Nineteen-step Total Synthesis of (+) - Phorbol

Transcription

1 Nineteen-step Total Synthesis of (+) - Phorbol Shuhei Kawamura, ang Chu, Jakob Felding, and Phil Baran 1 Cyclase Phase TMS TBS xidase Phase Advanced Intermediate [1] (+) Phorbol [2] 2 xidase Phase [1] Science 2013, 341, 878. [2] Nature 2016, 0, 1. Evan Carder Wipf Group Current Literature April 09, 2016

2 Phorbol Background Phorbol and phorbol derivatives are members of the tigliane diterpenoid family. The tigliane diterpenoid family are isolated from the Euphorbiaceae and the Thymelaeaceae family members 1. Structural elucidation was confirmed by Xray crystallography of a phorbol derivative in C" A" D" 15 7 B" Structural characteristics: Tigliane diterpenoids have a 5/7/6/3- tetracyclic ring system consisting of a five-membered ring (A), a seven-membered ring (B), a six-membered ring (C), and a cyclopropane system (D). Phorbol has a polyhydroxylated tigliane carbon skeleton that contains eight contiguous asymmetric centers, six of which are sited around the sixmembered C ring. Phorbol derivatives are isolated as mixed esters, most commonly existing as 12,13 or 13,20-diesters. [1] Arch. Exp. Pathol. Pharmakol. 1935, 177, 212. [2] Angew. Chem. Int. Ed. Engl. 1967, 6, /09/16 Evan Wipf Group 2

3 Protein Kinase C (PKC) Activation and Tumor Promotion Stimuli As a downstream effector of G-protein coupled receptors and receptor tyrosine kinases, PKC propagates important signaling events. Deregulation of PKC has been associated with multiple cancer-promoting pathways, which can lead to an array of adverse phenotypes. PLC Therefore, PKC has been implicated in the development and progression of disease. DAG PKC is commonly activated by second messenger molecule 1,2-diacylglycol (DAG) at the cellular surface. PKC Phorbol Phorbol esters have been shown to strongly activate PKC and potently promote tumor development - tetradocecanoyl phorbol acetate is active at 20 nm. Paradoxically, deoxygenated derivatives can inhibit tumor formation; therefore, synthesis of phorbol and phorbol derivatives may provide therapeutically active agents toward the treatment of cancer. Anti-Apoptosis Survival P Effector DNA Synthesis Proliferation Motility Angiogenesis Carcinogenesis Tumor Progression [1] Nature Review 2011, 11, 937. [2] J. Bio. Chem. 2000, 275, /09/16 Evan Wipf Group 3

4 Efforts toward the synthesis of Phorbol Paul Wender and co-workers: Racemic total synthesis, 52 steps, 0.16% overall yield 1 Racemic formal synthesis, 42 steps, 0.02% overall yield 3 Asymmetric formal synthesis; 36 steps, 1.2% overall yield 4 2:1 E/Z Rigby Lab [4+2] cycloaddition 2 C 8 kbar 2:1 dr (exo) 60% Z is unreactive Tet. Lett. 1989, 30, C 2 Jin Kun Cha and co-workers: Asymmetric formal synthesis, 43 steps, 0.4% overall yield 5 Work from the labs of Shibasaki, Wilson, Rigby, arwood, Little, Page, Dauben, McMills, Paquette, Singh, vaska, West, Evans, Li, and others. A-B-C-D, B-C-D, A-B-C skeletal components Dauben Lab carbonyl ylide cycloaddition Et 2 C N 2 Ac Rh 2 (Ac) 4 toluene, 100 o C 86% (both isomers) J. rg. Chem. 1993, 58, Ac C 2 Et C" D" A" B" Paquette Lab anionic oxy-cope LDA TF, -78 o C 71% [1] J. Am. Chem. Soc. 1989, 111, [2] J. Am. Chem. Soc. 1989, 111, [3] J. Am. Chem. Soc. 1990, 112, [4] J. Am. Chem. Soc. 1997, 119, [5] J. Am. Chem. Soc. 2001, 123, Tet. 1994, 50, 4071.

