Advanced Organic Synthesis

Transcription

1 به نام خدا 10 Advanced rganic Synthesis Dr M. hrdad University of Guilan, Department of Chemistry, Rasht, Iran

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3 2. J. A. C. S. 1981, 103(25), 3

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5 Ratjadone potent cancerostaticum and fungicide Perhydro pyran Cala Ratjada (Mallorca) isolated from soil bacteria Perhydro pyran with double band trans,trans-diene cis,trans-diene disconnected by a retro-heck coupling Bhatt, U. et al., J. rg. Chem. 2001, 66, Wittig reactions

6 retro-opened to a -hydroxy epoxide hetero-diels-alder reaction of an acrolein derivative 6

7 Fostriecin antitumor activity Boger, D. L. et al., J. Am. Chem. Soc. 2001, 123,

8 contains four condensed rings: phenol isolated from a sponge is anti-inflammatory Frondosin B cyclohexene furane cycloheptene from a Diels-Alder reaction from an intramolecular Friedel-Crafts acylation Inoue, M. et al., J. Am. Chem. Soc. 2001, 123,

9 Furane from a base- and palladium-catalyzed intermolecular addition of a phenolate to an alkyne. Alkyne from a Sonogashira Coupling The rest is Sharpless and phenol chemistry 9

10 Batzelladine F An alkaloid was isolated from a Jamaican sponge useful to treat autoimmune responses, and inhibits protein-protein interactions attached via a -ketoester carbanion branched octanoic acid chain two tricyclic guanidine derivatives was disconnected to give a guanidine hemiaminal and a chiral alcohol in the sidechain, which could be substituted stereoselectively from a 1,3-diamine and Cbzprotected carbonimidothioate Cohen, F. et al., J. Am. Chem. Soc. 2001, 123,

11 A triazacyclophane Tripodal Receptor Molecules (as hinge) Deprotection -NBS (thiolysis) Aloc(Pd-catalyzed alkyl transfer to anilinium p-toluenesulfinate) i) triflate +methanol ii) Fmoc-N-hydroxysuccinimide Acetylation with alkyl chloroformate selectively sulfonated and trifluoroacetylated patz, T. et al. J. Comb. Chem. 2002, 4,

12 3. Tandem Reactions Tandem reactions form several covalent bonds in one sequence without isolating the intermediates. Also called domino or cascade reactions "Multistep reaction'' or "one-pot sequence (descriptions of the procedure) The ACS search program produces: 507 tandem, 115 cascade and 34 domino titles published since tandem, 576 cascade and 297 domino titles published since

13 Some sterically hindered, SnCl 4 -catalyzed hetero-diels-alder cyclizations of -unsaturated ketoesters with alkene alcohols do not occur intramolecularly. Large substituents on the ketoester prevent the formation of medium-sized rings and the first reaction is a linear dimerization combined with the formation of one dihydropyran unit. The second reaction then gives a second dihydropyran and produces a macrocyclic oligo-ether with good yield. 13

14 Chain extension-aldol addition tandem Acetylacetate reacts with zinc methylene iodide (Furukawa reagent) zinc enolate add its methylene group to the enolate's double bond Aldehydes then decompose the cyclopropane formed and undergo a Reformatsky addition. 14

15 three-step reaction a cyclohexanone derivative underwent zinc enolate formation and Michael addition in one step Acetals were then reactive enough to decompose the enolate and form a second CC bond stereoselectively the presence of chiral phosphines 15

16 The synthesis of a highly functional arene derivative coupling of a cyanide Michael addition to propargylic acid Dieckmann cyclization with a neighboring benzyl ester 16

17 4. Green Chemistry There are U.S. and European Green Chemistry Programs, which try to establish environmentally benign synthetic procedures. Energy requirements, waste, and the number of separation steps are all minimized by increased selectivity of the reactions catalyzed. Heck-, Sharpless- and Noyori-type reactions are successful endeavors. Another approach is to replace solvents by water or by supercritical fluids, in particular C 2. C 2 can replace chlorinated solvents. Replacement of soluble Lewis acids by mesoporous solids containing bound sulfonates or aluminum chloride should also become common practice. The solids can be filtered off and usually reactivated and recycled. This helps to prevent waste. 17

18 most typical for green chemistry, educts should preferably come from renewable sources, in particular glucose Furthermore syntheses should be atom-efficient, and reagents as simple as possible. Catalysed reactions are preferable. 18

19 Household and large-scale industrial chemicals, e.g. chelators, should always be biodegradable, as should the intermediates in their synthesis. Boger's iminodiacetic acids are good examples, because they only use succinic acid derivatives 19

