Journal Club. Nick Tappin Renaud Group 21 May 2015
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1 Journal Club Nick Tappin Renaud Group 21 May 2015
2 Total Synthesis of the AnAmitoAc Marine Macrolide ( )- Leiodermatolide ACE 2014, 53, an Paterson*, K. K.- H. Ng, S. Williams, D. C. Millican, and S. M. Dally H 2 N H H ( )-leiodermatolide 23 steps, 3.2% yield
3 Total Synthesis of the AnAmitoAc Marine Macrolide ( )- Leiodermatolide ACE 2014, 53, an Paterson*, K. K.- H. Ng, S. Williams, D. C. Millican, and S. M. Dally H 2 N H H ( )-leiodermatolide 23 steps, 3.2% yield = 0.031* *if linear; this synthesis is actually convergent (see summary)
4 verview. Preamble i. Paterson Group ii. solaaon, Toxicity, Mode of AcAon, JusAficaAon. RetrosyntheAc Analysis i. Structural Features ii. Fürstner s Approach iii. Maier s Approach iv. Paterson s Approach. Forward Synthesis i. Western Fragment ii. Eastern Fragment iii. Endgame V. Conclusions and utlook 4
5 Paterson Group Total synthesis of biologically acave natural products New syntheac methodologies, asymmetric Famous for asymmetric aldol reacaon from geometrically defined boron enolate structural assignments based on NMR studies and synthesis As well as synthesizing hot molecules (polyols). PKS. Fellow of Jesus College, FRSE FRS PhD (Fleming), PostDoc (Stork), 5
6 Paterson: flavour of his work rg. Biomol. Chem. 2015, 13,
7 solaaon Wright group 2008 Submersible near Florida (410m not 2.5km) AnAproliferaAve acavity against human cancer cell lines inc. C 50 =3.3nM for lung and 5.0nM for PANC- 1 AcAng through disrupaon of tubulin (mitosis stage) dynamics but in disanct way from other tubulin- targeang drugs Vinca alkaloids, Taxol, etc. Most chemotherapy drugs target tubulin This could be a new lead for anacancer agents Leioderma-um sp., a deepwater sponge. mage courtesy of slands in the Sea 2002, NAA/ER. 7 U.S. Pat. Appl. Publ. (USA), US , 14pp, 2008
8 hkp:// 8
9 Tubulin 9
10 Mode of acaon: tubulin disrupaon Nature Reviews Cancer 2010, 10,
11 hkp:// 11
12 12
13 Structural features H 2 N H H 16- membered (plateau), triply- unsaturated macrolactone (E- E)- diene in macrolactone, (Z- Z)- diene in side chain TerminaAng d- lactone Synthesis needed to determine full configuraaon of certain stereoclusters 5 alkenes and 9 stereocentres QuesAon: Propose disconnecaons.? ConfirmaAon of relaave stereo in macrolactone core: L 2011, 13, and Maier s work 13 RelaAve structural assignment: ACE 2011, 50,
14 Retrosynthesis: Maier H 2 N H H 25 1 Julia-Kocienski olefination P N S N N N Ph P 25 L 2011, 13, and Maier s work Synlek 2011,
15 Retrosynthesis: Maier 9 12 Sonogashira 15 P 15 P PMB RCM 1 H TBDPS + 1 Ms Marshall Tamaru TBS Ph 3 P, Pd(Ac) 2 Et TMS 2 Zn, THF, 10 C Tamaru Marshall H H TBDPS MsZn H TBDPS TMS TMS Chem. Rev. 2011, 100, (pp ) Marshall- Tamaru, chiral mesylates: JC 2011, 63,
