Organic Cumulative Exam October 15, 2015

Answer only three of the six questions. No more than three question answers will be graded and any work not to be considered must be marked as such. Clearly indicate which questions are to be graded on the front of your answer booklet.

1. (33 points) Sherburn, Paddon–Row, and co-workers recently disclosed a synthesis of pseudopterosin aglycones. The synthetic route is shown schematically below. Nature Chem. 2015, 7, 82–86.

A. Give the structure of intermediates A – H (be sure to indicate stereochem). B. Show how the starting material (SM) could be prepared as a single enantiomer. C. Two steps used high pressure (19 kbar). Explain why high pressure was successful in promoting these particular transformations (be specific). D. Show the curved arrow mechanism for the transformation F ! G.#

Ni(dppp)Cl2 Ph3P, THF MeOH –20 oC 19 kbar, CH2Cl2 A B CO Et O Me OHC 2 CHO S BrMg (C10H14) SM O O

RhCl(Ph3P)3 (2.5 mol%) nPrCN, 119 oC DIBAL (1 equiv.); 19 kbar, CH2Cl2 C D E F then: NO2 Ph3P (C17H26O2)

tBuOK, THF, KHMDS, THF (COCl)2, DMSO o H then H O, –78 oC, then: Et3N, CH2Cl2, –78 C OH 2 G H then: O O O TsN (C H O ) OH Ph 20 30 2

pseudopterosin G aglycone 2. (33 points) (a) Please provide a complete mechanism for the following transformation recently reported by Seidel and co-workers. J. Org. Chem. 2015, 80, 9628-9640.

O Ph AcOH PhMe N 52% NO2 NH H 9:1 dr 4 Å MS O2N 1 2 reflux, 1 h 3 Ph

(b) Seidel reported the application of this method for a short synthesis of (–)-protoemetinol. Provide a complete ASYMMETRIC synthetic pathway for its construction from the building blocks provided below.

O MeO

MeO 5 N NO2 MeO NH Me H MeO OH 7 4 OH 6 OH (-)-protoemetinol (8)

(c) Interestingly, the authors discovered that alteration of the reaction conditions led to a different product 9. Provide a complete mechanism for its formation.

NO H 2 O Ph 2-Et-hexanoic acid Ph xylenes NO2 NH N 2 reflux, 1 h 1 9 (slow addition)

3. (33 points) Humpf and co-workers recently isolated and characterized fujikurins A-D, fungal metabolites synthesized by a previously silent gene cluster in Fusarium. J. Nat Prod. 2015, 78, 1809-1815 O O

O OH

Fujikurin D

(a) Gene cluster PKS19 is responsible for the production of these molecules.

• What does PKS stand for? • Name common building blocks, enzyme domains, and chemical reactions that are involved the biosynthesis of PKS-derived natural products.

(b) Starting with a linear precursor still attached to PKS19, how can fujikurin D be formed?

(c) NMR structure elucidation of fujikurin D turned out to be difficult, as four dynamic isomers were found in equilibrium in the NMR tube.

• Draw the four isomers. • Name an NMR experiment that can help with identifying the isomers? • What method would you use to learn more about the equilibrium?

(d) High-resolution mass spectrometric fragmentation experiments were used to further support – the structure of fujikurin D (C12H17O4; m/z [M-H] 225.1133). Negative ionization and stepwise fragmentation (MS2) yielded four major fragments with m/z = 125.0611; 137.0975; 181.0872; 141.0561. • Suggest structures for the four fragment ions.

4. Nicewicz and coworkers recently reported a regioselective oxidative amination of arenes of broad applicability that utilizes acridinium salt 3 as a photoredox catalyst. A representative example of the reaction is shown below. Nicewicz et al. Science 2015, 349, 1326.

