Welcome to the Retrosynthesis Course. This is a 6 week course that will give you an introduction to designing syntheses of organic molecules.
Retrosynthesis is important in Organic Synthesis, which is “The preparation of a desired organic compound from commercially available starting materials via some multi-step procedure” . Organic synthesis is used widely within the chemical industry. For example, it is very important in making pharmaceuticals, agrochemicals, perfumes, dyes and polymers. Many people who go into the chemical industry will do work that involves organic synthesis in some way.
Many of the molecules that are used in industry are very complex. Here’s a couple of examples from the pharmaceutical industry, Doxazosin, which is used to treat high blood pressure, and Sildenafil, which is better known as Viagra, and you probably have a good idea what that does! At some point, someone must have come up with a way of synthesising these compounds. But how did they do that? Where do you start from when faced with the task of synthesising complex molecules. Which of the thousands of available reactions should you chose? The answer, is to start from the product, and work backwards. This process is called retrosynthesis, and this is what this lecture course is about.
Retrosynthesis is “The analytical process of designing a synthetic route for the preparation of an organic compound from readily available starting materials.” Retrosynthesis is similar to playing a game of chess. There are rules that have to be followed. Just as certain pieces on a chess board are allowed to move in a certain way, so certain molecules and groups will behave in a certain way. It is possible to learn certain moves that enable you to deal with certain situations. You have tricks like the 4 move checkmate in chess and similarly in synthesis you can learn patterns and certain steps to prepare a particular product. However, to fully understand retrosynthesis and be able to apply it to many different situations, you need to understand the underpinning strategies. This course will introduce you to some rules, give you some moves to learn, and also help you understand some of the most important underpinning strategies. It is important at this stage to also realise that retrosynthesis is not something that can just be learnt, practice is needed to become proficient and those who do well in the exams will be those who have done most practice.
There are a 3 main considerations in synthesis. Firstly, we must construct the carbon framework for our molecule. This requires a good knowledge of Carbon-Carbon bond forming reactions, as well as some carbon-heteroatom bond forming reactions. We must use this knowledge to make decisions about the bonds that should be made. Another consideration is Functional Group Interconversions, or FGIs. Often a certain functional group will be needed to carry out a reaction at a certain step, but this functional group may need to be converted to a different one in order to arrive at the correct product. Commonly used examples of FGI’s are Oxidation, Reduction and Hydrolysis. There is an FGI tool online that will help you find out how to carry out any functional group interconversion. Stereocontrol is an important consideration when a target molecule contains stereocentres. However, this course is an introduction to the topic of retrosynthesis and so will only briefly touch on this aspect.
So what so we actually do when we carry out retrosynthetic analysis? Our aim is to design a synthetic route by taking one or more backwards, or retrosynthetic steps. First we must define some terms. The Target Molecule is the molecule that we are trying to prepare, and this is what we start from when carrying out retrosynthetic analysis. A disconnection is an analytical operation of breaking a bond. The bond that is being broken is shown by putting a wavy line though it. This is the reverse of a chemical reaction, and is indicated by a retrosynthesis arrow, as shown. A disconnection will normally generate 2 synthons. A synthon is an imaginary idealised fragment, usually an ion, that corresponds to a nucleophilic or electrophilic species. It is important to note that these are not themselves real species, but they have synthetic equivalents, which are real reagents that correspond to synthons. The synthetic equivalents are the molecules that are actually used within a synthesis, whereas the synthons are just used for the retrosynthetic analysis. A Functional Group Interversion, or FGI, as we’ve previously discussed, is the process of replacing one functional group with another. This may be necessary within a synthesis to allow certain steps to be carried out, or to achieve the correct product.
