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Lecture 1 ADVANCED SYNTHESIS Stereochemistry Introduction • One of the most important issues in modern organic synthesis • Most natural compounds are enantiomerically pure • Frequently different enantiomers have different biological properties O • two possible compounds N O O N H O (S)-thalidomide • Only one stereocentre so two possible compounds OH HO OH HO O OH D-glucose • Glucose has four stereocentres so 24 = 64 possible diastereoisomers • So need effective means of isolating the one compound we want Resolution • The separation of enantiomers • Can be achieved by chiral chromatography • Can be achieved by selective recrystallisation (although this requires luck) • Can be achieved by derivatisation • Convert enantiomers into diastereoisomers • 2 enantiomers can not be separated by standard chromatography • Equivalent by nmr and all physical data except optical rotation CO2Me F 3C OMe HN + NH2 O O CO2Me Ph + Cl CO2Me F 3C OMe F 3C OMe • Diastereoisomers, physically different and seperable by chromatography HN Ph O • Biggest disadvantage with such a route is the waste • Maximum yield of 50 % as the wrong enantiomer is discarded • So various methods have been developed for stereoselective synthesis Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Advanced Synthesis 1 Lecture 1 Stereoselective Organic Chemistry • There a five broad strategies for the synthesis of optically pure compounds • Over the next few lectures we will look at: 1. The Chiral Pool (chiral starting materials) (1/2 lecture) 2. Substrate Control (1/2 lecture) 3. Chiral Auxiliaries (1 lecture) 4. Chiral Reagents (1 lecture) 5. Chiral Catalysis (2 lectures) The Chiral Pool (Chiral Starting Materials) Substrate do chemistry Functionality • use existing stereochemistry Substrate Modified • Use the stereochemistry available in readily available natural materials • Most commonly used materials used are amino acids and carbohydrates • Remember you can destroy stereocentres by oxidation, reduction and displacement • Wasteful but sometimes useful -Amino Acids NHBoc NH2 NHBoc NH CO2H O Cl DCC Ph N Cl O Ph HBr-AcOH O N Cl Ph C N • a coupling reagent that activates / dehydrates acids • Synthesis of the pharmaceutically important benzodiazepines • Incorporate stereocentre from alanine • Amino acids used to prepare chiral auxiliaries and chiral ligands (the use of which should become apparent) Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Advanced Synthesis 2 O H N Lecture 1 Carbohydrates • Carbohydrates are (frequently) cheap, readily available materials • Contain up to 5 stereocentres so offer plently of opportunity • Ideally use all stereocentres • Swern oxidation OH 3 HO 2 1. TBS-Cl, base 2. acetone, H+ 4 OH O O OH OH BnO 1 O 5 1. DMSO, (COCl)2 then Et 3N 2. NaBH4 3. Ms-Cl, Et3N 4. NaN3 BnO O N3 • SN2 OTBS O O BnO OTBS O benzyl D-mannose • acetal formation (2nd year) • Swern & Wittig (2nd year) 1. TBAF 2. DMSO, (COCl)2 then Et3 N 3. Br–Ph 3P+ CHCHO • deprotection CHO O O O 1. Pd / black, H2, AcOH H N O H H N O 1. Pd / C, H 2 O N3 H BnO HO O BnO H O CHO • acetal hydrolysis HO 1 O + 1. H3 O O 3 2 N HO N 4 H H HO 5 HO swainsonine • Due to the ready availability of carbohydrates and their low cost frequently destroy chirality to get desired compound • Glyceraldehyde intermediate derived from D-mannitol (open chain form of mannose) • Used in preparation of Tomolol, a potent β-adrenergenic blocking agent OH O MeO O O SnCl2 O OH HO OH NaIO4 D-mannitol OH OH tBuHN O O OH OH O O OH OMe tBuHN O O O N N N S • only one of the 5 stereocentres remains • yet a profitable synthesis Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Advanced Synthesis 3 Lecture 1 • Carbohydrate used in the synthesis of a fragment of indanomycin antibiotic • Destroy 2 chiral centres • But use one of the remaining centres to form two new ones • Transfer / induction of chirality OH HO OH O O OH O TsO O O O O laevoflucosan • Ireland-Claisen rearrangement OTMS O O H CO2H O OTMS O OTMS O OTMS O • Which brings us nicely on to.... Substrate Control New chirality Substrate do chemistry Substrate Existing chirality Existing chirality • Use of chirality present within the substrate to control the introduction of new chirality • This is a diastereoselective reaction • If the starting material is enantiopure then the product will be enantiomerically pure • Last year you would have briefly met: Felkin-Ahn Model O Nuc– L R M Nuc OH L R M S S • place largest substituent perpendicular to carbonyl S O O L Nuc M OH M OH L M L M Nuc R R Nuc L S R R minor major Nuc S S minor major • nucleophile will attack along Bürgi-Dunitz angle passed smallest group Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Advanced Synthesis 4 Lecture 1 • Stereochemistry of the substrate influences the face of the carbonyl the nucleophile adds to • If there is chelating heteroatom: Cram-Chelation Control • chelating metal or Lewis acid Met OH PO O O OP R S L ≡ L Nuc S • again attacks passed smallest group PO L Nuc R S R • There are many other directing effects • In Steve Caddick's course last year you would have seen conjugate (Michael) additions O O • nucleophile approaches from least hindered face 1. LiCuMe2 Epoxidation • Allylic alcohols undergo diastereoselective epoxidation • If we use a free hydroxyl group then the peracid hydrogen bonds to the hydroxyl group • Results in a pseudo-intramolecular reaction • If alcohol is protected then epoxidation occurs from least hindered face OH OR mCPBA, R = H OAc mCPBA, R = Ac O O O H H O O O Ar What have we learnt? • It is very important to perform stereoselective synthesis • It can be achieved in a number of ways • Resolution is (normally) wasteful • Utilising the chiral pool allows incorporation of stereochemistry • Substrate control allows diastereoselective reactions As you may have noticed there are some gaps in the notes. A fully annoted version will be placed on the Web at the end of course. Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Advanced Synthesis 5