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Monday, 26 January 2015

Synthesis of Prostaglandin Analogues, Latanoprost and Bimatoprost, Using Organocatalysis via a Key Bicyclic Enal Intermediate

Figure

Synthesis of Prostaglandin Analogues, Latanoprost and Bimatoprost, Using Organocatalysis via a Key Bicyclic Enal Intermediate

School of Chemistry, University of Bristol, Cantock’s Close, Bristol, BS8 1TS, U.K.
Org. Lett., Article ASAP
DOI: 10.1021/ol503520f
Publication Date (Web): January 12, 2015
Copyright © 2015 American Chemical Society

Two antiglaucoma drugs, bimatoprost and latanoprost, which are analogues of the prostaglandin, PGF, have been synthesized in just 7 and 8 steps, respectively. The syntheses employ an organocatalytic aldol reaction that converts succinaldehyde into a key bicyclic enal intermediate, which is primed for attachment of the required lower and upper side chains. By utilizing the crystalline lactone, the drug molecules were prepared in >99% ee.


Image result for univ of bristol
Professor Varinder Aggarwal

Professor Varinder Aggarwal 
BA, PhD(Cantab), FRS

Professor

Area of research

Asymmetric synthesis, methodology and applications.

Asymmetric synthesis, methodology and applications.

My research interests include; the development of new catalytic processes for asymmetric synthesis; the development of chiral carbenoids and their use and subsequent applications in catalysis and synthesis; the development of new methodology and its applications in synthesis; total synthesis of biologically important targets.

Research keywords

  • catalytic processes
  • asymmetric synthesis
  • reactive intermediates
  • synthesis
  • carbenes
  • carbenoids

Latest publications

Map of University of Bristol, Cantock's Cl, Bristol, City of Bristol BS8 1TS, UK

Cantock's Close



BRISTOL







Monday, 12 January 2015

Efficient Metathesis of Terminal Alkynes





http://onlinelibrary.wiley.com/doi/10.1002/anie.v51.52/issuetoc



Efficient Metathesis of Terminal Alkynes (pages 13019–13022)
Dipl.-Chem. Birte Haberlag, Dr. Matthias Freytag, Dr. Constantin G. Daniliuc, Prof. Dr. Peter G. Jones and Prof. Dr. Matthias Tamm
Article first published online: 14 NOV 2012 | DOI: 10.1002/anie.201207772
Thumbnail image of graphical abstract
Now even terminal: The 2,4,6-trimethylbenzylidyne complexes [MesC[TRIPLE BOND]M{OC(CF3)2Me}3] (M=Mo, W) were synthesized from [Mo(CO)6] and [W(CO)6], respectively. The molybdenum complex is an efficient catalyst for the metathesis of internal and terminal alkynes and also for the ring-closing metathesis of internal and terminal α,ω-diynes at room temperature and low catalyst concentrations.

Sunday, 11 January 2015

"Cyclizative Atmospheric CO2 Fixation by Unsaturated Amines with t-BuOI Leading to Cyclic Carbamates"


"Cyclizative Atmospheric CO2 Fixation by Unsaturated Amines with t-BuOI Leading to Cyclic Carbamates"
Youhei Takeda, Sota Okumura, Saori Tone, Itsuro Sasaki, and Satoshi Minakata*
Org. Lett. 201214, 4874–4877. DOI: 10.1021/ol302201q 

* Highlighted in "Noteworthy Chemistry" (ACS, October 1, 2012)! see the detail
Abstract: A cyclizative atmospheric CO2 fixation by unsaturated amines such as allyl and propargyl amines under mild reaction conditions, efficiently leading to cyclic carbamates bearing a iodomethyl group, have been developed utilizing tert-butyl hypoiodite (t-BuOI).

Thursday, 8 January 2015

Continuous Synthesis of Organozinc Halides Coupled to Negishi Reactions


Continuous Synthesis of Organozinc Halides Coupled to Negishi

Reactions

 Article first published online: 20 JUN 2014

DOI: 10.1002/adsc.201400243

 

Advanced Synthesis & Catalysis

Volume 356Issue 18pages 3737–3741December 15, 2014

Nerea Alonso2,3,

L. Zane Miller1,

Juan de M. Muñoz2,

Jesus Alcázar2,*

D. Tyler McQuade1,*

 
1Department of Chemistry and Biochemistry, Florida State University, USA
2Janssen Research and Development, Janssen-Cilag, Toledo, Spain
3Facultad de Química, Universidad de Castilla-La Mancha, Spain


 
The Negishi cross-coupling is a powerful CC bond forming reaction. The method is less commonly used relative to other cross-coupling methods in part due to lack of availability of organozinc species. While organozinc species can be prepared, problems with reproducibility and handling of these sensitive species can complicate these reactions. Herein, we describe the continuous formation, using an activated packed-bed of metallic zinc, and subsequent use of organozinc halides. We demonstrate that a single column of zinc can provide excellent yields of organozinc halides and that they can be used downstream in subsequent Negishi cross-couplings. The preparation of the zinc column and the scope of the reaction are discussed.
Click here to go straight to the publication

http://onlinelibrary.wiley.com/doi/10.1002/adsc.201400243/abstract

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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