A Claisen approach to 4'-Ed4T.

An efficient, stereoselective synthesis of 4'-Ed4T is demonstrated. The synthesis is highlighted by a regioselective TMSOTf-mediated acetal opening, a Claisen rearrangement to set the key 4'-stereocenter as well as the olefin, and a one-pot nonaflation/elimination to deliver the alkyne moiety. The synthesis proceeds in eight steps from 5-methyluridine and occurs in 37% overall yield.

Microbial hydroxylation of o-bromophenylacetic acid: synthesis of 4-substituted-2,3-dihydrobenzofurans.

Microbial hydroxylation of o-bromophenylacetic acid provided 2-bromo-5-hydroxyphenylacetic acid. This enabled a route to the key intermediate 4-bromo-2,3-dihydrobenzofuran for synthesizing a melatonin receptor agonist and sodium hydrogen exchange compounds. Pd-mediated coupling reactions of 4-bromo-2,3-dihydrobenzofuran provided easy access to the 4-substituted-2,3-dihydrobenzofurans.

Discovery of dapagliflozin: a potent, selective renal sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes.

The C-aryl glucoside 6 (dapagliflozin) was identified as a potent and selective hSGLT2 inhibitor which reduced blood glucose levels in a dose-dependent manner by as much as 55% in hyperglycemic streptozotocin (STZ) rats. These findings, combined with a favorable ADME profile, have prompted clinical evaluation of dapagliflozin for the treatment of type 2 diabetes.

Remarkable beta-selectivity in the synthesis of beta-1-C-arylglucosides: stereoselective reduction of acetyl-protected methyl 1-C-arylglucosides without acetoxy-group participation.

An efficient and practical process to generate beta-C-arylglucoside derivatives was achieved. The process described involves Lewis acid mediated ionic reduction of a peracetylated 1-C-aryl methyl glucoside derived from the addition of an aryl-Li to selectively protected delta-D-gluconolactone. The reduction of the 2-acetoxy-1-C-oxacarbenium ion intermediates proceeds with a high degree of selectivity to give beta-C-arylglucosides without 2-acetoxy group participation. Furthermore, during the reduction process we also identified an unprecedented critical role of water. By changing from the usual benzyl ether protecting groups because of cost and chemical compatibility concerns, the new process is made additionally efficient and highly selective.

Constructing an adenocarcinoma vaccine: immunization of mice with synthetic KH-1 nonasaccharide stimulates anti-KH-1 and anti-Le(y) antibodies.

There is mounting evidence to suggest that immunization-based strategies can be used to mobilize the human immune system against specific carbohydrate antigens displayed on the surface of cancer cells. Following isolation and identification, such antigens can be administered as conjugate vaccines. The tumor-associated carbohydrate antigen KH-1 is 1 such antigen and may serve as a potential target for immunization against adenocarcinoma. However, a serious impediment to the application of a vaccine-based approach involving this antigen is that its availability from natural sources is severely limited. In order to overcome this limitation, we have developed an efficient total synthesis of this complex glycolipid. We have extended our synthesis to reach a structurally related analog in which the ceramide portion of KH-1 is replaced with an allyl substituent. These synthetic advances have led to the preparation of 2 potential vaccine constructs, each based on the conjugation of the KH-1 nonasaccharide and the carrier protein keyhole limpet hemocyanin (KLH). In 1 construct (KH-1-Et-KLH), the nonasaccharide is conjugated to KLH via a simple ethyl linkage, while in the other (KH-1-MMCCH-KLH), conjugation is mediated by a 4-(4-N-maleimidomethyl)cyclohexane-1-carboxyl hydrazide (MMCCH) cross-linker. We report here the immunological properties of these 2 constructs. Mice were immunized with either of the 2 KH-1-KLH vaccine candidates or the KH-1 ceramide, along with the immunological adjuvant QS-21. Immunization with the ceramide served as a negative control and, as expected, failed to stimulate the production of antibodies against the KH-1 glycolipid. The construct in which the KH-1 nonasaccharide is linked to KLH via a simple alkyl chain stimulated significant quantities of IgM antibodies, whereas the construct linked to KLH by MMCCH induced high titers of both IgM and IgG antibodies. Inhibition data demonstrated that antibodies generated in response to immunization with the KH-1-KLH constructs recognize not only the KH-1 antigen but also the Lewis(y) (Le(y)) antigen, which, from a structural perspective, is similar to the 4 residues located at the non-reducing end of the KH-1 nonasaccharide. Thus, the KH-1-KLH constructs elicit an immune response that successfully targets 2 adenocarcinoma markers. As assessed by FACS analysis, the antibodies raised were strongly reactive with the KH-1/Le(y) positive cell line MCF-7 but not with KH-1 and Le(y) negative melanoma cell lines. Based on the results of our study, a KH-1-KLH plus QS-21 vaccine is being prepared for clinical evaluation.

A Concise, Enantioselective Synthesis of (-)- and (+)-Hongconin.

Optically pure enone 9c, available in three steps from known 6-deoxy D-galactal derivative 7b, reacts with cyanophthalide 6 to directly afford the natural product (-)-hongconin (1), a compound from traditional Chinese medicine recently shown to exhibit antianginal activity. The enantiomer of 1 and its (+)-cis-diastereomer were also synthesized in a parallel fashion from the L-sugar counterpart. The use of C-glycoside Michael acceptors, as opposed to their O-glycoside counterparts, represents a potentially useful simplification of phthalide annulation methodology in synthesizing numerous other such optically pure isochromanquinoids, since it obviates the inconvenience of additional steps late in the synthetic scheme associated with reductive manipulation of a remaining acetal moiety into the desired pyran ring substituent.