Analisi Retrosintetica

(1a PARTE)
 Ultime Lezioni ed Esercitazioni
12/05: Intro Retrosintesi per molecole complesse
16/05: Regole Analisi Retrosintetica
16/05: Approcci RA via Software
18/05: Installazione Programmi per RA
20/05: Ultima Lezione Teorica RA
20/05: Esercitazione RA
23/05: Esercitazione RA

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 The Nobel Prize in Chemistry 1990
The Royal Swedish Academy of Sciences has awarded this year's Nobel Prize
in Chemistry to

Elias J. Corey
Harvard University, Cambridge, MA, USA
for his development of the theory and methodology of organic synthesis

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 Organic synthesis science and art
The history of organic synthesis starts with the German chemist Friedrich Whler
who, in 1828, succeeded to make urea from simple materials. This was the first
time when organic (=living) matter was produced from inorganic (=dead) matter.
This was not believed to be possible, at the time.
By the end of the nineteenth century valuable colours, such as indigo and many
aniline-colours, became available through synthesis from cheap starting
materials by, among others, Adolf von Baeyer, Germany (1905*). At the turn of
the century Emil Fischer (1902*) in Berlin had started his elegant elucidation of
the structure and stereochemistry of sugars. At the same time new methods to
make carbon-carbon bonds were developed by, among others, the Frenchman
Victor Grignard (1912*).
At the end of the 1920's the art of synthesis had made major advances. Hemin,
the oxygen-binding part of the red bloodplates, was synthesised by the German,
Hans Fischer (1930*). Vitamin B6 was synthesised in 1939 and vitamin A in
1949. The Germans, Otto Diels and Kurt Alder (1950*) discovered one of the
most simple and elegant methods that exists for the synthesis of rings with six
carbon atoms.

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 Organic synthesis science and art
During the 1950's the development was rapid and many challenging molecules
such as strychnine and morphine were made synthetically. Cortisone was
prepared synthetically in 1951 by the Englishman Sir Robert Robinson (1947*)
and the American Robert B. Woodward (1965*), penicillin in 1957 by John C.
Sheehan and chlorophyll by R.B. Woodward in 1960.
The art of organic synthesis continues to develop. In 1979 Herbert C. Brown,
USA and Georg Wittig, Germany, shared the Nobel Prize in chemistry for their
development of boron and phosphorous compounds, respectively, into useful
reagents in organic synthesis.
The discovery of the prostaglandins was made by Sune Bergstrm and Bengt
Samuelsson in Sweden and by Sir John R. Vane in England (1982*). The
prostaglandins occur in very small amounts in the body and take part in
important life processes. With great skill, E.J. Corey has determined the
structure of many prostaglandins and synthesized them. Through his
contributions many of these are now available to medicine.

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 Organic synthesis science and art
A number of other chemicals with complicated structures has been synthesized
during the last three decades and this year's Nobel Laureate, Elias J. Corey, has
played a key role also in these developments. Some examples of biologically-
active compounds synthesized in Corey's laboratory are shown in this poster.

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 Organic synthesis science and art

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 Organic synthesis science and art

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 The logic of chemical synthesis
Products such as plastics, synthetic fibres, paints and pigments,
pharmaceuticals and pesticides and many others have become readily available
through the dynamic development of organic synthesis (the science of building
organic molecules).
There are many ways to build a complex molecule from simple starting
materials but to find the simplest way is often difficult. It is necessary to
proceed not only in a creative but also in a systematic and logical way.
Elias J. Corey has developed theories and methods by which the organic
chemist can handle these problems. He begins with the target molecule, i.e. the
molecule he wants to make, and then, using methods described in the section
below, he breaks the target molecule down into several simple "building
blocks", starting material. This process, in itself, is nothing new. However, the
method for doing this is new and is called: retrosynthetic analysis.

