Stephen M. Canham, Larry E. Overman, Paul S. Tanis Tetrahedron 2011, ASAP, DOI: /j.tet Current Litetature Juraj Rehák 10/8/2011

Transcription

1 Identification of an Unexpected 2-xonia[3,3]sigmatropic Rearrangement/Aldol Pathway in the Formation of xacyclic Rings. Total Synthesis of (+)-Aspergillin PZ. Stephen M. Canham, Larry E. verman, Paul S. Tanis Tetrahedron 2011, ASAP, DI: /j.tet Current Litetature Juraj Rehák 10/8/2011 Juraj Wipf Group Page 1 of 15 12/28/2011

2 (+)-Aspergillin PZ N (+)-Aspergillin PZ The (+)-Aspergillin PZ was isolated from the soil fungus Aspergillus awamori. The isolation and identification were reported by by Pei and coworkers in (1) The structure of aspergillin PZ was proved by 2D NMR studies and X-ray analysis. The aspergilin PZ has pentacyclic structure with isoindolone moiety and unusual 12-oxatricyclo[ ,7 ]dodecane ring system. Pei and coworkers also described morphological deformation of the conidia of Pyricularia oryzae at µm induced by aspergillin PZ. (1) (1) Zhang, Y.; Wang, T.; Pei, Y.; ua,.; Feng, B. J. Antibiot. 2002, 55, Juraj Wipf Group Page 2 of 15 12/28/2011

3 Retrosynthetic analysis of (+)-Aspergillin PZ. N Diels-Adlder R 1 NR 2 Aspergillin PZ R 5 R 1 R 4 R 3 Prins-pinacol R 1 R 3 Juraj Wipf Group Page 3 of 15 12/28/2011

4 Stereochemical analysis of the Prins-pinacol reaction R 1 R 3 R 1 R 1 R 4 R 5 R 3 Me R 5 Pr ins chair R 3 Me R 5 R 1 R 3 R 1 R'' C R 5 Me R 5 R 3 R 1 R 4 R 5 R 3 R 1 R 3 Me R 5 R 1 R 3 Me R 5 R 1 R 3 Pr ins boat R 3 C R'' R 5 R 1 R 5 Me Juraj Wipf Group Page 4 of 15 12/28/2011

5 Synthesis of the Prins-pinacol rac-precursors. 1-r ac C 2 Me m-cpba, Me, 0 o C 90%, d.r.: 4:1 Me C 2 Me 2-r ac 1) TBSCl, imidazole, DMF 2) DIBAL-, Et 2, -78 o C 85%, 2 steps TBS Me 3-r ac TBDPS i) n-buli, TF, -78 o C ii) 3-r ac, TF, -78 o C to rt 95% d.r.: 1.3:1 TBS TBDPS TBS TBDPS Me 4a-rac Me 4b-r ac 1) TBSTf, pyridine, DCM, -78 o C 2) Lindlar cat., 2, Et %, 2 steps TBDPS TBDPS TBS TBS Me TBS Me TBS 5a-rac 5b-r ac Juraj Wipf Group Page 5 of 15 12/28/2011

6 Unexpected formation of the trans aldehydes Br TBS Me 5a-rac TBDPS SnCl 4, DCM, 0 o C 49% TBS TBS 6a-rac TBDPS 1) NaB 4, 2) p-brbzcl, DMAP, TEA 3) TBAF, Ac 73%, 3 steps TBS 7-r ac TBS TBDPS Me 5b-rac TBS SnCl 4, DCM, 0 o C 58% TBS 6b-rac TBDPS Juraj Wipf Group Page 6 of 15 12/28/2011

7 Synthesis of the Prins-pinacol rac-glycosyl acetate. 1-r ac C 2 Me i) DMD 1) TBSCl, imidazole TBS ii) EtS, TFAA 2) DIBAL-, Et 2, -78 o C 69%, d.r.: 7:1 EtS C 2 Me 70%, 2 steps EtS 8-r ac 9-r ac TBDPS i) n-buli, TF, -78 o C ii) 9-r ac, TF, -78 o C to rt 98%, d.r.: 1.3:1 TBS EtS 12-rac TBDPS TBS 1) Pd/CaC 3, 2, quinoline 2) TBSTf, 2,6-lutidine 84 %, 2 steps TBS EtS TBDPS 11-rac 1) Swern oxid. 2) DIBAL- 60%, 2 steps TBS EtS TBDPS 10-rac Juraj Wipf Group Page 7 of 15 12/28/2011

8 Initiation of the Prins-pinacol cascade at low temperature from glycosyl acetate 13-rac TBS TBDPS 1) MeI, Ag 2 C 3, MeCN/ 2 2) Ac 2, DMAP, pyridine TBS TBDPS SnCl 2, DCM, -78 o C TBS 6a-r ac TBDPS EtS 12-rac TBS 93 %, 2 steps Ac 13-r ac TBS 42%, d.r.: 1.3:1 TBDPS TBS 14-r ac Juraj Wipf Group Page 8 of 15 12/28/2011