Let’s look at an example of how we would write out a retrosynthesis. We will use this target molecule. If you have not come across the Ph notation before, that represents a phenyl ring. Starting with this target molecule, we can carry out an FGI, in the case to go back to a ketone from an alcohol. This backwards step corresponds to a reduction reaction as the forward step. The FGI is represented by an retrosynthesis arrow, with FGI over the top. This shows that a retrosynthetic step is being taken, but an FGI is taking place, rather that a bond being broken. Our next step is to break a carbon-carbon bond. For this molecule, there are a number of bonds we could break and this decision is often an important one, and we will discuss how you choose between bonds later, but for now it is not important, so let us chose the one shown here by the wavy line. Disconnecting at this bond gives the 2 fragments shown. A disconnection step is represented by the retrosynthesis arrow. We then assign a positive charge to one fragment and a negative charge to the other. This gives our synthons. We will discuss how you decide which charge to assign to which fragment later and it is another important consideration. We must then identify real reagents that are our synthetic equivalents to the synthons. In this case, we need a bromide and a ketone. The ketone can be deprotonated by a base at the alpha position to generate an enolate, which gives us our synthon. These synthons and their reactions will again be covered in much more detail later in the course. This is the way you should always write out a retrosynthesis, starting from the target molecule, carrying out as many retrosynthetic steps, either disconnections or FGIs, as required to get back to reasonable starting materials, writing out your synthons and synthetic equivalents on the way. From this retrosynthesis, it would then possible to write out the forward reaction, as you will see in examples later in the course.
So we’ve identified a couple of important steps that we must take when performing a disconnection. First we must identify the best disconnection, as there are usually a number of options within any molecule. This can be quite difficult in some situations, but we can follow some simple rules to try to pick the best bond to disconnect. Firstly we need the disconnection to correspond to a reliable, and preferably high yielding forward reaction. The functional groups within a molecule are a good guide, as these are likely to be involved in the most useful reactions. It is also best to make a disconnection that gives significant simplification. This generally involves making a disconnection at the centre of the molecule. It is also important to consider branch points, as a disconnection at a branch point will lead to simpler, straight chain fragments. In this molecule, there are a number of bonds that can be broken. However, if we want to make use of the hydroxyl functional group, we would immediately be drawn to break one of the 2 bonds next to this. It should then be fairly obvious that one of these 2 bonds is preferable, as it is not only more central, but it is also next to a branched, tertiary carbon. This disconnection is then preferred as it will give greatest simplification. Symmetry can be another useful guide to consider. It will lead to a more straightforward synthesis if 2 disconnected synthons are the same, and so the same reagent can be used for both. If we look at this molecule, we can see we have 2 phenyl groups attached. We want to disconnect two of the groups attached to the hydroxyl carbon. It is best to disconnect both of the phenyl groups, rather than one of them and the propyl chain, as we can then use an excess of the synthetic equivalent to the phenyl synthon in the synthesis. It is also important that the fragments generated by a disconnection can be equated to reasonable synthetic equivalents, more details of which will be covered later. The is a multiple choice quiz on Moodle that will allow you to practice choose the correct disconnection from a number of options. This can be found under Lecture 1 of the online course for this module.
The second important step is to assign the charges the correct way round to give the best pair of synthons. At least to start with it is best to write out and consider both possible pairs of synthons. You can then decide which is the better pair. To do this it is important to consider the latent polarity of the fragments. Latent polarity refers to the imaginary charges that can be assigned to atoms as a result of the inductive effects of certain groups. For example, in the molecule shown, the oxygen is an electron withdrawing group, polarising the C-O bond, and making the carbonyl carbon delta positive. This in turn makes the alpha carbons delta negative, the beta carbons delta positive and so on. This alternating pattern of imaginary charges, as shown, can guide the assignment of charges when a disconnection is made. A similar pattern is observed with other electron withdrawing groups, such as halides, and nitrogen based functional groups. There are exceptions to these polarities, but they will be covered later. Synthons also need to correspond to synthetic equivalents that are reactive and available, to buy or can be easily prepared. For example, and this is an important example to remember, we might think bromobenzene is a suitable synthetic equivalent to a positive phenyl synthon, but this is not the case, as it does not undergo substitution reactions. A positive phenyl ring is generally not a helpful synthon. You are not expected to have a definitive knowledge of what reagents are available to buy. Questions will often give a maximum number of carbons that your starting materials are allowed to contain.