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 The logic of chemical synthesis

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 Retrosynthetic tree
Retrosynthetic analysis can be compared to the climbing of a tree. You are
at the root of the tree (the target molecule) and want to climb to the top branches
(the starting materials). The tree branches off many times. You have to choose
your way! Which way is the fastest, the easiest and the most reliable to the best
starting materials? E.J. Corey has developed and analysed many different
strategies for making such a choice. One might e.g. choose to use a specific
reaction. Alternatively, one might choose to build (synthesize) a particular part of
the target molecule first or choose to solve some specific problem associated
with the three-dimensional structure of the target, its stereochemistry.

Today, the analysis can be performed

with computers in which an ever
increasing number of reactions are
stored. The computer gives
suggestions, but the chemist must
choose the way and reactions from
his/her own qualifications and
experience

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 Retrosynthetic tree

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 To build molecules
In order to develop the logic of organic synthesis, a thorough knowledge of the
individual chemical reactions which make up a method of synthesis is required. New
types of organic reactions are constantly being invented all over the world and give
rise to new methods. Many of these have been created and developed by E.J. Corey.
In many cases E.J. Corey uses a metal, often a transition metal, to keep the reactive
centres of two molecules together and to affect the reactivity of certain carbon atoms in
each unit.
In the picture, a reaction is shown by which a new carbon-carbon bond is created
using copper and lithium. This type of reaction is very common and a large number of
different organic groups can be bound to one of the carbons in a double bond next to
a carbonyl group .
However, it is not sufficient to know the starting material and the product in a
reaction. To predict the three-dimensional structure of the product, its stereochemistry,
one has to understand the reaction mechanism in great detail. E.J. Corey has revealed
the detailed mechanisms of many useful reactions.

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 To build molecules

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To build "left or right handed" molecules
Organic molecules are three-dimensional and can exist in two mirror image
forms, one left handed and one right handed. A synthesis gives, in general,
equal amounts of the two mirror image forms of the molecule. These might have
completely different biological activity. Natural products, i.e. chemicals found in
Nature, are usually either "left- or right handed".
E.J. Corey has contributed to the development of new methods in asymmetric
synthesis, which give only one of the mirror image forms. In the reaction shown
below only one of the mirror image forms of a Corey-reagent is used. It contains
an important nitrogen-boron bond. The reagent is first reacted with borane (BH3)
which can then reduce a carbonyl group to an alcohol . The reagent contains
very large groups which allow it to reach the carbonyl group from one side only
(from above as drawn). Thus, one of the two mirror image forms is formed
selectively.

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To build "left- or right handed" molecules

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 Further reading
E.J. Corey, X.-M. Cheng: The Logic of Chemical Synthesis, Wiley
Interscience, 1989.
E.J. Corey, A.K. Long, S.D. Rubenstein: Computer-Assisted Analysis
in Organic Synthesis, Science, Vol 228, 1985, pp 408-418.

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 Introduction to Retrosynthetic Analysis
Chemical reactions can be viewed in two directions: the synthetic
direction, corresponding to laboratory operations, and the
retrosynthetic (or antithetic) direction, going backwards from a target
molecule to starting materials by way of retro-reactions or
transforms. Retrosynthesis is often applied when a synthetic route to a
target molecule has to be developed. The term retrosynthetic
analysis, a synonym for retrosynthesis, expresses more clearly its
`imaginary' character.
The most important computer programs for synthesis design (a prime
example is LHASA) operate in a retrosynthetic fashion. The reason for
this is that retrosynthetic analysis lends itself well to a description in
algorithms and thence in computer programs

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 Introduction to Retrosynthetic Analysis
The following chapters provide an overview of
retrosynthetic analysis:

1. Analysis of Complex Synthetic Problems

2. Terminology
3. Retrosynthetic Strategies
4. Goals and Subgoals
5. Computer-Assisted Retrosynthetic Analysis

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Analysis of Complex Synthetic Problems
The total synthesis of structurally complex compounds is a challenging
undertaking, in intellectual as well as practical respects. Whereas simple
compounds can usually be made by synthesis routes comprising a few reaction
steps (say two to five), complicated molecules may require a lengthy sequence
of reactions, not seldom more than twenty. Most such multi-step syntheses
are executed, or at least attempted, according to a plan designed
beforehand on paper or blackboard. How do chemists arrive at such
synthetic plans? Traditionally, synthesis design was based upon associative
thinking processes, the most important of which were:
Association with existing syntheses of similar compounds
Association with known starting material(s)
Association with a hypothetical advanced intermediate
The last of these represents an attempt to reduce the complexity of the design
problem, but the selection of a suitable intermediary structure is still a highly
intuitive process. The associative approach to synthesis design becomes less
opportune as the complexity of the problem, and hence the number of steps
required, increases.

