哈佛大学：《高等有机化学》（英文版）Lecture 29 Advanced Organic Chemistry

D. A. Evans Pairwise Functional Group Relationships Chem 206 The /mine aldol reaction New Information http:/lwww.courses.fas.harvardedu/-chem206/ recent relevant paper: KobayashI, JACS 2001, 123, 9493-9499 NHBZ sclk0°C x Chemistry 206 NHB Advanced Organic Chemistry anti diastereoselection 99: 1 /NHBZ Lecture Number 29 X=SICl3 79% Ambiphilic Functional Groups-4 anti diastereoselection 78: 22 Construction of Consonant& Dissonant FG Relationships E Charge Affinity Inversion Operators 晚一∠2 NHBZ Pummerer reviews Application of the Pummerer reaction toward the synthesis of complex carbocycles and heterocycles. Padwa, A Gunn, D. E: Osterhout, M. H Synthesis1997,1353-1377. Cume Question, Fall 2001. The reaction illustrated below was recently Asymmetric pummerer-type reactions induced by o-silylated ketene reported by Murry and co-workers from the Merck Process Group(JACS 2001 acetals. Kita, Y. Shibata, N. Synlett 1996, 289-296 123, 9696-9697). Provide a mechanism for this transformation Grierson, D. S. Husson, H.-P. Polonovski-and Pummerer-type Reactions and the Nef Reaction. Trost, B M. and Fleming, L, Ed. Pergamon Press: Oxford 191:vol.6,pp909 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 ompounds. " Carreno, M. C. Chem. Rev. 1995, 95, 1717-1760 Matthew d shair Monday, December 2. 2002

http://www.courses.fas.harvard.edu/~chem206/ Ph H N NHBz Ar1 H O SiCl3 Me Ph H N NHBz Me SiCl3 SiCl3 Me Ar2 N H SO2 Tol OCMe3 O C N SiCl3 Me H Ph R H N S Me CH2CH2OH Ph XN NHBz Me Ph XN NHBz Me N H Ar2 OCMe3 O Ar1 O Ph XN NHBz Me D. A. Evans Chem 206 Matthew D. Shair Monday, December 2, 2002 Chemistry 206 Advanced Organic Chemistry Lecture Number 29 Ambiphilic Functional Groups–4 ■ Construction of Consonant & Dissonant FG Relationships ■ Charge Affinity Inversion Operators A recent relevant paper: Kobayashi, JACS 2001, 123, 9493-9499 The Imine Aldol Reaction: New Information X = SiCl3 X = H anti diastereoselection 99:1 0 °C 79% X = SiCl3 X = 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, CH2Cl2 35 °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

D A. Evans Summary of Functional Group Classification Scheme Chem 206 Classification of Functional Groups G-Functions (-)(+)(-) G--C-C-C Each substituent attached to carbon activates that carbon toward a polar reaction by either resonance or induction or boti Those ideal FGs which create nucleophilic carbon at point of attachment Exhibit strictly alternate charge affinity patterns Induction F3C F4C These are your metallic FGs such as Li, Mg, etc Resonance CH3-CH2 CH2-CH--CH2-Mg Br Symbol E-c(+) A-C(±) G-c(-) Note that a 2-electron reduction (or oxidation) will transform an E-Class FG to a G-Class FG Charge Affinity Patterns +2e E{88 CH3-CH2--Br CH3-CH2-MgBl Real functional groups are assigned to a class designation by inspection of the A-FunctionsA-C-CA-c-C A-c chemistry of that FG, along with that of its conjugate acid and conjugate base All sites activated equally for electrophilic nucleophilic reactivity Charge affinities of real functional groups form a subset of the ideal FG classes. Those ideal FGs which exhibit nonaltermate polar site reactivity are included E-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 e-+9e89 CH2-CH- BNoeaoA-ccc (王)(±)(王) For example CH3-c=0 is represented as -E and not: C-c-E2 A-functions are some of the most useful FGs in organic synthesis because of the unique reactivity provide

