Thesis (B.S.) in Chemistry -- University of Illinois at Urbana-Champaign, 1990.Includes bibliographical references (leaves 18-19)Microfiche of typescript. [Urbana, Ill.]: Photographic Services, University of Illinois, U of I Library, [1990]. 1 microfiche (24 frames): negative.s 1990 ilu n 

Bostrom, Lori L.

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' TV 4 —* ...... '■ " " /■  7 .........:..........,> -*  /  i f  5  > /  -i*" ‘J V  F 4 Vv- V  * -  *-■»,►*>*V*** • *".*'»«**»# »«*« 4 » * 4 «• 4 4 •« S * * *,.* rt *•»#••»■ *•■¥ t ► * ■» * > '#..» V» i K.»-*.V. I '*** ■"Instructor in Charge« » » i » 4 » e 4 k 4 4 i i M «  .HEAD OF DEPARTMENT OF.....UtoMJ.ftS..U.... »■■* *« *•♦•*• *#.»■* *.«»* #*»«* «-»•* *i|itl>< *♦*•#*'*•*(#&El: -%: ' iv£~ -L o-ijw.. > 4 .-1- ^  y . m iu jrs i' , 1 ' *5*. « iMolecular Tweezers and Chiral Reagents: Synthesis of Novel Disubstituted5,6,8,9-Tetrahydrodlbenz[«J]anthracenesByl.ori L. BostromThesis for theDegree of Bachelor of Science inChemistryCollege of Liberal Arts and Sciences University of Illinois Urbana, Illinois1990Table of ContentsIntroduction IResults und Discussion 4Experimental *Figures & Schemes I 2References 18IntroductionRigid molecular spacers have found widespread utility in bioorganic chemistry. They have proved useful in such diverse areas as polymer chemistry,> porphyrin2* and crown ether linkage,2*1 and in the creation of a variety of rigid molecular clefts.5 Zim m erm an and coworkers have described the use of the rigid dibenzacridinc and dibenzanthracenc spacers to form the basis of molecules known as "molecular tweezers.”4’fi When these spacers are substituted atC*2 and C*I2 with two aromatic chromophores, they are capable of1110Figure 1: Numbering Scheme tor dibenzanthracenecomplcxing small aromatic guest molecules in a double tt-stacking interaction described as a Jt-sandwich.4 The rigidity of the spacer and the position of the chromophores can greatly enhance the n- sandwich interaction by forcing the chromophores to maintain a syn cofacial orientation with a separation of ca. 7 A.5 Zimmerman andWu have discovered that guest complexation can be improved1further by introducing « carboxylic acid functional group into the host cleft to provide hydrogen bonding interactions.7 In this paper, the synthesis of a new molecular tweezer 13b is described, which is one of a series of four tweezers (see Figure 2) designed to investigate the importance of interchromophore distance in determining the host-guest binding constant. The four spacers have C-2 to (M2 distances ranging from 7.52A for tweezer 19 to 8.2()A for tweezer 17.6'* All four will be substituted with identical mcthylanthraccnc chrotnophores. Thus, any discrepancies in the binding constants should be due to the spacing of the chrotnophores.As a precedent to a second project, X-ray crystallography has revealed that the presence of an ester functionality at C-14 in the cleft of the dibenzanthracene spacer induces the aromatic system to twist 43° from end to end.6 It was proposed that the inherent chiral nature of the helical twist could be further enhanced by the substitution of bulky groups at C-2 and C-12. This would provide a greater barrier to interconversion of the right- and left-handed helices in solution. It was also proposed that, if the bulky groups were themselves chiral, the resulting molecular cavity would provide an environment capable of inducing chirality on other small molecules. Replacement of the ester functionality in the