به نام خدا

Dr Morteza Mehrdad

University of Guilan, Department of Chemistry,

Rasht, Iranm-mehrdad@guilan.ac.ir

Advanced

Organic

Synthesis

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SYNTHETIC DESIGN

1. Retrosynthetic Analysis

2. Reversal of the Carbonyl Group Polarity (Umpolung)

3. Steps in Planning a Synthesis

4. Choice of Synthetic Method

5. Domino Reactions

6. Computer-Assisted Retrosynthetic Analysis

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1. Retrosynthetic Analysis

Basic Concepts

The construction of a synthetic tree by workingbackward from the target molecule (TM) is calledretrosynthetic analysis or antithesis.

The symbol signifies a reverse synthetic step and iscalled a transform.

The main transforms are disconnections, or cleavage of C-C bonds, and functional group

interconversions (FGI).

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Synthons are fragments resulting from disconnectionof carbon-carbon bonds of the TM.

The actual substrates used for the forward synthesisare the synthetic equivalents (SE).

Also, reagents derived from inverting the polarity (IP)of synthons may serve as SEs.

Synthetic design involves two distinct steps:1) retrosynthetic analysis and2) subsequent translation of the analysis into a

"forward direction" synthesis.

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Chemical bonds can be cleaved:

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Donor and Acceptor Synthons

Heterolytic retrosynthetic disconnection of a carbon-

carbon bond in a molecule breaks the TM into

o an acceptor synthon, a carbocation,

o and a donor synthon, a carbanion.

In a formal sense, the reverse reaction - the formation

of a C-C bond - then involves the union of

o an electrophilic acceptor synthon

o and a nucleophilic donor synthon

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Often, more than one disconnection is feasible: A & B

inverting the polarity

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inverting the polarity

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Alternating Polarity disconnection

• The question of how one chooses appropriate carbon-carbon bond disconnections is related to functionalgroup manipulations since the distribution of formalcharges in the carbon skeleton is determined by thefunctional group(s) present.

• The presence of a heteroatom in a molecule imparts apattern of electrophilicity and nucleophilicity to theatoms of the molecule.

• The concept of alternating polarities or latent polarities(imaginary charges) often enables one to identify thebest positions to make a disconnection within acomplex molecule.

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Functional groups may be classified as follows:

E class: Groups conferring electrophilic character to

the attached carbon ( + ):

-NH2, -OH, -OR, =O, =NR, -X (halogens)

G class: Groups conferring nucleophilic character to

the attached carbon(-):

-Li, -MgX, -AlR2, -SiR3

A class: Functional groups that exhibit ambivalent

character (+ or -):

-BR2, C=CR2, C≡CR , -NO2, ≡N, -S(O)R, -SO2R 12

The positive charge (+) is placed at the carbon attached

to an E class functional group (e.g., =O, -OH, -Br) and the

TM is then analyzed for consonant and dissonant

patterns by assigning alternating polarities to the

remaining carbons.

In a consonant pattern, carbon atoms with the same

class of functional groups have matching polarities,

Consonant patterns: Positive charges are placed at carbon atoms bonded to the E class groups. 13

whereas in a dissonant pattern, their polarities areunlike.If a consonant pattern is present in a molecule, a simplesynthesis may often be achieved.

Dissonant patterns: One E class group isBonded to a carbonwith a positive charge,whereas the other E class group resideson a carbon with anegative charge.

Examples of choosing reasonable disconnections offunctionally substituted molecules based on the conceptof alternating polarity are shown below. 14

One Functional Group

Analysis

2-pentanol

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In the example shown above, there are two possibleways to disconnect the TM, 2-pentanol. Disconnection close to the functional group (path a)

leads to substrates (SE) that are readily available. Moreover, reconnecting these reagents leads

directly to the desired TM in high yield using well-known methodologies.

2-pentanol

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Disconnection via path b also leads to readilyaccessible substrates.

