Pharma Disconnections NC N N N HN Prof Edward A

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O OH N NH N N MeO N NH2 O O

MeO O N NH2 O H OH

Pharma Disconnections NC N N N HN Prof Edward A. Anderson HO

Synthesis for Biology and Medicine CDT CN O N H OH October 26th-27th 2016

O N MeO H N N N N O N F

HN O N N O Aims of the Course

• Cover ‘classical’ ways to disconnect molecules, which are fundamental to organic synthesis

• Develop an understanding of how these disconnections link to heterocycle synthesis

• Recognize how multiple solutions are available for given target molecules, and how to critically assess retrosynthetic options

• Interactive Problem session: Extended practice with ‘classical’ disconnection problems through teamwork

2 Retrosynthesis: Course Outline

The principles of retrosynthesis

• Introduction to retrosynthesis: The origins of the subject, nomenclature, how we go about breaking up molecules

• Key strategic considerations: Functional group interconversions, selectivity, protecting groups

• Synthons and Reagents: Acceptor and Donor synthons – how to recognise these disconnections and the importance of (di)oxygenation relationships

• Focus on specific reaction types and methods to install functionality (e.g. amines, alkenes, cycloadditions, cross-coupling)

• Worked examples throughout these topics

• Interactive Problem session: Extended practice with ‘classical’ disconnection problems

Retrosynthesis in medicinal chemistry

• Coverage of 5- and 6-membered aromatic heterocycle disconnections with worked examples

• Advanced disconnections of arenes

• Asymmetric synthesis including worked examples

• Case studies to illustrate principles

• Interactive Problem session: Extended practice with a range of pharmaceuticals

3 Retrosynthesis: Supporting Material

Stuart Warren’s ‘Disconnection approach’ is the classic text on this subject, and highly recommended!

Joule and Mills’ classic Heterocyclic Chemistry textbook also provides a useful introduction

4 Introduction: The history of retrosynthesis

• The birth of retrosynthesis can be traced to Sir Robert Robinson’s landmark synthesis of the alkaloid tropinone in 1917.

Recognition of available starting materials!

Me O N

NHMe2 O

O O

R. Robinson, J. Chem. Soc., Trans., 1917, 111, 762 5 Introduction: The history of retrosynthesis

• The birth of retrosynthesis can be traced to Sir Robert Robinson’s landmark synthesis of the alkaloid tropinone in 1917.

Me N O

NHMe2 O

O O

In the event, use of the calcium salt of acetone dicarboxylic acid at neutral pH facilitates the Mannich reactions:

O Me CO2Ca N pH 7, H2O NHMe2 O 92% O CO2Ca O

R. Robinson, J. Chem. Soc., Trans., 1917, 111, 762; C. Schöpf, G. Lehmann, Leibigs Annalen, 1935, 518, 1. 6 Introduction: Getting started!

• Retrosynthesis arrows: Forward reaction (Synthetic connection) Retrosynthetic disconnection

• A disconnection is the reverse of a known reaction (known by YOU!)

• WHERE should we start to disconnect molecules?

Example 1: Synthons Reagents

O HO NaH, THF or Br DMF a O d O

Br O OH NaH, THF or DMF

d a Risk of E2; SN2 on 2° halide not great!

Key principle: Disconnect at a bond that is EASY TO MAKE; it may be a strong bond!

• A synthon is an imaginary (charged) species formed by the conceptual process of breaking a bond in a molecule (retrosynthetically). Our job is to identify real-life reagents that correspond to these synthons. • Synthons are assigned labels (a (acceptor), d (donor)) so we can talk about what type of disconnection we are using. 7 Introduction: Synthons

• A synthon is an imaginary (charged) species formed by the conceptual process of breaking a bond in a molecule (retrosynthetically). Synthons are assigned labels (a (acceptor), d (donor)) so we can talk about what type of disconnection we are using. The subscript number refers to the position of the charge relative to a heteroatom that forms part of the functional group.

OH OH Acceptor Synthons: a a1 a2

O O Donor Synthons: d d1 d2

Reagents (e.g.):

HO Example 2: OH + / H+ (Fischer esteriﬁcation) Synthons: O

O O / Et3N; or Cl O O O or NaHCO3 aq. / Et2O a1 "Schotten-Baumann conditions" d N or Bu O Bu • Why use pyridine in this reaction? O O

8 Introductions: Functional group interconversions

• In addition to disconnections that break / make bonds, we can carry out functional group interconversions that change either the nature, or number, of functional groups present in a molecule.

C–O O ester O Problem: (a / d) • We cannot directly introduce either of these OEt OH EtOH functionalities H N • The acid group is meta-directing in SEAr 2 H2N benzocaine FGI

C–N O nitration FGI Me (a / d) Me OH O2N O2N O2N a d

Solution: Interconvert functional groups to enable ring functionalization (FGI)

Synthesis:

O HNO3 / H , H+ / Me Me CO H 2 CO H H2SO4 KMnO4 2 cat. Pd/C 2 EtOH OEt

O2N O2N H2N H2N benzocaine • Me is o,p-directing; p-nitration favoured by sterics • Amine does not react as it is • Mono-nitration as product less protonated (protected!) under reactive than sm the reaction conditions 9 Order of events

One of the crucial considerations in planning a synthesis is to consider the order of events of the planned reactions. This is particularly important in the manipulation of aromatic rings where regioselectivity is paramount; directing effects rule!

O deactivating, meta-directing deactivating, o,-p- directing Cl see Appendix for aromatic chem recap activating, o,-p- directing

The best electron donating group (activator) is the one that ‘wins’ – stabilisation is more important than ‘lack of destabilisation’

Q: Should we acylate or chlorinate ﬁrst? A: Sterics suggest we should acylate then chlorinate; the alkyl group favours p-substitution so chlorination ﬁrst would give poor selectivity.

Q: How do we introduce the alkyl group? A: NOT Friedel-Crafts alkylation...

AlCl rearrangement 3 Cl Al H Cl 3 Cl NOT

t-Bu t-Bu polyalkylation t-Bu product is more reactive than sm

Key principle: To achieve / guarantee mono-substitution, the product must be less reactive than the starting material... 10 Order of events

O deactivating, meta-directing deactivating, o,-p- directing Cl

activating, o,-p- directing

• Solution: Use Friedel-Crafts Acylation then remove carbonyl group. This again uses the important concept of FGI to reintroduce functionality into the molecule to enable control.

C–C O C–Cl O (a1 / d) O Cl (a / d) F–C acylation Cl

Cl2 / FeCl3 AlCl3 Wolff-Kishner redn. NH2NH2 / OH– / heat

FGI or Clemmensen Zn / HCl C–C (a1 / d) or H2, Pd/C F–C acylation O Cl O

AlCl3

11 Exercise

Plan a synthesis of the following molecule from m-cresol:

NO2

NO2 OMe OH m-cresol A synthetic musk (available)

Retrosynthesis:

NO 2 2 x C–N C–C nitration F-C alkylation Cl =

NO2 OMe OMe OMe OMe

Note: this is a ‘good’ F-C disconnection as cation rearrangement is unlikely

Synthesis:

NO2 K2CO3 / MeI or (MeO)2SO2 AlCl3, t-BuCl HNO3 H SO Friedel-Crafts 2 4 NO2 OH OMe alkylation via OMe OMe

regioselectivity: ortho to MeO, not Me (sterics)

12 Selectivity

Control / selectivity is paramount in planning a synthesis. There are three main considerations we need to think about:

1a. Chemoselectivity. WHICH group will react?

a) Differentiating between different functional groups:

O H O O NH2 N NaBH Cl 4 OMe OMe ? O ? HO py HO O OH

The amine is more nucleophilic than the alcohol... The ketone is more electrophilic than the ester... (see Appendix for stereoelectronic discussion) (see Appendix for stereoelectronic discussion)

b) Differentiating between the same functional group in different environments:

TBSCl / 1 equiv. TBAF OH OH imdazole TBSO OTBS or TBSO OH 1. PCC OH O Classical: R R PPTS, R 2. TBAF R H CH2Cl2 / MeOH

OH OH OH O Contemporary, cat. , PhI(OAc) chemoselective: 2 R N R H O TEMPO / BAIB

TEMPO / BAIB mech: e.g., Eur. J. Org. Chem., 2006, 4323 13 Selectivity

1b. Chemoselectivity: over-reaction. O O NH NH 2 2 NH NH Br Br Br2 / FeBr3 Br2 / FeBr3

Br Br

The aniline nitrogen atom is such a powerful activating The acetamide nitrogen atom is now a weaker group that it is difﬁcult to prevent over-bromination, activating group due to conjugation. Mono- despite the lower reactivity of the product. bromination can now be achieved.

Key principle: Modifying functional groups (by FGI) can help us to control / inﬂuence selectivity

... or an alternative disconnection?

NO2 NH2

HNO3 Sn / HCl

Br Br Br

Mono-nitration occurs as product is less reactive than sm. Reduction reveals the powerful amine activating group

Key principle: To achieve / guarantee mono-substitution, the product must be less reactive than the starting material...

14 Selectivity

1b. Chemoselectivity: over-reaction.

O O Br2 Br OH– or H+ ?? The haloform reaction can be quite a useful route to • Under basic conditions: carboxylic acids!

O Br O Br O O OH O H Br Br OH OH CBr Br Br 3

pKa = 25 pKa = 21

Carbonyl less basic due to inductive EWG from Br! • Under acidic conditions: OH Br O OH 2 OH O + Br H H H Br –H+

Key principle: To achieve / guarantee mono-substitution, the product must be less reactive than the starting material...

Key principle: Thinking about mechanism can also help us to control selectivity 15 Protecting groups

Protecting groups provide an obvious way to protect reactive functionality and achieve chemoselectivity. The cost is at least one additional step in a synthesis, usually two. • Sometimes the deprotection of protecting groups can be the most challenging step in a synthesis! • Protecting group-free synthesis preferred – and may be achieved using a careful ordering of steps...

See Appendix for a short summary of PG methods

1. Protection for alcohols

• Silyl ethers • Benzyl ethers • Esters / carbonates • Acetals • Other ethers

O Ph SiR Ph O 3 O Me O R O O O O O Ph X

2. Protection for amines 3. Protection for carbonyls (and diols!) 4. Protection for carboxyls

• Carbamates • Sulfonamides • Acetals • Esters / carbonates

O O O O R S HN O HN R O O O R

16 Introduction: Selectivity

2. Regioselectivity. WHERE will the molecule or functional group react? a) Aromatic compounds: Directing effects

X • We have already looked at this. The best cation stabilising group wins! Y b) Hard vs Soft

HO H HO Me NaBH4, CeCl3, MeOH, –78 °C MeLi or MeMgBr (Luche) O

O O

[Ph3PCuH]6 Me2CuLi or (Stryker) MeMgBr, cat. CuI H Me

• 1,2-Addition = ‘hard’: These reactions are charge controlled and depend on electrostatic attraction of nucleophile and electrophile. Highly charged / charge dense reagents.

• 1,4-Addition = ‘soft’: These reactions are orbital controlled and depend on the overlap and energies of the HOMO and LUMO. Neutral / polarisable reagents.

