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 O H (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 CO2Me by standard chromatography F C OMe • Equivalent by nmr and all physical 3 HN data except optical rotation Ph O O CO2Me + + Cl NH2 CO Me F3C OMe 2 F3C OMe • Diastereoisomers, physically different HN and seperable by chromatography 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 • use existing (Chiral Starting Materials) stereochemistry Substrate do chemistry Substrate Functionality 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 NHBoc H O NH2 N NH CO2H HBr-AcOH O O Cl O N DCC Cl Cl Ph Ph Ph N 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 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 1. DMSO, (COCl)2 then Et3N 2. NaBH OH 4 1. TBS-Cl, base O 3. Ms-Cl, Et3N O 3 + 4. NaN HO 2 4 OH 2. acetone, H 3 O OH O N3 OH • S 2 BnO 1 O 5 OTBS N OTBS BnO O BnO O benzyl D-mannose • acetal formation (2nd year) • Swern & Wittig 1. TBAF (2nd year) 2. DMSO, (COCl)2 then Et3N 3. Br–Ph P+CHCHO • deprotection 3 O CHO O O H 1. Pd / black, H2, H H N AcOH O N 1. Pd / C, H2 O O N3 H HO BnO O H BnO O CHO • acetal hydrolysis HO O 1 2 1. H O+ 3 3 N O N HO H 4 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 b-adrenergenic blocking agent OH O MeO OMe OH OH O OH O HO SnCl2 O OH OH OH NaIO D-mannitol 4 OH O O O tBuHN O N O O tBuHN O N N • only one of the 5 stereocentres remains S • 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 O OH TsO HO OH O O O O O O laevoflucosan • Ireland-Claisen rearrangement OTMS O O O OTMS O H CO H 2 OTMS OTMS O 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 OH Nuc– L L R R M S M S • place largest substituent perpendicular to carbonyl O O OH OH S M L M L M L L Nuc R R Nuc Nuc M S Nuc R R S S minor major 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 Met or Lewis acid OH PO O O PO L OP R º S L L Nuc R Nuc S S • again attacks passed R smallest group • There are many other directing effects • In Steve Caddick's course last year you would have seen conjugate (Michael) additions O O • nucleophile 1. LiCuMe2 approaches from least hindered face 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 OAc mCPBA, R = H mCPBA, R = Ac O O H O 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.