Chapter 22 Reactions of Carbohydrate Derivatives With Titanocene(III) Chloride

Transcription

1 Chapter 22 Reactions of Carbohydrate Derivatives With Titanocene(III) Chloride I. Introduction II. Reactions A. Halogen-Atom Abstraction Glycal Formation Replacement of a Halogen Atom with a Hydrogen Atom Addition Reactions Cyclization Reactions B. Glycosyl 2-Pyridyl Sulfone Reaction C. Ring pening of Epoxides D. Pinacol Formation III. Electron Donation by a Ruthenium Complex IV. Summary V. References I. Introduction Titanocene(III) chloride [, bis(cyclopentadienyl)titanium(iii) chloride] is an oxygen-sensitive compound that is prepared by reaction of 2 with metals such as zinc, aluminum, or manganese. exists as a dimer in the solid state, but coordinating solvents (e.g., tetrahydrofuran) dissociate the dimer into a reactive monomer (eq 1). 1,2 (Although the monomer is coordinated with a solvent molecule, it usually is represented simply as ; more generally, can be looked upon as representing all the Ti(III) species present in a solution of titanocene(iii) chloride. 1 3 ) Ti Ti + 2 Ti ( 1 ) = II. Reactions Three types of carbohydrate derivatives form carbon-centered radicals upon reaction with. Halogen-atom abstraction from glycosyl halides produces furanos-1-yl and pyranos-1-yl

2 504 Chapter 22 radicals. 1,4 11 Radicals also can be generated by abstractive ring opening of epoxides Finally, produces pyranos-1-yl radicals when it reacts with glycosyl 2-pyridyl sulfones. 7 An example of the first type of reaction is found in eq 2, 5,6 one of the second type in eq 3, 16 and one of the third in eq 4. 7 These radical-forming reactions have the attractive, chemoselective feature that does not affect acetal, ester, or silyl ether protection. 5,6 C 6 H 5 Ac Br Ac - Br C 6 H 5 Ac Ac ( 2 ) BnCH 2 BnCH 2 Bn + Bn ( 3 ) Bn 1 Bn BnCH 2 BnCH 2 Ac Ac Bn + Bn + (S 2 R) ( 4 ) Bn S 2 R Bn R = A. Halogen-Atom Abstraction Since halogen-atom abstraction by requires a substrate with a reactive carbon halogen bond, glycosyl bromides are natural starting materials for this type of reaction (eq 2). The radical formed by abstraction from such a compound typically combines with a second molecule of to produce an organotitanium compound. If a hydrogen-atom donor or an unsaturated compound is present in a reaction mixture, radical combination with will be in competition with hydrogen-atom abstraction or addition to a multiple bond (Scheme 1). 1. Glycal Formation If a pyranos-1-yl radical is formed by halogen-atom abstraction by, the products from combination of this radical with a second molecule of are a pair of glycosyltitanium anomers. The most likely fate for these anomers is an elimination reaction that produces a glycal (Scheme 2). 6 Such elimination depends upon the presence of a leaving group (e.g., Ac) attached

3 Reactions of Carbohydrate Derivatives With Titanocene(III) Chloride 505 to C-2. Since the D-gluco- and D-mannopyranosyl halides 2 and 3 each give good glycal yields (Scheme 2), C-2 stereochemistry is not critical in the elimination process. For elimination to produce high glycal yields either the intermediate glycosyltitanium anomers 5α and 5β must be capable of both syn and anti elimination, or if only anti elimination takes place, 5α and 5β must be able to interconvert (Scheme 2). Scheme 1 Br Ac = - 2 TiBr Ac SH S CH 2 =CHZ, SH, - S Ac Z = an electronwithdrawing group SH = a hydrogen donor (e.g., THF) H H Ac Ac Z Scheme 2 CH 2 Ac CH 2 Ac CH 2 Ac Ac Ac R 1 Br - 2 TiBr Ac Ac R 1 Ac Ac R 1 R 2 2 R 1 = H, R 2 = Ac 3 R 1 = Ac, R 2 = H 4 R 2? 5 R 2 - (Ac) Ac CH 2 Ac Ac R 1 - (Ac) Ac CH 2 Ac Ac 5 R 2 82% (from 2) 94% (from 3) In the absence of a C-2 substituent no elimination takes place when a pyranos-1-yl radical forms by reaction of a glycosyl halide with ; instead, an anomeric mixture of glycosyl-