cleft of the molecule with an acid or a peroxyacid would facilitate the possibility of performing asymmetric protonations or epoxidations on small molecules entering the cleft. Structures la  and lb  (see Scheme 2) were proposed as possible protonation and epoxidizing reagents,3respectively, and progress towards the synthesis of these molecules is presented in this paper.As a third and final project, molecular tweezer 16 (Figure 3) was proposed which would be capable of forming both a x-sandwich and as many as four hydrogen bonds with guest molecules. Previous studies have shown that the presence of two hydrogen bonding interactions greatly enhances the binding constant of small molecules with the Zimmerman tweezer.7 It was thus expected that additional hydrogen bonding interactions should enhance binding to an even greater degree. Thus, the synthesis of tweezer 16 was pursued.Results and DiscussionThe synthesis of di benzanthracene spacer 7a followed previous work in our laboratory (Scheme 1). Bromotetralone 4 was synthesized as previously described.9 Bromobenzene was reacted with with succinic anhydride to form the phenylketobutyric acid 2 . Wolff-Kishner reduction of the ketone followed by cyclization with polyphosphoric acid yielded 7-bromotetralone 4 in overall 43% yield from succinic anhydride. Aldol condensation of 4 with benzaldehyde yielded the corresponding benzylidine 5 in 78% yield.10 Tetralone 4 and benzylidine 5 were coupled in B FvEtjO  to give the crude pyrylium salt 6 ,10 which was then condensed with irinicthyl- phosphonoacetate to produce the desired spacer 7a in 25% overall yield from bromotetralone.1 1At this point it was necessary to effect the substitution of the dibromide 7a at C-2 and C-12. Previously, substitutions involving related spacers were carried out according to Scheme 3.5 According to this method, the acridine chromophores were added to the ketal- protected bromotetralone 9 before conversion to the benzylidine I I and coupling to form the pyrylium salt. This method involved several steps and had the added disadvantage of requiring a uniquely substituted tetralone for each desired tweezer. If the substitution could be effected simultaneously at both positions of the dibromide 7a, this would facilitate the use of Scheme I for the45large-scale synthesis of a common spacer, which could then be substituted with a variety of groups. Scheme 2 shows the procedure developed to effect the disubstitution, which proceeded in a similar overall yield to Scheme 3. Treatment of dibromide 7a with t-Bul.i*2 followed by a deuterium quench yielded the dideuterated spacer 7 b in 95% yield, evidence that the lithium-halogen exchange did proceed with high efficiency to yield the dianion. However, when either benzaldehyde or pivaldchyde was used to quench the dianion, the diadduct was obtained in only 37% and 60%> yield, respectively.Since it has already been shown that the dianion is formed nearlyquantitatively, it is likely that the lower yield of the aldehyde adducts was due to stcric interactions with the new carbon centers. Additional evidence to this effect is given by the fact that no starting material was recovered, and the monoprotio/monoadduct was isolated in both cases.At this point in the synthesis it was desirable to resolve themixture of stereoisomers of 8a and 8 b , before completing theconversion to the more reactive acid la  and peracid lb . Attempts at selective recrystallization of the stereoisomers were unsuccessful. Therefore, separation by chiral HPLC was investigated. Although no resolution was obtained for the benzaldehyde adduct 8 a , the pivaldehyde adduct did show some separation as the alpha-napthyl urethane derivative on a chiral Pirkle column. 