http://www.courses.fas.harvard.edu/~chem206/ Ph H N NHBz Ar1 H O SiCl3 Me Ph H N NHBz SiCl3Me SiCl3 Me Ar2 NH SO2Tol OCMe3 O C N SiCl3 Me H Ph RH N S CH2CH2OHMe Ph XN NHBz Me Ph XN NHBz Me NH Ar2 OCMe3 O Ar1 O Ph XN NHBz Me Chem 206D. A. Evans Matthew D. Shair Monday, December 2, 2002 Chemistry 206 Advanced Organic Chemistry Lecture Number 29 Ambiphilic Functional Groups–4 a73 Construction of Consonant & Dissonant FG Relationships a73 Charge Affinity Inversion Operators A recent relevant paper: Kobayashi, JACS 2001, 123, 9493-9499 The Imine Aldol Reaction: New Information X = SiCl3X = H anti diastereoselection 99:1 0 °C 79% X = SiCl3X = H anti diastereoselection 78:22 0 °C 79% Cume Question, Fall 2001. The reaction illustrated below was recently reported by Murry and co-workers from the Merck Process Group (JACS 2001, 123, 9696-9697). Provide a mechanism for this transformation. 1 (used as catalyst) 10 mol% 1 Et3N, CH2Cl235 °C + Pairwise Functional Group Relationships ? Pummerer Reviews "Application of the Pummerer reaction toward the synthesis of complex carbocycles and heterocycles.", Padwa, A.; Gunn, D. E.; Osterhout, M. H. Synthesis 1997, 1353-1377. "Asymmetric pummerer-type reactions induced by O-silylated ketene acetals.", Kita, Y.; Shibata, N. Synlett 1996, 289-296. Grierson, D. S.; Husson, H.-P. Polonovski- and Pummerer-type Reactions and the Nef Reaction.; Trost, B. M. and Fleming, I., Ed.; Pergamon Press: Oxford, 1991; Vol. 6, pp 909. "The Pummerer reaction of sulfinyl compounds.", De Lucchi, O.; Miotti, U.; Modena, G. Org. React. (N.Y.) 1991, 40, 157. "Applications of sulfoxides to asymmetric synthesis of biologically active compounds.", Carreno, M. C. Chem. Rev. 1995, 95, 1717-1760. F1 C F2 C F3 C F4 C (+) (+) (–) (+) (–) (+) (–) (–) CH CH2 BrCH2 CH3 CH2 OR C CCE E C C C CH2 BrCH3 CH OCH3 E C C CA A C C CH3 CH2 NR2 A C C CH3 C O OR A C C CCG G C ECC CC E2 E1 C OR OCH3 C CA C C CA C C CA C A C C CH3 CH2 Br E C C CA CH3 CH2 Li C CG C A C C C CE C CH2 MgBrCH3 G C G C C C CHCH2 CH2 MgBr Chem 206Summary of Functional Group Classification SchemeD. A. Evans (+)(+)(–)(–) (± ) (±) (–) (–)(+)(–) (+)(+) Charge Affinity Patterns Symbol (+) (–)(±) Classification of Functional Groups Each substituent attached to carbon activates that carbon toward a polar reaction by either resonance or induction or both. Induction Resonance (+) (+)(–)E-Functions (–) (–)(+) (–) (–)(+) (+) (–) (+) (–) Real functional groups are assigned to a class designation by inspection of the chemistry of that FG, along with that of its conjugate acid and conjugate base Charge affinities of real functional groups form a subset of the ideal FG classes. a73 Note that the issue of oxidation state in not explicitly incorporated. This issue is subordinate to that of defining site reactivity. (–)(+)(–) (–) (+) For example, is represented as: and not: (+)(–) (–)(+)(+) (–)(+) +2 e – (–)(+) (+) (–) a73 Note that a 2-electron reduction (or oxidation) will transform an E-Class FG to a G-Class FG. (–)(–)(–) These are your metallic FGs such as Li, Mg, etc. a73 Those ideal FGs which create nucleophilic carbon at point of attachment.a73 Exhibit strictly alternate charge affinity patterns. (–) (–)(+)G-Functions One might visualize a process wherein A-functions are gradually polarized towards either E– or G– behavior in response to changes in inductive and resonance effects. a73 All sites activated equally for electrophilic & nucleophilic reactivity.a73 Those ideal FGs which exhibit nonalternate polar site