Year 3 Understanding Organic Synthesis Course; Professor Martin Wills Contents of the Course

Year 3 Understanding Organic Synthesis Course; 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.

Baldwin's rules and related cycloaddition reactions, including radicals.

Stereoelectronic effects: How such effects can be moderated to the advantage of the synthetic chemist.

Detailed example of the application of several stereoelectronically controlled reactions.

Reading: Clayden et al.; “Organic Chemistry” by Clayden, Greeves, Warren and Wothers, Oxford 2001. R. B. Woodward and R. Hoffmann in Angew. Chem., Int Edn. Engl., 1969, 8, 781. “Organic Reactions and Orbital Symmetry”, T. L Gilchrist and R. Storr, CAP, 1979.

Note: Since not all the material is in the handout, it is essential to attend ALL the lectures.

Professor M. Wills CH3B0 Understanding Organic Synthesis 1 Introduction: Unexpected results of cyclisation reactions.

Pericyclic reactions are; “Any concerted reaction in which bonds are formed or broken in a cyclic transitions state”.

i.e. there is a single transition state from start to finish, in contrast to a stepwise reaction.

Concerted reaction Multistep reaction Transition state Transition states

Energy Energy inter- starting product starting mediate inter- material material mediate product

reaction co-ordinate reaction co-ordinate

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. 2 Examples of pericyclic reactions:

1) Electrocyclisation reactions – Linear conjugated polyene converted onto 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.

Me heat Me

Me Me

Me irradiation (hυ) Me

Me Me

2) Cycloaddition reactions – Towo linear conjugated polyenes converted onto a cyclic product in one step. Again, the stereochemistry of the reaction is remarkably reproducible. e.g.

(two cis or Z alkenes) irradiation (hυ) + but no

3 Examples of pericyclic reactions, continued:

Example of a cycloadditions to give a 6-membered ring: O Me O Me

heat One diastereo- O isomer is favoured. (Diels-Alder reaction!) O Me O Me (one cis or Z alkene, and a E,E-diene)

3) Sigmatropic rearrangement reactions: This involves a concerted migration of atoms or of groups of atoms. E.g.

H H This would be classified as a [1,2]-sigmatropic rearrangement (or shift).

Me Me This would be classified as a [1,5]-sigmatropic rearrangement (or shift). H H The numbering refers to the number of atoms in the transition state on either side of where bonds are made or broken. 4 Examples of pericyclic reactions, continued:

3) Sigmatropic rearrangement reactions: A high level of stereochemical control is often observed.

Me Me Me only, no: observed Me Me Me This would be classified as a [3,3]-sigmatropic rearrangement (or shift).

Other concerted reactions:

a) Ene reaction (synthetic chemists), or Norrish rearrangement (photochemists) or McLafferty rearrangement (for mass spectrometrists).

O O enol n.b. enolate = O H H alkene

b) Decarboxylation reaction: + H H O O O CO 5 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. The are also the ‘outermost’ orbitals (of highest energy) in a structure, hence the term ‘frontier’. For a more detailed introduction to the theory, please refer to the recommended reading material.

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. irradiation (hυ) or heat (∆)

∆) υ Heat ( E,Z E,E irradiation (h ) cis

Heat (∆) irradiation (hυ) E,E trans E,Z 6 Woodward-Hoffmann theory applied to cyclobutene formation.

What is happening in the cyclisation is that p-orbitals (which form the pi-bonds) are combining in order for a new sigma 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 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.

Energy 3 nodes ψ=4 There are 4 electrons in this ψ=3 H H 2 nodes bonding system. H H Filling orbitals from HH the lowest first soon Note: the view of the ψ=2 reveals the nature butadiene is 'edge-on' 1 nodes of the outermost or with the single bond 'frontier' orbital. 'further back'. 0 nodes ψ=1

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. 7 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):

XY H H H H X YY X Y X

X Y X Y ψ=2 X X Y Y (HOMO) Y X Y X

Orbitals of same heat sign form a bond overall: X X Y X YY XY

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. 8 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.

thermal photochemically (unexcited) excited ψ=4 ψ=4 Energy

ψ=3 ψ=3 H H H υ HH H h Note: the view of the ψ=2 ψ=2 butadiene is 'edge-on' with the single bond 'further back'. ψ=1 ψ=1

Now (see the next page), the manner in which the molecule changes shape upon cyclisation is very different. 9 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’.

