FLOW CHEMISTRY: SOME RECENT APPLICATIONS & FUTURE THOUGHTS. October FROST 6 Budapest Steven V Ley University of Cambridge

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1 LW CEMITRY: ME RECET APPLICATI & UTURE TUGT ctober RT 6 udapest teven V Ley University of Cambridge

2 election of natural products and pharmaceutical agents made by our group using flow methods Grossamide ynlett 2006, 427 xomaritidine Chem. Comm. 2006, 2566 Et 2 Π-pioid receptor agonist Chem. Eur. J. 2010, 16, Casein kinase inhibitor rg. iomol. Chem. 2010, 8, T 1 antagonist ynlett 2010, 505 -thylsiphonazole ynlett 2011, 1375 PQ rg. iomol. Chem. 2011, 9, 57 Imatinib J. d. Chem. 2013, 56, 3033 clinertant Chem. Eur. J. 2013, 19, 7917 ( )-ennoxazole ynlett 2013, 514 Zolpidem Chem. ci. 2013, 4, 764 Pr 2 Alpidem Chem. ci. 2013, 4, 764 anetizole rg. Proc. Res. Dev. 2013, 17, Tamoxifen rg. Proc. Res. Dev. 2013, 17, pirodienal A Angew. Chem. Int. Edn. 2014, 53, pirangien A Angew. Chem. Int. Edn. 2014, 53, azlinine rg. Lett. 2014, 4618 () (R) C 2 Et acubitril rg. Lett. 2015, 17, 5436 Z439 rg. Lett. 2015, 17, 3218 C 3 2 Celecoxib In press Isoborreverine Aus. J. Chem. 2015, 68, 693 eauvericin In press assianolide In press

3 arnessing Reactive Intermediates: Discovering ew Chemical Reactions In atch In low A + Reagent + A* A + pent Reagent Reagent A* A ne environment eparated chemical environment Issues: Exothermic reactions unctional group incompatibility Reagent incompatibility Coupling substrate incompatibility

4 AREIG REACTIVE ITERMEDIATE arnessing Diazo Compounds Generate Translocate React 2 Mn psi 2 ubstrate Products R 2 R 2

5 Use in Cyclopropanation C 2 Ac 0.5 ml min M in EtAc Mn 2 2 R ml min-1 2 Mn psi R 2 rt 100 psi R 2 Ac C M in EtAc DIPEA 2 eq Generation Reactive Intermediate Cyclopropanation Ac C 2 Et Ac C 2 Et Ac C 2 Et 2 Ac C 2 Et Ac C 2 99% 97% 59% 79% 55% Ac C 2 Et Ac C 2 Et Ac C 2 Ac C 2 80% 99% 63% 39% Ac C 2 Et Ac C 2 89% r 89% 10:1 low cyclopropanation using in-situ generated diazo compounds.m Roda, D. Tran, C. attilocchio, R. Labes, R.J. Ingham, J. awkins and.v Ley, rg. iomol. Chem., 2015, 13,

6 Di-substituted Allene ynthesis in low R eq 0.1M in C ml/min activated Mn 2 rt 100 psi R 2 + R' Et 3 10% CuI dioxane rt, 10 min R' R Ts r 69% X = 98% X = r 81% R = X or R 82% X = 93% X = r I 4 91% X = 99% X = r 93% X = C 93% R= 75% X or R 41% 53% Et Et Ph e C 3 99% 93% 92% 89% (1:1 d.r.) C 63% (1.5:1 d.r.) 82% (1:1 d.r.) A versatile room-temperature route to di- and trisubstituted allenes using flow-generated diazo compounds J.. Poh, D.. Tran, C. attilocchio, J.M awkins,.v. Ley Angew. Chem. Int. Ed. 2015, 54, Rapid asymmetric synthesis of disubstituted allenes by coupling of flow-generated diazo compounds and propargylated amines J-. Poh,. Makai, T. v.keutz, D.. Tran, C. attilocchio, P. Pasau,.V. Ley Angew. Chem. Int. Ed. 2017, 56,

