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Organic

Synthesis

6

Dr Morteza Mehrdad

University of Guilan, Department of Chemistry,

Rasht, Iranm-mehrdad@guilan.ac.ir

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1. Elementary Retrosynthetic Analysis

1.1. Open-chain Compounds

1.2. Mono- and Bicyclic target Molecules

1.3. Bridged Polycyclic Molecules

1.4. Summary of Antithetical Analysis of Simple Molecules

2. Learning from Research papers

3. Tandem reactions

4. Green Chemistry

2.

3

J. A. C. S. 1981, 103(25), ……

4

Cala Ratjada (Mallorca)isolated from soil bacteria

Ratjadonepotent cancerostaticumand fungicide

trans,trans-diene

cis,trans-diene

Perhydro pyran

Perhydro pyranwith double band

disconnected by a retro-Heck coupling

Wittig reactionsBhatt, U. et al., J. Org. Chem. 2001, 66, 1885-1893 5

6

hetero-Diels-Alder reaction of an acrolein derivative

retro-opened to a -hydroxy epoxide

A

B

7

antitumor activity

D-glutamic acid(chiral pool)

*

Boger, D. L. et al., J. Am. Chem. Soc. 2001, 123, 4161-4167

Fostriecin

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Sharpless Asymmetric Dihydroxylation

AD mix

water, t-BuOH

CH2OH

OHH

*

9

10

Standard Dihydroxylation

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Possible [3+2] Cycloaddition

(DHQD)2PHAL (found in AD-mix )1,4-bis(9-O-dihydroquinidine)phthalizine

• Coordination of a chiral amine to the OsO4

leads to an asymmetric complex.

12

(DHQD)2AQNdihydroquinidine (anthraquinone-1,4-diyl) diether

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Sharpless Asymmetric Dihydroxylation

14

Use a Pre-mix of reagent components

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16

98

98

The Ligand Accelerates the Reaction Transfers the Chiral Information

M. H. Junttila, O. E. O. Hormi, J. Org. Chem., 2004, 69, 4816-4820.

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Horner–Wadsworth–Emmons Reaction

The Horner–Wadsworth–Emmons (HWE) reaction involves theaddition of a stabilized phosphonate anion to an aldehyde or ketoneto afford an intermediate which undergoes an elimination reaction toform predominately the (E)-alkene. The HWE reaction has beenapplied inter- and intramolecularly to simple as well as highlyfunctionalized systems.

19

Masamune–Roush Modification of theHorner–Wadsworth–Emmons Reaction

The Masamune–Roush modification of the HWE is a very mildvariant that does not require the use of a strong base (i.e., NaH orn-BuLi) to generate the phosphonate anion. Instead, in thepresence of LiCl, a lithium chelate forms which enhances the acidityof the α-protons. Hence, DBU (1,8-Diazabicycloundec-7-ene) issufficiently basic to carry out the deprotonation of thephosphonate.

20

Since the original paper, milder bases have been used, includingtriethylamine and disopropylethylamine (Hunigs’ base). Again, thereis strong preference for the formation of the (E)-alkene when thecoupling partner is an aldehyde.

21

Still–Gennari Modification of theHorner–Wadsworth–Emmons Reaction

The Still–Gennari modification of the HWE reaction was amajor achievement, because this modification allowed access to(Z)-olefins with high stereoselectivity using a phosphonate. In this

version of the HWE, strong preference for Z-alkenes is achievedwith the phosphonate bearing electron withdrawing groups underionic dissociating conditions (crown-ether).

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Ando Modification of theHorner–Wadsworth–Emmons Reaction

The Ando modification of the HWE reaction is yet another majorcontribution to the formation of (Z)-alkenes via phosphonates. In

this version of the HWE, diarylphosphonates are utilized.

