pk organometallics l4 2014m tif

8/10/2019 PK Organometallics L4 2014m Tif

1/147

Organometallics in

Organic Synthesis

Pavel Koovsk

[email protected]

Charles University, Prague


2/147

1. Fundamentals

1.1. Introduction Zeise (1827), Frankland (1849),Grignard (~1900), Pauson (1951)

1.2. The 18-Electron Rule Exceptions: Ti, Zr, Ni, Pd, Pt - 16e -

Types of ligands (Ph 3P, CO;1

,2

,3

...)Electron book-keeping

1.3. Coordination of hydrocarbon ligands and its consequencesChatt-Dewar-Duncanson model

1.4. Fundamental reactions and catalytic cycles- coordination - dissociation- oxidative addition - reductive elimination- (migratory) insertion- -elimination - addition


3/147

2. Obtaining Complexes and Decomplexation

Three stages:

- Forming a complex- Reaction of the coordinated ligand- Release of the organic product

Examples of obtaining 1, 2, 4 .... complexes and decomplexation


4/147

3. Reactions of -Complexes withNucleophiles

3.1. Reactions of olefinic 2-complexesTwo different courses: ant i (Markovnikov); s y n (anti-Markovnikov)Pheromone synthesis (Semmelhack)

3.2. Reactions of allylic 3-complexes

Regioselectivity - less substituted carbonStereoselectivity - depends on the nucleophileSynthesis of flexibilene (McMurry)Carbonates, carbamates, protecting groups

3.3. Allylic rearrangements[3,3] Sigmatropic rearrangement catalyzed by PdAsymmetric versionDiastereoselective versionApplications


5/147

3.4. Reactions of 4- and 5-complexesStoichiometric functionalisation of dienes using Mo and Fe

(Birch, Pearson, Liebeskind)

Catalytic functionalisation of conjugated dienes(Bckvall reaction); Cl effectSynthesis of monarch butterfly pheromone ( Bckvall )Synthesis of bridged heterocycles ( Bckvall )Synthesis of heliotridane ( Bckvall )Carbocycles (Oppolzer)

4. Reactions of -Complexes4.1. Reactions involving an sp 3- or sp 2-carbon (Heck addition)

Heck reaction (mechanism, stereochemistry,asymmetric induction, chiral ligands)

ExamplesAppl.: Synthesis of 25-OH vitamin D (Trost)Pd(II) Pd(0) in s i tu


6/147

4.2. Reactions involving an sp 2-carbonHydrozirconationMethylzirconation (synthesis of farnesol)

Suzuki and Stille couplingsHartwig-Buchwald amination, aryl ethers

4.3. Reactions involving an sp-carbonAcetylide couplingSynthesis of calicheamicin 1I


7/147

5. Metallocarbenes

5.1. Tebbe Reaction

5.2. Metathesis and cyclopropanationCarbene generationIntramolecular cyclopropanation

5.3. Ring-closing metathesis (Grubbs and Schrock)CatalystsRing-closureMedium and large ring construction

5.4. Cyclopropanation

6. Cycloadditions6.1. Pauson-Khand reaction

6.2. Negishi cyclization


8/147

7. Oxidation

7.1. Epoxidation: Sharpless7.2. Epoxidation: Sharpless-Katsuki

7.3. Epoxidation: Yamamoto

7.4. Epoxidation: Jacobsen-Katsuki

7.5. Aziridination

7.6. Dihydroxylation

7.7. Aminohydroxylation

7.8. Hydrogen-transfer oxidation


9/147

8. Reduction 8.1. Catalytic hydrogenation of olefins

8.2. Catalytic hydrogenation of ketones

8.3. Transfer hydrogenation

9. Nucleophilic additions to C=O

9.1. 1,2-Addition

9.2. 1,4-Addition

10. C-H Activation 10.1. Aromatics

10.2. Allylic position

10.3. Ketone -position

10.4. Aliphatic C-H insertion


10/147

1. Fund amentals _____________________________________

1.1. In tro d u ctio n

New avenues in synthetic methodologyGoals that cannot be attained by othermeans (Mg, Cu, transition metals, . )

His tory

1827 Zeise salt (first organometallic cpd. with a transition metal)

William Christopher Zeise


11/147

1.1. Int r od uc t ion _____________________________________

1849 Sir Edward Frankland: Et 2Zn

1900 Victor Grignard: R Mg X

1951 Peter Pauson: ferrocene

(+ Wilkinson, Cotton, Woodward, and Rosenblum)


12/147

1.2. The 18-Electr o n Ru le _____________________________________

General desire to reach the e -configuration of thenearest noble gas, i.e., to have 18 e in valence shell(s 2p 6d 10 ).


