Historically accessed through two-electron, anionic chemistry, ketones, alcohols, and amines are of foundational importance to the practice of organic synthesis. After placing this work in proper historical context, this Article reports the development, full scope, and a mechanistic picture for a strikingly different way of forging such functional groups. Thus, carboxylic acids, once converted to redox-active esters (RAEs), can be utilized as formally nucleophilic coupling partners with other carboxylic derivatives (to produce ketones), imines (to produce benzylic amines), or aldehydes (to produce alcohols). The reactions are uniformly mild, operationally simple, and, in the case of ketone synthesis, broad in scope (including several applications to the simplification of synthetic problems and to parallel synthesis). Finally, an extensive mechanistic study of the ketone synthesis is performed to trace the elementary steps of the catalytic cycle and provide the end-user with a clear and understandable rationale for the selectivity, role of additives, and underlying driving forces involved.

The development of a versatile platform for the synthesis of 1,2-difunctionalized bicyclo[1.1.1]pentanes to potentially mimic ortho/meta-substituted arenes is described. The syntheses of useful building blocks bearing alcohol, amine, and carboxylic acid functional handles have been achieved from a simple common intermediate. Several ortho- and meta-substituted benzene analogs, as well as simple molecular matched pairs, have also been prepared using this platform. The results of in-depth ADME (absorption, distribution, metabolism, and excretion) investigations of these systems are presented, as well as computational studies which validate the ortho- or meta-character of these bioisosteres.

In vivo deastatination has been a major problem in the development of reagents for therapeutic applications of the α-particle emitting radionuclide 211 At. Our prior studies demonstrated that the use of a closo-decaborate(2-) ([closo-B 10 H 9 R] 2− ) moiety for 211 At labeling of biomolecules provides conjugates that are stable to in vivo deastatination. In this investigation, the closo-decaborate(2-) moiety was compared with the structurally similar closo-dodecaborate(2-) ([closo-B 12 H 11 R] 2− ) to determine if one has more favorable properties than the other for use in pendant groups as 211 At labeling molecules. To determine the differences, two sets of structurally identical molecules, with the exception that they contained either a closo-decaborate(2-) or a closo-dodecaborate(2-) moiety, were compared with regards to their synthesis, radiohalogenation, stability to in vivo deastatination and tissue distribution. Quite different rates of reaction were noted in the synthetic steps for the two closo-borate(2-) moieties, but ultimately the yields were similar, making these differences of little importance. Differences in radiohalogenation rates were also noted between the two closo-borate(2-) moieties, with the more electrophilic closo-decaborate(2-) reacting more rapidly. This resulted in somewhat higher yields of astatinated closo-decaborate(2-) derivatives (84% vs 53%), but both cage moieties gave good radioiodination yields (e.g. 79-96%). Importantly, both closo-borate(2-) cage moieties were shown to have high stability to in vivo deastatination. The largest differences between pairs of compounds containing the structurally similar boron cage moieties were in their in vivo tissue distributions. I]1b, was evaluated, the route of excretion appeared to be hepatobiliary rather than renal. Identical biotin derivatives containing the two closo-borate(2-) cage moieties had similar tissue distributions, except the closo-decaborate(2-) derivative had lower concentrations in kidney (1h, 19.9%ID/g; 4h, 24.4%ID/g vs. 1h, 38.9%ID/g; 4h, 40.6%ID/g). In summary, the higher reactivity, faster tissue clearance, and lower kidney concentrations make the closo-decaborate(2-) more favorable for further studies using them in reactive groups for 211 At labeling of biomolecules.

Lepadiformine A, B and C were synthesized in enantiomerically pure form using a reductive cyclization strategy. N-Boc α-amino nitriles were deprotonated and alkylated with enantiomerically pure dibromides to afford the first ring. The products were manipulated to introduce phosphate leaving-groups, and subsequent reductive lithiation followed by intramolecular alkylation formed the second ring with high stereoselectivity. The third ring was formed by intramolecular displacement of a mesylate by the deprotected amine. Lepadiformine A and B contain a hydroxymethyl group adjacent to the amine. This appendage was introduced in a sequence using a Polonovski-Potier reaction as the key step. The synthetic strategy is stereoselective and convergent, and demonstrates the utility of N-Boc α-amino nitriles as linchpins for alkaloid synthesis.

Reductive lithiation of N-Boc α-amino nitriles generated α-amino alkyllithium reagents with unexpected selectivity. The intermediate radical prefers to align with the nitrogen lone pair, and this interaction leads to an A 1,3 -strain effect that biases the conformation of the radical. In cyclohexane rings with α-substituents the net effect is an inversion of configuration on reductive lithiation. In the presence of a tethered electrophile the alkyllithium cyclizes to produce a spiro compound, again with inversion of configuration. The overall result is retention of configuration in the cyclization reaction. The same overall selectivity is found with α-oxygen alkyllithium cyclizations, but in this case both steps proceed with retention. The difference can be explained by careful consideration of the intermediate geometries. The α-amino spirocyclization was utilized in a concise and stereoselective synthesis of lepadiformine C.Stereoselective construction of fully-substituted carbon atoms is a challenge that is often at the heart of a successful complex natural product synthesis. Several years ago we reported a synthesis of spirocycles that was based on stereoselective generation of alkyllithium reagents arising from anomeric stabilization of radical intermediates.1 , 2 Herein we describe studies on the generation of α-hetero alkyllithium reagents where classic anomeric stabilization is not relevant, but that still show highly stereoselective transformations. This new stereoselective strategy leads to fully substituted carbon atoms and is illustrated with a concise synthesis of lepadiformine C.3Reduction of N-protected α-amino nitriles with Freeman's reagent (LiDBB)4 is an effective strategy to generate tertiary α-amino alkyllithium reagents.5 An N-alkyl 2-cyano piperidine generally leads to the alkyllithium with high selectivity, but when the nitrogen atom is protected as a Boc carbamate the alkyllithium is produced as a 1.5:1 mixture of isomers.6 The reductive lithiation of N-Boc piperidine 1 in Scheme 1 was instigated to probe the reactivity of the Boc-protected α-amino alkyllithium reagent. Although the lithiation is not stereoselective, both alkyllithium isomers cyclize effectively at −78 °C to produce the bicycle 2 in excellent yield. These tertiary N-Boc α-amino alkyllithium reagents are expected to be conformationally stable at −78 °C, with inversion barriers ca. 20 kcal/mol.7 This experiment demonstrated that tertiary N-Boc alkyllithium reagents may cyclize with retention (SE ret ) or inversion (SE inv ), and the suitably constrained systems can produce single isomers in high yields.8 , 9* srychnov@uci.edu .Supporting Information Available: Experimental procedures for all compounds, X-ray analysis of compound 21 and configuration assignments for compound 26 and 31 are included. The spirocyclizations of nitriles 3 and 5 were highly stereoselective. Both cyclizations proceed with overall retention at the fully substituted center,10 and the heteroatom ends up in the equatorial position. The rationale...