16 Retrosynthesis: Furstner H 2 N RCAM/semireduction carbamolyation H H 25 1 Suzuki-Miyaura H H + [B] H or [B] H ACE 2012, 51, AC 2012, 124,
17 RetrosyntheAc Analysis: Paterson H 2 N Stille carbamolyation H H 25 1 macrolaconization aldol SnBu Heck 18 H 25 1 H Suzuki TBS C1 C11 "western" fragment C12 C25 "eastern" fragment 17
18 RetrosyntheAc Analysis: Paterson aldol SnBu 3 1 Suzuki TBS C1 C11 "western" fragment PMB Tf TBS SnBu 3 PMB Bz R N Me aldols 1 & 4 18
19 RetrosyntheAc Analysis: Paterson Heck 18 H 25 H C12 C25 "eastern" fragment H H TBS aldol 2 18 TMS aldol 3 33 aldol 4 25 Bz S aldol 2 HC Bz R aldols 1 & 4 (C21 C23) 19
20 Forward Synthesis: Western PMB 1) TBS(CH 2 ) 4 MgBr, N THF, 78 C Me PMB (MeB) 3, [Pd(PPh 3 ) 4 ] 10mol% PMB 1) DDQ, ph 7 buffer, DCM, 84% 2) LiHMDS, ArNTf 2, THF, C, 78% over 2 steps Tf TBS dioxane, 50 C, 96%, >20:1 E/Z TBS 2) DMP, NaHC 3, DCM, 82% R Bz c-hex 2 BCl, NEt 3, H Bz 1) TMSCl, mh, DCM, 96% H TBS Et 2, C, 96%, d.r.>20:1 TBS 2) LiC CTMS, THF, 78 C 3) K 2 C 3, MeH 4) Na 4 /Si 2, DCM 69% over 3 steps TBS Na, AcH H 1) Me 4 NBH(Ac) 3, MeCN/AcH (3:1), 30 C, 97% (d.r.>20:1) t-buli; Bu 3 SnCl, SnBu 3 THF, 81% TBS 2) Me 2 C(Me) 2, PPTS, DCM, 99% TBS Et 2, 30 C, 81% TBS C1 C11 "western" fragment 20
21 TMB PMB (MeB) 3, TMB, trimethylboroxine, or the anyhdride of methylboronic acid is a cheaper Suzuki-Miyaura coupling partner than methylboronic acid, MBA Tf TBS 2 N Gray, M.; Andrews,. P.; Hook, D. F.; Kitteringham, J.; Voyle, M. Tetrahedron Lett. 2000, 41, TMB Pd(PPh 3 ) 4 10mol% 2 N B B B Pd(PPh 3 ) 4 10mol% dioxane, 50 C, 96%, >20:1 E/Z H 2 N CF 3 Br K 2 C 3, DMF, 120 C 23h, 75% TMB Pd(PPh 3 ) 4 10mol% H 2 N CF 3 CF 3 Br K 2 C 3, dioxane, 17h, 95% CF 3 PMB N TMB Pd(PPh 3 ) 4 10mol% N TBS N 2 Cl K 2 C 3, dioxane, 46h, 72% N 2 21
22 AnA- aldol Cl B soft enolization operation: 2 + Bz R operation: 1 + NEt 3 Bz R NEt 3 Bz R H A 1,3 strain Bz R B(c-hex) 2 Bz R B(c-hex) 2 disfavoured A 1,3 strain Bz B(c-hex)2 favoured Review: rg. React. 1997, 51, 1 NEt 3 / c-hexbcl: TL 1994, 35, 9083 & 9087 Synthesis 1998,
23 Na/ AcH addiaon to ynone H Na, AcH H TBS THF, 81% TBS Taniguchi, TL 1986, 27, R H R' excellent regioselectivity when R'=H, i.e. terminal ynone Na/ AcH R Na/H H R E-enone major + R Z-enone minor equilibrium: may be recycled (thermo control) 23
24 Forward Synthesis: Eastern Bz S c-hex 2 BCl, NEt 3, Et 2, C, 90%, d.r.>20:1 Bz H 1) TBSTf, 2,6-lutidine, DCM, 78 C 2) LiAlH 4, THF, 78 C 3) K 2 C 3, MeH 91% over 3 steps H H TBS Bz R c-hex 2 BCl, NEt 3, Et 2, C, 94%, d.r.>20:1 Bz H TBSTf, 2,6-lutidine, DCM, 78 C, 98% Bz TBS 1) allylmgbr, THF, 78 C TMS Et BF 3 Et 2 DCM, 78 C Et 2) Na 4, MeH, ph7 buffer 85% over 2 steps TBS 3M HCl, THF, H 2 85% over 2 steps d.r. 10:1 H H 24
25 Forward Synthesis: Eastern H TMSCl, mh DCM, 97% TMS H H TBS Pd(Ac) 2 10mol% Ag 2 C 3, DMF, 80 C 73% H TMS H TBS Na 4, Si 2, DCM PPh 3 TMS NaHMDS, THF, 78 C TMS TBS 62% over 2 steps TBS C12-C25: Eastern fragment 25
26 Forward Synthesis: Endgame TMS TBS SnBu 3 + C12-C25: Eastern fragment TBS C1 C11 "western" fragment H Pd(PPh 3 ) 4 10 mol% CuTC, Bu 4 NPh 2 P 2 DMF, 80% H H 1 15 TBS TMS 21 1) HF.Py (C1 & C21) 2) TEMP (C1) 3) NaCl 2 (C1) 4) TBAF (C15) 51% over 4 steps TBS 26
27 Forward Synthesis: Champagne Ame H NH 2 H H H H TCBC, NEt 3, DMAP, PhMe, 80% 2) Dowex 50WX8 MeH, 91% H H TMS-m, DCM; PPTS, MeH; ClCCNC, DCM, 78 C; Al 2 3 ; PPTS, MeH 53% '1-step' 27
28 Reverse deprotect/ Yamaguchi H H 1) TBAF; Dowex 50WX8 H MeH, 41% 2) TCBC, NEt 3, H DMAP, PhMe, 83% H H H H 7 9 H 15 H tetraol H 21 via C21 C15 C9 C7 Ring size comment tertiary good (allylic) v. poor good, but 3 alkenes Reviews Macrolactonization: Chem. Rev. (2006, 106, ) 2013, 113, PR1-PR40 Ring size: Acc. Chem. Res. 1981, 14, 95 Yamaguchi macrolactonization: Bull. Chem Soc. Jpn. 1979, 52, TCBC = 2,4,6-trichlorobenzoyl chloride 28
29 Carbamate formaaon H H Conditions: Cl 3 CCNC, DCM, 78 C; Al 2 3 ; PPTS, MeH H NH 2 H 1eq H Cl 3 C H H Reagent: TL 1986, 27, 5521 Cl 3 C NC 4eq RH Cl 3 C N H R Al hydolysis Cl 3 C H H 2 N R PPTS, MeH H 2 N R 29
30 Carbamate formaaon But why does silylation occur exclusively at more accessible C9? Think about mechanism... H H TBS H whereas H H Cl 3 C NC Cl 3 C HN H Unusual mechanism has been suggested: JC 1998, 63, 6878 H H H H R N C H H R N C R N H H Cl 3 C H observed major product HN 30
31 Summary PMB N Me 14 steps, 20.3% SnBu 3 TBS Bz R 7 (6) steps, 62.1% TMS 3 steps, 45.3% (coupling step, 73%) TBS TBS 9 (7) steps, 15.8% ( )-leiodermatolide (coupling step, 80%) Bz S 4 steps, 80.2% H S H TBS longest linear sequence = (21 or) 23 steps; 0.158*0.203 = 3.2% real overall yield = ((((( )/2)*0.453)+0.203)/2)*0.158 = 4.2% (((((Y av 4 + Y av 7 )/2)*Y av 3 ) + Y av 14 )/2)*Y av 9 = 4.2%; solve, Y av = 82.4% 31
32 3 syntheac approaches Style of synthesis: what is the point? Reliability, efficiency, control, cost, structure determinaaon (dynamic/ modifiable route), PC, or even being there first? Maier had more unknowns (influence disconnecaons) Found had epimers of natural prod Clever use of Marshall Tamaru aldol alternaave (point- axial- point) Furstner first but racemic, keeping unknown stereocentres at least harmful stage Paterson strategic first disconnecaons gives two fragments with 14 steps and 4 stereocentres, and 14 steps (but convergent) and 5 stereocentres xidaave glycol cleavage removes many stereocentres and material: Control at the cost of atom economy (but good SMs synthesized one enanaomer!) n the end all strategies using same major disconnecaons the devil is in the detail H H H 32
33 Marshall- Tamaru 33
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