13/147


Non-hy droc arbo n ligands

0 e : Lewis acids, e.g., AlCl 3 , BF 3 , etc.

1 e : halide, CN, H, (NO)

2 e : Lewis bases, e.g., R 3P, (RO) 3P, CO, RC N,

RN C, R 3N, R 2O, R 2S, etc.

3 e : NO


14/147


Hydroca rbon l igands

1 (1 e -): alkyl (R), aryl (Ar), -allyl2 (2 e -): olefins, carbenes (C=M)3 (3 e -): -allyl4 (4 e -): conjugated dienes5 (5 e -): dienyls, e.g., cyclopentadienyl (Cp)6

(6 e-

): conjugated trienes, arenes7 (7 e -): trienyls, e.g., cycloheptatrienyl8 (8 e -): cyclooctatetraene (COT)


15/147


Elect ron bo ok -keeping

Mo (CO) 6

6 + (6 2) = 18

(Ph 3P) 2Cp Ru Cl

(CO)2Cp Fe (CH

2=CH

2)

(2 2) + 5 + 8 + 1 = 18

(2 2) + 5 + 8 + 2 = 19

+

(2 2) + 5 + 8 + 2 - 1 = 18


16/147


Tutor ia l


17/147

1.3. Coord ina tion o f hyd rocarbon l igands _____________________________________

Chat t -Dew ar-Dunc anso n mo del

Joseph Chatt Michael Dewar


18/147

1.3. Coord ina tion o f hyd rocarbon l igands _____________________________________Consequences : Donation/back-donation and acidity of benzoic acid

Donat ion

Back-dona t ion


19/147

1.3. Coord ina tion o f hyd rocarbon l igands _____________________________________Consequences : Reactivity


20/147

1.3. Coord ina tion o f hyd rocarbon l igands _____________________________________Consequences : Stability


21/147

1.4. Fun dam ental React ion s and Catal. Cycles _____________________________________Metal - must be capable of temporary changing the number of sharedelectrons ( 18 16 14 )


22/147

1.4. Fun dam ental React ion s and Catal. Cycles _____________________________________Hydrogenation using Wilkinson catalyst ( catalyt ic cyc le )


23/147

2. Com plexat ion and decom plexat ion _____________________________________

Ap pl ica tion o f t rans i t ion m eta ls in o rg anic sy n thes i s :

- forming a complex (organic substrate + metal)- reaction of the coordinated organic molecule- release of the organic product

Stab i l i ty o f the com plexes :

Some are fairly stable (chromatography, crystallization,heat, air, moisture)

Some are highly unstable (inert atmosphere,water exclusion, low temp.)


24/147

2.1. 1 -Complexes _____________________________________


25/147

2.2. 2 -Complexes _____________________________________

Olef inic : Formation: by ligand exchange (Zeise salt)Decomplexation: ligand exchange

(Ph 3P, CO, pyridine, CN -)

Carbenes: Fischer complexes (free carbenes are extremely

unstable no decomplexation)Stabilization:

Ernst Otto Fischer


26/147

2.3. 4 -Complexes _____________________________________

Format ion :

Decomplexa t ion : - Oxidation (Me 3NO, Ce 4+ , FeCl 3)- Ligand exchange (Ph 3P)


27/147

2.4. 5 -Complexes _____________________________________

Format ion : Nucleophilic substitution

Decomplexa t ion : None really (very stable)Cp = spectator ligand


28/147

2.5. 6 -Complexes _____________________________________

Format ion : Ligand exchange (thermolysis)

Decomplexa t ion : Oxidation (Ce 4+ , I2, KMnO 4, O 2 /h )


29/147

3. Reactio n s o f -com plexes w i th n uc leophi les _____________________________________

Olefins normally do not react with nucleophiles.Coordination to a metal makes it possible.


30/147

3.1. Reactio n s o f o lefinic 2 -co m plexes (Pd) _____________________________________

Often highly regio- and stereo-selective ( s y n or anti )Pd - best understood (kermark) .

