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

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

Sébastien Prévost , Karen Thai , Nina Schützenmeister , Graeme Coulthard , William Erb , and Varinder K. Aggarwal *

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

*E-mail: v.aggarwal@bristol.ac.uk.

Two antiglaucoma drugs, bimatoprost and latanoprost, which are analogues of the prostaglandin, PGF2α, 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.

Professor Varinder Aggarwal 
BA, PhD(Cantab), FRS

Professor

Area of research

Asymmetric synthesis, methodology and applications.

Office N226
Cantock's Close,Clifton, Bristol BS8 1TS(See a map)

Tel. +44 (0) 117 954 6315
v.aggarwal@bristol.ac.uk

http://www.chm.bris.ac.uk/org/aggarwal/

School of Chemistry

HIGHLIGHTS

2014
• Nature: Assembly-line synthesis
• Nature Chemistry: Traceless coupling
• Nature Chemistry: sp2-sp3 Coupling
2012
• RSC Symposium: Sven Fritz wins Best Oral presentation
• Nature: Synthesis of prostaglandin PGF2a
• FRS: Varinder elected a Fellow of the Royal Society!
• University College of Dublin: Cath Fletcher wins Best Poster Prize. 
2010
• RSC Symposium: Muhammad Arshad wins Best Prize Prize
• Varinder appears on TV!
2009
• Mike Shaw is awarded Fulbright Distinguished Scholar Fellowship.
2008
• Nature: Enantioselective Conversion of Secondary Alcohols into Tertiary Alcohols

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

• Bonet, A, Odachowski, M, Leonori, D, Essafi, S & Aggarwal, VK 2014, ‘Enantiospecific sp(2)-sp(3) coupling of secondary and tertiary boronic esters’. NATURE CHEMISTRY, vol 6., pp. 584-589
• Hesse, MJ, Essafi, S, Watson, CG, Harvey, JN, Hirst, D, Willis, CL & Aggarwal, VK 2014, ‘Highly Selective Allylborations of Aldehydes Using alpha,alpha-Disubstituted Allylic Pinacol Boronic Esters’. Angewandte Chemie International Edition, vol 53., pp. 6145-6149
• Blair, DJ, Fletcher, CJ, Wheelhouse, KMP & Aggarwal, VK 2014, ‘Stereocontrolled Synthesis of Adjacent Acyclic Quaternary-Tertiary Motifs: Application to a Concise Total Synthesis of (-)-Filiformin’. Angewandte Chemie International Edition, vol 53., pp. 5552-5555
• Pulis, AP, Fackler, P & Aggarwal, VK 2014, ‘Short Stereoselective Synthesis of the Phytophthora Universal Mating Hormone alpha 1 Using Lithiation/Borylation Reactions’. Angewandte Chemie International Edition, vol 53., pp. 4382-4385
• Mohiti, M, Rampalakos, K, Feeney, KMJ, Leonori, D & Aggarwal, VK 2014, ‘Asymmetric addition of chiral boron-ate complexes to cyclic iminium ions’. Chemical Science, vol 5., pp. 602-607
• Roesner, S, Brown, CA, Mohiti, M, Pulis, AP, Rasappan, R, Blair, DJ, Essafi, S, Leonori, D & Aggarwal, VK 2014,‘Stereospecific conversion of alcohols into pinacol boronic esters using lithiation-borylation methodology with pinacolborane’. Chemical Engineering Communications, vol 50., pp. 4053-4055

Cantock's Close

BRISTOL

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

Now even terminal: The 2,4,6-trimethylbenzylidyne complexes [MesCM{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.

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"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. 2012, 14, 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).

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 356, Issue 18, pages 3737–3741, December 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