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Modern Organic Synthesis an Introduction

G. S. Zweifel

M. H. Nantz

W.H. Freeman and Company

Chapter 1 Synthetic Design

• What is an ideal or viable synthesis, and how does one approach a synthetic project?

• The overriding concern in a synthesis is the yield, including the inherent concepts of simplicity (fewest steps) and selectivity(chemoselectivity, regioselectivity, diastereoselectivity, and enantioselectivity).

• This chapter outlines strategies for the synthesis of target molecules based on retrosynthetic analysis.

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1.1 Retrosynthetic Analysis

Basic Concept

The symbol signifies a reverse synthetic step and is called a transform.

The main transforms are disconnections, or cleavage of C-C bonds, andfunctional group interconversions (FGI)

Retrosynthetic analysis involves the disassembly of a TM into available starting materials by sequential disconnections and functional group interconversions(FGI).

Synthons are fragments resulting from disconnection of carbon-carbonbonds of the TM.

The actual substrates used for the forward synthesis are the syntheticequivalents (SE).

Synthetic design involves two distinct steps(1) Retrosynthetic analysis(2) Subsequent translation of the analysis into a “forward direction” synthesis.

Chemical bonds can be cleaved heterolytically, homolytically, orthrough concerted transform.

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Donor and Acceptor Synthons

Table 1.1 Common Acceptor Synthon

Acceptor synthon carbocation (electrophilic)Donor synthon carbanion (nucleophilic)

Synthetic equivalents

Common Acceptor Synthon Synthetic equivalents

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Table 1.2 Common Donor Synthons

Common Donor Synthon Synthetic equivalents

Retrosynthetic Analysis A

Synthesis A

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Retrosynthetic Analysis B

Synthesis B

Alternating Polarity Disconnections

The presence of a heteroatom in a molecule imparts a patternof electrophilicity and nucleophilicity to the atom of the molecule.

The concept of alternating polarities or latent polarities (imaginary chargies)often enables one to identify the best positions to make a disconnectionwithin a complex molecule.

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, CCR3, -NO2, N, -SR, -S(O)R, -SO2R

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Alternating Polarity Disconnections

Consonant Pattern: Positive charge are placed at carbon atom bondedto the E class groups.

Dissonant Pattern: One E class is bonded to a carbon with a positivecharge, whereas the other E class group resides on a carbon with anegative charge.

Consonant

Dissonant

Simple synthesis

One Functional Group

Analysis

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Synthesis

Two Functional GroupsIn a 1,3-Relationship

Analysis

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Synthesis (path a)

Synthesis (path b)

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Two Functional Groups in 1,4-Relationship

Analysis

The α-carbon in this synthon requires an inversion of polarity(umpolung in German) from the negative (-) polarity normallyassociated with a ketone α-carbon.

α-bromoketone

Synthesis

Enolate cannot be used because of the formation of an epoxy ketone(Darzens condensation). Instead, enamine is used.

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Analysis Umpolung

Synthesis

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Regioselective opening of epoxide by nucleophilic reagent providesFor efficient two-carbon homologation reactions.

1.2 Reversal of the Carbonyl Group Polarity (Umpolung)

The carbonyl group is electrophile at the carbon atom and hence is susceptibleto attack by nucleophile.

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Reversal of polarity of a carbonyl group has been explored and systemizedby Seebach.

Umpolung in a synthesis usually requires extra steps.

Unnatural negative charge

negativelycharged ccarboxylic synthon

Since formyl and acyl anions are not accessible,one has to use synthetic equivalents of these anions.

Formyl and Acyl anion derived from 1,3-dithianes

2-lithio-1,3dithian species; acyl anion equivalents

EtSH: pKa 11 (more acidic)EtOH: pKa 16

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With HMPA (hexamethylphosphoramide), [(Me2N)3P=O], dithiane-derivedcarbaions may serve as Michael donors. But without HMPA, 1,2-additionto the carbonyl group prevails.

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Acylanions derived from Nitroalkanes

CH3NO2, pKa 10.2; CH3CH2NO2, pKa 8.5

Nitronates of primary nitro compounds yield carboxylic acid.

Nef Reaction under acidic condition

NO

O

R1

R2

H+

NOH

OH

R1

R2

H2ON

OH

OH

R1

R2

HO HR1

R2

O +H2O

HNO

hyponitrous acid

TiCl3-Cl- N

O-TiCl2

O

R1

R2

NO

R1

R2

-O=TiCl2 TautomerizationN

OH

R1

R2

oximenitroso compound

work up

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Acyl anions derived from cyanohydrins

O-protected cyanohydrins contains a masked carbonyl group with invertedpolarity.

(Stetter reaction)

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Acyl anion synthon derived from cyanohydrins may be generated catalyticallyby cyanide ion via the Stetter reaction.