However, their reconnection to furnish the TMrequires more steps and involves two criticalreaction attributes: quantitative formation of the enolate ion and control of its monoalkylation by ethyl

bromide.

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Synthesis (path a)

Two Functional Groups in a 1,3-Relationship

Analysis

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Synthesis (path a)

Synthesis (path b)

Thc consonant charge pattern andthe presence of a -hydroxyketonemoiety in the TM suggest a retroaldol transform. Either the hydroxy-bearing carbon orthe carbonyl carbon of the TM mayserve as an electrophilic site and the corresponding -carbons as the nucleophilic sites.

However, path b is preferable since it does notrequire a selective functional group interconversion(reduction).

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Two Functional Groups in a1,4-Relationship

Analysis

2,5-hexanedione

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The dissonant charge pattern for 2,5-hexanedione exhibits a positive(+) polarity at one of the -carbons, as indicated in the acceptorsynthon above.

Thus, the -carbon in this synthon requires an inversion of polarity(Umpolung in German) from the negative (-) polarity normallyassociated with a ketone -carbon.

An appropriate substrate (SE) for the acceptor synthon is theelectrophilic -bromo ketone.

It should be noted that an enolate ion might act as abase, resulting in deprotonation of an -halo ketone, areaction that could lead to the formation of an epoxyketone (Darzens condensation).

To circumvent this problem, a weakly basic enamine isused instead of the enolate.

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Synthesis

In the case of 5-hydroxy-2-hexanone shown below,Umpolung of the polarity in the acceptor synthon isaccomplished by using the electrophilic epoxide as thecorresponding SE.

Analysis

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5-hydroxy-2-hexanone

Synthesis

The presence of a C-C-OH moiety adjacent to a potential nucleophilicsite in a TM, as exemplified below, points to a reaction of an epoxidewith a nucleophilic reagent in the forward synthesis.The facile, regioselective opening of epoxides by nucleophilicreagents provides for efficient two-carbon homologation reactions.

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2. Reversal of the Carbonyl Group Polarity (Umpolung)

In organic synthesis, the carbonyl group is intimately

involved in many reactions that create new carbon-

carbon bonds.

The carbonyl group is electrophilic at the carbon atom

and hence is susceptible to attack by nucleophilic

reagents.

Thus, the carbonyl group reacts as a formyl cation or

as an acyl cation.

A reversal of the positive polarity of the carbonyl group

so it acts as a fomyl or acyl anion would be syntheti-

cally very attractive.25

2. (Umpolung)- Continue …

To achieve this, the carbonyl group is converted to a

derivative whose carbon atom has the negative

polarity.

After its reaction with an electrophilic reagent, the

carbonyl is regenerated.

Reversal of polarity of a carbonyl group has been

explored and systematized by Seebach.

Umpolung in a synthesis usually requires extra steps.

Thus, one should strive to take maximum advantage of

the functionality already present in a molecule.

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The following example illustrates the normal disconnec-tion pattern of a carboxylic acid with a Grignard reagentand carbon dioxide as SEs (path a)and a disconnection leading to a carboxyl synthon withan "unnatural" negative charge (path b).Cyanide ion can act as an SE of a negatively chargedcarboxyl synthon.Its reaction with R-Br furnishes the corresponding nitrile,which on hydrolysis produces the desired TM.

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Formyl and Acyl Anions Derived from 1,3-Dithianes

• The most utilized Umpolung strategy is based on

formyl and acyl anion equivalents derived from

2-lithio-1,3-dithiane species.

• These are readily generated from 1,3-dithianes

(thioacetals) because the hydrogens at C(2) are

relatively acidic (pKa~3 I ).

• In this connection it should be noted that thiols (EtSH,

pKa 11) are stronger acids compared to alcohols (EtOH,

pKa 16). 29

• Also, the lower ionization potential and the greaterpolarizability of the valence electrons of sulfurcompared to oxygen make the divalent sulfurcompounds more nucleophilic in SN2 reactions.

