Making Molecules: March of the Machines: Steven V. Ley

MAKING MOLECULES MARCH OF THE MACHINES

Steven V. Ley Department of Chemistry, University of Cambridge, UK

Creator Space Science Symposium BASF Chicago June 23 2015

A New World for Molecule Makers

Synthesis Serves SocietyAgrochemicals Sustainable food & flavors Vitamins & nutrition supplements New medicines Chemical sensors & diagnostics Perfumes, fragrances & cosmetics Polymers, plastics, pigments & paints Catalysts Color printing Explosives & fireworks Data storage LED’s & energy storage systems Molecular & micro electronics Clean fuels, photocells Petrochemicals & propellants Commodity chemicals Surface & membrane science Security chemicals

Principles of Green Chemistry Charter for Life as a

Synthesis Chemist

PT Anastas and JC Warner Green Chemistry: Theory and Practice Oxford University Press, New York, 1998, p.30.

1. Prevent waste not treat/clean later 2. Use atom economy 3. Design safer chemicals 4. Use & generate less toxic substances 5. Massively cut quantities of solvents used 6. Design syntheses for energy efficiency 7. Renewable feedstocks for large scale 8. Minimize synthesis steps 9. Use highly-selective catalytic reagents 10. Design materials that degrade 11. Monitor pollution prevention 12. Minimize potential for accidents

1. Improve waste & energy management 2. Use atom economy 3. Avoid labor intensive practices 4. Accept responsibility for our actions 5. Massively cut quantities of solvents used 6. Efficiency: avoid downstream processing 7. Use sustainable feedstocks incl. gases 8. Minimize synthesis steps 9. Use highly-selective catalytic reagents 10. Design molecules for the future 11. Challenge dogmas 12. Minimize potential for accidents

Principles of Green Chemistry Charter for Life as a

Synthesis Chemist

Synthesis Process Complex Decision Tree

Retrosynthetic analysis Chemo- / stereo- / regio- control Mechanism knowledge Reagent compatibility Starting material availability Safety factors Logic vs creativity / innovation

SYNTHESIS PLAN

Equipment needs (flow vs. batch) Reagents / conditions ? Safety factors / experience Temperature / solvents / pressure / speed Scale vs cost

REACTION CONDITIONS &

REAGENTS

Temperature (exothermic ?) Reaction times TLC, LCMS HPLC, GC IR, Raman, NMR, Camera monitoring

REACTION MONITORING

Distillation / crystalliszation Liquid extraction Filtration / chromatography Use of immobilized scavengers Waste product issues

REACTION WORK-UP &

PURIFICATION

Non-trivial Desired property / function Single / family of compounds Natural product Test hypothesis

WHAT TO MAKE

TARGET MOLECULE

OO

O

OOH

H

HO

O

OO

O

OMe

OMe

HOH

O

BrTBDPSO

O

O

O

PhSO2

HOH

OHOTBDPS

OPhSO2 HO

HO

OH

MeO

Ascend® Fire Ant Bait

Total synthesis of the anthelmintic macrolide avermectin B1a S.V. Ley, A. Armstrong, D. Díez-Martín, M.J. Ford, P. Grice, J. Knight, H.C. Kolb,

A. Madin, C.A. Marby, S. Mukherjee, A.N. Shaw, A.M.Z. Slawin, S. Vile, A.D. White, D.J. Williams, M. Woods, J. Chem. Soc., Perkin Trans. 1 1991, 667-692.

Synthesis Process Complex Decision TreeNature as an Inspiration Avermectin B1a Synthesis

• Active ingredients of avermectin-based insecticides: 80% B1a and 20% B1b

• Nerve poison stimulates GABA (γ-aminobutyric acid) system

• Affected insect is paralyzed, stops feeding, and dies after a few days

Synthesis of Avermectin B1a

Synthesis Process Complex Decision TreeMaking Molecules Flask vs. Cell

• Wide range of reactions and reagents • Massive diversity/versatility • Established protocols • On demand synthesis • Mostly non-aqueous media • Poor by-product and waste management

Synthesis in a flask

Synthesis in a cell

• Highly efficient yet limited chemical scope • On board synthesis of reaction catalysts • Reagents can be recycled • Continuous molecule processing • Reactions occur on surfaces/compartments • Aqueous reaction media • Limited tolerance to harsh environments

Microfluidic Chips

Continuous flowreactor chip

channel 1

channel 2

n µL/min

n µL/min

sample loop

pump 1

pump 2solvent Collect and screen

Recycle

HPLCSurface coatedreagents

A Systems Approach to Synthesis

Can innovative flow technologies for multistep synthesis help?