7 Discovering ew Reactions: Cross Coupling Pin Ph Ph 83% Ph Ph 81% Mn Ph-() rt 100 psi Ph Ph Ph Ph Protodeboronation 2 2 rt Δ. akagawa et al. ChemdChem 2012, 7, ; J. Wang rg. Lett. 2009, 11, ; J. arluenga et al. at. Chem. 2009, 1, A. Kirschning et al. J. low Chem. 2013, 3, Ph Ph etc. 68% tal-free coupling of saturated heterocyclic sulfonylhydrazones with boronic acids D.M. Allwood, D.C. lakemore, A.D. rown,.v. Ley, J. rg. Chem. 2014, 79,

8 arnessing Reactive Intermediates: Unstable oronic Acids 2 R 1.5 eq rt, 2h R R reactive boronic species = alkyl C 3 C 3 C 2 C % 84% 84% 52% 30% 83% 74% 92% (C 3 ) 2 (C 3 ) 2 C C 89% 69% 57% 10% 86% 68% 78% 92% I I I I r C 3 62% 90% 61% 66% 94% 49% 82% 88%

9 arnessing Reactive Intermediates: Unstable oronic Acids equential Diazoaddition: Protodeboronated etero-trimers 1 st diazo species 2 nd diazo species 3 rd diazo species eq R eq R 2 1 st boronic reactive species R eq R 3 R 2 2 nd boronic reactive species R eq R 4 R 3 R 2 3 rd boronic reactive species Protodeboronation R 3 R 4 R 2 r 32% 28% 25% 34%

10 Linking Coupling teps 1 st diazo 2 nd unsat. diazo 2 2 R R 1 R R R R R R 2 3 C r 70% 43% 73% Iterative reactions of transient boronic acids enable sequential C-C bond transformation C. attilocchio,. eist, A. afner, M. imon, D.. Tran, D.M. Allwood, D.C. lakemore,.v. Ley, ature Chem. 2016, 8, 360.

11 Multicomponent omoallylic Alcohol ynthesis: Under low Conditions + 2 R 2 TM 20 ml, 60 o C 7 bar R 2 () 2 P-Ts 2 in r 95% 88% 84% 85% 97% 89% C 3 r 70% 78% 84% 88% 90% C 3 C 3 r r r 65% 55% 70% 91% A multicomponent approach for the preparation of homoallylic alcohols J-. Poh, -. Lau, I.G. Dykes, D.. Tran, C. attilocchio and.v. Ley, Chem. ci. 2016, 7,

12 Multicomponent omoallylic Alcohol ynthesis: Under atch Conditions () 2 2 R 2 R 2 TM C2 2 :T (4:1), rt r r r 71% 62% 60% 65% 73% 68% 82% oc r r C 2 72% C 3 62% 75% 79% 75% 76% 92% r 73% 83% 61% 2 C 66% 67%, 1:1 d.r. 71%

13 Iterative Chain Elongation for Polyol ynthesis TE r A P A r P r 77% yield (over two steps) 89% yield (over three steps) TE TE r A r P A 86% yield (over two steps) TA T 68% yield (over three steps) r P Acetal Protection - CA (20 mol%), Acetone:DMP (4:1), rt 99% yield zonolysis - 3, C 2 2 : (9:1), -78 o C then P-PPh 3 A Allylation - Vinyl boronic acid, TMC 2, C 2 2 :T (4:1), rt P TE Protection - TETf, DIPEA, C 2 2, rt

14 i) 2Ac (1.1 eq), Ph reflux (Dean-tark), 2 h R1 R2 J. Warkentin et al. J. rg. Chem. 1989, 54, Cross-Couplings p2-p3 ii) PhI(Ac) 2 (1 eq), 0 C, 1 h Vapourtec Photoreactor 9 W UV lamp 310 nm () 2 Ar M in C 2 2 R1 R1 PR ml min-1 R2 0.1 M in C eq. 10 ml 10 C t R = 80 min Ar TA (3 eq.) R2 () 2 r.t., 16 h 90% r 60% 81%, 1:1 dr 32% 3C r 57% 69% 2C C 68% 56% Ac 58% oc 89% 84%, 60% 53% 88% 56%* 69%* 30% 38% oc oc 61% 65% 71% 74% 86% 58% 74% 64% 60% 85% R2 42% 89% Ar P Et Et R1 lowir TM 55% A Divergent Aryl-Alkyl Cross Coupling Protocol A. Greb, J.-. Poh,. Greed, C. attiocchio, P. Pasau. D.C. lakemore,.v. Ley (submitted) 96%

