Lecture3: 123.312

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A brief look at alcohol protecting groups and then an introduction to carboxylic acid derivatives. Start of the reactions of carboxylic acids.

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Lecture3: 123.312

  1. 1. FUNCTIONALGROUP 123.312 Alcohols are very useful starting materials... INTERCONVERSIONS functional group H OH O O CHAPTER4 interconversions R O R O previously, we2 R R R introduced the alcohol (hydroxy) group ... R O R2 R OH R CHAPTER four protecting groups R O R Cl R2 R O E 1 2 O R2 3 so the general scheme is... we had found the protecting Text fully protected AcO OAc substitution was hard unless we derivatised the alcohol groups intermediate during the OTBS HO first. synthesis of O vancomycin O Cl R Nuc O O O O Nuc R OH O O R S 1 TBSO O Cl O OTBS O R O Cbz S 1 H N H H O R N N N N N O H H O H O NH O NH2 we looked at sulfonates, MeO2C halides & reactions such as OTBS the mitsunobu OTBS ©gianni d.@flickr TBSO 4 5 6 protecting protecting groups... groups... why do we need add at least two steps to synthesis (bad) protecting groups ? but allows chemistry that might not have been possible ©showtime ...a necessary evil. ©showtime ...a necessary evil. (good) 7 8 9
  2. 2. so we must protect reaction occurs at the alcohol prior to the alcohol first reaction O HO Nuc O O O R1 R2 Nuc X R1 R2 R1 R2 Nuc R1 R2 R2 OH OH O O R1 H O why does this reaction we have removed PG fail? acidic hydrogen 10 11 12 many reactions are many reactions are by blocking certain reactivity we not chemoselective not chemoselective control chemoselectivity OH OH Br Nuc OH OH Nuc Nuc OH OH +PG Nuc Nuc –PG Br Br the use of protecting groups permits selective PG PG O O synthesis of the desired O O Nuc this reaction gives a mixture product Br Nuc of products due to the reactivity of the alcohol 13 14 15 be attached in high yield +PG O R OH R PG OH how would you selectively a protecting make the other product? Nuc group should have OH Br Nuc the following properties: O ©leo reynolds@flickr 16 17 18
  3. 3. survive reaction be removed in conditions high yield +PG O +PG O R OH R PG R OH R PG examples of protecting reaction reaction groups: O –PG O R* PG R* OH R* PG 19 20 21 Silyl protecting groups Synthesis Synthesis: mechanism Me Me O Me Me Me O Me R OH N NH R Si R OH N NH R Si Si Me Si Me O R1 Cl t-Bu t-Bu Cl t-Bu t-Bu R Si HN N R1 based on strength of the R1 oxygen-silicon bond (think about Me Me R OH H Si O Me glass or the most common form N t-Bu R Si of sand) note: we do not often use HN Me very easy to prepare Me3Si (trimethylsilyl/TMS) as t-Bu stable to nucleophiles & Carbon or it is relatively unstable Nitrogen bases 22 23 24 Synthesis: mechanism Synthesis: mechanism Synthesis: mechanism Me Me O Me Me Me O Me Me Me O Me R OH N NH R Si R OH N NH R Si R OH N NH R Si Si Me Si Me Si Me Cl t-Bu t-Bu Cl t-Bu t-Bu Cl t-Bu t-Bu note: initially, imidazole does not act as a base (it is too HN N HN N HN N weak a base to deprotonate an alcohol Me Me H Me Me H Me Me H R OH R OH R OH Si O Me Si O Me Si O Me N t-Bu R Si N t-Bu R Si N t-Bu R Si HN Me HN imidazole activates the silyl Me HN note: the reactions of siliconMe t-Bu reagent (this kind of behaviour is t-Bu groups are not actually snt-Bu 2 but important to the reactivity of the we will let than one slip for the amino acid histidine time being 25 26 27
  4. 4. deprotection: fluoride deprotection: Acid tetrahydropyranyl (THP) group H O Me H3O O Me F R Si O Me R OH R Si Me R Si R OH Me t-Bu (Bu4N+F–) t-Bu H2O: Me t-Bu R the silicon fluorine O O bond is one of the can also use acid note: an excellent review strongest known bonds, so to remove some on the selective removal this reaction is pretty silyl ethers of silyl ethers is: effective synthesis 1996, 1031 stable to strong bases 28 29 30 synthesis do you know the acetal formation / hydrolysis mechanism? H R OH R O O O H Text R OH R O O O H H R OH Yes, look at O O it...it’s an acetal! 31 32 33 deprotection do you know the acetal formation / hydrolysis H3O mechanism? H3O R OH R OH R R O O HO O O O HO O H H2O R R OH Yes, look at it...it O O O is an acetal! H 34 35 36
