An Integrated Flow and Batch-Based
Approach for the Synthesis of O-Methyl Siphonazole

Marcus Baumann; Ian R. Baxendale; Malte Brasholz; John J. Hayward; Steven V. Ley; Nikzad Nikbin

doi:10.1055/s-0030-1260573

LETTER

An Integrated Flow and Batch-Based Approach for the Synthesis of O-Methyl Siphonazole

Marcus Baumann, Ian R. Baxendale, Malte Brasholz, John J. Hayward, Steven V. Ley, Nikzad Nikbin
Innovative Technology Centre, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK
e-Mail: theitc@cam.ac.uk;

Abstract

Alle Artikel dieser Rubrik

Abstract

The bisoxazole containing natural product O-methyl siphonazole was assembled using a suite of microreactors via a flow-based approach in concert with traditional batch methods. The use of a toolbox of solid-supported scavengers and reagents to aid purification afforded the natural product in a total of nine steps.

Key words

oxazoles - Claisen condensation - flow chemistry - microreactors - solid-supported reagents

Volltext

Referenzen

References and Notes

<A NAME="RD05911ST-1A">1a</A> Bull JA. Balskus EP. Horan RAJ. Langner M. Ley SV. Angew. Chem. Int. Ed. 2006, 45: 6714

<A NAME="RD05911ST-1B">1b</A> Bull JA. Balskus EP. Horan RAJ. Langner M. Ley SV. Chem. Eur. J. 2007, 13: 5515

<A NAME="RD05911ST-1C">1c</A> Enriquez-Garcia A. Ley SV. Collect. Czech. Chem. Commun. 2009, 74: 887

<A NAME="RD05911ST-2">2</A> Nett M. Erol . Kehraus S. Köck M. Krick A. Eguevera E. Neu E. König GM. Angew. Chem. Int. Ed. 2006, 45: 3863

<A NAME="RD05911ST-3A">3a</A> Linder J. Moody CJ. Chem. Commun. 2007, 1508

<A NAME="RD05911ST-3B">3b</A> Linder J. Blake AJ. Moody CJ. Org. Biomol. Chem. 2008, 6: 3908

<A NAME="RD05911ST-4A">4a</A> Zhang J. Ciufolini MA. Org. Lett. 2009, 11: 2389

<A NAME="RD05911ST-4B">4b</A> Zhang J. Polishchuk EA. Chen J. Ciufolini MA. J. Org. Chem. 2009, 74: 9140

<A NAME="RD05911ST-5A">5a</A> Noël T. Naber JR. Hartman RL. McMullen JP. Jensen KF. Buchwald SL. Chem. Sci. 2011, 2: 287

<A NAME="RD05911ST-5B">5b</A> Ceylan S. Coutable L. Wegner J. Kirschning A. Chem. Eur. J. 2011, 17: 1884

<A NAME="RD05911ST-5C">5c</A> Polyzos T. O’Brien M. Petersen TP. Baxendale IR. Ley SV. Angew. Chem. Int. Ed. 2011, 50: 1190

<A NAME="RD05911ST-5D">5d</A> Ngamsom B. Hickey AM. Greenway GM. Littlechild JA. McCreedy T. Watts P. Wiles C. Org. Biomol. Chem. 2010, 8: 2419

<A NAME="RD05911ST-5E">5e</A> Bagley MC. Fusillo V. Jenkins RL. Lubinu MC. Mason C. Org. Biomol. Chem. 2010, 8: 2245

<A NAME="RD05911ST-5F">5f</A> Wegner J. Ceylan S. Friese C. Kirschning A. Eur. J. Org. Chem. 2010, 4372

<A NAME="RD05911ST-5G">5g</A> McMullen JP. Stone MT. Buchwald SL. Jensen KF. Angew. Chem. Int. Ed. 2010, 49: 7076

<A NAME="RD05911ST-5H">5h</A> McMullen JP. Jensen KF. Org. Process Res. Dev. 2010, 14: 1169

<A NAME="RD05911ST-5I">5i</A> Damm M. Glasnov TN. Kappe CO. Org. Process Res. Dev. 2010, 14: 215