Many other examples such as: Enolisation (see d2): Control over the site of enolisation for non-symmetrical carbonyls; Elimination (e.g. Hofmann vs Saytzeff elimination), etc.

17 Introduction: Selectivity

3. Stereoselectivity / Stereospeciﬁcity: We may need to control stereochemistry in a given step

Stereoselective: One stereochemical outcome is favoured over two (or more) possible outcomes

Examples: generally stepwise (non-concerted) processes E1 elimination Felkin-Anh model (addition to α-chiral carbonyls) Chiral auxiliary-mediated reactions Carbonyl oleﬁnation (e.g. Wittig, etc.) O RM O attack HO Nu Nu RL attack hindered RL The facial selectivity of reactions of alkenes R R favoured! RL R R R R The facial selectivity of reactions of bicyclic systems M S Nu M S R Nu Diels-Alder reaction (endo vs exo) S R Aldol reactions (syn vs anti)

Stereospeciﬁc: A reaction where only one stereochemical outcome is possible due to the reaction mechanism.

Examples: generally concerted processes

SN2 E2 EDG EDG EDG Ring-opening of epoxides EWG H EWG

Diels-Alder reaction (and pericyclics in general) EWG H Electrophilic addition to alkenes Hydrogenation of alkenes Stereo- and regioselective reaction, but Many rearrangements (e.g. Baeyer-Villiger) stereospeciﬁc reaction mechanism 18 The ideal synthesis

1. Linear vs. convergent strategies: Key Principle: make disconnections in the middle of molecules!

6 4 SM 1 SM 1 13 1 4 1 Linear: SM 1 Target Convergent: Target Multicomponent: SM 2 Target 6 4 SM 3 13 steps @ 90% = 0.913 = 25% yield SM 2 6 steps @ 90% + 1 step @ 90% 4 steps @ 90% + 1 step @ 90% = 0.97 = 48% yield = 0.95 = 59% yield

2. Stereocontrol: Substrate stereocontrol, chiral auxiliaries, catalyst stereocontrol, chiral pool, enzymes

3. Atom economy: (B. M. Trost, Science 1991, 254, 1471) and Green chemistry – minimise waste! Compare Wittig / oleﬁn metathesis – Catalytic vs stoichiometric: R' PPh3 O R' R O R + vs. R R R' PPh3 + Ru cat. R' MW = 262 MW = 28

4. Step economy: Use of cascade strategies, multicomponent reactions, no protecting groups. Aim for e.g. 10 steps in total from cheap starting materials (not possible for really complex molecules).

5. Redox economy: (N. Z. Burns, P. S. Baran, R. W. Hoffmann, Angew. Chem. Int. Ed. 2009, 48, 2854): Installing functional groups at the required oxidation state avoids excessive manipulations and protecting groups strategies.

O 1. O3; PPh3 [OX] 2. Ph3P=CO2Me Grubbs II cat. Contemporary, O R Classical: R R redox economic: 3. LiAlH4 [RED] atoms introduced at 4. PCC [OX] ?? required oxidation level 19 Acceptor synthons a synthons: Essentially alkyl halides, etc.

X Synthon: R Reagents: R X = I, Br, Cl, OTs

Synthesis of these reagents is most commonly achieved from alcohols:

SOCl2 or POCl TsCl, py, CH Cl R 3 R 2 2 R Cl OH OTs or CCl4 / PPh3

or CBr / PPh PBr 4 3 NaI, acetone 3 (Appel reaction) (Finkelstein reaction) or Br2, PPh3, imidazole

R R (use LiBr or LiCl to Br I install other halides) a1 synthons

OH OH O O RO

O O O O O O O Reagents = H X Cl OR N CO2 RO X OMe O O = H X H N

20 Acceptor synthons

Synthons Reagents a2 synthons OH OH OH O OH Problem: Ph Ph Regioselectivity O Ph d a Br

OH O O HO Ph Ph a2 d

OH NaH, THF; then Synthesis: HO O Ph O Ph

O O R Problem: O OH Cl R Synthesis of Ph Ph O hydroxyketone? O d a1 O O R

O O O R O HO R Ph O Ph 2 d a Br O

Note: Poor nuc. so O NaHCO O 3 not suitable for Br O R Synthesis: epoxide disconn. Ph HO R Ph as used above O O 21 Exercise

Plan a synthesis of the the Pfizer anti-fungal agent fluconazole from 1,3-difluorobenzene and 1,2,4-triazole using two a2 disconnections

C–N N OH N N N H N N F N F N Fluconazole N F F

N N N N N a2 N a2 OH N O O O C–N N FGI N N N N F F N F = F N N

F F F F N N N N Synthesis: N N H O H O N O O Cl N N N 1. Ph3P=CH2 F Cl F F 2. m-CPBA F Cl N N Fluconazole or AlCl3 K2CO3, DMF, O CTAB (R NBr) heat F F F 4 F S NaOH, tol, 100 °C

O O O Corey-Chaykovsky epoxide S S epoxide synthesis O US Patent 4,404,216 22 Donor synthons

These are typically carbanions or anionic / neutral heteroatoms. Here we have two considerations: is the reagent hard or soft d synthons: (i.e. does it match the electrophile); and, can multiple reactions occur?

Carbon nucleophiles: Heteroatom nucleophiles: Hard: organolithium, organomagnesium. Hard: alkoxides, amide anions. Soft: cuprates, malonate, nitroalkane anion Soft: sulﬁdes, thiolate anions, amines, alcohols

Amine synthesis: As amines are such good nucleophiles, polyalkylation is a big risk!

C–N alkylation Et Et Ph N Ph NH2 I Ph N or Ph N I H Et Et Et

... different solutions are required for the synthesis of highly nucleophilic amines and sulﬁdes! a) Synthesis of sulﬁdes:

i) Using thiourea: S NaOH / H2O NH work-up Na2S H2N NH2

S Br S NH2 SH

Not isolated

ii) Using thioacetate: O AcS Na K2CO3, MeOH Br S SH

Can be isolated! (and does not smell) – protected thiolate anion 23 Donor synthons b) Synthesis of 1° amines:

Step 1: Introduce N Step 2: Reveal Amine

NaCN LiAlH4 or H2, Pd/C R Polyalkylation can N be a problem.... NH R 2

NO2 NO H2, Pd/C R 2 or TiCl3, H2O (McMurray) + or H /H2O (harsh)

NaN 3 PPh ; H O (Staudinger) DMSO 3 2 R Br R N3 or H2, Pd/C

TsBocNH, Mg, MeOH PPh3, DIAD then TFA R NTsBoc R NH2 (Mitsunobu) Mitsunobu: pKa must be <10 for success! O NH2NH2, (Gabriel) heat R N O O NaN

24 Donor synthons

b) Synthesis of 1° amines:

NH OH•HCl H 2 H • From oximes: base (e.g. NaOH) LiAlH4 OH R NH R O R N 2

O OH– / H O 2 NH2 PhO P R • From acids (Curtius): OH N3 PhO N R C R O (DPPA) O H N Ot-Bu R t-BuOH O

c) Synthesis of 2° and 3° amines:

There are two important methods for the synthesis of secondary amines, both of which feature reductive processes that again avoid revealing the amine too early in the reaction.

i) Reductive amination of aldehydes and ketones

2 2 2 R R O R NH2 N NaBH3CN HN chemoselective reduction of imine over aldehyde + + acid-stable mild R R1 mild H e.g. NH4 R R1 R R1 or AcOH reducing agent

R2 R3 N R2 R3 R2 R3 R2 R3 O H N N NaBH3CN N

R + + R R R R1 mild H e.g. NH4 R1 R1 R1 or AcOH

Review of synthesis of 2° amines: Salvatore et al., Tetrahedron 2001, 57, 7785. 25 Donor synthons ii) Reduction of amides

O O O R2 Cl LiAlH 3 R1 1 4 1 R Cl 2 1 R 2 R N R R NH2 N R N R2 H H O R3 Selective mono-acylation n-BuLi or NaH LiAlH4

O O This trick is relevant for the 1 3 LiAlH 1 R R I 4 R 2 alkylation of all amide derivatives N R2 R1 N R N R2 R3 R3 iii) Other methods:

1 R O OH R1 N Branched amine 1 N R NH synthesis: the Ritter + H / H2O reaction

Methylamine synthesis: R1 H H R1 R1 N R2 N R2 N R2 the Eschweiler-Clarke reaction H O Me H O H stable iminium ion 26 Exercise

Plan a synthesis of the sedative captodiamine from thiophenol, HSC6H5

NMe S 2

S captodiamine C–S d / a

Na2CO3 2-chloroethyl dimethylamine

NMe SH Cl 2 Bu S

thiourea; FGI OH–

C–C C–S FGI d / a1 d / a Cl O Bu Bu Bu S HS S S NaBH4; PhCOCl, Na2CO3, SOCl BuCl 2 AlCl3

27 Exercise

Plan a synthesis of the following amine from any available starting materials!

N Ph

suggests epoxide?

C–N H C–N N Ph O HN Ph O H2N Ph NaBH CN / H+ 3 NaBH3CN / H+ Disconnect at centre (COCl) , DMSO; of molecule FGI 2 Et3N C–C a2 / d

OH Br Mg O

28 Donor synthons 2: Enolates

2 An extremely useful disconnection of carbonyls via the enolate. Enolates of almost all carbonyl derivatives are used for both d synthons: alkylation, aldol, and Michael addition chemistry.

Alkylation Multiple FGIs will O be required for this

This ketone is symmetric so we do not a1 d need to worry about regioselectivity

O O O

I d2 a Reaction conditions: LDA, THF, –78 °C; O O then add iodide I d2

CH a 3 This ketone is not – so the alkylation disconnection will never work!

Key principle: Look for symmetry to help with disconnections!

Note that alkylation doesn’t always work: the following two compounds are challenging for ‘normal’ enolate alkylation...

O O

29 Donor synthons 2: Enolates

Speciﬁc enol equivalents: When the direct alkylation won’t give good selectivity, or in the absence of symmetry, we need to improve the regioselectivity of alkylation. For this, we can use a ‘speciﬁc enol equivalent’ – a compound with the reactivity of an enol that affords control.

a) Silyl enol ethers O O vs

Kinetic lithium enolate EtI

Li O OTMS

LDA, THF, TMSCl –78 °C O ‘Thermodynamic’ lithium enolate

Li OTMS O O MeLi EtI Et3N, DMF, TMSCl

Thermodynamic silyl enol ether

• Silyl enol ethers are also useful (required!) for (Mukaiyama) aldol chemistry...

30 Donor synthons 2: Enolates b) 1,3-dicarbonyls (malonates and beta-ketoesters). These enable regioselective enolisation and are also ‘soft’ (i.e. good!) nucleophiles

2 d2 d O FGI O O O O O

OMe OMe O OMe

Problem: two possible a sites of enolisation... a

Key principle: Re-introducing a directing functionality can greatly facilitate a synthesis!

