Literature Report

Transcription

1 Literature Report 高凯 检查 : 王躲生 Modular Total ynthesis of Archazolid A and B Menche, D.* et al J. rg. Chem. AAP

2 Me R 1 Archazolid A (R = Me) 2 Archazolid B (R = )

3 Retrosynthetic analysis WE 9 P(Me) Me TB Me PMB eck 20 R Archazolid A (R = Me) 2 Archazolid B (R = ) WE 7 R P(Et) 2 8 (R = Me) 9 (R = )

4 PMBTCA 77% PMB (Me) 2 P Me KMD, TF, rt, 24 h 62% PMB 1. DBAL 2. Mn 2 PMB Me 96% Bz 15 (E/Z = 2 : 1) % dr >20:1 Et 3, (c-ex) 2 BCl TB PMB 1. TBTf 2. LiB 4 3. a 4 Bz 85% 19 (3 steps) 18 PMB

5 TB PMB Me P(C 2 CF 3 ) 2 20 TB PMB KMD, 18-c %, dr >20:1 Me 21 92% (2 steps) 1. DBAL 2. Mn 2 TB PMB 20, KMD 18-c-6 TB PMB Me 23 87% dr >20:1 22 Me TB 1. DBAL 2. DMP 90% (2 steps) TB 23 6 PMB PMB

6 R 1. Cl 2,Me 2. 3,Me 2 68% (2 steps) a 2, + 68% 24 R= 2 (L-eucin) 25 R= 26 74% TBCl, imidazol 92% TBCl, imidazol TB 1. BC, MM % TB

7 Me P P Me TB 2 Lawesson reagent TB 2 Br C 2 Et 93% 79% C 2 Et C 2 Et C 2 Et DMP TB TBAF 96% 90% B 3, (R)-CB quant

8 C 2 Et C 2 Et 1. CD 2. 2 Me 90% s-buli, (-)-sparteine 2. Br C 2 Et C 2 Et 1. CD 2. 2 Me 94% DBAL 75% B(-pc) 2 65% (dr > 20 : 1) 7 36

9 C 2 Et 1. a, C 3, Δ C 2 Et Cp 2 ZrCl 2, Me 3 Al, 2 22% LA 2 C 85% C 2 77% (2 steps) C 2 Et 40 C 2 Et 2. K, Δ

10 39 Mn 2 quant. 1. Bn 43 MgCl 2,Et 3, TMCl 2. Me, TFA 29% (dr >20:1) 42 96% (dr >20:1) Ph Me Bn 2 Mes 44 (c-ex) 2 BTf, Et 3 Ph Me Bn Bn 2 Mes 45 46

11 Ph Ph Me Me Bn 2 Mes 46 Me, Ag 2 94% Me Bn 2 Mes 47 38% 48, BuLi 9% Me Me 48 P 1. LA 2. DMP 3. 48, BuLi 4. DMP Me Me P + Me Me P Me 44% (4 steps) 49 5

12 i-pr Me Bn Ph 2 Mes i-prmgcl Me Bn Ph 2 Mes Mg 50 Me P Me , KMD 80% 86% 2. 48,BuLi Me Me P Me Me, Ag 2 87% Me Me P Me Me P

13 PMB TB Me P(Et) 2 LiCl, DBU 63% 6 Me TB 5 54 PMB Ph TB Me Bn 2 Mes PMB 1. Ac 2, DMAP 2. DBU 95% (3steps) 1. Me, Ag 2 2. LiAl 4 3. DMP 4. MeMgBr 5. DMP 83% (5 steps) Me (c-ex) 2 BCl, Et 3, 6 TB 55 Me 56 (dr 2:1) PMB

14 Mg i-pr Ph Ph Me i-prmgcl Me Bn 2 Mes 46 Bn 2 Mes Me Me 1. Me, Ag 2 (80%) 2. MeMgBr (93%) Me 55 Me 59

15 PdCl 2 (PPh 3 ) 2, TBACl, Et 3, ac 3, DMF/C 3 C, 2 80 o C TBDP R PdCl 2 (PPh 3 ) 2, TBACl, Et 3, ac 3, DMF/C 3 C, 2 80 o C 62 TECl 82% 7 R = 61 R = TE Me 55 TBDP Me R 63 (E/Z = 6 : 1), 61% 64 R = (E/Z = 5 : 1), 54% 65 R = TE (E/Z = 6 : 1), 39%

16 Me TB PMB 54 + PdCl 2 (PPh 3 ) 2 55% 20-E/Z 6:1 7 Me TB PMB P(Et) 2 8 BP, DMAP 2. DDQ 3. wern xidation 77% (3 steps) Me TB 8 7 P(Et) 2

17 Me TB 8 7 a, 4 Å M, TF 0 o C to RT 44% Me TB 67 P(Et) 2 68 Me 1. ()-CB, B 3 2. F/pyridine 58% 1 Archazolid A

18 P(Et) 2 9 BP, DMAP 62% 7 69 P(Et) 2 Me TB 1. DDQ, 2. wern xidation 89% (2 steps) Me TB 54 PMB 70

19 69 P(Et) 2 + Me 70 TB a 66% Me TB 1. PdCl 2 (MeC) 2 2. ()-CB, B 3 3. F/pyridine Me 41% 71 2 Archazolid B

20 Myxobacterial fermentation broths of Archangium gephyra and Cystobacter violaceus are the natural sources of the archazolids, structurally complex polyketide macrolactones, which were originally reported by the group of ofle and Reichenbach. They constitute highly potent antiproliferative agents which inhibit the growth of various cancer cell lines in subnanomolar concentrations. n a molecular level, they constitute powerful and selective inhibitors of vacuolar type ATPases (V- ATPases), heteromultimeric, proton translocating proteins that are localized in a multitude of eukaryotic membranes, where they energize many different transport processes. As a malfunction of these enzymes is associated with various diseases such as cancer and osteoporosis, the development and molecular understanding of novel inhibitors present important research goals.

21 n conclusion, based on a modular synthetic strategy, an expedient and joint total synthesis of the potent antiproliferative polyketide macrolactone antibiotics archazolid A and B has been accomplised. Key steps for their syntheses involve an aldol condensation to construct the (Z,Z,E)-triene system, an E-selective eck reaction for the (22,23)-diene moiety, and an WE coupling. Two different methods, an WE reaction and a eck coupling, were successfully utilized to forge the macrocyclic core of these polyketides. otably, the joint synthesis of archazolid A and B was enabled by late-stage diversification of joint late-stage intermediates, demonstrating an expedient and flexible endgame strategy. Furthermore, in the course of this campaign, efficient protocols for an E-selective eck reaction of nonactivated alkenes, a direct nucleophilic displacement of the Abiko-Masamune auxiliary by Lewis acid activation, and a mild and highly reactive WE protocol were developed. With the established robust and flexible synthetic approach to the archazolids in hand, efforts can now be directed for further AR studies and more detailed target-inhibitor evaluations.