Organic Synthesis: March of the Machines S.V. Ley, D.E. Fitzpatrick, R. J. Ingham, R.M. Myers, Angew. Chem. Int. Edn. 2015, 54, 3449.

column for solid-supported

reagents

IR

in-line detectorreactor coil

75 PSI

sample loops

HPLC pumps

backpressure regulator

PRODUCT

Increased process safety through containment of hazardous or

malodorous substances

Continuous processing machine-assisted 24/7 working

Control over reaction parameters leads to

reproducibility and rapidoptimisation

Ability to carry out multistep sequences, many unit

operations saved

In-line purification methods minimise manual

handling and lessens waste

INPUT 1

INPUT 2

INPUT 3

real-timediagnostics

Pressurised system allows superheating of solvents, superior

reaction profiles

Flow Reactors Vapourtec R2 + R4 Reactors


Flow Reactors Uniqsis FlowSyn Reactor


Product

Waste

Reagents Priming / Injection valve

Pump 10mL

LCD display Experiment setup tool

Chip or column

Flow Reactors Vapourtec R2 + R4 Reactors

Lab of the Future: The Importance of Remote Monitoring and Control M.D. Hopkin, I.R. Baxendale and S.V. Ley, Chim. Oggi./Chemistry Today, 2011, 29, 28-32.

Camera enabled techniques for organic synthesis S.V. Ley, R.J. Ingham, M. O’Brien, D.L. Browne, Beilstein J. Org. Chem. 2013, 9, 1051-1072.

Flow Chemistry Advantages

• Machine assisted processing • Inline purification • Inline analysis • Multistep sequencing • Continuous processing • Contain hazardous/sensitive compounds

Natural Product Synthesis Challenges • Constant need for early intermediates • Purification difficulties at late stage steps • Irreproducibility upon scale up • Overall number of synthetic steps • Lack of new methods • Overall financial and physical effort

How do we integrate the science?

Is flow chemistry helpful in the synthesis of complex molecules?

Flow Reactors Vapourtec R2 + R4 ReactorsFlow Chemistry in Natural Product Synthesis

Flow-assisted natural product synthesis

A flow process for the multi-step synthesis of the alkaloid natural product oxomaritidine: a new paradigm for molecular assembly I.R. Baxendale, J. Deeley, C.M. Griffiths-Jones, S.V. Ley, S. Saaby and G. Tranmer, J. Chem. Soc., Chem. Commun. 2006, 2566-2568.

The use of a continuous flow-reactor employing a mixed hydrogen–liquid flow stream for the efficient reduction of imines to amines S. Saaby, K. Rahbek Knudsen, M. Ladlow S.V. Ley Chem. Commun., 2005, 2909–2911

Oxomaritidine A Flow Synthesis of a Natural Product

MeO

MeO

NH

O

Br

HO

NMe3N3

N3

HO

O

MeOOMe

1.

2.

catch, react, release

MeOOMe

N

HOPh(nBu)2P

H2O

H2 (g)

H-Cube

10% Pd/C, THF

MeOOMe

NH

HO

O

F3C O

O

CF3

MeOOMe

N

HO

CF3O

NMe3RuO4

OH

MeOOMe

PhI(O2CX3)2

NMeO

MeO

CF3

O

O

MeOH / H2O

NMe3OH

Oxomaritidine

Isolated from Sorangium cellulosum So ce90

Spirangien A diameter of inhibition zones:

Three published syntheses containing the functionalised C14-C28 spiroketal core

Spirodienal A isolated from Sorangium cellulosum KM0141

Exhibits antifungal activity against Botrytis cinerea

Relative configuration of core and double bond geometries based on 2D-NMR and ROESY correlations

Structurally similar to the spirangien molecules

Spirangiens A and BR = CH3 or CH2CH3

OO

OHMeO

HO

R

HH

O

OH

MeO

HO

14

28

OO

HOOH

1414MeO

HO

2828

3232

HH 1010

SpirodienalDegradation product (C10-C32) retains biological

activity (IC50 = 7 ng/mL)

CHO

Isolation: J.-W. Ahn Bull. Korean Chem. Soc. 2009, 30, 742

Isolation: Höfle et al. Eur. J. Org. Chem. 2005, 70, 5013

Flow Synthesis of Spirodienal & SpirangiensFlow Synthesis of Spirangien & Spirodienal

