Problem session (3) Yuri Takada. Please fill in blanks and provide the mechanism of the following reactions. 1.

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1 Prolem session () Plese fill in lnks nd provide the mechnism of the following rections Yuri Tkd , ()-,'- 2 -BL (20 mol%) t-bu, Å MS, Ph, 0 C, 80% MMCl, ipr 2 Et, C 2 Cl 2, rt 2. C 2, Et 2, 70%, 2 steps. [Cu(C) ]Tf ( mol%), -py ( mol%), AB (1 mol%), -methylimidzole (1 mol%), C, rt; open to the tmosphere, 92% the sme conditions ove C 9 C9 1- : 1- = 1.2 : 1 (distereomer) 1- MM 1. Sm 2 ( eq.), 2 (6 eq.), TF, 0 C; TMSCl, ( eq.), 9%, d.r. = 2:1 2. LiMDS, TPSTf, TF, -78 to 0 C, 76%. Mn(dpm) (1 mol%), PhSi, TBP, ipr, rt, %. Li/, Et, -78 C, 61%, d.r. = :1 MM 1-1. Sm 2 ( eq.), 2 (6 eq.), TF, 0 C; TMSCl, ( eq.), 20% MM TPS 1-2. Piv Sm 2 (2. eq.), TF/tBu, 0 C, 88% Piv steps C , % Pd/C, Et, rt, 9%, d.r. = :1 2. 1,2-ethnediol, C(C ), Amerlyst 1 ( eq.), Ph, C, rt, 96%. Sm 2 (20 eq.), pyrrolidine (60 eq.), 2 (60 eq.), TF, rt, 9% 2 C 2-2 TBS 2 C 2-2- TBS TBS () 2 B 1-2 Trt ()-,'- 2 -BL -1- AB t-bu t-bu Mn(dpm) Mn

2 Prolem session ()-Answer Yuri Tkd ntroduction 1 pleuromutilin (0-1) 9 <soltion> from edile mushroom Pleurotus mutilus (Clitopilus scyphoides) (Kvngh, F.; ervey, A.; oins, W. J. Proc. tl. Acd. Sci. USA 191, 7, 70.) <Bioctivity> nticteril ctivity (Grm-positive) y inding to the riosome 0-2 retpmulin (ALTABAX, GlxoSmithKline) ntiiotics for humn S (W 201/081 A1) 0- timulin (Denegrd, ovrtis Animl elth) ntiiotics for pigs nd poultry S Et 2 S 0-2 -epi derivtive ctive ginst Grm negtive cteri 6 2 <Structurl fetures> * * * 9 * * * * * <proposed iosynthetic pthwy> structurl fetures tricyclo skeleton 8-memered ring 8 stereogenic centers* three quternry crons (C, 9, ) PP Clss domin PP 6 PP 0- B PP Clss domin 2 pleuromutilin (0-1)

3 <Totl synthesis> rcemic totl synthesis Gions, E. G. J. Am. Chem. Soc. 1982,, Boeckmn,. K. Jr.; Springer, D. M.; Alessi, T.. J. Am. Chem. Soc. 1989, 1, 828. ) (10622_PS_Tro_ASABA) enntiomeric totl synthesis Fzkerley,. J.; helm, M. D.; Procter, D. J. Chem. Eur. J. 201, 19, (prolem 2) Murphy, S. K.; Zeng, M.; erzon, S. B. Science, 2017, 6, 96. (170617_LS_iroki_Mto) Frney, E. P.; Feng, S. S.; Schäfers, F.; eismn, S. E. J. Am. Chem. Soc., 2018, 0, 67. (prolem 1) Gions (1982) MM MM 8 Gro frgmenttion 0-1 MM Bn 17 steps Bn Bn (totl: 27 steps) Boeckmn (1989) K, het oxy-cope Procter (201), prolem 1 Piv Sm 2 2 C 2 C 8 steps steps (totl: 27 steps) Piv steps (totl: steps) erzon (2017) t-buli; Boc Cl PMB i(cod) 2, Pr steps Et Si; eismn (2018), prolem 2 TBAF PMB 7 steps (totl: 19 steps) 0-1 MM MM 0- steps 0-22 Sm steps (totl: 18 steps)