Bjrn kermark


31/147

3.1. Reactio n s o f o lefinic 2 -co m plexes (Pd) _____________________________________Orbital interactions in the palladium 2-complexes


32/147



33/147


Wacker oxidation


34/147


Wacker-Tsuji oxidation


35/147


Ap pl .: Pherom one syn thesis (Sem m elhack)


36/147


an ti

Ap pl .: R ing c los ure in s te ro ids (Ko o v s k )


37/147


Ap pl .: Isoxazol id ines (Ko o v s k )


38/147

3.2. Reactio n s o f al lyl ic 3 -complexes _____________________________________

Mainly Pd , some Mo , W, Ir , Rh , Fe

Mechan ism (Pd: Tsuji, Trost)

Regioselec t iv i ty (Tsuji, Trost, Hayashi )

Jiro Tsuji Tamio Hayashi


39/147

3.2. Reactio n s o f al lyl ic 3 -co m plexes (Pd) _____________________________________

Stereochemis t ry (Trost, Hayashi, Schwartz, Fiaud, Bckvall, Ko ovsk)

Barry Trost


40/147

144


Appl . : Synthesis of Flexibilene (McMurry)

John McMurry


41/147


Allyl carbonates - no base required (Tsuji):

Protection of OH and NH via allylic carbonates/carbamates(extremely mild and selective deprotection)


42/147

3.2. Reactio n s o f al lyl ic 3 -co m p lexes (Rh , Ir) _____________________________________

Oxygen nucleophiles (Evans, Hartwig, Helmchen, Ko ovsk ):

Stereochemistry

Paul Evans

Yellow


43/147

3.2. Reactio n s o f al lyl ic 3 -co m p lexes (Ir) _____________________________________

Oxygen nucleophiles with chiral ligands (Ko ovsk ):

Alexakis-Feringa ligand

Alex Alexakis Ben Feringa


44/147

3.3. A llyl ic rearrang em ents (Pd) _____________________________________

[3,3] Sigmatropic rearrangement catalyzed by Pd

Asymmetric version

Lary Overman


45/147

3.3. A llyl ic rearrang em ents (Pd) _____________________________________

Diastereoselective version

Applications

Andy Sutherland

4


46/147


Stoichiometric functionalisation of dienes using Mo and Fe (Birch, Pearson, Liebeskind, etc.).

Arthur Birch

Lanny Liebeskind

4


47/147


Tutorial : Explain the following transformations and rationalize thestereostructure of the intermediates and of the final product

f l l l 4 l ( l )


48/147

3.4. Reactio n s o f al lyl ic 4 -co m plexes (catalyt ic) _____________________________________Catalytic 1,4-functionalisation of dienes using Pd ( Bckvall reaction )

Jan Bckvall

3 4 R i f l l l i 4 l ( l i )


49/147

3.4. Reactio n s o f al lyl ic 4 -co m plexes (catalyt ic) _____________________________________

Chloride effect in Bckvall reaction:

3 4 R i f l l l i 4 l ( l i )


50/147


Tutorial : suggest the experimental conditions for the following transformations.

Which diastereoisomer of the starting compound will be suitable in part (c)?

3 4 R i f l l l i 4 l ( l i )


51/147


A p p l : Synthesis of the Monarch butterfly pheromone (Bckvall)

3 4 R i f l l l i 4 l ( l i )


52/147


A p p l : Bridged heterocycles - synthesis of tropane alkaloids (Bckvall)


53/147

3 4 R ti f l l l i 4 l ( t l t i )


54/147


A p p l : Spirocyclic heterocycles (Bckvall)

3 4 R ti f l l l i 4 l ( t l t i )


55/147


A p p l : Synthesis of heliotridane (Bckvall)

3 4 Reactio n s o fal lyl ic 4 co m plexes(catalyt ic)


56/147


A p p l : Carbocycles (Oppolzer)

Wolfgang von Oppolzer

4 Reactio n so f complexes


57/147

4. Reactio n s o f -complexes _____________________________________

4.1. React ion s in vo lvin g an s p 2 - or s p 3 -carbon

(Heck reactio n )

Richard Heck

4 1 Heckreactio n


58/147

4.1. Heck reactio n _____________________________________

Mechanism

:NEt 3

4 1 Heckreactio n


59/147

163

4.1. Heck reactio n _____________________________________

4 1 Heckreactio n


60/147

4.1. Heck reactio n _____________________________________

Enant iose lec t ive Heck react ion (Hayashi)