YY H H H H X YY X X X

Y Y Y Y ψ=3 X X Y Y X X X X Orbitals of same heat sign form a σ−bond overall: X X X X YY YY i.e., A suprafacial, disrotation process.

n.b. Note that the hybridisation of the carbon atoms at the ends of the diene changes from sp2 to sp3 in the process.

10 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:

∆) υ Heat ( E,Z E,E irradiation (h ) cis suprafacial antarafacial conrotation disrotation

Heat (∆) irradiation (hυ) E,E trans E,Z antarafacial conrotation suprafacial disrotation

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.

∆) υ Heat ( E,Z E,E irradiation (h ) cis suprafacial antarafacial conrotation disrotation

Although it should be noted that sometimes stereocontrol is lost due to competing radical reactions. 11 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: (E,Z,E)

Heat (∆) irradiation (hυ)

X X X X X X Stereochemistry? Stereochemistry?

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 pi-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. If you are comfortable with the process then try the same for a tetraene and pentene. Can you see a pattern? 12 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.

H sunlight H H photochemically- H HO promoted electrocyclisation (antarafacial, conrotation) provitamin D ergosterol HO 2

{1,7]-sigmatropic shift.

H HO vitamin D2

13 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.

Ph H

H H H H H H H H Ph Ph HO2C HO2C HO2C Endiandric acid A Endiandric acid D Endiandric acid E

All of these are derived from the linear polyene shown below:

Z E Ph E E HO2C E Z

Although the compound has no chiral centres, the double-bond stereochemistry is critical.

14 Synthetic applications of electrocyclisation reactions:

The endiandric acids are biosynthesised through the following process: conrotation (antarafacial)

Ph Ph HO2C HO2C

disrotation (suprafacial) Ph Ph H Diels-Alder H H (cycloaddition H H H H reaction

HO2C HO2C Endiandric acid A Endiandric acid E

The first two steps are electrocyclisations, whilst the final step, to make acid A, is a cycloaddition (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. 15 Step 1: 4n, thermal conrotation (antarafacial) Ph Ph HO2C HO2C Ph Ph H

Ph HO2C H

HO2C HO2C

4n+2, thermal Ph disrotation Step 2: (suprafacial) H H

Ph HO2C HO2C Endiandric acid E

R R H H HO C HO C HO2CPh2 H 2 16 H H H You might want to consider how Endiandric acid D is formed….

In 1982, 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.

MeO2C Ph

H2 Lindlar catalyst Ph (Pd/CaCO3, + Pb or quinine poison) H

o 100 C H (not isolated) H Toluene H H

Ph MeO2C MeO2C Endiandric acid A (methyl ester derivative) 17 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:

O O O H H irradiation (hυ) Heat (∆)

and acid H H for catalysis H H (AcOH or H3PO4) cis trans

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 protons is controlled.

Mechanism: H H H O O O next slide

18 Nazarov cyclisation, cont....

H H O O O H H enol -> ketone

-H H H H H H H

Stereochemistry in the key cyclisation step:

OH 4n, thermal OH H hence conrotation, H antarafacial

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

H H 19 Electrocyclisations of anions also obey the rules, but be careful when counting the electrons (remember that there are two on the position bearing the negative charge, if the structure is drawn in a localised manner:

acid nBuLi (strong base) workup H H H H a proton is removed 4n+2 H thermal disrotation nBu suprafacial Confused? Try making a model.

Ring-openings also obey the rules, e.g.: The ring opening counts as a 4n+2 reaction, under thermal conditions, hence Cl suprafacial and with disrotation. heat or Lewis acid (loss of Cl anion) Me Me

Me H H Me Me Me

as above Me H

Me H Me Me Me Me 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):

The reaction is usually heat-promoted, but sometimes it is carried out photochemically.

In this process the reagents approach each other in a ‘face to face’ manner, i.e. so that the p- orbitals of the π-system can combine with each other. The relevant orbitals are shown below:

H H H H LUMO H H H H LUMO H H Alkene Butadiene H H H H H HOMO H H HOMO H H H 21 Woodward-Hoffmann theory for prediction of the stereochemistry of pericyclic reactions: Cycloaddition reactions.