15 Cross-Couplings 9 W UV lamp 310 nm () 2 Ar M in C ml min -1 air R 2 PR Ar R 2 Ar R 0.1 M in C 2 () 2 2 r.t., 16 h 2 2 eq. 10 ml 10 C t R = 80 min lowir TM oc 67% 93% 70% 71% traces 83% 87%, 1:1 dr 83% 87% 84% r 60% P 83% Et Et 76% 58% 43% 78% 20% 57% 55% 76% oc 57% r 71% 3 C 6y, 70% 2 C 31% Ac 53% 65% 80% oc

16 Derivatisation of Tertiary Cyclobutylated oronic Pinacol Esters () M in C ml min -1 9 W UV lamp 310 nm PR () M in C eq. 10 ml 10 C t R = 80 min lowir TM pinacol (5 eq.) r.t., 16 h i) K 2 ii) i 4 (2 eq.), DCE, r.t. then n 3 (2 eq.), DCE, 80 C Li (2 eq.) -78 C, T then pin 74% 0.1 ml min -1 C n + 70% cyclobutylated 3 amine Ir C 3 C 3 t u t u + P 6-47% cyclobutylated 4 furan 49% cyclobutylated 4 isoquinoline PR 17 W blue LEDs 420 nm 10 ml 60 C t R = 100 min 0.25 M in acetone + Ir III photocatalyst (1 mol%) Ir III photocatalyst

17 Three-tep ynthesis of (±)-aclofen (GAA Receptor Agonist) () M in C ml min -1 oc 0.1 M in C eq. 9 W UV lamp 310 nm 10 ml 10 C t R = 80 min lowir TM PR TA (3 eq.) () 2 r.t., 16 h oc C 2 6 (aq.) oc Ru 2 /ai 4 oc >99% (±)-baclofen aclofen reflux, 16 h 50% (+ 29% regioisomer) EtAc/ 2, r.t., 3 h 60%

18 Engineering Chemistry: Integrating atch & low on a ingle Automated Reactor 1. a, Et 2. Ethyl 2-mercaptoacetate 3. K, 2 P 3, DM Intermediate A AZ82 anticancer agent Aq. waste out DCM yringe PR P 3 90oC Waste DM, DCM Intermediate A Phase 1 atch & low Phase 1 DCM Et 2 1 Automated Extraction 2 olvent witch/distillation Reservoir odium Acetate 1 2 Drying exanone, DCM Reservoir DCM Phase 2 low tep 3) Phase 2 tep 4) K tep 2) Ethyl 2-rcaptoacetate yringe tep 1) a, Et Engineering chemistry: integrating batch and flow reactions on a single, automated reactor platform D.E. itzpatrick and. V. Ley, React. Chem. Eng., 2016, 1, Phase 3 atch

19 Integrating atch & low Reactions

20 Challenges & Thoughts for the uture ew methods / discovery of new reactivity ew computational algorithms Machine learning Delivering on the Green Agenda Greater interdisciplinary interactions uperior downstream processing tools etter self-optimizing tools Improved reaction monitoring / control More telescoping / multistep processes olistic planning and design Make & creen methods More diverse applications e.g materials etter integration with batch processing More use of multi-enzyme cascades Incorporate wider use of enabling tech Establish wider processing windows ew imaging tools (AR / VR) Use of robotics & cameras Internet of Chemical Things Improved in-line analysis

21 LW CEMITRY: ME RECET APPLICATI & UTURE TUGT Acknowledgements C. attilocchio,. eist, A. afner, M. imon, D.. Tran, D.M. Allwood, D. E. itzpatrick, A. Greb, J.-. Poh,. Greed, I.G Dykes,.-. Lau, R. Mutton.M. Roda, R. Labes, R.J. Ingham P. Pasau (UC), J.M awkins (Pfizer), A.D.rown (Pfizer) and D.C. lakemore (Pfizer)