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Synthesis 2012(4): 635-647  
DOI: 10.1055/s-0031-1289676
PAPER
© Georg Thieme Verlag Stuttgart ˙ New York

Scale-Up of Flow-Assisted Synthesis of C 2-Symmetric Chiral PyBox Ligands

Claudio Battilocchioa,c, Marcus Baumanna, Ian R. Baxendalea, Mariangela Biavac, Matthew O. Kitchinga, Steven V. Leya, Rainer E. Martin*b, Stephan A. Ohnmachtb, Nicholas D. C. Tappina
a Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK
e-Mail: theitc@ch.cam.ac.uk;
b F. Hoffmann-La Roche Ltd., Pharmaceuticals Division, Chemistry Technology and Innovation, 4070 Basel, Switzerland
c Department of Pharmaceutical Chemistry and Technology, Sapienza University of Rome, Rome, Italy
Further Information

Publication History

Received 19 November 2011
Publication Date:
25 January 2012 (online)

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Abstract

A series of PyBox ligands were prepared from commercially available chelidonic acid by a multistep flow sequence using mesoreactor technology. A chloro group introduced onto the ligand scaffold was subsequently exploited to give amine derivatives ready for immobilization through microencapsulation technologies.

Key words

ligands - macrocycles - flow chemistry - solid-supported reagent - asymmetric synthesis - scale up

