Tissue regeneration is a medical challenge faced in injury from disease and during medical treatments such as bone marrow transplantation. Prostaglandin PGE2, which supports expansion of several types of tissue stem cells, is a candidate therapeutic target for promoting tissue regeneration in vivo. Here we show that inhibition of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), a prostaglandin-degrading enzyme, potentiates tissue regeneration in multiple organs in mice. In a chemical screen, we identify a small-molecule inhibitor of 15-PGDH (SW033291) that increases prostaglandin PGE2 levels in bone marrow and other tissues. SW033291 accelerates hematopoietic recovery in mice receiving a bone marrow transplant. SW033291 also promotes tissue regeneration in mouse models of colon and liver injury. Tissues from 15-PGDH knockout mice demonstrate similar increased regenerative capacity. These findings raise the possibility that inhibiting 15-PGDH could be a useful therapeutic strategy in several distinct clinical settings.

[reaction: see text] A new nickel-based catalytic system has been developed for phosphorus-carbon bond formation. The addition of alkyl phosphinates to alkynes is catalyzed by nickel chloride in the absence of added ligand. The reaction generally proceeds in high yields, even with internal alkynes, which were poor substrates in our previously reported palladium-catalyzed hydrophosphinylation of alkyl phosphinates. The method is useful for the preparation of H-phosphinate esters and their derivatives. The one-pot synthesis of various important organophosphorus compounds is also demonstrated. The reaction can be conducted with microwave heating.

The enzyme 15-prostaglandin dehydrogenase (15-PGDH) catalyzes the first step in the degradation of prostaglandins including PGE2. It is a negative regulator of tissue repair and regeneration in multiple organs. Accordingly, inhibitors of 15-PGDH are anticipated to elevate in vivo levels of PGE2 and to promote healing and tissue regeneration. The small molecule SW033291 (1) inhibits 15-PGDH with Ki = 0.1 nM in vitro, doubles PGE2 levels in vivo, and shows efficacy in mouse models of recovery from bone marrow transplantation, ulcerative colitis, and partial hepatectomy. Here we describe optimized variants of 1 with improved solubility, drug-like properties and in vivo activity.

Organoboranes react with phosphorus-containing carbenoids to produce a variety of functionalized organophosphorus compounds under mild conditions. In some cases, selective migration of one group attached to boron can be observed. Phosphonite-borane complexes are introduced as novel synthons for the synthesis of phosphinic esters.

The preparation and reactivity of novel (R 1 O)(R 2 O)P(BH 3 )H [R 1 , R 2 = Et, TIPS] synthons is investigated. The direct alkylation of these compounds with lithium hexamethyldisilazide (LiHMDS) and various electrophiles, provided new series of phosphonite-borane complexes, which can be converted into H-phosphinates and boranophosphonates.

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Vinyl, aryl and alkynyl organometallics add to ketones containing a stereogenic sulfoxide. Tertiary alcohols are generated in diastereomerically and enantiomerically pure form. Reductive lithiation converts the sulfoxide into a variety of useful functional groups.Efficient organic synthesis requires control over absolute and relative stereochemistry. Among the many chemical transformations that form stereogenic centers, additions to ketones and aldehydes are especially important.1 Their value to organic synthesis arises from several characteristics: many types of nucleophiles will react with ketones and aldehydes; addition reactions display high atom economy and represent convergent fragment couplings; the products, secondary and tertiary alcohols, are ubiquitous in natural products, pharmaceutical agents and other biologically active materials; and the secondary and tertiary alcohol products are substrates for a rich diversity of subsequent synthetic transformations.Owing to the utility secondary alcohols, significant attention has focused on the asymmetric addition of hard nucleophiles to aldehydes.2 , 3 , 4 , 5. In contrast, asymmetric additions of alkynyl, vinyl and aryl groups to ketones have proven more elusive.6 , 7 For example, amino alcohols and phosphorylated diamines promote the addition of Ph 2 Zn to ketones.8 Bissulfonamide ligands promote the same reaction in the presence of stoichiometric Ti(O i Pr) 4 , 9 and aryl aluminum reagents effect arylation in the presence of 10-20 mol% BINOL and excess Ti(O i Pr) 4 .10 These approaches generally require expensive arylating agents, often in large excess, stoichiometric quantities of an additional metal salt, and/or structurally complex ligands. With regard to alkenylation, a bis-sulfonamide ligand enables the asymmetric addition of terminal vinyl zinc reagents to ketones with high selectivity.11 Finally, asymmetric catalytic additions of alkynyl zinc reagents have been reported, 12 , 13 , 14 , 15 but high catalyst loadings, long reaction times, and large excesses of reagent are generally required.6 , 16We considered the use of chiral auxiliaries to effect the stereoselective addition of hard nucleophiles to ketones. Most applications of chiral auxiliaries incorporate the stereodirecting group onto the nucleophilic component of the reaction.17 The sulfoxide group represents a rare example of a chiral auxiliary which usually resides on the joseph.ready@utsouthwestern.edu . Supporting Information Available Supporting information for this article is available on the WWW under http://pubs.acs.org. Here we show that the toluene sulfinyl group effectively controls the asymmetric addition of simple alkynyl, aryl and vinyl organometallic reagents to aryl ketones (eq 1). In contrast to most previous studies, the methodology utilizes readily available Grignard reagents and lithium acetylides. Furthermore, we demonstrate the reductive lithiation of the sulfoxide and its conversion to other useful functionality. NIH Public Access

Organo-phosphorus compounds S 0080NiCl 2 -Catalyzed Hydrophosphinylation. -NiCl 2 -catalyzed addition of alkyl phosphinates to alkynes offers a new and inexpensive method to prepare synthetically useful alkenyl phosphinates. They can be smoothly converted into other interesting derivatives such as (VIII) and (XI). Hydrophosphinylation of allene (XVII) affords the isomers (XVIII) and (XIX). -(RIBIERE, P.; BRAVO-ALTAMIRANO, K.; ANTCZAK, M. I.; HAWKINS, J. D.; MONTCHAMP*, J.-L.; J. Org. Chem. 70 (2005) 10, 4064-4072; Dep. Chem., Tex. Christian Univ., Fort Worth, TX 76129, USA; Eng.) -Jannicke 41-177