5 Wender s racemic total synthesis 5 steps TBS Ac 1. MCPBA, TF 2. Ac 2, DMAP, pyr Ac Ac TBS DBU 92% dr 2:1 - + TBS Ac xidopyrylium-lefin [5+2] Cycloaddition Ac TBS B and C ring Ac Ac Ac 7 steps C TMS 1. N 2 2. NaCl 46% - N + TMS 1,3-dipolar cycloaddition NTMS TBS TBS A ring TBS Ac Ph 2 SC() 2 Ac TF, C 2 Cl 2, -78 o C 14 steps TBS 85% TBS 20 steps D ring Phorbol 52 steps 0.16% Total yield [1] J. Am. Chem. Soc. 1989, 111, [2] J. Am. Chem. Soc. 1989, 111, /09/16 Evan Wipf Group 5

6 Wender s racemic formal synthesis 6 steps TBS TBS heat 71% - TBS + TBS xidopyrylium-lefin [5+2] Cycloaddition TBS TBS B and C ring Ac Ac 5 steps TMS TBS Cp 2 ZrBu 2, TF, rt then, Ac 69% TMS TBS 1. 3 ; NaB methoxypropene, PPTS 2. PCC, NaAc 24%, three steps TBS A ring 16 steps, 1% total yield original: 26 steps. 11% total yield 26 steps Phorbol 42 steps 0.02% Total yield [1] J. Am. Chem. Soc. 1990, 112, /09/16 Evan Wipf Group 6

7 Wender s asymmetric formal synthesis TBS C + Bn N 7 steps TBS Ac Ac DBU 79% - + TBS Ac xidopyrylium-lefin [5+2] Cycloaddition Ac TBS B and C ring 6 steps Ph TMS Ac TBS 1. Cp 2 ZrCl 2, nbuli then, Ac 2. PCC, NaAc 84% Ph TMS Ph A ring Ac TBS 21 steps Phorbol 36 steps 1.2% Total yield [3] J. Am. Chem. Soc. 1997, 119, /09/16 Evan Wipf Group 7

8 Current work: Two phase synthetic strategy Cyclase Phase TMS TBS xidase Phase (+) 3-Carene Advanced Intermediate [1] (+) Phorbol [2] 1 Cyclase Phase NCS, DMAP Cl 3, C 2 Cl 2 / -78 o C Cl Li-napthalenide, TF, -78 o C then, MPA, I, -78 o C -rt (+)-3-carene DCM, rt then, thiourea -78 o C - rt Two steps, 48% then, LiMDS, -78 o C 44% BrMg TF, -78 o C - 15 o C 81% TBSTf, Et 3 N C 2 Cl 2, 0 o C then, TMSTf, Et 3 N 71% TMS TBS [RhCl(C) 2 ] 2, C p-xylene, 140 o C 72% TMS TBS [1] Science 2013, 341, 878. [2] Nature 2016, 0, 1. Advanced Intermediate LE Pharmaceutics > 100 grams 04/09/16 Evan Wipf Group 8

9 2 xidase Phase TMS TBS Mn(acac) 2 (4.5 eq.) PhSi 3 (7.0 eq.), 2 Et then, TMSTf (28 eq.), Et 3 N (42 eq.), 0 o C 70% TMS TMS TBS TFD (1 eq.) C 2 Cl 2 0 o C TMS TMS TBS then, ZnI 2 (5.0 eq.) MgI 2 (5.0 eq.) Et 2 TMS TBS TBS 1.25 g scale 1.04 g scale TMS TBS TBS Mn(acac) 2 (4.0 eq), 2 PhSi 3 (3.5 eq.), PPh 3 (1.5 eq.) Et 2 steps, 34% SM, 62% TMS TMS TBS RuCl 3 (0.61 eq.) NaBr 3 (54 eq.) NaC 3 (3.1 eq.) EtAc/C 3 CN/ M, (6/6/1) 96% TMS TMS TBS TFAA (10 eq.) DMAP (3.0 eq.) C 2 Cl 2, 0 o C then, Zn (120 eq.) Ac, C 2 Cl 2 TMS TMS CF 3 TBS 2.16 g scale g scale 1.01 g scale then, Ac 2 (4.0 eq.) DMAP (2.5 eq.) C 2 Cl 2, 0 o C TMS TMS CF 3 TBS Et 3 N DMF, 60 o C 64% TMS TMS Ac TBS TsNN 2 (6.0 eq.), reflux then, NaB 3 CN (18 eq.) Ac, reflux 40% TMS TMS Ac TBS 0.7 g scale 04/09/16 Evan Wipf Group 9

