Christopher D. Spilling

The enantioselective addition of dialkylphosphites to aldehydes: Catalysis by a lanthanum binaphthoxide complex

Abstract The enantioselective addition of dialkylphosphites to aldehydes was catalyzed by a lanthanum ( R )-binaphthoxide complex to give ( S )-hydroxy phosphonates in good yield and modest enantioselectivity.

New homochiral cyclic diol ligands for titanium alkoxide catalyzed phosphonylation of aldehydes

Abstract An investigation of the structural effects of chiral diol ligands on the enantioselectivity of phosphonylation was performed. Cyclic diols, and cyclohexanediol in particular, were identified as effective ligands for titanium alkoxide catalyzed asymmetric phosphonylation.

The regio- and stereo- selective epoxidation of alkenes with methyl trioxorhenium and urea-hydrogen peroxide adduct

Abstract Alkenes are expoxidized with methyltrioxorhenium and urea-hydrogen peroxide adduct in CH2Cl2 solution.

Asymmetric synthesis of α-hydroxy- phosphonamides, phosphonates and phosphonic acids

Abstract The addition of the anion of the bicyclic chiral phosphorous acid diamide 1a to aldehydes in THF solution gave α-hydroxy phosphonamides in good yield and good diastereoselectivity (54–93% de). The phosphonamides were hydrolyzed with aqueous HCl in dioxane to give α-hydroxy phosphonic acids. Methylation of the resulting phosphonic acids with diazomethane gave α-hydroxy dimethyl phosphonates without loss of stereochemical integrety.

The synthesis of 1-hydroxy phosphonates of high enantiomeric excess using sequential asymmetric reactions: titanium alkoxide-catalyzed PC bond formation and kinetic resolution

Abstract Titanium alkoxide-catalyzed asymmetric phosphonylation of aldehydes yields hydroxy phosphonates in moderate to good enantiomeric excess (e.e.s ∼70%). The hydroxy phosphonates were acetylated and the acetates were subjected to enzyme-catalyzed kinetic resolution. The non-racemic acetates 2 (predominantly (R)-enantiomer) were hydrolyzed with an (R)-enantiomer-selective lipase, resulting predominantly in the hydrolysis of the (R)-isomer (at 85% conversion) to give the alcohols 3 with high e.e. Alternatively, hydrolysis of the minor enantiomeric (S)-acetate to approximately 20% conversion left the enriched (R)-configured acetate with improved e.e. (>90%). The moderate enantioselectivities obtained in the catalytic PC bond formation are enhanced during the enzymatic hydrolysis. Furthermore, availability of the non-racemic phosphonates permits the use of less selective enzymes, resulting in higher yields in comparison with the standard resolution of racemic materials.

Determination of the enantiomeric purity and absolute configuration of α-hydroxy phosphonates

Abstract The absolute configuration of α-hydroxy phosphonates was determined by NMR spectroscopy of the O-methyl mandelate ester derivatives. The O-methyl mandelate ester diastereoisomers are distinguishable by their 1 H and 31 P NMR spectra and the observed chemical shifts allow assignment of the absolute configuration of the phosphonate C-1. The crystal structure of (1R) dimethyl 1-[(2′R)-2′-methoxy-2′-phenylacetoxy]-3-phenyl-2 E -propenyl phosphonate was determined by X-ray diffraction. The enatiomers were separable by HPLC on a chiral stationery phase and therefore the enantiomeric purity of the hydroxy phosphonates could accurately be determined.

Synthesis of the C(18)-C(34) fragment of amphidinolide C and the C(18)-C(29) fragment of amphidinolide F.

A convergent synthesis of the C(18)-C(34) fragment of amphidinolide C and the C(18)-C(29) fragment of amphidinolide F is reported. The approach involves the synthesis of the common intermediate tetrahydrofuranyl-β-ketophosphonate via cross metathesis, Pd(0)-catalyzed cyclization, and hydroboration-oxidation. The β-ketophosphonate was coupled to three side chain aldehydes using a Horner-Wadsworth-Emmons (HWE) olefination reaction to give dienones, which were reduced with l-selectride to give the fragments of amphidinolide C and F.

Stereoselective Synthesis of Cyclic Ethers via the Palladium-Catalyzed Intramolecular Addition of Alcohols to Phosphono Allylic Carbonates

Cross metathesis of the acrolein-derived phosphono allylic carbonate and hydroxy alkenes using second generation Grubbs catalyst and copper(I) iodide gave the substituted phosphonates in good yield. Stereospecific palladium(0)-catalyzed cyclization gave tetrahydrofuran and tetrahydropyran vinyl phosphonates. Regioselective Wacker oxidation of the vinyl phosphonate gave the beta-keto phosphonate, which underwent HWE reaction with benzaldehyde to yield the unsaturated ketone. The utility of the cross metathesis/cyclization protocol was further demonstrated by a formal synthesis of centrolobine.

Synthesis of cyclopentenones via intramolecular HWE and the palladium-catalyzed reactions of allylic hydroxy phosphonate derivatives.

Palladium-catalyzed decarboxylative rearrangement of nonracemic phosphono allylic acetoacetates, or the intermolecular allylic substitution of nonracemic phosphono allylic carbonates with tert-butyl acetoacetate followed by hydrolysis and decarboxylation, gave omega-ketovinyl phosphonates. A highly regioselective Wacker oxidation gave the omega,beta-diketophosphonates which underwent intramolecular HWE reaction to give nonracemic cyclopentenones. An aldol condensation leading to phosphonocyclopentenones was competitive with the HWE reaction. The stereochemistry of the cyclopentenone and the ratio of HWE to aldol products were dependent upon the choice of base used in the reaction.

Effects of proline analog binding on the spectroscopic and redox properties of PutA.

The PutA flavoprotein regulates proline metabolism in Escherichia coli by performing two distinct functions. First, in the cytoplasm, PutA represses transcription of the put (proline utilization) regulon. Second, PutA associates with the membrane to oxidize proline to glutamate using discrete proline dehydrogenase and Delta(1)-pyrroline-5-carboxylate dehydrogenase domains. Here, we identify a proline analog that will be useful for testing the role substrate binding has in regulating PutA functions. L-Tetrahydro-2-furoic acid (L-THFA) was found to display simple competitive inhibition of proline dehydrogenase activity in PutA (apparent K(i)=0.2mM) and to perturb the flavin adenine dinucleotide (FAD) absorbance spectrum upon complexation to PutA. At pH 7.5, a reduction potential (E(m)) of -0.089V for the FAD/FADH(2) couple in L-THFA-complexed PutA was determined by potentiometric titrations. The E(m) value for L-THFA-complexed PutA is 12mV more negative than the E(m) for uncomplexed PutA (E(m)=-0.077V, pH 7.5) and corresponds to just a twofold increase in the dissociation constant of L-THFA with PutA upon reduction of FAD.