Br O O O O O NaH O O NaH; OMe OMe OMe Br alkylation 1 O OMe alkylation 2 pKa ~ 12 Allyl bromide is the better electrophile

O O O O H H H+ / heat O

O O O

Key principle: Introduce the better electrophile / nucleophile in the more difﬁcult step

31 Donor synthons 2: Enolates b) 1,3-dicarbonyls (malonates and beta-ketoesters)

Note: A trick for alkylation at the other position: form the dienolate:

Br O O NaH O O BuLi O O O O OMe OMe OMe OMe

pKa ~ 12 pKa ~ 35 “Last in – First out”

c) enamines. These ‘soft’ enol equivalents can be isolated, and are useful to control site selectivity of alkylation. The resultant iminium ions hydrolyse on work up. For aldehydes, they provide an attractive alternative to aldehyde enolates, which are prone to undergo self-aldol reaction.

O N N N O + H Et–I H / H2O mild H+

1,3-allylic strain N This isomer is disfavoured by 1,3-allylic strain

...although enamines can be useful for alkylation, they are potentially more useful to control selectivity in aldol- or Michael-type processes... 32 Donor synthons 2: Enolates

The Aldol and Michael Reactions This will be one of the main methods by which we assemble heterocycle precursors! Example 1: Reagents: C–C FGI (aldol) O OH O OH O O O

Ph rehydration Ph Ph Ph H a1 d2

This aldeyde is This ketone is non-enolisable! symmetrical! O O NaOH aq. O Synthesis: This is a good aldol disconnection as we have Ph H Ph excellent control over the reacting partners.

Example 2: Dieckmann cyclisation (intramolecular Claisen) C–N O O O O C–C O O O O O (aldol) d / a3 EtO OEt OEt OEt = EtO OEt = OEt N N N N a3

O O O O O O O EtONa Synthesis: EtO OEt OEt OEt MeNH2 OEt N EtOH N N

Note: EtO– used as base to Note: Reaction driven by ‘avoid’ transesteriﬁcation product deprotonation 33 Acceptor synthons 2: Conjugate Addition

In the previous slides, we used a conjugate addition reaction of an amine and an α,β-unsaturated ester to construct a a3 synthons: piperidone. We also used a 1,5-dicarbonyl as a source of a 6-membered ring via aldol chemistry. Where did this 1,5- dicarbonyl come from? In both cases we needed an a3 synthon – a Michael acceptor.

O O O O Example: Problem: The d2 reagent must be soft = MeO to avoid competing 1,2-addition HO a3 d2 O OMe

O C–O O 2 (d / a ) O OH FGI O O Solution: Use a O O = HO HO 1,3-dicarbonyl

Key principle: Re-introducing functionality can alter O O O O reactivity and therefore selectivity = HO MeO d2 a3 MeO O Synthesis: LiCl, O O O O wet DMSO, O O O NaOMe heat NaBH4 MeO MeO MeO O Krapcho chemoselective O OMe O O reduction Me Cl

O O NaOH H+ / heat HO

O OH 34 Exercise

Plan a synthesis of the following diketone from any available starting materials!

O C–C C–C O aldol O Michael

O NaOEt O O NaOEt O O O Note: Aldol is under TD control. Na C–C O Enolisation at other sites leads NaOEt aldol to strained rings (i.e. reversible) Note: product ‘protected’ as enolate O

OEt

Note: NaOEt ‘matches’ ester, which is non-enolisable

35 Donor synthons 3: Umpolung

Synthons such as d1 represent the reversal of natural polarity of the functional group. O O d1 synthons These synthons are very useful as they increase the number of methods available for R' R' bond formation! R R d1 a a) Dithiane: A classical umpolung reagent, which truly converts a carbonyl into the umpolung synthon, then back to C=O.

Note: The dithiane anion is quite ‘hard’

PIFA (PhI(O CCF ) ) O SH SH S n-BuLi S R' Br S S 2 3 2 O R' R' R H BF3•OEt2 R S R S R or R H 2+ Hg / H2O pKa ~ 31 O acyl anion Raney Ni = R' equivalent R R b) Nitroalkanes: A nitroalkane, although not prepared from the original carbonyl or amine, can serve as a versatile d1 equivalent.

O O Problem: polyalkylation possible TiCl3 / = H O R' 2 R R NO2 Br R' R' R NH NH 2 = 2 NO2 weak base NO2 H , Pd/C R' 2 R R R R pKa ~ 10 R O R' R' H2, Pd/C NH2 O2N R' R Note: The nitroalkane anion is ‘soft’ 36 Donor synthons 3: Umpolung

c) Cyanohydrin and related umpolung agents (Thiazolium salts, other heterocyclic carbenes)

Recall the benzoin condensation: O

O NaCN HO CN OH– HO CN R H HO CN OH– O R R R H R H R R R OH OH

This classical reaction has been superseded by soft carbene nucleophiles such as:

Cl N-Heterocyclic carbenes Mes N N Mes

HO These reagents can effect benzoin Cl type reactions, Stetter reactions (d1 Thiazolium salts Readily conjugate addition), Baylis-Hillman S N (thiamine mimics) deprotonated at Bn type reactions, and so on. See 1,4- dicarbonyl synthesis, later.... O BF N 4 Triazolium salts N N C6F5

Reviews: K Scheidt et al., Angew. Chem. Int. Ed. 2012, 51, 11686. A. Grossmann and D. Enders, Angew. Chem. Int. Ed. 2012, 51, 314 37 Latent functionality

In the previous section, we saw the nitro group serving as an umpolung reagent which was later ‘revealed’ to be a ketone (or amine). Although on the face of it this is just an FGI, the nitro group was serving as a ‘latent’ carbonyl. A more accurate deﬁnition of ‘latent’ functionality is the introduction of a reactive functional group in unreactive form, that can be revealed at a chosen stage of a synthesis.

Example 1: Alkenes Typical Reagents / Synthons

Br MgBr MgBr

O O O O a2 d2 d1 O3; PPh3 R

BH3; R R a3 d3 d2 – OH OH OH OH H2O2, OH

O O O O a2 d2 d1 Pd(II) / Cu(II), R O2, H2O

The alkene serves as a latent carbonyl or alcohol, and as an acceptor or donor synthon; it is unreactive towards conditions which the carbonyls and alcohols are reactive.

Example 2: Silanes

TBAF; then H2O2, SiMe Bn OH 2 KHCO3, MeOH, THF ...note analogy to protecting groups... R R' R R' 38 Exercise

Plan a synthesis of the following enone from any available starting materials!

O Note symmetry in the enamine disconnection Ph C–C a2 d2 O O O C–C O + EtO Ph or Ph Br N O O Ph O

FGI C–C

O HO O O Cl Ph Ph Ph S N NO a3 O d1 Bn 2 O

Ph NO2

39 Alkene / Alkyne synthesis

Alkenes are not only useful as masked functionality, or as a source of diols, epoxides, etc., but are also found in many bioactive targets, particularly natural products. An example of this is Novartis’ everolimus. Although not directly prepared by synthesis, its parent rapamycin has been synthesised a number of times, and chemists need to address this alkene synthesis. Here we recap some important methods for doing just that.

O HO

MeO

Everolimus (immunosuppressant) O O OH (Novartis) N O O O O MeO HO O OMe

Oleﬁnation methods:

• Aldol / dehydration • Heteroatom mediated: Wittig, Horner-Wadsworth Emmons, Julia, Peterson • Metathesis • Cross-coupling (for dienes etc.), Heck reaction • Alkyne semihydrogenation • Metal-mediated oleﬁnations: (Takai, etc.)

Key Principle: Aside from metathesis, aldehydes are key precursors to alkenes and alkynes

40 Alkene / Alkyne synthesis

Heteroatom Method 1: Wittig

Br 1. NaH, THF Non-stabilized ylid: R1 PPh 1 2 3 2. R R (Z)-selective O R2

Br 1. NaH, THF EWG Stabilized ylid: EWG PPh 3 2. (E)-selective O R2 R2

EWG = ester, ketone, aldehyde, nitrile, aryl

Heteroatom Method 2: Horner-Wadsworth-Emmons: A VERY NICE WAY TO MAKE MICHAEL ACCEPTORS!

O O P EtO R2 electron-rich EtO O R3 phosphonate: R1 O R1 R2 (E)-selective base (e.g. LDA, 3 NaH, MHMDS) R

O O electron-poor EWG–O P 2 phosphonate: R 1 EWG–O R (Z)-selective R1 O base (e.g. KHMDS) R2 O For mechanisms: EWG = CH2CF3 Still-Gennari See Appendix EWG = Ph Ando 41 Alkene / Alkyne synthesis

Heteroatom Method 3: Julia

Base (e.g. n- R1 BuLi, LDA); 1. Ac2O, py Ph R2 Ph R2 R1 S S R1 H 2. Na/Hg O O HO O O R2 O

Highly (E)-selective

Heteroatom Method 4: Modiﬁed Julia

t-Bu N N N N 2 2 2 Base (e.g. LDA); R O R O N R O N N N N N 2 N R 1 R1 S N N N O R H R1 S N R1 S N R1 S O O t-Bu O O O t-Bu 2 t-Bu R2 O O

One step – but selectivity can be variable

A heteroaromatic group capable of acting as an electrophile. Commonly phenyltetrazole (PT), benzothiazole (BT), t-butyltetrazole (TBT)

Recent review: C. Aïssa, Eur. J. Org. Chem. 2009, 1831 42 Alkene / Alkyne synthesis

Metal-Mediated reaction 1: Metathesis

Mes N N Mes Mes N N Mes Cl Cl Ru Ru Catalysts of choice: Cl Ph Cl Drawback: PCy 3 i-PrO

Grubbs II Hoveyda-Grubbs II

Classes of alkene for cross-metathesis:

Type 1: Rapid homodimerization, homodimers consumable e.g. R1 Ar R2 Type 2: Slow homodimerization, homodimers sparingly consumable e.g. O 2 Type 3: No homdimerization e.g. R R1 Type 4: Olefins inert to CM but do not deactivate catalyst e.g. NO2

Examples of reactions for which metathesis is particularly useful:

RCM for ring sizes ≥5. Particularly useful for medium X X ring synthesis, and macrocycles. And normal rings.

2 2 R R High E-selectivity. For a beneficial effect of CuI on R1 O R1 O this reaction (yield / rate) see JOC 2011, 76, 4697

For classiﬁcation of alkenes in cross-metathesis, see: Grubbs et al. JACS 2003, 125, 11360 For a review of cross-metathesis, see: Blechert and Connon, Angew. Chem. Int. Ed. 2003, 42, 1900 43 Alkene / Alkyne synthesis

Metal-Mediated reaction 2: Heck Reaction Ar–I, cat. Pd(PPh3)4, NaHCO3, Bu4NCl, O DMF Ar O

OR OR

cat. Pd(0) Metal-Mediated reaction 3: Cross-coupling R1 R2 R2 X M R1

See appendix for synthesis of alkenyl halides and metals

Catalysts: H2, Pd/BaSO4 or Pd/CaCO3 Conditions H H Poisons: quinoline, ethylenediamine Metal-Mediated reaction 4: Lindlar Hydrogenation R R'

R R' P-2-Ni: Ni(OAc)2 + NaBH4, MeOH

R O Conditions Conditions Synthesis of Alkynes: R H R R' H

• Corey Fuchs: CBr4 / 2 PPh3 (often w/ Zn or Et3N) n-BuLi; R’–I (or other electrophile) • Ohira-Bestmann: • Gilbert-Seyferth: Pd(0), CuI, Ar–I O O (Sonogashira) TMS P(OMe)2 / n-BuLi

N / K CO , MeOH N2 See appendix for 2 2 3 other methods 44 Exercise

Plan a synthesis of terbinaﬁne (lamisil).