So the following combinations can be employed in the cycloaddition reaction:

H H H H Butadiene LUMO H H HOMO H H H H H H

H H H Alkene LUMO H HOMO H H H H

In both cases, the appropriate signs 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).

22 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.

Butadiene Alkene Alkene with H H e-withdrawing groups H H H H H H H H H H O O O Ψ4

Ψ3 Energy LUMO LUMO Ψ2 HOMO

HOMO Ψ1 HOMO

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. 23 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.

[2+2] [4+4] H H H H HOMO H H LUMO H H H H thermal antarafacial H H H H H LUMO H H HOMO H H H

[2+2] [4+4] H H H H HOMO H H LUMO H H H H supra- photo- (excited state) facial chemical H H H H H H LUMO H H HOMO H H (excited state)

24 Woodward-Hoffmann theory for prediction of the stereochemistry of cycloaddition reactions: summary:

Ring size No. electrons Thermal Photochemical

4,8,12… 4n Antarafacial Suprafacial 6,10,14… 4n+2 Suprafacial Antarafacial

Note…the rules also work in reverse: H Me Me heat + antarafacial H Me Me

Although you might also get competing radical reactions:

H H Me Me Me heat + . . Me H Me Me 25 [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.

O ketene H O C

Cl H Cl Cl Cl

H H Cl C O Cl O Cl Cl O

Ar Ar O ketene How would you make a ketene? N N O n.b useful for beta-lactam synthesis: C R R H OPh OPh

Some examples of Diels-Alder reactions will be given at this stage 26 Endo selectivity in the Diels-Alder reaction.

The reaction of an alkene bearing a carbonyl group with a 1,3-diene is known to proceed with a high degree of endo selectivity. What this means is that the product is formed through a transition state in which the carbonyl group lies 'underneath' the diene, a conformation which is favoured by a secondary orbital interaction:

MeO2C H O e.g. H MeO H OMe O +

endo -CO2Me is on same side of molecule Secondary orbital as the double bond. interaction Primary orbital controls interaction creates stereochemistry bonds

When attempting to answer a question in this area, first redraw the molecules with the carbonyl underneath the diene as shown below, then draw the cyclised product without altering the positions of the groups. Finally redraw a tidy' version with the same relative stereochemistry. Note: Ys and Bs are on the same side.

(see next slide) 27 X X X X X X Y Y Y Y Y Y A CO2Me A CO2Me ACO2Me B B B B B B line up form ring redraw

Example: Intramolecular version

X X' X X Y Y Y Y MeO2C A MeO2C A MeO2C B B' B B (Y=H, X=Me, X'-B' is three carbon bond, A, B=H) redraw

replace Remember: XX Me groups try to redraw the molecule Y Y as few times as possible as H H MeO2C A each will result in a higher MeO2C H B chance of errors slipping in. H B Don't redraw again 28 Make sure you can draw the transition state for the following process:

O O H O + H O O H O O O H O Endo is major exo product is minor product side-product

Intramolecular Diels-Alder reactions are very powerful methods for constructing target molecules:

MeO2C MeO2C Me H Me heat

One step: 2 C-C bonds, H 4chiral centres.

These reactions are often catalysed by Lewis acids (see section on the orbitals involved in Diels- Alder reactions. 29 Application of the Diels-Alder reaction to Taxol synthesis.

AcO NHBz O O Taxol is a potent anti- OH Ph O cancer compound OH HO H O Taxol O O AcO Ph A possible approach (model system):

H H H O O

How might you be able to construct the substrate?

30 Further applications of Diels-Alder reactions: Alkaloid synthesis:

O O CHO Diels- P Alder CHO MeO nPr MeO + O O base N OBn (Wadsworth-Emmons) N OBn Bn=CH2Ph H H

O H2, Pd/C O (removes CO2Bn + nPr and reduces alkene) nPr H (catalytic) O

N OBn NH2 H

H H NaBH4 Pumiliotoxin C ('poison arrow' toxin) (reduces C=N nPr N N H H H H not isolated 31 Hetero Diels-Alder reactions can be useful too:

Alkaloid H (isomer of Pumilio- NH4Cl toxin) H O 2o N 75 C N O H H2 H H2 Cl

BnO BnO BnO O O O A novel approach to + the synthesis of OMe OMe OMe carbohydrates.

Me3SiO Me3SiO Me3SiO Danishefsky diene.