  5. 5. problem: we have added benzyl (bn) ether Synthesis Text a stereocentre so could have diastereoisomers R O Br R NaH O R R OH O O good on nitrogen as well as oxygen simplest synthesis involves sn2 vrey robust protecting group; displacement of a halide ©camil tulcan@flickr stable to just about everything 37 38 39 deprotection Aromatic ring is its achilles’s heel deprotection R O R R HBr or O O H2, Pd / C R OH R OH cleaving an ether can be aromatic ring increases the hard (hence it’s a robust but the benzyl activity of this particular ether, protecting group) group as a weak permitting selective spot... deprotections ©Warner Bros / DC Comics 40 41 42 Acid-mediated removal hydrogenation hydrogenation R H2, R H2, R O Pd/C H O Pd/C H O HBr Br R OH R OH R OH Br H mechanism not fully understood hydrogenation with (it is a surface reaction & R palladium on charcoal consequently hard to study) O H H H H (pd/c) allows selective & H H H (relatively) mild H H deprotection the first step is for acid permits Pd metal Pd metal but the acid must surface surface adsorption of the hydrogen removal by sn2 on the palladium (interaction of be very strong (which limits its use) the H2 with the surface 43 44 45
  6. 6. hydrogenation hydrogenation hydrogenation R H2, R H2, R H2, O Pd/C H O Pd/C H O Pd/C H R OH R OH R OH interaction of the aromatic group & the Pd/C facilitates substrate adsorption... H H H H H H O R H H H H H H H H ...this places the benzylic Pd metal once on the surface Pd metal the activated hydrogen Pd metal ether in close proximity to surface the hydrogen is surface is now ready to react surface the activated hydrogen activated... with the benzyl ether so... 46 47 48 hydrogenation hydrogenation R H2, R H2, O Pd/C H O Pd/C H R OH R OH an example of the use of H H protecting H H O O H H O O groups: R R R R H H H H H H H H H H H Pd metal hydrogen adds Pd metal surface across the reactive surface & somehow it all benzylic C-O bond comes to an end... 49 50 51 during the synthesis of milbemycin synthesis Text b3, the following conversion was required MeO2C O OH MeO2C H O H O O O Me Me MeO2C OH BnO LiAlH4 O O Me Me add THP protecting group Ph Br prior to reduction (reactivity & this is a Ph O O primarily differentiation of the two O HO O O natural product that is readily available alcohols NaH will be formed) that used to control pests starting material Me Me OH on pets mibemycin !3 (Roche ester) 52 53 54
  7. 7. synthesis synthesis synthesis protect second alcohol as robust MeO2C benzylOgroup so that original MeO2C O OH H3O Ph O OH OH alcohol can be MeO2C selectively reacted MeO2C H O O Ph O O O H O O Me Me Me Me Me Me LiAlH4 LiAlH4 PBr3 why not just use the initial alcohol? Li Ph Br BnO Ph O Br Ph Br Ph O O O NaH HO O O THpMe removed before simple Me Ph O O O NaH HO O O Me Me functional group interconversion Me Me ©mag3737@flickr 55 56 57 synthesis synthesis synthesis of this fragment is MeO2C O finished by the addition of the OH MeO2C H3O alkyne (C-C Ph formation) bond O OH H O O Ph O O O Me Me Me Me LiAlH4 PBr3 why couldn’t we use Ph Br Li this molecule? BnO Ph O Br Ph or this alcohol? O O O Why add so HO O O Me Me Me many steps? NaH Me HO OH ©sarawestermark@flickr ©ocreactive@flickr Me 58 59 60 FUNCTIONALGROUP it is a meso 123.312 compound INTERCONVERSIONS functional group CHAPTER5 interconversions HO OH CHAPTER five Me carboxylic acids & which means we their derivatives would have to resolve the E compound at some point achiral 61 62 63
  8. 8. Alcohols are very useful fully carboxylic acids & their derivatives starting materials... protected AcO OAc H OH O O intermediate during the synthesis of HO O OTBS O R O R O R R2 R vancomycin previously, we O Cl introduced the alcohol O O (hydroxy) group ... R O R2 R OH R TBSO H N O Cl H N N O H N OTBS O Cbz N R X X = OH, OR2, ...& looked at some of O H N H H their simple reactions O O NH R O O NH2 then we looked at NR2, Cl etc. R2 MeO2C protecting groups. now we turn R Cl R O OTBS O R2 OTBS our attention to carboxylic acids TBSO & their derivatives 64 65 66 O Text causes diarrhetic Text shellfish used in research; H poisoning... NZD$975 per 1 mg H O formic acid O OH O OH H H H H O O O O HO HO O O O O O O OH H OH H found in nature OH O O OH O O ©Richard Bartz ©Michelle Selvans okadaic acid OH ©adamjtaylor@flickr okadaic acid OH 67 68 69 esters proteins carboxylic acids are useful FG... amides are obviously O O O O found in proteins R S R1 R H R O R1 O O O O R Cl R OH R R1 esters are often responsible for sweet smells (like bananas) R1 O R3 O O O O H H N N R OH N N R O R1 R N R1 H H H ©Telrúnya@german wikipedia O R2 O R4 © Thomas Splettstoesser 70 71 72
