Synthesis. Introduc)on

Transcription

1 Synthesis Introduc)on During the first 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.

2 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 first 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 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 the disconnec;on of a bond Synthe2c equivalent (Reagent): compound used in prac;ce for a synthon.

3 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 can t 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.

4 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.

5 Disconnec)on approach A key concept in Corey s 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 (d N ) Func;onalized nucleophile with the heteroatom of the func;onal group joined to the N th carbon atom. Acceptor Synthon (a N ) Func;onalized electrophile with the heteroatom of the func;onal group joined to the N th carbon atom.

6 Examples of synthons and the corresponding reagents

7 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.

8 Example 1 Example 2 Example 3

9 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

10 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.

11 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 affords alterna;ve routes for 1,4- bifunc;onal compounds

12 1,5- bifunc)onal compounds Disconnec;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 with ozonolysis.

13 Func)onal Group interconversion Some;mes adding further steps to the synthesis helps solving problems.

14 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.

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

16 Olefins Olefins 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 or carboxylic acid; epoxida;on and opening with a nucleophile affords 1,2 disubs;tuted compounds; Diels- Alder reac;ons which affords cyclic compounds and also reduc;on to afford alkanes.

17 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 1960 s because of the poten;al use as nontoxic insect control. The molecule was synthesized in about 20 chemical steps using Corey s disconnec;on approach.

18 2 Viagra (Sildenafil Citrate) Sildenafil is a drug synthesized by pharmaceu;cal company Pfizer 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

19 Synthesis:

20 3 α- kainic acid α- 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, Parkinsons s disease and Alzheimer s disease. Retrosynthesis:

21 Synthesis:

22 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 1950 s by John C. Sheehan. Retrosynthesis:

23 Synthesis:

24 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 the total synthesis of natural products. The highly stereoselec;ve synthesis of the five- membered core was accomplished using transforma;ons on a norbornene system. Retrosynthesis:

25 Synthesis:

26 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 affec;ng the force of contrac;on. The ability of these drugs to dilate peripheral blood vessels also makes them agents for hypertension. Retrosynthesis:

27 Synthesis: