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

Subscribe to RSS

Please copy the URL and add it into your RSS Feed Reader.

https://www.thieme-connect.de/rss/thieme/en/10.1055-s-00000083.xml

Share / Bookmark

Facebook X Linkedin Weibo

Download PDF

Synlett 2011(10): 1375-1380
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;

Further Information

Publication History

Received 21 February 2011
Publication Date:
23 May 2011 (online)

Abstract
Full Text
References

Permissions and Reprints All articles of this category

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

References and Notes

1a Bull JA. Balskus EP. Horan RAJ. Langner M. Ley SV. Angew. Chem. Int. Ed. 2006, 45: 6714

Google Scholar
1b Bull JA. Balskus EP. Horan RAJ. Langner M. Ley SV. Chem. Eur. J. 2007, 13: 5515

Google Scholar
1c Enriquez-Garcia A. Ley SV. Collect. Czech. Chem. Commun. 2009, 74: 887

Google Scholar
2 Nett M. Erol . Kehraus S. Köck M. Krick A. Eguevera E. Neu E. König GM. Angew. Chem. Int. Ed. 2006, 45: 3863

Crossref Google Scholar
3a Linder J. Moody CJ. Chem. Commun. 2007, 1508

Google Scholar
3b Linder J. Blake AJ. Moody CJ. Org. Biomol. Chem. 2008, 6: 3908

Google Scholar
4a Zhang J. Ciufolini MA. Org. Lett. 2009, 11: 2389

Google Scholar
4b Zhang J. Polishchuk EA. Chen J. Ciufolini MA. J. Org. Chem. 2009, 74: 9140

Google Scholar
5a Noël T. Naber JR. Hartman RL. McMullen JP. Jensen KF. Buchwald SL. Chem. Sci. 2011, 2: 287

Google Scholar
5b Ceylan S. Coutable L. Wegner J. Kirschning A. Chem. Eur. J. 2011, 17: 1884

Google Scholar
5c Polyzos T. O’Brien M. Petersen TP. Baxendale IR. Ley SV. Angew. Chem. Int. Ed. 2011, 50: 1190

Google Scholar
5d Ngamsom B. Hickey AM. Greenway GM. Littlechild JA. McCreedy T. Watts P. Wiles C. Org. Biomol. Chem. 2010, 8: 2419

Google Scholar
5e Bagley MC. Fusillo V. Jenkins RL. Lubinu MC. Mason C. Org. Biomol. Chem. 2010, 8: 2245

Google Scholar
5f Wegner J. Ceylan S. Friese C. Kirschning A. Eur. J. Org. Chem. 2010, 4372

Google Scholar
5g McMullen JP. Stone MT. Buchwald SL. Jensen KF. Angew. Chem. Int. Ed. 2010, 49: 7076

Google Scholar
5h McMullen JP. Jensen KF. Org. Process Res. Dev. 2010, 14: 1169

Google Scholar
5i Damm M. Glasnov TN. Kappe CO. Org. Process Res. Dev. 2010, 14: 215

Google Scholar
5j Riva E. Gagliardi S. Martinelli M. Passarella D. Vigo D. Rencurosi A. Tetrahedron 2010, 66: 3242

Google Scholar
5k Amemiya F. Fuse K. Fuchigami T. Atobe M. Chem. Commun. 2010, 46: 2730

Google Scholar
5l Brandt JC. Elmore SC. Robinson RI. Wirth T. Synlett 2010, 3099

Google Scholar
5m Nagaki A. Takabayasi N. Tomida Y. Yoshida J. Beilstein J. Org. Chem. 2009, 5: No. 16

Google Scholar
5n Gustafsson T. Pontén F. Seeberger PH. Chem. Commun. 2008, 26: 1100

Google Scholar
5o Sahoo HR. Kralji JG. Jensen KF. Angew. Chem. Int. Ed. 2007, 46: 5704

Google Scholar
5p Mason BP. Price KE. Steinbacher JL. Bogdan AR. MacQuade DT. Chem. Rev. 2007, 107: 2300

Google Scholar
6a Baumann M. Baxendale IR. Ley SV. Mol. Diversity 2011, in press; DOI: 10.1007/s11030-010-9282-1

Google Scholar
6b Bogdan AR. James K. Chem. Eur. J. 2010, 16: 14506

Google Scholar
6c Hessel V. Chem. Eng. Technol. 2009, 32: 1655

Google Scholar
6d Ley SV. Baxendale IR. Chimia 2008, 62: 162

Google Scholar
7a Irfan M. Glasnov TN. Kappe CO. Org. Lett. 2011, 13: 984

Google Scholar
7b Martin LJ. Marzinzik AL. Ley SV. Baxendale IR. Org. Lett. 2011, 13: 320

Google Scholar
7c Smith CJ. Nikbin N. Ley SV. Lange H. Baxendale IR. Org. Biomol. Chem. 2011, 9: 1938

Google Scholar
7d Malet-Sanz L. Madrzak J. Ley SV. Baxendale IR. Org. Biomol. Chem. 2010, 8: 5324

Google Scholar
7e McPake CB. Murray CB. Sandford G. Chimica oggi 2010, 26: 6

Google Scholar
7f O’Brien M. Baxendale IR. Ley SV. Org. Lett. 2010, 12: 1596

Google Scholar
7g Bartrum HE. Blakemore DC. Moody CJ. Hayes CJ. J. Org. Chem. 2010, 75: 8674

Google Scholar
7h Brandt JC. Wirth T. Beilstein J. Org. Chem. 2009, 5: No. 30

Google Scholar
7i Bogdan AR. Sach NW. Adv. Synth. Catal. 2009, 351: 849

Google Scholar
7j Baumann M. Baxendale IR. Nikbin N. Ley SV. Smith CD. Tierney JP. Org. Biomol. Chem. 2008, 6: 1577

