Retrosintesis
Retrosintesis
Retrosintesis
If Chemistry is the science of matter and of its transformations Synthetic chemistry is the
science of constructing molecules from atoms and/or simpler molecules.
The discipline may be divided, according to the molecules involved, into Synthetic Organic
Chemistry and Synthetic Inorganic Chemistry.
The term Organic Synthesis is often used may be incorrectly in strict terms to mean the
same as Synthetic Organic Chemistry
Nicolaou, K. C. Classics in Total Synthesis
The most fundamental and lasting objective of synthesis is not production of new
compunds but production of properties
George S. Hammond
Norris Award Lecture, 1968
Very little planning was needed in this relatively simple synthesis ...
Deliberate syntheses could be developed using associative mental processes ...
Associative thinking or thinking by analogy was sufficient ...
Corey, E. J. The Logic of Chemical Synthesis
In contrast to the former syntheses, which were based on the availability of starting
materials that contained a major portion of the final atomic framework, these 20th
century syntheses depended on the knowledge of reactions suitable for forming
polycyclic molecules and on detailed planning to find a way to apply these methods.
Corey, E. J. The Logic of Chemical Synthesis
Robert B. Woodward was probably the first to integrate mechanistic organic chemistry
into his planning of syntheses in a consistent manner...
Woodward's real achievements is that he intellectualized synthetic organic chemistry...
Robert B. Woodward was awarded the Nobel Prize for Chemistry in 1965
for his outstanding achievements in the art of Organic Synthesis
Like the artist, the chemist engraves into matter the products of creative imagination...
The essence of chemical science finds its full expression in the words of that epitome of the artistscientist Leonardo da Vinci:
"...dove la nature finisce di produrre le sue spezie, l'uomo quivi comincia con le cose naturali,
con l'aiutorio di essa natura a creare infinite spezie
Lehn, J. M. Supramolecular Chemistry. Concepts and Perspectives. VCH, 1995
Retrosynthetic analysis
Retrosynthetic analysis: the logical process of analyzing the structure of a target
molecule to transform the target to a sequence of progressively simpler structures along
a pathway which finally will lead to simple or commercially available starting materials.
This can be accomplished by the application of a transform, the exact reverse of a
synthetic reaction, to a target structure.
The transform is applied on a structural subunit contained into the target compound,
called retron.
Disconnection approach
Kinds of transform: there are many thousands of transforms potentially useful in
retrosynthetic analysis. They can be classified as follows:
Functional group interconversion: FGI
Functional group addition: FGA
Functional group removal: FGR
Disconnection: the formal reverse of a bond forming reaction (cleavage of a bond to
break the target into two possible starting materials)
Synthon: An idealized (often charged) molecular fragment.
dn synthon: functionalized nucleophile (d, donor, n defines the distance between the FG
and the reactive center)
an synthon: functionalized electrophile (a, acceptor)
Reagent or synthetic equivalent: a chemical compound used in practice for a synthon
Disconnection approach
Some definitions
Target molecule
the molecule to be synthetized
Retrosynthetic analysis or retrosynthesis
the process of mentally breaking down a molecule into starting material
Transform
the exact reverse of a synthetic reaction
Retron
structural subunit on the target that enables a transform to operate
Disconnection
an imaginary bond cleavage corresponding to the reverse of a real reaction
Synthon
idealized fragments resulting from a disconnection
Reagent
a real chemical compound used as the equivalent of a synthon
Synthesis tree
set of all the possible disconnections and synthons leading from the target to the
starting materials of a synthesis
Disconnection approach
Synthons and reagents
dn synthon: functionalized nucleophile (d, donor)
an synthon: functionalized electrophile (a, acceptor)
Reagent or synthetic equivalent
Disconnection approach
Two types of useful general strategies:
Transform-based strategies rely on the application of powerfully simplifying
transforms.
Structure-based strategies rely on the recognition of possible starting materials
or key intermediates for a synthesis.
Three other general strategies can be identified.
Functional group-based strategies identify functional groups as key structural subunits.
Topological-based strategies depend on the identification
of one or more individual bond disconnections or
correlated bond-pair disconnections as strategic.
Stereochemical-based strategies remove stereocenters and stereorelationships under
control.
Corey, E. J. The Logic of Chemical Synthesis
Disconnection approach
Transform based strategies
Types of Transforms
Disconnection approach
Structurally simplifying transforms by disconnecting molecular skeleton.
Disconnection approach
Structurally simplifying transforms by disconnecting functional groups or stereocenters
Disconnection approach
Structurally increasing complexity transforms includes addition of rings, functional groups
(FGA), or stereocenters
Disconnection approach
Disconnections
Other guidelines for retrosynthesis are given below:
1. It is better to use convergent approach rather than divergent for many complex molecules.
2. Use only disconnections corresponding to disconnect CC bonds and CX bonds wherever possible.
3. Disconnect to readily recognizable synthons by using only known reactions (transform).
4. The synthesis must be short.
5. It is better to use those reactions which do not form mixtures.
6. The focus is on the removal of stereocentres under stereocontrol. Stereocontrol can be achieved
through either mechanistic control or substrate control.