Three component [2+2+2] Cycloadditions: 4n+2 electron + process. 3-body collision Is unlikely. N 32 N N 1,3-Dipolar cycloaddition reactions

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.

Ph Ph Zn(s) O [3+2] (reducing Ph Ph agent) Ph HO cycloaddition N O NH N N O Ph Ph Ph Ph Ph Ph Ph

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:

Ph Zn(s) O [3+2] (reducing Ph cycloaddition N O agent) N N O

Ph Ph Ph Ph

O HO Zn(s) (reducing Ph N HO + agent) H /H2O Ph Ph Ph Ph 33 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: O O O 4n+2 electrons suprafacial + O O O H H H O O O (sp3)

Orbital picture: H H

O O O O O O The intramolecular version is particularly useful, and selective: H H MeAlCl2 (the side chain (Lewis acid) is below the ring) δ+ O O O H One step, H Cl MeAl δ- H 2 H new ring, 2 chiral H centres 34 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.

H2, Pd/C ZnBr2 ZnBr (catalyst) 2 O O OH OH H

L-menthol

ZnBr2 ZnBr2 O O O via H H H

This process allows menthol to be made more efficiently than through extraction from natural sources. How would you make the starting material? 35 Woodward-Hoffmann theory for prediction of the stereochemistry of pericyclic reactions: Sigmatropic reactions.

This time the rules will be given first, then the examples:

Ring size No. electrons Thermal Photochemical

4,8,12… 4n Antarafacial Suprafacial 6,10,14… 4n+2 Suprafacial Antarafacial

a [1,3] sigmatropic shift (or rearrangement) H H H H

Thermal conditions: Photochemical conditions: H suprafacial antarafacial H H (disfavoured) H H (favoured) H H H H 'H' needs to migrate to other face 'H' is on correct side for easy migration (difficult) 36 Sigmatropic [1,5]-reactions proceed suprafacially under thermal conditions

6 electron (4n+2) process hence suprafacial H H H

Classic experiment:

Me D H Me S D E Me D Me H H Me

Me D H E Z Me D D Me D Me Me Me S R Me H H H Me

From the (S,E) starting material, both the (E, R) and the (Z,S) products are formed. However the (Z,R) and (E,S) products are not formed. This proves that the reaction proceeds in high stereoselectivity. 37 The isomerisation of cyclopentadienes involves a very rapid sigmatropic [1,5]-reactions (try taking an NMR spectrum of one)

H H 2 2 R 1 R R etc. R3 R3 R 4 R 4 R R R1

[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 D2 synthesis?

{1,7]-sigma- H tropic shift.

H H

HO vitamin D HO provitamin D2 2

The rules make this a (4n) antarafacial reaction. H (nb the step from ergosterol was H OH photochemically induced) 38 But the molecule is flexible enough to allow it. H Sigmatropic [3,3]-reactions proceed suprafacially and are of great synthetic utility:

COPE rearrangement CLAISEN rearrangement

O O

often reversible usually irreversible

H H O O Me Me Me Me Me Me Me Me

H H Both reactions proceed via a chair-like transition state.

Orbital picture: forming (4n+2) system hence bond Suprafacial on each 3-carbon component. breaking bond

39 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:

O O Li MeO MeO O MeO

H H O H+ O MeO MeO O

H H MeO

40 Sigmatropic [3,3]-reactions – CLAISEN rearrangement applications

Claisen reactions are generally irreversible and synthetically useful:

re- aromatises O O O OH

A [3,3]-sigmatropic reaction is pivotal to the Fischer indole synthesis: H H H steps H N N NH N NH NH NH -NH3

n.b. Don’t get confused with the Claisen reactions of esters.

41 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?

OMe O O O OMe OMe

Some more complex examples: H O O H n n via H OO O O O

O n n

OSi(tBu)Me Application to the 2 synthesis of H OSi(tBu)Me ascidialactone, a 2 O OSi(tBu)Me marine natural OO 2 product. O OSi(tBu)Me 42 2 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.