12 However, the separation was not sufficient to warrant the cost of scale-up, and the6synthesis of the chiral acid and peracid reagents was ended at this point.The synthesis of tweezer 13a was accomplished by Grignard addition of methyl bromoanthracene to spacer 7a (Scheme 4 ).14 9- B rom o-10-m etnylanthracene was obtained from 9,10- dibromoanthracene by monoli'hiation with n-BuLi followed by addition of methyl iodide.14a The Grignard 12 was formed in the presence of magnesium metal with >2 and dibromoethane catalysts in refluxing ether. This was added to spacer 7a in the presence of Ni(acac)2 as catalyst.1411 The tweezer 13a was thus obtained in >50% yield. Conversion to the carboxylic acid with boron trichloride15 is currently in progress. After tweezer 13b is thus obtained, itsbinding constant with small aromatic guests will be determined and compared to the binding constants of tweezers 17 ,18, and 19.Synthesis of macrocyclic tweezer 16 began with the conversion of spacer 7a to the diamine IS (Scheme 5). Several methods for the conversion of aromatic bromides to aromatic amines have precedent in the literature. 16.17 Treatment of the dibromide with n-BuLifollowed by a methoxylamine/methyllithium quench16 yielded a complex mixture of products from which the amine could not be isolated. In a second attempt, the method of Shioiri et. al.,*7 was attempted. Scheme 3 shows the conversion of the dibromide 7a to the dicarboxylic acid 14 by formation of the dianion with n-BuLi and7quenching with CO j.18 Schmidt rearrangement of the diacid with diphenylphosphorylazide was expected to yield the diamine, 17 but once again the result was a complex mixture of products, A new method for this conversion is presently being sought. Once the diamine is obtained, it will be condensed with a variety of dianhydrides (Scheme 5) to yield the corresponding macrocyclcs shown in Figure 3. An appropriate guest molecule will be selected, which will be capable of interacting with the tweezer in four hydrogen bonding interactions and an aromatic n-stacking interaction. The binding constant of this molecule will then be compared with the binding constant of the Wu tweezer7 to determine the contribution of the new hydrogen bonds.ExperimentalMe t h y l  2 , 1 2 * d l d e u t e r o > 7 - p h e n y l - 5 , 6 , 8 , 9 - t e t r a h y d r o .  d iben /.[av/]anthracene-14*carboxylate(7b). A solution of 43.5mg (0.076 mmol) dibromide 7a in 1.0 mL THF under a dry N2 atmosphere was cooled to -65°C. t-BuLi (180 pL, 0.31 mmol) was added and stirred at -65°C for 5 minutes. The reaction was quenched with 300 |il. CH3OD and warmed slowly to room temperature. The reaction mixture was concentrated under reduced pressure, redissolved in CIICI3, and filtered through glass wool. The clear solution was then partitioned between CII2C I2 aid 50% saturated NaCI. The aqueous layer was washed once with CII2CI2, the organic layers were combined, and the solvent was removed under reduced pressure to yield 30.0 mg (94.7%) of 7b as a creamy white solid: mp >240°C; Ml NMR: (300 MHz. CDCI3) 8 7.47 (m, 511. H-2', II­S’, H-4', H-5', 11*6'), 7.22 (m, 6H, H-l, H-3. H-4, H-10. H-l I. 11-13), 3.80 (s. 3H, methyl ester), 2.68 (t. 4H. H-6, H-8), 2.47 (t. 4H, H-5. H- 9). MS (El, 70eV) mle 