Recent Highlights from the                Nicolaou Laboratory                                            Me               ...
Haplophytine                                                               Me                                             ...
Retrosynthesis of the “Left Domain” of Haplophytin                                                       CO2Me            ...
Synthesis of indole fragment    NH      NCCO2Me, CH2Cl2, 0 °CN                                       NH                   ...
Synthesis of the indoline fragment            CHO          1. Ac2O, Et3N, cat. DMAP                        CHO            ...
Coupling of indole and indoline fragments                                                                         N CO2Me ...
Completion of the construction of the   “left domain” of haplophytin
Uncialamycin                          Me             O   HN        OH                      O                          OH  ...
Nicolaou’s retrosynthesis of uncialamycin                                                                   Me            ...
Synthesis of the substituted quinoline system                                            O                                ...
Introduction of the enediyne functionality                                                                TMS       Me    ...
Intramolecular acetylide addition to form the enediyne ring system                            H                           ...
Synthesis of Biyouyanagin A  (H. chinense L. var. salicifolium)• Isolated from the leaves of a Hypericum species in 2005.•...
Structural assignment of biyouyanagin A                H                                                         HMe      ...
Biyouyanagin A retrosynthesis              H                                            HMe                Me             ...
Synthesis of the terpene-derived diene                                         Cl                                         ...
Formation of the spirolactone
[2+2] Photocycloaddition              H                                                                             HMe   ...
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Nicolaou

