Will Watson, Scientific Update

This was the 6th in Scientific Update’s current series of conferences on Modern Synthetic Methods.  Attendance at this event may have been lower than previous years, presumably due to the current economic conditions, but the standards of the presentations were as high as ever.  There were 18 different speakers with the usual mixture of industrial and academic chemists and a range of nationalities with speakers from the USA, UK, Netherlands, Germany and Canada.  A number of companies took the opportunity to have stands in an adjoining exhibition room.   There were three keynote speakers with Barry Trost on day 1, Richard Schrock on day 2, and André Charette on day 3.

On the Design of Chiral Space for Asymmetric Induction in Catalytic Synthetic Reactions
Professor Barry Trost, Stanford University, USA

The conference was opened by Prof. Trost who gave an excellent presentation on his work on the use of dinuclear zinc catalysts for carrying out a variety of enantioselective nucleophilic addition reactions such as the aldol reaction and the Michael reaction.  The catalyst is unusual in that it contains 2 metal atoms, mimicking some natural aldolases.  A summary of the chemistry is given in Scheme 1.

Scheme 1- Right - Reaction scope using dinuclear zinc catalysts.

 

Under Pressure: Rapid development of Scaleable Asymmetric Hydrogenation Catalysts
Dr André de Vries, DSM Pharmaceutical Products, The Netherlands

This presentation described the synthesis and application of the monophos family of ligands.  A wide variety of ligands are easily made in 2 steps by reacting a chiral binaphthol with PCl3 and then displacing the P-Cl with an alcohol or an amine.  The ligand and the appropriate metal (typically Rh, Ru or Ir) are good asymmetric catalysts particularly for asymmetric hydrogenation.  In some cases even small changes to the ligand can have big effects on the conversion and/or enantioselectivity.  In the example shown in Scheme 2 the ligand prepared from 3,3’-dimethytlbinaphthol, PCl3 and methylamine was almost completely inactive for the transformation shown.  Simply using tert-butanol in place of methylamine gave a catalyst that effected the hydrogenation with 97% conversion and 95% ee.

  

 

Asymmetric Hydrogenations with BIPI Ligands, Including the Development of New Organophosphorus Chemistry
Dr Carl Busacca, Boehringer-Ingelheim Pharmaceuticals, USA

Dr Busacca discussed the optimisation and synthesis of BIPI ligands for the asymmetric hydrogenation of an ene-carbamate intermediate.  BIPI ligands are bidentate ligands consisting of an ortho-disubstituted benzene ring with a chiral imidazoline group in one position and a phosphine in the other position.  There were some problems during the synthesis of one of the ligands with an unexpected racemisation taking place (see J. Org. Chem., 2008, 73, 9756-9761).

A wide variety of BIPI ligands were screened for the key asymmetric hydrogenation and the breakthrough came when the ortho-disubstituted phenyl core was changed to naphthalene.  The first system tested was a 1,2-disubstituted naphthalene, but a working hypothesis on how the enantioselectivity of the hydrogenation is derived suggested that the 2,3-disubstituted napthalene based ligand should be even better.  This was borne out in practice with the ee of the product increasing from 61% with 1,2-disubstituted naphthalene ligand to 90% with the 2,3-disubtituted naphthalene ligand.

Novel Syntheses of Carbocycles and Heterocycles via Iodine, Palladium and Aryne Chemistry
Professor Richard Larock, Iowa State University, USA

The first part of Prof. Larock’s talk concerned the synthesis of a wide variety of heterocycles (benzofurans, benzothiophenes, indoles, chromones, pyrazoles) by acetylene addition to a suitable substrate and then iodine-mediated cyclisation of the appropriate hetero-atom on to the acetylene giving a product with an iodine substituent in the 3 position for further functionalisation.  The second part of the talk centred on palladium catalysed annulations and towards the end on some unusual reactions involving palladium migrations (see Angew. Chem. Internat. Ed., 2005, 44, 1873).