4 1 Heckreactio n


61/147

4.1. Heck reactio n _____________________________________

Stereodisc r im inat ing Heck react ion

In t ramo lecular Heck react ion - Unus ual regioselec t iv i ty

4 1 Heckreactio n


62/147

4.1. Heck reactio n _____________________________________

Catalyst: Pd (0) vs Pd (II); in s i tu generation of Pd( 0) from Pd( II):

4 1 Heckreactio n


63/147

167

4.1. Heck reactio n _____________________________________Multiple Heck reaction in complex synthesis: Vitamin D (Trost)

4 1 Heckreactio n


64/147

4.1. Heck reactio n _____________________________________

Tutor ia l : Exp la in the fo l lowing reac t ions

4 2 Cyclo fun ct io nal izat ion


65/147

4.2. Cyclo fun ct io nal izat ion _____________________________________Cycloo xyp al ladat ion - aryla tion

4 2 Cyclo fun ct io nal izat ion


66/147

4.2. Cyclo fun ct io nal izat ion _____________________________________Cycloam idop al ladat ion - arylat ion

4 3 React ion s Inv olv ing ans p 2 -Carbon


67/147

4.3. React ion s Inv olv ing an s p Carbon _____________________________________

Hydroz i rcona t ion

4 3 React ion s Inv olv ing ans p 2 -Carbon


68/147


Methylz i rconat ion (Negishi react ion)

Ei-ichi Negishi

4.3.React ion s Inv olv ing ans p 2 -Carbon


69/147


Coupl ing reac t ions sp 2 -s p 2



70/147

174


Makoto Kumada

Ei-ichi Negishi Tamejiro Hiyama

John Stille Akira Suzuki

Richard Heck



71/147


Suzuki -Miyaura co up l ing

EPSRC: If the reac t ion wo rks , why d o yo u need to kno w th e mechan i sm??

4.3. React ion s Inv olv ing an s p 2 -Carbon


72/147

. . g p _____________________________________



73/147

g p _____________________________________

Anny Jutand



74/147

g p _____________________________________

Examp les o f Suzuk i cou p l ing : o r tho-d i rec ted m eta ll at ion

Victor Snie kus



75/147

g p _____________________________________

Examp les o f Suzuk i coup l ing :



76/147

g p _____________________________________

Har twig-Bu chw ald coup l ing

John Hartwig

Steve Buchwald

L i g a n d key ro le



77/147

g p _____________________________________

Har twig-Bu chw ald coup l ing : Mechan i sm



78/147

g p _____________________________________

Har twig-Bu chw ald coup l ing : L i g a n d



79/147

g _____________________________________

Har twig-Bu chw ald coup l ing : L i g a n d

Guy Lloyd-Jones(+ PK)