<A NAME="RD05911ST-5J">5j</A> Riva E. Gagliardi S. Martinelli M. Passarella D. Vigo D. Rencurosi A. Tetrahedron 2010, 66: 3242

<A NAME="RD05911ST-5K">5k</A> Amemiya F. Fuse K. Fuchigami T. Atobe M. Chem. Commun. 2010, 46: 2730

<A NAME="RD05911ST-5L">5l</A> Brandt JC. Elmore SC. Robinson RI. Wirth T. Synlett 2010, 3099

<A NAME="RD05911ST-5M">5m</A> Nagaki A. Takabayasi N. Tomida Y. Yoshida J. Beilstein J. Org. Chem. 2009, 5: No. 16

<A NAME="RD05911ST-5N">5n</A> Gustafsson T. Pontén F. Seeberger PH. Chem. Commun. 2008, 26: 1100

<A NAME="RD05911ST-5O">5o</A> Sahoo HR. Kralji JG. Jensen KF. Angew. Chem. Int. Ed. 2007, 46: 5704

<A NAME="RD05911ST-5P">5p</A> Mason BP. Price KE. Steinbacher JL. Bogdan AR. MacQuade DT. Chem. Rev. 2007, 107: 2300

<A NAME="RD05911ST-6A">6a</A> Baumann M. Baxendale IR. Ley SV. Mol. Diversity 2011, in press; DOI: 10.1007/s11030-010-9282-1

<A NAME="RD05911ST-6B">6b</A> Bogdan AR. James K. Chem. Eur. J. 2010, 16: 14506

<A NAME="RD05911ST-6C">6c</A> Hessel V. Chem. Eng. Technol. 2009, 32: 1655

<A NAME="RD05911ST-6D">6d</A> Ley SV. Baxendale IR. Chimia 2008, 62: 162

<A NAME="RD05911ST-7A">7a</A> Irfan M. Glasnov TN. Kappe CO. Org. Lett. 2011, 13: 984

<A NAME="RD05911ST-7B">7b</A> Martin LJ. Marzinzik AL. Ley SV. Baxendale IR. Org. Lett. 2011, 13: 320

<A NAME="RD05911ST-7C">7c</A> Smith CJ. Nikbin N. Ley SV. Lange H. Baxendale IR. Org. Biomol. Chem. 2011, 9: 1938

<A NAME="RD05911ST-7D">7d</A> Malet-Sanz L. Madrzak J. Ley SV. Baxendale IR. Org. Biomol. Chem. 2010, 8: 5324

<A NAME="RD05911ST-7E">7e</A> McPake CB. Murray CB. Sandford G. Chimica oggi 2010, 26: 6

<A NAME="RD05911ST-7F">7f</A> O’Brien M. Baxendale IR. Ley SV. Org. Lett. 2010, 12: 1596

<A NAME="RD05911ST-7G">7g</A> Bartrum HE. Blakemore DC. Moody CJ. Hayes CJ. J. Org. Chem. 2010, 75: 8674

<A NAME="RD05911ST-7H">7h</A> Brandt JC. Wirth T. Beilstein J. Org. Chem. 2009, 5: No. 30

<A NAME="RD05911ST-7I">7i</A> Bogdan AR. Sach NW. Adv. Synth. Catal. 2009, 351: 849

<A NAME="RD05911ST-7J">7j</A> Baumann M. Baxendale IR. Nikbin N. Ley SV. Smith CD. Tierney JP. Org. Biomol. Chem. 2008, 6: 1577

<A NAME="RD05911ST-7K">7k</A> Wiles C. Watts P. Eur. J. Org. Chem. 2008, 5597

<A NAME="RD05911ST-7L">7l</A> Sandford G. J. Fluorine Chem. 2007, 128: 90

<A NAME="RD05911ST-8A">8a</A> Hodgkinson JT. Galloway WRJD. Shreya S. Baxendale IR. Ley SV. Ladlow M. Welch M. Spring DR. Org. Biomol. Chem. 2011, 9: 57

<A NAME="RD05911ST-8B">8b</A> Carter CF. Baxendale IR. Pavey JBJ. Ley SV. Org. Biomol. Chem. 2010, 8: 1588