Where should I choose to disconnect?
Disconnections very often take place immediately adjacent to, or very close to functional groups in
the target molecule (i.e. the one being disconnected). This is pretty much inevitable, given that
functionality almost invariably arises from the forward reaction.
Disconnection approach
Disconnections
How do I decide which synthon carries which charge?
A good trick here is to consider whether you can draw a resonance form of the
synthon which looks more like a real reactive intermediate If it does, youve
clearly made a good choice of polarity, and youve most likely gone a long way to
identifying the synthetic equivalent!
Disconnection approach
Disconnections
Basic Guidelines:
1. Use disconnections corresponding to known reliable reactions, choose
disconnection corresponding to the highest yielding reaction.
Diazonium salt and propargylic Grignard
Phenyl Grignard and propargylic halide
synthons
reagents
Disconnection approach
Disconnections
Disconnection approach
Disconnections
3. Aim for simplification:
disconnect in the middle of the molecule
Disconnection approach
Disconnections
3. Aim for simplification:
Disconnection approach
Transform based strategies
A case: six-membered cyclic motif
Disconnection approach
Transform based strategies
In the case of tetrahydropyran a straightforward disconnection, based on SN2 or SN1 processes, can
be easily envisaged
Disconnection approach
Transform based strategies
However, it becomes more difficult to identify a similar transform in the cyclohexane case ...
Disconnection approach
Transform based strategies
The powerful Diels-Alder reaction: a [4 + 2] cycloaddition
Disconnection approach
Transform based strategies
Regioselectivity: orto-para rule
Site selectivity
For a site selectivity analysis in unsymmetrical quinones, see Corey, E. J. JACS 2004, 4800
Disconnection approach
Transform based strategies
Relative stereochemistry: endo rule
Disconnection approach
Transform based strategies
There are Diels Alder reactions in which an heteroatom is part of the dienophile (or the
diene) systems, which gives access to heterocycles.
It is the called hetero Diels Alder
Disconnection approach
Transform based strategies
An intramolecular hetero Diels-Alder exploiting symmetry: carpanone by Chapman
Disconnection approach
Transform based strategies
Olefin Metathesis:
... olefin metathesis has come to the fore in recent years owing to the wide range of
transformations that are possible with commercially available and easily handled catalysts.
Consequently, olefin metathesis is now widely considered as one of the most powerful synthetic
tools in organic chemistry....
Disconnection approach
Transform based strategies
The power of RCM: laulimalide by Ghosh and Mulzer
Disconnection approach
Transform based strategies
The retron for the cation -cyclization transform can be defined as a carbocation with charge to a
ring bond which is to be cleaved.
Radical -cyclization
In a similar way, the retron for the radical -cyclization transform can be defined
as a radical with electron to a ring bond which is to be cleaved, but ...
Disconnection approach
Transform based strategies
Baldwin rules
6 membered rings
Disconnection approach
Transform based strategies
Just a classic of cation -cyclization: progesterone by Johnson
Disconnection approach
Transform based strategies
A nice solution to a difficult problem: aspidophytine by Corey
Disconnection approach
Transform based strategies
Just two classics of radical -cyclization: hirsutene and 9(12)-capnellene by Curran
Disconnection approach
Functional group based strategies
Corey classifies the functional groups, FG, in three families:
1st Level: the most important FG
3rd Level: peripheral, which are associated with useful reagents providing activation or control in
chemical processes, or combination of more fundamental groups
They can also be associated into super-set or super-families depending on their electronic
behaviour: EWG: CO, CN, SOR, NO2 or EDG: OR, NR2
Disconnection approach
Functional group based strategies
Furthermore, many retrons contain only a single FG, while others consist of a pair of FG's separated
by a specific path
Transforms involving a single FG
Removal of an appendage
FG interconversion
Rearrangement
Disconnection approach
Functional group based strategies
Disconnection approach
Disconnections
Disconnection approach
Functional group based strategies
Latent Polarity
Latent polarity is the imaginary pattern of alternating positive and negative charges used to assist in
the choice of disconnections and synthons. Sticking to latent polarity usually gives the best choice
of synthons. However, this is not always possible!
Disconnection approach
Functional group based strategies
Functional groups relationships
Taking into account that most common synthetic reactions are polar, a bond forming process (and the
corresponding transform) can be viewed as a combination of donor, d, and acceptor, a, synthons.
Then, it might be useful to consider the carbon framework of any molecule as an ionic aggregate,
whose origin relies on the presence of functional groups.