Review: Ando, K. J. Org. Chem. 1998, 63, 8411−8416.23

Direct Synthesis of Z-unsaturated esters; a useful modification of the Horner-Emmons Olefination

Still, W.C., JACS, 1979, 101(9), 2493 & Adams, M.A.; Nakanishi, K.; Still, W.C.; Arnold, E.V.; Clardy, J.; Persoons, C.J.; JACS, 1979, 101(9), 249524

Still – Gennari Modification

Horner-Wadsworth-Emmons

Still – Gennari Modification

- Still–Gennari modification selective for Z-alkenes ( cis):

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26

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DMP = Dess-Martin periodinane

Preparation of the Dess−Martin Reagent

The Dess−Martin oxidation is the method of choice for theoxidation of alcohols bearing sensitive functional groups.

CAUTION! The Dess−Martin precursor [1-hydroxy-l,2-benziodoxol-3(1H)-one (IBX)]was reported to be explosive under excessive heating (> 200 ºC) or impact.Sporadically, IBX did not decompose explosively at 233 ºC, but melted withbrowning.However, this cannot be taken as an indication of absence of explosivity as thesame batch showed inconsistent results. An analytically pure sample (≥ 99%) wassubjected to explosibility tests.

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Dess–Martin periodinane

The Dess–Martin (D−M) oxidation is the method of choice forthe oxidation of alcohols bearing sensitive functional groups tothe corresponding carbonyl compounds.The reagent that accomplishes this oxidation is 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one or simply the Dess–Martin periodinane (DMP).

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Stille couplingThe Stille reaction, or the Migita-Kosugi-Stille coupling, isa chemical reaction widely used in organic synthesis whichinvolves the coupling of an organotin compound (also knownas organostannanes) with a variety of organic electrophilesvia palladium-catalyzed coupling reaction.

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Mechanism

The mechanism of the Stille reaction is one of the most extensivelystudied pathways for coupling reactions.The basic catalytic cycle, asseen below, involves an oxidative addition of a halide orpseudohalide (2) to a palladium catalyst (1), transmetalationof 3 with an organotin reagent (4), and reductive elimination of 5 toyield the coupled product (7) and the regenerated palladiumcatalyst (1)

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Cram’s Rule

C X* diastereomericfaces

X = C, O, N

stereogeniccenter How does this center control

The direction of attack atThe trigonal carbon?

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R

MS

L

O

LRNu

OHMS

LNuR

OHMS

Nu:

Less steric effects

Major product

Nu:

Minor product

OMS

RL

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R

MS

L

O

L

M

S R

O

L

S

MR

O

This is the important

interaction that must be

minimized. Thus, in this

approach the carbonyl

substituent plays the major

role.

Favored Conformer

for Attack

The interpretation of Felkin and Anh

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Bürgi-Dunitz

trajectory

109°

Obtuse attack trajectory

minimizes unfavorable

interactions between these

orbitals

C OR

M

L

S

s

p*

Nu

Houk computational view:

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The obtuse angle of attack supports the nonpassive role of theR-group in ketones. Not only will there be steric interactionsbetween the S or M groups and the R-group, but also interactionswith the incoming nucleophile due to the attack trajectory. In this model one would predict an increase of stereodifferentiation as thesize of R increases. This has been found experimentally

O O

R R

Preferred conformation.

Less interaction between

the small group and the

R-group. Note that this

model "feels" the influence

of increasing size of R.

In this coformer, an

increased interaction

is seen between the

medium group and R.

Also, there is more

interaction with the

nucleophile. 36

A useful orbital approach by Cieplak, suggests that the nucleophilewill attack the carbonyl anti to the best donor ligand.

A.S. Cieplak, B.D. Yait and C.R. Johnson, J. Am. Chem. Soc., (1989), 111, 8447

A.S. Cieplak, J. Am. Chem. Soc., (1981), 103, 4548.

Donor

O

s* of nucleophileCarbon donors-bond

Nu:

E

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Cases for Modification of the Models

Compare the "normal" situation with the influence ofa sterically bulky Lewis acid

L

S

MO

H

O

H

S

M

L

Lewis acid

Nu:

As the bulk of the

Lewis acid increases

Lewis acid

:Nu

This gives the

Cram product

This gives the

"anti-Cram" product

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Dipolar Model

often described as the Cornforth model

R'

RH

Cl

R"M

R'

RH

Cl

OHR"O

Preferred direction

of attack.

favored conformer

S

X L

O

R X

L S

O

R

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Chelation ControlSee: M.T. Reetz, Acc. Chem. Res., (1993), 26, 462.