10 2 xidase Phase Ac TMS TBS TMS 0.2 g scale Cr 3 (100 eq.) 3,5-DMP (105 eq.) C 2 Cl 2, 0 o C - rt 46% Ac TMS TBS TMS 13 mg scale 1. TMSN 2 (218 eq.) DCE, 70 o C then, I 2 (339 eq.), pyrdine 2. 4 Sn, AsPh 3 PdCl 2 (PhCN) 2 CuI, NMP, 80 o C two steps, 64% SM, 33% Ac Ac TMS 1. F-Py, TF, 0 o C 2. Martin sulfurane (8.0 eq.) TBS DCE, 60 o C TMS then, Se2 (12 eq.) benzene, 80 o TMS C two steps, 51% 13 mg scale 13 mg scale NaB 4,, -40 o C then, Ac 2 (7.0 eq.) DMAP (5.0 eq.), C 2 Cl 2 93% TMS Ac Ac NaB(Ac) 3 benzene, reflux then, TBAF, TF, 0 o C then, Ba() 2, 72% 13 mg scale (+) - Phorbol 15 mg 04/09/16 Evan Wipf Group 10

11 Notable steps: C- Activation TMS TBS TFD (1 eq.) C 2 Cl 2 0 o C TMS TBS then, ZnI 2 (5.0 eq.) MgI 2 (5.0 eq.) Et 2 TMS TBS TMS TMS TBS C- Activation Considerations Eq. vs Ax. Considerations Steric shielding of C6, C7, C8, and C11. igher s-character of tertiary cyclopropane C- bonds (C13/C14). Compared to the remaining carbon centers, C 13 NMR suggests C12 is the most nucleophilic position. yperconjugation from the pi-like cyclopropane system should facilitate oxidation Activation by cyclopropane occurs through electron donation of its C-C bonding orbital to neighboring C- antibonding orbitals. Proper orbital overlap is required in order for activation through cyclopropane hyperconjugation. indered C- bonds can experience reduced rates of oxidation. Eq. 12 Ax. Si TMS TBS Angew. Chem. Int. Ed. 2011,50, /09/16 Evan Wipf Group 11

12 Notable steps: 1,2 Diketone TMS TBS RuCl 3 (0.61 eq.) NaBr 3 (54 eq.) NaC 3 (3.1 eq.) EtAc/C 3 CN/ M, (6/6/1) TMS TBS TMS 96% TMS g scale 04/09/16 Evan Wipf Group 12

13 Notable steps: Reforming the cyclopropane ring TMS TMS TBS TFAA then, Zn, Sc(Tf) 3 TMS TMS TBS product not obtained Alternative product TFAA then, Zn acetylation then, reduction TMS TMS TFA TBS Sc(Tf) 3 ring closure TMS TMS TBS 62% 1,2 - shift TMS TMS TBS not observed 04/09/16 Evan Wipf Group 13

14 Notable steps: Reforming the cyclopropane ring TMS TMS TBS 1.TFAA (10 eq.) DMAP (3.0 eq.), C 2 Cl 2, 0 o C 2. Zn (120 eq.) Ac, C 2 Cl 2 3. Ac 2 (4.0 eq.) DMAP (2.5 eq) C 2 Cl 2, 0 o C 4. Et 3 N, DMF, 60 o C 64% TMS TMS Ac TBS Desired product TFAA then, Zn acetylation then, reduction TMS TBS CF 3 aldol TMS CF 3 TBS Ac 2 acetylation TMS CF 3 TBS TMS TMS TMS Et 3 N retro-aldol TMS Ac TFA TBS ring closure TMS Ac TBS TMS TMS 04/09/16 Evan Wipf Group 14

15 04/09/16 Evan Wipf Group 15

16 TMS TBS xidase Phase Advanced Intermediate [1] (+) Phorbol [2] Conclusions Accomplished an enantiospecific total synthesis of (+) Phorbol in 19 steps. Demonstrated an effective, symbiotic relationship between an academic organic chemist and a pharmaceutical company in a collaborative pursuit toward a complex natural product synthesis. 04/09/16 Evan Wipf Group 16