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Nicolaou

  1. 1. Recent Highlights from the Nicolaou Laboratory Me H Me Me Me O HN OH H H H O O Me OH O O H Ph O Me O OH Biyouyanagin ATruncated Haplophytine Uncialamycin Christina S. Stauffer Ch i ti S St ff February 27, 2008
  2. 2. Haplophytine Me N O O N N HO O MeO N O H OMe Me Haplophytine p p y CO2Me N N O O N 9 9 O 15 MeO N O H N OMe Me MeO OMe CO2Me Aspidophytine Truncated haplophytine Syntheses: Corey, 1999 Fukuyama, 2003 Padwa, 2006 Marino, 2006• Potent insecticidal alkaloid alkaloid.• Isolated in 1952 by Snyder and co-workers from Mexican plant Haplophyton cimicidum.• Consists of a central indole moiety with two tetracyclic heterocycles attached. attached• Four reported syntheses of aspidophytine, while only one report of studies towards the left-hand domain (Corey, 2006).
  3. 3. Retrosynthesis of the “Left Domain” of Haplophytin CO2Me N O O N 9 15 MeO M O N OMe CO2Me Truncated haplophytine N N CO2Me H HO N OH CO2Me CO2Me Nicolaou, K. C.; Majumder, U.; Roche, S. P.; Chen, D. Y.-K. Angew. Chem. Int. Ed. 2007, 46, 4715-4718.
  4. 4. Synthesis of indole fragment NH NCCO2Me, CH2Cl2, 0 °CN NH N CO2Me 51% H CO2Me CO2Me
  5. 5. Synthesis of the indoline fragment CHO 1. Ac2O, Et3N, cat. DMAP CHO 2. fuming HNO3HO HO NO2 3. aq. KOH, reflux OMe OMe 69%1. K2CO3, BnBr, DMF2. CH3NO2, NaOH, , NO2 1. Fe, AcOH, tol, 110 °C MeOH/H2O, 0 °C 2. KHMDS, NCCO2Me,3. Ac2O, NaOAc, 140 °C BnO NO2 THF, -78 °C 88% OMe 96% 1. Pd/C, H2, MeOH , HO NBnO N 2. BBr3, CH2Cl2, -78 °C to 0 °C OH CO2Me OMe CO2Me 86%
  6. 6. Coupling of indole and indoline fragments N CO2Me PIFA = PhI(CF3CO2)2 OH O CH2Cl2, CH3CN, -40 °C NN CO2Me HO N OH 25% OH CO2Me N CO2Me N CO2M Me H CO2Me N CO2Me N CO2Me OMe OM OMeCs2CO3, MeI DMF OMe NaH, THF OMe 60% N 80% N N CO2M Me N CO2Me O CO2Me
  7. 7. Completion of the construction of the “left domain” of haplophytin
  8. 8. Uncialamycin Me O HN OH O OH O OH Cladonia uncialis• A recently discovered enediyne antibiotic isolated in 2005 by Anderson from the surface of the lichen, Cladonia uncialis.• The scarcity of uncialamycin (300 μg) limited structural elucidation (C26 hydroxyl group was unassigned).• Potent biological activity demonstrated against S. aureus, E. coli, and B. cepacia.
  9. 9. Nicolaou’s retrosynthesis of uncialamycin Me O HN OH O OH O OH Me CN N O O OTES H TMS O ODMBNicolaou, K. C.; Zhang, H.; Chen, J. S.; Crawford, J. J.; Pasunoori, L. Angew. Chem. Int. Ed. 2007, 46, 4704-4707.
  10. 10. Synthesis of the substituted quinoline system O Me HN O CO2H OMe O Me1. 48% aq. HBr, N Me HCO2H, Et3N, N nBu4NBr, 110 °C O CH2Cl2, 0 °C CO2DMB2. DMBBr, K2CO3, O nBu4NI, DMF Me Me ODMB ODMB 55% Ts Ph N Ru N Me Ph H2 Cl 95%, 98% ee Me OMe N 1. DIBAL-H, CH2Cl2 O O DMB = 2. TESCl, im, DMF OTES Ph OMe 86% OR ODMB
  11. 11. Introduction of the enediyne functionality TMS Me Me TMS 1. AcOH, MeCN, MeN AllocN H2O, 91% O H TMS O 2. NaBH4, MeOH AllocN OH O OTES EtMgBr, AllocCl OTES 3. mCPBA, CH2Cl2 92% 80% (2 steps) OAcODMB ODMB 4. AcCl, collidine, 82% ODMB TMS H Me 1. TESCl, Im, Me 1. Dess-Martin AllocN OH DMF O AllocN OTES O 2. 2 NaBH4, MeOH 2. 2 K2CO3, THF OAc MeOH 90% OH 78% ODMB ODMB
  12. 12. Intramolecular acetylide addition to form the enediyne ring system H H Me 1. Dess-Martin, 87% Me CeCl3, KHMDS - 78 °C to - 40 °C AllocN OTES 2. DDQ, 2 DDQ CH2Cl2/H2O AllocN OTES O O 61% 87% (30% C17 epimer) OH O ODMB OH Me Me 1. PhI(OAc) MeOH 1 PhI(OA )2, M OH AllocN OTES 80% N OTES CN O 17 O OH OH 1. 2. [Pd(PPh3)2Cl2] O nBu3SnH, H2O, CH2Cl2, 74% O OH O LiHMDS, 63% 2. 3HF•Et3N, THF 92% Me O HN OH O OH O OH Uncialamycin
  13. 13. Synthesis of Biyouyanagin A (H. chinense L. var. salicifolium)• Isolated from the leaves of a Hypericum species in 2005.• Traditionally used as folk remedy for female disorders.• Shows significant activity against HIV and lipopolysaccharide-induced cytokine production.• Stereochemistry at C24, C17, C18 needs to be elucidated.
  14. 14. Structural assignment of biyouyanagin A H HMe Me Me Me Me Me H H H O H H H O Me Me O O O O H Ph O H Ph O Me Me Originally proposed possible structures H H Me Me Me Me Me H H H O Me H 24 H H O Me Me 17 18 O O O O H Ph H Ph O Me O Me Nicolaou, K. C.; Sarlah, D.; Shaw, D. M. Angew. Chem. Int. Ed. 2007, 46, 4708-4711.
  15. 15. Biyouyanagin A retrosynthesis H HMe Me Me Me Me O Me H H H O Me H Me [2 + 2] O O O O Ph H Ph O Me O Me
  16. 16. Synthesis of the terpene-derived diene Cl Tf N N Tf Comins reagent
  17. 17. Formation of the spirolactone
  18. 18. [2+2] Photocycloaddition H HMe Me Me Me O Me Me H h , 2-acetonaphthone H H H O Me Me CH2Cl2, rt, 5h O O O Ph 46% O O H Ph O Me Me H Me Me H Me OO Me O O Me (exo)

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