Terbinaﬁne (Lamisil) (Antifungal) (Novartis)

cat. PdCl2(PhCN)2 expensive e.g. X = Br: K2CO3 C–C C–C cat. CuI e.g. X = OAc: Pd(0) allylation Sonog. piperidine

NHMe N Cl expensive

PBr FGI 3 E/Z imperfect

K2CO3, KI, DMF

NHMe Cl Cl OH

C–C

toxic expensive O TL 1996, 37, 57. EP1753770 45 Exercise

Process route:

dialkylated amine in organic phase desired monoalkylated in aqueous phase silylation improves amine stability

Cl Cl TMSCl, Et3N HN Cl N Cl NH2 TMS (excess)

cheap! Cl 2 eq. n-BuLi cat. Ni(PPh3)2Cl2 cheap! Cl Cl FeCl3 Cl Cl Li

TBAB N Terbinaﬁne TMS Cl

TL 1996, 37, 57. EP1753770 46 Diels-Alder disconnection

Diels-Alder chemistry allows us to construct cyclohexene systems with high efﬁciency and stereocontrol:

EDG EDG EDG EWG H EWG

EWG H

Selectivity: HOMO EDG H • Orbital energy considerations mean ideal DA setup is electron rich diene (HOMO) + electron poor dienophile (LUMO) EWG H LUMO (or π4s + π2s)

OMe OMe EDG H • Regioselectivity reflects overlap of the largest coefficients of EWG these orbitals O O H

R R

(–) EDG H

• Endo-stereoselectivity classically explained by secondary orbital effects, EWG but is more likely due to electrostatic or steric effects (+) H H H 47 Diels-Alder disconnection

Example 1: N O O Ar O N O H H Check TS: all Hs syn H H R O in Endo TS (correct) N H O H O2N O2N

O2N O2N O2N PPh3Br Wittig PPh3Br O O

cross-coupling Wittig • enal easy to make by aldol / dehydration • stereoselectivity of Wittig is wrong! FGI

Wittig O OH

OMe

Example 2:

H HO FGI D-A?? [2+2] O • We need a ‘ketene equivalent’ HO O O O H cat. OsO4, NMO TiCl , H O ‘ketene DA Note: stereoselective exo-face 3 2 equivalent’ dihydroxylation O e.g.

Cl CN , NO2 NO2 ‘enamine DA H2, Pd/C equivalent’ NH 2 48 Exercise

Plan a synthesis of the following molecules using Diels-Alder chemistry

HO OH OH

CO2Me

CO Me 2 Whilst we could probably OMe OH HO do FGIs to make this work, there is an alternative.... Recognise potential dienophile HO 6 HO OH OH OH – C–O CO2Me CO2Me ? O

CO2Me CO2Me OMe OMe 1 OH OH HO HO – H+ 1,6-O O3; NaBH4 ozonolysis OH H OH CO2Me CO2Me OH CO Et CO2Me 2 MeO CO2Me OMe CO Et D-A OH LiAlH4 2 D-A

OMe CO2Me Good electronics! Alkene ozonolysis CO2Et (furan e-rich) O can reconnect 1,6-dioxygenation EtO C CO2Me 2 49 Saturated Heterocycles

The synthesis of saturated heterocycles can be achieved in many ways; the common theme to most of these is to use the nucleophilicity of the heteroatom.

1. SN2 Cyclisation onto halides, epoxides, etc.

basic conditions • Works well for 3, 5, 6 and 7-membered rings, and azetidines

X Cl X • Irreversible – SN2 reactivity – stereochemistry of sm converted into products basic conditions • However this means stereochem of sm must be controlled

X X O OH

2. Cyclisation onto Michael acceptors

cat. KOt-Bu, THF, • Particularly good for pyran synthesis. 0 °C O R1 OH • Usually operates under thermodynamic control, so equatorial R1 O OMe product is favoured. MeO O

3. Palladium-mediated cyclisations

• Wacker or Tsuji-Trost type reactivity; stereochemistry cat. Pd(II) reoxidant controlled by equatorial disposition of sidechain; or potentially R1 X by carbonate stereochemistry R1 X R2 R2 Reviews: Muzart, J. Mol. Cat. A: Chemical 2010, 319, 1 Wolfe, Eur. J. Org. Chem. 2007, 571 cat. Pd(0) R1 X General reviews of oxacycle synthesis: R1 X R2 Larossa, Romea, Urpi, Tetrahedron 2008, 64, 2683 MeO CO R2 Wolfe, Tetrahedron 2007, 63, 261 2 50 Saturated Heterocycles

4. Electrophile-promoted cyclisation onto alkenes

I2 I • Iodoetherification or iodolactonisation, and other good electrophiles, R1 OH R1 O promote this reaction. Stereoselective for equatorial sidechain. R2 R2

5. Reductive cyclisation processes (cyclisation onto carbonyls)

+ R1 1 2 H / NaBH3CN 1 R R H N R2 N R H R1 N R2 R2 H NH O H H 2 Nu axial delivery of nucleophile Nu

• Nucleophile delivered axial for stereoelectronic reasons 6. RCM

n cat. Ru=CHR n • Particularly useful for medium-sized rings! N N R m R m

7. Hetero-Diels-Alder reactions and other cycloadditions

OTES OTES R1 R1 cat. Cr(III)(salen)

1 N O R O EWG N R2 R2 O R1 R2 R2 O EWG

For a review, see: Pellissier, Tetrahedron 2009, 65, 2839 51 Disconnection Strategy Summary

1. Make the synthesis as short as possible!

Linear Convergent Multicomponent

6 4 SM 1 SM 1 1 1 13 4 SM 1 Target Target SM 2 Target

6 4 13 steps @ 90% = 0.913 = 25% yield SM 2 SM 3

6 steps @ 90% + 1 step @ 90% 4 steps @ 90% + 1 step @ 90% = 0.97 = 48% yield = 0.95 = 59% yield

2. Use only known disconnections

3. Disconnect back to oxygen where possible (provides better control)

4. Disconnect C–C bonds using available (or reintroduced) FGs, and:

5. Disconnect near the middle of the molecule (e.g at branch points, or disconnect rings from chains)

6. Use symmetry

7. Use the ‘best’ disconnection / forward reaction as late as possible in the synthesis

8. Use FGIs – but as few as possible

9. Look for available sms hiding in the molecule

52 Problem Session 1

Propose syntheses of the following compounds from starting materials of your choice

O O OH O a) b) CO Et c) Ph OEt d) OEt 2 OH O

O N Ph O MeO e) N f) g) h) OAc O

O HO Ph t-Bu i) from t-Bu O j) k) NH2

O O O O O Ot-Bu OH BocHN OH l) O m) n) NH o) Ph

53 Problem Session 1

Propose syntheses of the following pharmaceutical agents from starting materials of your choice

Me O N H O N 2 N N NH 2 CN O Cl HO CO2H OH O Baclofen Entacapone Tropisetron (Novartis) (Parkinson's) (antiemetic) (Novartis) (Novartis)

HO HN N OH N N NH2 H Antazoline Maprotiline Fingolimod (Antihistamine) (antidepressant) (Immunosuppressive) (Novartis) (Novartis) (Novartis)

OBn

OH O N HO MeO O O O O MeO

Vernakalant (benzyl ether) Mycophenolic acid antiarrhythmic agent (Immunosuppressant) Merck (Novartis) 54 Retrosynthesis: Course Outline

The principles of retrosynthesis

• Introduction to retrosynthesis: The origins of the subject, nomenclature, how we go about breaking up molecules

• Key strategic considerations: Functional group interconversions, selectivity, protecting groups

• Synthons and Reagents: Acceptor and Donor synthons – how to recognise these disconnections and the importance of (di)oxygenation relationships

• Focus on specific reaction types and methods to install functionality (e.g. amines, alkenes, cycloadditions, cross-coupling)

• Worked examples throughout these topics

• Interactive Problem session: Extended practice with ‘classical’ disconnection problems

Retrosynthesis in medicinal chemistry

• Coverage of 5- and 6-membered aromatic heterocycle disconnections with worked examples

• Advanced disconnections of arenes

• Asymmetric synthesis including worked examples

• Case studies to illustrate principles

• Interactive Problem session: Extended practice with a range of pharmaceuticals

55 Aromatic heterocycle synthesis 1: Furans, Pyrroles, Thiophenes

The general theme disconnecting aromatic heterocycles is to cleave C–X bonds within the ring, with a carbonyl precursor. Here we recognise these C–X bonds as being enols, or imines / enamines (for O, N heterocycles).

Furans: Recognise 2 x enol in target • Although not technically correct, this manner of 1 2 R O R heterocycle analysis can be very convenient.

2 x enol

O FGI C–O + OH R1 H R2 R1 R2 R1 R2 R1 R2 O O O (–H2O) O 1,4-dicarbonyl (See earlier slides on carbonyl synthesis + next section)

Extensions: As more substituents are present, modify the 1,4-dicarbonyl synthesis!

O I O O OH FGI OEt 2 x C–O O R1 R1 R2 EtO R2 1 2 1 2 R O R R O R O O O OEt

Reality!: Outcome depends on electrophile and conditions....

CO Et CO2Et CO2Et CO Et 2 EtO– / EtOH Cl O O EtO– / EtOH 2 HO R2 R2 2 2 EtO R NaI R2 O R O O O Cl O O 56 Aromatic heterocycle synthesis 1: Furans, Pyrroles, Thiophenes

Pyrroles: Simply use ammonia (or primary amine) to effect cyclization!

C–N C–N imine R2 enamine R2 + NH R1 R2 3 N O O H R1 R1 O NH2

FGI (tautomerise)

C–C Br R2 d2 / a2 R2 O 1 O 1 R NH R NH2

C–Br: SOFT

O O NH3 NH2 O NH NH2 R2 R2 R2 R1 cat. H+ R1 R2 R1 R1 Br Br O O

Enamine: SOFT H NH3

R1 R2 1 2 1 2 1 2 N R N R R N R R N R H OH OH H H 2 H2 57 Aromatic heterocycle synthesis 1: Furans, Pyrroles, Thiophenes

Thiophenes: Recognise 2 x thioenol in target – disconnect back to 1,4-di-carbonyl again!