reactivity are included. A-Functions (+)(+)(–)(–) (± ) (±) A-functions are some of the most useful FGs in organic synthesis because of the unique reactivity provided. (+-)(+-)(+-) (–)(+)(–) (–) (+)(+)(± ) (±)(±) (± ) (±) (± ) S RR P RR PR R R E# C C C C + + (–)(–) (+)(+) A C C A C C C CA C CCC E# NO2 NOH NNR2 N NR2 N(O)R N N S R N S R O S O R O P O R R E C C C C E C C CC G E' C C C CC E C CCC E E C C E C C C C C G Me OH O O O NR2Me O HO NH2 OH Cl Li Cl E G C E CCC E# E# C C C C E E# C C C C E E E' E E' Chem 206Pairwise Functional Group RelationshipsD. A. Evans a73 Functional groups derived from many of the transition elements a73 A-functions are composed of second-row elements such S and P. A-Functions: Real Examples (±)(± ) (–) (–)(+) (+)A-Functions a73 A-functions are composed of polyatomic arrangements of N & O. Given the resident E-function, the charge affinity pattern dictates the nature of the polar coupling process and thus functional groups to be employed in synthesis. (–)(+) (+)(–)(–)(–) (+)(+) (–)(–)(+)(+) (+)(–) (–) G–FG lostin construction (+)(–) (–)(+) Transforms utilizing target E-function in synthesis plan given highest priority. (–)(–) (+)(+) Synthesis of Targets containing E-Functions G–FG lostin construction E'–FG lostin construction Pairwise relationship is "dissonant". Pairwise relationship is "consonant". Charge affinity patterns are "unmatched." (–)(–) (+)(+) add E (+) (+)(–) (–) Charge affinity patterns are "matched." (–)(–) (+)(+) add E (+) (+)(–) (–) Consider the paired relationships of E-functions. There are two relationships. Consonant & dissonant relationships may be established with E-E, E-G, or G-G pairings. Most target structures are composed of E-functions. Classification: 1,1-Dsymbolic representation Classification: 1,2-Dsymbolic representation Classification: 1,3-C symbolic representation Representative difunctional relationships Classification of Pairwise Difunctional Relationships (+) E E E E O OMe R MeO O NH2 HN O Cl OH O Me Me O O O Me Me R OMe HO O O OMe R CH2N2 Me Me O O Me Me OR O R OMe O –O OMe R O OMe R O Chem 206D. A. Evans Classification of Pairwise Difunctional Relationships Dissonant cyclesConsonant cycles a73 A single FG residing either in or appended to a cycle may establish a FG relationship with itself. Consonant & Dissonant Relationships: Path-Cycle Interconversions Linear molecules may be transformed into cycles & vice-versa: (+)(+) (+)Relationship: 1,5-C (+)(+)(+) Relationship: 1,5-C Consonant Cycles Relationship: 1,4-D Dissonant Cycles Path-cycle interconversions such as those illustrated permute, but do not eliminate the relationship. i.e. D-bond paths are transformed into D-cycles. General Rule For [m,n] Sigmatropic Rearrangements: When the sum of m+n is even, the FG relationship is maintained, e.g. C→C' When the sum of integers is odd, the FG relationship is changed, e.g. C→D a73 For these rearrangements, C→C', D→D' but C→D not possible 1,5–C1,2–C 1,4–D1,2–D [3,3] Sigmatropic Rearrangements: Pairwise Relationships: Path-Path Interconversions via Sigmatropic Rearrangements [1,2] Sigmatropic Rearrangements: C– cycle D– cycle [2,3] Sigmatropic Rearrangements: 1,3–C1,2–D – Pairwise Functional Group Relationships–2 C CCC E# E E# C C E C C C EE# C C C C C E# C C E C CCC E# E E# C C C C C E C C C E# C E C C C C CCC E# E C EE# C C C C EE# C C C C CCC E# E (–)(–) (+)(+)(–)(–) (+)(+) (–)(–) (+)(+)(+) (+)(–) (–) (+) (–)(–)(–) (+)(+) (+) (–) (–)(–) (+)(+)(+) (+)(–) (–) (–)(–) (+)(+) (–)(–) (+)(+) (+) (+)(–) (–) (–)(–) (+)(+) HO