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Multicomponent Reactions in Total Synthesis: Generation of Complex Ph OEt Ph O Ph O N Ph MeO O O O 3 Å MS O H + MeO + O O HN O H N toluene, rt HN H OEt Multicomponent Reactions in Total Synthesis Generation of Complex Polyfunctionalized Molecules Using Convergent One-Pot Transformations O OEt TFE HN N + + aq. HCHO H rt O NH2 OEt O OEt Kevin Allan Stoltz Group Literature Meeting Monday, February 5, 2007 8:00 PM 147 Noyes Ph Ph Ph OTBS Ph HN Ph PhHN 1. LDA (3.3 equiv) Ph HN N N Ph N Ph N 2. PhCN Ph Ph Ph Ph Ph Ph N Ph O Ph H 3-CR 4-CR 5-CR Multicomponent Reactions in Total Synthesis · Introduction to Multicomponent Reactions · Reactions Involving Activated Carbonyl Species · Mannich Reaction / Petasis (Boronic Acid Mannich) Reaction · Biginelli Dihydropyrimidinone Synthesis A · Passerini Reaction · Ugi Reaction · Cycloadditions · Povarov Reaction B C · Knoevenagel / Hetero-Diels-Alder Cycloaddition · 1,3-Dipolar Cycloadditions · Multiple Anion Capture · Heterospirocyclic Compounds and Medium-Sized Lactones · Radialene-Shaped Pyrroles A · Allene Dianions and Nitrile Oligomers · One-Pot Total Syntheses B D · Nitaramine · Glyantrypine, Fumiquinazoline F, Fiscalin B · Schlerotigenin, Circumdatin F, Asperlicin C C · Conclusions Reviews: Dömling, A. Chem. Rev. 2006, 106, 17-89. Multicomponent Reactions. Zhu, J.; Bienaymé, H., eds. Wiley-VCH; Weinheim, 2005. Orru, R. V. A.; de Greef, M. Synthesis 2003, 10, 1471-1499. Ugi, I. Pure Appl. Chem. 2001, 73, 187-191. Bienaymé, H.; Hulme, C.; Oddon, G.; Schmitt, P. Chem. Eur. J. 2000, 6, 3321-3329. Ugi, I. J. Prakt. Chem. 1997, 339, 499-516. Ugi, I.; Dömling, A.; Hörl, W. Endeavour 1994, 18, 115-122. Multicomponent Reactions An Introduction "Multicomponent reactions (MCRs) are processes involving sequential reactions among three or more reactant components that co-exist in the same reaction mixture. In order to be efficient, MCRs rely on components that are compatible with each other and do no undergo alternative irreversible reactions to form other products or by-products." -- Jieping Zhu in Multicomponent Reactions · Addendum: The products of multicomponent reactions comprise a portion of each individual reactant component. · Multicomponent reactions are sometimes referred to as tandem or domino reactions. · Multicomponent reactions may be further classified by the number of molecules and the number of functional groups participating in the reaction. Example: A + B + C + D A B C D 4-component reaction A + B C + D A B C D 3-component-4-center reaction · Multicomponent reactions are also classified by the reversibility of steps leading to the product. Type I Substrates Intermediates Product Type II Substrates Intermediates Product Type III Substrates Intermediates Product Ugi, I. J. Prakt. Chem. 1997, 399, 499-516. Bienaymé, H. Chem. Eur. J. 2000, 6, 3321-3329. Multicomponent Reactions A New Approach to Total Synthesis · Linear total syntheses require significant amounts of time and money to advance starting materials to complex targets. A B C A D 1 mol 1 mol 1 mol A A B B D 50% 50% 50% B C C 1 mol 0.5 mol 0.25 mol 0.125 mol · MCRs minimize cost in the form of time and material by generating complex targets in a single convergent step. A 50% A + B + C + D B D C 1 mol 1 mol 1 mol 1 mol 0.5 mol · MCRs typically run at mild temperatures and do not require many reagents in excess of the participating substrates. This has made them ideal for combinatorial library synthesis as well as industrial pharmaceutical synthesis. (1) 1 1 1 1 A B C D A1 An (2) A2 B2 C2 D2 · · + · + · + · B1 D1 · · · Bn Dn · · · · · · · · · · (n) An Bn Cn Dn C1 Cn m component reaction with n types of each component → nm products n = 5 (20 SM cmpds) → 625 products n = 10 (40 SM cmpds) → 10,000 products n = 50 (200 SM cmpds) → 6.25 mill products Mannich Reaction Three-Component Synthesis of β-Aminocarbonyls · In 1903, B. Tollens and C. M. van Marle observed the formation of a tertiary amine from the treatment of an aqueous solution of acetophenone and formaldehyde with ammonium chloride. O O O NH4Cl + N H H H2O 3 Tollens, B.; van Marle, C. M. Ber. 1903, 36, 1347-1351. · In 1917, Carl Mannich (Berlin, Germany) reported the formation of a number of β-aminoketones under the same conditions. O O H O O H 2 + + N N H H 100 °C O O H2O + + NH4Cl several products H H 100 °C O O O H2O + + NH4Cl + several side products H H 100 °C N Mannich, C. Archiv. Pharm. 