Modern Organic Synthesis an Introduction G. S. Zweifel M. H. Nantz W.H. Freeman and Company Chapter 1 Synthetic Design • What is an ideal or viable synthesis, and how does one approach a synthetic project? • The overriding concern in a synthesis is the yield, including the inherent concepts of simplicity (fewest steps) and selectivity (chemoselectivity, regioselectivity, diastereoselectivity, and enantioselectivity). • This chapter outlines strategies for the synthesis of target molecules based on retrosynthetic analysis. 1 1.1 Retrosynthetic Analysis Basic Concept The symbol signifies a reverse synthetic step and is called atransform. The main transforms are disconnections, or cleavage of C-C bonds, and functional group interconversions (FGI) Retrosynthetic analysis involves the disassembly of a TM into available starting materials by sequential disconnections and functional group interconversions(FGI). Synthons are fragments resulting from disconnection of carbon-carbon bonds of the TM. The actual substrates used for the forward synthesis are the synthetic equivalents (SE). Synthetic design involves two distinct steps (1) Retrosynthetic analysis (2) Subsequent translation of the analysis into a “forward direction” synthesis. Chemical bonds can be cleaved heterolytically, homolytically, or through concerted transform. 2 Donor and Acceptor Synthons Acceptor synthon Æ carbocation (electrophilic) Donor synthon Æ carbanion (nucleophilic) Table 1.1 Common Acceptor Synthon Synthetic equivalents Common Acceptor Synthon Synthetic equivalents 3 Table 1.2 Common Donor Synthons Common Donor Synthon Synthetic equivalents Retrosynthetic Analysis A Synthesis A 4 Retrosynthetic Analysis B Synthesis B Alternating Polarity Disconnections The presence of a heteroatom in a molecule imparts a pattern of electrophilicity and nucleophilicity to the atom of the molecule. The concept of alternating polarities or latent polarities (imaginary chargies) often enables one to identify the best positions to make a disconnection within a complex molecule. Functional groups may be classified as follows. E class: Groups conferring electrophilic character to the attached carbon (+): -NH2, -OH, -OR, =O, =NR, -X (halogens) G class: Groups conferring nucleophilic character to the attached carbon (-): -Li, -MgX, -AlR2, -SiR3 A class: Functional groups that exhibit ambivalent character (+ or -): -BR2, C=CR2, CCR3, -NO2, N, -SR, -S(O)R, -SO2R 5 Consonant Pattern: Positive charge are placed at carbon atom bonded to the E class groups. Dissonant Pattern: One E class is bonded to a carbon with a positive charge, whereas the other E class group resides on a carbon with a negative charge. Alternating Polarity Disconnections Consonant Simple synthesis Dissonant One Functional Group Analysis 6 Synthesis Two Functional Groups In a 1,3-Relationship Analysis 7 Synthesis (path a) Synthesis (path b) 8 Two Functional Groups in 1,4-Relationship The α-carbon in this synthon requires an inversion of polarity (umpolung in German) from the negative (-) polarity normally associated with a ketone α-carbon. Analysis α-bromoketone Enolate cannot be used because of the formation of an epoxy ketone (Darzens condensation). Instead, enamine is used. Synthesis 9 Analysis Umpolung Synthesis 10 Regioselective opening of epoxide by nucleophilic reagent provides For efficient two-carbon homologation reactions. 1.2 Reversal of the Carbonyl Group Polarity (Umpolung) The carbonyl group is electrophile at the carbon atom and hence is susceptible to attack by nucleophile. 11 Reversal of polarity of a carbonyl group has been explored and systemized by Seebach. Unnatural negatively negative charge charged c carboxylic synthon Since formyl and acyl anions are not accessible, one has to use synthetic equivalents of these anions. Umpolung in a synthesis usually requires extra steps. Formyl and Acyl anion derived from 1,3-dithianes 2-lithio-1,3dithian species; acyl anion equivalents EtSH: pKa 11 (more acidic) EtOH: pKa 16 12 13 With HMPA (hexamethylphosphoramide), [(Me2N)3P=O], dithiane-derived carbaions may serve as Michael donors. But without HMPA, 1,2-addition to the carbonyl group prevails. 14 Acylanions derived from Nitroalkanes CH3NO2, pKa 10.2; CH3CH2NO2, pKa 8.5 Nitronates of primary nitro compounds yield carboxylic acid. Nef Reaction under acidic condition R O + H O 1 H R1 OH H2O R1 OH R1 2 N N HO N H O + R O HNO 2 R2 OH R2 OH R2 hyponitrous acid work up R O-TiCl R Tautomerization R TiCl3 1 2 -O=TiCl2 1 1 N N N -Cl- R2 O R2 O R2 OH nitroso compound oxime 15 16 Acyl anions derived from cyanohydrins O-protected cyanohydrins contains a masked carbonyl group with inverted polarity. (Stetter reaction) 17 Acyl anion synthon derived from cyanohydrins may be generated catalytically by cyanide ion via the Stetter reaction. 