Products from reactions of carbon nucleophiles and carbon electrophiles used in the 14 C Game and our course:

Transcription

1 synthesis strategies, hem / / Beauchamp roducts from reactions of carbon nucleophiles and carbon electrophiles used in the Game and our course: arbon electrophiles methyl primary organolithium reagents (Mg) organolithium reagents u cuprates coupling reaction coupling reaction arbon and hydrogen nucleophiles a cyanide nitriles nitriles a acetylides alkynes alkynes ylid Wittig reagents Al (LA) a B alkyls alkyls alkyls alkyls Al diisobutylaluminium hydride (DIBA) lithium diisopropyamide (LDA), -8 o S S dithiane anion S, hydrolysis makes = S, hydrolysis makes = secondary coupling reaction nitriles E alkyls alkyls S, hydrolysis makes = (aldehydes & ) ethylene oxide propylene oxide o o o o o o nitriles alkynes o o o o nitriles alkynes o o o o E, make allylic alcohols epoxide addition epoxide addition isobutylene oxide o o o o o nitriles alkynes o o E, make allylic alcohols epoxide addition methanal o o not used cyanohydrin o in our course alkynes specific alkenes methanol methanol = addition simple aldehydes o o cyanohydrin o alkynes specific alkenes o o enolate chemistry = addition simple cyanohydrin o o unless sterically o hindered alkynes specific alkenes o o enolate chemistry = addition simple esters o o (u: twice) (u: twice) not used in our course o aldehydes enolate chemistry not used in our course simple carboxylic acids use equivalents (B: once u: once) acid/base no net rxn acid/base no net rxn acid/base no net rxn = danger acid/base no net rxn acid/base no net rxn acid/base no net rxn acid/base no net rxn enolate chemistry not used in our course l simple acid chlorides simple nitriles ' o amides carbon dioxide α,β-unsaturated o (u: twice) use equivalents (B: once u: once) o o (u: twice) carboxylic acids o conjugate addition conjugate addition carboxylic acids o o o amines (also amines from amides) alcohols alcohols WK = normal workup to neutralize the reaction conditions. For the basic reactions (like above) above this would require mild acid neutralization ( + ). = no reaction or no productive result or not emphasized aldehydes aldehydes (also aldehydes from o amides) E, make ketenes enolate chemistry not used in our course = substitution not used in our course not used in our course not used in our course Z:\classes\\special handouts\ Syn & strategies.doc

2 synthesis strategies, hem / / Beauchamp nucleophile (u) =? In our course every carbon-carbon bond made with asterisked carbon must be made with a electrophile (E) =? nucleophile/electrophile reaction. E E u E E u clue: group could have been an electrophilic = group (aldehyde or ketone) + nucleophilic Grignard or lithium reagent. u clue: group could have been an electrophilic = group (ester) + nucleophilic Grignard or lithium reagent (x). u E E E E u clue: group could have been an electrophilic = group (carbon dioxide) + nucleophilic Grignard or lithium reagent. u E clue: group could have been an electrophilic epoxide group + nucleophilic Grignard or lithium reagent. u electrophiles = nucleophiles = u clue: (aldehyde) group can be made from nucleophilic Grignard or lithium reagents + electrophilic dimethylformamide (DMF). Mg or u (Mg) or u clue: = group could have been a (nitrile + Grignard or lithium reagent), a ( o amide + Grignard or lithium reagent), an (acid chloride + cuprate) or a (carboxylic acid + eqs. of -). E electrophiles = nucleophiles = nitriles ' o amides l acid chlorides carboxylic acids equivalents u (Mg) or Mg and organometallics cuprates organolithium reagents β α electrophiles = α α α β β β u clue: = group could have been an electrophilic α,β-unsaturated = (+ nucleophilic cuprate = conjugate addition). cuprate nucleophiles = α,β-unsaturated = u Z:\classes\\special handouts\ Syn & strategies.doc

3 synthesis strategies, hem / / Beauchamp arbon skeletons from a b a b c skeleton skeleton skeleton skeletons skeletons a b c d e skeletons a b c d e skeletons f g h i Seven carbon skeleton isomer c with variable labels -star -star -star -star -star -star -star Seven carbon skeleton - isomer c with variable, no labels no label Seven carbon skeleton isomer c with label on first carbon (-star) and variable -star, - -star, - -star, - -star, - -star, - -star, - -star, - Z:\classes\\special handouts\ Syn & strategies.doc

4 synthesis strategies, hem / / Beauchamp Z:\classes\\special handouts\ Syn & strategies.doc The following carbon skeletons represent parts of structures that can be made with or without labeled positions. carbon skeletons are all shown, with to indicate the location of any label. In structures with carbon atoms, or more, the first structure drawn represents the parent skeleton and the second structure shows all of the different positions that a single label could be inserted (a number indicates each different possibility). "" represents a simple functional group or a point of attachment in a functional group pattern that could have more than one carbon portion. (See example page with several examples of functional group patterns that could have or more branches.) Synthetic targets can be randomly generated by drawing out a number for the carbons in the skeleton (-), then picking a random pattern, then picking a random isomer with or without a label. This can be done once, twice or times for each branch in the selected functional group pattern (which can also be picked at random). The possibilities are effectively endless for organic synthesis problems (there are about 0 skeletal patterns, including labels). These problems are relatively straight forward because there is only functional group. More than one functional group may require protection/deprotection steps and the difficulty of such synthetic problems can rapidly go up. Some patterns may have limitations due to steric crowding. ( =,,,,,, and many other possibilities) carbon carbons carbons carbons pattern pattern pattern pattern pattern pattern pattern pattern pattern carbons: = parent skeleton without any label, numbers = skeleton location with a label at that position (for reference in synthesis problems) = parent skeleton pattern pattern pattern pattern pattern 8 carbons: = parent skeleton without any label, numbers = skeleton location with a label at that position (for reference in synthesis problems) pattern = parent skeleton pattern pattern pattern pattern pattern pattern 8 pattern 9 pattern 0 pattern pattern pattern pattern pattern pattern

5 synthesis strategies, hem / / Beauchamp Z:\classes\\special handouts\ Syn & strategies.doc carbons: = parent skeleton without any label, numbers = skeleton location with a label at that position (for reference in synthesis problems) pattern = parent skeleton pattern 8 pattern pattern 8 8 pattern 8 pattern pattern pattern 8 pattern 9 pattern 0 pattern 8 pattern 8 pattern pattern pattern pattern pattern pattern 8 pattern 9 pattern 0 pattern pattern pattern pattern 8 pattern pattern pattern pattern 8 pattern 9 pattern 0 pattern pattern pattern pattern pattern pattern pattern pattern 8 pattern 9