Why is it that a primary amine normally adds to the Whereas the equivalent intramolecular cyclisation beta-position of an unsaturated ester: proceeds via addition to the carbonyl group?:

O O β R OMe OMe NH2 NH2 O OMe O N H R NH OMe H

H O workup H O N R NH OMe 43 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.:

Endo: X Exo: X

c) The hybridisation of the C atom undergoing attack in the cyclisation: X

If this is an sp3 (tetrahedral) atom then this is classified as ‘TET’ X If this is an sp2 (trigonal) atom then this is classified as ‘TRIG’

If this is an sp (digonal) atom then this is classified as ‘DIG’ X

44 Baldwin’s rules for ring formation (sizes 3-7); examples

So, for example:

Y + Y

X X is a 5-Exo-Tet reaction

O O

X X is a 6-Exo-Trig reaction

X N X N is a 5-Endo-Dig reaction

45 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 cyclistation 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:

Ring size TET TRIG DIG Endo Exo Endo Exo Endo Exo N= no reaction cyclisation fails 3 N Y N Y Y N

Y= successful 4 Y N N Y N Y cyclisation

5 N Y N Y Y Y i.e.

6 N Y Y Y Y Y Y= allowed N=diallowed 7 Y Y Y Y Y Y

46 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:

Nu + Br TET sp3 systems Nu Br

Must approach from behind leaving group.

Nu ca. 109o Nu TRIG sp2 systems O OH

Must approach at this angle

Nu Nu DIG sp systems ca. 60o

N N Must approach at this 47 angle Tetrahedral (TET) systems

A clever deuterium-labelling experiment served to prove that 6-endo-tet processes are not intramolecular:

O O2 O2 2 S S S O nBuLi O O CH CH3 (strong CH3 3 base) These would be O S O2S O2S 2 the only products if the reaction was CH CH3 CH3 3 intramolecular.

O O2 O2 2 S S S O nBuLi O O CD CD3 (strong CD3 3 base) O S O2S O2S 2 CD CD3 CD3 3

O O2 2 S S O O Hence 'scrambling' is taking place But you also get: CD CH3 3 and the reaction is intermolecular.

O S O2S 2 48 CH CD3 3 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):

6-exo-tet 5-exo-tet but O O O O disfavoured favoured

5-exo-tet 4-exo-tet but O O O O disfavoured favoured

4-exo-tet 3-exo-tet but O O O O favoured disfavoured 49 rate: 3>4>5<6 for ring size. 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:

OTBDMS OTBDMS CN OTBDMS CN CN

mCPBA NaOMe O O E base

4-exo-tet OTBDMS OTBDMS

H O mCPBA = HO CN CN O O Cl H O OH 'steps' OTBDMS= OSitBu(Me)2 (the silyl group protects the alcohol, and is removed with fluoride). Grandisol CH3 (racemic product is formed, but this is the correct diastereoisomer) 50 Iodonium cations promote cyclisations in a very similar manner to epoxides.

Iodine reacts with a double bond to form an iodonium cation, which can then promote a cyclisation:

O O I O I 2 I I OH OH OH -I

I O I O

O O H

Note that the selectivity can change according to the substitution level:

CN CN H 5-exo-tet Favoured by attack O at least hindered end.

51 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

Me N O Me N O 2 H Me Selective 2 H Me oxidation H O H O O O O Me Me H H Me Me Me Me

BF3 OH H Me N O O OH 2 H Me O O H O O O BF Me2N O O Me 3 Me H H Me Me hydrolysis So far this has been H OH used to give relatively O OH small products in the O Complex target molecule laboratory O O O 52 Me H 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. HO O

H O H O H H H H O O H H H O O O H O O HH O O O H H H H

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)

53 Trigonal (TRIG) systems

The following reaction works in acid but not in base; why is this? O O

base (NaOMe) 0% O acid (HCl) 100% OH

OMe OMe

In base the reaction fails because it requires a disfavoured 5-endo-trig cyclisation. Why is it disfavoured – consider the orbital alignments?

O O O

H O O (quench) O

OMe OMe OMe 54 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:

H H O O OH

OH OH (quench) OH

OMe OMe OMe

OH O

5-exo-trig O O H

OMe OMe 55 This accounts for the earlier question about amine addition in inter- and intramolecular reactions:

Intramolecular reactions prefer addition Whereas the equivalent intramolecular cyclisation to the β-carbon on enthalpic grounds: proceeds via a 5-exo-trig cyclisation. This overcomes the enthalpic advantage of addition to the β-carbon, which O would require a 5-endo-trig step: β R OMe O NH2 O O 5-exo-trig OMe OMe H N N H O NH2 H R NH OMe The same cyclisation of a 6-membered ring precursor H works, because the 6-endo-trig process is allowed: workup O OOMe O OMe O OMe R 6-endo-trig OMe NH H

