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synthesis chemical basics
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Introduc)on
During the first half of the 20th century most syntheses were developed by selec;ng acommercially available star;ng material having a structural resemblance to the targetmolecule. Synthe;c planning in most of the cases was strongly dependent on anassumed 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 synthesisplanning and by the use of new synthe;c methods. For instance the total syntheses ofvitamin 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 chemistryto R. B. Woodward (1965) and later to E. J. Corey (1990), the father of retrosynthe;canalysis.
Synthesis
Target molecule: the molecule to be synthesized (o?en abbreviated as TM)
Retrosynthe2c analysis: the process of breaking down a TM into available star;ngmaterials. The first step in a retrosynthe;c analysis will be the last one in the forwardsynthesis, the TM and the precursors are connected by retrosynthe;c arrows (NO reac;oncondi;ons are specified 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 affording“synthons”.
Synthon: an idealized fragment, most o?en a ca;on or anion, resul;ng from thedisconnec;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 buildingblocks together at the same ;me) to increase the overall yield. If the yield of a singletransforma;on is 90% (op;mis;c) in a linear synthesis the overall yield a?er 5 stepscan’t exceed 59%.
With the same assump;on (90 % yield per step) a convergent synthesis with the sameamount of steps would have an overall yield of 73 %. Purely convergent synthesis isidealized, 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 makethan C-‐C bonds;• If a C-‐C disconnec;on has to be done, analyze the func;onal groups and theirrela;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 Corey’s disconnec;on approach is the synthon. A synthon is aconceptual en;ty; it does not have to exist as a chemical structure, but can bereconducted 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;cdisconnec;ons. Two general rules can be applied:1) Disconnect the molecule in the center, trying to obtain two about equally sizedfragments (convergent synthesis);2) A disconnec;on at a branch-‐point is most likely to give a linear (therefore simpler)precursor.
Example 3
Example 2
Example 1
Classes of retrosynthe)c disconnec)ons for bifunc)onal compoundsIt is useful to recognize the rela;ve posi;on of two func;onal groups within a molecule inorder to choose the best retrosynthe;c disconnec;on.
1,3-‐bifunc)onal compounds1,4-‐bifunc)onal compounds1,5-‐bifunc)onal compounds
1,3-‐bifunc)onal compoundsVarious 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 upfor an aldol reac;on.
1,4-‐bifunc)onal compoundsDisconnec;on between 2-‐3 leads us to synthons, which do indeed have synthe;cequivalents, but are not compa;ble. Alterna;ve disconnec;on between 1-‐2 leads to a 1,4addi;on.
Simple func;onal group interconversion affords alterna;ve routes for 1,4-‐bifunc;onalcompounds
1,5-‐bifunc)onal compoundsDisconnec;on between 2-‐3 affords synthons set up for a 1,4 addi;on.
The same subs;tu;on pajern can be obtained from subs;tuted cyclopentadiene withozonolysis.
Func)onal Group interconversion
Some;mes adding further steps to the synthesis helps solving problems.
AminesMany natural products and synthe;c targets contain amine func;onality; some generalways to introduce it in the molecule are depicted below.Amines can arise from: halides via displacement with an azide and Staudingerreduc;on; ketones or aldehydes via reduc;ve amina;on; reduc;on of a nitrocompound and from amides.
KetonesKetones can arise from alcohols via oxida;on, Weinreb amides via 1,2 addi;ons, oralkenes via ozonolysis.
A carbonyl group in a molecule opens up many possibili;es to introduce otherfunc;onali;es (α-‐func;onaliza;on), form new C-‐C bonds and bring bigger fragmenttogether (cross couplings).
OlefinsOlefins can be made from ketones or aldehydes via Wimg and related reac;ons, alkynes(reduc;ons), and other olefins via metathesis or cross couplings.
Various transforma;ons can also be preformed with olefins such as: hydrobora;on-‐oxida;on sequence to afford an alcohol which can be transformed into a ketone orcarboxylic acid; epoxida;on and opening with a nucleophile affords 1,2 disubs;tutedcompounds; Diels-‐Alder reac;ons which affords cyclic compounds and also reduc;on toafford alkanes.
1. The importance of total synthesis.Chemical synthesis of complex natural products is in many cases essen;al for biologicalstudies 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), whichplays a central role in insect development and generated immense interest in the 1960’sbecause of the poten;al use as nontoxic insect control. The molecule was synthesized inabout 20 chemical steps using Corey’s disconnec;on approach.
2 Viagra® (Sildenafil Citrate)Sildenafil is a drug synthesized by pharmaceu;cal company Pfizer used to treat erec;ledysfunc;on and pulmonary arterial hypertension. Viagra is one of the top selling drugs inrecent years. The industrial synthesis of Viagra involves very simple reac;ons. It is a goodexample illustra;ng bond disconnec;ons and func;onal group transforma;ons.
Retrosynthesis
Synthesis:
3 α-‐kainic acidα-‐kainic acid 1 is a potent agonist for glutamate receptors in the nervous system and iswidely used in neuroscience as neurodegenera;ve agent modeling epilepsy, Parkinsons’sdisease and Alzheimer’s disease.
Retrosynthesis:
Synthesis:
4 Penicillin VPenoxymethylpenicillin (Penicillin V) is a penicillin an;bio;c which is orally ac;ve againstGram-‐nega;ve bacteria. Its total synthesis was accomplished in the late 1950’s by John C.Sheehan.
Retrosynthesis:
Synthesis:
5 Prostaglandin F2α :The first total synthesis of Prostaglandin F2α 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 thetotal synthesis of natural products. The highly stereoselec;ve synthesis of the five-‐membered core was accomplished using transforma;ons on a norbornene system.Retrosynthesis:
Synthesis:
6 Dil)azemDil;azem is a calcium channel blocker used as a drug for the treatment of angina pectoris.It reduces the heart rate without affec;ng the force of contrac;on. The ability of thesedrugs to dilate peripheral blood vessels also makes them agents for hypertension.
Retrosynthesis:
Synthesis:
