Answer 3 out of the following 6 questions.

Answer 3 out of the following 6 questions.

. J. Chem. Theory Comput. 205,, 4054 4063. (DI: 0.02/acs.jctc.5b00359) A. What is DLP-CCSD(T)? What does DLP stand for? Why is DLP-CCSD(T) faster than CCSD(T)? Just how much faster is it? B. The paper discusses basis set effects, particularly errors stemming from basis set truncation explicitly. What is a basis set? Why is basis set truncation a problem in quantum chemistry? Describe one way the authors deal with it in this publication. C. ow is the accuracy of DLP-CCSD(T) evaluated in the paper? ow accurate do they conclude it to be? D. Why is the advent of DLP-CCSD(T) important? There is no shortage of new theoretical methods in the chemistry literature why is this one special? E. There is a major assumption throughout this publication what is it?

2. Benzynes, and analogous reactive intermediates containing formal six-membered cycloalkynes, are highly electrophilic and trap a wide variety of nucleophiles. Two recent papers highlight the versatility of such reactions using both traditional (elimination, Garg et al.) and non-traditional (hexadehydro-diels-alder reaction, oye et al.) methods to access the cycloalkynes. oye et al. J. Am. Chem. Soc. 206, 38, 438. Garg et al. J. Am. Chem. Soc. 206, 38, 4948. Et 3 Si Tf Me IPh Me 2 C 2 CsF TF, 60 C CsF TF, 60 C 3 (a) Devise a (multistep) synthesis of from 4-oxotetrahydropyran. (b) Formulate a mechanism for the transformation of to 2. What product would you anticipate being formed from essentially the same reaction if the silyl and triflate groups in were transposed? (c) Reaction of with CsF in the presence of the illustrated iodonium ylide gives fused heterocycle 3. Give a mechanism and attempt to explain the regioselectivity. PhSC 3 4-C 6 4 C C 8 7 7 5 Ph, 75 C Ph, 75 C 4 6 SPh + (d) Show how a sequence of two pericyclic reactions gives 5 from 4 and furan. (e) Reaction of 4 with thioanisole in the presence of 4-chlorobenzaldehyde generates benzene derivative 6 and compound 7. Formulate a mechanism to account for the formation of 6 and in doing so identify the structure of 7. (9 points)

3) 33Pts. Colibactins are microbial natural products predicted from genome mining of the human gut microbiota. Recently, Balskus, Crawford, and erzon have explored the structure, biosynthesis, and cytotoxicity of colibactin precursors (precolibactins). at. Prod. Rep. 205, 32, 534; ature Chem. 205, 7, 4; JACS 206, DI:0.02/jacs.6b02276 A) Philosophy 6pts uman microbiota is important for our health status. What roles can human associated bacteria play? What functions can you envision for small molecules produced and released by human gut microbiota? B) Biosynthesis 2pts The colibactin class of compounds is made by a hybrid RPS-PKS gene cluster. What does the abbreviation RPS and PKS stand for? ame building blocks that are commonly used by RPS enzymes. ow is the thiazole ring formed? ame building blocks that are commonly used by PKS enzymes. ame all enzymes involved in the biosynthesis of the C3 fatty acid chain derived from the PKS module. C) Structure elucidation 8pts A Knoevenagel condensation is suggested for the colibactin warhead formation. Show the mechanism to form the colibactin warhead starting with enzyme bound intermediate (right)? D) Bioactivity 7pts The colibactins are potent genotoxic (DA targeting) molecules. The pre-colibactins are cleavage with a peptidase to release the active colibactin warhead. DA acts as nucleophile. Show two positions in the colibactin structure prone to undergo nucleophilic attack and show the mechanism for DA binding. ame three different assays to test colibactin activity as DA binder and cytotoxic reagent. 2 Carrier Protein S R