4 506 Chapter 22 titanium compounds is produced (eq 5). 6,9 The formation of these compounds and the failure of this reaction (eq 5) to generate a glycal has mechanistic significance because the existence of these titanium compounds supports the idea that glycosyltitanium intermediates (e.g., 5α and 5β) are produced during glycal formation when a reactive, C-2 substituent is present. Ac Br + Ac C 2 6 H TiBr ( 5 ) Ac Ac In most instances of glycal formation involving, the C-2 substituent is an acetoxy group, but elimination also occurs in high yield when a less effective leaving group (a hydroxyl, trimethylsilyloxy, benzyloxy, or methoxy group) is attached to C-2. 6 A substituent at C-3 can have a role in the reaction of a furanosyl halide because once elimination of the group at C-2 has occurred, a C-3 substituent also can depart to produce a furan derivative (eq 6). 6 AcCH 2 Br THF AcCH 2 ( 6 ) Ac Ac Modification of the original procedure for halogen-atom abstraction by simplifies the conduct of this reaction by eliminating the necessity for the special (glove-box) techniques used for the preparation and handling of an oxygen-sensitive compound. 7 In the modified procedure is generated in situ by reduction of the oxygen-insensitive 2 with manganese; thus, normal laboratory procedures for running a reaction in an inert atmosphere can be followed. Since manganese is the stoichiometric reactant, it is possible to conduct this reaction with as little as 30 mol% of. 8 Ac CH 2 Ac Br Ac Ac 2 TiBH 4 THF Ac CH 2 Ac H Ac H Ac 100% ( 7 ) 2. Replacement of a Halogen Atom with a Hydrogen Atom When glycosyl halides react with titanocene(iii) chloride, the radicals produced can abstract hydrogen atoms from a solvent such at THF. As pictured in Scheme 1, this reaction is in compe-

5 Reactions of Carbohydrate Derivatives With Titanocene(III) Chloride 507 tition with radical capture by a second molecule of. If glycal formation is desired, reaction is run with an excess of. 9 If hydrogen-atom abstraction is the reaction goal, a different titanocene(iii) reagent is a better choice. Hydrogen-atom abstraction by a pyranos-1-yl radical completely replaces combination with a titanocene(iii) reagent when 2 TiBH 4 replaces in the reaction mixture. 2 TiBH 4 not only is able to abstract halogen atoms, but it also serves as an effective hydrogen-atom donor (eq 7). 4 CH 2 Ac Scheme 3 Ac Ac Br - 2 TiBr CH 2 =CHC 2 Me CH 2 CHC 2 Me Ac Ac Ac CH 2 Ac Ac Ac CH 2 CH 2 CMe H 2 - H CH 2 CH C Ac Ac Me Ac Br Ac 1) CH 2 =CHC 2) H 2 Ac CH 2 CH 2 C Ac ( 8 ) Ac 1) CH 2 =CHC 2) H 2 Ac H H ( 9 ) Ac Ac 6 3. Addition Reactions Characteristic addition of a nucleophilic radical to a compound with an electron-deficient double bond takes place when halogen-atom abstraction by occurs in the presence of methyl acrylate (Scheme 3). 10 A similar reaction, one in which a pyranos-1-yl radical adds to acrylonitrile, is shown in eq 8.The possibility that the species adding to the double bond in this reaction (eq 8) actually is an intermediate organotitanium compound is rendered unlikely by the failure of the titanocene derivative 6 to add to acrylonitrile (eq 9). 10