F1 C F2 C F3 C F4 C (+) (+) (–) (+) (–) (+) (–) (–) CH2 CH CH2 Br CH3 CH2 OR E C C C E C C C CH3 CH2 Br CH3 CH O E C A C C A C C CH3 CH2 NR2 A C C CH3 C O OR A C G C C C G C C C E C C E2 E1 C OR CH O 3 A C C C A C C C A C C C A C C CH3 CH2 Br E C A C C CH3 CH2 Li G C C C A C C E C C C CH3 CH2 MgBr G C G C C C CH2 CH CH2 MgBr D. A. Evans Summary of Functional Group Classification Scheme Chem 206 (–) (–) (+) (+) (±) (+) (–) (+) (±) (–) (+) (–) 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. ■ 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 (+) – (–) (+) (–) ■ 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. ■ Those ideal FGs which create nucleophilic carbon at point of attachment. ■ 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. ■ All sites activated equally for electrophilic & nucleophilic reactivity. ■ 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. (+-) (+-) (+-) (–) (+) (–) (+) (–) (+) (±) (±) (±) (±) (±) (±)

D.A. Evans Pairwise Functional Group Relationships Chem 206 A-Functions: Real Examples Classification of Pairwise Difunctional Relationships A-Functions A-8{A-828A-88 Consider the paired relationships of E-functions. There are two relationships. A-functions are composed of polyatomic arrangements of N&o add e C-C-C-C C-C-C-c Charge affinity patterns -NO2 =NOH NNR2-N=NR2 -N(O)R=N=N=N Pairwise relationship is A functions are composed of second-row elements such S and P consonant add e S-r S-R -SR-S Charge affinity -R C-C-C Pairwise relationship is R R dissonant Functional groups derived from many of the transition elements Consonant dissonant relationships may be established with E-E, E-G, or G-G pairings Synthesis of Targets containing E-Functions Most target structures are composed of E-functions Transforms utilizing target E-function in synthesis plan given highest priority E E C=CC-Cc今C C-C G-FG lost Representative difunctional relationships (-)(+)(-) in construction C-C-C-C C-C m E-FG lost symbolic representation E G-FG (+)(-)(+) 2=8888 lassification: 1, 2-D in const embolic representation Given the resident E-function, the charge affinity pattem dictates the nature of the polar coupling process and thus functional groups to be employed in synthesis symbolic representation Classification: 1.1-D

S R R P R R P R R R E # C C C C + + (+) (–) (+) (–) A C C A C C A C C C C C C 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 C C G E' C C C C C E C C C C E E C C E C C C C C G Me OH O O O Me NR2 O HO NH2 OH Cl Li Cl E G C E C C C E # E # C C C C E E # C C C C E E E' E E' D. A. Evans Pairwise Functional Group Relationships Chem 206 ■ Functional groups derived from many of the transition elements ■ A-functions are composed of second-row elements such S and P. A-Functions: Real Examples (±) (±) (+) (+) (–) (–) A-Functions ■ 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 lost (+) (–) (+) (–) in construction Transforms utilizing target E-function in synthesis plan given highest priority. (+) (–) (+) (–) Synthesis of Targets containing E-Functions G–FG lost in construction E'–FG lost in 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-D symbolic representation Classification: 1,2-D symbolic representation Classification: 1,3-C symbolic representation Representative difunctional relationships Classification of Pairwise Difunctional Relationships (+)

D A. Evans Pairwise Functional Group Relationships-2 Chem 206 Classification of pairwise Difunctional relation Pairwise Relationships: Path-Path Interconversions via Sigmatropic Rearrangements I A single FG residing either in or appended to a cycle may establish a FG(3, ]Sigmatropic Rearrangements relationship with itself 00 14-D OMe 1,2-C 1.5-C Consonant Dissonant Relationships: Path-Cycle Interconversions Linear molecules may be transformed into cycles& vice-versa ■ For these rearrangements,C→C,D→ D but C-D not possible Relationship. Meo(+) H2→ [1, 2]Sigmatropic Rearrangements Consonant Cycles Relationship:C、 15-C [2,3]Sigmatropic Rearrangements: 0、R Dissonant Cycles 1,2-D 13-C 14D OMe General Rule For [m, n] Sigmatropic Rearrangements Path-cycle interconversions such as those illustrated permute, but do not When the sum of m+n is even, the FG relationship is maintained, e.g. C-C eliminate the relationship. i.e. D-bond paths are transformed into D-cycles When the sum of integers is odd, the FG relationship is changed, e.g. C-D