Spirangiens

Spirodienal

Pichia membranaefaciens 24 mm – film on surface of wine

Rhodotorula glutinis 19 mm – ubiquitous saprophytic yeast

Botrytis cinerea 11 mm – airborne plant pathogen

+O O

HOOHMeO

HO

R

HH

O O

TESOOTESMeO

TESO

R

TMS

HH

4433 CO2H

MeOGold-catalysed

spiroketalisation

Bu3Sn

MeO

MeOO

HO OH

OH

OHOH

OH

Common fragment

OO

OH

Roush crotylation

OO O

TESO

O

+

O TMS

H

Diastereoselectivehomologation

R

OO

O

TESO

OOMe

TMS

Carreiraenantioselective coupling

R

Diastereoselectivehomologation

Left-hand fragment Right-hand fragment

Side chain

Flow Synthesis of the Spirangiens Retrosynthesis

Flow Synthesis of the Spirangiens Common Olefin Fragment

HOOH

OH

OH

OHOH

O

O

OO

O

O

OH

2

OO

O

O

O

M

CH2Cl2

acetone

FeCl3, AcOH

acetone

OMe

O

OO

40 oC, 20 mL

P+Ph

Ph

OO

NMe3OH /celite

BO

O CO2i-Pr

CO2i-Pr

OO

OH

dr > 11 : 1

50 oC

rt, 30 mL

OO

O

O

MeO

O

Multigram (>100 g) synthesisof bis-protected D-mannitol

GPR

250

psi

OO

O

OMeO

O

Wittig in flow usingPPh3 monolith

Asymmetric homogeneoushydrogenation

in flow

H2

20 barrt

50 oC, 20 mL

2.5 mol% Catalyst CUbaPhox

dr > 7:1

Al2O3 / QP-BZA

Toluene

IRA-743 / SiO2

SelectiveDIBAL-H reduction

in flow

Roush crotylationin flow

–

–+

73% over 5 steps

H

Acetal switch

NMe3IO4

Common fragment

100 psi

Periodate oxidationQP-BZArt

QP-BZA

Toluene

Al+H–

–78 oC, 10 mLInfrared

detector–78

oC, 10 mL

MeOH

MeOH

100 psi

Flow Synthesis of the Spirangiens Left Hand Fragment

FLLEX

OB

O

CO2iPr

CO2iPr

1.7 eq TESOTf2 eq DIPEA

0 oC argon vent

filter

84% TESO

OO

O

1.5 M in PhMe

–78 oC

74%; dr = 16:1

TESO

OO

OH

+ BF3·Et2O (30 mol%)

PS-hydroxide/Celite

acetone

QP-SA

85%O

OO

O

argonvent

NaBH4MeOH, 0 oC

CH2Cl2–MeOH (1:1)

aqueousworkup

99%

O

OO

O OH

0 oC

1.7 eq TBSOTf2 eq DIPEA

saturatedNH4Cl solution

aqueouswaste

70 mbarCMP

89%

O

OO

O OTBS

3-way valve

R

R

Common fragment

PPh3

MeOH

PhMe

CH2Cl2

OO

OH

75 psi 100 psi

O3

3-way valve

100 psi

75 psi

Ozonegenerator

O3

Ozonegenerator

Flow Synthesis of the Spirangiens Left Hand Fragment

FLLEX

O

OO

O OTBS

40 oC

Ohira–Bestmann reagent 1.5 eq KOt-Bu 2 eq

40 oC

79%O O OTBS

CuCN, PhMe-SiLiTHF, 0 oC then MeI, 0 oC, 90% O O OTBS

PhMe2Si

saturatedNaS2O3 solution

aqueouswaste

0 mbarCMP

80%O O OTBS

I

PdCl2(PPh3)2Me2Zn, THF

rt, 82%

O O OTBS

CH2Cl2 / MeCN (1:1)

50 oC 1 M TBAF

in THF

>99%

O O OH40

oC

TEMPO (20 mol%)PS-S2O3/

silica64%

O O O

+ 2 eq BAIB

NIS

1. TMSOTf, DIPEA, CH2Cl22. NaIO4, THF-H2O (1:1)

Left-hand fragment

MeOH

THF

75 psi

75 psi

100 psi

CH2Cl2

O O OTBS

O

Flow Synthesis of the Spirangiens Right Hand Fragment

3.4 eq TESOTf4 eq DIPEA

0 oC 80

oC

54%

TESO O

AcO

TESO

95%; dr = 7:1

TESO OH

AcO

TESO TMS

MsOTMS

acetone

40 oC

TEMPO (20 mol%)

PS-S2O3/silica

69%

O O

AcO

O TMSPPh2

Br Br

72%

O O

AcO

TMSBrBr

QP-SA–20

oC

–20 oC

+ BAIB (2.0 equiv.)