RLS

Het O

M

Preferred

direction

of attack

Het = heteroatom

M = metal

L

S

HetO

R

M

OTi

O

Cl

ClCl

ClH

Me

R

Ph

40

OS O

SMe

Me

Me Me

Me

MePh Ph

O O

Mg

MeI

MeMgI H3O+

Predict a product from the following reaction

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A potentially useful extension of Cram's rule is the asymmetricinduction provided by a remote ester (Prelog's rule):

RO L

O

O S M

R'MgX

Why would you think this might not provide as

important directing influences?

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The Evolution of Models for Carbonyl Addition

Fischer Cram Cornforth Felkin Anh/Eisenstein Cieplak Tomoda

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Frondosin B

contains four condensed rings:

phenol

furane cycloheptene

cyclohexene

from a Diels-Alder reaction

from an intramolecularFriedel-Crafts acylation

Inoue, M. et al., J. Am. Chem. Soc. 2001, 123, 1878-1889

isolated from a sponge is anti-inflammatory

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The rest is Sharplessand phenol chemistry

Furane from a base- and palladium-catalyzedintermolecular addition of a phenolate to an alkyne.

Sonogashira Coupling

Alkyne from a

The Sonogashira Coupling

16. L. Cassar, J. Organomet. Chem. 1975, 93, 253 – 259.

17. H. A. Dieck, F. R. Heck, J. Organomet. Chem. 1975, 93, 259 – 263.

18. K. Sonogashira, Y. Tohda, N. Hagihara, Tetrahedron Lett. 1975, 16, 4467 – 4470.

19. For a brief historical overview of the development of the Sonogashira reaction, see: K. Sonogashira, J. Organomet. Chem. 2002, 653, 46 – 49.

20. R. D. Stephens, C. E. Castro, J. Org. Chem. 1963, 28, 3313 – 3315.

21. a) M. Alami, F. Ferri, G. Linstrumelle, Tetrahedron Lett. 1993, 34, 6403 – 6406; b) J.-P. Genet, E. Blart, M. Savignac, Synlett 1992, 715 – 717; c) C. Xu, E. Negishi, Tetrahedron Lett. 1999, 40, 431 – 434;

• The coupling of terminal alkynes with vinyl or aryl halides via palladium catalysis was first reported independently and simultaneously by the groups of Cassar[16] and Heck[17] in 1975.

• A few months later, Sonogashira and co-workers demonstrated that, in many cases, this cross-coupling reaction could be accelerated by the addition of cocatalytic CuI salts to the reaction mixture.[18,19]

• This protocol, which has become known as the Sonogashira reaction, can be viewed as both an alkyne version of the Heck reaction and an application of palladium catalysis to the venerable Stephens–Castro reaction (the coupling of vinyl or aryl halides with stoichiometric amounts of copper(I) acetylides).[20]

• Interestingly, the utility of the “copperfree” Sonogashira protocol (i.e. the original Cassar–Heck version of this reaction) has subsequently been “rediscovered” independently by a number of other researchers in recent years.[21]

R2 Xcat. [Pd0Ln]

base

R1 = alkyl, aryl, vinyl

R2 = alkyl, benzyl, vinyl

X = Br, Cl, I, OTf

R2R1 H R2

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Mechanism of the Sonogashira Coupling

PdPh3P PPh3

Ph3P PPh3

PdPh3P

Ph3P PPh3Pd

Ph3P

Ph3P

- PPh3

- PPh3

Pd0

Pd0

Pd0

Br

PdPh3P

Br PPh3

PdII

PdPh3P

PPh3

R1

R1

Cu

CuBr

H

R1

NEt3

PdPh3P

Ph3P

R1

R1

R1

NEt3H

PdII

PdII

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K. C. Nicolaou, S. E. Webber, J. Am. Chem. Soc. 1984, 106, 5734 – 5736

The Sonogashira Coupling: Eicosanoid 212

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P. Wipf, T. H. Graham, J. Am. Chem. Soc. 2004, 126, 15346 –15347.

