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.

1 1.1 Retrosynthetic Analysis Basic Concept

The symbol signifies a reverse synthetic step and is called atransform. The main transforms are disconnections, or cleavage of C-C bonds, and functional 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-carbon bonds of the TM.

The actual substrates used for the forward synthesis are the synthetic equivalents (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, or through concerted transform.

2 Donor and Acceptor Synthons

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

Table 1.1 Common Acceptor Synthon Synthetic equivalents

Common Acceptor Synthon Synthetic equivalents

3 Table 1.2 Common Donor Synthons

Common Donor Synthon Synthetic equivalents

Retrosynthetic Analysis A

Synthesis A

4 Retrosynthetic Analysis B

Synthesis B

Alternating Polarity Disconnections

The presence of a heteroatom in a molecule imparts a pattern of 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 disconnection within 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

5 Consonant Pattern: Positive charge are placed at carbon atom bonded to the E class groups.

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

Alternating Polarity Disconnections

Consonant

Simple synthesis

Dissonant

One Functional Group

Analysis

6 Synthesis

Two Functional Groups In a 1,3-Relationship

Analysis

7 Synthesis (path a)

Synthesis (path b)

8 Two Functional Groups in 1,4-Relationship

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

α-bromoketone

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

Synthesis

9 Analysis Umpolung

Synthesis

10