<A NAME="RD05911ST-8C">8c</A> Wheeler RC. Benali O. Deal M. Farrant E. MacDonald SJF. Warrington BH. Org. Process Res. Dev. 2007, 11: 704

<A NAME="RD05911ST-8D">8d</A> Hornung CH. Mackley MR. Baxendale IR. Ley SV. Org. Process Res. Dev. 2007, 11: 399

<A NAME="RD05911ST-8E">8e</A> Smith CJ. Iglesias-Sigüenza FJ. Baxendale IR. Ley SV. Org. Biomol. Chem. 2007, 5: 2758

<A NAME="RD05911ST-8F">8f</A> Roberge DM. Ducry L. Bieler N. Cretton P. Zimmermann B. Chem. Eng. Technol. 2005, 28: 318

<A NAME="RD05911ST-9A">9a</A> Rasheed M. Wirth T. Angew. Chem. Int. Ed. 2011, 50: 357

<A NAME="RD05911ST-9B">9b</A> Smith CJ. Smith CD. Nikbin N. Ley SV. Baxendale IR. Org. Biomol. Chem. 2011, 9: 1927

<A NAME="RD05911ST-9C">9c</A> Venturoni F. Nikbin N. Ley SV. Baxendale IR. Org. Biomol. Chem. 2010, 8: 1798

<A NAME="RD05911ST-9D">9d</A> Baxendale IR. Griffiths-Jones CM. Ley SV. Tranmer GK. Synlett 2006, 427

<A NAME="RD05911ST-10A">10a</A> Baumann M. Baxendale IR. Kirschning A. Ley SV. Wegner J. Heterocycles 2011, 82: 1297

<A NAME="RD05911ST-10B">10b</A> Hopkin MD. Baxendale IR. Ley SV. Chem. Commun. 2010, 46: 2450

<A NAME="RD05911ST-10C">10c</A> Qian Z. Baxendale IR. Ley SV. Chem. Eur. J. 2010, 16: 12342

<A NAME="RD05911ST-10D">10d</A> Brasholz M. Johnson BA. Macdonald JM. Polyzos A. Tsanaktsidis J. Saubern S. Holmes AB. Ryan JH. Tetrahedron 2010, 66: 6445

<A NAME="RD05911ST-10E">10e</A> Tamborini L. Conti P. Pinto A. Micheli CD. Tetrahedron: Asymmetry 2010, 21: 222

<A NAME="RD05911ST-10F">10f</A> Herath A. Dahl R. Cosford NDP. Org. Lett. 2010, 12: 412

<A NAME="RD05911ST-10G">10g</A> Baxendale IR. Schou S. Sedelmeier J. Ley SV. Chem. Eur. J. 2010, 16: 89

<A NAME="RD05911ST-10H">10h</A> Baxendale IR. Ley SV. Mansfield AC. Smith CD. Angew. Chem. Int. Ed. 2009, 48: 4017

<A NAME="RD05911ST-10I">10i</A> Baxendale IR. Deeley CM. Griffiths-Jones CM. Ley SV. Saaby S. Tranmer GK. Chem. Commun. 2006, 24: 2566

<A NAME="RD05911ST-10J">10j</A> Baxendale IR. Ley SV. Smith CD. Tranmer GK. Chem. Commun. 2006, 4835

<A NAME="RD05911ST-12A">12a</A> Middleton WJ. J. Org. Chem. 1975, 40: 574

<A NAME="RD05911ST-12B">12b</A> Phillips AJ. Uto Y. Wipf P. Reno MJ. Williams DR. Org. Lett. 2000, 2: 1165

Use of DAST in flow:

<A NAME="RD05911ST-12C">12c</A> Baumann M. Baxendale IR. Ley SV. Synlett 2008, 2111

<A NAME="RD05911ST-12D">12d</A> Baumann M. Baxendale IR. Martin LJ. Ley SV. Tetrahedron 2009, 65: 6611

QP-SA and QP-DMA resins are commercially available from Johnson Matthey. Website: http://www.matthey.com/.

