1. 1 Professor M. Wills CH3B0 Understanding Organic Synthesis Year 3 Understanding Organic Synthesis Course 2009-2010; Professor Martin Wills Contents of the course: Introductory lecture describing the contents of the course. Pericyclic reactions and Woodward-Hoffmann rules for concerted cycloadditions, electrocyclisations and sigmatropic rearrangements. FMO theory. Baldwin's rules and related cyclisation reactions. Stereoelectronic effects: How such effects can be moderated to the advantage of the synthetic chemist. Additional reading: Clayden et al.; “Organic Chemistry” by Clayden, Greeves, Warren and Wothers, OUP, 2001. R. B. Woodward and R. Hoffmann in Angew. Chem., Int Edn. Engl., 1969, 8, 781. “Molecular Orbitals and Organic Chemical Reactions”, Ian Fleming, Wiley, 2009 (new edition). Note: Since not all the material is in the handout, it is essential to attend ALL the lectures.

2. 2 Introduction: Unexpected results of cyclisation reactions. Pericyclic reactions are; “Any concerted reaction in which bonds are formed or broken in a cyclic transitions state”. (electrons move around in a circle). i.e. there is a single transition state from start to finish, in contrast to a stepwise reaction. Properties of pericyclic reactions: (a) Little, if any, solvent effect (b) No nucleophiles or electrophiles involved. (c ) Not generally catalysed by Lewis acids. (d) Highly stereospecific. (e) Often photochemically promoted.

3. 3 Examples of pericyclic reactions: 1)Electrocyclisation reactions – Linear conjugated polyene converted into a cyclic product in one step. The mechanism is not particularly surprising, but the stereochemistry changes depending on whether heat or irradiation (typically UV-light) is used to promote the reaction. e.g. 2) Cycloaddition reactions – Two linear conjugated polyenes converted onto a cyclic product in one step. Again, the stereochemistry of the reaction is remarkably reproducible. e.g.

4. 4 Examples of pericyclic reactions, continued: Example of a cycloaddition to give a 6-membered ring: 3) Sigmatropic rearrangement reactions: These involve a concerted migration of atoms or of groups of atoms. E.g. migration of a  -bond. The numbering refers to the number of atoms in the transition state on either side of where bonds are made or broken.

5. 5 Examples of pericyclic reactions, continued: 3) Sigmatropic rearrangement reactions: A high level of stereochemical control is often observed. Other concerted reactions: a)Ene reaction (synthetic chemists), or Norrish rearrangement (photochemists) or McLafferty rearrangement (for mass spectrometrists). b)Decarboxylation reaction:

6. 6 Woodward-Hoffmann theory for prediction of the stereochemistry of pericyclic reactions: Electrocyclisations. The ‘Woodward-Hoffmann’ theory explains the stereochemical outcome of pericyclic reactions by considering the symmetry of the ‘frontier orbitals’ which are involved in the reaction. These are the orbitals which actually contribute to the bond making and breaking process. They are also the ‘outermost’ orbitals (of highest energy) in a structure, hence the term ‘frontier’. Electrocyclisations. Consider the conversion of butadiene into cyclobutene: The mechanism is quite simple, but the stereochemistry of the product is directly related to (i) the stereochemistry of the starting material and (ii) whether heat or irradiation is employed to promote the reaction.

7. 7 What is happening in the cyclisation is that p-orbitals (which form the  -bonds) are combining in order for a new  bond to be formed between the ‘ends’ of the conjugated system. However, in order for this process to happen efficiently, it is necessary for the orbitals with the same wave-function sign (phase) to ‘join up’. In order to work out where these are, a quick analysis of the four molecular orbitals (formed from the 4 atomic – p – orbitals) is required. Woodward-Hoffmann theory applied to cyclobutene formation. Note: ‘n’ atomic orbitals, when combined, result in the formation of ‘n’ molecular orbitals. Low-energy orbitals are generally bonding and high energy ones are antibonding. Because the lower orbitals are filled in the butadiene system, the molecule is stable.

8. 8 Woodward-Hoffmann theory applied to cyclobutene formation. So it is now possible to see what happens when butadiene is converted to cyclobutene. In order for the new sigma bond to be formed between the newly-connected carbon atoms, the ends of the molecule have to ‘rotate’ in a very specific way for this to happen. We only need to consider the highest-energy molecular orbital (highest occupied molecular orbital, or HOMO): The result is that the ‘X’ groups end up trans to each other, as do the ‘Y’ groups. Because this involves a concerted rotation of each end of the diene in the same direction (clockwise is illustrated, although anticlockwise would give same result) this is referred to as a ‘conrotatory’ process. It is also referred to as ‘antarafacial’ because the orbitals which link up have identical signs on opposite faces of the diene.