6 synthesis strategies, hem / / Beauchamp either side problems in one structure (ester) joined (acid + ) by S chemistry, (acid-l + alcohol),(acid + alcohol) by acyl substitution problems in one structure (alkyne) by terminal acetylide + Me or o, S chemistry both sides either side problems in one structure (ketone) (acid chloride + cuprate),(aldehyde + ) (cyanide to nitrile to ketone) problems in one structure (amide) (joined acid-l + amine) by acyl substitution, amine =,, Wittig Some of the Synthetic Strategies in Game problems in one structure (alkene) from reduction of alkyne or Wittig reaction all sides Up to problems in one structure, can have,, or branches, by Gabriel amine syn and imine reduction chemistry either side problems in one structure (ether) (alcohol/alkoxide + ), (alcohol + alcohol) by S chemistry Up to problems in one structure, can have,, or branches Multiple problems in one. all sides ow can one cut up these molecules into simpler parts?. Every - (carbon-carbon) bond to a must be made. If atoms have been joined together, is there an obvious nucleophile (alkyne, cyanide, Mg or reagent) and/or electrophile (an that was a = or an epoxide)? You need one of each. If one part is obvious, can you think of how the other part might be made? ould you join the atoms in the opposite fashion (umpolung)? Think in both directions.. Functional Group Interconversions (FGI) are often used (i.e. ketone to alcohol, or alcohol to ketone, or alcohol to bromoalkane, which can be a leaving group for an S reaction or made into Grignard or thium reagents). Which carbon could have been a carbonyl (=) functional group and altered by the reactions shown? (such as methanal, general aldehyde, ketone, ester, carbon dioxide)? r, could have been some other functional group (alkene, compound, epoxide)?. Alcohols are often oxidized to carbonyls (alcohols aldehydes,, carboxylic acids) (carboxylic acids esters, acid chlorides) (acid chlorides esters, o, o, o amides,, aldehydes, thiolesters), which can be used as electrophiles (etc.).. Many organic groups can be reduced (alkene alkane, alkyne Z-alkene, E-alkene, alkane, carbonyl alcohol, alkane, etc.). Additional special reactions of course (Wittig, Wolff-Kishner, lemmenson, enamine, imines, cuprates, etc.).. rotections are sometimes necessary (acetals, ketals = protected with ethylene glycol or protected as T ether). There are many other kinds of protections besides those discussed in our course.. If starting from some functional group, what features are retained in the target structure? 8. If thinking back from the product, what features need to be generated in the product? 9. Draw a possible starting structure and consider what reactions possible reactions that we have studied could make the target functional group? Does one seem better suited than another? Z:\classes\\special handouts\ Syn & strategies.doc

7 synthesis strategies, hem / / Beauchamp onnecting or patterns from above in the functional groups below. Several of the patterns below may require an additional or carbon atoms at the connecting point, in addition to the and patterns. esters carboxylate + acid chloride + Fischer ester synthesis o amides acid chlorides + o amines ethers + (S ) + (S ) alkene + o amides acid l + o amines, o amines use ald / ket + o amine, then imine reduction with a B, LA reduction of o amide oxidation of o nitrile + -/-Mg acid chloride + cuprate o amide + -/-Mg carboxylic acid + eqs. - alkyne hydrolysis dithiane (react twice), Friedel rafts acylation o alcohols ketone + LA aldehyde + -/-Mg epoxide + LA epoxide + -/-Mg alkene hydrolysis, S, S and more o alcohols ketone + -/-Mg epoxide + LA epoxide + -/-Mg ester + -/-Mg ( eqs.) alkene hydrolysis S, S and more o amines use ald / ket + o amine, then two couplings using imine reduction with a B, enolate chemistry of LA reduction of o amide various carbonyl patterns, enamines or enol ethers too cis disubstituted alkenes using Wittig reaction or reduction of alkyne (ndlar's) (alkynes have some limitations), some E or E reactions trans disubstituted alkenes using reduction of alkyne (a/ ) (alkynes have some limitations), some E or E reactions trisubstituted alkene using Wittig reaction, some E or E reactions cuprate coupled sp /sp all carbon linkagess, reduction or other functional groups (aldehyde, ketone, alkene, alkyne, etc.) (hard to see) disubstituted alkynes ( and must be primary or methyl when = S ), open epoxides, or attack carbonyls cuprate conjugate addition followed by reaction with enolate intermediate (tandom reaction) aldehydes oxidation of o DIBA reduction of ester, nitrile, acid l, anti-markovnikov addition to alkyne; dithianes (x); oxonolysis of alkenes (WK = S ); etc. single coupling using enolate chemistry of various carbonyl patterns, enamines or enol ethers too anhydrides from acid chlorides + carboxylates nitriles + a S at Me, o, o o amide + Sl Sandmeyer rxn makes aromatic nitriles alkynes + a (make) (S at Me, o ) zipper reaction double elimination (E) S thiols + S l = single groups (a few examples) many possibilities - + /hν; S, S at + / /S a. Tsl/py, b. a (avoids rearrangement) addition to alkenes (Markovnikov, anti-markovnikov) o amides acid (l/ ) or base hydrolysis of nitriles; acid l + carboxylic acid + Sl or l or oxalyl chloride o amines Gabriel amine syn ( o ) use ald / ket +, then imine reduction with a B, LA reduction of o amide carboxylic acids Mg or + Jones oxidation of o acid or base hydrolysis of esters, acid or base hydrolysis of nitriles ozonolysis of alkenes (WK = ); etc. alcohols = many possibilities S, S at addition to alkenes (Markovnikov, anti-markovnikov) LAl or ab reduction of carbonyls and epoxides, ozonolysis of alkenes (WK = ab ); etc. E, E with / S / reduction of alkynes Wittig reactions aromatic derivatives Friedel rafts alkylation or acylation; cuprate coupling; Ar-Mg or Ar- reactions, and more etc. (ethers, sulfides,...) Z:\classes\\special handouts\ Syn & strategies.doc

