Memory of Chirality: A Strategy for Asymmetric Synthesis

Transcription

1 Memory of Chirality: A trategy for Asymmetric ynthesis David J. Richard eptember 14, 2005

2 Two Forms of Chirality Absolute (tatic) Chirality 2 - Absolute chirality - orientation of functional groups at a stereocenter Dynamic (Conformational) Chirality C 2 2 C - Dynamic chirality - chirality present only when C-C single bond rotation is restricted 3 C C 3 C 3 3 C Barrier of rotation = 18 kcal/mol

3 Memory of Chirality in Enolate Chemistry - In 1981, eebach and Wasmuth made the following observation: LDA t-bu t-bu t-bu TF, t-bu Li t-bu t-bu then MeI C 3 Li 15%, 60% ee - o mechanism was established; however, one hypothesis was that reaction occurred through an axially chiral intermediate - Mixed aggregates involving the chiral enolate below were later implicated t-bu t-bu Li eebach, D.; Wasmuth, D. Angew. Chem., Int. Ed. Engl. 1981, 20, 971. eebach, D.; ting, A. R.; offman, M. Angew. Chem., Int. Ed. Engl. 1996, 35, 2708.

4 Memory of Chirality: Definition Problem: Can stereochemical information be retained during a process in which the sole stereogenic center of a substrate is destroyed? R 1 C 3 R 1 R C 3 * R 1 C 3 M > 0% ee Memory of chirality (MC) has been defined as a process in which: "the chirality of the starting material is preserved in a reactive intermediate for a limited time" Fuji, K.; Kawabata, T. Chem.-Eur. J. 1998, 4, This process has also been described as follows: "A 'memory of chirality' reaction can be defined as a formal substitution at an sp 3 stereogenic center that proceeds stereospecifically, even though the reaction proceeds by trigonalization of that center, and despite the fact that no other permanently chiral elements are present in the system." Zhao,.; su, D. C.; Carlier, P. R. ynthesis 2005, Additional Review: Kawabata, T.; Fuji, K. Top. tereochem. 2003, 23,

5 Enolate Alkylation: Design of amemory of Chirality ystem R 1 R 3 Base M R 1 R 3 R 2 R 2 R 1 M A M A R 1 R 2 R 2 B B M M R 1 R 1 R 2 R 3 R 3 R 2 - Fuji and co-workers proposed two strategies for the establishment of conformationally chiral enolates - axially chiral enolates or planar chiral enolates Kawabata, T.; Yahiro, K.; Fuji, K. J. Am. Chem. oc. 1991, 113, 9694.

6 tereoselectivity by Memory of Chirality: General Considerations ubstrate* Fast (M)-Intermediate Fast (R)-Product A C Very low Very low B Very low (P)-Intermediate Fast ()-Product A Reaction at stereogenic center (e.g., enolate formation) generates conformationally chiral intermediate B Conformationally chiral intermediate must not readily racemize C Reaction must occur with high stereospecificity -Critical issue: reaction kinetics

7 Enolate Alkylation Utilizing Memory of Chirality (MC) Et Et C 3 K 18-crown-6 Toluene Et K C 3 MeI Et Et C 3 C 3 93% ee Et 54%, 73% ee Et Et C 3 Et C 2 C 3 Et C 3 Et 3 C C 3 Et Et Et Et 65% ee 67% ee 48% ee 70% ee - -methylated product also isolated in 65% ee by chiral PLC - alf-life of racemization determined to be 53 minutes at room temperature Kawabata, T.; Yahiro, K.; Fuji, K. J. Am. Chem. oc. 1991, 113, 9694.

8 Asymmetric yntheses of Amino Acid Derivatives R 1 R 4 Base M R 1 R 4 R 2 R R 2 R 3 3 R 3 M R 1 R 2 M R 4 R 2 R 1 R 4 R 3 Axial Chirality Planar Chirality R 2 R 3 R 1 M R 4 Central Chirality Kawabata, T.; Wirth, T.; Yahiro, K.; uzuki,.; Fuji, K. J. Am. Chem. oc. 1994, 116,

9 Asymmetric Alkylation of Amino Acid Esters 3 C Boc Et LiTMP TF - 78 C, then C 3 I 3 C Et C 3 Boc 40%, 82% ee 3 C Boc Et KMD Toluene-TF (4:1) - 78 C, then C 3 I MM Et C 3 Boc 96 %, 81% ee Boc MM Boc C 3 Et MM Boc C 3 Et MM MM Boc C 3 Et 78%, 78% ee 83%, 93% ee 88%, 76% ee Kawabata, T.; Wirth, T.; Yahiro, K.; uzuki,.; Fuji, K. J. Am. Chem. oc. 1994, 116, Kawabata, T.; uzuki,.; agae, Y.; Fuji, K. Angew. Chem. Int. Ed. 2000, 39, 2155.

