ARTICLE pubs.acs.org/joc
Synthesis of Functionalized Cinnamaldehyde Derivatives by an Oxidative Heck Reaction and Their Use as Starting Materials for Preparation of Mycobacterium tuberculosis 1-Deoxy-D-xylulose5-phosphate Reductoisomerase Inhibitors Anneli Nordqvist,† Christofer Bj€orkelid,‡ Mounir Andaloussi,† Anna M. Jansson,‡ Sherry L. Mowbray,‡ Anders Karlen,† and Mats Larhed*,† †
Division of Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry, Uppsala University, Biomedical Center, Box 574, SE-751 23 Uppsala, Sweden ‡ Department of Cell and Molecular Biology, Uppsala University, Biomedical Center, Box 596, SE-751 24 Uppsala, Sweden
bS Supporting Information ABSTRACT: Cinnamaldehyde derivatives were synthesized in good to excellent yields in one step by a mild and selective, basefree palladium(II)-catalyzed oxidative Heck reaction starting from acrolein and various arylboronic acids. Prepared α,βunsaturated aldehydes were used for synthesis of novel α-aryl substituted fosmidomycin analogues, which were evaluated for their inhibition of Mycobacterium tuberculosis 1-deoxy-D-xylulose 5-phosphate reductoisomerase. IC50 values between 0.8 and 27.3 μM were measured. The best compound showed activity comparable to that of the most potent previously reported α-aryl substituted fosmidomycin-class inhibitor.
’ INTRODUCTION The palladium(II)-mediated oxidative Heck reaction with an organoborane substrate was first reported by Dieck and Heck in 1975,1 but it was not until the development of a catalytic protocol2 that this reaction began to receive more attention.3 Initially the Cu(OAc)2 reoxidant4 was used to regenerate Pd(II) from Pd(0) but could in 2003 be replaced by molecular oxygen,5 avoiding the generation of stoichiometric amounts of heavy metal salts. In 2004 the ligand-modulated oxidative Heck reaction with arylboronic acids was introduced, in which the 2,9dimethyl-1,10-phenanthroline (dmphen) ligand facilitated palladium reoxidation, catalytic stability, and control of the regioselectivity with electron-rich olefins.6,7 The reaction conditions became even milder when the base-free reaction using boronic acids was discovered.8 Some recent developments involve oxygen and base-free reactions without external oxidant9 and the identification of new nonphenanthroline type ligands.10 α,β-Unsaturated aldehydes are important starting materials in various synthetic applications.11,12 Cinnamaldehydes are commonly synthesized in one or more steps by the Wittig reaction13 or crossed aldol condensation,13 but various additional methods can be employed, such as HornerWadsworthEmmons reaction,14,15 Peterson reaction,16 oxidation of primary allylic alcohols,13 and reduction of carboxylic acid derivatives.13 The use of a palladium-catalyzed reaction with aryl halides and acetal protected acrolein, with subsequent acetal deprotection under acidic conditions, is another convenient possibility to obtain cinnamaldehyde derivatives.17 A major drawback of many of the methods mentioned is the harsh reaction conditions. In contrast, r 2011 American Chemical Society
the oxidative Heck reaction employs very mild, base-free conditions at room temperature.8,18 The readily available, low toxicity, and easily handled starting materials in the form of boronic acids,19 used together with various olefins, provides an excellent framework for the synthesis of α,β-unsaturated aromatic derivatives. The use of acrolein as the olefin has been troublesome in the base-requiring palladium(0)-catalyzed HeckMizoroki reaction at elevated temperatures, providing low yields due to competing polymerization processes.20,21 Thus only a limited number of palladium(0)-catalyzed HeckMizoroki reactions with acrolein2230 have been reported. The use of acrolein in an oxidative Heck is limited,18 but the palladium(II)-catalyzed Heck coupling of the related methyl vinyl ketone with various boronic acids has been reported with yields between 50% and 88%.4,8,10,31 Tuberculosis (TB) is still one of the most serious infectious diseases, with 9.4 million new cases and almost 1.7 million deaths in the year 2009.32 The lengthy and complicated treatment and the emergence of multidrug-resistant strains make the need for new drugs acting on new targets urgent. DXR (EC 1.1.1.267) is the second enzyme in the nonmevalonate pathway that is present in most eubacteria, including Mycobacterium tuberculosis (Mt), many parasites, and the plastids of plants.33 It catalyzes the conversion of 1-deoxy-D-xylulose 5-phosphate (DOXP) to 2-Cmethyl-D-erythrose 4-phosphate (MEP), which is used for the biosynthesis of isopentyl diphosphate (IPP) and dimethylallyl Received: August 18, 2011 Published: September 21, 2011 8986
dx.doi.org/10.1021/jo201715x | J. Org. Chem. 2011, 76, 8986–8998
The Journal of Organic Chemistry
ARTICLE
arylboronic acids as arylating agents are reported. Five of the resulting cinnamaldehyde derivatives were used for the synthesis of 11 fosmidomycin analogues to further explore α-aryl substitutions, which were evaluated for inhibition of MtDXR.
Figure 1. Structures of known MtDXR inhibitors.
Table 1. Optimization of the Reaction Conditions with Acroleina
GCMS entry
catalytic mixb
1 2
responsec
ratio 4a:5j
rt
80
1:2
rt
85
1:2
24 h
rt