<A NAME="RD05911ST-14">14</A> Williams DR. Lowder PD. Gu Y.-G. Brooks DA. Tetrahedron Lett. 1997, 38: 331

<A NAME="RD05911ST-15">15</A> Doleschall G. Seres P. J. Chem. Soc., Perkin Trans. 1 1988, 1875

<A NAME="RD05911ST-16">16</A>Compound 12 was prepared by ring opening of 2,2,6-trimethyl-4H-1,3-dioxin-4-one with phenol, see:

<A NAME="RD05911ST-16">16</A> Clemens RJ. Hyatt JA. J. Org. Chem. 1985, 50: 2431 . Followed by diazo group transfer, see: Tullis JS. Helquist P. Org. Synth. 1997, 74: 229

<A NAME="RD05911ST-17">17</A> Bagley MC. Buck RT. Hind SL. Moody CJ.
J. Chem. Soc., Perkin Trans. 1 1998, 591

<A NAME="RD05911ST-18">18</A> Wipf P. Miller CP. J. Org. Chem. 1993, 58: 3604

An Omnifit column was used, www.omnifit.com.

For related applications of PS-BEMP iminophosphorane base, see:

<A NAME="RD05911ST-20A">20a</A> Bensa D. Constantieux T. Rodriguez J. Synthesis 2004, 923

<A NAME="RD05911ST-20B">20b</A> Baumann M. Baxendale IR. Ley SV. Smith CD. Tranmer GK. Org. Lett. 2006, 8: 5231

<A NAME="RD05911ST-21A">21a</A> Krapcho AP. Jahngen EGE. Lovey AJ. Tetrahedron Lett. 1974, 15: 1091

<A NAME="RD05911ST-21B">21b</A> Krapcho AP. Weimaster JF. Eldridge JM. Jahngen EGE. Lovey AJ. Stephens WP. J. Org. Chem. 1978, 43: 138

<A NAME="RD05911ST-22A">22a</A> Mori K. Tetrahedron 1974, 30: 3810

<A NAME="RD05911ST-22B">22b</A> Grieco PA. Galatsis P. Spohn RF. Tetrahedron 1986, 42: 2847

<A NAME="RD05911ST-23">23</A> Poulain RF. Tartar AL. Déprez BP. Tetrahedron Lett. 2001, 42: 1495

NMR Data
^¹H NMR (600 MHz, CDCl₃): δ = 2.64, 2.67 (2 s, 2 × 3 H, 18-H, 19-H), 3.92, 3.93 (2 s, 2 × 3 H, 20-H, 21-H), 4.03 (t, J = 5.8 Hz, 2 H, 1′-H), 4.41 (s, 2 H, 5-H), 5.06 (d, J = 10.3 Hz, 1 H, 5′-H), 5.18 (d, J = 17.0 Hz, 1 H, 5′-H), 5.73 (td, J = 5.8, 15.0 Hz, 1 H, 2′-H), 6.22 (dd, J = 10.3, 15.0 Hz, 1 H, 3′-H), 6.31 (td, J = 10.3, 17.0 Hz, 1 H, 4′-H), 6.75 (d, J = 16.4, 1 H, 10-H), 6.88 (d, J = 8.2 Hz, 1 H, 16-H), 7.00 (t, J = 5.8 Hz, 1 H, NH), 7.07 (d, J = 1.6 Hz, 1 H, 13-H), 7.09 (dd, J = 1.6, 8.2 Hz, 1 H, 17-H), 7.44 (d, J = 16.4 Hz, 1 H, 11-H) ppm. ^¹³C NMR (150 MHz): δ = 11.7, 12.4 (2 q, C-18, C-19), 39.4 (t, C-5), 40.3 (t, C-1′), 55.9, 56.0 (2 q, C-20, C-21), 108.9 (d, C-13), 110.8 (d, C-10), 111.2 (d, C-16), 117.4 (t, C-5′), 121.5 (d, C-17), 128.1 (s, C-12), 129.45, 129.49 (2 d, C-2′, C-3′), 132.8 (s, C-2), 134.5 (s, C-7), 136.1 (d, C-4′), 137.3 (d, C-11), 149.3, 150.6 (2 s, C-14, C-15), 153.8 (s, C-3), 155.3 (s, C-8), 155.6 (s, C-4), 159.1 (s, C-9), 161.7 (s, C-1), 189.4 (s, C-6) ppm.