Lecture 1 ADVANCED SYNTHESIS Stereochemistry Introduction

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1 ecture 1 ADVACED YTEI tereochemistry Introduction ne of the most important issues in modern organic synthesis ost natural compounds are enantiomerically pure Frequently different enantiomers have different biological properties two possible compounds ()-thalidomide nly one stereocentre so two possible compounds D-glucose Glucose has four stereocentres so 4 = 64 possible diastereoisomers o need effective means of isolating the one compound we want esolution 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 enantiomers can not be separated by standard chromatography Equivalent by nmr and all physical data except optical rotation C e + F 3 C e Diastereoisomers, physically different and seperable by chromatography C e F 3 C e + C e F 3 C e Biggest disadvantage with such a route is the waste aximum yield of 50 % as the wrong enantiomer is discarded o various methods have been developed for stereoselective synthesis Gareth owlands (g.rowlands@sussex.ac.uk) Ar40, Advanced ynthesis 1

2 ecture 1 tereoselective rganic Chemistry There a five broad strategies for the synthesis of optically pure compounds ver the next few lectures we will look at: 1. The Chiral Pool (chiral starting materials) (1/ lecture). ubstrate Control (1/ lecture) 3. Chiral Auxiliaries (1 lecture) 4. Chiral eagents (1 lecture) 5. Chiral Catalysis ( lectures) The Chiral Pool (Chiral tarting aterials) use existing stereochemistry ubstrate do chemistry ubstrate Functionality odified Use the stereochemistry available in readily available natural materials ost commonly used materials used are amino acids and carbohydrates emember you can destroy stereocentres by oxidation, reduction and displacement Wasteful but sometimes useful -Amino Acids Boc DCC C Boc Br-Ac C a coupling reagent that activates / dehydrates acids ynthesis 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 owlands (g.rowlands@sussex.ac.uk) Ar40, Advanced ynthesis

3 ecture 1 Carbohydrates Carbohydrates are (frequently) cheap, readily available materials Contain up to 5 stereocentres so offer plently of opportunity Ideally use all stereocentres wern oxidation TB-, base. acetone, + 1. D, (C) then Et 3. ab 4 3. s-, Et 3 4. a 3 3 Bn 1 5 benzyl D-mannose Bn TB Bn TB acetal formation (nd year) deprotection wern & Wittig (nd year) 1. TBAF. D, (C) then Et 3 3. Br 3 P + CC C 1. Pd / black,, Ac 1. Pd / C, 3 Bn Bn C acetal hydrolysis 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 ai 4 e e n D-mannitol tbu tbu only one of the 5 stereocentres remains yet a profitable synthesis Gareth owlands (g.rowlands@sussex.ac.uk) Ar40, Advanced ynthesis 3

4 ecture 1 Carbohydrate used in the synthesis of a fragment of indanomycin antibiotic Destroy chiral centres But use one of the remaining centres to form two new ones Transfer / induction of chirality Ts laevoflucosan Ireland-aisen rearrangement T C T T T Which brings us nicely on to... ubstrate Control ew chirality ubstrate Existing chirality do chemistry ubstrate 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 ast year you would have briefly met: place largest substituent perpendicular to carbonyl Felkin-Ahn odel uc uc uc uc uc minor major nucleophile will attack minor major along Bürgi-Dunitz angle passed smallest group Gareth owlands (g.rowlands@sussex.ac.uk) Ar40, Advanced ynthesis 4 uc

5 ecture 1 tereochemistry of the substrate influences the face of the carbonyl the nucleophile adds to If there is chelating heteroatom: Cram-Chelation Control et P chelating metal or ewis acid P uc uc again attacks passed smallest group There are many other directing effects In teve Caddick's course last year you would have seen conjugate (ichael) additions P 1. icue nucleophile 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 esults in a pseudo-intramolecular reaction If alcohol is protected then epoxidation occurs from least hindered face mcpba, = mcpba, = Ac Ac Ar What have we learnt? It is very important to perform stereoselective synthesis It can be achieved in a number of ways esolution is (normally) wasteful Utilising the chiral pool allows incorporation of stereochemistry ubstrate 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 owlands (g.rowlands@sussex.ac.uk) Ar40, Advanced ynthesis 5