Alpha fluorinated aromatic ketone as nucleophile in asymmetric organocatalytic c n and c c bonds formation reactions 2

Chapter Chapter Enantioselective H/D exchange reaction catalyzed by chiral bicyclic guanidine 27 Enantioselective H/D exchange reaction 2.1 Introduction Hydrogen/deuterium (H/D) exchange between organic compounds and deuterium sources is very important for a wide range of applications such as protein dynamics, labeled drugs and mechanistic studies of organic reactions. Recently, there are only scattered reports of organic base-mediated H/D exchange reactions. The initial experiment was established by Drueckhammer and his coworkers1 in 1998. The H/D exchange reaction was performed between various -substituted propionate ethyl thioesters 75 and CD3OD catalyzed by triethylamine in toluene-d8. The -thio derivatives (X = PhS, PhCH2S), as well as the halo and azido compounds showed half-lives for H/D exchange of a few hours while the -aryl compounds showed half-lives of 2.5 days or more. These studies were used for further understanding of the utility of thioesters as substrates in enzymatic dynamic resolution procedures (Scheme 2.1). O O X SEt CH3 + CD3OD Et3N (0.5 equiv.) toluene-d 75 X = PhS, PhCH2S, halogen,N3,Ar X SEt + CD3OH D CH3 75-d t 1/2 (h): 1.3-108 Scheme 2.1 H/D exchange of -substituted propionate ethyl thioesters Babas et al.2 reported the deuterium exchange experiments of trifluoroethyl thioesters catalyzed by 50 mol% Oct3N. The H/D exchange reaction was utilized for studying the role of -proton acidity of the thioesters and its influence on 28 Chapter reactivity and enantioselectivity in the Michael reaction. There was a correlation between the exchange rate and the Michael reaction (Scheme 2.2 Eq vs Eq 2). The trifluoroethyl thioester of propoinic acid (77: R1 = Me) did not undergo -proton exchange and was not active in the Michael reaction (Scheme 2.2). O F3C R1 S + CD3OD Toluene-d F3C S D H + F3C R1 S D D 77-d R1 = Ar, t1/2 = 5min-230min R1 = Me, t1/2 = >5000min O O S R1 77-d 77: R1 = Ar, Me F3C O O Oct3N R1 + CHO R2 78 77: R1 = Ar, Me R2 cat 76 PhCO2H (10 mol%) MeOH,RT Ar Ar N OTMS H cat: 76 F3C CHO S 79 R1 R1 = Ar, yield:45-88%; ee: 33-98% R1 = Me, No reaction Scheme 2.2 H/D exchange of trifluoroethyl thioester Scheme 2.3 H/D exchange of ketones Recently, Mioskowski and his coworkers3 reported the high level of deuterium 29 Enantioselective H/D exchange reaction incorporation of aromatic 80a-80d and aliphatic ketones 80e-80f, which were performed in CDCl3 with TBD (triazabicyclo[4,4,0]dec-5-ene) as organic base catalyst. It is the first example using aprotic media CDCl3 as deuterium source for H/D exchange reaction of ketones. TBD, a much stronger base (pKa = 26.2), led to the high deuterium incorporation for all the ketone substrates via deprotonation/deuteriation process. 2.2 Enantioselective H/D exchange of -fluorinated aromatic ketones 2.2.1 Synthesis of -fluorinated aromatic cyclic ketones and chiral bicyclic guanidine catalyst. -Tetralone derivatives 81a-81g, 81l were easily transformed into fluorinated ketones 82a-82g, 82l using fluorinating reagent Selectfluor according to the reported procedure4 (Scheme 2.4 Eq 1). For the uncomercially available substrates 81c and 81g, we prepared them from the substituted 4-oxo-4-phenylbutanoic acid 83 in a two-step protocol. Intermediates 84 were prepared by the reduction of 83, followed cyclization in polyphospheric acid (PPA) at 110 oC to give the desired products 81c and 81g (Scheme, 2.4 Eq 3)5. The fluorinated chroman-4-one derivatives 82h-82k were synthesized from the commercially available starting material 81h-81k. Because dimethylketal form were formed partly in the crude -fluorinated ketone products, the hydrolysis step with 