OH Br Br R Me O -HBr Br2 H2N NH2 HO NH2 O R Br R R H2O Br2 R R Br OH RO Me O OMe Me RO Me O OH RO OLi O XRO Me O O MeRO Me OLi O MeH MeMe OO MeRO OLi RO HO Me O RO O Me Me OO MeRO OHO MeRO RO Me O OH [H] Me Me OMe RO Me O O OLi Me [H] OHO MeRO Chem 206D. A. Evans These reagents are used to construct D-Relationships: In each of these reagentsthere is a 0,0-D relationship There exist an important family of reagents which have E-FGs directly coupled: E–E Reagents a73 E-functions in their most stable oxidation states (HO–, NH3, Cl –) are represented as E(–). Pairwise Relationships in Inorganic Reagents ConjugateAddition Aldol, ClaisenMannich Rxns E #(–) E (–) Consonant difunctional relationships can be constructed from just the functions illustrated& polar bond constructions. Synthesis of Targets containing Consonant Pairwise Relationships Given the oxidation state in the target, the second synthesis looks the best and the fourth looks the worst. Step II: Evaluate the efficiency of the 4 plausible routes to the target from available precursors. Step I: There are 4 bonds interconnecting E & E'.Hence generate the 4 transforms leading to mono- functional precursors: Target structure: [Ox]HO – HO – A Specific Case If a quaternary center occurs along the consonant bond path, one is limited to bond constructions on either side of that restriction The Constraint of Quaternary Centers Pairwise Functional Group Relationships–3 N H Me O Me H H H H H N Me O MeH N H Me O Me H H H N H Me O Me H H H H N Me O MeH X H H N Me HO MeH2C H H H N Me O MeH E# C C E R RSS C A C E C E# H HH N Me O MeH R R S PhO NO O – RR E# C E C C C C E# O RR C E R R O CF3CO2 SPh RR E# C C A C E E# C C A E# C C E Chem 206D. A. Evans Quaternary Centers & Bridgehead Restrictions The two permitted bond constructions along illustrated bond path flank the bridgehead carbon Lucidulene Synthesis: JACS 94, 4779 (1972) (+) (–) Focus on the shortest consonant bond path: (+) (+) (–) (+) + Mannich Transform (CH2O)n ?, isoamyl alcohol + Enamine Acylation Option Selected: a73 Corrolary: pi-conjugation cannot be extended through bridgehead or quaternary centers This transform defined a path-cycle permutation of the D-relationship (+)(+) Hence dissonant pairwise relationships may not be constructed via just the functions present in the target. In the illustrated polar disconnections, one of the fragments may exploit the charge affinity pattern of the resident FG while the other may not. E (+)(+) (–)(–)(+) Resident E-functions do not provide required charge affininty pattern for coupling (–)(+) The pairwise relationship is "unmatched"; hence, theillustrated E-functions cannot be used exclusively to construct the bond path. Let's consider the simplest case: a 1,2-D relationship. Synthesis of Dissonant Pairwise Relationlships (–)(+) The Nef Reaction The Pummerer Rearrangement 1) OH 2) H3O + HO – trifluoroacetic anhydride In implementing this strategy you must know all important 1,1-A E FG transformations. (±)(+)(±)(+)(+) (–) Dissonant Pairwise Relationlships via A-Functions "The Pummerer reaction of sulfinyl compounds.", De Lucchi, etal. Org. Reactions 1991, 40, 157. Pairwise Functional Group Relationships–4 E1 E2 E1 E2 C E2 E1 E2 E1 (–) E1 E2 E1 E2 (+) (+) (+) (+) (+) (+) (+) (+) (+) (+) (+) (+) (+) (+) (+) (+) (+) (+) (+) (+) (+) (+) (+) (+) (+) (+) (+) (+) (+) (+) (+) (+) (+) (+) (+) (+) N CH2OH NO Me OMe OMe C–E2 N CH2=O N C OHX N CHO H N CH2 H2O C–C C–C C–E1 C–E2 E2 Ar E1 C–E1 C–C C–C T1 T1 T1 T1 E2 Ar