2 x C–S O R1 R2 R1 R2 S O 1,4-dicarbonyl

Methods to cyclise the 1,4-dicarbonyl: H2S

P2S5 S MeO P S Lawesson’s reagent S P OMe S

All of these heterocycles arise from 1,4-dicarbonyls, which need to be made using unnatural synthons. Two disconnections are possible:

O O O R2 2 1 R2 R R R1 R1 O 3 a2 d2 O a O d1

umpolung umpolung 58 1,4-dicarbonyl synthesis revisited

can decarboxylate if needed O O CO2Et O CO2Et NaH, THF R2 R2 R2 R1 R1 R1 a2 d2 O Br O O

O 2 O 1 R R H+/ H O w up R2 α-halocarbonyl = soft 2 R1 Br N Enamine / 1,3-diCO= soft O

2 O Note: this disconnection will also 1 R 1. LDA R R2 work with enamine or malonate as R1 Br O 2. O ; PPh nucleophile 3 3 O Alkene = latent carbonyl

NO2 CO2Et O CO2Et 1. NaH, THF R2 R2 R1 R1 2. H O+ O 3 O

Nef reaction

• Mechanistic focus: Nef reaction

H+ HO O O H+ HO O HO OH +/- H+ OH N N N HO N O

H OH2 59 1,4-dicarbonyl synthesis revisited

+ various O SN2 O O then H O+ d1 reagents R2 3 R1 Br R1 3 a O d1 O R2 1. Base (e.g. Al2O3, R1 OH–, etc.) Et N, EtOH O 3 O R2 O H R2 2. H O+ or TiCl S 1 3 3 1 R NO N Bn R O 2 HO Cl Stetter reaction

• Mechanistic focus: Stetter reaction

Cl Bn Bn Bn N Et3N, EtOH N N H nucleophilic carbene HO S HO S HO S

Breslow Intermediate Bn Bn R H N R +/– H+ N R O O R' S H R' S OH

H O O O R1 Bn O R1 Bn R2 R2 N R2 N R1 O O S O S R' R' Review of nitroalkane conjugate addition: Ballini et al., Chem. Rev. 2005, 105, 933. 60 For recent leading references on the Stetter reaction, see: Org. Biomol. Chem., 2011, 9, 8437; JACS 2005, 127, 14675. Aromatic heterocycle synthesis 1: Furans, Pyrroles, Thiophenes

Further functionalization of the heterocycle nucleus can be be achieved under a variety of conditions; these heterocycles react readily with electrophiles as they are electron rich. a) Direct metallation (deprotonation):

deprotonate at 2-position with t-BuLi in Et2O O

N H deprotonate at N with NaH (pKa = 16.5)

b) Reaction with electrophiles: generally at the 2-position see Tam et al. Synth. NBS / DMF Commun. 2010, 40, 2138 O Br H E+ O O E Br / MeOH 2 MeO O OMe Superior stabilisation of charge from electrophilic attack at 2-position c) Diels-Alder reactions:

O O O O O Br O 1. Br2 O Heat O Br O O 2. amine O O base O

Note exo-selective 61 Case Study: Atorvastatin

The Pﬁzer synthesis of atorvastatin contains a classic example of Paal-Knorr pyrrole synthesis, combined with the highly efﬁcient Stetter protocol to prepare the 1,4-dicarbonyl.

HO O Sidechain prepared by chemical CO2H CO2t-Bu synthesis or biocatalysis HO O d1 Stetter substrate F N NH 2 x C–N 2 O F O O C–C O O H F Stetter NH Pivalic acid, tol; 3 steps HN HN O O Cl Bn Atorvastatin (Lipitor) Et3N / N (cholesterol lowering) (Pﬁzer) S Recognise 1,3-dicarbonyl HO , EtOH, 70 °C HOAc, C–C hexane Knoevenagel

O O C–N NH2 O O HN OMe O toluene

http://www2.chemistry.msu.edu/courses/cem958/FS06_SS07%5CAmand.pdf 62 Aromatic heterocycle synthesis 2: Azoles

For 5-membered rings with two heteroatoms, look for ring-opening C=O disconnections which form C–Heteroatom bonds Oxazoles: R2 Example 1: Use dehydrating conditions R2 N e.g. POCl3, SOCl2,etc. R1 1 NH R O R3 O Cl R3

R2 R2 C–N R2 C–O acylation N R1 R1 NH NH Cl R1 R 2 O 3 O O O R3 O R3 enol C=O

Example 2: Using TosMIC (good for monosubstituted azoles)

C Ts N + N O O - H O C N N N Ph O Ph H K2CO3 Ph Ph Ts 'TosMIC'

H O O O C N N N Ph Ph Ph Ts Ts Ts

63 Aromatic heterocycle synthesis 2: Azoles

Isoxazoles: Isoxazole formation can lead to regioselectivity issues... R2

N e.g. POCl3 O O R2 1,3-dipolar R2 cycloaddition Synthesis of the nitrile oxide is achieved by R1 N N O R2 dehydration R1 O NCS N then HO KHCO3 R2 C–N C–O 1 2 R R • How can we control 1 N H N OH R 2 the regioselectivity? O O O

Regioselectivity: e.g. Hydroxylamine reacts with the most electrophilic of the two carbonyls:

MeO O O O OH O N

MeO NO2 MeO NO2

H2N OH NO2 Less-populated but more electrophilic R2 OH O protonated ketone 2 x C–N R1 R2 R1 N H2N NH2 N O O H MeO NO2

Note identical disconnection for pyrazoles 64 Aromatic heterocycle synthesis 2: Azoles

Imidazoles, Thiazoles: Similar disconnections can be used to form these heterocycles. S 1 2 R N R Example 1: O O Et3N OH 2 HO S – H2O S S R S R2 S R2 R1 R1 1 1 2 1 2 R R N R R N R X NH2 NH NH H

soft-soft NH4OAc

O O Et N HS R2 3 S R2 R1 R1 X O O

Example 2: TosMIC again...! C X X Ts N X N N X = S, N Ph Ph H K2CO3 Ph

O R3 Example 3: By exhaustive imine synthesis! O O R3 H HN N 1 R1 R2 XS NH4OAc R R3 R2 HN N 3 R R3 R3 1 R NH H2N 2 2 R HN NH N H2N HN R1 N N 3 R H R1 R1 R1 R2 H N R2 2 H2N R2 H3N R2 65 Aromatic heterocycle synthesis 2: Azoles

Further functionalization of azoles is possible with nucleophilic or electrophilic reagents:

Lithiation: X n-BuLi X n-BuLi X X Reaction fails for isoxazoles Y Y Li Y Li Y

Reaction with electrophiles: E + + N E N E e.g. E = Me+, AcCl, N N N N N N E Cu-cat. N-arylation H H

Largest HOMO coeff. / most stable intermediate cation E e.g. E = Br+, + + + X E X E NO2 (forcing) E X X Y Y Y Y Assisted by EDGs on ring

Reaction with nucleophiles: Cl Nu X Nu– X Nu– X X Y Cl Y Nu Y Y

(prepare from azolidinone)

66 Exercise

Plan a synthesis of the non-steroidal anti-inﬂammatory drug tolmetin, from N-methylpyrrole.

CO2H N O tolmetin

Retro: C–C FGI acylation tolmetin CN CN CN N N N O O

Friedel-Crafts equivalent or direct reaction with acid chloride Synthesis:

NMe2 1. MeI NMe2, CH2O 2. NaCN O NMe2 CN CN N Mannich N N POCl3 N Villsmeier O Reaction at C2 Reaction at C5 NaOH via NMe3 N N

CO2H N O

67 Exercise

Propose a synthesis of of the anti-asthma drug broxaterol:

N O N H OH O Broxaterol OH N HO H2N Br2

C–N Br Br Br a2 / d FGI Br Br N N N N O N O O HO H O O OH O

Br2, NaBH4; NaH Br cat. H+ K2CO3 Br O N O Br N O O

68 Exercise

Propose a synthesis of of the angina / hypertension drug amlopidine:

Amlopidine stepwise Cl Cl Hantzsch MeO2C CO2Et O H CO Et O MeO2C 2 amine N NH2 protection H O O O NH2 required??

Synthesis: available EtO C 2 HO CO2Et CO2Et N3 NH4OAc O O O NaH O N3 H2N N3 Cl Cl available MeO2C CO2Et O N N3 Cl H MeO2C NaOMe Cl MeO2C O H2, Pd/CaCO3 O H O

Amlopidine MeO2C CO2Et O N NH2 H 69 Aromatic heterocycle synthesis 3: Pyridines

The classical pyridine disconnection is to recognise a 1,5-dicarbonyl precursor:

–H O 2 NH2OH

R1 N R2 OH O O Here we can use our vast array of 1,5-di-CO or R1 N R2 R1 R2 disconnections....!!

[ox] 1 2 R N R NH OAc e.g. DDQ, Ce(IV) H 4

This is the basis of the classic Hantzsch dihydropyridine synthesis:

2 2 2 x O O O O R O O R O NH EtO R2 3 EtO R2 EtO OEt EtO OEt

R1 O R1 O R1 R1 R1 N R1 O O H O may proceed via EtO 1 R NH2

70 Aromatic heterocycle synthesis 3: Pyridines

Variants: To avoid the use of overly reactive Michael acceptors or aldehydes:

NMe 2 O O EtO OEt heat NH2OH•HCl OEt CO2Et O Ph O Ph N Ph NH OAc O O 4 N OEt

Mannich base – equivalent to O O equivalent to malondialdehyde Ph O H H

Further examples of useful pyridine chemistry...

PBr3

H O H NR 2 2 Ac2O POCl3 2 R R R R R R N N N O N Cl N N H H O

NaOMe susceptible to SEAr reactions... R NBS Br R N OMe N OMe

71 Aromatic heterocycle synthesis 4: Diazines

The synthesis of Diazines and derivatives simply involves putting the disconnections we have seen so far together! Also remember oxydiazines...

2 x C–N R2 + ox. O R2 1 H N NH N R 2 2 R1 N Pyridazine: O Note: Oxydiazines are easy to O convert to chlorides using POCl3. 2 x C–N This provides a straightforward H N NH O 2 2 way to perform SNAr reactions.

O R2

N R2 1 2 x C–N O O NH R N O N H 3 R1 R2 H2N R Pyrimidine: R1 N R3 POCl3 Note: can also include R3 = O, N, S R2 2 x C–N X R2 N O 1 2 H N NH N R1 N X R R 2 2 X = O, N, S R1 N Cl

Nu 2 x C–N N R2 + ox. NH2 R2 x 2 1 Pyrazine: R N R1 O N

2 x C–N 1 1 2 1 2 R N Nu R N R + ox. R O H2N R

1 3 1 3 R N R R O H2N R 72 Aromatic heterocycle synthesis 5: Benzannulated heterocycles

Obviously a very important class of compounds – we will again look brieﬂy at some trends, which can equally be applied to bis-heterocyclic systems.