80/147

_____________________________________

Har twig-Bu chw ald coup l ing : Lig and accelera t ion

Gregory Fu

4.4. React ion s Inv olv ing an sp -Carb on


81/147

_____________________________________Sonog ash i ra cou p l ing

Syn thes i s o f ca l icheamic in 1 I

Kenk-ichiSonogashira

Kyriakos C.Nicolaou

5. Metal lo carb enes


82/147

_____________________________________

5.1. Tebb e reacti o n

Frederick Tebbe

Reagent

Reaction

5.1. Tebb e reacti o n


83/147

_____________________________________

Appl ica t ion

Andy Holmes

5.2. Metathesis and Cyclo pr op anat ion


84/147

_____________________________________

Yves Chauvin Bob Grubbs Richard Schrock



85/147

_____________________________________

Carbene g enerat ion



86/147

_____________________________________

In te rmolecu lar cyc lop ropana tion

Rearrangements in vo lv ing oxon ium y l ides and inse r t ion in C-H bond

Louis Hegedus

Stephen Clark

5.3. Ring -Clos in g Metath esis


87/147

_____________________________________

Catalys ts

Ring-c losure


88/147



89/147

_____________________________________

R in g c o n s t r u c t io n



90/147

_____________________________________

Medium and l arge r ing c ons t ruc t ion



91/147

_____________________________________

Other r ings co ns t ruc t ion


92/147

196

5.4. Cyclo pr op anat io n


93/147

_____________________________________

S im m o n s S m i t h

5.4. Cyclo pr op anat io n


94/147

_____________________________________

D ia zo c o m p o u n d s


95/147

5.4. Cyclo pr op anat io n _____________________________________


96/147

_____________________________________

Diazo com pou nds - in t ramolecu lar

6. Cyclo add i t ion s _____________________________________


97/147

6.1. Paus on -K hand react io n

Peter Pauson

Billy Kerr

6.1. Paus on -K hand react io n _____________________________________


98/147

6.1. Paus on -K hand react io n _____________________________________


99/147

Catalyt ic and enant ios e lec t ive vers ion

6.2. Negish i cy clizat ion _____________________________________


100/147

7. Oxid ation _____________________________________


101/147

7.1. Epo xid at ion : Sharpless


102/147

7.2. Epo xid at ion : Sharp less -K atsuk i _____________________________________


103/147

Mechan ism and s t e reoch emis t ry



104/147

Examples



105/147

Racemate reso lut ion

Chemo select ive epoxid at ion



106/147

De nov o syn thes i s o f ca rbohydra tes

ill Roush



107/147




108/147


7.3. Epo xid at ion : Yamam oto _____________________________________


109/147

Hisashi Yamamoto

Advantages:- No water sensitivity

- Low catalyst loadingDisadvantages:

- Vanadium is more expensive- Long reaction times

(e.g., -20 oC, 4 days)

7.4. Epo xid at ion : Jacob sen-Katsu ki _____________________________________


110/147

Eric Jacobsen

- Works ONLY with c is -olefins- NOT effective with allylic ROH



111/147

Catalys t des ign



112/147

Epox idat ion (c is -o lef ins)



113/147

Stereospeci f ic i ty

Radical s tabi l izat ion (by co nju gat ion) enc ou rages radica l mech anism .



114/147

Examples



115/147

App l .: Syn thes i s o f Cromaka lim

App l .: Syn thes i s o f Ind inav i r scaffo ld

Tutor ia l : (1) Identify the absolute configuration of Salen ligand required.(2) Show the mechanism for the formation of s y n -amino alcohol.

7.5. A zirid in ation _____________________________________


116/147

7.6. Dihyd ro xy lat ion _____________________________________


117/147

Upjohn catalytic method


118/147

7.6. Dihyd ro xy lat ion : enant ios elect iv i ty _____________________________________


119/147

Scaffold: pseudoenantiomers Ligands: C 2- symmetrical pseudoenantiomers

7.6. Dihyd ro xy lat ion : enant ios elect iv i ty _____________________________________


120/147

7.7 . A m inhy dro xyla t ion _____________________________________


121/147

Reagent and catalyst

Catalytic cycle

7.7 . A m inhy dro xyla t ion : enant iose lec t iv i ty _____________________________________


122/147

7.8. Hyd ro gen-t rans fer ox idat ion _____________________________________


123/147

8. Redu ct io n _____________________________________


124/147

Hydrogena t ion

William Knowles

Henri Kagan

Catalyt ic hy drog enat ion

L i g a n d s

Ryoji Noyori

8.1. Hyd ro g enation o f C=C _____________________________________


125/147

Xumu

Zhang

Andreas

Pfaltz

Frank

Glorius



126/147

Rh : Requ i res a coord ina t ing g roup in the m olecu le.



127/147

Rh



128/147

Ru : - Broader sco pe than Rh (e .g . , do es no t require amide m oiety).

- High er pressure



129/147

Ru and C=C



130/147

Ru and C=C



131/147

Ir and C=C

8.2. Hyd ro g enation o f C=O _____________________________________


132/147

Ru and C=O


133/147


134/147

8.3. Transfer hy dr og enat ion _____________________________________


135/147

Ru : Dynamic racemate resolut io n

9. Nucleoph i l ic add i t ion to c arbon yl d er iva tives _____________________________________


136/147

9.1. 1,2-A d d itio n

9.1. 1,2-A d d itio n _____________________________________


137/147

9.2. 1,4-A d d itio n _____________________________________


138/147

10. C-H Ac tivatio n _____________________________________10 1 A ro m atics


139/147

10.1. A ro m atics

10.1. A ro m atics _____________________________________


140/147

10.1. A ro m atics _____________________________________


141/147

10.1. A ro m atics _____________________________________


142/147

10.2. A l lyl ic po si t io n _____________________________________


143/147

10.3. Keto n e -pos i t ion _____________________________________


144/147

10.4. A liph atic C-H in sert io n _____________________________________


145/147

10.4. A liph atic C-H in sert io n _____________________________________


146/147


147/147

pk organometallics l4 2014m tif

Documents