  9. 9. carboxylic acids are useful FG... R carbonyl group is the foundation of O much organic Ssynthesis R1 R O H R O O R1 Text O infrared spectroscopy good at identifying different acid derivatives O O O properties R Cl R OH R R1 R O O O R1 R OH R O N H R1 R ©wonderferret@flickr X 73 74 75 Bond strength and IR stretch Bond strength and IR stretch Bond strength and IR stretch O O O O > R X R X R C=O X R C=O X C O frequency inductive effect frequency (electronegativity) shortens reduced & strengthens c=O bond increased stronger c=o results in a conjugation lengthens & higher wavenumber stretch weakens c=O bond in Ir spectra 76 77 78 Bond strength and IR stretch carboxylic acid derivatives Text !+ !– O > O O R O > OR R O NH2 R O O C O R O R R Cl inductive inductive inductive conjugation conjugation effect effect effect ~1650 cm–1 ~1630, 1815 cm–1 ~1810, (just) 1360 cm–1 stronger c=o often has 1790 cm–1 1745 cm –1 more positive carbon... ...more positive carbon most reactive least reactive reactivity is the more reactive ©stuck in customs@flickr 79 80 81
  10. 10. reactivity of carboxylic acid derivatives the mechanism of substitution is carboxylic acids acid (acyl) O addition / elimination... O chlorides R Cl H2O shows relationship R2CO2 between various acid O O H2 O derivatives addition anhydrides O O Nuc O R O R2 Nuc LG R2OH R LG R LG R Nuc esters R2OH R O OR2 H2O R2OH R O carboxylic OH acid elimination H R O NH3 one underlying mechanism for most of the chemistry ...specific reactions NH3 O H2O we will be talking about normally differ by how amides the leaving group (LG) R NH2 is formed ©pawpaw67@flickr 82 83 84 Reaction of carboxylic acids: mechanism mechanism acid chloride formation O O O SO2 S O O HCl SOCl2 Cl Cl S S O or PCl5 O O Cl O Cl S S O O Cl O Cl O Cl H Cl H H R O R O H Cl H R Cl R O R Cl R O R O O R many reagents can need to achieve this reaction dehydrate acid thus activate hydroxyl group 85 86 87 2nd mechanism Reaction of carboxylic acids: similar mechanism. This one Cl relies on strength of P=O bond O O Ester synthesis O O PCl4 H O PCl4 R O R O R O PCl4 Cl N O O H H Cl HO R1 H R1 O R OH R O O PCl3 O H Cl Cl H O O catalytic Cl this reaction can be Cl P PCl4 my favourite R Cl O Cl uses (COCl)2 & achieved directly as stated above, but R Cl R O catalytic DMF there are many better, milder conditions can you work out that can be employed the mechanism? 88 89 90
  11. 11. why can’t you use mechanism of acid catalysed mechanism of acid catalysed base catalysis? ester formation ester formation H H O H O HO OH H H O OH R1 R OH R O R1 R OH R O note: all steps are hopefully this is reversible. so how do we get just revision... R1 OH the product we want HO OH H HO OH O O R1 this is a first year R1 R O R1 question so you better R O R O R1 know the answer! H R O 91 92 93 Reaction of carboxylic acids: mechanism of ester formation Text Ester synthesis H2C N N O O O O H H3C N N H2C N2 R O R O CH3 R OH R O H2C N N N2 need to disrupt equilibrium; O remove water or at more alcohol diazomethane offers a mild, will force the reaction in the CH3 almost neutral route to R O direction we want methyl esters ©fortinbras@flickr 94 95 96 Reaction of carboxylic acids: diazomethane is explosive, sharp edges like scratches on glass or Amide synthesis ground-glass joints are enough to detonate it most safer routes to esters involve functional group O reagents O interconversion H2N R1 R1 first R OH R N H there are many ways to convert acids into amides (due to researchers wanting to make proteins etc) ©Roy lichtenstein 97 98 99

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