NH2 N H N H H 56 Rules on 5-endo-trig reactions often dictate mechanism

Predict the mechanism of this reaction:

O O + MeOH OMe + HN NH

H2NNH2

6-endo-trig reactions are permitted O O

base (e.g.) NaOMe

6-endo-trig OH R O R

6-endo-trig H HCO H 2 O O O N O O N OH N

OH O H

N-acyliminium cation 57 You may have seen the Pictet-Spengler synthesis of isoquinolines:

MeO MeO CH O 2 6-endo-trig N NH2 HCl (catalyst) MeO MeO H

MeO MeO

N N MeO H MeO H H

Enolate cyclisations are also controlled by Baldwin’s rules:

Br O O O O Br

Can you explain the results above? 58 Digonal (DIG) systems

Endo-cyclisations work well, and these cyclisation are useful for making small heterocycles:

isonitrile

O Base RCHO O2 C 2 C O2 C SN SN SN Ph Ph e.g. NaOMe Ph H R O MeO R O

O O 2 2 SN SN quench Ph Ph 5-endo-dig C H C H R O R O

R R base R H H N N N C C (after 59 protonation) Digonal (DIG) systems

R' R' R R H2NNH2 R 5-endo-dig R' N O N N NH2 H

Certain exo- cyclisations also work:

CN CN RO CN RO RO C C base N NH N N H NH2 N H

CN CN RO RO workup H H NH N N 2 N H H H 60 Some genuine exceptions to Baldwin’s rules

In some cases, if there is no choice, Baldwin’s rules can be overridden.

HO OH O HO OOH OOH H H

5-endo-trig H OO OO

SO Ph SO2Ph SO2Ph 2 base via N NH NH2 H 5-endo-trig

SO Ph SO2Ph SO2Ph 2 base via S S SH 61 5-endo-trig A summary of the Woodward-Hoffmann and Baldwin Rules: Reaction conditions Thermal Photochem. Thermal Photochem. no. electrons 4n+2 4n 4n 4n+2

Electrocyclisation Disrotation Disrotation Conrotation Conrotation Suprafacial Suprafacial Antarafacial Antarafacial

Cycloaddition Suprafacial Suprafacial Antarafacial Antarafacial

Sigmatropic reactions Suprafacial Suprafacial Antarafacial Antarafacial

TET TRIG DIG Ring size N= no reaction Endo Exo Endo Exo Endo Exo cyclisation fails

3 N Y N Y Y N Y= successful cyclisation 4 N Y N Y Y N i.e. 5 N Y N Y Y Y Y= allowed 6 N Y Y Y Y Y N=diallowed 7 Y Y Y Y Y Y 62 Stereoelectronic effects in organic synthesis

These are directing effects which work through a combination of steric and electronic effects. An example is epoxide opening, which operates in a predictable regiochemical manner:

OH MeOH OMe MeO Na O acid catalysis OH OMe R R R via attack on least hindered R=alkyl or aryl group via most substituted carbon atom cation formation

The situation is less predictable when the epoxide is symmetrically substituted. However in some cases there is a high degree of control:

H H H MeO Na

OMe OH H O OMe H H OH OMe not formed Major product

63 This is selective because the SN2 ring-opening of the epoxide at the ‘right hand’ side leads smoothly to a chair/chair product with minimal molecular reorganisation,

OH O MeO Na H HH H OMe OMe

In contrast the addition to the other end leads initially to a twist-boat structure, which is less favourable

O MeO Na H

HH H

OMe MeO

64 Bond alignments can also have a significant effect on the outcome of reactions:

H OH O heat via t-Bu N2 CHO N 2 H O N2 but

H H OH O heat O via t-Bu

N2 N2 H H O t-Bu

65 Stereoelectronic effects in anomeric bond formation in carbohydrates

Six-membered carbohydrates, HO HO O O such as glucose, exist as a HO OH HO mixture of ‘anomers’ HO HO OH OH Nb : α-is axial, β- is equatorial α OH β-anomer -anomer

When an ether is formed at the ‘anomeric’ centre, two new anomers can be formed. The α-anomer is more thermodynamically stable, and usually the major product.

