with the known compound oxohygrolidin (2). During the structure elucidation process, it was discovered that oxohygrolidin is actually identical to halichomycin and the structure for the latter (previously thought to be 3) was therefore revised. Tetrahedron Lett. 206, 57, new macrolide H 2 H H ' H H H 2 20 oxohygrolidin = revised structure for halichomycin (2) originally proposed erroneous structure for halichomycin (3) H (a) Structure elucidation: i. Attempt to assign proton and carbon MR signals for macrolide using LY the onedimensional H and 3 C MR spectral data (overleaf). Write atom numbers by relevant signals on the spectra to indicate your assignments and label any uncertain assignments with an asterisk ( ). (0 points) ii. ow use the HSQC and HMBC data. Can you confirm/reject any of your earlier assignments? iefly describe your reasoning and add arrows to the structures on the HSQC and HMBC spectra to illustrate the diagnostic correlations. (4 points) iii. What further experiments do you suggest to confirm the relative and absolute stereochemistry of this compound to be published in a chemistry journal? ame at least three and explain each experiment and the information that you can gain. (6 points) iv. Suggest reasons why the structure for halichomycin was originally miss assigned? What other methods for establishing proof of structure can you think of (name three)? (6 points) (b) Biosynthesis: name the biosynthetic pathway used in the production of? (4 points) (c) Macrolides and 2 both belong to the bafilomycin family of compounds; 6-membered lactones with conjugated diene moieties and various bioactivities. Can you think of another type of bioactivity manifested by these compounds in addition to their antifungal action? (HIT: consider the latest obel prizes). (3 points) TE: for parts (a)i/ii, annotate the spectra as indicated, detach the pages, & staple them in answer book page 5 of

6 new macrolide H 2 2 ' H H page 6 of

7 new macrolide H 2 2 ' H H page 7 of

8 H 2 2 ' H H 8 page 8 of

9 H 2 2 ' H H 8 page of