6 508 Chapter 22 Scheme 4 + h RI 2 Ti 2 Ti + R I R I ring formation I H C 2 t-bu THF 7 + H CH 2 C 2 t-bu ( 10 ) CMe 2 CMe 2 7 no irradation irradition 99% 1% 25% 49% 4. Cyclization Reactions A modification of the typical conditions for halogen-atom abstraction allows reaction of otherwise unreactive halides to take place. Subjecting the primary iodide 7 to under normal reaction conditions does not cause halogen-atom abstraction (eq 10), but irradiation of this reaction mixture with visible and UV light ( nm) produces a radical (Scheme 4) that then undergoes ring formation (eq 10). 20 The reaction shown in eq 10 also occurs when the iodide 7 reacts with either SmI 2 or Bu 3 SnH, but photolysis in the presence of has the advantage of using a relatively inexpensive, nontoxic reagent. 20 BnCH 2 BnCH 2 Ac Bn Bn X THF, rt Bn Bn ( 11 ) 10 8 X = Br 87% 9 X = S 2 70% B. Glycosyl 2-Pyridyl Sulfone Reaction Formation of the D-glucal 10 occurs when either the glycosyl bromide 8 or the glycosyl 2-pyridyl sulfone 9 reacts with (eq 11). 7 Presumably, both the sulfone and the bromide are

7 Reactions of Carbohydrate Derivatives With Titanocene(III) Chloride 509 forming pyranos-1-yl radicals by electron transfer that leads to loss of the C-1 substituent. Capture of the radical in each case by and then an elimination reaction from the resulting organotitanium compound produces the final product (10). Scheme 5 uc 11 - () 2 uc unlikely radical reactions Scheme 6 Ti Ti 2 Ti Ti C. Ring pening of Epoxides Titanocene(III) chloride opens the three-membered ring in an epoxide to generate a carbon-centered radical (11) that undergoes characteristic radical reactions (Scheme 5) The usefulness of is these reactions depends on several reactivity characteristics The first of these is the relatively low Lewis acidity of, a factor that favors radical reaction but not nucleophilic (two-electron) ring opening. This low acidity also is helpful in preventing decomposition of acid-sensitive reaction products. 22 A second reactivity characteristic of is that it is an effective agent for transferring an electron to a three-membered ring containing an oxygen atom. Also, combination of with a ring-open radical such as 11 is sufficiently slow that 11 can exist long enough in solution to undergo radical reactions such as hydrogen-atom abstraction and ring formation. The half-open dimer 12 (Scheme 6) has been proposed to participate in reaction by binding with the epoxide oxygen atom. 24,25 Radical intermediates produced by abstractive ring opening by have reaction pathways available that are similar to those created when abstracts a halogen atom from a glycosyl halide; thus, radicals 13 and 14 (Scheme 7) either can react with a second molecule of

8 510 Chapter 22 or undergo a radical reaction such as hydrogen-atom abstraction. 13 If radical capture by is the planned result, having an excess of this reagent in the reaction mixture is helpful. If the goal of a reaction is ring opening to be followed by hydrogen-atom abstraction, then adding a hydrogen-atom donor and maintaining a low concentration of will minimize radical capture by the titanocene reagent (Scheme 7). (As mentioned in discussing reactions of glycosyl halides, if hydrogen-atom abstraction is desired, one possibility is to replace with 2 TiBH 4. 4 ) Scheme 7 Ar Ar added hydrogen donor (SH) Me H H 12% (after workup) 65% Me Ar Ar = C 6 H 5 Me excess SH - S SH - S Me Me Me Me - () 2 - Me Ar Ar Me H 78% (after workup) 16%