3 (5 mol%) Mes – BF4

MeO MeO N t-Bu N t-Bu N + NH Ph + N N N MeO 1(1 eq) 2 (1.25 eq) N O TEMPO + 455 nm light (20 mol%) 4p, 79% 4o, 9% (blue LEDs) DCE, 20 h, O2, 33 °C

(a) How is the introduction of nitrogen to benzene derivatives typically achieved? (be specific, give at least two examples). List some potential advantages and disadvantages of the above chemistry as compared to more traditional approaches. (7 points)

(b) Formulate a detailed mechanism for the reaction that accounts for the following facts: • the reaction does not occur in the absence of light or acridinium salt 3 • TEMPO is not an essential additive, but its presence boosts yield by >20% • amination occurs preferentially para to electron donating groups (e.g., OMe), meta products are not observed

• other nitrogen nucleophiles can be used including PhNH2 and ammonia equivalents (e.g., + – NH4 NH2CO2 ) (15 points)

(c) For each of the following three polyfunctional molecules, comment on whether or not you would expect successful addition of pyrazole (2) under the reaction conditions shown above. If so, predict the site of amination, and if not, explain what side-reactions are likely to thwart the transformation. (7 points)

Et N AcO H OMe HO N MeO O MeO O MeO N

(d) There is a great deal of current interest in photoredox catalysis in the synthetic organic chemistry community. Give a specific example of another reaction process involving photoredox catalysis from the recent literature. (4 points) 5. (a) Orthoquinone methide (oQM) is a very common intermediate in total synthesis, synthetic methodology, and biosynthesis, and can be prepared with relative ease in mild conditions. In stark contrast, the aza-orthoquinone methide (aoQM) is remarkably rare – in fact, an example published by Corey and coworkers is one of two examples that features a room temperature transformation involving aoQM. It turns out that the aoQM is remarkably unstable compared to the oQM, and this is the reason why aoQM is so hard to prepare and use. Why is the aoQM so unstable compared to the oQM? (10 points) Angew. Chem. Int. Ed. 1999, 38, 1928.

Cl Base

OH ∆G << 0 O

Cl Base ∆G >> 0 NHBoc NBoc

(b) Draw the most stable conformation of the following molecule. Explain why it adopts that geometry. (9 points) J. Am. Chem. Soc. 1967, 96, 4186. Me Me N N N N Me Me

(c) The two protons indicated in the following molecule have differing C-H bond lengths. Which one is longer? Why? (6 points) J. Am. Chem. Soc. 1967, 89, 3761.

H N

H

(d) Why does the aldehyde C–H have a distinctly different IR frequency than the alkene C–H? Explain. (8 points)

R R O C C R H R H -1 -1 νC–H = 2730 cm νC–H = 3050 cm

6. (33 points) Radialenes are a topologically interesting class of molecules defined by an internal ring where each carbon is part of an exocyclic double bond. These have presented synthetic challenges in large part due to their high reactivity. A synthesis and computational study of [5]- radialene was reported recently (McKay, E. G. et al., J. Am. Chem. Soc., 2015, 137, ASAP, http://pubs.acs.org/doi/ipdf/10.1021/jacs.5b07445). (Both intermediates A and B can be advanced via similar approaches.) Intermediate F was converted to a bis-Fe(CO)3 complex (not shown) and characterized by X-ray crystallography.

A. Provide appropriate reagents (1-6) for each step of the synthesis shown above.

B. [5]-radialene is observable in the final reaction mixture at -78°C, but a 30 μM solution had a half-life of 16 minutes at -20°C. State the characterization techniques you expect the authors to have used (including complete prediction for what they should have seen). Explain whether a reviewer should accept the evidence you predict as being compelling and convincing.

C. You should remember that the simple Huckel MO picture for the cyclopropenyl system is as shown below

Construct a qualitative HMO digram for the pi system of [3]- radialene. (Hint: use symmetry-adapted linear combinations of p orbitals interacting with a cyclopropenyl core.)

D. Based on the results of (C), make a qualitative prediction about the nature of the frontier MOs for [5]-radialene.

E. What are likely reaction modes for decomposition of [5]-radialene? How would you test your hypothesis/hypotheses, either experimentally or computationally?