E1 E1 E1 E2 Ar E1 E2 Ar E1 E2 Ar E1 E2 Ar E2 Ar HO– MeO RO2C N Ar Me N Ar HO Me HN Ar O Me N Ar Me N Me Ar Chem 206D. A. Evans Bond path analysis of simple alkaloids Pairwise Functional Group Relationships–5 Mesembrine Every complex polyfunctional molecule may be analyzed structurally in terms of itsindividual consonant or dissonant construction paths or cycles. For example, in the alkaloid lupinine all possible construction paths interconnecting E1 and E2 areconsonant. Consonant paths within the polyatomic framework define seams in the structure that may be constructed using aldol and related processes. lupinine Begin the disconnection process by focusing on the shortest consonant bond path. In this case, there are 4 bonds, hence 4 disconnections. Note that oxidation states of precursors is not yet considered. Curphey, T. J.; Kim, H. L. Tetrahedron Lett. 1968, 1441. Keely, S. L.; Tahk, F. C. JACS. 1968, 90, 5584. Stevens, R. V.; Wentland, M. P. JACS 1968, 90, 5580 Shamma, M.; Rodrigues, H. R. Tetrahedron 1968, 24, 6583 In the analysis of potential routes to structures like mesembrine , identify the shortestconsonant bond path and then proceed to carry out all polar disconnections along that bond path. Since there four bonds interconnecting =O and N (E1 and E2), there will be four associated transforms which one may execute using the illustrated functional groups. (–) (–) (+)(+) Shortest consonant bond path (+) (–)(+) equivalent to: equivalent to: (+) (–)(+)(–) (–) (+) (–)(+) equivalent to: equivalent to: (+) (–)(+)(–) (–) (–) equivalent to: equivalent to: equivalent to: equivalent to: Now consider further analysis of T1: Again, select the shortest E1-E2 bond path and disconnect next to quaternary center. Dissonant element is localized in 5-membered enamine (+) (–)(+)(–) (+) (+) (–)(+)(–) (+) (–) (–) equivalent to: Keely, S. L.; Tahk, F. C. JACS. 1968, 90, 5584. Stevens, R. V.; Wentland, M. P. JACS 1968, 90, 5580Handouts X X OH QR N OH CNPh How do we classify the functional group? H O C O MeH Me O O CH2H O MeH R C O O HR QR H O OH ElR QR El O O HPh CNPh H O OH ElPh CN C NH OH PhPh O CMe N C NMe Q CN CH2C N C N Me Nu O OH Ph H O – :C N Ph C O C EC C G C E Chem 206Inversion Operators-1: The Electronic Characteristics of Cyanide IonD. A. Evans Can one design "catalysts" which will provide access to carbonyl anion equivalents in situ?? carbonyl anion inaccessible homoenolate anion inaccessible Example: base Inaccessible Reactivity Modes in Carbonyl Deprotonation Equivalent to: Let Q – be such a catalyst, we will call it an "inversion operator" (–) (+) (+)–Nu: – + H + a73 Acetonitrile can be deprotonated by strong bases (pKa DMSO ~ 30) – (–) a73 Acetonitrile can be attacked be nucleophiles: + H + a73 Hydrogen cyanide is a fairly good Bronsted acid (pKaHOH 9.5) – :CN– :CN 2 Equivalent to: a73 Cyanide ion is such a "catalyst" The Benzoin Condensation C O – + a71a71 R H O O HAr R C CN OH Me3Si–CN CO2Et OEt O ZnI2 DMF Na–CN HR CN O–SiMe3 O–SiMe3 CNR O HR O CNR H Et OEt OEt Et O R CN – :C N OH CNR H LiNR2 LiNR2 O–SiMe3 CNR H OEt Ar O O OEt OEt O OH Ar CN OEt Et O HR CN CO H Me N SMe N N NH2 N S Me Me OH H Me N S Me H Me H O Me OH O O R Li R C Li O Me N S Me R C O O HMe OH O MeMe R C OLi Me N S Me Me N S Me C O O Me N SMe C O R R R OLi OLi Chem 206D. A. Evans a73 The in situ use of cyanide ion as an inversion operator is limited. Greater generality may be achieved by multistep alternatives: The C–C Bond Construction 44% yield a73 Extensions of the Benzoin condensation concept are possible in some instances: Aldehyde Derivatization Step Cyanide-based Carbonyl Anion Equivalents G. Stork JACS 93, 5286 (1971) Substrate Deprotonation Step Deprotonation possible for All R groups Deprotonation possible only for R = Ardue to Si migration. + Reactions catalyzed by thiamine a71a71 a71a71 base In the absence of electrophiles 1 & 2 dimerize as would be expected for carbene reactivity. 