Google Scholar
7k Wiles C. Watts P. Eur. J. Org. Chem. 2008, 5597

Google Scholar
7l Sandford G. J. Fluorine Chem. 2007, 128: 90

Google Scholar
8a Hodgkinson JT. Galloway WRJD. Shreya S. Baxendale IR. Ley SV. Ladlow M. Welch M. Spring DR. Org. Biomol. Chem. 2011, 9: 57

Google Scholar
8b Carter CF. Baxendale IR. Pavey JBJ. Ley SV. Org. Biomol. Chem. 2010, 8: 1588

Google Scholar
8c Wheeler RC. Benali O. Deal M. Farrant E. MacDonald SJF. Warrington BH. Org. Process Res. Dev. 2007, 11: 704

Google Scholar
8d Hornung CH. Mackley MR. Baxendale IR. Ley SV. Org. Process Res. Dev. 2007, 11: 399

Google Scholar
8e Smith CJ. Iglesias-Sigüenza FJ. Baxendale IR. Ley SV. Org. Biomol. Chem. 2007, 5: 2758

Google Scholar
8f Roberge DM. Ducry L. Bieler N. Cretton P. Zimmermann B. Chem. Eng. Technol. 2005, 28: 318

Google Scholar
9a Rasheed M. Wirth T. Angew. Chem. Int. Ed. 2011, 50: 357

Google Scholar
9b Smith CJ. Smith CD. Nikbin N. Ley SV. Baxendale IR. Org. Biomol. Chem. 2011, 9: 1927

Google Scholar
9c Venturoni F. Nikbin N. Ley SV. Baxendale IR. Org. Biomol. Chem. 2010, 8: 1798

Google Scholar
9d Baxendale IR. Griffiths-Jones CM. Ley SV. Tranmer GK. Synlett 2006, 427

Google Scholar
10a Baumann M. Baxendale IR. Kirschning A. Ley SV. Wegner J. Heterocycles 2011, 82: 1297

Google Scholar
10b Hopkin MD. Baxendale IR. Ley SV. Chem. Commun. 2010, 46: 2450

Google Scholar
10c Qian Z. Baxendale IR. Ley SV. Chem. Eur. J. 2010, 16: 12342

Google Scholar
10d Brasholz M. Johnson BA. Macdonald JM. Polyzos A. Tsanaktsidis J. Saubern S. Holmes AB. Ryan JH. Tetrahedron 2010, 66: 6445

Google Scholar
10e Tamborini L. Conti P. Pinto A. Micheli CD. Tetrahedron: Asymmetry 2010, 21: 222

Google Scholar
10f Herath A. Dahl R. Cosford NDP. Org. Lett. 2010, 12: 412

Google Scholar
10g Baxendale IR. Schou S. Sedelmeier J. Ley SV. Chem. Eur. J. 2010, 16: 89

Google Scholar
10h Baxendale IR. Ley SV. Mansfield AC. Smith CD. Angew. Chem. Int. Ed. 2009, 48: 4017

Google Scholar
10i Baxendale IR. Deeley CM. Griffiths-Jones CM. Ley SV. Saaby S. Tranmer GK. Chem. Commun. 2006, 24: 2566

Google Scholar
10j Baxendale IR. Ley SV. Smith CD. Tranmer GK. Chem. Commun. 2006, 4835

Google Scholar
12a Middleton WJ. J. Org. Chem. 1975, 40: 574

Google Scholar
12b Phillips AJ. Uto Y. Wipf P. Reno MJ. Williams DR. Org. Lett. 2000, 2: 1165

Google Scholar
Use of DAST in flow:
12c Baumann M. Baxendale IR. Ley SV. Synlett 2008, 2111

Google Scholar
12d Baumann M. Baxendale IR. Martin LJ. Ley SV. Tetrahedron 2009, 65: 6611

Google Scholar
14 Williams DR. Lowder PD. Gu Y.-G. Brooks DA. Tetrahedron Lett. 1997, 38: 331

Crossref Google Scholar
15 Doleschall G. Seres P. J. Chem. Soc., Perkin Trans. 1 1988, 1875

Google Scholar
16Compound 12 was prepared by ring opening of 2,2,6-trimethyl-4H-1,3-dioxin-4-one with phenol, see:
16 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

Google Scholar
17 Bagley MC. Buck RT. Hind SL. Moody CJ.
J. Chem. Soc., Perkin Trans. 1 1998, 591

Google Scholar
18 Wipf P. Miller CP. J. Org. Chem. 1993, 58: 3604

Crossref Google Scholar
For related applications of PS-BEMP iminophosphorane base, see:
20a Bensa D. Constantieux T. Rodriguez J. Synthesis 2004, 923

Google Scholar
20b Baumann M. Baxendale IR. Ley SV. Smith CD. Tranmer GK. Org. Lett. 2006, 8: 5231

Google Scholar
21a Krapcho AP. Jahngen EGE. Lovey AJ. Tetrahedron Lett. 1974, 15: 1091

Google Scholar
21b Krapcho AP. Weimaster JF. Eldridge JM. Jahngen EGE. Lovey AJ. Stephens WP. J. Org. Chem. 1978, 43: 138

Google Scholar
22a Mori K. Tetrahedron 1974, 30: 3810

Google Scholar
22b Grieco PA. Galatsis P. Spohn RF. Tetrahedron 1986, 42: 2847

Google Scholar
23 Poulain RF. Tartar AL. Déprez BP. Tetrahedron Lett. 2001, 42: 1495

Crossref Google Scholar

11

13

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

19

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

24

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.