Synthesis

Introduc)on
During the rst half of the 20th century most syntheses were developed by selec;ng a
commercially available star;ng material having a structural resemblance to the target
molecule. Synthe;c planning in most of the cases was strongly dependent on an
assumed star;ng point.
A?er World War II the synthesis of a series of complex molecules was achieved,
propelled by the availability of more powerful conceptual processes for the synthesis
planning and by the use of new synthe;c methods. For instance the total syntheses of
vitamin A (O. Isler, 1949), cor;sone (R.B. Woodward, R. Robinson, 1951), morphine (M.
Gates, 1956), penicillin (J.C. Sheehan, 1957) and chlorophyll (R. B. Woodward, 1960)
were achieved.
The striking leap forward was recognized by the award of the Nobel Prize for chemistry
to R. B. Woodward (1965) and later to E. J. Corey (1990), the father of retrosynthe;c
analysis.

Target molecule: the molecule to be synthesized (o?en abbreviated as TM)

Retrosynthe2c analysis: the process of breaking down a TM into available star;ng
materials. The rst step in a retrosynthe;c analysis will be the last one in the forward
synthesis, the TM and the precursors are connected by retrosynthe;c arrows (NO reac;on
condi;ons are specied on the arrow!)

Forward synthesis: the actual synthesis from the star;ng materials to the TM.
Disconnec5on: the reverse opera;on to a reac;on; the cleavage of bond aording
synthons.
Synthon: an idealized fragment, most o?en a ca;on or anion, resul;ng from the
disconnec;on of a bond
Synthe2c equivalent (Reagent): compound used in prac;ce for a synthon.

Linear vs. convergent synthesis

Whenever possible one should try to use a convergent synthesis (bringing bigger building
blocks together at the same ;me) to increase the overall yield. If the yield of a single
transforma;on is 90% (op;mis;c) in a linear synthesis the overall yield a?er 5 steps
cant exceed 59%.

With the same assump;on (90 % yield per step) a convergent synthesis with the same
amount of steps would have an overall yield of 73 %. Purely convergent synthesis is
idealized, for all syntheses un;l some degree are linear.

General guidelines for a retrosynthe;c analysis

The synthesis should be as short as possible;
Look for the retrosynthe;c steps that lead to known, reliable reac;ons;
Disconnect preferen;ally C-X bonds, because they are generally easier to make
than C-C bonds;
If a C-C disconnec;on has to be done, analyze the func;onal groups and their
rela;onship;
Repeat the disconnec;ons un;l you reach available star;ng materials;
Analyze all the steps in the forward synthesis and detect possible problems:
- func;onal group compa;bility (use of protec;ng groups);
- chemo- and stereoselec;vity.

Disconnec)on approach
A key concept in Coreys disconnec;on approach is the synthon. A synthon is a
conceptual en;ty; it does not have to exist as a chemical structure, but can be
reconducted to reagents with the corresponding polarity.

Donor Synthon (dN)

Func;onalized nucleophile with the heteroatom of the func;onal group joined to the Nth
carbon atom.

Acceptor Synthon (aN)

Func;onalized electrophile with the heteroatom of the func;onal group joined to the Nth
carbon atom.

Examples of synthons and the corresponding reagents

How to select a disconnec)on

Even for very simple molecules there are several possible retrosynthe;c
disconnec;ons. Two general rules can be applied:
1) Disconnect the molecule in the center, trying to obtain two about equally sized
fragments (convergent synthesis);
2) A disconnec;on at a branch-point is most likely to give a linear (therefore simpler)
precursor.

Example 1

Example 2

Example 3

Classes of retrosynthe)c disconnec)ons for bifunc)onal compounds

It is useful to recognize the rela;ve posi;on of two func;onal groups within a molecule in
order to choose the best retrosynthe;c disconnec;on.
1,3-bifunc)onal compounds
1,4-bifunc)onal compounds
1,5-bifunc)onal compounds

1,3-bifunc)onal compounds
Various 1,3-bifunc;onal compounds can be made from ketone 1.