HO HO O O ROH HO HO HO HO HO acid catalysis OH OH O OR HO α− HO or ROH OH OH HO α or β-anomer H HO ROH O O HO HO OR HO HO OH OH β−

66 Stereoelectronic effects in anomeric bond formation in carbohydrates

The α- 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 β-anomer.

HO HO O O HO HO OR HO HO OH OH α− OR β−

Effectively a ‘partial double-bond’.

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 SN2 substitution. c) Use neighbouring-group effects.

67 a) i) Exploit normal anomeric effect:

RO RO RO Ag salt O O O RO RO RO RO RO RO OBn OBn OBn Br OR α β Bn=CH Ph α− or -anomer Ag 2 ROH

An axial adjacent group strengthens this effect (galactose):

RO RO RO RO RO RO Ag salt O O O RO RO RO RO RO RO α− Br OR α β or -anomer Ag ROH

ii) This can be overridden by a large adjacent group:

RO RO Ag RO ROH O O O RO RO RO OR RO RO RO O Br O O α or β-anomer The large group β− blocks the lower face. 68 b) Use SN2 displacement strategy- an excellent leaving group is required:

RO TsCl RO RO O O O RO OR RO Et N RO ROH RO 3 RO RO OR OR OR β− OH OTs α-anomer Likewise, the α- product can be made from the β- starting material

c) Neighbouring-group effect: an adjacent acetyl group is required (for a)-b) above, a group such as Bn is used):

RO RO Ag salt O O RO RO RO RO O O O α or β-anomer Br Ag O ROH RO RO O O RO H RO OR RO RO O O O β− SN2 O 69 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. O β-, prepared HO NHCO2Me using (b); SN2 process with OTs leaving group. MeSSS α -, prepared O using method I O O H c) (OAc on S O O adjacent OH) N H HO OH O β-, prepared O OMe α-, prepared using using (a,ii); anomeric thio- (a, i); anomeric control OMe ester control overidden by O bond H O large group on HO N adjacent OH. MeO HO MeO

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. 70 Cyclic imines are subject to similar stereoelectronic control:

R R Acid R Me catalysis N N N H (dehydra- H tion) R R O H R

N R N Me

R' R'

Spiro acetal compounds are bicyclic acetals:

HO OH RO OR O acid catalysis O O

-H2O spiro acetal acetal

71 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

O O O O O O O O spiro acetal 2 anomeric effects 1 anomeric effect 0 anomeric effects -most stable isomer intermediate stablity least stable 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. O

Me Me The stereoselective HO Erythromycin formation of a spiro OH aglycone Me Me acetal is pivotal to the OH total synthesis of the (in the full molecule, two aglycone of the Me O OH * carbohydrates antibiotic erythromycin H are attached Me to OHs *) O OH *

Me 72 Total synthesis of the erythromycin aglycone:

Spiroacetal formation leads selectively to a single isomer:

MeO2CCO2Me CO2Me CO2Me acid catalysis Me CO2Me Me CO2Me HO -H2O O O OH O HO O (2 anomeric OH H interactions

Me Me

The rest of the synthesis involves some chemistry featured earlier in this course:

steps: i) MeMgBr - CO Me Me CO Me i) Oxidation to enone Me 2 axial addition 2 ii) Me CuLi conjugate ii) Elimination Me 2 Me CO2Me O addition O of CO2Me Ph O Ph O iii) Dibenzoyl peroxide O O O oxidation O Me OH O Me Me 73 Total synthesis of the erythromycin aglycone cont.:

Me Me CO2Me O Me i) LiAlH Me O 4 O OMe Ph O Ph O O O (MeO) CH, H O Me 3 O Me

OH OH Me Me

I Claisen H rearrangement I [3.3] sigmatropic O O Me Hydrolysis Me Me of acid Me OMe O Me Me O Ph O Ph O O O O O Me O Me

OH OH Me Me 74 Total synthesis of the erythromycin aglycone completion.:

(from previous slide) I O O O O Me Me I (iodine) Me 2 Me Reduction Me 5-exo-trig O Me O Me iodolactonisation Ph O Ph O O O O OMe Me OH OH Me Me Open ester and convert to aldehyde

OH OH Me Me Me Me Me Me Me O Me O HO Deprotect O HO O OH OH Ph O H HO Ring-open O Me spiroacetal OMe form with aqueous acid OH ester OH Me here Me

Erythromycin aglycone 75