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 D. A. Evans Chem 206 Classification of Pairwise Difunctional Relationships Consonant cycles Dissonant cycles ■ 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 ■ For these rearrangements, C®C', D®D' but C®D not possible 1,2–C 1,5–C 1,2–D 1,4–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: 1,2–D 1,3–C – Pairwise Functional Group Relationships–2

D A. Evans Pairwise Functional Group Relationships-3 Chem 206 Pairwise Relationships in Inorganic Reagents A Specific Case E-functions in their most stable oxidation states(HO, NH3, CI)are Target structure onds interconnecting E&E. transforms leading to mono- There exist an important family of reagents which have E-FGs directly coupled: E E Br-Br Ho--NH2 In each of these reagents Ho-OH H2 N-NH2 there is a 0,0-D relationship EFE hese reagents are used to construct D-Relationships (+)(-)(+)(-) R Me -HBr H Synthesis of Targets containing Consonant Pairwise Relationships EE EF E C-C—C (+)(-)(+)(-) (+)(-)(+) )(-) Aldol, Claisen Step ll: Evaluate the efficiency of the 4 plausible routes to the target from available Mannich Rxns Given the oxidation state in the target, the second synthesis looks the best and the fourth looks the wo (+)(-)(+)(-) The Constraint of Quaternary Centers If a quatenary center occurs along the consonant bond path, one is limited to bond constructions on either side of that restriction (+)(-)(+)( (+)(-)(+)(-) 0 (+)(-)(+)(-) (+)(-)(+)(-) Me me Consonant difunctional relationships can be constructed from just the functions illustrated polar bond constructions

C C C C E # E E # C C E C C C E E # C C C C C E # C C E C C C C E # E E # C C C C C E C C C E # C E C C C C C C C E # E C E E # C C C C E E # C C C C C C C 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 Me Me O RO Me O OH RO OLi O RO X Me O O RO Me Me OLi O H Me O Me Me O RO Me OLi RO HO Me O RO O Me Me O O RO Me O OH RO Me RO Me O OH [H] Me Me Me O RO Me O O OLi Me [H] O OH RO Me D. A. Evans Chem 206 These reagents are used to construct D-Relationships: In each of these reagents there is a 0,0-D relationship There exist an important family of reagents which have E-FGs directly coupled: E–E Reagents ■ E-functions in their most stable oxidation states (HO– , NH3, Cl – ) are represented as E(–). Pairwise Relationships in Inorganic Reagents Conjugate Addition Aldol, Claisen Mannich 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: HO [Ox] – 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

D A. Evans Pairwise Functional Group Relationships-4 Chem 206 Quaternary Centers Bridgehead Restrictions Synthesis of Dissonant Pairwise RelationIships The pairwise relationship is unmatched", Lucidulene Synthesis: JACS 94, 4779(1972) illustrated E-functions cannot be used excusively to construct the bond path. Let's consider the simplest case E (+)(-) Resident E-functions do not provide required charge affinity pattern for Focus on the shortest consonant bond path coupling (+)(-) The two permitted bond constructions along illustrated bond path flank the bridgehead carbon This transform defined a path-cycle M permutation of the D-relationship In the illustrated polar disconnections, c fragments may exploit the charge affinity pattem of the resid nile the other may not. Hence dissonant pairwise relationships may not be constructed via just the functions H present in the target nich Transform Dissonant Pairwise Relation/ships via A-Functions E”A In implementing this strategy you must know all important 1, 1-A+EFG Option Selected CH2O) △, isoamyl alcohol The Pummerer Rearrangement The Pummerer reaction of sulfinyl compounds. " De Lucchi, etal. rrolary: I-conjugation cannot be extended through bridgehead or Org. Reactions 1991, 40, 157. quaternary -1)OH The Nef reaction