10% HCl aq. was necessary for achieving the pure products 82h-82k 30 Chapter (Scheme 2.4 Eq. 2). Scheme 2.4 Fluorination of ketones Scheme 2.5 Synthesis of the chiral bicyclic guanidine 25. The chiral bicyclic guanidine was prepared by the well-established procedure published in our lab6. N-Tosyl aziridine 86 was readily prepared from its corresponding commercially available α-amino alcohol 85 via a two-step protocol. Triamine unit 87 was easily obtained by treating N-tosyl aziridine 86 in MeOH saturated with NH3 gas in a sealed vessel. After removing the solvent and the residue was dissolved in MeCN and refluxed for days. The subsequent removal 31 Enantioselective H/D exchange reaction of tosyl groups was conducted in liquid ammonia in the presence of sodium. After the final cyclization step, the triamine intermediate was cyclized to give the chiral bicyclic guanidine 25. It was basified with 5M KOH aqueous solution or solid K2CO3 (Scheme 2.5). 2.2.2 Optimization studies on asymmetric H/D exchange reaction Scheme 2.6 Chiral bicyclic guanidine 25 catalyzed asymmetric H/D exchange reaction in different conditions. 7-Bromo-2-fluoro-3,4-dihydronaphthalen-1(2H)-one 82a was selected for the model H/D exchange reaction catalyzed by the chiral bicyclic guanidine catalyst 25. The deuterium incorporation was monitored by H NMR and enantioselectivity was checked by chiral HPLC. The initial experiment was carried out in THF in the presence of 100 equivalents D2O catalyzed by 30 mol% chiral guanidine at room temperature. After 24 hours, over 95% deuterium incorporation of 82a-d1 was obtained with 4.8% ee. When the temperature was lowered to oC, the enantioselectivity increased to 9% ee. Three more reactions were also carried out for comparison (Scheme 2.7). When -fluorinated ketone 82a was treated with 30 mol% chiral bicyclic guanidine catalyst in the presence of 100 equivalents H2O, there was no enantioselectivity over 24 h (Scheme 2.7 Eq 1). The same result was observed when the racemic 32 Chapter 82a-d1 was treated with 100 equivalents D2O under the same catalytic conditions (Scheme 2.7 Eq 2). However, there was some enantioselectivity (9% ee) when the racemic 82a-d1 was treated with 100 equivalents H2O (Scheme 2.7 Eq 3). So the H/D exchange process is enantioselective. tBu O F H Br N tBu N N H 25: 30 mol% O Br F H F D THF/H2O (100 equiv.) 0oC No ee 82a tBu O F D Br N tBu N N H 25: 30 mol% O Br THF/D2O (100 equiv.) 0oC No ee 82a-d (racemic) tBu O Br F D 82a-d (racemic) N tBu N N H 25: 30 mol% O F D(H) Br THF/H2O (100 equiv.) 0oC 24 h, 3% ee d, 9% ee Scheme 2.7 Chiral bicyclic guanidine 25 catalyzed asymmetric H/H, D/D and H/D exchange reaction (THF/H2O = 200μL/μL). In our optimization studies with -fluorinated ketone 82a, we screened different solvents for asymmetric H/D exchange reaction at room temperature (Table 2.1). The chlorinated solvents gave much better enantioselectivities with high deuterium incorporation (entries 1, 5, 7). The racemic product was obtained when trifluoroethanol was used as solvent (entry 6). For deuterated solvents (entries 9-10), ee values dropped a few percents comparing to corresponding 33 Enantioselective H/D exchange reaction non-deuterated ones. When the reaction temperature was lowered to -20 oC, no enatioselectivity was observed (entry 11). Moreover, the catalyst loading did not affect the enantioselectivity too much (entries 12-13). Table 2.1 Optimization of the asymmetric H/D exchange reaction of -fluorinated ketone 82a in different conditions (Scheme 2.6). a incorporation entry solvent 25/mol % D2O temp/oC CH2Cl2 30 100 70 18 THF 30 100 >95 Toluene 30 100 >95 10 CH3CN 30 100 100 18 CHCl3 30 100 100 12 CF3CH2OH 30 100 100 ClCH2CH2Cl 30 100 100 24 hexane 30 100 70 5.2 CDCl3 30 100 >95 19 10 CD2Cl2 30 100 100 20 11 ClCH2CH2Cl 30 100 −20 >95 12 ClCH2CH2Cl 10 100 >95 21 13 ClCH2CH2Cl 50 100 100 23 yield/% a ee/%b Monitored by 1H NMR; b Chiral HPLC analysis. The effect of the amount of D2O on the asymmetric H/D exchange reaction was investigated. As shown in Figure 2.1, the enantioselectivities increased when the amount of D2O increased from 10 equivalents to 80 equivalents. Nevertheless, the 34 Chapter ee values changed a little from 80 equivalents to 170 equivalents and reached to the highest 24.4% ee (150 equiv. D2O). When more than 200 equivalents D2O was used in the reaction, the ee values dropped a lot. At last, we used 150 equivalents D2O as the optimal amount for the following reactions. Figure 2.1 Asymmetric H/D exchange reaction of -fluorinated ketone 82a in different amount of D2O. Determined by 1H NMR and Chiral HPLC analysis. To determine the optimal reaction time, the asymmetric H/D exchange reaction was carried out at different durations ranging from h to 36 h (Table 2.2). At the beginning of the reaction, we observed that the enantioselectivity increased sharply from h to h and reached the maximum at about h with 26% ee. After the -fluorinated ketone 82a was fully converted to the deuterated product 82a-d1, the ee value of the deuterated product decreased slowly. We stopped monitoring the experiment at 36 h but the trend indicated that the ee will approach 0% with prolonged reaction time. 35 Enantioselective H/D exchange reaction Table 2.2 Optimization of the asymmetric H/D exchange reaction of -fluorinated ketone 82a in different reaction time. entry a Reaction time/h Incorporation yield/%a ee/%b 45 60 18 79 24.4 87 26 15 100 24 36 100 13.7 Determined by 1H NMR. b Chiral HPLC analysis. tBu O F + R1 n D2O N tBu N N H 25: 30 mol% O R1 DCE, 0oC 150 equiv.) n 82-d 82 O O O F D O F D F D Br F D F D TsO 82a-d 82d-d 82b-d 14 h, 3% ee, 70% D 15 h, 24% ee, 100% D 24 h, 30% ee, >95% D O O O F D O2N F D F D F 82e-d 24 h, 5% ee, 100% D CH3 O F D O 82f-d 24 h, 0% ee, 100% D 82g-d 82h-d 14 h, 13% ee, 53% D 24 h, 0% ee, 100% D 82l-d 24 h, 7% ee, 67% D Scheme 2.8 Chiral bicyclic guanidine 25 catalyzed asymmetric H/D exchange reaction. 36 Chapter Based on the optimized reaction conditions, -fluorinated ketones 82a-82h and 82l were chosen as substrates for the asymmetric H/D exchange reaction (Scheme 2.8). The highest enantioselectivity of 30% ee was obtained with -fluorinated ketone 82b. For substrate 82f with a strong electron-withdrawing nitro group on the aromatic ring, there was no enantioselectivity observed. The -fluorinated 4-chromanone derivative 82h was not effective, either. 2.3 DFT calculation for the enantioselective H/D exchange reaction The asymmetric deuterium exchange reaction of -fluorinated ketone was further examined by density functional theory (DFT) calculations.7 As these reactions were conducted in the presence of water (H2O or D2O), both the direct and water-assisted protonation/deprotonation of 82b by chiral guanidine 25 were evaluated. In the direct process, two transition states, S-TS and R-TS, were located for S-1b and R-1b, with an overall activation free energy of 19.9 and 21.2 kcal/mol, respectively. When a water molecule participates in the protonation/deprotonation reaction, overall activation free energy is lowered to 16.4 and 17.0 kcal/mol, for S-82b and R-82b, respectively. Transition states S-H2O-TS and R-H2O-TS support the model of bifunctional activation by guanidine catalyst 25,8 and more importantly, suggest that in the presence of water, the water-assisted protonation/deprotonation processes are more favorable than direct ones (Figure 2.2). Isotope effects were estimated by frequency 37 Enantioselective H/D exchange reaction calculations on S-H2O-TS