The Sonogashira Coupling: Disorazole C1

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The Sonogashira Coupling: Dynemicin

a) J. Taunton, J. L. Wood, S. L. Schreiber, J. Am. Chem. Soc. 1993, 115, 10 378 – 10379

b) J. L. Wood, J. A. Porco, Jr., J. Taunton, A. Y. Lee, J. Clardy, S. L. Schreiber, J. Am. Chem. Soc.

1992, 114, 5898 – 5900

c) H. Chikashita, J. A. Porco, Jr., T. J. Stout, J. Clardy, S. L. Schreiber, J. Org. Chem. 1991, 56, 1692 – 1694

d) J. A. Porco, Jr., F. J. Schoenen, T. J. Stout, J. Clardy, S. L. Schreiber, J. Am. Chem. Soc. 1990, 112, 7410 – 7411. 50

51Cohen, F. et al., J. Am. Chem. Soc. 2001, 123, 10782-10783

An alkaloid was isolated from a Jamaican sponge useful to treat autoimmune responses, and inhibits protein-protein interactions two tricyclic

guanidine derivatives

branched octanoic acid chain

was disconnected to give a guanidine hemi-aminal and a chiral alcohol in the side-chain, which could be substituted stereoselectively

attached via a-ketoester carbanion

from a 1,3-diamine and Cbz-protected carbonimidothioate

Batzelladine F

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A triazacyclophaneTripodal Receptor Molecules(as hinge)

selectively sulfonatedand trifluoroacetylated

Acetylation with alkylchloroformate

i) triflate +methanolii) Fmoc-N-hydroxy-

succinimide

DeprotectionO-NBS (thiolysis)Aloc(Pd-catalyzed alkyl transfer to aniliniump-toluenesulfinate)

Opatz, T. et al. J. Comb. Chem. 2002, 4, 275-284

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3. Tandem Reactions

Tandem reactions form several covalent bonds in one sequence without isolating the intermediates.Also called “domino” or “cascade” reactions"Multistep reaction'' or "one-pot sequence“

(descriptions of the procedure)

The ACS search program produces:507 “tandem”, 115 “cascade”and34 “domino”titles

published since 1996-2002

1250 “tandem”, 576 “cascade”and297 “domino”titles

published since 2008-14

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Some sterically hindered, SnCl4-catalyzed hetero-Diels-Aldercyclizations of -unsaturated ketoesters with alkene alcohols donot occur intramolecularly.

Large substituents on the ketoester prevent the formationof medium-sized rings and the first reaction is a linear dimerization combined with the formation of one dihydropyranunit. The second reaction then gives a second dihydropyran and producesa macrocyclic oligo-ether with good yield.

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Acetylacetate reacts with zinc methylene iodide (Furukawa reagent)

zinc enolate add its methylene group to the enolate's double bond

Aldehydes then decomposethe cyclopropane formedand undergo a Reformatskyaddition.

Chain extension-aldol addition tandem

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Acetals were then reactive enough to decompose the enolate and form a second CC bond stereoselectively the presence of chiral phosphines

three-step reaction a cyclohexanone derivative underwent zinc enolate formation and Michael addition in one step

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Dieckmann cyclization with a neighboring benzyl ester

The synthesis of a highly functional arene derivative

coupling of a cyanide Michael addition to propargylic acid

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4. Green Chemistry

There are U.S. and European Green Chemistry Programs, which tryto establish environmentally benign synthetic procedures.Energy requirements, waste, and the number of separation stepsare all minimized by increased selectivity of the reactions catalyzed.Heck-, Sharpless- and Noyori-type reactions are successfulendeavors.Another approach is to replace solvents by water or by supercriticalfluids, in particular CO2.CO2 can replace chlorinated solvents.Replacement of soluble Lewis acids by mesoporous solidscontaining bound sulfonates or aluminum chloride should alsobecome common practice.The solids can be filtered off and usually reactivated and recycled. This helps to prevent waste.

