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Sulfoxide-ligand exchange (SLE) and asymmetric halogen-metal exchange (AHME) processes were separately examined for the enantioselective synthesis of functionalized alpha-haloalkylmetal (carbenoid) reagents. Carbenoids derived from SLE were used to effect stereospecific reagent-controlled homologation (StReCH) of boronic esters and those generated via AHME were engaged in Darzens-type chemistry with aldehydes. Abstract for Part 1. Scalemic syn alpha-chloroalkylsulfoxides p-TolS(O)CHClR [R = allyl, (1,3-dioxolan-2-yl)methyl, proparygyl, and 2-(benzyloxy)ethyl] were prepared from the corresponding thioethers by Jackson-Ellman-Bolm catalytic enantioselective sulfoxidation [cat. VO(acac)₂, tert-leucinol derived chiral Schiff base ligand, aq. H₂O₂, CHCl₃; 76-80% yield, >98% ee] followed by non-racemizing chlorination mediated by N-chlorosuccinimide in the presence of potassium carbonate (84-86% yield, syn:anti ≥ 20:1). The corresponding anti diastereoisomers were accessed from their syn epimers by sodium hexamethyldisilazide mediated deprotonation (THF, –78 °C) followed by treatment with either CH₃OH or CD₃OD to yield alpha-[¹H] or alpha-[²H] isotopomers, respectively (88% yield, anti:syn ≥ 17:1). Allyl and (1,3- dioxan-2-yl)methyl substituted chlorosulfoxides reacted with R'Li (t-BuLi or PhLi, THF, –78 °C) to give the expected products of SLE [p-TolS(O)R' and LiCHClR or LiCDClR]; however, neither the benzylether nor propargyl substituted substrates gave wholly satisfactory results under the same reaction conditions. The functionalized carbenoid reagents so obtained, 1-chloro-3-butenyllithium and 1-chloro-2-(1,3- dioxolan-2-yl)ethyllithium, were applied to the StReCH of B-(2-chloropyrid-5-yl) pinacol boronate but only the latter gave acceptable yields of chain extended products. The anti alpha-[²H]-chlorosulfoxide dioxolanyl bearing carbenoid precursor gave superior results to the analogous syn or anti alpha-[¹H]-chlorosulfoxides for StReCH of the B-pyridyl boronate [79% conversion, ≥ 89% ee (99% stereofidelity), vs. ≤ 68% conversion for non-deuterated chlorosulfoxides]. The origin of this isotope effect was traced to a deleterious proton transfer pathway between the alpha- chloroalkyllithium reagent and its chlorosulfoxide precursor. Sequential double iterative StReCH of B-(2-chloropyrid-5-yl) pinacol boronate with two separate portions of (S)-1-[²H]-1-chloro-2-(1,3-dioxolan-2-yl)ethyllithium (generated via SLE with phenyllithium) followed by oxidative work-up (with KOOH) gave (1R,2R)-1,2- [²H]₂-2-(2-chloropyrid-5-yl)-1,2-bis[(1,3-dioxolan-2-yl)methyl]ethanol (40% yield, ≥ 98% ee, dr = 85:15). Substitution of the (R)-configured carbenoid for its antipode in the second StReCH stage above gave the unlike (1S,2R)-isomer of the same pyridylethanol derivative (49% yield, ≥ 98% ee, dr = 79:21). The unlike diastereoisomer was advanced to the trifluoroacetamide of (1R,2R)-1,2-[2H]2-1- amino-2-(2-chloropyrid-5-yl)cyclohex-4-ene (6 steps, 5% overall yield); the non- deuterated isotopomer of this compound was previously advanced to the analgesic alkaloid (–)-epibatidine by Corey and co-workers. Abstract for Part 2. Scalemic planar chiral N,N-dialkyl 2-iodoferrocene carboxamides envisioned as recyclable precursors to ferrocenyl metal reagents for AHME, were prepared from ferrocene carboxylic acid by a three step sequence of: acid chloride formation [(COCl)₂ and cat. DMF)], aminolysis (with R₂NH, R = Me, Et, i-Pr; 65- 80% yield over 2 steps), and sec-butyllithium/(–)-sparteine mediated enantioselective directed ortho-metallation (DoM) followed by iodinolysis (87% yield, ≥ 96% ee). Attempts to access more elaborate 5-substituted 2-iodoferrocene carboxamides via DoM/iodinolysis of ortho-substituted ferrocene carboxamides (Me, Ph, or SiMe₃ substituents) mostly failed; however, analogous trisubstituted ferrocene oxazolines could be synthesized. Treatment of N,N-diisopropyl 2-iodoferrocene carboxamide (298, ≥ 96% ee) with n-BuLi (THF, –78 °C) resulted in complete conversion to the corresponding lithioferrocene (327) via I/Li interchange; subsequent iodinolysis initiated reverse Li/I exchange and