Benzannulated 5-membered rings Key intermediates: Issues: a) Indoles 2 R2 R 1 O R 1 Fischer R R2 Regioselectivity NH2 1 NH N N R N in [3,3] H AcOH H H

OMe N Leimgruber-Batcho Nitro reduction N MeO N NO2 NO2 H 1. heat 2. reduce NO2 DMFDMA

R2 R1 R2 I 1 2 Larock R1 R R Pd(II) Regioselectivity in carbopalladation N NH2 H NH2 Pd(0) b) Benzofurans O [3,3] C–O

OH O3; SMe2 OH heat O R R R O R Ac O, NaOAc, CHO 2 C–C AcOH, heat O O CO2H R R 73 Aromatic heterocycle synthesis 5: Benzannulated heterocycles

c) 1,3-Benzimidazoles, C–X Benzothiazoles, C–N X " " R / H+ HN X O e.g. Benzoxazoles R R reagent at acid H oxidation level MeO OMe N , H2N NH2 HO OMe Ph X C–X I X X = S: K Fe(CN) X OAc R 3 6 via X = NH: PhI(OAc)2 N N R N R H

LG d) Indazoles, X N–X X Examples: Benzisothiazoles, N OH O Benzisoxazoles NH DEAD, PPh3 N R N R OH R R X N–X X N N LG R R

NMe2 R R C–C X N N X N NH Cl Cl N 2 N R R N NMe via NH 2

Cl NMe2 X C–X F X SNAr N N R R 74 Aromatic heterocycle synthesis 5: Benzannulated heterocycles

2. Benzannulated 6-membered rings

a) Quinolines

R2 R2 C–C C–N O O Combes O 1 2 1 1 R R N R N R NH2 H+ H+ or heat

R2 R2 R2 R3 C–C C–N O Friedländer O O R3 (acid or base) 1 1 R N R NH NH2 H+ H+ R1 R3

b) Isoquinolines

FGI C–C Bischler-Napieralski / POCl3 N N N HN O

R R R R

the equivalent reaction with imines is the Pictet-Spengler tetrahydroquinoline synthesis

75 Aromatic heterocycle synthesis 6: Rings with ≥ 3 heteroatoms

To prepare triazoles, oxadiazoles, tetrazoles, etc. we simply modify our disconnections used so far with an emphasis on carbonyl recognition. The strategies below are colour coded into cycloadditions, excision of a single atom, cyclisation (dehydration), and ‘stepwise cycloaddition’.

1,2,3-triazoles

N R N N R N N N R cat. Cu(I) R

O N R N N N N N R R 1,2,4-triazoles

R PPh3 R' O O N R' R R R R NH R N N HN NH 2 N R O N N R' N R N N N H2N R OR R O R R R PPh3 PPh3 N N H2N N O

H N R N R tetrazoles R R H2N NH N N O O R N R HN N R N N N N SnBu3 N or TMSN3 R or LiCl, NaN3, NH4Cl

N R R N N NH N NaN3, Tf2O R R O 76 Aromatic heterocycle synthesis 6: Rings with ≥ 3 heteroatoms

1,2,3-oxadiazoles

O N N HO N N OH + dehydrating agent (e.g. Ac2O) R R R R 1,2,4-oxadiazoles and thiadiazoles

R O R O O R R + dehydrating agent N N HN NH (e.g. (EtO)3CH)

O R OH N N O N Cl R R R NH2

S N N H2N NH2 + S2Cl2 (oxidative method) purines R R R R

N N NH2 O R N N N Cl R H N NH2 O O N HN N Y R H2N N X Z X N H N N H R 2

77 Exercise

Plan a synthesis of deferasirox from starting materials of your choice

HO2C

N N

N OH HO

Deferasirox

HO2C

HN NH2 N N 2 x C–N O O O N N = N OH H OH HO Et3N OH HO O

Symmetry suggests hydrazine disconnection C–N

O O O NH Cl 2 N OH H OH HO O OH

Eur. J. Inorg. Chem. 2004, 4177 78 Exercise

Propose a synthesis of the antimalarial agent amodiaquine OH

N HN

Amodiaquine Cl N (antimalarial)

OH OH C–N OH

N N N HN C–N H2N H2N

Cl Cl N Problem: Regio/chemoselectivity

Cl N

Et2NH, C–N CH2O

OH OH

HN H2N C–N Cl O OEt C–N FGI C–C Cl N O Cl N Cl N Cl NH O CO Et H 2 2 + – POCl3 H ; then heat, OH

79 Exercise

Plan a synthesis of valatinib from starting materials of your choice

Cl H2N HN Cl O O C–N FGI FGI N Valatinib N NH OH NH (cancer) 2 N (Novartis) N N O NH2 heat POCl3

N N N N

Note elements of FGI hydrazine and suggestive SNAr disconnection O O C–C O O

NaOMe N O N

In reality, the condensation product rearranges...

O O O OH NH OMe H N NH O OMe 2 2 N N

N O N O N

J. Med. Chem. 2000, 43, 2310 80 Revisiting arenes – advanced disconnections

A number of speciﬁc and reliable methods are available to functionalize arenes.

1. ortho-Functionalization. This is a very large topic. Some highlights are selected below.

a) Classical methods O O OH i) Claisen rearrangement – a very convenient ~200 °C method to install an allyl group at the 2-position. H

O R very versatile functionality O OH O for further manipulation! R ii) Fries rearrangement – also generally quite AlCl3 selective for functionalization at the 2-position.

iii) Other ortho-selective classical reactions such as Reimer-Teimann, Gattermann-Koch, etc.

b) Directed ortho-Metallation. DMG DMG DMG n- or s-BuLi Li E+ E

Mechanism: NEt NEt2 2 NEt2 Good Directing groups: Amides, thioamides, O O O O s-BuLi, O O + carbamates, oxazoles, etc. TMEDA E Li H Li E E = RCHO, R–I, X2, TMSCl, B(OMe)3 ....

Review of directed metallation: V. Snieckus et al., Chem. Rev. 1990, 90, 879. 81 Revisiting arenes – advanced disconnections

Regioselectivity: TMS = blocking group NEt2 NEt2 NEt2 NEt2 O O O O O O O O OH NEt s-BuLi, s-BuLi, 2 Li TMS TMS Li warm to RT TMS TMEDA TMSCl TMEDA O

Cl Cl Cl Cl anionic Fries Cl rearr. iterative DoM

E+ E+ inductive effect controls NEt2 NEt NEt regioselectivity 2 2 O O O O O O Review of directed metallation: E E H+ or TBAF TMS E V. Snieckus et al., Chem. Rev. 1990, 90, 879. For a review of the uses of metallated heterocycles in organic chemistry, see: Cl Cl Cl Chem. Rev. 2004, 104, 2667.

• Heteroaromatics: DoM can be useful in heteroaromatic systems, but often the anion can be unstable.

B(OH) LTMP; B(OMe)3; 2 • Lithiation ‘directed’ by H+ N Cl N Cl halogens and alkoxy groups is OMe OMe particularly effective • Anions adjacent to N can be CHO n-BuLi; DMF unstable (lp-lp repulsion?)

MeO N OMe MeO N OMe

Reviews of heteroaromatic lithiation: Tetrahedron 2001, 57, 4059; Tetrahedron 2001, 57, 4489 82 Revisiting arenes – advanced disconnections

2. Palladium / copper catalyzed cross-coupling: An obviously important strategy. The synthesis of boronic esters and acids is key to this chemistry; common methods include:

R B(OH)2 H+

R Bpin PdCl2dppf R Br BuLi; R B(OMe)2 R Bpin pinB–Bpin B(OMe)3 pinacol [Ir(OMe)cod] / dtbpy hexane, rt R See Hartwig, Chem. Soc. Rev., 2011, 40, 1992 pinB–Bpin

Copper-catalyzed amination / amidation is a very attractive and cheap route into aryl amines etc.:

N NH Cu2O, ligand, N Cs2CO3, MeCN, reﬂux N Br I N N 92% See Beletskaya, Organometallics 2012, 31, 7753 N then add NH

3. C–H activation. A very large and rapidly expanding topic which we will not cover in detail!

Reviews: 2 x C–H activation: Chem. Rev. 2011, 111, 1215 Arene arylation by C–H activation: Angew. Chem. Int. Ed. 2009, 48, 9792 Pd-cat C–H activation: Angew. Chem. Int. Ed. 2009, 48, 5094

Chem Soc Rev 2011 issue 4 83 Asymmetric Synthesis

Due to the breadth of this area, we will not cover in detail! General strategies to bear in mind: 1. Look for available chiral sms, such as amino acids, sugars, epoxides (epichlorohydrin)

O OH O OH O H N RO 2 OH OR Cl OMe O R O OH

Amino acids Carbohydrates etc. Epichlorohydrin The 'Roche' ester (both enantiomers available) (both enantiomers available) (both enantiomers available) (both enantiomers available)

2. Look for ‘high quality’ catalytic asymmetric processes such as Sharpless AD and AE, Jacobsen epoxidation and hydrolytic kinetic resolution, Noyori hydrogenations, CBS reduction, organocatalysis (!)

Sharpless AD Sharpless AE

DHQD ‘Down’ DHQD ligands D-tartrate ‘Down’ (–)-D-Tartate AD-mix α

R R1 S SAD RS OH RS RM OH SAE OH RM RM O R R R H OH L L L R1 R1 OH

DHQ ligands (+)-L-Tartate AD-mix β Large goes ‘Left’

84 Asymmetric Synthesis

Jacobsen epoxidation Jacobsen HKR

Mn(III)(S,S)Salen Cr(III)(R,R)SalenOAc OH OH R1 N N Mn O H2O R O O R R1 Cl TMSN3 1 OTMS 1 R R R RL R RL N3 Cr(III)(R,R)SalenN3 R1 aq. NaOCl O

Various Noyori Hydrogenations: cat. RuCl2((R)-BINAP), O O H2 (100 atm), MeOH OH O R1 OMe 99% ee R1 OMe Ts Ph N R-BINAP gives R-stereocentre Ru (when ester has highest priority) Ph N O H , i-PrOH OH R1 R1 >95% ee cat. RuCl ((R)-BINAP)(diamine), R2 R2 2 O H2 (8 atm), MeOH OH R1 R1 (R,R)-Tsdpen ligand gives R- Ar 99% ee Ar stereocentre (when alkyne has highest priority) R-BINAP gives S-stereocentre (when arene has highest priority) 85 Asymmetric Synthesis

3. Look for ‘high quality’ chiral auxiliary / reagent approaches: Asymmetric allylation, Evans auxiliary, etc.

Evans auxiliary

M O O O O base, M+ R1 O N O N R1 Bn Bn

Leighton allylation / crotylation

N Si / cat. Sc(OTf)3, N Cl CH2Cl2, –30 °C

4. Look for high quality substrate stereocontrol, e.g. Felkin-Anh, Allylic strain, ring functionalisation (stereoelectronics), steric effects (less- hindered face approach in bicyclics), stereospecific reactions (e.g. epoxide opening with amines or azides to prepare aminoalcohols)

5. Use enzymatic or chemical resolution, which can work really well at an early stage of a synthesis

86 Case Study: Indacaterol

The synthesis of this drug requires the installation of a chiral benzylic alcohol adjacent to an amine. This could well suggest an epoxide strategy, albeit with regiocontrol issues in the ring-opening due to benzylic stabilisation of the SN2 reaction.