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most typical for green chemistry, educts should preferably comefrom renewable sources, in particular glucose

Furthermore syntheses should be atom-efficient, and reagents assimple as possible. Catalysed reactions are preferable.

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Household and large-scale industrial chemicals, e.g. chelators,should always be biodegradable, as should the intermediates intheir synthesis.Boger's iminodiacetic acids are good examples, because they onlyuse succinic acid derivatives

The Heck Reaction• Broadly defined as the palladium-catalyzed coupling of

alkenyl or aryl (sp2) halides or triflates with alkenes to

yield products which formally result from the

substitution of a hydrogen atom in the alkene coupling

partner.

• First discovered by Mizoroki, though developed and

applied more thoroughly by Richard F. Heck in the early

1970s.[3]

• Generally thought of as the original palladium catalysed

cross-coupling, and probably the best evolved,

including a multitude of asymmetric varients.[4]

3. R. F. Heck, J. P. Nolley, Jr., J. Org. Chem. 1972, 37, 2320

4. Review on asymmetric Heck reactions: A. B. Dounay, L. E. Overman, Chem. Rev. 2003, 103, 2945 – 2963

H

R1

R2

R3

R4 X R4

R1

R2

R3

cat. [Pd0Ln]

base

R4 = aryl, benzyl, vinyl

X = Cl, Br, I, OTf

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Mechanism of the Heck Reactionneutral

PPh3

PdPh3P PPh3

Ph3P PPh3

PdPh3P

Ph3P PPh3Pd

Ph3P

PPh3

- PPh3

- PPh3

Pd0

Pd0

Pd0

Br

PdPh3P

Br PPh3

PdII

O

O

PdPh3P

Br PPh3

O

O

PdII -Complex

PdPh3P

Br

O O

H H

PdII -Intermediate

PdPh3P H

Br PPh3

O

O

PdII -Complex

PdPh3P H

Br PPh3

B

HBr / B

PdIIO

O

OxidativeAddition

-hydrideElimination

ReductiveElimination

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Mechanism of the Heck Reactioncationic

PPh3

PdPh3P PPh3

Ph3P PPh3

PdPh3P

Ph3P PPh3Pd

Ph3P

PPh3

- PPh3

- PPh3

Pd0

Pd0

Pd0

BrPd

Ph3P

Br PPh3

PdII

O

O

PdPh3P

PPh3

O

O

PdII -Complex

PdPh3P

O O

H H

PdII -Intermediate

PdPh3P H

PPh3

O

O

PdII -Complex

PdPh3P H

PPh3

B

PdIIO

O

OxidativeAddition

-hydrideElimination

ReductiveElimination

BrAg

HB

Ag

Abelman, M. M.; Oh, T.; Overman, L. E. J. Org. Chem. 1987, 52, 4133–4135. 63

Regioselectivity in the Heck Reaction

a) Cabri, W.; Candiani, I. Acc. Chem. Res. 1995, 28, 2–7.

b) Cabri, W.; Candiani, I.; Bedeschi, A.; Penco, S.; Santi, R. J. Org. Chem. 1992, 57, 1481–1486.

Ph

Y N

CH3 OH

O

OH

100 90 100

10

100 60 80

40 20

Y = CO2R CN CONH2

Ph

Y N

CH3 OH

O

OH

60 5

95

100 10

100 90

Y = CO2R CN CONH2

40 100

Neutral Catalytic Cycle Cationic Catalytic Cycle

• The type of mechanism in action is incredibly important, as it can manifest itself in a variety

of ways, especially the regioselectivity.

• In the neutral catalytic cycle, the regioselectivity is governed by steric factors – generally

addition occurs to the terminal end of the alkene.

• However, in the cationic cycle, regiochemistry is affected by electronics. The cationic Pd

complex increases the polarization of the alkene favouring transfer of the vinyl or aryl group

to the site of least electron density.

• The type of mechanism in effect is generally controlled by choice of halide/pseudohalide

acting as a leaving group in the cationic cycle; triflate promotes, whereas bromide detracts.

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