Problem Seminar (2) 17/02/10 Yuki Fujimoto Please provide following reaction mechanisms O 1. piperylene O HN Rh (OAc) (1 mol%) HN N 2 4 3 2 benzene, reflux NH slow addition of 1-1 in CH 2Cl 2, 71 % 2. 1-3 , MgI 2 (1 eq.), THF, sealed tube, 75 °C 68 % (dr = 6:1 at C3) TIPS 1-1 3. Pd(PPh 3)4 (6 mol%), NDMBA (3.2 eq.) 1-2 CH 2Cl 2, 30 °C, 86 % O O HN N 3 N 1. Dess-Martin periodinane, CH 2Cl 2, rt 18 2. 2-3 , t- BuOK H O O CH 2Cl 2, -78 °C to rt, 64 % (2 steps) N SEM 3. [Pd (dba) ] CHCl (10 mol%) 2-2 spirotryprostatin B I 2 3 3 o + OH P( -tol) 3 (40 mol%), AcOK O O THF, 70 °C, 72 % (dr = 1:1) 4. Me AlCl, CH Cl , -78 °C to rt HN N 2 2 2 3 2-1 5. i- Pr 2NEt, MeOH, 45 °C, 93 ~ 95 % (2 steps) N 18 H O 2-2' 3,18-epi-spirotryprostatin B EtO 2C O O 1. 3-3 , 3-4 , 3ÅMS, toluene, 60 °C, 82 % O H HN 2. H2, PdCl 2 (1 eq.), THF/EtOH, 4 atm, rt, 99 % HN N N CO 2Et 3. D-Pro-OBn, BOP, Et N, MeCN, 0 °C to rt, 74 % 3 H 4. H2, Pd/C, EtOH, rt O 5. BOP, Et 3N, MeCN, rt, 94 % (2 steps) OMe 3-1 3-2 O AcO OAc O O N I OAc P MeN NMe MeO N O MeO HN TMS O O O TIPS O H O 1-3 NDMBA Dess-Martin periodinane 2-3 SEM N O N N O HN O HN BnO PF Ph O OMe N P N 6 Ph O N 3-3 3-4 D-Pro-OBn BOP Problem Seminar (2) 17/02/10 Yuki Fujimoto Topic: total synthesis of spirotryprostatin O O H O O HN N HN N N N H H O O MeO spirotryprostatin A spirotryprostatin B Isolation fermentation broth of Aspergillus fumigatus Osada, H. et. al. J. Antibiot. 1996 , 49 , 832. Osada, H. et. al. Tetrahedron 1996 , 52 , 12651. Biological activity inhibition the G2/M phase of mammalian cell cycle Structual features pentacyclic skeltone including spirooxyindole and diketopiperazine prenyl side chain total synthesis spirotryprostatin A Danishefsky, S. J. et. al. J. Am. Chem. Soc . 1999 , 121 , 2147. Williams, R. M. et. al. Org. Lett. 2003 , 5, 3135 Horne. D. A. et. al. Org. Lett. 2004 , 6, 4249. Fukuyama, T. et. al. Chem. Sci. 2014 , 5, 904. spirotryprostatin B Sebahar. P. R. and Williams, R. M. J. Am. Chem. Soc . 2000 , 122 , 5666. (problem 3) Wang. H. and Ganesan, A. J. Org. Chem. 2000 , 65 , 4685. Overman, L. E. and Rosen, M. D. Angew. Chem. Int. Ed . 2000 , 39 , 4596. (problem 2) von Nussbaum. F. and Danishefsky. S. J. Angew. Chem. Int. Ed. 2000 , 39 , 2175. Fuji. K. et. al. Org. Lett . 2002 , 4, 249. Meyers, C. and Carreira, E. M. Angew. Chem. Int. Ed. 2003 , 42 , 694. (problem 1) Horne, D. A. et. al. Angew. Chem. Int. Ed . 2004 , 43 , 5357. Trost, B. M. and Stiles, D. T. Org. Lett. 2007 , 9, 2763. How to construction C3 stereocenter Danishefsky (spirotryprostatin A), Ganesan: oxidative pinacol rearrangement Br O MeO CO Me MeO CO Me CO Me 2 2 HN 2 NBS N NBoc N NBoc NBoc H THF/H O/AcOH H OH 46 % SPh 2 SPh MeO SPh 0-1 0-2 0-3 Danishefsky, S. J. et. al. J. Am. Chem. Soc . 1999 , 121 , 2147. 1 Fuji: asymmetric nitroolefination N O2N 0-6 OLi OMe O Ph Ph NO 2 TBSN n-BuLi, Et 2O TBSN 86 % (97 %ee) 0-4 0-5 Fuji, K. et. al. Synlett 1995 , 367 . Danishefsky (spirotryprostatin B), Horne: Mannich type cyclization Br TrocN Br 1. O Br 2. CO 2Me CO 2Me Cl HN HN CO 2Me 0-8 HN NH 2 0-10 NH 2 + N O 0-7 0-7' Br Br 0-7 0-7' Br Br : = 3:4 Cl 0-9 O CO 2Me CO 2Me CO 2Me HN TrocN N TrocN HN TrocN Cl H O N N 2 N H H H O O O Br Br Br O O 0-11 H 0-12 0-13 HN N 3. Zn, MeOH N overall 56 % (3 steps) H O Horne. D. A. et. al. Org. Lett. 2004 , 6, 4249. Br 0-14 Trost: Asmmetric Allylic Alkylation Pd (dba) CHCl 2 3 3 Pd (10 mol%) O O O O OO O O O O ligand (12 mol%) HN N HN N HN N HN HN toluene, 60 °C HN H H 89 %, dr = 16:1 H O O O + 0-18 0-16 0-15 (S)(S) O O O O Pd NH HN HN N Ph Ph 0-19 HN P P H Ph Ph O ligand 0-20 Trost, B. M. and Stiles, D. T. Org. Lett. 2007 , 9, 2763. 