418.Met hy l  2 t l 2 * b l s ( l * h y d r o x y * l < p h e n y l me t h y l ) * 7 * p h e n y l *5,6,8,9 • tetrahydrodlbenz(flJ]anthracene • 14 • carboxylate(8a). To a solution of 50.0 mg (0.087 mmol) of dibromide 7a in 2.0 mL THF at *60°C under a dry N2 atmosphere was added 150 pL (0.23 mmol) n-BuLi. After stirring 30 minutes at -60°C the reaction89was quenched with 200 pL benzaldehyde and allowed to warm slowly to room temperature. The solvent was removed under reduced pressure, and the salts were removed by passing through a plug of silica eluted with EtOAc. The eluent was flash chromatographed (35% EtOAc/petroleum ether) to yield 20.0 mg (36.7%) of 8a as a white solid: 'H NMR: (300 MHz. CDCIj) 6 7.47-7.15(m. 22H. Il l, 11-3. 11-4. il-10. H-ll ,  H-13. H-2', H-3\ H-4', H-5', ll-6\  H-2", 11-3", 11-4". H-5", 11-6", H-2"'. H-3*". H-4"', H-5"', H-6 "), 5.80 (s.211, methine). 3.39 (d, 311, methyl ester), 2.64 (t, 411, H-6, H-8), 2.43 (t. 411, H-5, H-9), 2.31 (s, 2H, hydroxyl).Methyl  2,12-bis(  I - h y d r o x y -2,2-dimethyl  propyl  ) -7-phenyl -5,6,8,9 • tetrahydrodibenz[a,J]anthracene • 14 - carboxylate(8b). To a solution of 60.0 mg (0.104 mmol) dibromide 7a in 3.C mL THE at -54°C under a dry nitrogen atmosphere were added 200 pL (0.313 mmol) n-BuU. After stirring 70 minutes at -50°C, the reaction was quenched with 200 pL pivaldehyde and allowed to warm slowly to room temperature. The solvent was evaporated under reduced pressure, and the salts were removed by elution with EtOAc through a plug of silica. The eluent was flash chromatographed (15% EtOAc/petroleum ether followed by 25% EtOAc/petroleum ether) to provide 36.9 mg (60.1%) of 8b as a yellowish solid: mp >I70°C; >H NMR: (300 MHz, CDCI3) 8 7.42 (m, 511, H-2', H-3', H-4', H-5’, H-6 ), 7.18 (m. 6H, H-l, H-3, H-4, H-10, H-ll,  H- 13), 4.37 (s, 2H, methine), 3.87 (d, 3H, methyl ester), 2.65 (t, 4H, H-6,10H-8), 2.47 (t. 411, H-5, H-9), 1.87 (s, 2H, hydroxyU.Xl.93 (s, 1811, t-Bu). MS (El, 70eV) mle 588.Met hy l  2 , 1 2 - b i s [ 9 - ( 1 0 - m e t h y l a n t h r a c e n y l ) ] - 7 - p h e n y l -5,6,8,9 - tetrahydrodibenz[aly]anthracene • 14 • carboxylate(13a). F.I2O (25 mL) was added to 240 mg (0.89 mmol) 9-methyl- l()-bromoanthrucene, 417 mg (17.2 mmol) Mg metal, a Tew crystals I2. and 4 drops 1,2-dibromoethane under a dry N2 atmosphere, and the resultant slurry was heated to 65°C. After stirring 5.5 hours at 60-65°C, th** reaction mixture was cooled to 0°C and added via cannula to a cooled (0°C) solution of 100 mg (0.174 mmol) 7a and 7.0 mg Ni(acac)2 in 40 mL benzene. The resultant mixture was warmed to room temperature for I hour before heating to 65°C. The reaction was allowed to stir overnight (15 hours) before quenching with IN HCI. The reaction mixture was partitioned between CH2CI2 and 50% saturated Nal1CC>3. The aqueous layer was washed twice with CH2CI2. the combined organic layers were dried over MgS04 . and the solvent was removed under reduced pressure. The mixture was flash chromatographed (50% CH2Cl2/hexane) and recromatographed (20% C H 2C l2/hexane followed by 25% CH2C l2/hexane) to yield approximately 100 mg (95%) 13a as a yellow solid: mp >200°C; Ul NMR: (200 MHz, CDCIj) 8 8.31 (d. 2H, H-l, H-13), 7.62 (d. 2H, H-3, H- II), 7.55-7.13 (m, 23H, H-4, H-10, H-2\ H-3', H-4\ H-5', 11-6', H-l", H- 2", H-3", H-4", H-5", H-6", H-7", H-8", H-l ", H-2", H-3", H-4", H-5",H-6” , H-7” , 3.16 (s, 6H. methyl), 2.80 (m, 4H, H-6, H-8). 2.74(s, 3H, methyl ester). 