9 Potential Prins-pinacol and 2- oxonia[3,3]sigmatropic/aldol pathways. Prins-pinacol pathway TBS TBS TBS R 2 TBS R 2 TBS R 2 R 2 TBS X TBS SnCl 4, DCM TBS R 2 TBS epimerization X = Me X = Ac TBS R 2 TBS TBS TBS R 2 TBS R 2 2-oxonia[3,3]sigmatropic/aldol pathway Juraj Wipf Group Page 9 of 15 12/28/2011

10 Deuterium labeling experiments and epimerization of cis aldehyde epimer 14-rac under various reaction conditions TBDPS Conditions TBDPS TBDPS TBS 14-rac TBS 14-rac TBS 6a-rac syn anti TBS Ac 13-rac TBDPS TBS 2.1 eq., SnCl 2, 1.5 eq., CD 3 D DCM, -78 o C TBS 6a/14-r ac TBDPS Entry Conditions cis trans 1 BDU, toluene, r.t. 12 h - 100% 2 TEA, DCM. -78 C r.t. 12 h 100% - TBS Ac 15-rac TBDPS D D TBS 0.5 eq., SnCl 2, DCM, -78 o C TBS D D 16-rac TBDPS eq. SnCl4, DCM, -78 C, 30 min 100% eq. SnCl4, DCM, 0 C, 15 min 34% 66% eq. N(Tf)2, DCM, -78 C 0 C, 30 min 100% eq. N(Tf)2, DCM, 0 C, 30 min 20% 80% Ratio of cis/trans determined by integration of 1 NMR spectra Juraj Wipf Group Page 10 of 15 12/28/2011

11 Synthesis of enantioenriched trans-8- oxabicyclooctyl aldehyde. C 2 Me 1-(+) (92% ee) 1) m-cpba, Me 2) TBSCl, imidazole 3) DIBAL- 42%, 3 steps TBS Me Zn(Tf) 2, TEA, (+)-N-methylephedrine TBDPS TBS Me 3 92% 4a TBDPS 1) TBSTf, pyridine, DCM, -78 o C 2) Lindlar cat., 2, Et 2 80 %, 2 steps TBS 6a TBDPS SnCl 4, DCM, 0 o C 49% TBS Me 5a TBDPS TBS Juraj Wipf Group Page 11 of 15 12/28/2011

12 Preparation of cis-8-oxabicyclooctyl aldehyde. TBS 6a TBDPS TBAF, Ac 77% TBS 17 1) NaCl 2, Na 2 P 4 2-methyl-2-butene 2) EDCl, Bt, DMAP 66% 2 steps TBS 18 DBU, benzene reflux 83% TPAP, NM, 4Å MS 1) LiAl 4 2) TBDPSCl, DMAP, pyridine TBS 14 TBDPS 97% TBS 20 TBDPS 65% 2 steps TBS 19 cis-aldehyde 14 in 27% overall yield from its trans epimer 6a. Juraj Wipf Group Page 12 of 15 12/28/2011

13 Preparation of Diels-Alder precursor. I () 2 B CrCl 2, CI 3 44% PdCl 2 (dppf), K, TF, 2 93% TBS 14 TBDPS TBS 21 TBDPS TBS 22 TBDPS 1) TBAF, Ac 2) Swern oxid. 88% 2 steps i) LiMDS TBS NBz Dess- Martin periodinane NaC % TBS NBz ii) 23 Bz N 90% TBS Juraj Wipf Group Page 13 of 15 12/28/2011

14 Completion of the (+)-Aspergillin PZ. 1) 2 2, m-cpba TBS NBz i) LiMDS ii) PhSeCl 83% TBS PhSe NBz -50 o C to 0 o C 2) toluene 100 o C 56%, 2 steps TBS NBz ) Na, 2, Me 2) TBAF, TF 67%, 2 steps N (+)-Aspergillin PZ Juraj Wipf Group Page 14 of 15 12/28/2011

15 Conclusion. Autors showed evidence that the cascade transformation can take place by a 2-oxonia[3,3]sigmatropic/aldol pathway as well as by the more common Prins-pinacol mechanism. The (+)-Aspergillin PZ was synthesized in owerall 0.23 % yield after 25 steps. The syntetic sample of (+)-Aspergillin PZ was tested against two highly invasive tumor lines (A2058 melanoma and DU145 prostate cancer) and no useful activity (IC 50 >10 µm) was found in either cell line. Prins Pinacol N [3,3]sigmatropic aldol (+)-Aspergillin PZ Juraj Wipf Group Page 15 of 15 12/28/2011