18 Acycl anions derived from Enol ethers Acyl anions derived from lithium acetylide 19 1.3 steps in planning a synthesis • Construction of the carbon skeleton • Control of relative stereochemistry • Functional Group interconversion • Control of enantioselectivity Construction of the carbon skeleton Important C-C bond forming reactions encountered in organic synthesis • Reactions of organolithium and Grignard reagents, such as RLi, RC≡Cli, RMgX, and RC≡CMgX, with aldehyde, ketones, esters, epoxides, acid halides, and nitriles • Reactions of 1oalkyl halides with -C≡N to extend the carbon • Alkylations of enolate ions to introduce alkyl groups to carbons adjacent to a carbonyl group (e.g., acetoacetic ester synthesis, malonic ester synthesis) 20 • Condensations such as aldol (intermolecular, intramolecular), Claisen, and Dieckmann • Michael additions, organocuprate additions (1,4- additions) • Friedel-Crafts alkylation and acylation reactions of aromatic substrates • Wittig reactions, and Horner-Wadsworth-Emmons olefination • Diels-Alder reactions giving access to cyclohexenes and 1,4-cyclohexadienes • Ring-closing olefin metathesis Table 1.3 Summary of Important Disconnections 21 • Disconnections of bonds should be carried out only if the resultant fragments can be reconnected by known and reliable reactions. • fewest number of disconnections (see Section 1.4, convergent vs. linear synthesis) • It is often advantageous to disconnect at a branching point since fragments can be easily accessible, either by synthesis or from a commercial source. 22 • A preferred disconnection of cyclic esters (lactones) or amides (lactams) produces hydroxy-carboxylic acid or amino- carboxylic acids as targets. • Functional groups in the TM may be obtained by functional group interconversion. 23 • Symmetry in the TM simplifies the overall synthesis by decreasing the number of steps required for obtaining the TM. • Introduction of an activating functional group may facilitate carbon-carbon bond formation. After accomplishing its role, the activating group is removed. 24 •The presence of a 1,6-dioxygenated compound suggests opening of a six-membered ring. A variety of cyclohexene precursors are readily available via condensation and Diels-Alder reaction or via Birch reductions of aromatic compounds. • Disconnection of an internal (E)- or (Z)-double bond or a side chain of an alkene suggests a Wittig-type reaction or an alkylation of a vinylcuprate, respectively. 25 • The presence of a six-membered ring, especially a cyclohexene derivative, suggests a Diels-Alder reaction. • The structural feature of an α,β-unsaturated ketone or a β-hydroxy ketone in a six-membered ring suggests double disconnection coupled with functional group interconversions. (Robinson annulation) Functional Group Interconversion a. Alkyl Chlorides b. Alkyl Bromides 26 c. Allylic and Propargylic Bromides d. Alkyl Iodies e. Nitriles 27 f. 1o and 2o Alcohols g. 1o, 2o and 3o Amines 28 h. Aldehydes and Ketones 29 i. Carboxylic Acids 30 j. Alkenes k. Alkynes 31 Control of Relative Stereochemistry (stereoselctive and stereospecific) • SN2 displacement reaction; E2 elimination reactions • Catalytic hydrogenation of alkyne (cis product) • Metal ammonia reduction of alkyne (trans product) • Oxidation of alkenes with osmium tetroxide • Addition of halogens, interhalogens (e.g., BrI) or halogen-like species (e.g., PhSCl, BrOH) to double bond • Hydroboration reactions • Epoxidation of alkenes; ring-opening of epoxide • Cyclopropanation Control of enantioselectivity 32 1.4 Choice of Synthetic Methods The choice of a method for synthesizing a compound derived from a retrosynthetic analysis should be based on the following criteria • Regiochemistry, the preferential addition of the reagent in only one of two possible regions or directions. • Chemoselectivity, selective reaction of one functional group in the presence of other functional groups • Stereoselectivity, the exclusive or predominant formation of one of several possible stereoisomeric products. • Efficiency, fewest number of steps • High yields in each step • Availability and costs of starting material • Most environmentally friendly route. Ideally the atoms of substrate and any additional reagents used for the reaction should appear in the final product, called “atom economy” 33 • Simplicity of selected procedure. • Isolation and purification of reaction products. Ability and utility to separate and recover the reaction product from other materials • Possibility of a convergent synthesis or a “one-pot process. Linear and Convergent Syntheses • In a linear synthetic scheme, the hypothetical TM is assembled in a stepwise manner. If 80% yield is obtained in each step, 21% (0.87 x 100) overall