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21 The Sonogashira Coupling The coupling of terminal alkynes with vinyl or aryl halides via palladium catalysis was first reported independently and simultaneously by the groups of Cassar [16] and Heck [17] in A few months later, Sonogashira and co-workers demonstrated that, in many cases, this crosscoupling reaction could be accelerated by the addition of cocatalytic CuI salts to the reaction mixture. [18,19] This protocol, which has become known as the Sonogashira reaction, can be viewed as both an alkyne version of the Heck reaction and an application of palladium catalysis to the venerable Stephens Castro reaction (the coupling of vinyl or aryl halides with stoichiometric amounts of copper(i) acetylides). [20] Interestingly, the utility of the copperfree Sonogashira protocol (i.e. the original Cassar Heck version of this reaction) has subsequently been rediscovered independently by a number of other researchers in recent years. [21] R 2 cat. [Pd 0 L n ] R 1 H X R 2 base R 2 R 1 = alkyl, aryl, vinyl R 2 = alkyl, benzyl, vinyl X = Br, Cl, I, Tf 16. L. Cassar, J. rganomet. Chem. 1975, 93, H. A. Dieck, F. R. Heck, J. rganomet. Chem. 1975, 93, K. Sonogashira, Y. Tohda, N. Hagihara, Tetrahedron Lett. 1975, 16, For a brief historical overview of the development of the Sonogashira reaction, see: K. Sonogashira, J. rganomet. Chem. 2002, 653, R. D. Stephens, C. E. Castro, J. rg. Chem. 1963, 28, a) M. Alami, F. Ferri, G. Linstrumelle, Tetrahedron Lett. 1993, 34, ; b) J.-P. Genet, E. Blart, M. Savignac, Synlett 1992, ; c) C. Xu, E. Negishi, Tetrahedron Lett. 1999, 40, ;

22 chanism of the Sonogashira Coupling Ph 3 P Ph 3 P Pd R 1 Pd 0 Ph 3 P PPh 3 Pd Ph 3 P PPh 3 Pd II R 1 - PPh 3 Ph 3 P Pd R 1 Pd II PPh 3 Ph 3 P Ph 3 P Pd Pd 0 - PPh 3 Pd 0 Ph 3 P Pd Ph 3 P PPh 3 H NEt 3 R 1 CuBr R 1 Cu R 1 Ph 3 P Pd Br PPh 3 Pd II Br NEt 3 H

23 The Sonogashira Coupling: Eicosanoid 212 Br TBS 206 [Pd(PPh 3 ) 4 ] (4 mol%) CuI (16 mol%) n PrNH 2, C 6 H 6, 25 C R 207 TMS Sonogashira Coupling AgN 3, KCN TBS 208: R = TMS 209: R = H Br TBS 210 C 2 210, [Pd(PPh 3 ) 4 ] (4 mol%) CuI (16 mol%) n PrNH 2, C 6 H 6, 25 C 76% verall from 208 Sonogashira Coupling H TBS C 2 H C 2 H TBS K. C. Nicolaou, S. E. Webber, J. Am. Chem. Soc. 1984, 106,

24 The Sonogashira Coupling: Disorazole C 1 PMB R H 218 [Pd(PPh 3 ) 2 Cl 2 ] (4 mol%) CuI (30 mol%), Et 3 N CN, -20 C, 94% Sonogashira Coupling PMB H N N C 2 220, DCC, DMAP 80% PMB N I 221 N C 2 218: R = 220: R = H I disorazole 218 [Pd(PPh 3 ) 2 Cl 2 ] (5 mol%) CuI (20 mol%), Et 3 N CN, -20 C, 94% Sonogashira Coupling N N H PMB H H PMB C 2 N N 223: Disorazole C P. Wipf, T. H. Graham, J. Am. Chem. Soc. 2004, 126,

25 The Sonogashira Coupling: Dynemicin 2 CN Br [Pd(PPh 3 ) 4 ] (2 mol%) CuI (20 mol%) toluene, 25 C Intramolecular Sonogashira Coupling 2 CN Diels- Alder H 2 CN H H H CN 246 H 247 1) Br C 2 [Pd(PPh 3 ) 4 ] (2 mol %) CuI (20 mol %) toluene, 25 C 2) LiH, THF/H 2 65% overall Sonogashira Coupling 2 CN 2,4,6-Cl 3 C 2 H 2 CCl DMAP, toluene, 25 C 50% a) J. Taunton, J. L. Wood, S. L. Schreiber, J. Am. Chem. Soc. 1993, 115, H C 2 H Yamaguchi Macrolactonisation/ Diels-Alder dynemicin HN H C 2 b) J. L. Wood, J. A. Porco, Jr., J. Taunton, A. Y. Lee, J. Clardy, S. L. Schreiber, J. Am. Chem. Soc. 249: tri-- methyl dynemicin A 1992, 114, methyl ester c) H. Chikashita, J. A. Porco, Jr., T. J. Stout, J. Clardy, S. L. Schreiber, J. rg. Chem. 1991, 56, d) J. A. Porco, Jr., F. J. Schoenen, T. J. Stout, J. Clardy, S. L. Schreiber, J. Am. Chem. Soc. 1990, 112,