9. 9 Woodward-Hoffmann theory applied to cyclobutene formation under photochemical conditions. Under photochemical conditions, the orbitals are not changed in structure, but an electron is excited by one level. As a result, a new ‘highest occupied molecular orbital’ or HOMO, is defined. The photochemically-excited molecules, whilst not as numerous, are of much higher energy than the unexcited molecules, and dominate the resulting chemistry. Now (see the next page), the manner in which the molecule changes shape upon cyclisation is very different.

10. 10 Cyclisation under photochemical conditions: In the new HOMO, the ‘ends’ of the orbitals with the same sign are on the same face of the diene, or ‘suprafacial’. In order for these to ‘join up’ to form a bond, the ends of the alkene have to rotate in opposite directions. This process is described as ‘disrotation’. i.e., A suprafacial, disrotation process. n.b. Note that the hybridisation of the carbon atoms at the ends of the diene changes from sp 2 to sp 3 in the process.

11. 11 Woodward-Hoffmann theory applied to cyclobutene formation – conclusion: It is now possible to understand all the stereochemical observations for the butadiene cyclisations which were described at the start of the section: Note how antara/conrotation go together, as do supra/disrotation. Logical really. Note, also, that the rules also work in the reverse direction, e.g. Although it should be noted that sometimes stereocontrol is lost due to competing radical reactions.

12. 12 Woodward-Hoffmann theory applied to cyclohexene formation: Now that you can see how the theory applies to butadiene, try working out the stereochemical outcome of a triene electrocyclisation, the mechanism of which is given below: The mechanism, of course, will be the same whether heat or photochemically-induced. The difference will be in the observed stereochemistry of the products. Hopefully you will appreciate that the central alkene needs to be ‘Z’ configuration in order for the process to work. Why not revise E and Z notation to be on the safe side? In order to solve the problem, you need to be able to write down the possible molecular orbitals available to the  -system of the molecule, put them in order and fill them with electrons. Hint; as the energy of the orbital increases, so does the number of nodes. We shall work through the solution to this in a lecture. Then you should try the same for a tetraene and pentene. Can you see a pattern?

13. 13 Synthetic applications of electrocyclisation reactions: The conversion of ergosterol to vitamin D2 proceeds through a ring-opening (reverse) electrocyclisation to give provitamin D2, which then undergoes a second rearrangement (a [1,7]- sigmatropic shift). Stereochemical control in the sigmatropic shift process will be described in a later section of this course.

14. 14 Synthetic applications of electrocyclisation reactions: A spectacular example of the power of electrocyclisation reactions is in the biosynthesis of endiandric acids, which are marine natural products. All of these are derived from the linear polyene shown below: The double-bond stereochemistry is critical.

15. 15 Synthetic applications of electrocyclisation reactions: The endiandric acids are biosynthesised through the following process: The first two steps are electrocyclisations, whilst the final step, to make acid A, is a cyclo- addition (Diels-Alder reaction). There will be more discussion of cycloadditions later in this course. The stereochemical control in the first two steps is addressed in the next slide.

16. 16 Step 1: Step 2: Note: the product is racemic.

17. 17 K. C. Nicolaou’s research group achieved a direct synthesis of endiandric acid A in the laboratory. This was achieved by the reduction of the two alkyne groups in the molecule below by Lindlar catalyst (cis- alkenes are formed selectively) which then formed the product upon heating in toluene. A pretty impressive ‘one-pot’ cyclisation.

18. 18 Electrocyclisation reactions of cations and anions also follow the Woodward-Hoffmann rules. All you need to know is the number of electrons involved (i.e. 4n or 4n+2) and whether the reaction is photochemical or thermal: The reaction above is the Nazarov cyclisation (usually carried out under acidic/thermal conditions). Note that the position adjacent to the ketone is a mixture of isomers in each case. Only the relative stereochemistry between the lower hydrogens is controlled. Mechanism:

19. 19 Nazarov cyclisation, cont.... Note: although drawn as a localised cation, the positive charge is spread over five atoms through a delocalised  system of p-orbitals. There are a total of 4 electrons in the  system (i.e. two in each alkene), hence it is a 4n electron system, and obeys the rules as usual.

