Research in the  Friestad Laboratories Department of Chemistry, University of Iowa

Introduction

Basic research in organic chemistry has profound impacts in many fields, including medicine, animal health, and materials science.  Our program is designed to build foundations for health sciences research by achieving the following general goals: 

We've been applying these themes in several research projects which focus, in a variety of ways, on developing carbon-carbon bond construction reactions for asymmetric synthesis.  Some of this research is described below.  Newly emerging project areas are available also, so interested students should stop in for a chat to find out more.

 
1) Radical Addition to Imines and Related Compounds

One of our general approaches to asymmetric amine synthesis involves stereocontrolled addition of free radicals to carbon-nitrogen double bonds, leading directly to the chiral alpha-branched amine (Review: Tetrahedron 2001, 57, 5461).  This approach, shown retrosynthetically (in reverse) below, is inherently more efficient than commonly employed methods where C-N bonds, C-C bonds and stereocenters are made in separate steps, for example via alkene epoxidation and subsequent epoxide opening with a nitrogen nucleophile.  A major challenge which accompanies this approach is stereochemical control; this is still an unsolved problem in many radical reactions. 
 

"Formal Acyclic Stereocontrol" via Tethered Radical Precursors.  We have found that theoretical models for alkenyl radical cyclizations can be used to predict the stereochemical outcome of radical cyclizations of alpha-hydroxyhydrazones using a silicon tether for stereocontrolled radical addition to chiral hydrazones.  As shown below, the alpha stereocenter can be enlisted as a control element for a diastereoselective addition of functionalized carbon-centered radicals, including hydroxymethyl (Org. Lett. 1999, 1, 1499; J. Org. Chem. 2004, 69, 863), vinyl (Org. Lett. 2000, 2, 4237, Tetrahedron 2007, 63, 3964), and 2-acetyl (Tetrahedron: Asymmetry 2003, 14, 2853) radical synthons.  The latter two synthons are installed using a novel tandem thiyl addition/cyclization protocol with neutral, tin-free radical conditions.  This is the radical equivalent of an acetaldehyde Mannich reaction with acyclic stereocontrol.  An alternative 2-acetyl radical synthon is the haloacetal radical precursor, which can be tethered in a similar way leading to interesting stereocontrol in combination with the anomeric effect (Org. Lett. 2005, 7, 2393).  Successful applications to aminosugar synthesis have been achieved (Org. Lett. 2007, 9, 777, Tetrahedron 2007, 63, 9373, Tetrahedron 2008, 64, 11549).
 

N-Acylhydrazones for Stereocontrolled Intermolecular Radical Addition.  We are also developing ways to control stereochemistry through the use of chiral hydrazones (Review: Eur. J. Org. Chem. 2005, 3157), which are hydrolytically stable imines bearing removable chiral groups attached through nitrogen (J. Org. Chem. 2002, 67, 6236).  This chiral auxiliary approach is independent of any chirality of the starting carbonyl compound used to prepare a chiral hydrazone.  We have found that excellent facial differentiation is achieved using novel N-acylhydrazones derived from S-benzyloxazolidinone (J. Am. Chem. Soc. 2000, 122, 8329; J. Org. Chem. 2005, 70, 6330), and we have learned how to add a wide variety of alkyl halides, including primary and difunctional halides (J. Am. Chem. Soc. 2001, 123, 9922; J. Org. Chem. 2006, 71, 7016).  Either enantiomeric amine can be obtained by changing the roles of R1 and R2 groups in the figure below, or by using the enantiomeric auxiliary.  Reaction with ketone hydrazones has been applied to synthesis of alpha,alpha-disubstituted amino acids (Org. Lett. 2008, 10, 2311), and a general approach to gamma-amino esters was also established (Org. Lett. 2009, 11, 1095).  This reaction now has the broadest scope and greatest flexibility ever observed in any intermolecular radical addition to C=N bonds. 
 

Asymmetric Catalysis of Radical Addition to Imines and Related Compounds.  We have achieved the first asymmetric catalysis of intermolecular radical addition to C=N bonds, using N-acylhydrazones as substrates and Cu(II)bisoxazoline complexes as chiral Lewis acids (Angew. Chem. Int. Ed. 2003, 42, 5061).  High enantioselectivities (>90% ee) and good versatility for various hydrazones and various radicals make this a viable synthetic method at stoichiometric Cu loading.  A tentative stereocontrol model consistent with the observed configurations is shown below.  Catalyst turnover has been demonstrated, but high turnover numbers remain a challenging goal. 

2) Stereoselective Addition of Mild Nucleophilic Reagents to N-Acylhydrazones

We are also pursuing new methodology for addition of mild carbon nucleophiles to C=N bonds.  Ideally, the chiral alpha-branched amine products will contain functional groups in either branch which will permit further elaboration to more complex targets.