R

Pd(OAc)2, PPh3Et3Zn, THF

0 oC to –78

oC to 20

oC to rt

Common fragment

OO

OH

argon vent

filter

3-way valve

PPh3

100 psi

Ozonegenerator

O3

CH2Cl2

MeOH

CH2Cl2

100

psi

75 psi100 psi

M

O O

AcO

OH TMS

>99%

0 oC

IRA-743/silica

94%

O O

OH

TMSBrBr

FLLEX

aqueouswaste

0 mbarCMP

95%

O O

TESO

TMSBrBr

saturatedNH4Cl solution

aqueouswaste

85%

O O

TESO

TMS

2 eq TESOTf1.7 eq 2,6-lutidine

2.5 eq nBuLi

FLLEX

Right-hand fragment

CH2Cl2 75 psi

0 oC

CH2Cl2

1 M HCl

0 oC

0 mbarCMP

Et2OAl+H-

OO OH

TESO

OOOO O

TESO

OOn-BuLi, THF,–78 oC to rt

87%

dr = 2.2 : 1

1. MnO2, CH2Cl2, rt, 97%N B

O

PhPhH2. BH3.SMe2, THF, –30 oC, 16 h, 91%

OO OH

TESO

OO

dr > 20:1

1. NaH, MeI, THF,

TMS

TMSTMS

OHOH

OH

OH

OHOMe

MeOH, 16 h

SO3H

2. TBAF, THF, rt

3. >99%

+

0 oC, >99%

O O

HO OHMeO

HO

HH

AuCl, PPTSCH2Cl2, –20 oC, 2 min

30%

O O

TESOOTESMeO

TESO

HH

OO

HOOH

MeO

HO

HH

CHO

Spirodienal AOHI

1. [Pd(PPh3)4], CuI, Et3N, PhH, rt, 90 %

2. Zn(Cu/Ag), MeOH/H2O/THF (1:1:1), 40 oC, 59%3. MnO2, CH2Cl2, rt, 84%

TESOTf, 2,6-lutidineCH2Cl2, –78 oC-0 oC, 59%

Flow Synthesis of the Spirangiens Batch Fragment Coupling

OO

TESOOTES

MeO

TESO

HH

NIS, AgNO3acetone/DMF (5:1), rt

OO

TESOOTES

MeO

TESO

HH

I

49%

NO2

SO2NHNH2

CSA, Et3N, rt,THF/iPrOH (1:1), 93%

2. CSA, MeOH, rt, 91%

1.

OO

HOOH

MeO

OMe

O

MeO

HO

Spirangien A (OMe)

HH

OO

HOOHMeO

HO

HH

IPd2(dba)3, AsPh3, DMF/THF (4:1), rt

Bu3Sn

MeO

MeOO

43%

Accelerating Spirangien Natural Product Synthesis Using Flow Technologies S. Newton, C.F. Carter, C.M. Pearson, L.C. Alves, H. Lange, P. Thasandote, S.V. Ley, Angew, Chem. Int. Ed. 2014, 53, 4915-4920

Flow Synthesis of the Spirangiens Endgame

My Laboratory Today Transforming the way we work

Discovery of new reactions Machine-assisted synthesis Integrated ‘modelling and synthesis’ Superfast reaction optimising tools The ‘Smart’ Fumehood Web cams Use of open-source software Remote control and monitoring 24/7 Working regime Integrated Calorimetry Make and screen Lab apps, tablets, WiFi 3D printing Head-up displays Mini-mass spectrometry Under the bench NMR Linked reactors and multi-tasking Advanced processing methods The Internet of Things

Acknowledgements

A. Abad-‐Somovila A. Armstrong A. Boyer A. Brice A. Madin A. Ma8es A. Pinto A. Wood A.A. Denholm A.D. White A.M.Z. Slawin A.N. Shaw A.Q. Somers A.R. Pape B.J. Burke B.L. Gray

E. Beckmann E. Cleator E. Sliwinski F. Stelzer G. Tranmer G.E. Veitch H. Broughton H. Lange H.C. Kolb H.J. Lovell I.R. Baxendale J. Deeley J. Knight J.C. Anerson J.C. Pastre J.S. Sco8 K. Rahbek Knudsen L.B. Gobbi L.C. Alves

C. Ayats C. BaRlocchio C. Zumbrunn C.A. Marby C.D. Spilling C.E. Gu8eridge C.F. Carter C.F. McCusker C.M. Griffiths Jones C.M. Pearson D. Craig D. Díez-‐MarUn D. SanVianos D.C. Jennens D.E. Fitzpatrick D.J. Williams D.L. Browne

M. Gröbel M. Woods M.G. Brasca M.J. Ford M.L. de la Puente N. Hahn P. Grice P. Thasandote P.J. Lovell P.L. Toogood P.R.D. Murray R. Bänteli R.B. Grossmann R.J. Ingham R.M. Turner

S. Mukherjee S. Newton S. Saaby S. Vile S.C. Smith S.L. Harding S.L. Maslen T. Durand-‐Reville W-‐J Koot