N H Me O Me H H H H H N Me O Me H N H Me O Me H H H N H Me O Me H H H H N Me O Me H X H H N Me HO Me H2C H H H N Me O Me H E # C C E R R S S C A C E C E # H H H N Me O Me H R R S O Ph N O O – R R E # C E C C C C E # O R R C E R R O CF3CO2 SPh R R E # C C A C E E # C C A E # C C E D. A. Evans Chem 206 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 D, isoamyl alcohol + Enamine Acylation Option Selected: ■ Corrolary: p-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, the illustrated 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

D A. Evans Pairwise Functional Group Relationships-5 Chem 206 Bond path analysis of simple alkaloids OMe Mesembrine CH2OH rphey, T.J.; Kim, H. L Tetrahedron Lett. 1968, 1441 lupinine Keely, S. L: Tahk, F. C JACS. 1968, 90, 5584. V: Wentland. M. P JACS 1968. 90 Shamma, M. Rodrigues, H.R. Tetrahedron 1968, 24, 6583 Every complex polyfunctional molecule may be analyzed structurally in terms of its individual consonant or dissonant construction paths or cycles. For example, in the alkaloid lupinine all possible construction paths interconnecting E1 and E2 are In the analysis of potential routes to structures like mesembrine ne shortest consonant. Consonant paths within the polyatomic framework define seams in the consonant bond path and then proceed to carry out all polar disco structure that may be constructed using aldol and related processes bond path. Since there four bonds interconnecting=O and N(E1 ere will be four associated transforms which one may execute using the illustrated functional egin the disconnection process by focusing on the shortest consonant groups. Ar bond path. In this case, there are 4 bonds, hence 4 disconnections CH2=O T1 equivalent to: A equivalent to Ar equivalent to Shortest consonant equivalent to CHO Ar C-E1 equivalent to equivalent to E2(- enamine Note that oxidation states of precursors is not yet considered E2) Handouts Stevens .R V: Wentland M P JACS 1968.90.5580

E1 E2 E1 E2 C E2 E1 E2 E1 (–) E1 E2 E1 E2 (+) (+) (+) (+) (+) (+) (+) (+) (+) (+) (+) (+) (+) (+) (+) (+) (+) (+) (+) (+) (+) (+) (+) (+) (+) (+) (+) (+) (+) (+) (+) (+) (+) (+) (+) (+) N CH2OH O N Me OMe OMe C–E2 N CH2=O N C X OH 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– O Me RO2C N Ar Me N Ar HO Me HN Ar O Me N Ar Me N Me Ar D. A. Evans Chem 206 Bond path analysis of simple alkaloids Pairwise Functional Group Relationships–5 Mesembrine Every complex polyfunctional molecule may be analyzed structurally in terms of its individual consonant or dissonant construction paths or cycles. For example, in the alkaloid lupinine all possible construction paths interconnecting E1 and E2 are consonant. 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 shortest consonant 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. Handouts Stevens, R. V.; Wentland, M. P. JACS 1968, 90, 5580

D A. Evans Inversion Operators-1: The Electronic Characteristics of Cyanide lon Chem 206 Inaccessible Reactivity Modes in Carbonyl Deprotonation The Benzoin condensation CN 2 Cyanide ion is such a"catalyst base Can one design"catalysts"which will provide access to carbonyl anion CNO ⊙cN Let Q- be such a catalyst, we will call it an"inversion operator How do we classify the =N functional grou Equivalent to R⊙Q HC式N、 L Acetonitrile can be attacked be nucleophile Me-C=N NnC_ a Acetonitrile can be deprotonated by strong bases (pKa DMso"30) H2C-CEN

X X OH R Q N OH Ph CN How do we classify the functional group? H O C O H Me Me O O CH2 H O Me H R C O O R H Q R H O OH R El Q R El O O Ph H CN Ph H O OH Ph El CN H C N OH Ph Ph O Me C N Me C N Q CN H2C C N C N Me Nu O OH Ph H O – :C N Ph C O C C E C G C E D. A. Evans Inversion Operators-1: The Electronic Characteristics of Cyanide Ion Chem 206 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 + + ■ Acetonitrile can be deprotonated by strong bases (pKa DMSO ~ 30) – (–) ■ Acetonitrile can be attacked be nucleophiles: H + + ■ Hydrogen cyanide is a fairly good Bronsted acid (pKaHOH 9.5) – :CN 2 – :CN Equivalent to: ■ Cyanide ion is such a "catalyst" The Benzoin Condensation

