Organic Cumulative Exam January 26, 2017

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1 rganic Cumulative Exam January 26, 2017 Answer only three the six questions. o more than three question answers will be graded any work not to be considered must be clearly marked as such. Clearly indicate which questions are to be graded on the front your answer booklet. 1. Deprotonation carbonyl compounds bearing a-hydrogen atoms is the most common method for enolate formation. owever, many other methods exist for the formation enolates. Consider the three half reactions below, all involve the formation enolates by non-deprotonative methods. (a) Show the expected product each half reaction. (12 points) (b) In each case, explain the diastereoselectivity using appropriate stereochemical models. (13 points) (c) In addition to those represented below, give four additional non-deprotonative methods for the preparation enolates. (8 points) Br 1. i. BuLi, Et 2, TF, 78 o C ii. CuC, 0 to 78 o C iii. 78 o C Verwal et al. J. rg. Chem. 2010, 75, TMS 2. i. BuLi, Et 2, 0 o C ii. ZnCl 2, Et 2, 78 o C iii. C Si (enantiopure) SPh o C 2. Li, 3 ; I Iwata et al. Chem. Pharm. Bull. 1993, 41, C Li 78 o C to RT Moore et al. J. rg. Chem. 1998, 63, C ClP(Ph) 2 3. Pd(Ph 3 P) 4, Al 3 page 1 7

2 Com Commun 2. Aminoepoxycyclohexanone moieties (AECs, highlighted in blue) are commonly found in bioactive natural products (1-6). Recently, Antes, Sieber co-workers used synthetic AECs I to III) to evaluate the pharmacophore to identify their activity range against Gram negative pathogens. Mode action studies were accomplished by click-chemistry quantitative proteomics to identify new antibacterial protein targets involved in oxidative stress response. Communicat Communications Communications Angew. Chem. Int. Ed. 2016, 55, compound bacteria different st such as S. (MRSA), Interes FM24 inhibited strains, in inhibitory 10 mm. Co pounds w Scheme 1) (up to 300 or reduced for the AEBQs F Figure 1. Figure A) Representative natural products: 1. A) Representative natural p growth (a) Structure Chemistry points) A1 (2), epoxyquinomycin C (3), C cetoniacytone A (4) beloa A1 (2), epoxyquinomycin (3), (9 cetoniacytone S. ente Figure 1. A) Representative natural products: LL-C10037a (1), (6) are membe I/II). Epoxyquinomycin B (5) I/II). Epoxyquinomycin B (5) ar i. What reactive groupschave the natural products 1-6 in common? while(6)the A1 (2), functional epoxyquinomycin (3), A (4) belong to the AEC [4, 8] cetoniacytone III).B B)III). I III aminoepoxycycloh B)(6) type type I IIIthe aminoep epoxid I/II). Epoxyquinomycin (5) aretwo members the AEBQ ii. The authors show that cysteine reacts with AECs. Show possible reaction probes their corresponding benzoquinone controls. probes their III). B) typecorresponding I III ABPP benzoquinone did not affc mechanisms. probes their corresponding benzoquinone controls. displayed Figure A) other Representative natural products: LL-C10037a (1), iii. 1. What biological molecules can you think that could also react with AECs? Figure 1. A) Representative natural products: LL-C1003 totic cells) A1 (2), A1 epoxyquinomycin C (3), cetoniacytone A (4) belong the AEC (2), epoxyquinomycin C (3), cetoniacytone A (4) to belong to the cells at co (b) Biosynthesis (10 points) I/II). B (5) (6) are members theasaebq Epoxyquinomycin I/II). Epoxyquinomycin B (5) (6) are members ure S1). owever, thethe me III). B) type I III ABPP III). B) type I III i. ame the biosynthetic pathway responsible for the production 2. (Figure S2 human cells probes probes their corresponding benzoquinone controls. their corresponding benzoquinone complexcontrols. representative ii. ow is the AEC moiety formed? based on a whole organism. iii. What could be the origin the nitrogen atom in the amide moiety present all legans[9]intolerated high doses AECs? control FM375 (highest test ow question 2 is continued overleaf... ure S1 a period ure five S1). days wit developmental defects. Mor human cells huma larvae eggs was observe page 2 7 complex an comp Scheme 1. Synthesis type I II AECs type III AEBQs.[7] a toxic control, led to growth based on aw Reagents conditions: a) 1. Boc2, TF, 70 8C, 16 h, 99 %; 2. based extensive investigations

3 ... question 2 continued from page 2 (c) Chemical Biology (14 points) The protein targets AECs were identified using an alkyne tag uisgen/sharpless/ldal cycloaddition to rhodamine or biotin azides. i. Show a mechanism for this reaction. ame reasons why this type orthogonal modification is commonly used for protein identification. ii. ow would you perform a protein pull-down experiment? Describe briefly the steps from treating bacteria with an AEC-alkyne probe control probe, to how you would isolate analyze the target protein (name chromatographic spectroscopic techniques). iii. ow can stable isotope labeling help you in your workflow to add information on proteins that are truly interacting with AECs compared to control probes? page 3 7

