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Sunday, 14 December 2014

Phenols as Versatile Starting Materials

On Phenols





Phenols as versatile starting materials
FROM diagram: salicylic acid
Phenols are ubiquitous products in nature. They are also common starting materials for a number of products, but working with unprotected phenols is looking for trouble so usually all work is done with the phenol in a protected form. But what if the OH moiety is protected with a group that turns it into a very useful leaving group?

We present here three papers recently published on this topic. The first one is a work by Garg (UCLA, CA, USA). The paper describes the use of carbamates, carbonates, and sulfamates derived from phenols as useful substrates for Nickel-mediated cross-coupling with boronic acids. Thus, carbonates and carbamates can be coupled using NiCl2(PCy3)2 (10 mol %), ArB(OH)2 (4 equiv) and K3PO4 (7 equiv) in toluene at 130 °C for 24 h. 




The yields obtained are just from moderate to good, but at least the protocol opens the possibility of using other substrates when the corresponding aryl halide is not available. 
Very similar conditions are used with sulfamates, but in this case the yields obtained are usually excellent, using a lower boronic acid ratio, something always interesting when you think about the price of some boronic acids. One example of a heterophenol (a hydroxyindole) is included. 
The utility of the sulfamate cross-coupling methodology is further demonstrated through the synthesis of flurbiprofen using orthogonal cross-couplings. 
A substrate containing an iodide and a sulfamate is selectively coupled using different Nickel catalysts to obtain the desired product. As final comment, the NiCl2(PCy3)2 is commercially available from Strem Chemicals at a very reasonable price, shows marked stability toward air and water and can be used on the benchtop rather than in a glovebox.



diagram: Dettol, TCPFROMdiagram: chloro-phenols


photo: washingFROMdiagram: alkylphenols

The second paper by Snieckus (Queen’s University, Ontario, Canada) is closely related to the work by Garg with carbamates. In this case Snieckus is using the carbamate as directing group for an orthometallation. But since it is a potential leaving group for an organometallic coupling, they started trying conditions reported previously by Garg and in the end they came to the same solution: NiCl2(PCy3)2
However, the protocol is slightly different. In a typical example, once the DoM work is done and the orthosubstituent is in place, the carbamate is reacted with a boroxine, NiCl2(PCy3)2 (5 mol%), PCy3HBF4 as ligand (10 mol%) and K3PO4 as base in o-xylene at 150 °C for 5-20 h. The yields obtained go from 20-30% up to quantitative, but they are applied with excellent results to some nitrogen heterocycles, specially 3-pyridines.


The third paper by Buchwald et al (MIT, Mass., USA) expands the options for couplings with aminophenols, developing orthogonal protocols for the selective N or O coupling. 
Thus, for 3-aminophenols two sets of conditions are described for the O-arylation with iodides and bromides using CuI as catalyst and another two sets of conditions are described for the N-arylation with bromides and chlorides using BrettPhos precatalyst as Palladium source. Interestingly, though the O-arylation results are better using the iodides, for the N-arylation the use of chlorides or bromides is equivalent. 
The 4-aminophenols are also tried, with Oand N-arylation conditions being described with CuI and BrettPhos precatalyst respectively. Finally, 2-aminophenol is explored, but here only a selective N-arylation protocol is described due to the ability of the substrate to form a five membered chelate. These conditions will be useful for those medicinal chemists trying selective arylation with substrates like these.


Suzuki-Miyaura Coupling of Aryl Carbamates, Carbonates, and Sulfamates J. Am. Chem. Soc.2009131(49), pp 17748–17749. See: 10.1021/ja906477r


Orthogonal Cu- and Pd-Based Catalyst Systems for the O and N-Arylation of Aminophenols J. Am. Chem. Soc.2009131 (47), pp 17423–17429. See: 10.1021/ja9081815


N,N-Diethyl O-Carbamate: Directed Metalation Group and Orthogonal Suzuki-Miyaura Cross-Coupling Partner J. Am. Chem. Soc.2009131 (49), pp 17750–17752. See: 10.1021/ja907700e








