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Modern Organic Synthesis an Introduction

G. S. ZweifelM. 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, inc luding the inherent concepts of simplic ity (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 c leavage 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 electrophilic ity 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 c lass: 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 c lass 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