Disconnec;on of bond 2-3 leads to synthons which have synthe;c equivalents set up
for an aldol reac;on.

1,4-bifunc)onal compounds
Disconnec;on between 2-3 leads us to synthons, which do indeed have synthe;c
equivalents, but are not compa;ble. Alterna;ve disconnec;on between 1-2 leads to a 1,4
addi;on.

Simple func;onal group interconversion aords alterna;ve routes for 1,4-bifunc;onal

compounds

1,5-bifunc)onal compounds
Disconnec;on between 2-3 aords synthons set up for a 1,4 addi;on.

The same subs;tu;on pajern can be obtained from subs;tuted cyclopentadiene with
ozonolysis.

Func)onal Group interconversion

Some;mes adding further steps to the synthesis helps solving problems.

Amines
Many natural products and synthe;c targets contain amine func;onality; some general
ways to introduce it in the molecule are depicted below.
Amines can arise from: halides via displacement with an azide and Staudinger
reduc;on; ketones or aldehydes via reduc;ve amina;on; reduc;on of a nitro
compound and from amides.

Ketones
Ketones can arise from alcohols via oxida;on, Weinreb amides via 1,2 addi;ons, or
alkenes via ozonolysis.

A carbonyl group in a molecule opens up many possibili;es to introduce other

func;onali;es (-func;onaliza;on), form new C-C bonds and bring bigger fragment
together (cross couplings).

Olens
Olens can be made from ketones or aldehydes via Wimg and related reac;ons, alkynes
(reduc;ons), and other olens via metathesis or cross couplings.

Various transforma;ons can also be preformed with olens such as: hydrobora;on-
oxida;on sequence to aord an alcohol which can be transformed into a ketone or
carboxylic acid; epoxida;on and opening with a nucleophile aords 1,2 disubs;tuted
compounds; Diels-Alder reac;ons which aords cyclic compounds and also reduc;on to
aord alkanes.

1. The importance of total synthesis.

Chemical synthesis of complex natural products is in many cases essen;al for biological
studies and structural assignment. The target molecules are o?en very ac;ve compounds,
which are present in nature at extremely low concentra;ons.
An example is the insect juvenile hormone of Cecropia (TM in the scheme below), which
plays a central role in insect development and generated immense interest in the 1960s
because of the poten;al use as nontoxic insect control. The molecule was synthesized in
about 20 chemical steps using Coreys disconnec;on approach.

2 Viagra (Sildenal Citrate)

Sildenal is a drug synthesized by pharmaceu;cal company Pzer used to treat erec;le
dysfunc;on and pulmonary arterial hypertension. Viagra is one of the top selling drugs in
recent years. The industrial synthesis of Viagra involves very simple reac;ons. It is a good
example illustra;ng bond disconnec;ons and func;onal group transforma;ons.
Retrosynthesis

Synthesis:

3 -kainic acid
-kainic acid 1 is a potent agonist for glutamate receptors in the nervous system and is
widely used in neuroscience as neurodegenera;ve agent modeling epilepsy, Parkinsonss
disease and Alzheimers disease.
Retrosynthesis:

Synthesis:

4 Penicillin V
Penoxymethylpenicillin (Penicillin V) is a penicillin an;bio;c which is orally ac;ve against
Gram-nega;ve bacteria. Its total synthesis was accomplished in the late 1950s by John C.
Sheehan.
Retrosynthesis:

Synthesis:

5 Prostaglandin F2 :
The rst total synthesis of Prostaglandin F2 and Prostaglandin E2 was reported by E. J.
Corey in 1969 (J. Am. Chem. Soc. 1969, 91, 5675) and has become an all-;me classic in the
total synthesis of natural products. The highly stereoselec;ve synthesis of the ve-
membered core was accomplished using transforma;ons on a norbornene system.
Retrosynthesis:

Synthesis:

6 Dil)azem
Dil;azem is a calcium channel blocker used as a drug for the treatment of angina pectoris.
It reduces the heart rate without aec;ng the force of contrac;on. The ability of these
drugs to dilate peripheral blood vessels also makes them agents for hypertension.
Retrosynthesis:

Synthesis: