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Monday 15 June 2015

The rapid synthesis of oxazolines and their heterogeneous oxidation to oxazoles under flow conditions


C4OB02105C GA


image file: c4ob02105c-u2.tif2a

(4S,5S)-5-Methyl-2-phenyl-4,5-dihydro-oxazole-4-carboxylic acid methyl ester (2a).

The rapid synthesis of oxazolines and their heterogeneous oxidation to oxazoles under flow conditionsSteffen Glöckner, Duc N. Tran, Richard J. Ingham, Sabine Fenner, Zoe E. Wilson, Claudio Battilocchio and Steven V. Ley DOI: 10.1039/C4OB02105C, Paper From themed collection Recent Advances in Flow Synthesis and Continuous Processing

The rapid synthesis of oxazolines and their heterogeneous oxidation to oxazoles under flow conditions

*Corresponding authors
aDepartment of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK
E-mail: svl1000@cam.ac.uk Web: http://www.leygroup.ch.cam.ac.uk/
Org. Biomol. Chem., 2015,13, 207-214
DOI: 10.1039/C4OB02105C
A rapid flow synthesis of oxazolines and their oxidation to the corresponding oxazoles is reported. The oxazolines are prepared at room temperature in a stereospecific manner, with inversion of stereochemistry, from β-hydroxy amides using Deoxo-Fluor®. The corresponding oxazoles can then be obtained via a packed reactor containing commercial manganese dioxide
image file: c4ob02105c-f1.tif
Fig. 1 Oxazoline- and oxazole-containing natural products.
image file: c4ob02105c-s1.tif
Scheme 1 Optimised conditions for the flow synthesis of oxazolines.
image file: c4ob02105c-s2.tif
Scheme 2 Microchip reaction for the preparation of oxazolines.
image file: c4ob02105c-s3.tif
Scheme 3 Platform set up for the scale up experiment.
image file: c4ob02105c-s4.tif
Scheme 4 Flow oxidation of aryl-oxazolines using activated MnO2.
image file: c4ob02105c-s5.tif
Scheme 5 Flow oxidation of 2-alkyl-oxazolines using amorphous MnO2a[thin space (1/6-em)]Deprotection was observed.
image file: c4ob02105c-s6.tif
Scheme 6 Automated oxidation of oxazolines using a Raspberry Pi® computer and a multiple position valve.
Table 1 Flow cyclodehydration of β-hydroxy amides using Deoxo-Fluor®
EntryaSubstrateProductIsolated yieldb
a Reactions were run on a 2 mmol scale. b Compounds were isolated without purification. c The crude material was passed through a plug of calcium carbonate/silica in place of an aqueous work up. d Total flow rate = 10 mL min−1 with 2.6 eq. of Deoxo-Fluor®.
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  image file: c4ob02105c-u2.tif2a
(4S,5S)-5-Methyl-2-phenyl-4,5-dihydro-oxazole-4-carboxylic acid methyl ester (2a).

General protocol for the preparation of oxazoline in flow

A solution of Deoxo-Fluor® (1 mL, 50% in toluene) in CH2Cl2 (7.0 mL) and a solution of β-hydroxy amide (2 mmol) in CH2Cl2 (8 mL) were combined at a T-piece (each stream run at 3.0 mL min−1) and reacted at rt in a 10 mL PFA reactor coil. The combined stream was then directed to an aqueous quenching stream (9 mL min−1) and the solution directed to a liquid/liquid separator.22
(4S,5S)-5-Methyl-2-phenyl-4,5-dihydro-oxazole-4-carboxylic acid methyl ester (2a).

image file: c4ob02105c-u2.tif2a


 1H-NMR (600 MHz, CDCl3) δ = 7.98–7.96 (m, 2H), 7.49–7.46 (m, 1H), 7.40–7.38 (m, 2H), 5.05 (dq, 1H, J= 10.2, 6.4 Hz), 4.97 (d, 1H, J = 10.2 Hz), 3.76 (s, 3H), 1.37 (d, 3H, J = 6.5 Hz); 


13C-NMR (151 MHz, CDCl3) δ = 170.5, 166.2, 131.9, 128.6, 128.4, 127.3, 77.7, 71.8, 52.2, 16.3; 

HR-MS (ESI+) for C12H14NO3+ [M + H]+ calc.: 220.0974, found: 220.0981; 


FT-IR neat, [small nu, Greek, tilde] (cm−1) = 2953, 1736, 1645, 1603, 1580, 1496, 1450, 1384, 1349, 1244, 1197, 1174, 1067, 1045, 1001, 973, 934, 904, 886, 851, 778, 695; 


specific rotation: [α]24.1D = +58.58° cm3 g−1 dm−1 (c = 8.5 in ethanol). Lit.: [α]20D = +69.4° cm3 g−1 dm−1 (c = 8.5 in EtOH).39

39…………H. Aït-Haddou, O. Hoarau, D. Cramailére, F. Pezet, J.-C. Daran and G. G. A. Balavoine, Chem. – Eur. J., 2004, 10, 699–707


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Portrait of zw261

Dr Zoe Wilson

Post Doctoral Research Associate in the group of Professor Steven V. Ley working on the synthesis of complex natural products and synthetic methodology.
College Lecturer and Fellow at Murray Edwards College.

Research Group

Telephone number

01223 336698 (shared)

Email address

College

Email: zw261@cam.ac.uk    LinkedIn Profile
Zoe grew up on a farm in the small town of Warkworth, New Zealand. After completing her studies she moved to Auckland, New Zealand to attend the University of Auckland where she completed a Bachelor of Science in Medicinal Chemistry then a BSc (Hons) in Medicinal Chemistry under the supervision of Professor Margaret Brimble, working on the synthesis of anti-Helicobacter pylori compounds. She was then funded by a University of Auckland scholarship to carry out Ph.D. research with Professor Brimble into the synthesis of the extremophile natural product berkelic acid. Upon completion of her Ph.D. she was awarded a Newton International Fellowship from the Royal Society to move to the United Kingdom and join the research group of Professor Steven V. Ley in the Department of Chemistry, University of Cambridge. Upon completion of the two year Newton Fellowship, she was then employed as a Post-Doctoral Research Associate to continue working in the Ley group. While in Cambridge, she has been working on the total synthesis of the complex natural products azadirachtin and plantazolicins A and B, in the process developing novel chemistry. In October 2013 Zoe was appointed as a College Lecturer and Fellow at Murray Edwards College.
Teaching
Graduate Lecture Series – Reduction in Organic Chemistry (2 lectures) (2014, 2013)
Senior demonstrator Chemistry II laboratories (2014/2015)
Senior demonstrator Chemistry IB laboratories (2012/2013, 2013/2014)
College Lecturer at Murray Edwards College

Publications


12.          Zoe E. Wilson, Sabine Fenner and Steven V. Ley, “Total syntheses of linear poly-thiazole/oxazole plantazolicin A and its biosynthetic precursor plantazolicin B”, Angew. Chem. Int. Ed.201554, 1284 – 1288 DOI: 10.1002/anie.201410063R1
11.          Steffen Glöckner, Duc N. Tran, Richard J. Ingham, Sabine Fenner, Zoe E. Wilson, Claudio Battilocchio and Steven V. Ley, “The rapid synthesis of oxazolines and their heterogeneous oxidation to oxazoles under flow conditions”, Org. Biomol. Chem.,201513, 207–214, DOI: 10.1039/c4ob02105c
10.          Michael C. McLeod, Zoe E. Wilson and Margaret A. Brimble, “Formal synthesis of berkelic acid: a lesson in α-alkylation chemistry”, J. Org. Chem., 201277, 1, 400–416, DOI: 10.1021/jo201988m
9.            Michael C. McLeod, Margaret A. Brimble, Dominea C. K. Rathwell, Zoe E. Wilsonand Tsz-Ying Yuen, “Synthetic approaches to [5,6]-benzannulated spiroketal natural products”, Pure Appl. Chem.201284, 6, 1379-1390, DOI: 10.1351/PAC-CON-11-08-06
8.            Michael C. McLeod, Zoe E. Wilson and Margaret A. Brimble, “An enantioselective formal synthesis of berkelic acid”, Org. Lett.201113, 19, 5382 – 5385, DOI: 10.1021/ol202265g
7.            Zoe E. Wilson, Jonathan G. Hubert, Margaret A. Brimble, “A flexible approach to 6,5-benzannulated spiroketals”, Eur. J. Org. Chem.2011, 3938-3945, DOI: 10.1002/ejoc.201100345
6.            Jonathan Sperry, Yen-Cheng (William) Liu, Zoe E. Wilson, Jonathan G. Hubert, Margaret A. Brimble, “Synthesis of benzannulated spiroketals using an oxidative radical cyclization”, Synthesis20119, 1383-1398, DOI: 10.1055/s-003001259981
5.            Jonathan Sperry, Zoe E. Wilson, Dominea C. K. Rathwell and Margaret A. Brimble, “Isolation, biological activity and synthesis of benzannulated spiroketal natural products”, Nat. Prod. Rep.201027, 1117-1137, DOI: 10.1039/b911514p
4.            Zoe E. Wilson and Margaret A. Brimble, “A flexible asymmetric synthesis of the tetracyclic core of berkelic acid using a novel Horner-Wadsworth-Emmons/oxa-Michael cascade”, Org. Biomol. Chem., 20108, 1284-1286, DOI: 10.1039/B927219B
3.            Zoe E. Wilson and Margaret A. Brimble, “Molecules derived from the extremes of life”, Nat. Prod. Rep.200926, 44–71, DOI: 10.1039/b800164m
Featured as an Instant insight article in Chemical Biology (“Life at the extremes”,Chemical Biology20083, B95) and featured on the cover of the issue (Nat. Prod. Rep.,200926, 1-2, DOI: 10.1039/B821737H)
2.            Fiona J. Radcliff, John D. Fraser, Zoe E. Wilson, Amanda M. Heapy, James E. Robinson, Christina J. Bryant, Christopher L. Flowers, and Margaret A. Brimble, “Anti-Helicobacter pylori activity of derivatives of the phthalide-containing antibacterial agents spirolaxine methyl ether, CJ-12,954, CJ-13,013, CJ-13,102, CJ-13,104, CJ-13,108 and CJ-13,015”, Bioorg. Med. Chem.200816, 6179–6185, DOI: 10.1016/j.bmc.2008.04.037
1.            Zoe E. Wilson, Amanda M. Heapy and Margaret A. Brimble, “Synthesis of indole analogues of the anti-Helicobacter pylori compounds CJ-13,015, CJ-13,102, CJ-13,104 and CJ-13,108”, Tetrahedron200763, 5379–5385, DOI: 10.1016/j.tet.2007.04.067



Take a tour
Trobriand Island

Trobriand Islands - Wikipedia, the free encyclopedia

en.wikipedia.org/wiki/Trobriand_Islands
The Trobriand Islands are a 450 km² archipelago of coral atolls off the eastern coast of New Guinea. They are part of the nation of Papua New Guinea and are ...





Carrying cash: Along with yams, dried banana leaves are currency on the island. According to Lafforgue, this little girl's leaves are the equivalent of a bundle of £10 notes


Chief: Mr Tolobuwa is the head of Vaikiki village and always carries betel nuts, lime gourds and spatulas. The spatula is made from bird bone but human used to be used



Pretty: Little girls wear beautiful crowns of flowers and sea turtle shell earrings, some inherited from their mothers.

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Mourning: In the Trobriand Islands, those who have had a death in the family, such as this widow, shave their heads


Traditional: Trobriand Islanders wear red grass skirts unique to the islands for ceremonies and weddings. Completing the look are traditional feathered headbands

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Traditional: Trobriand Islanders wear red grass skirts unique to the islands for ceremonies and weddings. Completing the look are traditional feathered headbands


In charge: Girls are encouraged to take part in 'battles' and dance topless, with most choosing to wear red grass skirts, shells, feathers and fresh flowers



Elaborate: The skirts worn by the women are made from dried grass, while necklaces and bracelets are made from shells. Men wear cockatoo feather headdresses




Colourful: A woman from the Trobriand Islands

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Love shack: Each village has a special hut for teenagers who want to make love to their boyfriends and girlfriends - the doors are plastered with safe sex stickers

He was followed in the 1930s by a Catholic Mission but the islanders, although ruled by first the British and then the Australians, clung firm to their traditional ways.
Modernity: As more and more children go to school, some of the old ways are being lost

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Tradition: Other parts of Trobriand society, such as annual shell selling expeditions, continue



Chief's family: The house of the chieftain is recognisable by its height, shell decorations and the presence of a malagan - a carved, painted totem pole

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Chief's family: The house of the chieftain is recognisable by its height, shell decorations and the presence of a malagan - a carved, painted totem pole


Relaxed: While the islanders have tried hard to cling to their traditions, some have embraced parts of modern life such as instruments

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Pet: Pigs are eaten but they are considered to be pets and are treated like dogs



Changing times: Although some modern items such as musical instruments have been embraced, islanders cling to many traditions, including keeping pigs as pets



Is that a googly? Cricket is hugely popular and was introduced by colonial authorities. Banned from going to war, the Trobriand Islanders settle their differences with a game


Is that a googly? Cricket is hugely popular and was introduced by colonial authorities. Banned from going to war, the islanders settle their differences with a game
Home sweet home: In Obweria village, the many thatched huts are built on stilts around a central square, which is known to locals as the Buka



Big dreams: Seven-year-old Salome hopes to one day become a teacher

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Magic: According to the Trobriand Islanders, conception isn't linked to sex but instead to magic


Magic: Although many, among them seven-year-old Salome, go to school, the Trobriand Islanders continue to believe in magic and believe it is responsible for conception


Important: Because yams are the main sign of wealth, yam houses - huts where the tubers are stored - are very important. Those belonging to chiefs are highly decorated


Important: Because yams are a sign of wealth, yam houses - huts where the tubers are stored - are very important. Those belonging to chiefs are highly decorated


Pretty: Teenagers wear earrings made from tortoiseshell - keeping them in until they have a daughter of their own

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Fragile: One of the beautifully decorated kula boats, which comne covered in shells

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Delicate: Teenage girls wear tortoiseshell earrings which they eventually pass on to their daughters, while traditional kula boats come covered in cowrie shells


Jewellery: Most of the Trobriand Islanders sport elaborate bracelets and necklaces, all of which are made from natural materials such as shells, stones and feathers

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Jewellery: Most of the Trobriand Islanders sport elaborate bracelets and necklaces, all of which are made from natural materials such as shells, stones and feathers


Rare: Because the islands are coral atolls, anything made from stone is considered rare and valuable. This stone was polished and given as a wedding gift


Rare: Because the islands are coral atolls, anything made from stone is considered rare and valuable. This stone was polished and given as a wedding gift


Excitement: The weekly flight from Port Moresby, capital of Papua New Guinea, is the most exciting moment of the week for many and draws huge crowds


Excitement: The weekly flight from Port Moresby, capital of Papua New Guinea, is the most exciting moment of the week for many and draws huge crowds
War: During World War II, thousands of American soldiers were stationed on the Trobriand Islands. Vintage dog tags and other memorabilia can be picked up for as little as 20p


War: During World War II, thousands of American soldiers were stationed on the Trobriand Islands. Vintage dog tags can be picked up for as little as 20p
Remote: The idyllic islands are home to the Trobriand Islanders, who still live in much the same way as they always have - including fishing from wooden canoes


Remote: The idyllic islands are home to the Trobriand Islanders, who still live in much the same way as they always have - including fishing from wooden canoes

Paradise: The remote Trobriand Islands are a tiny knot of coral atolls sitting within the Solomon Sea and are part of Papua New Guinea









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