2.66 (m. 4H. H-5, H-9). MS (El, 70eV) mle 797.M e t h y l  2 , 1 2 " C a r b o x y l *7- p h e n y l - 5 , 6 , 8 , 9 - t e t r a h y d r o -  d i b e n / . [ a j ] a n t h r a c e n e - l 4 - c a r b o x y l a t e {  14).  Dibromide 7 a (500 mg, 0.871 mmol) was dissolved in 15 mL TUI- under a dry nitrogen atmosphere and cooled to -76°C. n-BuLi ( 1.66 mL, 2.61 mmol) was added and the reaction was stirred at -76°C for I hour. Dry ice (2.0 g.) was added and the reaction was stirred overnight (17 hours) while warming to room temperature. After quenching with water, the reaction mixture was made basic with 2N NaOil and extracted twice with lit20 . The aqueous layer was acidified with 2N HCI and extracted twice with 10% i-PrOII/CUCl3 . The organic layers were combined and the solvent was removed to yield 402 mg (91.5%) pure 14 as a white powder: <H NMR (200 MHz. DMSO) 8 8.04 (s, 211. 11-1. 11-13), 7.83 (dd, 2H. H-3, H-ll).  7.47 (m. 411, 114, H-10. 11-2', 11-6’), 7.30 (d, 311, H-3’, H-4', H-5’). 3.76 (s, .311, methyl ester). 2.70 (t, 411, H-6, H-8). 2.43 («, 411, H-5, H-9).1 1Figures and SchemesFigure 213FiquraS16a: FU — n16b 16cScheme 1A1CI3100C90%H2NNH2diethylene gtycoi KO H/ 140°C 57%43% from P  succinic anhydride4KOH / M eO H__PhCHO / 50 C 78%4 * 5 n ac48%N aH /T H F50%Scheme 215t BuLi / CH3OD r7 » : R *B r ■65 c  *7 b : R *D . 95%la : R '-H  1b: R‘*O HSchema-316Schem al1} rvBuU i  benzene / 65 C 2) Mel / THFVSchemas14 . 92%D2) sster hydrolyaiiReferences1 . Feldman, K. S.; Lee, Y. B. J. Am. Chem. Soc. 1987, 109, 5850.2. (a) Fillers, J P.; Ravichandran, K. G.; Abalmuhdi, I.; Tulinksy, A.; Chang, C. K. J. Am. Chem. Soc. 1986, 108, 417. (b) Johnson. M. R.; Sutherland, I. O.; Newton, R. F. J. Chem. Soc., Chem. Common. 1979,  309. Kotzyba-Hilbcrt, F.; Lehn, J. M.; Vierling, P. Tetrahedron Letters 1980, 941.3. Rebek, J., Jr. Science 1987,235, 1478.4. Zimmerman, S. C ; VanZyl, C. M.; Hamilton, G. S. ./. Am. Chem. Soc. 1 9 8 9 , / / / ,  1373.5. Zimmerman, S. C.; VanZyl, C. M. J. Am. Chem. Soc. 1987, 109, 7894.6. Zimmerman, S. C. Tetrahedron Letters 1988, 983.7. Zimmerman, S. C.; Wu. W. J. Am. Chem. Soc. 1989, l i t ,  8054.8. No data has yet been obtained for structures 13b and 18. Work is in progress.9. Newman, M. S.; Seshardi, S. J. Org. Chem. 1962,27, 76. Fieser, L. F.; Seligman, A. M. J. Am. Chem. Soc. 1938,60, 170.10 . Katritzky, A. R.; Thind, S. S. J. Chem. Soc., Perkin Trans. 1980, / ,  1895.11. Griffin, D. A.; Staunton, J. J. Chem. Soc., Chem. Commun. 1975, 675.1812. Modification of a procedure developed by Lehmstcdt. See Lehmstedt, K.; Dostal, F. Chem. Ber. 1939, 72, 804.13. Separations run by Andy Burke. Column = JFM 001 #501;eluted in methanol at 2 mL/min; detected at 254 nm.14. (a) Reaction conditions adapted from Trepka, W. J.; Sonnenfcld,R. J. J. Organometal. Chem. 1969, 16, 317. (b) Ibuki, K.; O/.asa, O.; Fujioka, Y.; Yanagihara, Y. J. Chem. Pharm. Bull. 1982,30, 802.15. Marchand, P. S. Chem. Comm. 1971, 667.16. Beak. P.; Kokko, B. J. J Org. Chem. 1982.47, 2823.17. Shioiri, T.; Ninomiya. K.; Yamada. S. J Am. Chem. Snc. 1972,94, 6203. Baumgarten, H. F..; Staklis, A. J Am. Chem. Soc.1965, 87, 1141.18. Organic Synthesis Vol. Ill 1955, p. 413, 553.

Molecular tweezers and chiral reagents: Synthesis of noval disubsituted 5,6,8,9-tetrahydrodibenz[a,j]anthracenes

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Molecular tweezers and chiral reagents: Synthesis of noval disubsituted 5,6,8,9-tetrahydrodibenz[a,j]anthracenes

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