9 Reactions of Carbohydrate Derivatives With Titanocene(III) Chloride 511 Another possibility for promoting hydrogen-atom abstraction by radicals formed in the presence of is to add water to the reaction mixture. The resulting complex is reported to be an effective hydrogen-atom donor that significantly increases hydrogen-atom transfer to carbon-centered radicals produced by epoxide ring opening. 26 Scheme 8 BnCH 2 Bn Bn 1 16 BnCH 2 Bn 15 Bn H CH 2 =CHC H 2 - H CH 2 CH 2 C CH 2 CHC CH 2 CHC 1) 2 Zr 2) H 3 CH H H + H H ( 12 ) 45% 6% Ring opening of the 1,2-anhydrohexopyranose 1 by and addition of the resulting radical to acrylonitrile occurs in a regiospecific and highly stereoselective fashion (Scheme 8). 16 Regioselectivity in the first step in this reaction is determined by ring opening that produces the more stable radical 15 rather than the less stable radical 16. Stereoselective reaction of 15 with acrylonitrile can be explained by the kinetic anomeric effect; that is, electrons in the p-type orbitals on C-1 and the ring oxygen atom maintain a stabilizing interaction when approach to the double bond is from the α face of the ring (Scheme 9). (An assumption in this explanation is that the

10 512 Chapter 22 conformation of 15 resembles that of the known conformation of the 2,3,4,6-tetra--acetyl-D-glucopyranos-1-yl radical ) Scheme 9 Bn C CH 2 Bn Bn 2 Ti 15 C C Ac CH 2 Ac Ac Ac 17 -face reaction -face reaction C C transition states 2 Ti C C C effective orbital interaction not maintained effective orbital interaction maintained -face addition not favored -face addition favored D. Pinacol Formation Titanocene(III) chloride reacts with aromatic aldehydes to produce pinacols, but reaction of aliphatic aldehydes with fails to form these compounds. The more reactive 2 Zr does produce pinacols from nonaromatic aldehydes, as is evidenced by the reaction shown in eq 12, 28 where 1,2-di--isopropylidene-D-glyceraldehyde is converted into a mixture of protected D-mannitol (18) and D-iditol (19) derivatives. III. Electron Donation by a Ruthenium Complex Ruthenium is a transition metal that, like titanium, can transfer an electron to a glycosyl halide. Photochemical reaction of [Ru(bpy) 3 ] 2+ with a tertiary amine produces [Ru(bpy) 3 ] +, a complex that then donates an electron to a glycosyl bromide to form a pyranos-1-yl radical (Scheme 10). 29,30 The radical formed in this way from the bromide 20 is capable of adding to a

11 Reactions of Carbohydrate Derivatives With Titanocene(III) Chloride 513 variety of electron-deficient alkenes (eq 13). The role of the additive in this reaction is to improve product yield by suppressing oligmerization. 29 Scheme 10 [Ru(bpy) 3 ] 2+ h [Ru(bpy) 3 ] 2+ * [Ru(bpy) 3 ] 2+ * + R 3 [Ru(bpy) 3 ] + + R 3 + [Ru(bpy) 3 ] + + RBr [Ru(bpy) 3 ] 2+ + R + Br - bpy = R = a pyranos-1-yl radical Ac CH 2 Ac Ac Br Ac + R h i-pr 2 Et [Ru(bpy) 3 ](BF 4 ) 2 additive CH 2 2 Ac CH 2 Ac Ac Ac R ( 13 ) R = C 2 Me, CMe, CH, C Et 2 C H H C 2 Et bpy = additive = Me H Me IV. Summary Titanocene(III) chloride reacts with glycosyl halides and with epoxides to generate carbon-centered radicals. The primary reaction of these radicals is combination with another molecule of. These radicals also can abstract hydrogen atoms from the solvent or other hydrogen-atom donors in the reaction mixture or undergo radical addition and cyclization reactions. If a radical combines with a second molecule of titanocene(iii) chloride, the resulting organotitanium compound typically undergoes a β-elimination reaction. The result of such a reaction usually is formation of a glycal. V. References 1. Spencer, R. P.; Schwartz, J. Tetrahedron 2000, 56, 2103.