8 synthesis strategies, hem / / Beauchamp 8 Use clues in the target molecule (TM) to determine what the last step could have been. nce you work back one step, use clues in that molecule (TM-) to determine how you could work back one additional step (TM-). epeat this process until you get to the necessary starting conditions (TM-n), i.e. allowable starting units (,, a where indicates a radioactive isotope) and other allowed starting materials. Until aromatic chemistry is covered bromobenzene is also available. You may use any reagents learned in our course. Many of the simpler starting structures below were prepared in the above reactions (, and examples). Starting Structures: Examples Target Molecules (TM - #) Straight chain alcohols a. TM -. a / d.. = - bond formed with nucleophile/electrophile strategy or or.. TM -. or. or / d. a. Z:\classes\\special handouts\ Syn & strategies.doc

9 synthesis strategies, hem / / Beauchamp 9 TM -. or or / d.. a. TM -. or. or. TM -. or. / d. a.. a. TM -. / d. a. TM -. Mg + -. aldehyde r (). r () / d. a. (see above). B. /. a. Z:\classes\\special handouts\ Syn & strategies.doc

10 synthesis strategies, hem / / Beauchamp 0 TM - 8. Mg +. aldehyde r ().. a. / d. Mg + -. aldehyde r (). r () / d. a.. Mg +. epoxide mba S / (- ). equivalents Mg + -. aldehyde. a. - TM - 9. or.. B. / / d quinoline (ndlar's). a. TM - 0. or. TM -. or. Z:\classes\\special handouts\ Syn & strategies.doc

11 synthesis strategies, hem / / Beauchamp TM -. / d. a. TM -. Mg + -. epoxide mba / d quinoline (ndlar's). a. (above, TM-). Mg +. aldehyde r (). B. /. B. / TM -. (above, TM-) or (above, TM-0) TM -. Mg +. ester eqs.. a. - TM -. Mg +. ester eqs.. a. - eqs.. Mg +. aldehyde. B. / Z:\classes\\special handouts\ Syn & strategies.doc

12 synthesis strategies, hem / / Beauchamp Examples Target Molecules (TM - #) chain with methyl branch alcohols TM-. or. or. or. TM-.. Ts-l. a (S ) (avoids rearrangement). Mg +. aldehyde r (). TM-.. Ts-l. a (S ) (avoids rearrangement). Z:\classes\\special handouts\ Syn & strategies.doc

13 synthesis strategies, hem / / Beauchamp TM-.. Ts-l. a (S ) (avoids rearrangement). Mg +. aldehyde r (). TM-.. Ts-l. a. (S ) (avoids rearrangement) TM-. or. (without label rearrangement is not a concern) same. / d. a. TM- (above, TM-). Mg + -. ketone r + / (Jones) S / (g + cat.). a.. Mg +. ketone r ().. a. / d Z:\classes\\special handouts\ Syn & strategies.doc

14 synthesis strategies, hem / / Beauchamp TM-8. Mg +. aldehyde r (). equivalents Mg + -. ester. a. - TM-0. Mg + -. aldehyde mba S / (- ). TM- (above, TM-). Mg + -. ketone r + / (Jones) S / (g + cat.). a. r. Mg +. ketone ().. a. / d TM-. Mg + -. epoxide. Mg + -. epoxide mba mba Z alkenes / d quinoline (ndlar's) a /. a. E alkenes.. or TM-. or. TM-8 eqs. Z:\classes\\special handouts\ Syn & strategies.doc