Allylsilane Addition to N-Acylhydrazones.  We have been using allylsilanes for addition to the chiral N-acylhydrazones described above, and have found that activation of allylsilanes with fluoride ion enables mild, stereoselective allyl addition to chiral N-acylhydrazones in the presence of mild Lewis acids (Angew. Chem. Int. Ed. 2001, 40, 4491). This "dual activation" protocol leads to an efficient homoallylic amine synthesis under mild conditions, which may be applied in conjunction with olefin metathesis to afford highly functionalized complex homoallylic amines (J. Org. Chem. 2006, 71, 281).  We've also found interesting catalytic conditions which enable rapid, efficient additions of allyltrimethoxysilane to N-benzoylhydrazones in the presence of substoichiometric amounts of fluoride ion.  These reactions give good yields from aliphatic hydrazones as well as ketone hydrazones (Synthesis 2004, 2216).  The latter substrates enable access to N-bearing quaternary centers (tert-alkylamines).  Applications in alkaloid synthesis are underway.

Hydride Addition to Ketone Hydrazones. We have studied the stereocontrol in hydride addition to ketone-derived hydrazones (Tetrahedron 2003, 59, 6393), and have found a new non-chelated binding mode in the presence of boron trifluoride.  The product diastereomer ratio is diminished if the starting hydrazone is not a single isomer with respect to the C=N bond geometry. However, the reaction is highly stereospecific. 

Other Reactions of Chiral Hydrazones.  Strecker reactions involve nucleophilic addition of cyanide ion to C=N bonds, leading to alpha-amino acids, and we have developed an asymmetric version of these reactions using chiral N-acylhydrazones (Heterocycles 2006, 70, 185).  Various mild methods for aziridine synthesis are available, including [2+1] cycloaddition of alkenes or imine derivatives.  We are developing new methodology for asymmetric induction of these processes.
 

3) Radical Addition to Enamides

We have reported a non-reductive radical addition to enamides, leading to radical polar crossover to afford an iminium ion, and reforming the enamide by proton loss.  This affords a variety of enamides which would otherwise be difficult to prepare (Org. Lett. 2009, 11, 819).

4) Total Synthesis of Biologically Active Natural Products

The inspiration for new methodology, as well as its proving ground, is total synthesis of natural products.  We are targeting various natural products with biological activity of interest in antibiotic development, cancer research, neuroscience, and other areas of medicinal chemistry. 

Development of New Methods and Strategies for Polyols and Oxacyclic Natural Products.  In a new research thrust begun in 2007, we are discovering interesting new methods to access alcohols and ethers in stereocontrolled fashion, and developing highly efficient strategies to take advantage of these reactions in complex molecule synthesis.  Our targets possess important biological properties including antitumor, antibiotic, and immunosuppressant activities.  In 2009 we reported that trans-2,5-disubstituted tetrahydrofurans can be obtained in diastereoselective fashion via additions of carbon nucleophiles to carbocations generated from a strained bicyclic acetal; an ion-pairing interaction seems to be responsible for the unusual selectivity (Org. Lett. 2009, 11, 3958-3961).

Applications of New Asymmetric Amine Synthesis Methodology.  Applied together with our new method for N-N bond cleavage (Org. Lett. 2004, 6, 637), the addition reactions we have developed (Eur. J. Org. Chem. 2005, 3157) allow access to a variety of new enantiomerically pure chiral amine building blocks for natural product synthesis and combinatorial chemistry.  Bolstered by the versatility of these reactions, we are now studying the disconnection of C-C bonds at nitrogen-bearing stereocenters as a strategic transform in retrosynthetic analysis of natural products including tubulysins, quinine, and other targets. Stereoselective carbon-carbon bond constructions at the chiral amine stereocenters are central to the strategies in each case.

Total Synthesis of Tubulysins.  Tubulysins are extraordinarily potent antimitotic agents, which suggests some potential as lead compounds for cancer drug development.  Two gamma-amino acid building blocks are the key structural novelty within the tubulysins.  Using a C-C bond construction approach to the chiral amine moiety, we have developed an efficient and highly stereoselective new synthesis of gamma-amino acids, exemplified by tubuphenylalanine and tubuvaline (Org. Lett. 2004, 6, 3249). 

Total Synthesis of Quinine.  A longstanding challenge to molecular synthesis, the historic antimalarial agent quinine remains an intriguing target.  Our interest stems from the potential to demonstrate new strategies for chiral amine synthesis, including a hybrid radical-ionic annulation.  This key step of the synthesis combines a radical addition to a chiral hydrazone with a nucleophilic cyclization to construct a substituted piperidine ring (Org. Lett. 2007, 9, 4243). 

Friestad Group Research Funding

National Science Foundation: Division of Chemistry, CHE-0749850

The University of Iowa