FGI For Owen: $189/kg

H2N H2N HN C–N O HO HO Br Indacaterol C–O (Chronic Obstructive Pulmonary Disease) O N (Novartis) O N O N Identify p-directing group H H H OH OH OH

FGI Asymmetric reduction

O Br C–C

N O N O N H H OH OBn OBn

Org. Proc. Res. Dev. 2006, 10, 135. See also: Bioorg. Med. Chem. 2011, 19, 1136. 87 Case Study: Indacaterol

Synthesis: O

1. AcCl / AlCl3 1. F3C OEt 2. H , Pd/C 2 Recognise symmetry 2. AcCl / AlCl3 3. NaOH / heat; NH NH NH •HCl 2 3. H2, Pd/C HCl 2 TFAc

O O O AcO 1. AcCl / AlCl3 1. m-CBPA 2. BnBr, K2CO3 2. Ac2O, 40 °C

N N O N N H OH OBn OBn O O OBn

Br , BF •OEt 2 3 2 O Ph H Ph O O HO / BH3•SMe2 O AcO Br N B Br K2CO3, H N acetone Me O O OBn 91% ee O N O N O N H H H OBn OBn OBn – AcOH, AcO–

Ph 2-pyridone 1. Heat with amine salt O 2. H2, Pd, AcOH N Me Ph B H H B Indacaterol O

H RS ‘Small’ group positioned here to minimise 1,3-allylic strain

Interestingly RL is the CH2Br Org. Proc. Res. Dev. 2006, 10, 135. RL See also: Bioorg. Med. Chem. 2011, 19, 1136. 88 Case study: Gleevec

Gleevac (Novartis) – Tyrosine kinase inhibitor used against gastrointestinal tumours. Process synthesis developed ca.1996.; several reports on improved syntheses including OPRD paper in 2008, and flow synthesis in 2010.

• Original process route (Zimmermann)

N N H H N N N N FGI OH N C–N N C–N N N HO HN pyridine NH2 Cl O N O N O (4-hydroxymethylbenzoic GleevecGleevac (Imatinib) acid is available) FGI

$4.6 billion sales in 2015 1 H H N N Me2N HN N H2N

N O NH2

NO2 i-PrOH, 2 NO2 H N N NO2 NaOH 2 N N

Key steps:

1. Convergent late stage aniline acylation Me2N OEt O 2. Pyrimidine ring formation used as arene coupling step OEt

Bioorg MCL 1996, 6,1221 89 Case study: Gleevec

• Improved ‘process’ route (Wang, 2008)

N H H N N N N N N C–N Cl N N N H HN heat HN 91% N O N O

GleevecGleevac (Imatinib) C–N 1. NH2NH2 / FeCl3 83% 2. acid chloride, Et3N, 93%

H Cl N N C–N N NH2 Br N N Cl NO2 DMEDA, CuI, NO2 O K2CO3, dioxane, N 100 °C, 82% N

guanidine nitrate, 2 x C–N NaOH, BuOH, 86%

Me N Key steps / features: 2 HN NH2 • Yields and cost improved through simplifying key steps – e.g pyrimidine O NH ring formation now with guanidine, not functionalised guanidine 2 • Copper-catalyzed pyrimidine–arene union N • Avoids use of H2NCN

OPRD 2008, 12, 490 90 Case study: PKI 166

OH OMe OMe OMe Reagents: OMe

C–N + FGI FGI 2 x C–N

HN HN HN HN HN

N NH N Cl N O H2N O H2N O N Ph N NH EtO H H2N Novartis PKI 166 NH O (anticancer) Ph H2N

Reagent:

MeO C–C MeO MeO Br NH NH NH2

NH2 NH2 NH2 O CO2Et O CO2Et O CO2Et

NH3

NH Cl N HCl, 2 EtOH OEt

CO2Et CO2Et

91 Case study: PKI 166

Synthesis:

Soft – reacts at bromide

Cl HCl, NH2 NH N EtOH NH3 NaOEt OEt NH2 CO Et CO Et CO Et 2 2 2 MeO NH

NH MeO 2 O CO2Et Br O α-methylbenzylamine: available

OH OMe OMe O OMe H N 2 H NH 1. Ph 2 POCl3 HCOOH

HN 2. BBr3 HN HN HN

N NH N Cl N O H2N O N Ph N NH EtO

Novartis PKI 166 (anticancer)

Synthesis: http://www.chem24h.com/drug/synthesis/ykkjfgvlg.html Traxler, P.; Bold, G.; Brill, W.K.-D.; Frei, J. (Novartis AG); Pyrrolopyrimidines and processes for the preparation thereof. EP 0836605; JP 1999508570; US 6140332; WO 9702266 . 92 Case Study: Linezolid

O O O N N H N $1.3 billion sales in 2013 F O O Linezolid Cl (antibiotic) (Pharmacia/Upjohn)

O O FGI C–C OH O N N H O N NH OH N O N NH2 NH F F NH O CDI, imid F O O Actual process synthesis: key step: FGI

O 1. NH3, PhCHO; then HCl aq. Cl 2. Ac O 2 O N NO 3. LiOMe 2 O F

NH O O C–N O OBn O N N OBn O N N OLi H LiOt-Bu F F NAc O NH F NO2 O F O O N N H N

F O OPRD 2003, 7, 533 J. Med. Chem. 1996, 39, 673 93 Case Study: Telcagepant

The azepane in this Merck migraine drug features two remote F3C O O stereocentres. These were installed using an organocatalytic N F asymmetric conjugate addition reaction: N N F H N N Telcageplant NH EtO2CN OL 2006 3307 (migraine) O (Merck) N OL 2006 3311 O H2N Cl 1. NaBH CN, TFA C–N 3 N 2 x C–N (CDI) C–N 2. ClO S then H O 2 O 2

F3C HN C–N HN F N O F N NO2 N N N O NH F 2 NH Cl O Pd(OAc)2 (1 mol%) H2N O F dppb (2 mol%) aq. i-PrOH, 83 °C FGI 99% C–N asymmetric conjugate addn

CF3 F3C NH NHAc NO2 NHAc NO2 F N O C–N FGI C=C F O CO2H CO2H NHAcNH2 F F F

F F F

JOC 2010, 75, 7829 Review: Chem. Soc. Rev., 2013, 42, 774 94 Case Study: Telcagepant

Synthesis highlights: F3C O O N F N N F H N N Telcageplant NH NO2 (migraine) O (Merck) Ph Ph N (5 mol%) H OTMS NO2 NO NHAc NHAc 2 PivOH, B(OH) , O 3 , DMA CO H aq. THF HO C CO H 2 O F 2 2 F F 73%, 95% ee F (35 mol%) F N F H 91%, Z:E = 94:6 steps

CF3 F3C 1. HCl, aq. i-PrOH NH NHAc O 1. PivCl, Et3N, 2. CDI N DMAP Telcageplant CO2H 3. KOt-Bu, NHAc 2. NaOH / F >99.9% ee DMSO HN F F F N N NH O

JOC 2010, 75, 7829 Review: Chem. Soc. Rev., 2013, 42, 774 95 Excellent reviews of recent / key methods to prepare important pharmaceuticals, and very readable!

96 Problem Session 2

NC N O N H N NMe2 N O N HN CF3 S O O N H Lestrozole Leﬂunomide (Breast cancer) (Arthritis) Sumatriptan (Novartis) CN (Sanoﬁ-Aventis) (Migraine)

O OH N NH N N N N N O N N O Cl F N N O H Valsartan Clozapine Risperidone N (Blood pressure) (Bipolar disorder) (Antipsychotic) (Novartis) (Novartis) (J&J) N

Pazopanib OH (Anticancer) N N (GSK) N N N N N N H2N N H O CN N Vildagliptin Famciclovir (Anti-diabetic) (Herpes virus) H2NO2S N N H (Novartis) (Novartis) OAc OAc

97 Problem Session 2

N NH NH2 N NC Br N NH N O Cl N N N O N S H N

Zolpidem Tizanidine Etravirine (Insomnia) (Muscle relaxant) (HIV) CN (Sanoﬁ-Aventis) (Novartis) (Tibotec)

O N OH F N NH N O H MeO N N N N N H N N N HN O O H2N N Fasiplon (Anxiolytic) N (Roussel Ucla) Abacavir O Raltegravir (HIV) N (HIV) (ViiV healthcare) HO (Merck)

OH O O F OH CN Alvimopan (Gastrointestinal) N N N N N Ruxolitinib Cl (Cancer) Ph (Novartis) H2N F N O NH Sitaﬂoxacin OH (Ulcer) N N (Daiichi Sankyo) H O 98 99 Appendix: Selectivity in Electrophilic aromatic substitution (SEAr)

Directing effects are crucial for arene functionalization:

Wheland intermediate • Electron-donating groups (R) stabilize this R R R R intermediate so favour ortho- and para-substitution RDS – H+ • Electron-withdrawing groups destabilize this intermediate so favour meta-substitution where the Wheland intermediate is less destabilized E H E H E E

• Activating electron-donating groups: • Electron-withdrawing groups:

π-donors: groups with lone pairs are o-, π-acceptors: groups with low-lying π* E p- directing E orbitals are m- directing HO O H e.g. OR, OC(O)R, NR2, NHAc, RS e.g. CO2R, NO2, COR, CONH2, H SO2R, etc.

These intermediates are disfavoured H E σ-donors: alkyl groups (inductive effect I+ and σ-conjugation) are o-, p- H σ-acceptors: groups with low-lying σ* H directing F E H orbitals are m- directing

F e.g. CF3 F H

• Deactivating electron-donating groups: Cl, Br, I, F partial positive charge on EWG also destabilizes these intermediates. E weak π-donor so still o-, p- directing but Cl strong I– deactivates H

100 Appendix: Selectivity in Nucleophilic aromatic substitution (SNAr)

We can also effect nucleophilic substitution in speciﬁc arene systems:

HNO , 3 O2N CF3 i-Pr2NH, O2N CF3 CF3 H2SO4 heat Triﬂuralin Cl i-Pr N (herbicide) Cl 2 NO2 NO2

– H+ i-Pr2HN

Note: CF3 introduction:

HF, SbF5 O SNAr requirements: Ar CCl3 N CF3 • electronegative group (Cl, F) at Ar CF O site of substitution SF4 3 Ar CO2H Cl • strong EWG at o- or p- position i-Pr2N NO2 • F– is the best LG as attack on the arene is the RDS, not ejection of the Meisenheimer complex LG!

Classical aromatic SN1 is particularly useful for the synthesis of aryl iodides, phenols, nitriles

N NH2 HONO N Nu or Cu(I)X Nu Particularly useful for Nu:

H2O, ROH Cu(I)X (Cl, Br, CN) N N F KI NaNO2, HBF4 BF4

101 Appendix: Arenes – other disconnections

4. Miscellaneous transformations R O R a) ipso-substitution O SiMe3 TMS / AlCl3 O TMS Cl R2 – TMSCl 1 R R R COR

σC–Si → p Regiospeciﬁc substitution b) oxidative OH O OH O dearomatisation [oxidant] [Oxidant] = DDQ, [oxidant] 1 1 1 1 R R Ce(IV)(NO3)6(NH4)2 (CAN), R R PhI(OAc)2, etc. O OMe O HO c) reductive dearomatisation (Birch)

EWG EWG EWG EDG EDG EDG Na/NH3 via Na/NH3 via

d) arynes EDG EDG regioselective due to anion stability EDG EDG R2NH NR NR (inductive effect) OTf CsF, rt/80 °C 2 2 EDG EDG OH TMS O O OMe OMe OMe 102 Revisiting arenes – advanced disconnections

4. Miscellaneous transformations a) reductive dearomatisation (Birch)

EWG EWG EWG EDG EDG EDG Na/NH3 via Na/NH3 via

b) arynes EDG EDG regioselective due to anion stability EDG EDG R2NH NR NR (inductive effect) OTf CsF, rt/80 °C 2 2 EDG EDG OH TMS O O OMe OMe OMe c) Inverse electron-demand Diels-Alder sequences

High energy HOMO CO2Me H N MeO2C N CO Me – MeO2C N 2 N – N2 N N N N CHCl3, N N N 30 min, 45 °C, 84% N enamine / 1,2,3-triazine Bicyclic pyridine cycloaddition

103 Recap: Chemoselectivity based on stereoelectronics

Nucleophile selectivity: In the absence of steric effects, nucleophile selectivity is based on the relative energies of the lone pairs – the higher the HOMO energy, the better the nucleophile...