• The polarizability factor may also be responsible for thestabilization of carbanions to sulfur.

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The anions derived from dithianes react with alkyl halides to give the corresponding alkylated dithianes.

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Their treatment withHgCl2-HgO regenerates aldehydes or ketones, respectively, as depicted below.

Dithiane-derived carbanions can be hydroxyalkylated

or acylated to produce, after removal of the

propylenedithiol appendage, a variety of difunctional

compounds, as shown below.

In the presence of HMPA (hexamethylphosphoramide,

[(Me2N)3P=O]), dithiane-derived carbanions may serve

as Michael donor.

However, in the absence of HMPA, 1,2-addition to the

carbonyl group prevails.

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An instructive example of using a dithiane Umpolungapproach to synthesize a complex natural product is theone-pot preparation of the multifunctional intermediateshown below, which ultimately was elaborated to theantibiotic vermiculin.

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Acyl Anions Derived from Nitroalkanes

The -hydrogens of nitroalkanes are appreciablyacidic due to resonance stabilization of the anion[CH3NO2, pKa 10.2; CH3CH2NO2, pKa 8.5].

The anions derived from nitroalkanes give typicalnucleophilic addition reactions with aldehydes (theHenry-Nef tandem reaction).

Note that the nitro group can be changed directly to acarbonyl group via the Nef reaction (acidicconditions).

Under basic conditions, salts of secondary nitrocompounds are converted into ketones by thepyridine-HMPA(Hexamethyl phosphoramide) complexof molybdenum (VI) peroxide.

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Nitronates from primary nitro compounds yieldcarboxylic acids since the initially formed aldehyde israpidly oxidized under the reaction conditions.

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An example of an -nitro anion Umpolung in the synthesis ofjasmone (TM)

Analysis

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Synthesis

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Acyl Anions Derived from Cyanohydrins

O-Protected cyanohydrins contain a masked carbonyl group withinverted polarity.

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The -carbon of an O-protectedcyanohydrin is sufficiently activatedby the nitrile moiety [CH3CH2CN, pKa

30.9] so that addition of a strongbase such as LDA generates thecorresponding anion.

Its alkylation, followed by hydrolysis of the resultant alkylatedcyanohydrin, furnishes the ketone.

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The overall reaction represents alkylation of an acylanion equivalent as exemplified for the synthesis ofmethyl cyclopentyl ketone.

An attractive alternative to the above protocol involvesthe nucleophilic acylation of alkylating agents witharomatic and heteroaromatic aldehydes via trimethyl-silyl protected cyanohydrins.

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Acyl anion synthons derived from cyanohydrins may begenerated catalytically by cyanide ion via the Stetterreaction.However, further reaction with electrophiles is confinedto carbonyl compounds and Michael acceptors.

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Acyl Anions Derived from Enol Ethers

The -hydrogens of enol ethers may be deprotonatedwith tert-BuLi.

Alkylation of the resultant vinyl anions followed byacidic hydrolysis provides an efficient route for thepreparation of methyl ketones.

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Acyl Anions Derived from Lithium Acetylide

Treatment of lithium acetylide with a primary alkyl halide(bromide or iodide) or with aldehydes or ketones producesthe corresponding monosubstituted acetylenes orpropargylic alcohols.Mercuric ion-catalyzed hydration of these furnishes methylketones and methyl -hydroxy ketones, respectively.

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Henry-Nef tandem reaction

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Nef reaction

The Nef reaction is an organic reaction describing the acid hydrolysis of

a salt of a primary or secondary nitroalkane (1) to an aldehyde or

a ketone (3) and nitrous oxide (4).

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Stetter reaction

The Stetter reaction is a reaction used in organic chemistry toform carbon-carbon bonds through a 1,4-addition reaction utilizinga nucleophilic catalyst.

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