15 synthesis strategies, hem / / Beauchamp TM-. Mg +. aldehyde r (). TM-. Mg + -. aldehyde r (). TM-. TM-. or. TM-8. or. equivalents Mg + -. ester. a. - TM-9. or. TM-0. or. TM-. Z:\classes\\special handouts\ Syn & strategies.doc

16 synthesis strategies, hem / / Beauchamp Some important, and building blocks that are used in the - syntheses that follow. arbon some examples of reagents that allow synthetic transformations among these structures. S hν (u: ) (Mg) (from + Mg) or (from + ) cuprate reactions ( reaction types for us) u (from + ui) Wittig reactions E. workup S S ( ) ( ) (S ) available make available ( ) available (Wittig salt). make. a Mg/ organometallic reactions. coupling with other compounds cuprate makes alkane-like structure ( ) ( ) ( ) available make make. coupling with l = acid chloride. n-butyl lithium (very strong base) cuprate l makes ylid nucleophile l (from + Sl ) oxidation r r + / Jones anhydride ( ) ester () o amide ( ) o amide ( ) o amide ( ) aldehyde ( Al = DIBA) ketone ( u + = cuprate). coupling with α,β-unsaturated carbonyl. carbonyl compound cuprate β addition to conjugated carbonyl compound makes very specific alkenes arbons some examples of reagents that allow synthetic transformations among these structures. hν S (u: ) S ( ) ( ). (S ) ( ) ( ) available make available ( ) available make make make. a oxidation r r + / Jones a available K + t-butoxide S / mba. a. next equivalents a. react with various electrophiles (or WK) Mg/ organometallic reactions (Mg) (or + ) Mg (or ) E. workup ( ) from Z:\classes\\special handouts\ Syn & strategies.doc

17 synthesis strategies, hem / / Beauchamp organocuprate reactions 0. u u cuprate nucleophiles ( reaction types for us) electrophile E + coupling with other compounds coupling with l (acid chloride) E + - = l makes alkane-like structure makes coupling with α,β-unsaturated carbonyl cuprate conjugate addition r / () ( eq.). E. WK electrophile E + α α β β. a. - β ( ) DMF α,β-unsaturated carbonyl compounds α acid chloride reactions (Sl ) l make (with) anhydride ( ) ester () o amide ( ) o amide ( ) o amide ( ) aldehyde ( Al = DIBA) ketone ( u + = cuprate). E a. workup electrophile Wittig reactions S (Wittig salt) nbu. n-butyl lithium (very strong base) acid/base reaction ylid nuclephile. carbonyl compound makes very specific alkenes (usually Z) imines and amines ( o, o and o ) o amine (from Gabriel o amine synthesis or LA reduction of nitrile) p (- ) imine. B a. workup reduced. p (- ). B o amine. workup a o amine makes iminium ion, then reduced enamines o amine p (- ) enamine alkylation. workup (regenerates = group) S / (g + ). B. / Markovnikov anit-markovnikov Z:\classes\\special handouts\ Syn & strategies.doc

18 synthesis strategies, hem / / Beauchamp 8 protection of aldehyde as acetal and ketone as ketal ketone Ts- (- ) ketal eaction occurs at, not ketone. a ketal ould also make Grignard here. ould attack with Grignard here in another reaction. dilute S Ketone is regenerated (deprotected). ketone protection of alcohol as T acetal alcohol D Ts- addition reaction T = (Mg) T =. workup acetal acetal dilute S Alcohol is regenerated (deprotected). arbons Just a few selective examples. There are too many possibilities to be comprehensive. hν S (u: ) ( ) make esters a make o alcohols. make. a Doesn't work because is secondary (E instead). ( ) ( ) oxidation K + t-butoxide equivalents. a. next a. react with various electrophiles (or WK) r r water Jones S / mba LDA r () α β Mg/ organometallic reactions Mg (Mg) or E. workup (from -) ( ) equivalents organometallic from organocuprate reactions ( ) 0. u u cuprate reactions ( reaction types for us) E + coupling with other compounds makes alkane-like structure coupling with l (acid chloride) coupling with α,β-unsaturated carbonyl cuprate l makes conjugate addition Z:\classes\\special handouts\ Syn & strategies.doc