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Analysis of Complex Synthetic Problems

Landmark total syntheses of the past century: (1) a-Terpineol (W.H. Perkin, 1904);
(2) Tropinone (R. Robinson, 1917); (3) Equilenin (W.E. Bachmann, 1939);
(4) Chlorophyll-a (R.B. Woodward, 1960); (5) Gibberellic Acid (E.J. Corey, 1978);
(6) Ginkgolide-B (E.J. Corey, 1988);

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 Analysis of Complex Synthetic Problems

These structures, made by total synthesis

during the past century, illustrate the
ever-increasing complexity of the
synthesis tasks that chemists have
imposed upon themselves, each success
prompting an even more challenging
undertaking. None of the targets above
give obvious handholds for synthesis
design by association; each of their
syntheses was a first and neither
starting materials nor promising
intermediary structures stand out. A more
systematic and generally applicable
problem-solving technique is clearly
called for, and is presented by
retrosynthetic analysis.

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 Terminology
Retrosynthetic analysis or retrosynthesis is a technique for solving
problems in synthesis planning, especially those presented by complex
structures. The retrosynthetic approach to synthesis planning was
formulated explicitly for the first time by Corey. The purpose of
retrosynthetic analysis (RA) is to transform the structure of a synthetic target
molecule to simpler molecules. Hence, in RA reactions are viewed in the
retrosynthetic direction, starting with the product of the reaction and going
backwards to the reactants. The terminology used with RA, as opposed to
synthesis, is summarized below.

Direction Synthetic Retrosynthetic or Antithetic

Step Reaction Transform or Retro-reaction

Arrow used in graphical depiction -----> =====>

`Starting' structure Reactant Target

`Resulting' structure Product Precursor

Substructure required for Reacting

Retron
operation functionality
Synthetic versus retrosynthetic analysis

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 Terminology
Transforms or retro-reactions, are the imaginary counterparts of reactions.
Each transform corresponds to a reaction, and vice versa, but of course it
cannot be carried out in the laboratory; it is purely a thought process.
Each reaction generates a characteristic structural element in the product, such
as the enone resulting from the above Aldol condensation. This substructure,
called the retron, must be present in a target to be able to apply the
corresponding transform to that target.

A transform, in this case the retrosynthetic counterpart of the aldol condensation.

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 Terminology
Retrosynthetic analysis, then, consists of applying transforms to a given target,
thereby generating all precursors from which that target can be made in a
single step. The analysis can be repeated for each precursor, generating a
second level of precursors.
It is possible that a transform generates a precursor actually consisting
of two or more fragments, as in the case of a convergent step; these
fragments can each be treated in the same way as single precursors. For
clarity, multiple fragments are not shown. Further analysis can generate deeper
levels of precursors. Each precursor generated can then be checked for
availability, thus defining an endpoint for that line of analysis.
The final result, a complete retrosynthetic tree, will contain all possible
syntheses of the given target, reasonable and unreasonable, efficient and
cumbersome ones. Of course, such a tree would be unmanageably large both
for man and computer, even when the number of precursor levels is limited.

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 Terminology
The combinatorial explosion, as this phenomenon is called, effectively
prohibits the use of retrosynthetic analysis in such an unconstrained way. To
keep the size of the retrosynthetic tree under control, a selection of transforms
to be considered must be made. The guiding principles for this selection are

called strategies.

Schematic depiction of a retrosynthetic tree.

