Huang, C.; Gevorgyan, V. J. Am. Chem. Soc. 2009, 131, Daniel Tzvi Cohen Short Literature Feb. 23, MeO HO OH. COOH ( )-Plicatic Acid OH OH

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1 Asymmetric Total Synthesis of ( )-Plicatic Acid via a Highly Enantioselective and Diastereoselective Nucleophilic Epoxidation of Acyclic Trisubstituted lefins H H H H CH ( )-Plicatic Acid H H Sun, B.F.; Hong,.; Kang, Y.B.; Deng, L. J. Am. Chem. Soc. 2009, 131, TBDPS and Br-TBDPS Protecting groups as Efficient Aryl Group Donors in Pd-Catalyzed Arylation of enols and Anilines Huang, C.; Gevorgyan, V. J. Am. Chem. Soc. 2009, 131, Daniel Tzvi Cohen Short Literature Feb. 23, 2010

2 ( )-Plicatic Acid Background!Isolated from western red cedar (Thuja plicata) by MacLean 1 in 1959! The relative and absolute configurations were determined by X-ray crystallography and D! Densely functionalized motif with contiguous quaternary-quaternary-tertiary stereocenters H 1 2 7' 7 8 8' H H H CH H H ( )-Plicatic Acid! First total synthesis reported 1. Gradner, J.A.F.; Barton, G.M.; Maclean, H. Can. J. Chem., 1959, 37, 1703

3 etro-synthesis of ( )-Plicatic Acid H 1 2 7' 7 8 8' H H H CH Bn H H H CEt Bn H CEt H Bn Bn = Ar H ( )-Plicatic Acid Bn Bn Bn Bn Ar Ar CEt CEt

4 Asymmetric Nucleophilic Epoxidation of Various Acrylate derivatives H + H TADH LiH (0.1 eq.), THF C days * * 1 = Aryl, ester 2 = Ethyl, allyl 3 = Aryl, alkyl yield = 60-99% ee = 84-96% 1) Sun, B.F.; Hong,.; Kang, Y.B.; Deng, L. J. Am. Chem. Soc. 2009, 131, ) Aoki, M.; Seebach, D. HelV. Chim. Acta 2001, 84, 187

5 Stepwise Synthesis of ( )-Plicatic Acid H 1) NaH, BnBr, quant. 2) a) NM, s 4 (cat.) b) NaI 4, quant. Bn SnCl 2 (cat.) N 2 CHCEt, 92% Bn + C 2 Et Bn CH Bn Piperidine, CH E/Z = 5:3 recycled 80% of E Bn Bn Bn Bn C 2 Et (S,S)-TADH LiH (cat.) 83%, 98% ee Bn Bn C 2 Et

6 chanism to accesses!-keto-ester LA LA + H N 2 Et H N Et N LA = BF 3, ZnCl 2, ZnBr 2, AlCl 3, SnCl 4, GeCl 2, SnCl 2-2 H 2 Formal [1,2] -N 2 Et Holmquist, C.., oskamp, E. J., JC 1989, 54, 3258

7 Continued Synthesis of ( )-Plicatic Acid Bn Bn C 2 Et TfH (0.04 eq.), 0 C to rt. 70% cis 17% trans Bn C 2 Et H Bn Friedel-Crafts Ar = Bn Bn Cl() 2 CH 2 Br, Imidazole 75% (94% brsm) H () 2 H SmI 2, NiI 2 (0.1 eq), Bn Ar C 2 Et H 0 C, 58% Barbier reaction Bn Ar C 2 Et () 2 CH 2 Br

8 Barbier eaction chanism Generation of rganometallic reagent X M SET + X + M (I) SET M X Concerted pathway 1 2 MX 1 2 MX MX 1 2 adical (stepwise) pathway MX SET 1 2 MX MX 1 2

9 Final Steps in the Synthesis of ( )-Plicatic Acid H () 2 H H 2 2, NaHC 3 H H Bn Ar C 2 Et H 87% (90% brsm) Fleming-Tamao-Kumada oxidation Bn Ar C 2 Et H n-prsna, DMF 97% H H H C 2 H H H H H 2, Pd/C, H then, Dowex-50 72% Bn Bn H H C 2 Na H Bn

10 Summary and Conclusions for the Synthesis of ( )-Plicatic Acid! First reported Total synthesis of ( )-Plicatic Acid! Development of an enantioenriched epoxidation methodology using TADH! Minimal use of protecting groups! 12 steps ( 20 mg, 14% overall percent yield)! Extensive spectroscopic and chromatographic analysis showed that the synthetic and natural ( )-plicatic acid were indistinguishable

11 TBDPS and Br-TBDPS Protecting groups as Efficient Aryl Group Donors in Pd-Catalyzed Arylation of enols and Anilines Huang, C.; Gevorgyan, V. J. Am. Chem. Soc. 2009, 131, 10844

12 Aryl-Aryl bonds ! Traditional methods of coupling are an arylhalide (or equivalent) and an arylmetal! ecently C H arylation methods have emerged, but there are limits! Intermolecular reactions suffer from low reactivity and/or regioselectivity!directing groups or activating groups are sometimes hard to remove Huang, C.; Gevorgyan, V. J. Am. Chem. Soc. 2009, 131, 10844

13 1 1 Chiral Biphenol-Based Monodentate osphoramidite Ligands P N 2 2 H H 2 S 4, 80 C, 6 hrs quant. H K 2 Cr 2 7 H 2 S 4, HAc, 60 C 30-40% H H 1 H H 1 P N 2 2 () or (S) Alexander, J. B., La, D. S., Cefalo,D.., Hoveyda, A. Shrock,..; J. Am. Chem. Soc. 1998, 120, 4041

14 eported Here:! Intramolecular aryl-aryl coupling with easily removable silicon tethers!tbdps used as an aryl donor for o-bromophenols via Pd-catalyzed intramolecular arylation n Br [Pd] base n! Br-TBDPS used as an aryl donor for simple phenols and anilines n X Br [Pd] base n X X=, N

15 1) Ease of deprotection (F - source) licon Motif X TBAF/THF X X = H or NH n 70 C n % 2) Easy access to deuteriated biaryls CsF, DMF, D 2 H D n 3) Easy access to biphenols 80 C, 46 hr 84% n F NaH, H, NMP TBAF F H 95% H

16 TBDPS used as an aryl donor for o-bromophenols Pd(Ac), 5 mol %, PCy 3 -BF 4, 10 mol%, n Br PivH, Cs 2 C 3, 3Å MS, p-xylene, 140 C n = H,,Cl, F F 2 N 73-96% 51% 49% Y F X F 1) X=Y= t Bu 30% 2) X= CH, Y= 52% 83% 100% 59%

17 Br-TBDPS Used as an Aryl Donor X Pd(Ac), 5 mol %, PCy 3 -BF 4, 10 mol%, X Br PivH, Cs 2 C 3, 3Å MS, p-xylene, 140 C X=, N N TBS 97% (10:1) 100% 77% 98% (2.9:1) 98% (2.9:1) 99%

18 Summary & Conclusions! Two intramolecular methods of Pd-catalyzed arylations of phenols and anilines! TBDPS protecting groups can be used aryl donors for o-bromophenols! Br-TBDPS can serve as a simple aryl group donor for simple phenols and anilines! Incorporation of deterium on biaryls!preparation of o-biphenols by desilylation and oxidation