4 , ()-,'- 2 -BL (20 mol%) t-bu, Å MS, Ph, 0 C, 80% MMCl, ipr 2 Et, C 2 Cl 2, rt 2. C 2, Et 2, 70%, 2 steps. [Cu(C) ]Tf ( mol%), -py ( mol%), AB (1 mol%), -methylimidzole (1 mol%), C, rt; open to the tmosphere, 92% the sme conditions ove C 9 C9 1- : 1- = 1.2 : 1 (distereomer) 1- MM ()-,'- 2 -BL () 2 B 1-2 Trt 1-7 B 1-7 Trt = B B 1-8 Trt 1-8c fvored disfvored Trt Trt B B Trt d not form Trt Trt not form 1- : 1- = 1.2 : (, -is-epi 1-)

5 MM Trt Cl Trt Trt MM MM MM Trt oxidtion 1-1- ctlytic cycle for Cu /AB-ctlyzed eroic lcohol oxidtion -py C C -methylimidzole (M) Cu Tf C C A sustrte oxidtion rte-determining step for CyC 2 oxidtion AB( ) 2 1/2 2 2 G Cu [Cu] M step step 6 Cu AB() F 2 2 Tf M step 7 Tf step 2 B Cu 2 AB( ) M E -- Cu Tf step 1 B 2 AB() Cu M M Tf M Sthl, S. S. et l. J. Am. Chem. Soc. 201, 1, 172. J. Am. Chem. Soc. 201, 1, M Tf Cu step Cu step 2 ( 2 ) D C M M Cu AB( ) (-py)cu (M) B -py ctlyst oxidtion rte-determining step for PhC 2 oxidtion Tf (-py)cu (M) B 2 2 (Tf) AB()

6 D LCu Cu L -1,2-peroxo LCu Cu L - 2 : 2 -peroxo LCu is( -oxo) Cu L ctlytic cycle 2 for Cu /AB-ctlyzed eroic lcohol oxidtion AB- L n Cu 1/2 2 AB L n = -py, M, C C M, L n Cu - M X - 1/2 [L n Cu ] AB- L n Cu - AB Cu L n -X M X - M, 2 1/2 [L n Cu ] 2 2 rte = k 1k 2 [Cu] 2 tot[ 2 ] k -1 k 2 [Cu] tot [Cu] tot k -1 1 = rte k 1 k 2 [Cu] tot [ 2 ] k 1 [ 2 ] 1/2 2 Cu/TEMP step 1 Cu 2 k 1 k -1 2 Cu k 1 =.2 M -1 s -1 k -1 /k 2 =.8 - M -1 step 2 Cu Cu k 2 Cu -( 2 )-Cu xommonium-bsed xidtion Pthwy 1/2 2 2 L n Cu X X X 2 2 L n Cu X 2-6-

7 MM 1. Sm 2 ( eq.), 2 (6 eq.), TF, 0 C; TMSCl, ( eq.), 9%, d.r. = 2:1 2. LiMDS, TPSTf, TF, -78 to 0 C, 76%. Mn(dpm) (1 mol%), PhSi, TBP, ipr, rt, %. Li/, Et, -78 C, 61%, d.r. = :1 MM 1-1. Sm 2 ( eq.), 2 (6 eq.), TF, 0 C; TMSCl, ( eq.), 20% MM TPS selectivity of reduction reduction potentil of cronyl groups (vs. SCE) < < < < < -2. V -2.2 V -1.8 V -1. V -1. V -1.2 V eduction of ldehyde is esier thn ketone eduction of, -unsturted ktone is esier thn ketone MM more ccecile MM MM pth MM electron rich rdicl 8-endo Sm 2 cycliztion Sm 2 congestion Sm Sm MM 1- electron deficient olefin MM MM pth selectivity of reduction (C nd C) pth : 8-endo cyclistion or pth : 7-exo cyclistion C:, -selectivity of -Sm 2 group exo Sm 2 cycliztion 1- Sm 2 MM MM MM Sm 2 Sm 2 1- Sm Sm 2-7-

