Adventures in Synthesis, or, Formic Acid is my Friend

1. Adventures in Synthesis, or, Formic Acid is my Friend David E. Lewis Department of Chemistry University of Wisconsin - Eau Claire Gustavus Adolphus College, April 8, 2005

2. Lewis Research Group Members contributing to this talk Graduates 2004

3. The Big Picture What got us started?

4. Flowers that are beautiful • Aconitum spp. — monkshoods (wolfsbane) • Ornamental species; late-flowering. • Beautiful blue or purple flowers resembling the hood of a monk’s habit (hence the name) • Delphinium spp. — larkspurs • Native to western USA • Beautiful blue flowers with a long “spur” resembling the foot of a lark (hence the name) • Many ornamental cultivars available

5. …but deadly • Aconitum spp. • – A. napellus one of the most toxic plants known • Delphinium spp. • – Responsible for cattle losses worth tens of millions of dollars annually in western states of United States • All parts of both species are toxic • – Occasionally responsible for poisoning by ingestion of honey (even the nectar and pollen contain the toxic compounds!)

6. ...., lurida terribiles miscent aconita novercae, Ovid, Metamorphoses, Book I, 144-150. huius in exitium miscet Medea, quod olim attulerat secum Scythicis aconiton ab orbis. .....quae quia nascuntur dura vivacia caute, agrestes aconitavocant. ..... Ovid, Metamorphoses, Book VII, 406-420. ..., nec miseros fallunt aconita legentis, Virgil, Georgics, Book II, 152. ....constat omnium venenorum ocissimum esse aconitum.... Pliny, Natural History, Book XXVII, II. That from the Echydnaean monster's jaws Deriv'd its origin, and this the cause. Thro' a dark cave a craggy passage lies, To ours, ascending from the nether skies; Thro' which, by strength of hand, Alcides drew Chain'd Cerberus, who lagg'd, and restive grew, With his blear'd eyes our brighter day to view. Thrice he repeated his enormous yell, With which he scares the ghosts, and startles Hell; At last outragious (tho' compell'd to yield) He sheds his foam in fury on the field,- Which, with its own, and rankness of the ground, Produc'd a weed, by sorcerers renown'd, The strongest constitution to confound; Call'd Aconite, because it can unlock All bars, and force its passage thro' a rock. — John Dryden’s translation of Ovid, VII, 404-420 An evil reputation since antiquity…

7. The aconitane skeleton The carbon skeleton has six rings: A, B, C, D, E and F aconitine: the defining toxin

8. The synthetic challenge: Bridged rings • The hexacyclic carbon skeleton of these molecules has: • 2 bridged-ring carbocyclic systems based on 5- and 6-membered rings • 2 bridged-ring heterocyclic systems based on 5- and 6-membered rings

9. The synthetic challenge: Fused rings • The hexacyclic carbon skeleton of these molecules has: • 3 fused-ring carbocyclic systems based on 5- and 6-membered rings • 1 fused-ring heterocyclic system ( a cis-perhydroquinoline) • 1 spirocyclic ring system

10. The synthetic challenge • These molecules are densely functionalized • In aconitine, only 8 of the 19 skeletal carbon atoms do not carry a functional group; in cardopetaline (the simplest member of this class), 5 of 19 skeletal carbons still carry a functional group • These molecules are densely populated with stereocenters • In cardiopetaline, only 7 of 19 skeletal carbons are not chiral centers (fortunately, all are not independent; in fact 9 chiral centers are fixed by the carbon skeleton)

11. Our focus • the “southern hemisphere” The spirocycic A/F ring system The heterocyclic ring

12. Retrosynthetic analysis of target

13. The first key intermediate The aldehyde group must be present in protected form capable of surviving a number of different reactions, but capable of being revealed at a later stage of the synthesis. An aryl group is the most logical precursor in light of our preliminary results.

14. Preparing the starting compounds:the Fossé reaction • Reaction succeeds when X = OH, OMe, NR2 Fossé, R. Compt. rend.1907, 145, 1290-1293; 1908, 146, 1039-1042, 1277-1280; Bull. Soc. Chim. France1909, 3, 1075; Ann. chim. phys.1910, 18, 400-432, 503-530, 531-569.

15. But… • Reaction fails when X = H • benzhydrol returns only starting material

16. A Partial Solution: Benzhydrylation of Active Methylene Compounds R1 = R2 = Me 73% R1 = Me; R2 = OEt 61% R1 = R2 = OEt trace R1, R2 = OCMe2O 29%* Gullickson, G.C.; Lewis, D.E. Aust. J. Chem. 2003, 56, 385-388. [Bowie Festschrift]

17. There are limitations… triphenylmethanol always returns triphenylmethane Aust. J. Chem. 2003, 56, 385-388.

18. …and unexpected results This Ritter reaction is highly reproducible, and highly chemoselective Aust. J. Chem. 2003, 56, 385-388.

19. Ritter reactions by solvolysis of benzhydrol in formic acid Gullickson, G.C.; Lewis, D.E. Synthesis, 2003, 681-684.

20. which may lead to a useful application… • only bornyl compounds are obtained: no isobornyl compounds are isolated • bornylamides are racemic • bornyl formate is a liquid, b. ≈50°C near 1 mm Hg • the bornylamides are solids, m. >100°C. • the products are easily separated by vacuum distillation Glen C. Gullickson, Joel D. Lischefski, Paul J. Erdman

21. Mechanism… By using a chiral nitrile, we may be able to obtain both amides optically pure

22. An alternative approach to the targetUse an aldol addition to build the system…

23. Aldol additions using amide dianions anti isomer obtained stereochemically pure from crude reaction mixture by direct crystallization. Typical recovery of unreacted propionanilide: 10-30%. Gullickson, G.C.; Khan, M.A.; Baughman, R.G.; Walters, J.A. Lewis, D.E. Synthesis, accepted for publication.

24. Stereochemistry assigned by single crystal X-ray structure analysis Baughman, R.G.; Gullickson, G.C.; Khan, M.A.; Lewis, D.E. Acta Crystallogr. C, submitted for publication; manuscript under revision.

25. anti Aldols from dilithiated propionanilidea aIsolated yields of purified anti isomer. Values in parentheses are isolated yields of crystalline material prior to recrystallization. bStructures of these compounds have been determined by single crystal X-ray structure analysis.

26. What’s happening here? • product ratio is largely insensitive to: • temperature • solvent • length of reaction • effects of other metal ions • zinc • 2 eq. ZnCl2 reverses stereochemical preference to approximately 70:30 syn. • 1 eq. ZnCl2 yields exclusively anti, but only in low yield. • magnesium • reaction fails when MgCl2 is added

27. Enolate stereochemistry

28. Rationalization of reaction stereochemistry • rapid equilibrium between aldols • slower equilibrium involving acetal dianion Z-azaenolate Z-enolate O-nucleophile

29. Cyclization of -hydroxyanilides R = C6H5 10%* R = p-MeOC6H5 33% R = -C10H7 69% *single run; not optimized • permits early incorporation of heterocyclic ring • reaction tolerates even sensitive functional groups • cinnamyl group does not lead to polymerization R = C6H5CH=CH 52% R = p-MeOC6H4 79% R = -C10H7 75 % R = -C10H7 40% E:Z ≈ 3:2 Glen C. Gullickson, Jessica A. Walters

30. The reaction has its limitations Similarly… Glen C. Gullickson, Jessica A. Walters

31. Attempts at an alternative approach to closing the A-ring

32. Attempted spirocyclization by reductive alkylation Joseph M. Schaefer, Paul J. Erdman

33. What’s happening? A putative answer…

34. How might we overcome the problem? …the plan…

35. …the reality… Erdman, P.J.; Gosse, J.L.; Jacobson, J.A.; Lewis, D.E. Synth. Commun.2004, 34, 1141-1149.

36. Have we tried anything about the “northern hemisphere”?

37. Retrosynthetic analysis of the “northern hemisphere”

38. Synthesis of the nortricyclane synthon: the norbornane pathway Joel D. Lischefski

39. Possible reaction pathways with base Base-Promoted Fragmentation Homoconjugate Addition

40. What actually happened? Joel D. Lischefski

41. Why the observed regiochemistry of cyclopropane cleavage? Calculations at the AM1 level predict an overwhelming preference for the endo bridged norbornane ring system. H°f = – 63.3 kcal/mole H°f = – 75.1 kcal/mole

42. Side benefit: a “green” synthesis sequence experiment for the organic laboratory Lischefski, J.D.; Lewis, D.E. J. Chem. Educ. accepted for publication

43. Attempted Grignard synthesis of allyl carbinols

44. This problem is not new… • formation of “biallyl” observed as a major problem by 1920’s • Gilman developed the method for preparing allylmagnesium bromide in the 1940’s • 3-fold excess of magnesium • slow addition of allyl bromide to magnesium • temperature control: temperature kept below 15°C throughout addition.

45. Our solution… • return to original method: the Barbier-Grignard addition • involves adding a solution containing both halide and carbonyl compound to magnesium in ether • traditionally, equimolar amounts of halide and carbonyl compound are used. • our modification: use 1 eq. excess of magnesium and allyl bromide

46. Barbier-Grignard addition of allylmagnesium bromide Sormunen, G.J.; Lewis, D.E. Synth. Commun.2004, 34, 3473-3480.

47. Some observations • a full equivalent excess of allyl bromide and magnesium is not needed • the aqueous quench after the addition gives copious quantities of gas • the minimum amount of allyl bromide and magnesium is under active investigation

48. And now for something completely different… An organic chemist’s adventures with fluorescence …with apologies to Monty Python

49. Fluorescent Tröger’s bases R = n-Bu 57% R = n-C6H13 74% R = n-C8H18 66% • Deprez, N.R.; McNitt, K.A.; Petersen, M.E.; Brown, R.G.; Lewis, D.E. Tetrahedron Lett.2005, 46, 2149-2153.

50. Fluorescence Microscopy • high selectivity for the target molecule or organelle. • resistant enough to photochemical degradation under normal illumination conditions to permit the target cell feature to be visualized conveniently. • preferably sufficiently non-toxic to allow live cells to be used for the experiment. • highly fluorescent (i.e. it should have a high quantum yield for fluorescence), so that only small amounts of the dye are needed to visualize the cell target of interest. • large Stokes shift to minimize problems from light scattering by the cell • preferably easy to make from readily available, inexpensive starting materials, and chemically stable to permit long-term storage.