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Acycl anions derived from Enol ethers

Acyl anions derived from lithium acetylide

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1.3 steps in planning a synthesis

• Construction of the carbon skeleton

• Control of relative stereochemistry

• Functional Group interconversion

• Control of enantioselectivity

Construction of the carbon skeleton

Important C-C bond forming reactions encountered in organic synthesis

• Reactions of organolithium and Grignard reagents, such as RLi, RC≡Cli, RMgX, and RC≡CMgX, with aldehyde, ketones, esters, epoxides, acid halides, and nitriles

• Reactions of 1oalkyl halides with -C≡N to extend the carbon

• Alkylations of enolate ions to introduce alkyl groups to carbons adjacent to a carbonyl group (e.g., acetoacetic ester synthesis, malonic ester synthesis)

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• Condensations such as aldol (intermolecular, intramolecular), Claisen, and Dieckmann

• Michael additions, organocuprate additions (1,4-additions)

• Friedel-Crafts alkylation and acylation reactions of aromatic substrates

• Wittig reactions, and Horner-Wadsworth-Emmons olefination

• Diels-Alder reactions giving access to cyclohexenes and 1,4-cyclohexadienes

• Ring-closing olefin metathesis

Table 1.3 Summary of Important Disconnections

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• Disconnections of bonds should be carried out only if the resultant fragments can be reconnected by known and reliable reactions.

• fewest number of disconnections (see Section 1.4, convergent vs. linear synthesis)

• It is often advantageous to disconnect at a branching point since fragments can be easily accessible, either by synthesis orfrom a commercial source.

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• A preferred disconnection of cyclic esters (lactones) or amides (lactams) produces hydroxy-carboxylic acid or amino-carboxylic acids as targets.

• Functional groups in the TM may be obtained by functional groupinterconversion.

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• Symmetry in the TM simplifies the overall synthesis by decreasing the number of steps required for obtaining the TM.

• Introduction of an activating functional group may facilitatecarbon-carbon bond formation. After accomplishing its role, theactivating group is removed.

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•The presence of a 1,6-dioxygenated compound suggests opening of a six-membered ring. A variety of cyclohexene precursors arereadily available via condensation and Diels-Alder reaction or via Birchreductions of aromatic compounds.

• Disconnection of an internal (E)- or (Z)-double bond or a side chainof an alkene suggests a Wittig-type reaction or an alkylation of avinylcuprate, respectively.

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• The presence of a six-membered ring, especially a cyclohexenederivative, suggests a Diels-Alder reaction.

• The structural feature of an α,β-unsaturated ketone or a β-hydroxyketone in a six-membered ring suggests double disconnection coupledwith functional group interconversions. (Robinson annulation)

Functional Group Interconversion

a. Alkyl Chlorides

b. Alkyl Bromides

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c. Allylic and Propargylic Bromides

d. Alkyl Iodies

e. Nitriles

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f. 1o and 2o Alcohols

g. 1o, 2o and 3o Amines

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h. Aldehydes and Ketones

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i. Carboxylic Acids

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j. Alkenes

k. Alkynes

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Control of Relative Stereochemistry(stereoselctive and stereospecific)

• SN2 displacement reaction; E2 elimination reactions

• Catalytic hydrogenation of alkyne (cisproduct)

• Metal ammonia reduction of alkyne (trans product)

• Oxidation of alkenes with osmium tetroxide

Control of enantioselectivity

• Addition of halogens, interhalogens(e.g., BrI) or halogen-like species (e.g., PhSCl, BrOH) to double bond

• Hydroboration reactions

• Epoxidation of alkenes; ring-opening of epoxide

• Cyclopropanation

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The choice of a method for synthesizing a compound derived from a retrosynthetic analysis should be based on the following criteria

• Regiochemistry, the preferential addition of the reagent in only one of two possible regions or directions.

• Chemoselectivity, selective reaction of one functional group in the presence of other functional groups

• Stereoselectivity, the exclusive or predominant formation of one of several possible stereoisomeric products.

1.4 Choice of Synthetic Methods

• Efficiency, fewest number of steps• High yields in each step• Availability and costs of starting material• Most environmentally friendly route. Ideally the atoms of substrate and any additional reagents used for the reaction should appear in the final product, called “atom economy”

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• Simplicity of selected procedure.

• Isolation and purification of reaction products. Ability and utility to separate and recover the reaction product from other materials

• Possibility of a convergent synthesis or a “one-pot process.

Linear and Convergent Syntheses

• In a linear synthetic scheme, the hypothetical TM is assembled in astepwise manner. If 80% yield is obtained in each step, 21% (0.87 x 100)overall yield of product can be isolated after 7 steps. If 70%, only 8% overall yield.

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• Convergent synthesis should be considered in which two or morefragments of the TM are prepared separately and then joined at thelatest-possible stage of the synthesis. Only three stages are involvedin the convergent strategy, with overall yield of 51% (0.83 x 100).

• Another important consideration in choosing a convergent protocolis that failure of a single step in a multistep synthesis does notnulify the chosen synthetic approach as whole, whereas failure of asingle step in a linear scheme may require a revision of the wholeplan.

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• Convergent syntheses involve consecutive reactions, where the reagentsor catalysts are added sequently into “one pot”.

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1.5 Domino Reactions (also called cascade or Tandem reactions)

• Domino-type reactions involve careful design of a multistep reactionin a one-pot sequence in which the first step creates the functionalityto trigger the second reaction and so on.

Robinson annulation (a Michael reaction followed by aldol condensation and dehydration)