19 synthesis strategies, hem / / Beauchamp 9. B.,. B., or a, DMS. electrophile organometallic reactions S (u: ) r r + / Jones S ( ) (S ). ( ) ( ) ( ). a acid chloride reactions (Sl ) l make (with) anhydride ( ) ester () o amide ( ) o amide ( ) o amide ( ) aldehyde ( Al = DIBA) ketone ( u + = cuprate) a E. workup Wittig reactions S (Wittig salt) Bu. n-butyl lithium (very strong base) acid/base reaction ylid nucleophile. carbonyl compound makes very specific alkenes (usually Z) imines and amines ( o, o and o ) o amine from Gabriel amine synthesis p (- ) imine. B a. workup (reduced). make iminium salt p (- ). o amine B. workup a o amine enamines o amine p (- ) enamine alkylation. workup regenerates = compound S / (g + ) Markovnikov. B. / anti-markovnikov Z:\classes\\special handouts\ Syn & strategies.doc

20 synthesis strategies, hem / / Beauchamp 0 Key strategies in a synthesis problem?. ow do you prepare compounds? (Use bromides as a consistent, reliable target.) a. from alkenes (Markovnikov reaction) b. from alkenes (anti-markovnikov reaction). B.,. B., c. from alcohols ( or ), S at o and S at o, o, use. make tosylate,. a to avoid rearrangement possible rearrangement at o possible rearrangement at o. Ts-l /. a (S ) avoids rearrangements. Generation of an organometallic carbanion nucleophile from an compound a. organomagnesium reagents (Grignard reactions) and organolithium reagents (mostly interchangeable in our course). Mg (Mg). rganometallic nucleophiles + organic electrophiles (e- pair acceptors), WK = work up = acidic neutralization a. formaldehyde (methanal) = extension of : -- with o alcohol functionality at the end (Mg). WK o alcohol b. ethylene oxide (epoxides) = extension of : -- with alcohol functionality. WK o alcohol. WK o alcohol. WK o alcohol c. general aldehydes = extension of : -- with o alcohol functionality (Mg) '. WK ' o alcohol Z:\classes\\special handouts\ Syn & strategies.doc

21 synthesis strategies, hem / / Beauchamp d. general ketone = extension of : -- with tertiary alcohol functionality (Mg) ' ". WK " ' o alcohol e. general ester = extension of : -- with tertiary alcohol functionality (at least two identical ' groups) equivalents (Mg) ' ". WK ' o alcohol with two identical groups, " is lost during the reaction. f. carbon dioxide = extension of : -- with carboxylic acid functionality (can be converted into ester with ) (Mg). WK carboxylic acids arbon dioxide is like having two carbonyl groups on one carbon, where only one actually reacts. rganolithium reagents can react twice and form.. emember additional reactions of alcohols, compounds, alkenes, alkynes, carbonyls (aldehydes,, esters, acids and others will accumulate). a. alcohols can be made into compounds (above, chlorides, bromides, iodides, tosylates). eactions occur by S at methyl and primary and S at secondary and tertiary (with possibility of rearrangement) in our course. l or l or Sl l or or Sl I I. Ts-l /. a (S ) (avoids rearrangement) b. compounds can react with nucleophiles in S (methyl, o and o ) and S ( o and o ) reactions i. cyanide (nitriles at methyl, o and o ) S / l a nitriles (S ). Al. WK. DIBA ( Al-). WK. '. WK ' Z:\classes\\special handouts\ Syn & strategies.doc