In order to be able to choose good disconnections and assign the charges to the synthons correctly, it is important to know what are reasonable synthons, and their corresponding real reagents. These are your most important tools for retrosynthesis. Let us first consider electrophilic carbon synthons, those to which we would assign a positive charge. These are simpler than Carbon Nucleophiles, and so we will just go through these now. For much of the remainder of the course we will be going through the Carbon Nucleophiles and how they react with these Electrophiles. Let’s start with the simplest positive synthon, an alkyl group with a positive charge, an alkyl cation. This is equivalent to an alkyl halide. Alkyl halides can undergo nucleophilic substitution, with the halide able to act as a leaving group. What about if our disconnection leaves us with a primary alcohol cation? This is equivalent to an aldehyde, as the electron withdrawing effect of the oxygen makes the carbonyl carbon delta positive, and so it can undergo nucloephilic addition reactions. Note that this ties in with the latent polarity we discussed earlier. Similarly, if we have a secondary alcohol, this is equivalent to the ketone. If we have an acyl cation, this is equivalent to the acyl group with a leaving group. This leaving group can either be the alkoxide from an ester or the halide from an acyl halide. This next synthon appears to go against the latent polarity argument, as it appears to have a positive alpha carbon. But remember this as an exception to the normal rules. This synthon is equivalent to an epoxide. The oxygen makes the 2 neighbouring carbons delta positive. These are then vulnerable to nucleophilic attack. However attack will generally take place at the least substituted position, as there is less steric hindrance. The oxygen effectively acts as a leaving group form the carbon to which the nucleophile adds. With acid workup this gives an alcohol, with the nucleophile added at the alpha position, hence an epoxide can be considered equivalent to this synthon. If we have a ketone synthon with the positive charge on the beta carbon, this is equivalent to an enone. This agrees with the latent polarity argument. The beta position is delta positive, and hence a nucleophile can attack at this position in a 1,4 conjugate addition reaction. The final synthon we will consider is a carboxylic acid cation. This is equivalent to carbon dioxide. It is important to know all of these synthons and their synthetic equivalents. They will repeatedly pop up throughout the course as we cover examples involving them, and it is important to be able to quickly recognise the synthetic equivalent that corresponds to each synthon. There is a quiz in the Lecture 1 section online that will help you learn these.
KIMIA ORGANIK III:Reaksi dan Sintesis Senyawa OrganikPolifungsional
KIMIA ORGANIKIII IDENTITAS MATA KULIAH NOMOR KODE : KI 513 JUMLAH SKS : 2 SKS SEMESTER : 4 dan 6 KELOMPOK MK : MKK (MATA KULIAH KEAHLIAN) PRODI PRASYARAT : KIMIA ORGANIK I dan KIMIA ORGANIK II TUJUAN MAHASISWA MAMPU MENJELASKAN REAKSI YANG TERJADI PADA SENYAWA ORGANIK POLIFUNGSIONAL BERDASARKAN MEKANISME REAKSINYA DAN MENGENAL PENDEKATAN RETROSINTESIS DALAM MERANCANG SINTESIS SENYAWA ORGANIK
DESKRIPSI ISI PENDEKATAN RETROSINTESIS DAN JENIS-JENIS REAKSI PADA SENYAWA ORGANIK POLIFUNGSIONAL (SENYAWA HETEROSIKLIS, POLISIKLIS, BIFUNSIONAL, KARBOHIDRAT, PROTEIN DAN LIPIDA) EVALUASI KEHADIRAN : MINIMAL 80 % PERTEMUAN TUGAS : 15 % KUIS : 10 % TES UNIT : 3 X 25 % BUKU Fessenden, R. j. dan Fessenden, J.S., terjemahan oleh Pudjaatmaka, 1982, Kimia Organik, Erlangga, Jakarta Solomon, Graham, T.W., dan Fryhle, C.B, 2004, Organic Chemistry, Eight edition, John Wiley & Sons, Singapura