20. 20 Woodward-Hoffmann theory for prediction of the stereochemistry of pericyclic reactions: Cycloaddition reactions. In cycloaddition reactions, the situation is slightly different because a) two molecules are used and b) electron flow takes place from the highest occupied molecular orbital (HOMO) of one molecule to the lowest unoccupied molecular orbital (LUMO) of the other. The stereochemistry therefore follows from the wavefunction signs of the orbitals on each molecule. Consider the reaction of a butadiene with an alkene (the Diels-Alder reaction): More details of the Diels-Alder reaction.

21. 21 This is because the electron- withdrawing group reduces the LUMO energy and improves the overlap with the orbitals in the diene – more information later in course.

22. 22

23. 23 All these observations can be explained by considering the orbitals involved in the reactions: In this Diels-Alder reaction the reagents approach each other in a ‘face to face’ manner, i.e. so that the p- orbitals of the  -system can combine with each other. The relevant orbitals are shown below:

24. 24 Woodward-Hoffmann theory for prediction of the stereochemistry of pericyclic reactions: Cycloaddition reactions. So the following combinations can be employed in the suprafacial cycloaddition reaction: In both cases, phases of the wavefunctions on the orbitals are matched so that the reagents can approach each other in a face to face manner and also form bonds easily. In practice, it is usually the combination of diene HOMO with alkene LUMO which leads to the product, rather than the diene LUMO and alkene HOMO. Electron-withdrawing groups on the alkene lower its LUMO energy and improve the matching to the diene HOMO. In turn this increases the reaction rate. Hence, electron-withdrawing groups on an alkene generally increase the reaction rate, often very significantly. As might be predicted, electron-donating groups on the diene also improve the rate – by pushing its HOMO energy closer to that of the alkene LUMO (see next slide).

25. 25 Diels-Alder reaction: energetics: More closely-matched orbitals give a greater energetic benefit when combined. Hence the closely related butadiene HOMO and alkene LUMO represent the favoured combination. When electron-withdrawing groups are present on the alkene, the benefit is even greater because the HOMO/LUMO levels are even closer. Lewis acids speed it even further. The Diels-Alder reaction proceeds in a suprafacial manner, i.e. the reagents add together in a perfectly-matched face-to-face fashion. Please note: the terms ‘dis- and conrotation do not apply to cycloadditions.

26. 26 Woodward-Hoffmann theory for prediction of the stereochemistry of cycloaddition reactions: If you examine [2+2] and [4+4] cycloadditions, you will find that the combination of a HOMO and a LUMO results in an antarafacial component. Often, as a result, the reactions simply fail under thermal conditions, although they might well succeed using photochemical methods.

27. 27 Woodward-Hoffmann theory for prediction of the stereochemistry of cycloaddition reactions: summary of the rules: No. electrons 4n 4n+2 Thermal Antarafacial Suprafacial Photochemical Suprafacial Antarafacial Ring size 4,8,12… 6,10,14… Note…the rules also work in reverse: Although you might also get competing radical reactions:

28. 28 [2+2] cycloadditions involving ketenes; an exception to the Woodward- Hoffmann rules. This is an important exception to the Woodward-Hoffmann rules which normally insist that [2+2] additions proceed in a (not very favourable) antarafacial manner. The trick here is that the ketene uses both the C=C and C=O p-orbitals in the reaction, through a ‘twisted’ transition state. How would you make a ketene? n.b useful for beta-lactam synthesis: Some examples of Diels-Alder reactions will be given at this stage

29. 29 Endo selectivity in the Diels-Alder reaction. (see next slide)

30. 30

31. 31 Make sure you can draw the transition state for the following process: Intramolecular Diels-Alder reactions are very powerful methods for constructing target molecules (try the one below): These reactions are often catalysed by Lewis acids (see section on the orbitals involved in Diels- Alder reactions.

32. 32 Application of the Diels-Alder reaction to Taxol synthesis. Taxol is a potent anti- cancer compound How might you be able to construct the substrate?

33. 33 Further applications of Diels-Alder reactions: Alkaloid synthesis:

34. 34 Hetero Diels-Alder reactions can be useful too: Three component Cycloadditions: 3-body collision Is unlikely.

35. 35 1,3-Dipolar cycloaddition reactions A similar cycloaddition of nitrile oxides provides a method for the synthesis of 3-hydroxy ketones, all these reactions involve 4n+2 electrons and are suprafacial: The cycloaddition of nitrones to alkenes (below) is a 6-electron process which proceeds in a suprafacial manner. The cycloaddition product can be reductively opened, thus providing a stereoselective method for the synthesis of 1,3-aminoalcohols.