4. (33 points) The following sequence of reactions was applied to a series of -naphthols to provide high yields of the target ring system. A. From the spectroscopic data for Compounds 2 and 3, deduce the structure of each. 2: RMS (M-) - : 26.277 IR: 3497, 2959, 389, 233, 826, 766, 72 cm -. MR (400 Mz, CD 3): 3 C MR (00 Mz, CD 3).33, 6, d, J = 6.8 z 23.9 26.84 49.8 3.0,, sept, J = 6.8 z 34. 27.5 53.2 5.60,, s.7 28.3 6.95,, dd, J = 7.3,.0 z 20.9 28.6 7.25,, dd, J = 6.8,.0 z 2.3 29.0 7.32-7.5, 6, m 24.8 35.7 7.53,, d, J = 7.8 z 26.76 36.5 7.89,, d, J = 7.8 z 26.82 4.2 3: RMS (M+) + : 245.3 IR: 3042, 2957, 456, 427, 84, 772, 606 cm -. MR (400 Mz, CD 3): 3 C MR (00 Mz, CD 3).36, 6, d, J = 6.4 z 24.2 27.9 3.05,, sept, J = 6.4 z 34.5 30.0 7.23,, d, J = 6.4 z 9.55 32.7 7.62,, d, J = 8.0 z 9.62 37. 7.64,, d, J = 4.0 z 9.8 37.2 7.66,, d, J = 4.0 z 2.3 37.3 7.82, 2, d, J = 8.0 z 25.9 39.7 7.85,, s 26. 48.7 7.88,, d, J = 6.8 z 26.5 7.93,, d, J = 6.8 z 27.8 B. There is a likely error in how the data for compound 3 is reported; identify this. C. Provide a mechanism for each step in this process. D. The final product 3 is observed in high regioselectivity. Explain this, based on your mechanism in (C). Ref: Yamaguchi, M. et al., J. rg. Chem., 206, ASAP, DI: 0.02/acs.joc.6b00553

5. Recently,Trushkovandcoworkersreportedaninterestingarene:to:areneconversion offuranstoindoles(rg.%lett.%206,&asap;%doi:0.02/acs.orglett.6b00805). i. Theauthorsreportthatfurfuralcanbeconvertedtocompound.Give conditionsforthistransformation. ii. Compoundisconvertedto2usingtheconditionsshown.Givethemechanism forthistransformationshowingallintermediatesthatareformed. iii. ThefirstsentenceoftheTrushkovpaperstates, Theincreasinguseofbiomass asarenewablesourceofrawmaterialsisoneoftheimperativesofmodern industrialorganicchemistryduetotherestrictedsupplyoffossilresources. Whataboutthereactionshownrelatestotheutilizationofbiomass? iv. furfural Aninterestingaspectofthese arene:to:arene transformationsisthedifferent aromaticstabilizationenergyofthearomaticsystems. a. Givethearomaticstabilizationenergiesofpyrrole(kcal/mol). b. Rankthearenesshowninthebottomrowintermsofleastaromatic stabilizationtomostaromaticstabilization.explainyourranking. c. owwouldyouexperimentallytestyouranswerinpartsaandbabove?be suretoindicatewhatmodelcompoundsorreactionsyouareusingasa comparison. C steps Me Ts Me. mcpba, C 2 2 0 o C, h 2. 0% TFA, RT, 20 h Me Ts 2 Me pyrrole pyrazole imidazole,2,4-triazole,2,3-triazole tetrazole

6. Recently Burns and co-workers reported the efficient synthesis of (-)-danicalipin (6) (JACS 206, 38, 550-558). B B 5 C 7 R 4 R = ) I, 2,6-lutidine 74% 2) Cy Cy Compound A C 6 26 B 2 LiC 2 Zn 2 a (aq) Br ( ) 4 TBS Me 4 2 Br MeC 87% : (4:5) Compound B C 7 27 B 2 2 Compound E C 27 50 5 D 2 Si t-buli, 2; MgBr 2 Et 2 then add B 24% (from A) CD 3 D then concentrate Compound C C 33 60 B 3 3 Si n-buli; TFAA; then add 3 75% Compound D C 27 5 5 2 Si 6 R = S 3 + 5 C 7 Br ( ) 4 5 TBS I 2 3 TBS C (a) Please provide the complete structure include stereochemistry for compounds A-D. (b) Provide a complete mechansim for the reaction of I with compound - including an explaination of any regio-and/or stereoselectivity in the reaction. (c) Provide a reasonable mechanism to explain the conversion of compound B into compound C. (d) Provide a reasonable model to explain the stereochemistry in the conversion of compound C into compound D. (e) Explain the role of the CD 3 D step in the subsequent reaction of compound E with Me 4 2 Br. Include what you think would happen if the CD 3 D step was omitted.