The symbol designations, + and , simply denote potentially electrophilic or nucleophilic site reactivity
(Attention: only the heteroatom is considered as the functional group)
Disconnection approach
Functional group based strategies
According to these ideas, it is possible to identify difunctional relationships (consonant or
dissonant) among the functional groups in a TGT
Disconnection approach
Functional group based strategies
Synthons identification
taking into account that most common synthetic reactions are polar, a bond forming process (and
the corresponding transform) can be viewed as a combination of donor, d, and acceptor, a, synthons.
Then,obvious rules can apply to arrangement of functionality in the product
Disconnection approach
Functional group based strategies
Synthons identification
Disconnection approach
Functional group based strategies
Synthons identification (1,2-Difunctional compounds, dissonant disconnection)
Solution. Masked acylanion: unpolung (German word used to describe cases in which a synthon of
opposite polarity to that normally associated with a required
functional group must be used)
Disconnection approach
Functional group based strategies
1,2-Difunctional systems: a1 + d1 combination
Disconnection approach
Functional group based strategies
1,3-Difunctional systems: a1 + d2 combination
Disconnection approach
Functional group based strategies
1,4-Difunctional systems: a2 + d2 combination
Forward synthesis
Disconnection approach
Functional group based strategies
1,4-Difunctional systems: a3 + d1 combination
Example
Nef reaction
Disconnection approach
Functional group based strategies
1,4-Difunctional systems: a2 + d2 combination
Disconnection approach
Functional group based strategies
1,5-Difunctional systems: a3 + d2 combination
Example
Disconnection approach
Functional group based strategies
1,6-Difunctional compounds: ozonolysis
Disconnection approach
Functional group based strategies
1,6-Difunctional compounds: ozonolysis
Disconnection approach
Structure based strategies
Chiron approach: synthesis of enantiomerically pure compounds
The chiron approach to synthesis involves disconnection of strategic bonds in a target molecule
with minimum pertubation of existing stereogenic centers.
This generates chirons with a maximum overlap of functional groups, of stereochemical features,
and of carbon framework with the target molecule (or a given substructure).
Such molecules normally contain one to five or six stereogenic centers and can originate from
Nature (terpenes, carbohydrates, -amino acids, -hydroxy acids,...), from asymmetric reactions on
achiral substrates, from resolution of racemates, and from enzymatic and related sources.
By relating a TGT to chiral starting materials as the outset, the scenario for a synthesis plan is
established.
In the chiron approach, it is the type of chiral substructure present in the molecules that will
dictate the strategy.
The main issue now deal with proceeding in the forward direction using the inherent or newlycreated chirality and building from there.
Hanessian, S. Total Synthesis of Natural Products: The Chiron Approach
Pure & Appl. Chem. 1993, 1189
Disconnection approach
Structure based strategies
The power of sugars: thromboxane B2 by Hanessian
Disconnection approach
Structure based strategies
The power of sugars: thromboxane B2 by Hanessian
Disconnection approach
Retrosynthesis of cis-3-oxabicyclo[3.3.0]octan-7-one
Disconnection approach
Retrosynthesis of an intermediate for carbaprostacycline
Disconnection approach
Retrosynthesis of Minaprine (antidepressant)
Disconnection approach
Total Synthesis of Erythronolide B
Erythronolide B is the biosynthetic precursor of all of the Erythromycins.
The land mark total synthesis was performed by E.J Corey and his co-workers at
Harvard in the 1970s.
Erythronolide B : 14-membered lactone10 asymmetric carbon atoms
Disconnection approach
Total Synthesis of Erythronolide B
Disconnection approach
Total Synthesis of Erythronolide B
Retrosynthetic Analysis and Strategy
Disconnection approach
Total Synthesis of Erythronolide B
Retrosynthetic Analysis and Strategy
Disconnection approach
Total Synthesis of Erythronolide B
Retrosynthetic Analysis and Strategy
Disconnection approach
Total Synthesis of Erythronolide B
Total synthesis
Disconnection approach
Total Synthesis of Erythronolide B
Synthesis of compound 17
Disconnection approach
Total Synthesis of Erythronolide B
Synthesis of intermediate 11
Disconnection approach
Total Synthesis of Erythronolide B
Synthesis of intermediate 11
Disconnection approach
Total Synthesis of Erythronolide B
Synthesis of intermediate (+)-12
Disconnection approach
Total Synthesis of Erythronolide B
Synthesis of intermediate (+)-12
Disconnection approach
Total Synthesis of Erythronolide B
Synthesis of intermediate 8
Disconnection approach
Total Synthesis of Erythronolide B
Synthesis of intermediate 8
Disconnection approach
Macrolactonization
Disconnection approach
Total Synthesis of Erythronolide B
Last steps
Corey, E.J.; Nicolaou, K.C.; J. Am. Chem. Soc. 1974, 96, 5614.
Nicolaou, K.C.; Sorenson, E. J. (1996). Classics in Total Synthesis; VCH Publishers. 167-184.