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Saturday, 13 December 2014

One day One Scientist Honoured........PROFESSOR DARREN J. DIXON 14 DEC 2014

PROFESSOR DARREN J. DIXON  

honoured on 14 Dec 2014

Department of Chemsitry


The research interests of the Dixon group lie mainly in the field of Organic Synthesis. We focus projects at the intersection between the discovery of new reactions and reactivity, the development of this into powerful synthetic methodology and its application to the total synthesis of natural products and molecules of biological significance. Furthermore we aim to make our chemistry accessible to the majority of organic synthesis chemists by making the reactions technically simple to perform, efficient, scaleable, selective and broad in scope. Our research is supported by a number of pharmaceutical companies (Pfizer, AstraZeneca, GlaxoSmithKline, UCB) largely through the CASE scheme and provides an excellent in-depth training in all aspects of organic synthesis. ‘Hot’ project areas where we have enjoyed significant successes include:asymmetric catalysis (organocatalysis and transition metal ion catalysis), reaction cascade catalysis (promoted by single and mutually compatible multiple catalysts), stereoselective methodology development and complex natural product synthesis.

http://research.chem.ox.ac.uk/darren-dixon.aspx

  1. Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA (UK)
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA (UK)


PROFESSOR DARREN J. DIXON


Department of Chemsitry








- See more at: http://organicchemistrysite.blogspot.in/#sthash.UFWwgFeS.dpuf



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Indoxamycin B

indoxamycin B

Indoxamycin B


In 2009 a research group in Japan isolated a novel class of polyketides, subsequently named indoxamycins, from saline cultures of  marine-derived actinomycetes. [1]
Within this family, indoxamycins A and F have been shown to display growth inhibition against HT-29 tumor cell lines (IC50 = 0.59 mm and 0.31 mm, respectively). Their biological activity in conjunction with the highly congested and stereochemically dense core render the indoxamycins notable as targets for synthetic studies.  The absolute and relative stereochemistry of indoxamycins was originally assigned based on a combination of one- and two-dimensional NMR experiments and CD studies.
The indoxamycins skeleton consists of an unprecedented [5,5,6] tricyclic cage-like carbon framework and two side chains having a trisubstituted olefin and an unsaturated carboxylic acid, respectively. The core structure features six contiguous stereogenic centers, of which three are quaternary, including two vicinal carbon atoms embedded in a sterically congested tetrahydrofuran subunit .
In 2012, Carreira and co-workers reported an elegant total synthesis of rac-indoxamycin B, which led to a structural reassignment of the relative configuration at the C2 position and the geometry of the trisubstituted alkene in the side chain.[2]Next year, Ding and coworkers have accomplished total synthesis of indoxamycins A, C, and F in their racemic and enantiomerically pure forms. [3]




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http://www.organic-chemistry.org/Highlights/2012/05November.shtm












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References
[1]  “Indoxamycins A−F. Cytotoxic Tricycklic Polypropionates from a Marine-Derived Actinomycete”
Sato, S.  Iwata, F.;  Mukai, T.;  Yamada, S.  Takeo, J.;  Abe, A.  Kawahara, H. J. Org. Chem. 200974, 5502. DOI: 10.1021/jo900667j
jo-2009-00667j_0001
Six antitumor antibiotics of a new structure class, indoxamycins A−F (16), were isolated from a saline culture group of marine-derived actinomyces whose strains showed approximately 96% sequence homology of 16S rDNA with the family streptomycetaceae. The structures of these indoxamycins, which are unusual polyketides composed of six consecutive chiral centers, were assigned by combined spectral and chemical methods. In feeding experiments using a stable isotope label, indoxamycin A was assembled from propionate units initially forming the “aglycon” pentamethyl indeno furan. The discovery of these unprecedented compounds from marine-derived actinomycetes, a low gene homology genus, offers a significant opportunity for drug discovery.
[2]  “Total Synthesis and Stereochemical Reassignment of (+-)-Indoxamycin B”
Jeker, O. F.; Carreira, E. M. Angew. Chem. Int. Ed. 201251, 3474–3477.
mcontent-1

Revised version: The first total synthesis of indoxamycin B leads to a stereochemical reassignment of the natural product (see picture). The synthetic route features an efficient carboannulation sequence to rapidly access the dihydroindenone system. Moreover, a series of AuI-catalyzed transformations served in the construction of the sterically congested core framework.
[3] “Divergent Total Synthesis of Indoxamycins A, C, and F”
He, C.; Zhu, C.; Dai, Z.; Tseng, C.-C.; Ding, H. Angew. Chem. Int. Ed. 201352, 13256–13260. DOI: 10.1002/anie.201307426 
mcontent
The concise and divergent: total synthesis of (−)-indoxamycins A, C, and F has been completed for the first time by using a tricyclic enone as the common late-stage intermediate. The key steps of the strategy are based on an Ireland–Claisen rearrangement, a stereodivergent reductive 1,6-enyne cyclization, and a tandem 1,2-addition/oxa-Michael/methylenation reaction.





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