Pyridylic anions are soft nucleophiles in the palladium-catalyzed C(sp3)-H allylation of 4-alkylpyridines.

We report a mild palladium-catalyzed method for the selective allylation of 4-alkylpyridines in which highly basic pyridylic anions behave as soft nucleophiles. This method exploits alkylidene dihydropyridines, which are semi-stable intermediates readily formed using a 'soft-enolization' approach, in a new mechanistic manifold for decarboxylative allylation. Notably, the catalytic generation of pyridylic anions results in a substantially broader functional group tolerance compared to other pyridine allylation methods. Experimental and theoretical mechanistic studies strongly suggest that pyridylic anions are indeed the active nucleophiles in these reactions, and that they participate in an outer-sphere reductive elimination step. This finding establishes a new pK a boundary of 35 for soft nucleophiles in transition metal-catalyzed allylations.

Welwitindolinone C synthetic studies. Construction of the welwitindolinone carbon skeleton via a transannular nitrone cycloaddition.

Described is the construction of the N-methylwelwitindolinone C core via an efficient strategy that employs a sequential rhodium carbenoid-mediated O-H insertion, Claisen rearrangement and transannular [3+2] nitrone cycloaddition.

Discovery of [3-(4,5,7-trifluoro-benzothiazol-2-ylmethyl)-pyrrolo[2,3-b]pyridin-1-yl]acetic acids as highly potent and selective inhibitors of aldose reductase for treatment of chronic diabetic complications.

Efforts to identify treatments for chronic diabetic complications have resulted in the discovery of a novel series of highly potent and selective [3-(4,5,7-trifluoro-benzothiazol-2-ylmethyl)-pyrrolo[2,3-b]pyridin-1-yl]acetic acid aldose reductase inhibitors. The lead candidate, [6-methyl-3-(4,5,7-trifluoro-benzothiazol-2-ylmethyl)-pyrrolo[2,3-b]pyridin-1-yl]acetic acid example 16, inhibits aldose reductase with an IC50 of 8 nM, while being inactive against aldehyde reductase (IC50>100 microM), a related enzyme involved in the detoxification of reactive aldehydes.

Educating women about breast cancer. An intervention for women with a family history of breast cancer.

OBJECTIVE: To evaluate an "information aid" for women with a family history of breast cancer. DESIGN: Before-after descriptive study. SETTING: Family practices in Ontario. PARTICIPANTS: Of 405 randomly selected Ontario physician members of the College of Family Physician's of Canada's National Research System, 97 agreed to participate and to recruit three consecutive female patients with any family history of breast cancer. INTERVENTIONS: Patients completed a baseline questionnaire and, after reviewing the information aid, a satisfaction questionnaire. Four weeks later, they completed a third questionnaire. MAIN OUTCOME MEASURES: Patient satisfaction, knowledge, worries related to breast cancer, risk perception, and attitudes toward screening. RESULTS: Of 203 patients recruited, 160 (79%) completed all three questionnaires. The information aid was rated excellent or very good by 91% of the women; 99% would recommend it to other women. Knowledge improved significantly; worry about breast cancer did not increase. CONCLUSION: The information aid is a useful resource for women and primary care physicians and could facilitate appropriate risk assessment and management of women with a family history of breast cancer.

Pilot study of an information aid for women with a family history of breast cancer.

OBJECTIVE: To develop and pilot study an information aid for women with a family history of breast cancer. DESIGN, SETTING AND PARTICIPANTS: The information aid, consisting of a booklet and audiotape, was developed by a multi-disciplinary team of health care professionals, breast cancer survivors and their relatives. Women with no personal history of breast cancer, on the waiting list for a familial breast cancer clinic at either of two centres, who could read English, were eligible for the pilot study which consisted of three sets of mailed questionnaires. MAIN OUTCOME MEASURES: The baseline questionnaires included: demographic information: the Breast Cancer and Heredity Knowledge Scale (BCHK); psychological measures (the State-Trait Anxiety Inventory [STAI], Centre for Epidemiologic Studies Depression Scale [CES-D] and an item about breast cancer worry), and an item about breast cancer risk perception. Immediately after reviewing the information aid, participants completed a satisfaction survey, the risk perception and cancer worry items and a checklist about their personal family history. The third set of questionnaires, completed 2-4 weeks after reviewing the aid, was identical to the first. Patients then attended their scheduled clinic visit and an objective hereditary breast cancer risk assessment was made by the genetic counselling team. RESULTS AND CONCLUSIONS: Of 97 eligible women who were contacted, 67 completed all three sets of questionnaires. Overall, women were very satisfied with the aid and 96% would recommend it to other women. There was a highly significant improvement in their knowledge scores after they reviewed the aid. Anxiety and depression did not change and there was a decline in breast cancer worry. Risk perception did not change significantly. Ninety per cent of women completed their personal family history checklist accurately. Several important improvements have been made in the information aid and it will now be evaluated in the community.

Total Synthesis of (+/-)-Tremulenolide A and (+/-)-Tremulenediol A via a Stereoselective Cyclopropanation/Cope Rearrangement Annulation Strategy.

Short total syntheses of (+/-)-tremulenolide A (1) and (+/-)-tremulenediol A (2) are described. The critical step is a dirhodium tetracarboxylate-catalyzed tandem cyclopropanation/Cope rearrangement between the vinyldiazoacetate 4 and the 2(Z),4(E)-hexadiene 5. This step results in full control of the relative stereochemistry at the three stereogenic centers that exist in the natural products. Due to problems with alkene face selectivity, the approach was not amenable to an efficient asymmetric synthesis of 1 and 2.

Relationships between depressive symptoms and descriptions of chronic pain.

The present study investigated the relationship between the severity of depressive symptoms and various qualitative and quantitative aspects of pain reported by chronic pain patients. The sample consisted of 73 patients from a heterogeneous pain population admitted to the Victoria General Hospital Pain Management Unit. Patients completed a comprehensive pain evaluation battery that included the Beck Depression Inventory (BDI) and the McGill Pain Questionnaire (MPQ). They rated their loss of desire and ability for various social and recreational activities, and the intensity of their pain for 8 periods of a typical day. Multivariate analyses of variance were used to assess the sensory, affective, and evaluative indices of the MPQ, daily pain intensity ratings, and reported impairment of activities of non-depressed, mildly depressed and moderate/severely depressed patients. The results indicate significant relationships between the degree of depression and (a) the number of sensory descriptors endorsed on the MPQ; (b) pain intensity ratings in the late evening and at bedtime; and (c) reported loss of ability for social and recreational activities. Depression is related to loss of desire for activity in women, but not in men. A discriminant analysis suggests that depressed and non-depressed pain patients can be distinguished with 78% accuracy on the basis of their MPQ Sensory scores, reported loss of ability for activities, and global pain ratings at late evening and bedtime. The findings are discussed in terms of their implications for research as well as for the assessment and treatment of chronic pain patients.