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 Retrosynthetic Strategies
Retrosynthetic analysis will only lead to useful results if it is directed towards
some goal. The basic goal is to generate precursors that correspond to
available starting materials. However, this goal can be used as a guiding
principle only when possible starting materials can be identified from the target
structure. In general, obvious starting points cannot be found when it comes to
complex target structures (and that is where RA is most useful). The basic
goal, then, becomes the generation of precursors that are easier to
synthesize than the original target; such precursors are likely to be closer to
available compounds than the original target. Stated differently, retrosynthetic
analysis is directed towards molecular simplification. Corey has
formulated five main types of strategies that lead to the desired
simplification. These will be treated briefly, each illustrated by a sample
analysis:

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 Retrosynthetic Strategies

(1) Functional-group based strategies

(2) Topological strategies

(3) Transform-based strategies

(4) Structure-goal strategies

(5) Stereochemical strategies

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 (1) Functional-group based strategies
Functional groups in the target structure may direct the transform search in
several ways:
Removal of reactive and masked functionality
Disconnection based on the location of functional groups
Reconnection of functional groups to form rings retrosynthetically
The reconnective strategy is constrained by strategic rules. Clearly, it is not
practical to attempt every possible reconnection.

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 (2) Topological strategies
The disconnection of specific, so-called strategic bonds can lead to major molecular
simplification. There are several types of strategic bonds:
Bonds in (poly)cyclic ring systems
Bonds in (poly)fused ring systems
Pairs of bonds in ring systems (disconnection by intramolecular cycloaddition
transforms)
Bonds connecting chains to rings
Bonds connecting chains to other chains
Bonds connecting chains to functional groups
Heuristics (empirical rules) have been devised to select these types of bonds from any
target structure. It is also possible to identify rings which should be disassembled early in
the retrosynthetic process, or rings which should be kept intact during these stages.

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 (3) Transform-based strategies
A very useful guidance for retrosynthetic analysis can be provided by the
application of a powerfully simplifying transform -- corresponding to a reaction
effecting a considerable increase in complexity. Very often such an application is
suggested by the presence of (functionalized) rings of specific sizes in the target
molecule. Some powerfully simplifying transforms are:

Diels-Alder Birch reduction

Hetero Diels-Alder Internal ene reaction
Robinson annulation Halolactonization

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 (4) Structure-goal strategies
The analysis can also be directed towards a particular (sub)structure. Such a
(sub)structure can be a:
Starting material
Chiral building block
Retron-containing structure
An analysis directed towards such a structure-goal does not need to be purely
retrosynthetic. It can even be synthetic, but probably the most efficient search
would be a bidirectional one.

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 (5) Stereochemical strategies

Here the focus is on removal of stereocenters under stereocontrol.

Stereocontrol can be achieved through either mechanistic control or substrate
control. Reconnections that move stereocenters from chains (where they are
difficult to introduce) into rings (where introduction is usually much easier) can
also be considered stereochemically strategic.

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 Goals and Subgoals

Although the general goal for RA is structural simplification, this does not mean
that each step in a retrosynthesis must be, or even can be, simplifying.
Certainly, if most steps are simplifying, the resulting synthesis is likely to
be very efficient. Many actual syntheses, however, contain fewer construction
steps than functional group manipulations which are generally non-simplifying.
Because RA is a goal-driven activity, synthesis routes produced by RA tend
to be quite efficient. Transforms which effect a desired simplification are called
goal transforms. It is not always possible to apply a goal transform directly; a
prerequisite is the presence of its retron in the target molecule. The range of
eligible goal transforms can be broadened by not only considering their exact
retrons, but also their so-called partial retrons.

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 Goals and Subgoals
A partial retron is derived from the exact or full retron by a structure
generalization. For instance, whereas the full retron for the Birch reduction
transform is the cyclohexenone substructure, its partial retron can be just a six-
membered carbocycle. Of course, when the target contains only the partial
retron, additional operations are required to establish the full retron. The
following sequences provide an illustration:

Two sequences in which subgoal transforms pave the way for a goal transform,
in both cases the Birch reduction transform.