and R-H2O-TS geometries with all protic hydrogen atoms replaced by deuterium atoms. The results indicate that overall activation free energies for both deuterated transition states are increased by 1.3 kcal/mol. Figure 2.2 Transition states for the protonation/deprotonation process. Non-hydrogen bonded hydrogen atoms are omitted for clarity. Relative energies are shown in parentheses. Dotted lines provide visual guides for the bond breaking and forming processes. All these results collectively accounted for the experimental observations: 1) While the protonation of the enolate intermediate (after 82b is deprotonated) to form S-82b is kinetically favored by 0.6 kcal/mol, the deprotonation of S-82b also proceeds faster than R-82b by 0.6 kcal/mol. As a result, no changes in ee can be expected when racemic 82b is treated with H2O in the presence of catalyst 25; 2) Since the dedeuteration of 82b-d1 is approximately seven times slower than the 38 Chapter deprotonation of 82b, enantiomerically enriched 82b-d1 will be produced upon the deprotonation of 82b and deuteration of the resulting enolate intermediate; 3) However, 82b-d1 also undergoes racemization reaction and as the deuterated product increases, racemization will become more pronounced which will lead to lower ee of 82b-d1, and eventually racemic 82b-d1. 2.4 Summary In summary, we have developed an asymmetric H/D exchange reaction via deprotonation/deuteration reaction catalyzed by chiral bicyclic guanidine 25. The best enantioselectivity was 30% for deuterated products 82b-d1. The level of deuteration at various time points was monitored using HPLC and 1H NMR. The results showed the racemization of the product 82b-d1 occurred and the trend seemed to indicate that the ee will approach 0% if the time of experiment is long enough. We also examined the asymmetric deuterium exchange reaction of -fluorinated aromatic ketone by DFT calculations. The computational results explained the asymmetric H/D exchange experiment well, and the S absolute configuration of products was achieved. 39 Enantioselective H/D exchange reaction References: 1. Um, P.-J.; Drueckhammer, D. G. J. Am. Chem. Soc. 1998, 120, 5605. 2. Alonso, D. A.; Kitagaki, S.; Utsumi, N.; Barbas III, C. F. Angew. Chem. Int. Ed. 2008, 47, 4588. 3. Sabot, C.; Kumar, K. A.; Antheaume, C.; Mioskowski, C. J. Org. Chem. 2007, 72, 5001. 4. Stavber, S.; Jereb, M.; Zupan, M. Synthesis, 2002, 17, 2609. 5. Owton, W. M.; Brunavs, M. Synth. Commun. 1991, 21, 981. 6. Ye, W.; Leow, D.; Goh, S. L. M.; Tan, C.-T.; Chian, C.-H.; Tan, C.-H. Tetrahedron Lett. 2006, 47, 1007 7. DFT calculations were performed by employing the Gaussian 09 program. The B3LYP method was applied with 6-31G (d) Pople basis set. 8. Lee, R.; Lim, X.; Chen, T.; Tan, G. K.; Tan, C.-H. Tetrahedron Lett. 2009, 50, 1560. 40 [...]...Chapter 2 Based on the optimized reaction conditions,  -fluorinated ketones 82a-82h and 82l were chosen as substrates for the asymmetric H/D exchange reaction (Scheme 2. 8) The highest enantioselectivity of 30% ee was obtained with  -fluorinated ketone 82b For substrate 82f with a strong electron-withdrawing nitro group on the aromatic ring, there was no enantioselectivity observed The  -fluorinated. ..  -fluorinated 4-chromanone derivative 82h was not effective, either 2. 3 DFT calculation for the enantioselective H/D exchange reaction The asymmetric deuterium exchange reaction of  -fluorinated ketone was further examined by density functional theory (DFT) calculations.7 As these reactions were conducted in the presence of water (H2O or D2O), both the direct and water-assisted protonation/deprotonation of 82b... the presence of catalyst 25 ; 2) Since the dedeuteration of 82b-d1 is approximately seven times slower than the 38 Chapter 2 deprotonation of 82b, enantiomerically enriched 82b-d1 will be produced upon the deprotonation of 82b and deuteration of the resulting enolate intermediate; 3) However, 82b-d1 also undergoes racemization reaction and as the deuterated product increases, racemization will become more... become more pronounced which will lead to lower ee of 82b-d1, and eventually racemic 82b-d1 2. 