I. Liu Lab. Ka<e Boknevitz 1

Transcription

1 A ighly Convergent Total Synthesis of Leustroducsin B Barry M. Trost,* Berenger Biannic, Cheyenne S. Brindle, B. Michael Keefe, Thomas J. unger, and Ming-Yu gai Department of Chemistry, Stanford University, Stanford, CA, United States J. Am. Chem. Soc. 2015, 137, ntroduc@on 3 P Leustroducsins A-C isolated from soil bacterium Streptomyces platensis SAK in 1993 by Kohama et al. 2 oslactomycin family Leustroducsin B has shown: Leustroducsin B (1) in vitro inducwon of cytokine producwon by KM-102 cells ncrease of host n vivo resistance to E. coli infecwon Thrombocytosis inducwon in mice 5 previous syntheses of Leustroducsin B, shortest one being 37 linear and 64 total steps 3 1. Trost, B. M. et al. J. Am. Chem. Soc. 2015, 137, a. Kohama, T. et al. J. An<biot. 1993, 46, b. Kohama, T. et al. J. An<biot. 1993, 46, a. Shimada, K. et al. J. Am. Chem. Soc. 2003, 125, b. Miyashita, K. et al. Tetrahedron Le. 2007, 48, c. Miyashita, K. et al. J. rg. Chem. 2008, 73, d. Mise, J. et al. Synle 2008, 2008, e. Druais, V. et al. Tetrahedron 2010, 66, f. Grezler, S.. et al. rg. Le. 2011, 13, g. Matsuhashi,. et al. Tetrahedron 2002, 58, Ka<e Boknevitz 1

2 Analysis of Leustroducsin B. Analysis PMB 3 6 P steps Me TBS Proenol aldol Leustroducsin B (1) 2 Evans aldol Pd AAA C 7 C 8 : α-alkoxy-directed diastereoselecwve vinyl zinc addiwon between 2 and 3 C 13 C 14 : modified iyama cross-coupling to introduce 4 Eastern fragment 2: Evans aldol Central fragment 3: zinc-proenol-catalyzed aldol reacwon Western fragment 4: Pd-catalyzed asymmetric allylic alkylawon 4 2

3 V. Forward Synthesis Synthesis of Eastern Fragment Si 3 Bu 2 BTf, 3 87%, dr > 20:1 7 Si 3 DBAL- 90% conv 8 Si 3 9 P 3 Br TDA, K 2 C 3 56% (from 7) + 2:1 Si Si 3 5 to 7: Evans aldol 3 Bu 2 BTf 5 BBu Si [B] 3 Si [B] 7 7 to 8: DBAL reduction 7 Al Al Al 2 Al 2 8 TDA 3 8 to : ase-transfer Wittig condtions TDA P 3 Br P 3 9 ' 3 P ' 10 Si 3 B Si 3 PT 11 3

4 Synthesis of Eastern Fragment 2 + 2:1 Si Si 3 Ts, Me then K 2 C 3 Me 11a Cp 2 ZrCl then 2 62% Me to 11a: Ketalization Me Me 10 Si 3 - Si 3 Me K 2 C 3 Me 11a Me Si 3 Si 3 Me 11a to 2: ydrozirconation/iodination Me Cp 2 ZrCl ZrCp 2 Cl 11a 2 ZrCp 2 Cl Me 2 4

5 Synthesis of Central Fragment 3 LDA 3 PC 2 Br DBAL MeC atbu 66% for 45% 2 steps a 14 Me 15 (S,S)-Proenol cat. Zn 2 cat. 78%, 99% ee to 13: Aldol addition 12 Li Li Me Li Me to 16: Zinc--Proenol-catalyzed aldol reaction Me 2 Zn (2 equiv.) TF Zn Zn Me 14, 15 Me 2 Si Zn Zn 16 Trost, B. M.; to,.; Silcoff, E.. J. Am. Chem. Soc., 2001, 123, Trost, B. M.; Fehes A.; Shireman, B. T. J. Am. Chem. Soc., 2004, 126, Me 5

6 Synthesis of Central Fragment 3 (,)-oyori cat. TBSCl imidazole TBS 16 ipr 16a 80% dr >20: to 16a: oyori asymmetric transfer hydrogenation ' 16a Ts ul Ts u ' 16 Ts 2 ul (,)-TsDPE-u(p-cymene) TBS PMB 18 Cl PMB TBS Ac, 2, Me 2 C then a 3 PMB 3 TBS 17 i-pr 2 97% 19 91% 3 19 to PT a 3 6