D A. Evans Thiazolium Salts as Inversion Operators Chem 206 Cyanide-based Carbonyl Anion Equivalents Thiazolium Salts: Nature's Inversion Operators I Extensions of the Benzoin condensation concept are possible in some instances Reactions equivalent to the benzoin are catalyzed by biological co-factors to make The pka of this proton has been the subject of considerable study. The current estimates 44% yield that the value falls in the range of 16-20 b F.G.Bordwell JACS 113, 985, (1991) eege590404 The thiamine cofactor The C-C Bond construction I The in situ use of cyanide ion as an inversion operator is limited. Greater generality may be achieved by multistep altematives lions might be 2 stabilized Aldehyde Derivatization Step In the absence of electrophiles 1&2 dimerize as would be expected for carbene O-SiMe3 reactivity Me3 SHCN -H -base n=→ +0R-L Substrate Deprotonation Step 0-SiMe3 LiNR Deprotonation possible only for R Reactions catalyzed by thiamine 个 OOEt LiNR2 o oEt Deprotonation possible for All groups G. Stork JACS 93, 5286 (1971)

C O – + ●● R H O O Ar H R C CN OH Me3Si–CN CO2Et OEt O ZnI2 DMF Na–CN H R CN O–SiMe3 O–SiMe3 R CN O R H O R CN H Et OEt OEt Et O R CN – :C N OH R CN H LiNR2 LiNR2 O–SiMe3 R CN H OEt Ar O O OEt OEt O OH Ar CN OEt Et O H R CN C O H Me N S Me 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 Me H OH O Me Me R C OLi Me N S Me Me N S Me C O O Me N S Me C O R R R OLi OLi D. A. Evans Chem 206 ■ 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 ■ 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 = Ar due to Si migration. + Reactions catalyzed by thiamine ●● ●● base In the absence of electrophiles 1 & 2 dimerize as would be expected for carbene reactivity. 2 1 ●● ●● Carbonyl anions might be ●● similarly stabilized ●● 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

D A. Evans Thiazolium Salts as Inversion Operators-2 Chem 206 Aldehyde dimerization by Thiazolium Salts Cataylzed Michael Reactions by Thiazolium Salts 12-D 14-D The Catalytic C The con The Catalyst EtoH or DMF Examples: "The catalyzed nucleophilic addition of aldehydes to electrophilic double bonds. Stetter, H. Kuhlmann, H. Org. Reactions 1991, 40, 407. 61% yield ⊙ Me 41% yield 21% yield a Hence dissonant relationships may made from E-functions if inversion H operator is employed ■14- D relationsh inversion operator employed C-C-C-C 1.2-D E (+ (+)(-)(+) a The is a fundamental strategy for handling the formation and cleavage of C +C-C-C C-C-C-C 14-D a There is no analogue to this reaction in nature

R S N R Me OH H O Me C C E OH Me Me O O Me H R N S R E C C Me H O R N S R O Me H OH O Me Me Me OH R N S R E C C C C E Me H O Me C O O n-H7C3 H H O Me Me E C O Me H Me H O C C E C R H O Ph O Ph Me O Ph Me O O Me Me N S HO CH2Ph H R' R"" O Ph Ph n-H7C3 O O O O Me Me Me Me Me O O O O Me Me Ph E C C C C E O R R'' R' O D. A. Evans Thiazolium Salts as Inversion Operators–2 Chem 206 Aldehyde dimerization by Thiazolium Salts Thiazolium ion catalysis base Equivalent to: – The Catalytic Cycle The Reaction ■ Hence dissonant relationships may made from E-functions if "inversion operator" is employed (–) (+) (+) (–) + inversion operator 1,2–D ■ 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, Et3N or NaOAc, EtOH or DMF at 60-80 °C The Catalyst: 1,4–D inversion operator (–) (+) ■ 1,4-D relationships may also be made from E-functions if "inversion operator" is employed. The Reaction Cataylzed Michael Reactions byThiazolium Salts ■ There is no analogue to this reaction in nature. 1,2–D 1,4–D 1,2–D