4 Summary In summary, we have developed an asymmetric H/D exchange reaction via deprotonation/deuteration reaction catalyzed by chiral bicyclic guanidine 25 The best enantioselectivity was 30% for deuterated products 82b-d1 The level of deuteration at various time points was monitored using HPLC and 1H NMR The results... the racemization of the product 82b-d1 occurred and the trend seemed to indicate that the ee will approach 0% if the time of experiment is long enough We also examined the asymmetric deuterium exchange reaction of  -fluorinated aromatic ketone by DFT calculations The computational results explained the asymmetric H/D exchange experiment well, and the S absolute configuration of products was achieved... Transition states S-H2O-TS and R-H2O-TS support the model of bifunctional activation by guanidine catalyst 25 ,8 and more importantly, suggest that in the presence of water, the water-assisted protonation/deprotonation processes are more favorable than direct ones (Figure 2. 2) Isotope effects were estimated by frequency 37 Enantioselective H/D exchange reaction calculations on S-H2O-TS and R-H2O-TS geometries... by chiral guanidine 25 were evaluated In the direct process, two transition states, S-TS and R-TS, were located for S-1b and R-1b, with an overall activation free energy of 19.9 and 21 .2 kcal/mol, respectively When a water molecule participates in the protonation/deprotonation reaction, overall activation free energy is lowered to 16.4 and 17.0 kcal/mol, for S-82b and R-82b, respectively Transition... breaking and forming processes All these results collectively accounted for the experimental observations: 1) While the protonation of the enolate intermediate (after 82b is deprotonated) to form S-82b is kinetically favored by 0.6 kcal/mol, the deprotonation of S-82b also proceeds faster than R-82b by 0.6 kcal/mol As a result, no changes in ee can be expected when racemic 82b is treated with H2O in the... protic hydrogen atoms replaced by deuterium atoms The results indicate that overall activation free energies for both deuterated transition states are increased by 1.3 kcal/mol Figure 2. 2 Transition states for the protonation/deprotonation process Non-hydrogen bonded hydrogen atoms are omitted for clarity Relative energies are shown in parentheses Dotted lines provide visual guides for the bond breaking... achieved 39 Enantioselective H/D exchange reaction References: 1 Um, P.-J.; Drueckhammer, D G J Am Chem Soc 1998, 120 , 5605 2 Alonso, D A.; Kitagaki, S.; Utsumi, N. ; Barbas III, C F Angew Chem Int Ed 20 08, 47, 4588 3 Sabot, C. ; Kumar, K A.; Antheaume, C. ; Mioskowski, C J Org Chem 20 07, 72, 5001 4 Stavber, S.; Jereb, M.; Zupan, M Synthesis, 20 02, 17, 26 09 5 Owton, W M.; Brunavs, M Synth Commun 1991, 21 , 981 . aromatic cyclic ketones and chiral bicyclic guanidine catalyst. -Tetralone derivatives 81a-81g, 81l were easily transformed into fluorinated ketones 82a-82g, 82l using fluorinating reagent. the chiral bicyclic guanidine catalyst 25 . The deuterium incorporation was monitored by 1 H NMR and enantioselectivity was checked by chiral HPLC. The initial experiment was carried out in. ee 6d,9%ee Br Br 82a- d 1 (racemic) 1 2 3 Scheme 2. 7 Chiral bicyclic guanidine 25 catalyzed asymmetric H/H, D/D and H/D exchange reaction (THF/H 2 O = 20 0μL/μL). In our optimization studies with  -fluorinated ketone