7 Synthesis of Western Fragment 4: Materials K (6 eq.) 2 (1.05 eq.) ac 3 (3 eq.) 2 80% DBU (1.5 eq.) TF, reflux 92% (+/-)-20 2 odolactonization/elimination (+/-)-20 TBS Tf nbuli 52% TBS 2, Pd/C 100% conv. TBS 1) CSA, Me 2) Jones eagent 76% 22 TBS nbuli TBS Li Tf TBS Jones oxidation Cr 3 2 S 4 2 Cr Cr - Cr 2 PT 2 Trost, B. M.; ichardson, J.; Yong, K. J. Am. Chem. Soc. 2006, 128, Marshall, J. A.; Xie, S. J. rg. Chem. 1995, 60,

8 Synthesis of Western Fragment 4 t-buk cat. ClC 2 Me 3 70% over 2 steps (+/-)-20 (+/-)-20a (+/-)-21 C 2 Me 22 (S,S)-Trost Ligand cat. (n 3 C 3 5 PdCl) 2 cat. a, TAB 93%, 99% de to 21 Cl Me C 2 Me (+/-)-20 (+/-) to 23: Allylic asymmetric alkylation 23 C 2 Me 2 P P 2 Pd 0 L n * Pd 0 L n * (+/-)-21 (S,S)-Trost ligand ' C 2 Me Pd 0 L n * Br a Pd L n * TAB 22 8

9 Synthesis of Western Fragment 4 1) 2, Pd/C DMP ac 3 ( 3 PC 2 ) amds 23 2) B 3 SMe 2 89% 24 C 2 Cl 2 24a 55% for 2 steps >20:1 Z:E 4 24 to 24a: Dess Martin oxidation Ac Ac Ac 24 Ac 24a 24a to 4: Stork-Zhao olefination 3 P 3 P 24a 4 9

10 Controlled of 2 to 3 Me 2 nbuli, Me 2 Zn TF, 78 C 10min Me ZnMe 2 Li 3 in C 2 Cl 2 78 C, 9h 75% dr > 20:1 PMB TBS 3 Me 26 3 PMB 3 TBS Me Lithium alogen Exchange Me Me 2 nbuli Li 25 ZnMe 2 Li PMB ' ' TBS ZnMe 2 Li " ZnMe 2 Li 3 " ZnMe 2 Li Me 26 10

11 of the Synthesis of Leustroducsin B PMB PMB PMB TBS 3 Me 26 PCC 67% 3 TBS 30 S % (76% brsm) 3 TBS 32 PMB TES 4 PMB 4 11 mol % Pd 2 dba 3 TBAF, Ac 70% 3 TMS 34 TESTf, lutidine then TMSTf 100% conv DDQ 66% (from 33) 3 TES TMS 35 Allyl P Allyl 36 tetrazole then tbu 50% Allyl P Allyl TES 3 TMS 37 11

12 of the Synthesis of Leustroducsin B 30 to 32: Diimide reduction TBS S 2 S 2 30 TBS TBS to 33: iyama cross-coupling ' 33 [Pd] 0 4 E A ' [Pd] [Pd] TM SiFMe 2 ' F TBAF ' 32 12

13 of the Synthesis of Leustroducsin B 34 to 35: DDQ deprotection of PMB Cl Cl ' C C 34 Me 2 Me ' PT Me ' ' to 37 Allyl P Allyl PT Allyl P Allyl Allyl P Allyl ' Allyl 35 P Allyl PT ' 36 PT tbu 37 Allyl Allyl P ' tbu ' Allyl P Allyl 13

14 of the Synthesis of Leustroducsin B Allyl P Allyl TES 3 P 3, 2 /TF then AllocCl, pyridine Alloc Allyl Allyl P TES TMS 37 72% TMS 38 Pd(P 3 ) 4 cat. C 3, 3 55% 1. F, pyridine 2. Pd(P 3 ) 4 cat. P 3, C 3, 3 3 P (+)-Leustroducsin B (1) 14

15 of the Synthesis of Leustroducsin B 37 to 38: Staudinger eaction 37 P 3 3 P 3 P 3 P 2 Cl Cl 2 37 to 38: Allyl deprotection and acidic desilylation Pd(P 3 ) 4 C 3, 3 Si Si [Pd] [Pd] 0 [Pd] Conclusion: Synthesis of Leustroducsin B achieved in 17 longest linear sequence and 39 total steps ighly efficient and convergent United 3 fragments for convergent synthesis Last step involved removal of 3 allyl and 2 silyl groups in one step 15