10 Mechanism of Memory of Chirality Effect - ne possibility - mixed aggregate mechanism Et t-bu MM K MM t-bu Et - Ruled out by competition experiments - ilyl enol ether prepared - exhibits rotational barrier of 16.8 kcal/mol by VT MR experiments Et Et MM TB t-bu MM TB t-bu - alf-life of approximately 7 days at -78 C - Variable reaction times explored for enolate deprotonation - rotational barrier calculated as 16.0 kcal/mol Kawabata, T.; uzuki,.; agae, Y.; Fuji, K. Angew. Chem. Int. Ed. 2000, 39, 2155.

11 Mechanism of Memory of Chirality Effect t-bu TM K TM t-bu C 3 I Et K t-bu C 3 Major product t-bu TM K TM C 3 I t-bu Et K t-bu 3 C Minor product - Additional evidence: di-boc and oxazolidinone analogs showed no enantioselectivity Kawabata, T.; uzuki,.; agae, Y.; Fuji, K. Angew. Chem. Int. Ed. 2000, 39, 2155.

12 Effect of Adjacent tereocenters Et Et Boc MM Boc MM KMD -78 C Et K C 2 C 3 C 2 t-bu Et K C 2 t-bu C 2 C 3 C 3 I MM Boc Et Et MM Boc 93%, 93% de 91%, 86% de Kawabata, T.; uzuki,.; agae, Y.; Fuji, K. Angew. Chem. Int. Ed. 2000, 39, 2155.

13 Asymmetric Alkylation - Intramolecular Cyclization Boc Et Br KMD DMF -60 C Et 2 C Boc 94%, 98% ee Et 2 C Et 2 C Et 2 C Boc Boc Boc 84%, 97% ee 61%, 95% ee 31%, 83% ee - ther six-membered rings were produced in excellent ee (94-97%) t-bu Br t-bu Et K Et 2 C Boc Favored conformation Br Kawabata, T.; Kawakami,.; Majumdar,.J. Am. Chem. oc. 2003, 125,

14 Additional Applications of Memory of Chirality trategy C 2 C 3 2 ac 3 C 3 C 2 C 3 35% Et 3, C 3 = 65% - MR studies of M indicate presence of three rotamers 3 C 3 C C 2 C 3 bserved C 2 Me Me C 2 C 3 ot observed Beagley, B.; Betts, M. J.; Pritchard, R. G.; chofield, A.; toodley, R. J.; Vohra,. J. Chem. oc., Perkin Trans. I 1993,

15 Extension of Methodology: Cyclization of ulfoxides C 2 C 3 2 Et 3 C 3 C 2 C 3 61% C 2 C C 2 C 3 Et 3 C 3 C 2 C 3 C 2 C 3 65% 35% 63% 37% Betts, M. J.; Pritchard, R. G.; chofield, A.; toodley, R. J.; Vohra,. J. Chem. oc., Perkin Trans. I, 1999,

16 Additional Applications - Aldol Cyclization and Azetidinone Closure C 2 i-pr KC Me C 2 ipr + 49% 19% C 2 ipr C 2 t-bu Cs 2 C 3 Cl PMB C 3 C C 2 t-bu PMB 53%, 56% ee - Enantioselectivity highly substrate dependent (0-50% ee) - o specific models proposed - however, existence of axial chirality proposed Brewster, A. G.; Frampton, C..; Jayatissa, J.; Mitchell, M. B.; toodley, R. J. Chem. Commun. 1998, 299. Gerona-avarro, G.; Bonache, M. A.; erranz, R.; Garcia-Lopez, M. T.; Gonzalez-Muniz, R. J. rg. Chem. 2001, 66, 3538.