    References

  • 1 Desimoni G. Faita G. Quadrelli P. Chem. Rev.  2003,  103:  3119 
    Search in Google Scholar
  • 2a Evans DA. Sweeny ZK. Rovis T. Tedrow JS. J. Am. Chem. Soc.  2001,  123:  12095 
    Search in Google Scholar
  • 2b Zhao C.-X. Duffey MO. Taylor SJ. Morken JP. Org. Lett.  2001,  3:  1829 
    Search in Google Scholar
  • 2c Keith JM. Jacobsen EN. Org. Lett.  2004,  6:  153 
    Search in Google Scholar
  • 2d Schaus SE. Jacobsen EN. Org. Lett.  2000,  2:  1001 
    Search in Google Scholar
  • 3a Bhattacharyya S. Curr. Opin. Drug Discovery Dev.  2004,  7:  752 
    Search in Google Scholar
  • 3b Ley SV. Baxendale IR. Chem. Rec.  2002,  2:  377 
    Search in Google Scholar
  • 3c Ley SV. Baxendale IR. Nat. Rev. Drug Discovery  2002,  1:  573 
    Search in Google Scholar
  • 3d Kirschning A. Monenschein H. Wittenberg R. Angew. Chem. Int. Ed.  2001,  40:  650 
    Search in Google Scholar
  • 3e Thompson LA. Curr. Opin. Chem. Biol.  2000,  4:  324 
    Search in Google Scholar
  • 4a Cornejo A. Fraile JM. García JI. Gil MJ. Luis SV. Martínez-Merino V. Mayoral JA. J. Org. Chem.  2005,  70:  5536 
    Search in Google Scholar
  • 4b Cornejo A. Fraile JM. García JI. García-Verdugo E. Gil MJ. Legarreta G. Luis SV. Martínez-Merino V. Mayoral JA. Org. Lett.  2002,  4:  3927 
    Search in Google Scholar
  • 5 Tilliet M. Lundgren S. Moberg C. Levacher V. Adv. Synth. Catal.  2007,  349:  2079 
    Search in Google Scholar
  • 6 Zeng T. Yang L. Hudson R. Song G. Moores AR. Li C.-J. Org. Lett.  2011,  13:  442 
    Search in Google Scholar
  • 7a Bremeyer N. Ley SV. Ramarao C. Shirley IM. Smith SC. Synlett  2002,  1843 
  • 7b Yu J.-Q. Wu HC. Ramarao C. Spencer JB. Ley SV. Chem. Commun.  2003,  678 
  • 7c Mitchell C. Pears D. Ley SV. Yu J.-Q. Zhou W. Org. Lett.  2003,  5:  4665 
    Search in Google Scholar
  • 7d Siu J. Baxendale IR. Ley SV. Org. Biomol. Chem.  2004,  2:  160 
    Search in Google Scholar
  • 7e Baxendale IR. Griffiths-Jones CM. Ley SV. Tranmer GK. Chem. Eur. J.  2006,  12:  4407 
    Search in Google Scholar
  • 7f Sedelmeier J. Ley SV. Lange H. Baxendale IR. Eur. J. Org. Chem.  2009,  4412 
  • 8a Kobayashi S. Chem. Rev.  2009,  109:  594 
    Search in Google Scholar
  • 8b Pears DA. Smith SC. Aldrichimica Acta  2005,  38:  23 
    Search in Google Scholar
  • 9a Nishijama H. Sakaguchi H. Nakamura T. Horikata M. Kondo M. Kenji I. Organometallics  1989,  8:  846 
    Search in Google Scholar
  • 9b Desimoni G. Faita G. Guala M. Pratelli C. Tetrahedron: Asymmetry  2002,  13:  1651 
    Search in Google Scholar
  • 9c Lundgren S. Lutsenko S. Jönsson C. Moberg C. Org. Lett.  2003,  5:  3663 
    Search in Google Scholar
  • 10a Martin LJ. Marzinzik AL. Ley SV. Baxendale IR. Org. Lett.  2011,  13:  320 
    Search in Google Scholar
  • 10b Baumann M. Baxendale IR. Kirschning A. Ley SV. Wegner J. Heterocycles  2011,  82:  1297 
    Search in Google Scholar
  • 10c Polyzos A. Baxendale IR. Petersen T. Ley SV. Angew. Chem. Int. Ed.  2011,  50:  1190 
    Search in Google Scholar
  • 10d O’Brien M. Baxendale IR. Ley SV. Org. Lett.  2010,  12:  1596 
    Search in Google Scholar
  • 10e Hopkin MD. Baxendale IR. Ley SV. Chem. Commun.  2010,  46:  2450 
    Search in Google Scholar
  • 10f Qian Z. Baxendale IR. Ley SV. Synlett  2010,  505 
  • 10g Carter CF. Lange H. Ley IR. Baxendale IR. Wittkamp B. Goode JG. Gaunt NL. Org. Process Res. Dev.  2010,  14:  393 
    Search in Google Scholar
  • 10h Malet-Sanz L. Madrzak J. Ley SV. Baxendale IR. Org. Biomol. Chem.  2010,  8:  5324 
    Search in Google Scholar
  • 11a Riva E. Rencurosi A. G agliardi S. Passarella D. Martinelli M. Chem. Eur. J.  2011,  17:  6221 
    Search in Google Scholar
  • 11b Lange PP. Gooßen LJ. Podmore P. Underwood T. Sciammetta N. Chem. Commun.  2011,  47:  3628 
    Search in Google Scholar
  • 11c Batoul A.-O. Sanderson AJ. Org. Biomol. Chem.  2011,  9:  3854 
    Search in Google Scholar
  • 11d Rasheed M. Elmore SC. Wirth T. In Catalytic Methods in Asymmetric Synthesis: Advanced Materials, Techniques, and Applications   Gruttadauria M. Giacalone F. Wiley; Hoboken: 2011.  p.345 
  • 11e Ahmed-Omer B. Barrow DA. Wirth T. ARKIVOC  2011,  (iv):  26 
    Search in Google Scholar
  • 11f Rasheed M. Wirth T. Angew. Chem. Int. Ed.  2011,  50:  357 
    Search in Google Scholar
  • 11g Brandt JC. Elmore SC. Robinson RI. Wirth T. Synlett  2010,  3099 