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 Goals and Subgoals
In the first sequence, the olefin must be introduced before the Birch transform
can take place; in the second, the olefin must be shifted. Clearly, in both
sequences non-simplifying, or subgoal, steps are needed to pave the way for
the goal transform. The term subgoal is used because such a step is
subordinate to the application of a goal transform. Without a goal transform `in
mind', there is really no good reason to apply a subgoal transform. Subgoal
transforms which manipulate functional groups are very common:
functional group addition (FGA), functional group removal (FGR), functional
group interchange (FGI), and functional group transposition (FGT) are
frequently employed. But in fact any transform which assists in setting up
the retron for a goal transform can be thought of as a subgoal transform.

Two sequences in which subgoal transforms pave the way for a goal transform,
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in both cases theRetrosintetica
Birch reduction transform. 36
 Goals and Subgoals
There is an added bonus if the subgoal transform is itself also simplifying; the
combined sequence will probably have a high merit. This is clearly the case with
tactical combinations. A tactical combination is the retrosynthetic equivalent
of a standard reaction sequence (synthetic clich). The steps in a tactical
combination follow naturally after another because each step sets up the retron
for the next step. Tactical combinations are most powerful when they have a
high content of simplifying steps. The best-known tactical combination is
probably the Robinson annulation: an aldol transform followed by a Michael
transform. In fact, it is so common that it is often treated as a single-step
process. Another example is shown here:

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Analisi tactical combination.
Retrosintetica 37
 Goals and Subgoals
Tactical combinations can be used in RA as a type of super
transform; often they have more elaborate retrons than ordinary
transforms, which allows for their specific application. The availability of
a large collection of tactical combinations is a big asset in synthesis
design.

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Computer-Assisted Retrosynthetic Analysis
Retrosynthetic analysis in itself is already a powerful tool for the
chemist. However, the enormous amount of chemical knowledge
available nowadays makes it difficult to use RA efficiently and
thoroughly. Most of the information is relatively inaccessible, especially
the newer reactions and developments in scope of older ones. In
practice, the synthetic chemist is limited by the information that is most
readily available to her/him. Furthermore, there is a tendency to accept
the first reasonable solution and to focus attention to that direction,
whereas a more thorough analysis may result in a much better solution
saving weeks or even months work in the laboratory. The required
extra effort is almost always a worthwhile investment. The application
of a computer program which can assist in retrosynthetic analysis
is then of great value. A computer program has no bias and, of
course, has total recall.

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Computer-Assisted Retrosynthetic Analysis
AIPHOS
Artificial Intelligence for Planning and Handling Organic Synthesis
CHIRON
CHIRON (CHIRal synthON) is an interactive computer program for the analysis and
perception of stereochemical features in molecules and for the selection of
precursors in organic synthesis.
COMPASS
COMputer ASSisted organic synthesis
HOLOWin
IGOR
Interactive Generation of Organic Reactions.
LHASA
LHASA (Logistics and Heuristics Applied to Synthetic Analysis) is a retrosynthetic
interactive analysis program that assists in planning the most efficient synthetic
routes. LILITH
OSET
Organic Synthesis Exporation Tool

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Computer-Assisted Retrosynthetic Analysis
SCANCHEM
SECS
Simulation and Evaluation of Chemical Synthesis
SPURT
Synthesis Planning Using Reaction Types
SYNCHEM
SYNthetic CHEMistry
SYNGEN
SYNGEN (SYNthetic GENeration) automatically generates the shortest, most
economic organic synthesis routes for a given target compound.
SYNSUP-MB
Systematichem
Finds every conceivable route using specific reactions and organizes the solutions
by minimum cost and the lowest number of synthetic steps. Every solution starts
with commercially available materials and uses proven reactions at each proposed
step.
SYNTHON

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Computer-Assisted Retrosynthetic Analysis

Syntree
By entering a goal structure and mapping it against a transform database, a search
for precursors is undertaken which are one step removed from the goal.

TRESOR
TRacing and Evaluation of Syntheses in Organic Reactions

WODCA
WODCA (Workbench for the Organization of Data for Chemical Application) plans
organic synthesis in a retrosynthetic manner by providing commercially available
precursors for the target compound. Its two main features are 'similarity searches'
and the 'evaluation of strategic bonds'.

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