12 514 Chapter Enemærke, R. J.; Larsen, J.; Skrydstrup, T.; Daasbjerg, K. J. Am. Chem. Soc. 2004, 126, Enemærke, R. J.; Larsen, J.; Hjøllund, G. H.;Skrydstrup, T.; Daasbjerg, K. rganometallics. 2005, 24, Cavallaro, C. L.; Schwartz, J. J. rg. Chem. 1996, 61, Spencer, R. P.; Schwartz, J. Tetrahedron Lett. 1996, 37, Spencer, R. P. Cavallaro, C. L.; Schwartz, J. J. rg. Chem. 1999, 64, Hansen, T.; Krintel, S. L.; Daasbjerg, K.; Skrydstrup, T. Tetrahedron Lett. 1999, 40, Hansen, T.; Daasbjerg, K.; Skrydstrup, T. Tetrahedron Lett. 2000, 41, Cavallaro, C. L.; Schwartz, J. J. rg. Chem. 1995, 60, Spencer, R. P.; Schwartz, J. J. rg. Chem. 1997, 62, a) Xu, X.; Tan, Q.; Hayashi, M. Synthesis 2008, 770; b) Abel, M.; Segade, A.; Planas, A. Tetrahedron Asymmetry 2009, 20, RajanBabu, T. V.; ugent, W. A. J. Am. Chem. Soc. 1989, 111, RajanBabu, T. V.; ugent, W. A. J. Am. Chem. Soc. 1994, 116, RajanBabu, T. V.; ugent, W. A.; Beattie, M. S. J. Am. Chem. Soc. 1990, 112, Dötz, K. H.; Gomes da Silva, E. Tetrahedron 2000, 56, Parrish, J. D.; Little, R. D. rg. Lett. 2002, 4, Chakraborty, T. K.; Das, S. Tetrahedron Lett. 2002, 43, ishiguchi, G. A.; Little, R. D. J. rg. Chem. 2005, 70, Barrero, A. F.; Quílez del Moral, J. F.; Sánchez, E. M.; Arteaga, J. F. Eur. J. rg. Chem. 2006, Hersant, G.; Ferjani, M. B. S.; Bennett, S. M. Tetrahedron Lett. 2004, 45, Gansäuer, A.; Rinker, B. Tetrahedron 2002, 58, Gansäuer, A.; Bluhm, H. Chem. Rev. 2000, 100, Gansäuer, A.; Lauterbach, T.; arayan, S. Angew. Chem. Int. Ed. 2003, 42, Daasbjerg, K.; Svith, H.; Grimme, S.; Gerenkamp, M.; Müch-Lichtenfeld, C.; Gansäuer, A.; Barchuk, A.; Keller, F. Angew. Chem. Int. Ed. 2006, 45, Gansäuer, A.; Barchuk, A.; Keller, F.; Schmitt, M.; Grimme, S.; Gerenkamp, M.; Müch-Lichtenfeld, C.; Daasbjerg, K.; Svith, H. J. Am. Chem. Soc. 2007, 129, Cuerva. J. M.; Campaña, A. G.; Justicia, J.; Rosales, A.; ller-lópez, J. L.; Robles, R.; Cárdenas, D. J.; Buñuel, E.; ltra, J. E. Angew. Chem. Int. Ed. 2006, 45, Dupuis, J.; Giese, B.; Rüegge, D.; Fischer, H.; Korth, H.-G.; Sustmann, R. Angew. Chem. Int. Ed. Engl. 1984, 23, Barden, M. C.; Schwartz, J. J. rg. Chem. 1997, 62, Andrews, R. S.; Becker, J. J.; Gagné, M. R. Angew. Chem. Int. Ed. 2010, 49, Andrews, R. S.; Becker, J. J.; Gagné, M. R. rg. Lett. 2011, 13, 2406.