  • 11h Brasholz M. Macdonald JM. Saubern S. Ryan JH. Holmes AB. Chem. Eur. J.  2010,  16:  11471 
    Search in Google Scholar
  • 11i Wegner J. Ceylan S. Friese C. Kirschning A. Eur. J. Org. Chem.  2010,  4372 
  • 11j Grafton M. Mansfield AC. Fray MJ. Tetrahedron Lett.  2010,  51:  1026 
    Search in Google Scholar
  • 11k Tamborini L. Conti P. Pinto A. Micheli CD. Tetrahedron: Asymmetry  2010,  21:  222 
    Search in Google Scholar
  • 11l Bogdan AR. Poe SL. Kubis DC. Broadwater SJ. McQuade DT. Angew. Chem. Int. Ed.  2009,  48:  8547 
    Search in Google Scholar
  • 11m Seeberger PH. Nat. Chem.  2009,  1:  258 
    Search in Google Scholar
  • 11n Bogdan A. McQuade DT. Beilstein J. Org. Chem.  , 
  • 11o Rolland J. Cambeiro XC. Rodríguez-Escrich C. Pericàs MA. Beilstein J. Org. Chem.  2009,  5:  56 
    Search in Google Scholar
  • 11p Hessel V. Chem. Eng. Technol.  2009,  32:  1655 
    Search in Google Scholar
  • 13 Browne DL. Deadman BJ. Ashe R. Baxendale IR. Ley SV. Org. Process Res. Dev.  2011,  15:  693 
    Search in Google Scholar
  • 14 Sedelmeier J. Ley SV. Baxendale IR. Baumann M. Org. Lett.  2010,  12:  3618 
    Search in Google Scholar
  • 15a Tse M. K. Bhor S. Klawonn M. Anikumar G. Jiao H. Döbler C. Spannenberg A. Mägerlein W. Hugl H. Beller M. Chem. Eur. J.  2006,  12:  1855 
    Search in Google Scholar
  • 15b Bhattacharya S. Snehalatha K. Kumar V. P. J. Org. Chem.  2003,  68:  2741 
    Search in Google Scholar
  • 16 Clayden J. Organic chemistry   Oxford University Press; Oxford: 2001.  p.276-296  
  • 20a Parsons AT. Johnson JS. J. Am. Chem. Soc.  2009,  131:  3122 
    Search in Google Scholar
  • 20b Wang H. Wang H. Liu P. Yang H. Xiao J. Can Li C. J. Mol. Catal. A: Chem.  2008,  285:  128 
    Search in Google Scholar
  • For the chelation properties of dimeric macrocycles, see:
  • 21a Mammoliti O. Allasia S. Dixon S. Kilburn JD. Tetrahedron  2009,  65:  2184 
    Search in Google Scholar
  • 21b Bradshaw JS. Colter ML. Nakatsuji Y. Spencer NO. Brown MF. Izatt RM. Arena G. Tse P.-K. Wilson BE. Lamb JD. Dalley NK. J. Org. Chem.  1985,  50:  4865 
    Search in Google Scholar
  • 22 Baumann M. Baxendale IR. Ley SV. Synlett  2008,  2111 
  • 23 Baumann M. Baxendale IR. Martin LJ. Ley SV. Tetrahedron  2009,  65:  6611 
    Search in Google Scholar
  • For other examples of azide chemistry in flow from our group, see:
  • 24a Smith CJ. Smith CD. Nikbin N. Ley SV. Baxendale IR. Org. Biomol. Chem.  2011,  9:  1927 
    Search in Google Scholar
  • 24b Smith CJ. Nikbin N. Ley SV. Lange H. Baxendale IR. Org. Biomol. Chem.  2011,  9:  1938 
    Search in Google Scholar
  • 24c Smith CD. Baxendale IR. Lanners S. Hayward JJ. Smith SC. Ley SV. Org. Biomol. Chem.  2007,  5:  1559 
    Search in Google Scholar
  • 24d Baumann M. Baxendale IR. Ley SV. Nikbin N. Smith CD. Org. Biomol. Chem.  2008,  6:  1587 
    Search in Google Scholar
  • 24e Baumann M. Baxendale IR. Ley SV. Nikbin N. Smith CD. Tierney JP. Org. Biomol. Chem.  2008,  6:  1577 
    Search in Google Scholar
  • 24f Baxendale IR. Deeley J. Griffiths-Jones CM. Ley SV. Saaby S. Tranmer GK. Chem. Commun.  2006,  2566 
  • 25 The H-Cube flow hydrogenator is commercially available from ThalesNano, see: http://www.thalesnano.com. See also: Bryan MC. Wernick D. Hein CD. Petersen JV. Eschelbach JW. Doherty EM. Beilstein J. Org. Chem.  2011,  7:  1141 
    Search in Google Scholar
  • 26 Horvath G. Rusa C. Montos Z. Gerencser J. Huszthy P. Synth. Commun.  1999,  29:  3719 
    Search in Google Scholar
  • 27 Preston AJ. Gallucci JC. Parquette JR. Chem. Commun.  2005,  3280 
  • 28 Bradshaw JS. Huszthy P. Wang T.-M. Zhu C.-Y. Nazarenko AZ. Izatt RM. Supramol. Chem.  1993,  1:  267 
    Search in Google Scholar
  • 29 Chessa G. Canovese L. Visentin F. Santo C. Seraglia R. Tetrahedron  2005,  61:  1755 
    Search in Google Scholar
12

The use of a standard T or Y union gave rise to problems of back-mixing and build-up of blockages in the flow channel.

17

Commercially available from TCI Europe: Vilsmeier reagent N-(chloromethylene)-N-methylmethanaminium chloride [CAS Reg. No. 3724-43-4].

18

The Vapourtec R2+/R4 flow system used in this study is commercially available from Vapourtec; Web site: http://www.vapourtec.co.uk.

19

Quadrapure-DMA. Available from Johnson Matthey, see: http://www.scavengingtechnologies.com/site.asp?id = 1297&pageid = 1299.