Disulfonimide-Catalyzed Asymmetric Vinylogous and Bisvinylogous Mukaiyama Aldol Reactions

Transcription

1 Disulfonimide-Catalyzed Asymmetric Vinylogous and Bisvinylogous Mukaiyama Aldol eactions atjen, L. Garcia-Garcia, P., Lay, F., Beck, M. E., List, B.; Angew. Chem. Int. Ed. 2010, ASAP. Convergent Total Synthesis of (+)-TMC-151C by a Vinylogous Mukaiyama eaction and ing-closing tathesis Matsui,., Seto, K., Sato, Y., Suzuki, T., akazaki, A., Kobayashi, S.; Angew. Chem. Int. Ed. 2010, ASAP. Short Literature Presentation 1/11/2011 Erika A. Crane

2 Prof. Dr. Benjamin List 1968: born in Frankfurt, Germany 1993: undergraduate degree from Free University Berlin 1997: D at University Frankfurt with J. Mulzer : Postdoc at Scripps with. A. Lerner : Assistant Professor at Scripps : Group leader at Max-Planck-Institut Fur Kohlenforschung July 2005: director of at Max-Planck-Institut Fur Kohlenforschung

3 Asymmetric Induction for β-hydroxy-dioxinone Carreira methodology (JACS 1995) t-bu pros cons Ti Br t-bu first example good selectivity limited substrates (sp 2 v. sp 3 ) + CH TMS (1-3 mol %) t-bu H Scettri methodology (Tet. Asymm. 2003) pros cons TMS + CH Ti(i-Pr) 4, ()-BIL (8 mol %) H inexpensive catalyst system alkyl aldehydes sensitive conditions (reproducibility)

4 Asymmetric Induction for β-hydroxy-dioxinone Denmark methodology (JACS 2003) pros cons TBS + CH SiCl 4 P (CH 2 ) 5 2 H novel approach (activation of nucleophile) compatible with alkyl aldehydes stoichiometric catalyst catalyst availability awal methodology (rg. Lett. 2005) pros cons TBS + CH TADDL (20 mol %) H non-metallic catalyst hydrogenbonding catalysis aryl or sp 2 hybridized aldehydes only general selectivity

5 The Vinylogous Aldol eaction Fuson (1935): Electron density and reactivity is amplified along conjugated bonds of a π system "! M DFT calculations for attack by a electrophile gave the condensed Fukui functions (CFF) & electrostatic potentials (ESP) 0.14 "! 0.09 Si 3! # " 0.07 Si 3

6 Catalyst Development pseudo C2-symmetry P H exposed acid H buried acid 2 S 2 S C2-symmetry phosphoric acid disulfonimide resembles the relative reactivity of TfH and Tf2H! Garcia-Garcia, P., Lay, F., Garcia-Garcia, P., abalakos, C., List, B.; Angew. Chem. Int. Ed. 2009, 48,

7 Catalyst Development 2 mol % S 2 S 2 H Si 3 Si 3 C2 CH Et 2 (0.2 M), 78 C h product % yield e.r. TMS C :3 TBS C 2 ipr 92 96:4 TBS C 2 ipr 95 93: mol % 90 93:7 TBS C 2 ipr 5 mol % 59 75:25 Garcia-Garcia, P., Lay, F., Garcia-Garcia, P., abalakos, C., List, B.; Angew. Chem. Int. Ed. 2009, 48,

8 Substrate Scope of Vinylogous MA 5 mol % S 2 S 2 H Si 3 Si 3 CH Et 2 (0.2 M), 78 C h product % yield e.r. TMS 67 96:4 TIPS 73 95:5 TBS 96 97:3 silyl group didnʼt affect yield or selectivity

9 Substrate Scope of Vinylogous MA 5 mol % S 2 S 2 H Si 3 Si 3 CH Et 2 (0.2 M), 78 C h product % yield e.r. TBS 96 93:7 TBS ipr 61 95:5 TBS tbu 30 94:6 TBS 80 92:8 increasing ester bulkiness significantly reduced yields

10 Substrate Scope of Vinylogous MA 5 mol % S 2 S 2 H Si 3 Si 3 CH Et 2 (0.2 M), 78 C h product % yield e.r. TBS Et 60 94:6 TBS Et 78 81:19 β substituents are well-tolerated, while α substituents result in product with decreased enantioselectivity compliments Denmark s chemistry!

