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, 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.
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Donor and Acceptor Synthons
Acceptor synthon Æ carbocation (electrophilic)
Donor synthon Æ carbanion (nucleophilic)
Table 1.1 Common Acceptor Synthon
Common Acceptor Synthon
Synthetic equivalents
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 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
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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
Regioselective opening of epoxide by nucleophilic reagent provides
For 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 susceptible
to attack by nucleophile.
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Reversal of polarity of a carbonyl group has been explored and systemized
by Seebach.
Unnatural
negative charge
negatively
charged c
carboxylic
synthon
Since formyl and acyl anions are not accessible,
one has to use synthetic equivalents of these anions.
Umpolung in a synthesis usually requires extra steps.
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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13
With HMPA (hexamethylphosphoramide), [(Me2N)3P=O], dithiane-derived
carbaions may serve as Michael donors. But without HMPA, 1,2-addition
to 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
R1
R2
O
N
O
H+
R1
R2
OH
N
OH
H2O
R1
HO
R2
OH
N H
OH
H2O
R1
+
O
HNO
R2
hyponitrous acid
work up
TiCl3
-Cl-
R1
R2
O-TiCl2
N
O
-O=TiCl2
R1
R2
Tautomerization R1
N
O
nitroso compound
R2
N
OH
oxime
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16
Acyl anions derived from cyanohydrins
O-protected cyanohydrins contains a masked carbonyl group with inverted
polarity.
(Stetter reaction)
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Acyl anion synthon derived from cyanohydrins may be generated catalytically
by 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 (1,4additions)
• 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 or
from a commercial source.
22
• A preferred disconnection of cyclic esters (lactones) or
amides (lactams) produces hydroxy-carboxylic acid or aminocarboxylic acids as targets.
• Functional groups in the TM may be obtained by functional group
interconversion.
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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 facilitate
carbon-carbon bond formation. After accomplishing its role, the
activating 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 are
readily available via condensation and Diels-Alder reaction or via Birch
reductions of aromatic compounds.
• Disconnection of an internal (E)- or (Z)-double bond or a side chain
of an alkene suggests a Wittig-type reaction or an alkylation of a
vinylcuprate, respectively.
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• The presence of a six-membered ring, especially a cyclohexene
derivative, suggests a Diels-Alder reaction.
• The structural feature of an α,β-unsaturated ketone or a β-hydroxy
ketone in a six-membered ring suggests double disconnection coupled
with 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 (cis
product)
• Metal ammonia reduction of alkyne (trans
product)
• Oxidation of alkenes with osmium
tetroxide
• 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
Control of enantioselectivity
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1.4 Choice of Synthetic Methods
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.
•
•
•
•
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 a
stepwise 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 more
fragments of the TM are prepared separately and then joined at the
latest-possible stage of the synthesis. Only three stages are involved
in the convergent strategy, with overall yield of 51% (0.83 x 100).
• Another important consideration in choosing a convergent protocol
is that failure of a single step in a multistep synthesis does not
nulify the chosen synthetic approach as whole, whereas failure of a
single step in a linear scheme may require a revision of the whole
plan.
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• Convergent syntheses involve consecutive reactions, where the reagents
or 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 reaction
in a one-pot sequence in which the first step creates the functionality
to trigger the second reaction and so on.
Robinson annulation (a Michael reaction followed by aldol condensation
and dehydration)
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