π*C=O O H NH2 N S Cl ? O Better energy match = HO py HO N earlier / stronger bond in TS O

The amine is more nucleophilic than the alcohol...

Electrophile selectivity: Electrophile selectivity is based on sterics, electrostatics, and the relative energies of the acceptor orbitals – the lower the LUMO energy, the better the electrophile. Another way of looking at this is to consider the degree of stabilisation of the carbonyl, which will be lost on nucleophilic addition.

O O O O O O O < N < < < < < NR2 OR H O Cl

H R Good overlap of Lower energy R Poor overlap of Cl O N O Cl R high energy l.p. donor orbital – O l.p. (3p). Negative δ+ R stabilises the less stabilisation. inductive effect amide and raises Positive inductive increases nN π*C=O the π* energy σC–H π*C=O effect. nCl π*C=O electrophilicity +I effect –I effect

104 Appendix: Protecting groups

1. Protection for alcohols

• Silyl ethers Protection Deprotection

all alcohols: R3SiCl, imidazole, cat. DMAP, TBAF, HF•py, HF(aq.) SiR3 O DMF (concentrated) H+ / MeOH (e.g. CSA, PPTS, HCl aq.) R3SiOTf, 2,6-lutidine or Et3N, AcOH / THF / H2O (3:1:1) CH2Cl2

1° alcohol: R3SiCl, imidazole, CH2Cl2 1° alcohol: PPTS, MeOH/CH2Cl2 (<1:1)

Order of stability (towards acid): TMS < TES < TBS (TBDMS) < TPS (TBDPS) < TIPS • The TBDPS group is somewhat more base labile than expected – Ar–Si is more electrophilic.

• Benzyl ethers Protection Deprotection

Bn: H2, Pd/C; Raney Ni; etc. BnBr or PMBCl, NaH, THF or DMF Single electron transfer agents (e.g. Na/NH3, Li + O PMBTCA / cat. mild H (PPTS, CSA), naphthalenide) or Sc(OTf)3

X PMB: Ce(IV)(NH4)2(NO3)6 (CAN) NH BnTCA / cat. TfOH DDQ; SET-agents. Ar BBr3 or BCl3 O CCl3 'ArTCA'

Selective deprotection of silyl ethers: R. D. Crouch, Tetrahedron 2013, 69, 2383. 105 Appendix: Protecting groups

• Esters / carbonates

Protection Deprotection

O Esters: RCOCl or (RCO)2O, py, DMAP, CH2Cl2 NaOH (aq.), DIBALH. Others are case speciﬁc... O R Particular favourites: R = Me, Ph, CCl3 Halogenated: Use Zn Carbonates: ROCOCl, py, DMAP, Allyl: Use Pd(0) (generates pi-allyl)

Particular favourites: R = Me, Allyl, Bn, CH2CCl3 Benzyl: Use H2, Pd/C

• Acetals

Protection Deprotection

O O THP: Dihydropyran / PPTS Mild acid (aq. or methanolic) (e.g. PPTS or AcOH)

• Other ethers

Protection Deprotection Me O O MOMCl, Hunig’s base, CH2Cl2 HCl (aq.) (fairly concentrated!) MOMCl, NaH, THF TFA, CH2Cl2 Boron-based Lewis acids Ph Ph Trityl chloride, DMAP, DMF (selective for 1° OH) O Ph Ph3C BF4 very mild acid! (e.g. a column!)

106 Appendix: Protecting groups

2. Protection for amines

• Carbamates Protection Deprotection

ROCOCl or (ROCO)2O, py, CH2Cl2 The following conditions are particularly useful as O Particular favourites: they are orthogonal to other PGs: R HN O R = Bn (Cbz) Cbz: H2, Pd/C R = t-Bu (Boc) Boc: TFA / CH2Cl2 R = Allyl (Alloc) Alloc: Pd(0), dimedone R = Fluorenyl (Fmoc) Fmoc: Et3N

R = CH2TMS (Teoc) Teoc: TBAF

• Sulfonamides

Protection Deprotection O O RSO2Cl, py, CH2Cl2 Ts: Mg / MeOH, sonication. S HN R Particular favourites: or Na/Hg or other single electron reductants R = p-toluene (Ts) (e.g. Na naphthalenide) or strong base R = p-nitrophenyl (Ns) Ns: PhSH / K2CO3

3. Protection for carbonyls (and diols!) • Acetals Protection Deprotection

For carbonyl: MeOH, H2O, PPTS or HCl O O HOCH2CH2OH, PPTS or TsOH For alcohol: ketone / aldehyde / dimethyl acetal, PPTS or TsOH

107 Appendix: Alkene synthesis : Wittig Mechanisms

Mechanistic focus: Wittig reaction

Br 1. NaH, THF Non-stabilized ylid: R1 PPh 1 2 3 2. R R (Z)-selective O R2

Sterically disfavoured Approach of reagents Transition state but it’s TOO LATE!!

Ph R' Ph O R' Ph O R' Ph R retro [2+2] Ph [2+2] Ph P P P R Z O H Ph H Ph H Ph H R H H

Sterically favoured Puckered EARLY TS minimises sterics between R and R’

Ph Ph O R' Ph Ph R' O R' H retro [2+2] Ph [2+2] Ph P P P H E O H Ph H Ph H Ph R H R R

Sterically disfavoured Sterically disfavoured in the transition state • Reaction is irreversible, i.e. under kinetic control. • Mechanism is a concerted [2+2] cycloaddition

Recent literature: Gilheany et al., JACS, 2012, 134, 9255. Aggarwal et al., JACS, 2006, 128, 2394. 108 Appendix: Alkene synthesis : Wittig Mechanisms

Mechanistic focus: Wittig reaction 1. NaH, THF EWG Br Stabilized ylid: EWG PPh 3 2. (E)-selective O R2 R2

Note: This reaction is NOT under thermodynamic control

• The initial [2+2] is irreversible, and the geometry of the transition state is believed to be controlled by sterics and favourable dipole alignment: cis-Transition states trans- Transition states

EtO EtO O O Ph All structures beneﬁt from Planar Transition states Ph Ph R Ph H favourable opposed dipole P P O H O H alignment Ph Ph H Sterically R disfavoured

EtO EtO EtO R O H O Ph Ph Ph Ph O Puckered Transition H Ph Ph P states P H P R O O H O H Ph H Ph Ph R EtO Ph O O Puckered LATE TS minimises sterics Ph between R and Ph P R

Ph H Alternative Puckered-cis TS • Reaction is irreversible, i.e. under kinetic control. H has less favourable dipoles • Late TS due to more stable ylid being used Recent literature: Gilheany et al., JACS, 2012, 134, 9255. Aggarwal et al., JACS, 2006, 128, 2394. 109 Appendix: Alkene synthesis : HWE-type Mechanisms

Mechanistic focus: HWE reaction M M O O O O O O Sterically favoured TS R–O P R–O P R2 R2 R–O R–O H R1 R1 H

Kinetically-favoured Aldol Aldol Aldol

This is the RDS for M M stable (electron-poor) O O O O phosphonates O R–O P R–O P O R2 R2 R–O R–O H R1 R1 H

Rotate Rotate

O O O O This is the RDS for less stable (electron-rich) R–O P R–O P R1 R2 2 phosphonates R–O O R–O O H R M M

H R1 FAST for e--poor phosphonates due to highly electrophilic P Cyclise Cyclise Kinetically-favoured Cyclisation

O O O O R1 O O R–O P R–O P 2 2 R2 O R1 R O H R R2 R1 Z H H E H R1 110 Appendix: Methods for the synthesis of alkenyl halides and metals

Synthesis of alkenyl halides and alkenylorganometallics:

CrCl2, CHI3 HSnBu , cat. Pd(0) Takai: R O R JACS 1986, 108, 7408 3 I JACS 1993, 115, 4497 or heat (radical) dioxane R R SnBu3 Chem. Rev. 2000, 100, 3257 I Ph3P=CHI Stork-Wittig: R O R TL 1989, 30, 2173 THF H–Bpin R R Bpin cat. Cp ZrHCl I2 2 R R 'M' 'M' = SnBu , I Organometallics 1996, 14, 3127 3 Synthesis 2004, 1814 SiMe3, etc.

Cp2ZrHCl; I2 cat. PdCl2(dppf) or DIBALH; I2 pinB–Bpin R R R I I Bpin

R cat. Cp2ZrCl2, CrCl , CHCl Bpin Me3Al; I2 R 2 2 I R O R dioxane Bpin

Other methods for cis-reduction:

• Diimide and equivalents: KO2CN=NCO2K Conditions H H TsNHNH2 / base R R' NBSH = nitrobenzenesulfonyl azide R R' • hydrometallation / protodemetallation: BH3; HOAc

111 Case Study: Aliskiren

The aminoalcohol / diisopropyl core of this drug poses a significant chemical MeO challenge. Compare chiral auxiliary approaches (including those used by Novartis) NH2 O O with a superior recent development that recognises symmetry. MeO O N NH2 H OH • Approach 1: Novartis J. Med. Chem. 1997, 50, 4818 and 4832. Aliskiren (Hypertension) O O (Novartis) LiHMDS N O Li Bn O O N O O O Br BnO BnO BnO Br Bn N O steps

MeO MeO MeO Evans alkylation Bn

MeO MeO MeO Schöllkopf N H N N H N N H N OMe MeO R OMe Alkylation of less hindered face

MeO N OH O BrMg N BocHN BocHN OMe H OBn HCl BnO RO OBn RO steps MeO MeO non-selective MeO addition (~1:1) 112 Case Study: Aliskiren

The aminoalcohol / diisopropyl core of this drug poses a significant chemical MeO challenge. Compare chiral auxiliary approaches (including those used by Novartis) NH2 O O with a superior recent development that recognises symmetry. MeO O N NH2 H OH • Approach 2: S. Y. Ko Helv. Chim. Acta. 2012, 95, 1937 Aliskiren (Hypertension) (Novartis) Attack less-hindered face

O O O LiHMDS; O O O acetone PCl5 H2 / Pd/C HO OH

O O O O (from SAD) O O O O

Two approaches investigated to assemble symmetrical bis-lactone O O

Bn O O LDA; allyl O O O O bromide Grubbs II RO Li N O O N O N O N AD-mix α O O MeO Bn Bn Bn desymmetrisation

O O 1. H , Pd/C H2N NH2 O 2 O O 2. MsCl RO 1. O RO 3. LiBr (invert) Aliskiren OH 2. H , Pd/C N3 2 MeO 4. NaN3 (invert) MeO

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