22 synthesis strategies, hem / / Beauchamp ii. terminal acetylides (react at methyl and o, epoxides, and aldehydes), and can be converted into aldehydes,, alkanes, and E/Z-alkenes. ' (S ).. WK ' / d quinoline (ndlar's cat.) ' Z alkenes terminal alkynes. a acid/base a.. WK a / E alkenes ' S / (g + ) Markovnikov methyl aldehydes. B. / anti-markovnikov.. WK.. WK iii. triphenylphosphine (makes phosphonium salts, used in Wittig reactions with aldehydes/ to make alkenes) Wittig reaction S Wittig salt. nbu (acid/base) ylid nucleophile ' aldehydes and iv. phthalimide anion (make o amines after hydrolysis with aqueous hydroxide, or hydrazine, ). a (acid/base) S. a o amine ' Z alkenes throw away v. esters (acetates), then hydrolyze to form alcohols (most useful at o ), additional chemistry is possible. '. a (acid/base) S carboxylic acids carboxylates compounds esters ' a ' alcohols c. primary alcohols can be oxidized to aldehydes or carboxylic acids ( which can be made into esters, see above) o alcohols r / l () aldehydes r + / o alcohols (Jones) carboxylic acids. a (acid/base). ' S esters ' Z:\classes\\special handouts\ Syn & strategies.doc

23 synthesis strategies, hem / / Beauchamp d. secondary alcohols can be oxidized to with either of our r + oxidizing reagents r / l o alcohols () o alcohols r + / (Jones) e. aldehydes/ reduced to alcohols ( o and o ) by Al and ab after acid workup aldehydes. a B. WK o alcohols '. Al. WK ' o alcohols f. esters and acids are only reduced by Al (not ab ), to primary alcohols after acid workup esters '. Al. WK o alcohols ' maybe keep or maybe throw away esters. a B '. WK o reaction (slow reaction) bviously not ever reaction cannot be covered in this short handout, but this hopefully gives you a sample of reactions for approaching these kinds of problems. oints to ponder when considering a retrosynthetic step.. Which carbon could have been a carbonyl (=) functional group? (methanal, general aldehyde, ketone, ester, carbon dioxide)? r, some other functional group (alkene, compound, epoxide)?. To start from some functional group, what features (and skeletal parts) have to be retained from the target structure, or regenerated in the starting structure?. What features can be taken away from the target structure (that were originally in the starting structure, but are now lost)?. Draw a possible starting structure (or structures).. What portion has to be added and how can we do that (usually nucleophile/electrophile or functional group interconversion). Is protection required to keep some part of the starting structure from reacting (often more advanced than we consider)? Starting possibilities to produce alcohol or carboxylic acid (only ). methanal (formaldehyde) aldehydes ' esters ' carbon dioxide alkenes epoxides " ' compounds Z:\classes\\special handouts\ Syn & strategies.doc

24 synthesis strategies, hem / / Beauchamp ombination roblems Two (or more) structures in one target molecule. Esters Make and skeletons. acyl substitution l S (a) Fischer ester synthesis (Ts / - ) Alcohols o, o or o Ketones Alkynes Make and skeletons. nitrile approach cuuprate approach l l Wittig eactions traditional o alcohol approach (oxidize with r ) alkynes + /. eqs.. workup Make - and -skeletons. (must be primary) S Terminal Alkynes Ethers Amines Amides uprate ouplings Join in S, S and addition reactions to alkenes. Use amine/carbonyl synthesis of imine and reduce with sodium cyanoborohydride. Use acid chlorides and amines. Both and come from - compounds. ne is made into lithium reagent to react with other as. ard to see, because there are no clues. Generic examples of patterns with one - label and specific patterns using above functional groups Example patterns with - labels Esters - S, Fischer syn, acid chlorides + alcohol Alcohols - = + organometallic Ketones - from cuprates, nitriles, alcohols, carboxylic acids Amines - Gabriel, reductive amination Alkynes - Me, o Amides - acid chloride + amine Alkenes (Wittig) Ethers - S, S, alkene addition uprates - coupling ( x ) uprates - conjugate addition Anhydrides - use acid chloride onstruct two (or more) carbon patterns, then join them together using one of the above functional groups. Z:\classes\\special handouts\ Syn & strategies.doc