1917, 255, 261-276. Mannich, C. J. Chem. Soc. Abstr. 1917, 112, 634-635. · The Mannich reaction is a Type I MCR that proceeds under both acidic and basic conditions, though acidic conditions are more common. In 1969, Stephen Benkovic (Penn State) performed kinetics experiments over a broad pH range that supported the formation of a pH-dependent steady state iminium intermediate under acidic conditions. Under basic conditions, a carbinolamine intermediate presides. H N H Lewis or Bronsted acid H N N Polar solvent N HN N Ar N H N HN H N Base CO2Et Apolar solvent N CO2Et HN HO Ar Benkovic, S. J. J. Am. Chem. Soc. 1969, 91, 1860-1861. Mannich Reaction Select Total Syntheses Robinson's Synthesis of Tropinone: O O O N O N OMe HO OH OH + N N H2O HO O Me NH2 O rt, 50 h O - CO2 + O HO O O O H H O Atropine Cocaine O O Robinson, R. J. Chem. Soc. 1917, 762-768. Omura's Synthesis of (+)-Madindoline A and B: HO HO HO HO O N H H 37% aq. HCHO O O O Sc(OTf)3 (10 mol%) N TAS-F N N + H H + H Me Me Me H2O, rt, 24 h DMF, rt, 20 min O O O O O Me CO2Me (11% yield) (77% yield) TMSO CO2Me TMS n-Bu n-Bu n-Bu TMS n-Bu (+)-Madindoline A (+)-Madindoline B TAS-F = (Me2NH)3S Me3SiF2 Omura, S. Tetrahedron Lett. 2006, 47, 6761-6764. Petasis (Boronic Acid Mannich) Reaction Three-Component Synthesis of Allyl, Propargyl, and Benzylamines · In 1993, Nicos A. Petasis (USC) described the preparation of tertiary allylic amines from paraformaldehyde, secondary amines, and vinyl boronic acids under acid-free conditions. Yields ranged from 75-96%. NH N OH B (CH2O)n + OH dioxane 90 °C, 30 min OH O (CH2O)n O + B NH N n-C H n-C5H11 OH dioxane 5 11 90 °C, 30 min Petasis, N. A. Tetrahedron Lett. 1993, 34, 583-586. · The Petasis reaction is a Type II reaction, though the precise mechanism is still disputed: · Petasis noted that in the absence of acid, it was unlikely that significant amounts of the iminium salt would form. Also, boronic acids did not readily add to preformed iminium salts, though they did react with diamines. Based on these observations, Petasis proposed the formation of an intermediate ammonium borate complex followed by internal delivery of the vinyl nucleophile. OH SLOW 2 3 + R R B N N R N 2 H HO R Cl H OH R R2 HO B O N OH + O R3 R1 N R3 B OH FAST 1 1 + N R HO R H H R H H B N N HO R · However, the vast majority of cases in the literature employ an aldehyde substrate containing a directing group near the carbonyl, indicating a necessity for formation of a two-center ionic complex. In these cases, a protic solvent is typically used (MeOH, EtOH, TFE). R2 R3 2 3 R2 R3 R R O O N N OH H N O O H R H OH R H O + H H OH R1 O B OH N O OH HO R O B OH OH R R R OH R Bryce, M. R.; Hansen, T. K. Tetrahedron Lett. 2000, 41, 1303-1305. Petasis, N. A. Tetrahedron Lett. 2001, 42, 539-542. Schreiber, S. L. Angew. Chem. Int. Ed. 2006, 45, 3635-3638. McReynolds, M. D.; Hanson, P. R. Chemtracts 2001, 14, 796-801. Petasis (Boronic Acid Mannich) Reaction Substrate Scope O O S N O H H N NH2 N NH2 N H OH OMe R1 OR2 R N O H R = H, OH, OMe H N R1 = Me, t-Bu, Bn, Cy N NH2 N NH H 2 O R = H, Me N N N NH H 2 O O N NHR2 1 NH2 H R O N R N H NH N 1 2 R = H, OH, OMe N R = t -Bu, Bn, NH2 HO 2 R = H, Ph, Bn, CH2Cy N Ph H O CH2CO2Me HO O R O O Ph Ph NH O H S R = H, Me, Et, Ph, Bn t-Bu NH2 Ph NH2 Ph O B(OH)2 Br B(OH) R 2 B(OH) B(OH)2 2 B(OH)2 O O Br R R = H, Me, n-Bu, Ph R = H, Me, OMe R B(OH)2 B(OH) BF3 B(OH)2 O 2 N B(OH)2 K SO Ph S 2 R = H, OMe, Cl, Br Petasis (Boronic Acid Mannich) Reaction Pyne's Total Synthesis of Uniflorine A OH HO HO Ph H 1. Boc2O, Et3N HO OH B HO Ph EtOH 2. TrCl, pyr + OH O rt, 16 h HN st HO HO 3. Grubbs 1 gen. CH Cl , reflux H N 2 2 L-xylose 2 (73% yield) OH single diastereomer (30% yield, 3 steps) HO BnO OBn H 1. K OsO ·2H O, NMO H HO 2 4 2 BnO acetone / H2O, rt TFA OBn N 2.
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