Materials and Methods. Unless otherwise stated, reactions were performed in flame-dried glassware under an argon or nitrogen atmosphere using dry, deoxygenated solvents. Solvents were dried by passage through an activated alumina column under argon. Norcamphor, 3-chloroperbenzoic acid (m-CPBA), lithium aluminum hydride, sodium azide, trifluoroacetic acid (TFA), trifluoromethanesulfonimide, di-tertbutyl dicarbonate (Boc 2 O) and tetrafluoroboric acid in Et 2 O solution were purchased from Sigma-Aldrich Chemical Company and used as received. p-Toluenesulfonyl chloride was purchased from EM Science Inc. and purified prior to use. Triethylamine was purchased from Sigma-Aldrich Chemical Company and freshly distilled prior to use. Trifluoromethanesulfonic acid was purchased from SynQuest Laboratories, Inc. and used as received. 1,1-Dihydro-1,1,1-triacetoxy-1,2-benzoiodooxol-3(1H)-one (Dess-Martin periodinane, DMP) was prepared by known method 1 . Reaction temperatures were controlled by an IKAmag temperature modulator. Thin-layer chromatography (TLC) was performed using E. Merck silica gel 60 F254 precoated plates (0.25 mm) and visualized by UV fluorescence quenching, anisaldehyde or KMnO 4 staining. ICN Silica gel (particle size 0.032-0.063 mm) was used for flash chromatography. Optical rotations were measured with a Jasco P-1010 polarimeter at 589 nm. 1 H and 13 C, NMR spectra were recorded on a Varian Mercury 300 (at 300 MHz and 75 MHz, respectively). 1 H NMR spectra were reported relative to Me 4 Si (δ 0.0 ppm) or residual CHCl 3 (δ 7.26 ppm) or CHD 2 CN δ 1.94 ppm). 13 C NMR were reported relative to CDCl 3 (δ 77.0 ppm) and CD 3 CN (δ 118.69 ppm), respectively. FTIR spectra were recorded on a Perkin Elmer Paragon 1000 spectrometer and are reported in frequency of absorption (cm -1 ). High resolution mass spectra were obtained from the Caltech Mass Spectral Facility.

α-Quaternary ketones are accessed through novel enantioselective alkylations of allyl and propargyl electrophiles by unstabilized prochiral enolate nucleophiles in the presence of palladium complexes with various phosphinooxazoline (PHOX) ligands. Excellent yields and high enantiomeric excesses are obtained from three classes of enolate precursors: enol carbonates, enol silanes, and racemic β-ketoesters. Each of these substrate classes functions with nearly identical efficiency in terms of yield and enantioselectivity. Catalyst discovery and development, the optimization of reaction conditions, the exploration of reaction scope, and applications in target-directed synthesis are reported. Experimental observations suggest that these alkylation reactions occur through an unusual inner-sphere mechanism involving binding of the prochiral enolate nucleophile directly to the palladium center.

Materials and Methods. Unless otherwise stated, reactions were performed in flamedried glassware under an argon or nitrogen atmosphere using dry deoxygenated solvents. Solvents were dried by passage through an activated alumina column under argon. Diphenylphosphine, di-p-tolylphosphine, dicyclohexylphosphine, and diisobutylphosphine were purchased from Strem Chemicals, Inc. and were used as received. Copper (I) iodide, N,N′-dimethylethylenediamine, cesium carbonate, 2-bromobenzoyl chloride, tetrafluoroboric acid solution and molecular sieves 4Å were purchased from Sigma-Aldrich Chemical Company and used as received. Bis-(4-(trifluoromethyl)phenyl)phosphine was prepared by the known method. 1 (S)-Leucinol and (S)-tryptophanol were purchased from Sigma-Aldrich Chemical Company and Chem-Impex International, Inc., respectively. The other starting chiral amino alcohols were prepared by the reduction of the corresponding amino acids, 2 which were purchased from Chem-Impex International, Inc. 2-Bromo-5-methoxybenzoyl chloride and 2-bromo-5-(trifluoromethyl)-benzoyl chloride were prepared from the corresponding benzoic acid derivatives. 3Reaction temperatures were controlled by an IKAmag temperature modulator. Thin-layer chromatography (TLC) was performed using E. Merck silica gel 60 F254 precoated plates (0.25 mm) and visualized by UV fluorescence quenching, anisaldehyde, CAM, or KMnO 4 staining. ICN Silica gel (particle size 0.032-0.063 mm) was used for flash chromatography. Optical rotations were measured with a Jasco P-1010 polarimeter at 589 nm.

Previous studies have shown that prostaglandin E 2 (PGE 2 ) is involved in intestinal carcinogenesis through its binding to the PGE 2 receptor subtypes EP 1 and EP 4 and activation of downstream pathways. ONO-8711 and ONO-AE2-227, prostaglandin E receptor subtype EP 1 -and EP 4 -selective antagonists, respectively, are known to suppress formation of intestinal polyps in adenomatous polyposis coli gene-deficient mice. The present study was designed to investigate the combined effects of EP 1 and EP 4 antagonists on spontaneous polyp formation in APC1309 mice in order to determine the contribution of each receptor to intestinal tumorigenesis. APC1309 mice were treated with 400 ppm of ONO-8711 alone, 400 ppm of ONO-AE2-227 alone or both in combination in the diet for 6 weeks. The mean area of polyps found in the intestine, calculated as the longer diameter × × × × the shorter diameter × × × × π π π π, was reduced by 12%, 43% (P < < < <0.01) and 56% (P < < < <0.01) of the mean control value (8.8 mm yclooxygenase (COX) is a rate-limiting enzyme in the synthesis of prostaglandins (PGs), which affect cell proliferation, tumor growth, apoptosis and immune responsiveness. Two COX enzyme isoforms, known as COX-1 and COX-2, have been identified. COX-1 is constitutively expressed while COX-2 is transiently inducible by various agents such as cytokines, growth factors, and hormones, then contributing to inflammation and abnormal cell proliferation.1) There is evidence to suggest that COX-2 is involved in carcinogenesis in various organs, including the colon. 2-5) A possible contribution of COX-1 to colon carcinogenesis has also been reported. Genetic disruption of the COX-1 gene, as well as the COX-2 gene, decreased the number of intestinal polyps by around 80% in Min mice.6) It should be noted that prostaglandin E 2 (PGE 2 ) levels are elevated in intestinal polyps, compared with surrounding normal tissue, and both COX-1 and COX-2 contributed to PGE 2 production. 6) Moreover, we recently demonstrated that mofezolac, a COX-1 selective inhibitor, suppressed the development of azoxymethane (AOM)-induced colonic aberrant crypt foci (ACFs), putative preneoplastic lesions in F344 rats, and intestinal polyp development in mice with a truncated adenomatous polyposis coli (Apc) gene at codon 1309 (APC1309 mice), an animal model of human familial adenomatous polyposis.7) These findings point to a significant role for PGE 2 , produced by COX-1 and COX-2, in colon carcinogenesis.Previous studies demonstrated that PGE 2 exerts its biological actions through binding to four specific membrane receptor subtypes known as EP 1 , EP 2 , EP 3 and EP 4 . 8, 9) Genetic and pharmacological studies with specific inhibitors have suggested that EP 1 10) and EP 4 11) are important for carcinogenesis. For example, addition of 500 ppm ONO-8711 and 300 ppm ONO-AE2-227, targeting EP 1 and EP 4 , respectively, to basal diet of Min mice reduced the number of polyps by 44% and 31%, respectively. In addition, the numbers of AOM-induced colonic ACFs were also...