Diastereoselective labeling

The above examples demonstrate that diastereoselectively labeled substrates can be used to probe stereochemical features in gas-phase reactions of flexible molecules. In addition, this approach is not confined to metal-ion chemistry and not even to charged species, cf. the Barton rearrangement of neutral alkoxy radicals mentioned above. Instead, the decisive factor for the observation of a significant SE is a rate-determining activation barrier in an appropriate energy regime. 

A similar reaction the with rran.v-isomer 3b gave c -3,5-dimethylcyclohexene (4) with very high diastereoselectivity. Accordingly, the stereochemistry of this substitution is anti. Deuterium labeling experiments using the 1-deuterio or 3-deuterio derivative of 3 a showed that the ratio of SN2 /SN2 with lithium dimethylcuprate was about 50 50, while the ratio with lithium cyano(methyl)cupratc was >96 4. 

Deuterium-labeled organosilicon hydride alkene to alkane reductions, 34 disubstituted alkenes, 37-38 alkyl halide reduction, 29-31 Diastereoselectivity, ketone-alcohol reduction, 76-79... 

Although a cobalt-catalyzed intermolecular reductive aldol reaction (generation of cobalt enolates by hydrometal-lation of acrylic acid derivatives and subsequent reactions with carbonyl compounds) was first described in 1989, low diastereoselectivity has been problematic.3 6 However, the intramolecular version of this process was found to show high diastereoselectivity (Equation (37)).377,377a 378 A Co(i)-Co(m) catalytic cycle is suggested on the basis of deuterium-labeling studies and the chemistry of Co(ll) complexes (Scheme 81). Cobalt(m) hydride 182, which is... 

In summary, a stereoselective 10-step total synthetic route to the antimalarial sesquiterpene (+)-artemisinin (1) was developed. Crucial elements of the approach included diastereoselective trimethylsilylanion addition to a,p-unsaturated aldehyde 16, and a tandem Claisen ester-enolate rearrangement-dianion alkylation to afford the diastereomerically pure erythro acid 41. Finally, acid 41 was converted in a one-pot procedure involving sequential treatment with ozone followed by wet acidic silica gel to effect a complex process of dioxetane formation, ketal deprotection, and multiple cyclization to the natural product (+)-artemisinin (1). The route was designed for the late incorporation of a carbon-14 label and the production of a variety of analogues for structure-activity-relationship (SAR) studies. We were successful in preparing two millimoles of l4C-l73 which was used for conversion to I4C-arteether for metabolism75 and mode of action studies.76,77... 

Keywords. Chirality, Diastereoselectivity, Isotope labelling, Mass spectrometry, Stereochemistry... 

The diastereomers of EBTHI zirconaaziridines are formed in comparable amounts via C-H activation, but equilibrate quickly (within an hour) to yield a thermodynamic mixture of diastereomers. Grossman observed little difference in the loss of MeH vs MeD from deuterium-labeled (EBTHI)zirconium methyl amide complexes 161 (Scheme 2). Loss of MeH and of MeD lead to different diastereomers, although their relative rate will also reflect the primary kinetic isotope effect for C-H activation. Neither kxlk2 nor k3lk4 is large, and both are largely the result of isotope effects rather than diastereoselectivity [42]. 

Scheme 2 Deuterium labeling experiment to determine diastereoselectivity in zircona-aziridine formation...

The method has been used to prepare isotopically labelled amino acids. While Boc-BMI enolate adds to aldehydes with only moderate diastereoselectivity, reduction of the acylation products (5) gives allothreonine derivatives (6). Michael additions to o(,p-unsaturated esters, ketones, and nitro compounds lead to products of type (7) and (8) (for a general discussion see Suzuki and Seebach ). 

The exact mechanistic pathway of the classical J-L olefination is unknown. Deuterium-labeling studies showed that the nature of the reducing agent (sodium amalgam or Smb) determines what type of intermediate (vinyl radical or secondary alkyl radical) is involved. Both intermediates are able to equilibrate to the more stable isomer before conversion to the product. The high ( )-selectivity of the Kocienski-modified reaction is the result of kinetically controlled irreversible diastereoselective addition of metalated PT-sulfones to nonconjugated aldehydes to yield anti-P-alkoxysulfones which stereospecifically decompose to the ( )-alkenes. 

Aberhart and Weiller (183) used (2/ S,3S)-[4- Ci]valine 179 prepared as described in the previous section to synthesize samples of (2S, 4S)- and (2R, 4S)-[5- Ci]leucine 205. More recently, in need of a synthesis of large quantities of labeled leucine, we have devised a synthesis of (2S,4/ )-[5,5,5- H3]leucine 205b, starting from the pyroglutamic acid derivative 206 (184). This is shown in Scheme 59, chirality being achieved by diastereoselective catalytic reduction 207 208. 

Labelle M, Guindon Y (1989) Diastereoselective synthesis of 2, 3-disubstituted tetrahydrofuran synthons via the iodoetherification reaction. A transition state model based rationaU-zation of the allylic asymmetric induction. J Am Chem Soc 111 2204—2210... 

---