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Organic

Synthesis

6

Dr M. Mehrdad University of Guilan, Department of Chemistry,

Rasht, Iran

2

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

Ratjadone potent cancerostaticum and fungicide

trans,trans-diene

cis,trans-diene

Perhydro pyran

Perhydro pyran with double band

disconnected by a retro-Heck coupling

Wittig reactions Bhatt, 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

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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

*

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Standard Dihydroxylation

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Possible [3+2] Cycloaddition

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(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.

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(DHQD)2AQN dihydroquinidine (anthraquinone-1,4-diyl) diether

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Sharpless Asymmetric Dihydroxylation

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Use a Pre-mix of reagent components

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16

The Ligand Accelerates the Reaction Transfers the Chiral Information

M. H. Junttila, O. E. O. Hormi, J. Org. Chem., 2004, 69, 4816-4820. 17

Horner–Wadsworth–Emmons Reaction

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The Horner–Wadsworth–Emmons (HWE) reaction involves the addition of a stabilized phosphonate anion to an aldehyde or ketone to afford an intermediate which undergoes an elimination reaction to form predominately the (E)-alkene. The HWE reaction has been applied inter- and intramolecularly to simple as well as highly functionalized systems.

19

Masamune–Roush Modification of the Horner–Wadsworth–Emmons Reaction

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

20

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

21

Still–Gennari Modification of the Horner–Wadsworth–Emmons Reaction

The Still–Gennari modification of the HWE reaction was a major 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 achieved with the phosphonate bearing electron withdrawing groups under ionic dissociating conditions (crown-ether).

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Ando Modification of the Horner–Wadsworth–Emmons Reaction

The Ando modification of the HWE reaction is yet another major contribution 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), 2495

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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 the oxidation 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 with browning. However, this cannot be taken as an indication of absence of explosivity as the same batch showed inconsistent results. An analytically pure sample (≥ 99%) was subjected to explosibility tests.

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Dess–Martin periodinane

The Dess–Martin (D−M) oxidation is the method of choice for the oxidation of alcohols bearing sensitive functional groups to the 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).

29

Stille coupling The Stille reaction, or the Migita-Kosugi-Stille coupling, is a chemical reaction widely used in organic synthesis which involves the coupling of an organotin compound (also known as organostannanes) with a variety of organic electrophiles via palladium-catalyzed coupling reaction.

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Mechanism

The mechanism of the Stille reaction is one of the most extensively studied pathways for coupling reactions.The basic catalytic cycle, as seen below, involves an oxidative addition of a halide or pseudohalide (2) to a palladium catalyst (1), transmetalation of 3 with an organotin reagent (4), and reductive elimination of 5 to yield the coupled product (7) and the regenerated palladium catalyst (1)

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Cram’s Rule

C X * diastereomeric faces

X = C, O, N

stereogenic center How does this center control

The direction of attack at The trigonal carbon?

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R

M S

L

O

L R N u

O H M S

L N u R

O H M S

Nu:

Less steric effects

Major product

Nu:

Minor product

O M S

R L

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R

M S

L

O

L

M

S R

O

L

S

M R

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 O R

M

L

S

s

p *

N u

Houk computational view:

35

The obtuse angle of attack supports the nonpassive role of the R-group in ketones. Not only will there be steric interactions between the S or M groups and the R-group, but also interactions with the incoming nucleophile due to the attack trajectory. In this model one would predict an increase of stereodifferentiation as the size 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 nucleophile will 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.

D o n o r

O

s * of nucleophile Carbon donor s -bond

Nu:

E

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Cases for Modification of the Models

Compare the "normal" situation with the influence of a sterically bulky Lewis acid

L

S

M O

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 Control See: M.T. Reetz, Acc. Chem. Res., (1993), 26, 462.

R L S

H e t O

M

Preferred

direction

of attack

Het = heteroatom

M = metal

L

S

H e t O

R

M

OTi

O

Cl

ClCl

ClH

Me

R

Ph

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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 asymmetric induction provided by a remote ester (Prelog's rule):

R O 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 intramolecular Friedel-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 Sharpless and phenol chemistry

Furane from a base- and palladium-catalyzed intermolecular 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

51 Cohen, 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 triazacyclophane Tripodal Receptor Molecules (as hinge)

selectively sulfonated and trifluoroacetylated

Acetylation with alkyl chloroformate

i) triflate +methanol ii) Fmoc-N-hydroxy- succinimide

Deprotection O-NBS (thiolysis) Aloc(Pd-catalyzed alkyl transfer to anilinium p-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”and 34 “domino”titles

published since 1996-2002

1250 “tandem”, 576 “cascade”and 297 “domino”titles

published since 2008-14

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Some sterically hindered, SnCl4-catalyzed hetero-Diels-Alder cyclizations of -unsaturated ketoesters with alkene alcohols do not occur intramolecularly.

Large substituents on the ketoester prevent the formation of medium-sized rings and the first reaction is a linear dimerization combined with the formation of one dihydropyran unit. The second reaction then gives a second dihydropyran and produces a 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 decompose the cyclopropane formed and undergo a Reformatsky addition.

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 try to establish environmentally benign synthetic procedures. Energy requirements, waste, and the number of separation steps are all minimized by increased selectivity of the reactions catalyzed. Heck-, Sharpless- and Noyori-type reactions are successful endeavors. Another approach is to replace solvents by water or by supercritical fluids, in particular CO2. CO2 can replace chlorinated solvents. Replacement of soluble Lewis acids by mesoporous solids containing bound sulfonates or aluminum chloride should also become 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 come from renewable sources, in particular glucose

Furthermore syntheses should be atom-efficient, and reagents as simple 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 in their synthesis. Boger's iminodiacetic acids are good examples, because they only use succinic acid derivatives