RINCIAN MATERITOPIK SUBTOPIK1. PENDAHULUAN a. Cakupan materi b. Berbagai ketentuan perkuliahan : kehadiran, evaluasi, dll c. Pengantar umum pendekatan diskoneksi2. SENYAWA HETEROSIKLIK a. Definisi, klasifikasi, tatanama, dan struktur senyawa heterosiklis b. Reaksi-reaksi senyawa heterosiklis aromatis c. Pembuatan senyawa heterosiklis3. SENYAWA POLISIKLIK a. Definisi, klasifikasi, tatanama, dan struktur senyawa polisiklis b. Reaksi-reaksi senyawa polisiklis aromatis c. Pembuatan senyawa polisiklis.4. SENYAWA BIFUNGSIONAL a. Klasifikasi, tatanama senyawa bifungsional b. Pembuatan senyawa bifungsional c. Reaksi dan mekanisme reaksi diena d. Reaksi dan mekanisme reaksi diol e. Reaksi dan mekanisme reaksi karbonil tak jenuh f. Reaksi dan mekanisme reaksi hidroksi dan amino karbonil g. Reaksi dan mekanisme reaksi dikarbonil5. KARBOHIDRAT a. Definisi, struktur, klasifikasi, dan tatanama karbohidrat b. Reaksi-reaksi monosakarida c. Disakarida d. Polisakarida6. ASAM AMINO DAN PROTEIN a. Struktur dan sifat asam amino b. Sintesis asam amino c. Struktur, klasifikasi polipeptida dan protein d. Sintesis polipeptida7. LIPIDA DAN PRODUK ALAM TERKAIT a. Lemak dan minyak b. Fospolipida c. Terpena d. Steroida
SENYAWA ORGANIK POLIFUNGSIONAL Senyawa dengan dua atau lebih gugus fungsional. Senyawa organik yang ditemukan di alam, sebagian besar merupakan senyawa polifungsional. O OH CH geraniol (dari minyak mawar) OCH3 OH Sukrosa (gula pasir) vanilin
Sintesis Organik“Pe m bua ta n s e ny a wa o rg a nik te rte ntu d a ri ba ha n a wa ly a ng te rs e d ia s e c a ra ko m e rs ia l m e la lui be be ra p ap ro s e d ur m ulti-ta ha p ”Digunakan dalam: Farmasi Agrokimia Parfum Pewarna Polimer dst
Sintesis Organik O O O N Me N O O HN N O N N S O N N N N O O Me NH2 Doxazosin (Cardura) Sildenafil (Viagra)P. Dari mana memulai untuk mensintesis molekul kompleks ?J. Bekerja mundur, mulai dari produk RETROSINTESIS
Retrosintesis“Pro s e s a na litis d a la m p e ra nc a ng a n s ua tu rute p e m bua ta ns e ny a wa o rg a nik d a ri ba ha n a wa l y a ng te rs e d ia . ” Seperti permainan catur: Teratur Gerakannya dapat dipelajari Mempunyai strategi Practice makes Perfect!
Pertimbangan Utama Pembangunan Jaringan Karbon Memerlukan pengetahuan tentang reaksi pembentukan ikatan C- C Melibatkan keputusan tentang ikatan yang mana yang sebaiknya akan dibuat. Functional Group Interconversions (FGIs) Often require certain functional groups at certain stages in a synthesis E.g. Oxidation, Reduction, Hydrolysis Stereocontrol Often need to synthesise only one of a number of possible stereoisomers Only briefly touched on in this course
Beberapa Istilah Retrosintesis Molekul Target (MT) – Molekul yang akan dibuat Diskoneksi – operasi analitik pemutusan ikatan, kebalikan reaksi kimia, untuk menghasilkan dua sinton Sinton – suatu an imaginary idealised fragment, usually an ion, corresponding to nucleophilic or electrophilic species Synthetic Equivalent – a real reagent that is equivalent to a certain synthon Functional Group Interconversion (FGI) – the operation of replacing one functional group with another R3C CR3 R3C + -CR3 Panah Retrosintesis
Retrosintesis Interkonversi Gugus Fungsi FGI ditunjukkan oleh: Tanda diskoneksi OH FGI O menunjukkan ikatan yang pecahPh Ph Ph Ph Molekul Target Diskoneksi ditunjukkan oleh: O O + Ph CH3 Ph Ph Br Ph + Base Sintetik Sintetik ekivalen ekivalen Sinton
Tahap-tahap Penting1. Pemilihan diskoneksi yang benar Kaitkan dengan reaksi yang dapat dipercaya Gunakan pengetahuan tentang reaksi gugus fungsional Lakukan penyederhanaan penting: pusat molekul titik cabang simmetri Tunjukkan sinton yang mempunyai sintetik ekivalen yang mungkin. Me OH Me Ph Me Ph OH
Tahap-tahap Penting2. Tandai muatan kedua sinton Pertimbangkan kedua pilihan sinton Gunakan Polaritas Umum Must correspond to reactive and available synthetic equivalents Available to buy Can easily be prepared Br + O Ph Ph
ToolKit – Elektrofil Karbon Sintetik SintetikSinton Sinton Ekivalen Ekivalen + RX OH R X = Br, I O R + R OH O NucR + H R H O O + R R OH O OR + R R R CO2 + HO O O + LG = OR or Halogen R R LG