36. 36 The Ene reaction; a type of cycloaddition The ene reaction involves a cycloaddition between two alkenes, but with the formation of only a single C-C bond. A C-H bond is also formed in the process: Orbital picture:

37. 37 Menthol is prepared through an ene reaction: The reaction below uses a mild Lewis acid. The chirality of the product comes entirely from the single chiral centre of the starting material. Note that the lone pair on the carbonyl oxygen is available for participation in this cyclisation. This process allows menthol to be made more efficiently than through extraction from natural sources. How would you make the starting material?

38. 38 This time the rules will be given first, then the examples: Woodward-Hoffmann theory for prediction of the stereochemistry of pericyclic reactions: Sigmatropic reactions. No. electrons 4n 4n+2 Thermal Antarafacial Suprafacial Photochemical Suprafacial Antarafacial Ring size 4,8,12… 6,10,14…

39. 39 Sigmatropic [1,5]-reactions proceed suprafacially under thermal conditions

40. 40

41. 41 The isomerisation of cyclopentadienes involves a very rapid sigmatropic [1,5]-reactions (try taking an NMR spectrum of one) [1,7] sigmatropic rearrangements involves an antarafacial component if carried out thermally. Because the ring is quite large, this sometimes works smoothly. Remember the vitamin D 2 synthesis? The rules make this a (4n) antarafacial reaction But the molecule is flexible enough to allow it. In general, sigmatropic rearrangements: Under thermal conditions: 4n electrons; antarafacial. 4n+2 electrons: suprafacial.

42. 42 Sigmatropic [3,3]-reactions proceed suprafacially and are of great synthetic utility:

43. 43 Sigmatropic [3,3]-reactions proceed suprafacially and are of great synthetic utility:

44. 44 Sigmatropic [3,3]-reactions – COPE rearrangement applications Cope rearrangements are often limited due to the reversibility of the reaction. However the reaction can be made irreversible by release of strain:

45. 45 Sigmatropic [3,3]-reactions – CLAISEN rearrangement applications Claisen reactions are generally irreversible and synthetically useful: n.b. Don’t get confused with the Claisen reactions of esters.

46. 46 Sigmatropic [3,3]-reactions – CLAISEN rearrangement applications The Ireland-Claisen reaction is a useful method for constructing esters, particularly of difficult medium-ring products, with high stereoselectivity. How would you make the starting material? Application to the synthesis of ascidialactone, a marine natural product. Some more complex examples:

47. 47 A summary of the Woodward-Hoffmann rules.

48. 48 Baldwin’s rules for ring formation (sizes 3-7) Prof J. E. Baldwin formulated a number of rules which may be used to predict why some cyclisations work well, and others did not. These were initially empirical rules derived through a study of the literature, but have since been rationalised through experimentation and molecular modelling. e.g.

49. 49 Baldwin’s rules for ring formation (sizes 3-7); classification Baldwin first classified all reactions using three criteria: a)The size of the ring being formed, or the ring size of the cyclic transition state. b) ENDO (if the bond being broken is in the ring) or EXO (if the bond being broken is outside the ring, I.e.: c)The hybridisation of the C atom undergoing attack in the cyclisation: If this is an sp 3 (tetrahedral) atom then this is classified as ‘TET’ If this is an sp 2 (trigonal) atom then this is classified as ‘TRIG’ If this is an sp (digonal) atom then this is classified as ‘DIG’

50. 50 Baldwin’s rules for ring formation (sizes 3-7); examples So, for example:

51. 51 Baldwin’s rules for ring formation (sizes 3-7); The rules Baldwin examined the literature and classified all the reported cyclisation reactions according to his rules. A remarkable pattern emerged; some types of cyclisation had never been reported. When he had attempted these he found that some simply failed. In the end he came up with the following simple table of rules:

52. 52 The rules are now known to work because of orbital alignments. Nucleophiles have to approach single, double or triple bonds in very specific directions in order to overlap effectively with the antibonding orbitals. The requirements are summarised below:

53. 53 Tetrahedral (TET) systems A clever deuterium-labelling experiment served to prove that 6-endo-tet processes are not intramolecular:

54. 54 Tetrahedral (TET) systems Epoxide-opening reactions (all-exo-tet) are particularly useful because they exhibit a high level of regioselectivity (note that the epoxide is equally substituted at each end):

55. 55 Intramolecular epoxide opening reactions The synthesis of Grandisol, the sex pheromone of the male cotton boll weevil, has been achieved in a very concise and elegant synthesis using a key epoxide-opening step. The high level of ring strain provides a means for the synthesis of similarly strained targets:

56. 56 Iodonium cations promote cyclisations in a very similar manner to epoxides. Note that the selectivity can change according to the substitution level: Iodine reacts with a double bond to form an iodonium cation, which can then promote a cyclisation:

