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The regioselectivity of the hydroformylation reaction of 2-methyl-3-(3-acetyl pyrrol-1-yl)prop-1-ene catalyzed by an unmodified Rh catalyst has been investigated at the B3LYP/6-31G* level with Rh described by effective core potentials in the LANL2DZ valence basis set. Considering the population of all the H–Rh(CO)3-olefin transition state complexes, a regioselectivity ratio (B:L) of 12:88 has been obtained, in satisfactory agreement with the experiment producing the chiral linear aldehyde as the only product. The aldehyde, after complete diastereoselective cyclization, yields a 1:1 mixture of 1-acetyl-6R(S)-methyl-8R(S)-hydroxy-5,6,7,8-tetrahydroindolizine (having the same configuration on both stereogenic carbon atoms) and 2-acetyl-6-methyl-5,6-dihydroindolizine [Lett Org Chem (2006) 3:10–12]. The reason for such a high degree of diastereoselectivity has been elucidated examining the B3LYP/6-31G* potential energy surface for the reactions leading to the RR and RS diastereomers on a model system (without the acetyl substituent) and the actual compound. In the absence of a catalyst, a very high barrier is found along the reaction pathway, whereas spontaneous annulation occurs to a protonated pentahydroindolizine in the presence of H+. When a counterion (F–) is added, the proton on the newly formed tetrahedral carbon is abstracted, obtaining a structure closer to the final product (tetrahydroindolizine). Replacing H+ with Rh+, an initial adduct along the RS path much more favorable than any of those computed along the RR one is located because of the presence of the acetyl group. Tentative approaching paths obtained using [Rh(CO)3]+, bound to the aldehyde O, feature a higher barrier along the RS one, and offer a convincing explanation for the observed diastereoselectivity.

The rhodium catalyzed hydroformylation of beta-isophorone (1a) should afford, as only oxo-product, the aldehyde 4-formyl-3,5,5- trimethylcyclohexan-1-one (2a), an important intermediate for the preparation of delta-Damascone, a floral woody fragrance used for soaps, shampoos, foam baths, etc. Surprisingly, under the reaction conditions adopted by us, we obtained two isomeric aldehydes, namely the expected 2a, formed in a small amount, and the (3,3-dimethyl-5-oxo-cyclohexyl)acetaldehyde (5a), that resulted to be the preponderant oxo-product. The chemoselectivity of the reaction was strongly affected by the substrate isomerization to beta-isophorone (3a) and by the extensive formation of the corresponding saturated ketone 4a, so lowering the efficiency of the whole process. However, by perfoming the hydroformylation on a beta-isophorone derivative without the possibility of conjugation of the two double bonds, namely the ketal 7,9,9-trimethyl-1,4-dioxa-spiro[4.5]dec-7-ene (1b), the chemoselectivity of the reaction strongly increased and the amount of the hydrogenation product was rather low. In any case the predominant oxo-product was the acetaldehyde derivative 5b, while the aldehyde 2b, deriving from the attack of the formyl group on the less substituted carbon atom of the olefinic double bond, was produced in a very small amount.

The formation of 1-acetyl-6-methyl-8-hydroxy-5,6,7,8-tetrahydroindolizine (3) from 3-methyl-4-(3-acetylpyrrol-1-yl)butanal (2), coming from the rhodium catalyzed hydroformylation of 2-methyl-3-(3-acetylpyrrol-1-yl)prop-1-ene (1), is reported. Evidences for both the complete diastereoselective cyclization of 2 and configuration determination in 3 via 1H, 13C and IR spectra are reported.

Objective Supplementation of glutathione (GSH) may be a positive strategy to improve the endogenous antioxidant defense required to counteract many acute and chronic diseases. However, the efficacy of GSH treatment seems to be closely related to type of administration, degree of absorption, and increase of its concentrations. The aim of this study was to test a new sublingual formulation of L-GSH, which enters directly the systemic circulation, to assess its efficacy on circulating biochemical markers of hepatic metabolism, lipid profile, and oxidative stress and on peripheral vascular function compared with placebo in patients with cardiovascular risk factors (CVRF). Methods We enrolled 16 healthy men with CVRF in a double-blinded, randomized placebo-controlled crossover study. At each visit, blood samples were collected for biochemistry analyses and peripheral endothelial function (reactive hyperemia index [RHI]) and stiffness were measured by Endo-PAT2000. Results In the overall population, a decrease in total and low-density lipoprotein cholesterol was highlighted after L-GSH supplementation compared with placebo (P = 0.023 and P = 0.04, respectively). On the contrary, no difference was observed in RHI and oxidative stress markers between L-GSH and placebo in the study population. However, seven participants with baseline abnormal RHI (≤1.67) compared with those with normal RHI showed a significant reduction of arterial stiffness after L-GSH administration, (P = 0.007 and P = 0.037, respectively). Conclusions Supplementation of L-GSH compared with placebo influences the lipid profile of patients with CVRF. Sublingual L-GSH may represent a valid prevention of vascular damage in patients with CVRF and endothelial dysfunction.