11 Substrate Scope of Vinylogous MA 5 mol % electron rich or neutral aromatic aldehydes work the best S 2 S 2 H Si 3 Si 3 CH Et 2 (0.2 M), 78 C h product % yield e.r. TBS 65 82:18 F TBS Et 62 61:39 TBS Et 45 72:28 TBS Et 33 72:28

12 Substrate Scope of Bisvinylogous MA 5 mol % the first catalytic, asymmetric bisvinylogous aldol reaction! S 2 S 2 H Si 3 Si 3 CH Et 2 (0.2 M), 78 C h product % yield e.r.!/" TBS 75 95:5 5:1 TBS 46 87:13 8.4:1 TBS 47 54:46 3.2:1

13 Prof. Dr. Susumu Kobayashi : undergraduate degree from Tokyo Institute of Technology : D at Tokyo Institute of Technology with Prof. Mukaiyama 1975: Assistant Professor at Tokyo University : esearch at Yale with Prof. Danishefsky 1982: Associate Professor at Tokyo University : esearch Fellow at Sagami esearch Center 1996: Professor at Tokyo University of Science

14 (+)-TMC-151C Has significant cytotoxicity against HCT-116, B16 and HeLa cancer cell lines H H H H H H H H H H H (+)-TMS-151C isolated in 1999 from Gliocladium catenulatum (fungus) 3 contiguous anti homoallylic alcohols β-d-manoside & D-mannitol moieties

15 thodology Development remote asymmetric induction 1 2 CH 1 H H H TBS TiCl 4 2 H d.r. > 20:1 H H H H H H (+)-TMS-151C H H anti-δ-hydroxyα,γ-dimethyl α,β-unsaturated carbonyl product 3 iterative VMAs & 2 late-stage glycosylations Shirokawa, S., Kamiyama, M., akamura, T., kada, M., akazaki, A., Hosokawa, S., Kobayashi, S. J. Am. Chem. Soc. 2004, 126,

16 1st Generation oute H H H H H H H H H aldehyde made with egishiʼs Zr-catalyzed asymmetric carboalumination methodology H H (+)-TMS-151C VMA TBS VMA TiCl 4 91 % TES H TES H 1.) TESTf 2.) LiBH 4 3.) Mn 2 ~99 % over 3 steps 1.) TESTf 2.) LiBH 4 3.) Mn 2 ~96 % over 3 steps H TES H VMA 51 % H excess TiCl4 and,acetal necessary to get reaction to completion 13:1 d.r.

17 2nd Generation oute H H H H H H H H H H H (+)-TMS-151C C 7 H 15 HG-II benzoquinone C 7 H 15 Si 93% > 20:1 E:Z Si E-selective silicon-tethered ring-closing metathesis C 7 H 15 H H H Si crownlike conformation

18 2nd Generation oute: Left-Hand Fragment H H β-mannoside formation is often regarded as one of the most difficult glycosylation reactions H H H H H H (+)-TMS-151C H H H developed by Crich & Karatholuvhu, 2008!"mannosylation 82 % H p- C 6 H 4 H 1.) LiBH 4 2.) Li, H 3 (l) ~86 % over 2 steps Birch reduction TES TES TES TES H 4.7:1 d.r. 1.) TESTf 2.) AcH, H 2 3.) Mn 2 4.) oush asymmetric anti crotylation ~94 % over 4 steps H H H H H

19 2nd Generation oute: ight-hand Fragment H H H H H H H H H H H (+)-TMS-151C a problematic substrate TBS H VMA 65 % > 20:1 d.r. H 1.) PMB imidate 2.) LiH!H 2 H 2 2 ~76 % over 2 steps PMB H 1.) Piv 2 2.) H 3.) DDQ TES TES TES TES TES anhydride formation & esterification TES TES TES H TES TES

20 2nd Generation oute: Fragment Coupling H H H H H H H H H H H (+)-TMS-151C HF!pyr; HF 54% TES TES TES TES TES TES TES Si CM 87% TES TES > 20:1 d.r. TES TES Si TES TES TES TES TES TES TES Et 2 2 SiCl 81% b.r.s.m. TES TES TES TES TES H H TES TES TES TES