57. 57 Intramolecular epoxide opening reactions – complex natural products A large group of natural products contain a series of fused 5-8 membered ether rings, and are believed to have been formed by epoxide opening processes So far this has been used to give relatively small products in the laboratory

58. 58 Intramolecular epoxide opening reactions – complex natural products A prime example of a complex target of this type is Brevitoxin A marine neurotoxin associated with ‘red tide’ toxic marine organisms. For a total synthesis of this molecule see: K. C. Nicolaou et al; J. Am. Chem. Soc., 1995, 117, 1171, 1173. (The method was not prepared by polyepoxide cyclisations, but no doubt one day it will be)

59. 59 Trigonal (TRIG) systems The following reaction works in acid but not in base; why is this? In base the reaction fails because it requires a disfavoured 5-endo-trig cyclisation. Why is it disfavoured – consider the orbital alignments?

60. 60 Trigonal (TRIG) systems In acid the reaction mechanism changes due to carbonyl protonation, and it becomes a 5- exo-trig process at the key cyclisation step:

61. 61 This accounts for the earlier question about amine addition in inter- and intramolecular reactions:

62. 62 Alignment of nucleophile with C=C vs C=O bond:

63. 63 Rules on 5-endo-trig reactions often dictate mechanism 6-endo-trig reactions are permitted

64. 64 You may have seen the Pictet-Spengler synthesis of isoquinolines:

65. 65 Digonal (DIG) systems Endo-cyclisations work well, and these cyclisation are useful for making small heterocycles:

66. 66 Digonal (DIG) systems Certain exo- cyclisations also work:

67. 67 Some genuine exceptions to Baldwin’s rules In some cases, if there is no choice, Baldwin’s rules can be overridden.

68. 68 Stereoelectronic effects in anomeric bond formation in carbohydrates Six-membered carbohydrates, such as glucose, exist as a mixture of ‘anomers’ Nb :  - is axial,  - is equatorial When an ether is formed at the ‘anomeric’ centre, two new anomers can be formed. The  -anomer is more thermodynamically stable, and usually the major product. Oxonium cation

69. 69 Stereoelectronic effects in anomeric bond formation in carbohydrates The  - anomer is more stable because of an energetically-favourable overlap between one of the ring-oxygen lone pairs with an antibonding orbital in the C-O bond. The orbitals align because they are parallel to one another. This overlap is not possible for the  -anomer. Effectively a ‘partial double-bond’. Even stronger with electron-withdrawing group on R, e.g. R=Me 67:33 R=COMe 86:14 This anomeric bond effect can be used to control the stereochemistry of anomeric bonds in sugars, which is both challenging and essential for the properties of the compounds. There are three major methods for control: a)Use normal anomeric effect, or override this with a large group. b)Perform an S N 2 substitution. c)Use neighbouring-group effects.

70. 70 a) i) Exploit normal anomeric effect: An axial adjacent group strengthens this effect (galactose): ii) This can be overridden by a large adjacent group:

71. 71 b) Use S N 2 displacement strategy- an excellent leaving group is required: Likewise, the  - product can be made from the  - starting material c) Neighbouring-group effect: an adjacent acetyl group is required (for a)-b) above, a group such as Bn is used): (NaOMe can be Used to remove OAc group)

72. 72 The potent anticancer molecule Calicheamicin, which is one of a family of ‘enediyne’ natural products. It works by intercalating into, and then cleaving, DNA at selective positions. It has a remarkable mode of action. The oligosaccharide part acts as a ‘targeting’ mechanism and engages in a molecular recognition with the DNA strand. The enediyne unit acts as the ‘warhead’ which damages the DNA. In a total synthesis of the molecule (K. C. Nicolaou, 1992), the anomeric bonds in the sugars are made by a combination of the methods already outlined.

73. 73 Spiro acetals can adopt three possible conformations, the stability of which depends on the number of anomeric effects. The more anomeric effects there are, the more stable the isomer n.b. The formation of the spiro acetal is reversible. Initially a mixture of isomers is formed. As the reaction proceeds, the quantity of the major isomer increases. The stereoselective formation of a spiro acetal is pivotal to the total synthesis of the aglycone of the antibiotic erythromycin

74. 74 Total synthesis of the erythromycin aglycone: Spiroacetal formation leads selectively to a single isomer: (2 anomeric interactions The rest of the synthesis involves some chemistry featured earlier in this course:

75. 75 Total synthesis of the erythromycin aglycone cont.:

76. 76 Total synthesis of the erythromycin aglycone completion.: (from previous slide)