2 Fukuyama: Heck reaction Problem 1: Carreira's synthesis Retrosynthetic analysis O O O Julia-Kocienski O CO Me 2 HN BocN HN N olefination HN BocN N N N condensation H H H O O O O TIPS spirotryprostatin B 1-4 1-5 O O HN condensation C-H insertion HN NH N2 ring expansion TIPS rac-1-2 rac-1-1 O 1. piperylene O HN Rh (OAc) (1 mol%) HN N 2 4 3 2 benzene, reflux NH slow addition of 1-1 in CH 2Cl 2, 71 % 2. 1-3 , MgI 2 (1 eq.), THF, sealed tube, 75 °C 68 % (dr = 6:1 at C3) TIPS 1-1 3. Pd(PPh 3)4 (6 mol%), NDMBA (3.2 eq.) 1-2 CH 2Cl 2, 30 °C, 86 % N TIPS 1-3 Meyers, C. and Carreira, E. M. Angew. Chem. Int. Ed. 2003 , 42 , 694. 1. C-H insertion O O O O O O Rh II Rh II II II Rh 2(OAc) 4 Rh Rh O O O O 1-6 3 O O O HN HN HN N N O O 1-11 1-10 Rh II Rh II 1-1 1-6 O O N O O N O O HN HN RhIII Rh I RhIII Rh I 1-9 1-7 O O O HN RhIII Rh I 2. ring expansion N2 proposed by author (path A) 1-8 piperilene IMg IMg O O O MgI I HN HN HN 1-11 1-12 1-13 N IMg IMg O O O 1-3-( E) TIPS MgI HN HN HN I R N N stoichiometric MgI 2 R = TIPS 1-14 1-15TIPS 1-16 IMg IMg O O O HN N H2O HN N N N TIPS TIPS TIPS 1-17 1-18 1-16 4 3. removal of allyl group O O HN N MeN NMe 0 Pd L4 O O coordination TIPS decomplexation 1-16 1-20 oxidative addition O O MeN NMe HN O O N Pd PdL 4 1-17 TIPS 1-19 ligand exchange nucleophilic attack O O PdL 2 HN 1-18 MeN NMe NH O OH Discussion NDMBA another passway of ring expansion (path B) TIPS N 1-2 IMg O O I O HN 1-3-( E) TIPS HN HN I N N 1-14 TIPS 1-21 TIPS 1-2 my proposal of stereoselectivity path A O Allyl N TIPS HN OMgI N H bulky TIPS group avoid benzene ring NH 1-15 TIPS 1-2' path B TIPS O R HN N Allyl 6-membered TS make stereochemistry of 1-2 O Mg N N I ring expansion would proceed via pass B H 1-14, 1-3 TIPS 1-2 R = I 5 5-endo-trig VS 5-exo-tet path A path B IMg O O I HN HN R N N R = TIPS 1-15 TIPS 5-endo-trig (disfavored) 1-21 5-exo-tet (favored) example of 5-endo-trig Br Cl CO 2Me CO 2Me HN TrocN N TrocN 5-endo-trig cyclization seems to be allowed. N N But overlap of orbital is not good. H H O O Br Br 0-11 0-12 Problem 2: Overman's synthesis Retrosynthetic analysis O O Heck, Tsuji-Trost O O Horner-Wadsworth- O cascade reaction Emmons reaction HN N N N N O SEM SEM N I HN I H H O O spirotryprostatin B (2-2 ) 2-4 2-5 O O condensation MeO OAc MeO HO 2-6 2-7 O O 1. Dess-Martin periodinane, CH 2Cl 2, rt 2. 2-3 , t- BuOK HN N O 3 CH 2Cl 2, -78 °C to rt, 64 % (2 steps) N 18 N H SEM O I 3. [Pd 2(dba) 3] CHCl 3 (10 mol%) OH P( o-tol) 3 (40 mol%), AcOK THF, 70 °C, 72 % (dr = 1:1) 2-2 spirotryprostatin B 4. Me 2AlCl, CH 2Cl 2, -78 °C to rt O O 2-1 5. i- Pr 2NEt, MeOH, 45 °C, 93 % (2 steps) HN N O O 3 P N MeO N 18 MeO H HN O H O 2-2' 2-3 3,18-epi-spirotryprostatin B Overman, L. E. and Rosen, M. D. Angew. Chem. Int. Ed . 2000 , 39 , 4596. 6 1. Dess-Martin oxidation AcO OAc I OAc O V O O O N O N AcOH N SEM SEM SEM I I I OH AcO O H O AcOH OAc OAc I III V 2-1 O I 2-5 O O 2.