2 1 a71a71 a71a71 a71a71Carbonyl anions might be similarly stabilized a71a71 base F. G. Bordwell JACS 113, 985, (1991) The pka of this proton has been the subject of considerable study. The current estimates are that the value falls in the range of 16-20 but this number is not firm. The thiamine cofactor Reactions equivalent to the benzoin are catalyzed by biological co-factors to make (and break) dissonant difunctional heteroatom-heteroaton relationships Thiazolium Salts: Nature's Inversion Operators Thiazolium Salts as Inversion Operators Stetter, Org. Reactions 1991, 40, 407. R NS R OHMe OH Me C C E OH MeMe O O HMe R N S R E C C Me H O R N S R O Me H OH O MeMe Me OH R N S R E CC C C E Me H O Me C O O Hn-H7C3 H O Me Me E C O HMe Me H O C C E C R H O Ph O Ph Me O Ph Me O O Me Me N SHO CH2Ph H R' R"" O Ph Phn-H 7C3 O O O O MeMe Me MeMe O O O O Me Me Ph E C C C C E O R R'' OR' Chem 206Thiazolium Salts as Inversion Operators–2D. A. Evans Aldehyde dimerization by Thiazolium Salts Thiazolium ion catalysis base Equivalent to: – The Catalytic Cycle The Reaction a73 Hence dissonant relationships may made from E-functions if "inversion operator" is employed (+) (–)(–) (+) + inversion operator 1,2–D a73 The is a fundamental strategy for handling the formation and cleavage of D-relationships in nature. (+) + (+) "The catalyzed nucleophilic addition of aldehydes to electrophilic double bonds.", Stetter, H.; Kuhlmann, H. Org. Reactions 1991, 40, 407. 70% yield 21% yield 41% yield Examples: 61% yield The Conditions: 0.1 equiv catalyst, Et 3N or NaOAc, EtOH or DMF at 60-80 °CThe Catalyst: 1,4–Dinversion operator (+)(–) a73 1,4-D relationships may also be made from E-functions if "inversion operator" is employed. The Reaction Cataylzed Michael Reactions byThiazolium Salts a73 There is no analogue to this reaction in nature. 1,2–D 1,4–D 1,2–D X H O O – R NS R Me O Me OH RNS R R NS R O –Me H R O OH O ? O O OR H Me OH O O R N S R O O OHMe C O O O HMe O R M O M O R O Me H O O H R O OH O R C O O C O O C O O H2N R O R OHH2N N OH Phosphate–O Me OH N OH OH Me R H O N H2N OH R O R N N H H N N R O OH -CO2 R H2N N H R NH C O O C O O Chem 206Thiazolium Salts as Inversion Operators–3D. A. Evans + a73 Background: Decarboxylation from consonant difunctional relationships is facile: ? (+) (–)(+) (+) a73 The reverse processe can be achieved under basic conditions: (+) (+)(+) H + a73 Such consonant relationships may be readily made (and broken) via the resident functional groups. The analog reactions for dissonant relationships not possible. For example: a73 Nature uses inversion operators to break such 1,2-D relationships Decarboxylation Cataylzed by Thiazolium Salts (–) (–) (–) The Mechanism - H2O + H2O Tautomerization 1,6-Crelationship 1,2-D relationship1,4-Drelationship a70 a70 a70 a70 The critical difunctional relationlship is that between =O & =N. This is a 1,4-D relationship The pyridoxal Co-factor (Vitamin B6) Design Attributes of Inversion Operators Inversion operators are constructed from A-functions or molecules containing D-relationships. The Reaction (+) (+) (+) (+) a70 a70