4 3. Increasingly, multiple substoichiometric additives are being employed to mediate transformations. The term "cooperative catalysis" is ten applied to such reactions; two recent examples are illustrated below. Snaddon et al. J. Am. Chem. Soc. 2016, 138, Ph Ar 1 (1.0 eq) + Ms 2 (1.2 eq) Ph S Ph 2 P Pd PPh 2 3 (20 mol%) 4 (4 mol%) i-pr 2 Et (1.25 eq), TF, rt Ph 5 Ar = Ph: Ar = 4-2 C 6 4 : Ar = C 6 F 5 : 0% Ar 50%, 3% ee 88%, 92% ee Rovis et al. Synthesis 2017, 49, 293. Br 6 (1.0 eq) + Ph CF 3 7 (2.0 eq) BF 4 C 6 F 5 C 6 F 5 8 (20 mol%) 9 (10 mol%) KAc (2.0 eq), cyclohexane, rt P C 6 F 5 variation from illustrated rxn conditions none: leave out 9: ent-9 in place 9: 10 Ph CF 3 68%, 95% ee 53%, 77% ee 64%, 84% ee (a) Formulate detailed mechanisms for each the above transformations. Your answers should indicate the role played by each reaction component identify the step in which enantioselectivity arises. (12 points each) (b) Account for how the yield enantiomeric purity the product is affected as: (i) Ar is changed in the first reaction, (ii) phosphoric acid 9 is varied in the second reaction. (6 points) (c) What do you think the term "cooperative catalysis" actually means? Is the term being used in the same way for each the above reactions? (3 points) page 4 7

5 4. (33 points) As you know, olefin metathesis is a central reaction in modern organic chemistry with applications to both fine chemical commodity chemical synthesis. Gavin et al. report a novel catalyst developed with the specific intention allowing ethenolysis methyl oleate at catalyst loadings approaching as little as 1 ppm. Angew. Chem., Int. Ed. 2017, 56, 98. (a) Explain why methyl oleate might be a target for ethenolysis. (b) The authors focus the paper on use cyclic alkyl aminocarbenes rather than the more usual -heterocyclic carbenes used in more classical Grubbs oveyda catalysts. Detail the impact that this change should have on the following: thermodynamic kinetic acidity the iminium ion precursor during synthesis bonding stability the ruthenium complex reactivity intermediates in the catalytic cycle (c) The authors also change from a more typical benzylidene carbene to the indenylidene shown. What impact should this have on the behavior the catalyst? Bearing in mind the industrial focus this work, are there any other (non-technical) reasons for this change? (d) The process envisions using as much as 1 million metric tons methyl oleate; 1 metric ton = 1000 kg). Explain quantitatively how dropping the catalyst loading from 0.5 mol-per cent (a typical lab-scale loading) to 5 ppm or less would affect process design. (e) The results show that at 10 ppm, the catalyst provided a 69% conversion methyl oleate with 87% selectivity (the remainder being octadecene dimethyl octadecenedioic acid). Calculate the turnover number for the catalyst. page 5 7

6 5. (33 points) Maimone co-workers reported an elegant synthesis (+)-pseudoanisatin late last year. J. Am. Chem. Soc. 2016, 138, (+)-cedrol (1) step(s) K, t-buk DMS, 14 h 4:1 dr 45% yield 2 3 a, TBSCl then aq. Cl 88% 6 step(s) TBS 5 reagent(s) conditions TBS 4 s 4 TMEDA 7 reagent(s) conditions pseudoanisatin (8) (a) Provide a reasonable synthetic sequence for the conversion 1 to 2. You must include actual reagents conditions to receive full credit. (b) Provide a complete mechanism including stereochemical explaination for the conversion 2 into 3. (c) Provide actual reagents conditions for the conversion 4 to 5. ote this reaction is a SIGLE step process. (d) Provide a reasonable synthetic sequence for the conversion 5 to 6. You must include actual reagents conditions to receive full credit. (e) Provide actual reagent(s) conditions for the conversion 7 to 8. This transformation should take no more than two steps. page 6 7

7 6. (33 points) (a) In the figure below,* the computer located local minima for melalide A unsubstituted melalide A are shown. i. Explain what the effect(s) removing the substituents is(are). Why? ii. What is the Thorpe-Ingold effect? What is the origin the Thorpe-Ingold effect? (b) In the figure below,* the computer located local minima for ionomycin with without the calcium ion are shown. What effect(s) does(do) calcium have? Why? *figures taken from Cheong,.-Y. et al. in "Applied Theoretical rganic Chemistry, Ed. Tantillo, D., World Scientific, page 7 7