8 (cse: reduction from C -> C) MM MM MM Sm 2 Sm Sm 2 2 Sm 1-18 MM 8-memered ring formtion Sm 2 2 Sm pttern 1: 7-memered ring formtion MM Sm Sm 1-19 MM Bot form 1-20 MM Sm 2 7 Chir form MM 17 Sm 2 Sm MM -8-

9 pttern 2: 8-memered ring formtion (pth ) 8-memered ring formtion BC (Bot-Chir) CC (Chir-Chir) 2 eclipsed linkge more stle 8-memered ring conformtion eclipsed linkge BB (Bot-Bot) T MM Sm 2 MM 2 Sm MM MM Sm 2 MM Sm Sm 2 9 MM MM :

10 20 more ccecile MM TPS-Tf 1-27 Si Si Li MM TPS The chemoselective reduction of the more sustituted lkene likely reflects incresed trnsition stte stiliztion of the developing tertiry rdicl. Mn (dpm), PhSi -Mn (dpm) 2 -dpm MM Mn (dpm) 2 MM MM MM Mn (dpm) 2 Mn(dpm) [Mn ] [1,]-AT TPS TPS TPS TPS 1-2 MM C lcohol is protected perform poorly under the AT conditions suggests tht clevge of the - ond to form the C ketone serves s driving force for this trnsformtion. TPS 1- single distereomer MM MM X Mn(dpm), PhSi TBP, ipr, rt MM X 1- (X =/D) 1-6 (X =/D) = X =, 6% X = D, 7% >98% D trnsfer TPS 1- = protecting group X =, 6-% conversion C stereocenter: mixture of distereomer MM Li/ e - MM -Et MM e - TPS TPS TPS MM MM TPS 1-9 -Et TPS 1-0 d.r. = :1 2 steps -- ()-pleuromutilin

11 MM MM Sm 2 ( eq.), 2 (6 eq.), TF, 0 C; TMSCl, ( eq.) -epi (77%, d.r. = 17 : 1) -epi-1-16 (88%, d.r. = 2 : 1) MM Sm 2 MM Sm 2 8-memered ring formtion pth MM Sm 2 1- (, -is-epi ) MM pth 2 Sm 7-memered ring formtion 1- MM MM MM 2 Sm 2 Sm Sm 2 2 Sm MM MM

12 2. Piv 1. Sm 2 (2. eq.), TF/tBu, 0 C, 88% Piv steps C 2 2 C 1. 2, % Pd/C, Et, rt, 9%, d.r. = :1 2. 1,2-ethnediol, C(C ), Amerlyst 1 ( eq.), Ph, C, rt, 96%. Sm 2 (20 eq.), pyrrolidine (60 eq.), 2 (60 eq.), TF, rt, 9% C 2-2- TBS TBS Piv Piv Sm Sm Sm Piv 2-6 Piv Sm 2 Sm 2 2 C Piv 2-2 Sm 2-2 Piv cheltion-controlled ldol-cycliztion Sm 2 2 Sm Sm 2 Piv 2- Piv Piv Piv 2- Sm 2 nti--exo-trig cycliztion Piv 2-7 Sm 2 2- Sm 2 6-endo-trig cycliztion Sm Piv --

13 - TBS TBS C 2 TBS C 2-2 Pd/C TBS TBS C 2 C d.r. = : 1 TBS TBS C 2 2- TBS 2-1 TBS C 2 2 TBS TBS TBS TBS TBS C 2 TBS TBS TBS C 2 C 2 C Si TBS or TBS Si C 2 C TBS C = TBS Sm e Sm e e Sm e TBS Szostk, M.; Spin, M.; Procter, D. J. Chem. Commun. 20, 7,

14 effect of se Tle 1 eductnt 2- (%) 2-1 (%) 2-22 (%) LiAl 21 2 Sm 2 /Et / 2 Sm 2 /pyrrolidine/ 2 Sm 2 /MPA/ < The ddition of the se improved the reduction rte. TBS Tle 2 eductnt Stndrd Potentil, V (versus SCE) Sm 2 (TF) Sm 2 -MPA (TF) -1.7 Sm 2 /Et / 2 (TF) TBS Sm 2 TF Sm Sm 2- Sm 2-22 Sm 2- Sm two electron nd two proton trnsfers Sm 2-6 Sm Sm 2-7 Sm two electron nd two proton trnsfers