17 Memory of Chirality in Benzodiazepines i-pr Cl LDA MPA n-buli, then BnBr -78 C Cl i-pr 74%, 97% ee - With -Me amide: 0% ee - Alkylation with other electrophiles (Me, allyl, 2- C 6 4 C 2, 4-MeC 6 4 C 2 ) all proceed with 94-99% ee Cl Cl 3 C i-pr 3 C i-pr 0.0 kcal/mol t 1/2 (inversion) = C - Factors which lead to attack of electrophile on concave face yet to be determined C 3 i-pr 3 C i-pr kcal/mol Carlier, P. R.; Zhao,.; DeGuzman, J.; Lam, P.C.-. J. Am. Chem. oc. 2003, 125,

18 Memory of Chirality in Radical Chemistry Et LiDBB - 78 C R Cr(C) 3 TF, then RX Cr(C) 3 R = TMCl; 72%, 87% ee R = C 2 Br; 37%, 87% ee R = C 3 C()Cl; 67%, 86% ee R = (C 3 ) 2 C()Cl; 57%, 84% ee Et + 1 e C 3 Fast C 3 Fast C 3 R Cr(C) 3 Cr(C) 3 Cr(C) 3 Cr(C) 3 Cr(C) 3 low Configurationally table C 3 Cr(C) 3 chmalz,.-g.; Koning, C. B. D.; Bernicke, D.; iegel,.; Pfletschinger, A. Angew. Chem. Int. Ed. 1999, 38, 1620.

19 Reaction of Pyranyl Radicals hv 1M -78 C 92%, 88% ee LiDBB Li (6.4M)/ 3 C TF -78 C, then C 2 C 2 48% ee C TF -78 C, then 4 Cl 90% ee - Memory of original chiral center retained due to ring conformational preference - Furanyl radicals exhibit no enantioselectivity Buckmelter, A. J.; Kim, A. I.; Rychnovsky,. D. J. Am. Chem. oc. 2000, 122, 9386.

20 Radical Cyclization of Cyclodecenyl ystems Bn2 C C 2 Bn Toluene hv -15 C C 2 Bn C 2 Bn 51%, 68% ee C 2 Bn C 2 Bn C 2 Bn C 2 Bn - Barrier to ring inversion provides stereocontrol C 2 Bn C 2 Bn C 2 Bn C 2 Bn - Lower temp. provides no improvement of ee C 2 Bn C 2 Bn C 2 Bn C 2 Bn Dalgard, J. E.; Rychnovsky,. D. rg. Lett. 2004, 6,

21 Radical Cyclization of aloacrylanilides I Bu 3 n Et 3 B C 3 2 rt 84% ee Bu 3 n C 3 I Et 3 B 2 rt 82% ee - Chirality of atropisomer is maintained in radical - cylization proceeds faster than isomerization Curran, D. P.; Liu, W.; Chen, C..-T. J. Am. Chem. oc. 1999, 121,

22 Radical Cyclization to ubstituted Pyrrolidines 3 C 2 C Ts Et hv Benzene Ts C 2 C 3 C 2 Et + Ts C 2 C 3 C 2 Et 40%, 96% ee 7%, 94% ee 5 kcal/mol C 2 C 3 Et Ts Ts C 2 C 3 C 2 Et 3 C 2 C Et Ts elically chiral diradicals - When reaction is performed in the presence of a triplet sensitizer, no diastereoselectivity or enantionselectivity is observed Giese, B.; Wettstein, P.; tahelin, C.; Barbosa, F.; euburger, M.; Zehnder, M.; Wessig, P. Angew. Chem. Int. Ed. 1999, 38, inicropi, A.; Barbosa, F.; Basosi, R.; Giese, B.; livucci, M. Angew. Chem. Int. Ed. 2005, 44,

23 Cyclization via otodecarboxylation hv 13 kcal/mol C 2 K Acetone 2 45%, 86% ee - Via triplet diradical Griesbeck, A. G.;Kramer, W.; Lex, J. Angew. Chem. Int. Ed. 2001, 40, 577.

24 MC via a Carbocationic Intermediate ac 3 C 2 C 3 C 3 Graphite anode Pt cathode 69%, 39% ee ac 3 C 2 C 3 C 3 Graphite anode Pt cathode 69%, 39% ee C 3 C 2 C 3 Matsumura, Y.; hirakawa, Y.; atoh, Y.; Umino, M.; Tanaka, T.; Maki, T.; nomura,. rg. Lett. 2000, 2, 1689.

25 Conclusions - Memory of chirality represents an emerging strategy in the field of stereoselective synthesis - This method takes advantage of the dynamic, conformational chirality present in systems with restricted rotation about single bonds - Requires no external sources of chirailty - ighly time, temperature, and substrate dependent - Primary application has been in the area of enolate chemistry - limited number of examples involving radical and carbocationic intermediates