New Applications of PhI(OAc)² in Synthesis: Total Synthesis and SAR Development of Antitumor Natural Product Psymberin and Its Advanced Analogs
Dr Xianhai Huang, Schering-Plough, USA

One of the key structural features of psymberin, which is isolated from a marine sponge and is structurally related to the pederin family of natural products, contains an N-acetylhemiaminal attached to a pyran ring.  Model studies suggested that this fragment could be made by oxidative cyclisation of an ω-hydroxy-eneacetamide using diphenyliodonium acetate (PhI(OAc)2) and methanol in hexafluoroisopropanol.  This strategy was successfully used to prepare psymberin but required some experimentation to find the right substrate (protecting group strategy).  With a workable synthetic route in place a variety of analogues were synthesized with different N-acyl groups and other functional group changes as shown in Scheme 3 (see also Org. Lett., 2009, 11, 867).

Scheme 3- right: Synthesis of Psymberin and analogues

Thousands of in situ Catalysts for Olefin Metathesis
Professor Richard Schrock, Massachusetts Institute of Technology, USA

The second keynote presentation of the conference proved conclusively that the statement that “Because of the air, moisture, and functional group sensitivity of [Mo/W] catalysts, practical applications of those catalysts are limited” is incorrect.  In principle hundreds of different catalysts can be prepared, isolated and characterised but it is much easier to simply prepare and evaluate the catalysts in situ.  The starting point was a series of bispyrrolide arylimido molybdenum catalysts.  Theses bispyrrolides react very readily with a wide variety of alcohols and diols to provide a range of new catalysts where the pyrrolide ligands have been replaced by the alcohol/diol, which can of course be chiral.  When alcohols are used two possible catalysts can be produced – the bis alkoxide catalyst or the monoalkoxide monopyrrolide catalyst.  These compounds can catalyse a variety of metathesis reactions including RCM, desymmetrising RCM (with a chiral bixalkoxide ligand), enyne metathesis, and ROCM (ring opening cross metathesis) reactions.

The utility of desymmetrising RCM was demonstrated in the synthesis of (+)-Quebrachamine which has recently been published (see J. Am. Chem. Soc., 2009, 131, 943).  These catalyst systems do require dry oxygen free conditions, but do not have to be handled in dryboxes and can be used with standard Schlenk techniques in ordinary fumehoods.

Synthesis and Evaluation of 7H-Dihydropyrano[2,3c]imidazo[1,2-a]pyridines and 3,6,7,8-Tetrahydrochromeno[7,8-d]imidazoles as Potassium competitive Acid Blockers (P-CABs)
Dr Andreas Palmer, Nycomed GmbH, Germany

Dr Palmer described the development of a series of compounds to treat various acid-related diseases starting from first generation compounds based on an open 8-alkoxyimidazopyridine through to pyranoimidzopyridines and structural modifications of this framework.  The key chirality in the pyran ring was introduced by asymmetric hydrogenation of a ketone which was synthesized via ortho-dimethylaminomethylation with Eschenmoser’s salt followed by displacement of the dimethylamino group with a β-ketoester and subsequent hydrolysis and decarboxylation.  The scale up of the synthesis of the one of the compounds was also presented and this has been published in Org. Process Res. Dev., 2008, 12, 1170.

Two Asymmetric Syntheses of AMG 221, an Inhibitor of11β-Hydroxysteroid Dehydrogenase Type 1
Dr Seb Caille, Amgen, USA.

AMG 221 contains 2 chiral centres, both of which were set early in the synthetic sequence.  The aminonorbornane fragment could be produced by a low yielding classical resolution or preferably by chiral chromatography.  The other chiral centre was generated by enantioselective cyanohydrin formation from methyl isopropyl ketone and trimethylsilyl cyanide, using a chiral aluminium salen catalyst, in 88-90% yield, 85-91% ee.  Two approaches were used to put these two fragments together – an amine displacement route which proceeds with retention of chirality, and an intramolecular cyclisation approach which involves inversion of the chiral centre alpha to the carbonyl group (see Scheme).  Details of this work have subsequently been published (J. Org. Chem., 2009, 74, 3833-3842).

Scheme : Synthetic routes to AMG 221

 

New Discoveries with Carbene Catalysts
Professor Karl Scheidt, Northwestern University, USA

The carbene catalysts mentioned in the title of this talk are N-heterocyclic carbenes (NHCs) and are typically generated in situ by treatment from a suitable azolium compound with DBU.  These carbenes will react with α,β-unsaturated enals to generate intermediates that react as homo-enolate equivalents that will react with a variety of electrophiles.  If aldehydes with a leaving group at the alpha position, such as an alkoxide or phenoxide, are used the intermediate generated is an enolate equivalent (by loss of alkoxide of phenoxide) and will undergo Michael, Mannich and Aldol reactions.  See Org. Lett., 2009, 11, 2105-108 for one of the latest publications from Prof. Scheidt.

Stereoselective Synthesis of Cyclopropane Derivatives
Professor André Charette, Université de Montréal, Canada

Professor Charette gave the 3rd Keynote presentation of the conference and described his work on enantioselective cyclopropanation reactions and some downstream chemistry, which can, in many cases, be carried out in the same vessel.  Standard cyclopropanation with a zinc source and diiodomethane produces relatively simple cyclopropanes but if iodoform (CHI3) is reacted with ethylzinc iodide (EtZnI) two intermediates can be formed depending on the EtZnI stoichiometry.  With one equivalent of EtZnI the product is an iodocyclopropane which can be used for downstream chemistry.  If excess EtZnI is used the in situ product is a cyclopropylzinc iodide which can react with suitable electrophiles to produce more complex products.  These reactions can be asymmetric if a chiral tartrate-based dioxaborolane is used.  A recent improvement to this chemistry has seen the use of Indium in place of zinc which results in higher ee’s as less epimerisation takes place.

The synthesis of cyclopropylamino acids from α-nitroesters and styrenes using iodosobenzene and a copper bisoxazoline catalyst was presented, along with some work on the synthesis of cyclopropanes by reacting α-diazocarbonyl compounds with styrenes using rhodium catalysts.  Interestingly these latter reactions often work best if the α-diazocarbonyl compound is not too pure.  α-Diazocarbonyl compounds are often produced by reaction of a suitable precursor with triflic azide and it appears that the by-product, triflimide, is beneficial for the cyclopropanation reaction.

A scaleable asymmetric synthesis of a PARP inhibitor, employing a memory of chirality cyclization
Dr David Barnes, Abbott Laboratories, USA

This presentation centred on the synthesis of α-methylproline in enantiopure form so that it could be reacted with 2,3-diaminobenzamide to form a benzimidazole which was target PARP inhibitor compound.  Racemic α-methylproline can be resolved with quinine but the desired enantiomer has to be recovered from the crystallisation liquors.  Asymmetric alkylation of proline can be achieved but only by going via the pivaldehyde cyclic oxazolidinone.  Based on a literature report an alternative route was developed starting with L-alanine ethyl ester which is alkylated on nitrogen with 3-bromopropane, N-protected with a Boc group and then subjected to a “Memory Of Chirality” (MOC) cyclisation using KHMDS as base.  Modifications to the literature procedure such as changing to alanine benzyl ester, alkylating with 1-bromo-3-chloropropane, using LiHMDS as base provided a process that was readily scaled up to produce 30-35kg batches of N-Boc-α-methylproline benzyl ester in 96% yield, 92-94% ee.  The N-Boc amino acid, prepared by ester hydrogenolysis, could be crystallised to upgrade the ee to 99.6%.  The MOC cyclisation approach has been extended to hydroxyproline derivatives by alkylating alanine benzyl ester with epichlorohydrin and then cyclizing with LiHMDS in DMF.  Perhaps surprisingly the cyclisation works better with the free alcohol than when the alcohol is protected with a TES group.

This article was published in the September Issue of SP2.