returned iodoferrocene 298 without diminished enantiomeric excess, establishing configurational stability for the lithiated ferrocene intermediate. Prochiral (RCHI₂) and racemic (RCHICl) geminal dihalide substrates for AHME studies were prepared by electrophilic quench of dihalomethylsodiums with either Ph(CH₂)₃I or Me₃SiCl (50-78% yield). Of the four dihalides so produced, only prochiral substrate Me₃SiCHI₂ engaged in I/Li exchange with scalemic lithioferrocene 327 resulting in regeneration of its precursor iodoferrocene 298 and the formation of a putative chiral carbenoid Me₃SiCHLiI. Trapping of the carbenoid with aldehydes RCHO (R = Ph, 4-MeOC₆H₄, Ph(CH₂)₂, c-C₆H₁₁) in the presence of Me₂AlCl gave the expected epoxysilane products (35-40% yield, cis:trans ≥ 2:1) but without discernable enantiomeric excess. Hypotheses to account for the apparent lack of stereoinduction in this AHME cycle are presented. Comparable experiments using analogous magnesiated ferrocenes failed to produce putative carbenoid species from the same set of geminal dihalide substrates. / Graduation date: 2012

This thesis is concerned with the development and application of methods for the stereoselective cyclopropanation of allylic amines and derivatives. Firstly, a highly chemo- and stereoselective cyclopropanation of N,N-dibenzyl-protected allylic amines was developed using the highly reactive Shi’s carbenoid [CF₃CO₂ZnCH₂I]. Subsequent mechanistic studies revealed that the high diastereoselectivity of the reaction was likely to be due to coordination of the amine to the zinc carbenoid reagent. It is then shown that the reaction is general for a wide range of both cyclic and acyclic substrates giving the corresponding cyclopropanes in high yields and diastereoselectivities. Secondly, a novel stereodivergent cyclopropanation of allylic carbamates and amides was developed. It was found that reaction of cyclic allylic carbamates with the Wittig-Furukawa reagent [Zn(CH₂I)₂] typically gives the syn-diastereoisomer in high yields and diastereoselectivities, whilst treatment of the same substrates with Shi’s carbenoid [CF₃CO₂ZnCH₂I] gives the corresponding anti-diastereoisomers in high yields and diastereoselectivities. Mechanistic investigations suggested that reactions with the Wittig-Furukawa reagent proceed via a N-directed intramolecular cyclopropanation step whilst those with Shi’s carbenoid proceed via a sterically directed intermolecular cyclopropanation step. Unsuccessful investigations into an asymmetric variant of the cyclopropanation reaction utilising chiral carbamate protecting groups are then described. Finally, studies towards the total synthesis of the potential anti-obesity therapeutic trans-SCH-A and its epimer cis-SCH-A are described. A stereodivergent route towards the epimeric products was developed through the cyclopropanation of a common allylic carbamate intermediate with either the Wittig-Furukawa reagent or Shi’s carbenoid to give the corresponding trans-2-amino-5-arylbicyclo[3.10]hexane or cis-2-amino-5-arylbicyclo-[3.10]hexane intermediates respectively.

<div>Cyclopropanes are commonly found throughout synthetic and natural biologically active compounds. The Simmons–Smith cyclopropanation reaction is one of the most useful methods for converting an alkene into a cyclopropane. Zinc carbenoids are the active intermediate in the reaction, capable of delivering the methylene unit to a broad variety of substrates. Significant advances have been made in the field to increase overall efficiency of the reaction including the use of diethyl zinc as a precursor and allylic alcohols as directing groups.</div><div>Despite the many notable contributions in zinc carbenoid chemistry, persistent limitations of the Simmons–Smith reaction still exist. Zinc carbenoids exhibit poor steric discrimination in the presence of a polyolefin with minimal electronic bias. Additionally, due to the electrophilic nature of zinc carbenoid intermediates, the reaction performs inefficiently with electron-deficient olefins. Finally, alkyl-substituted zinc carbenoids are known to be quite unstable, limiting the potential for substituted cyclopropanation reactions.</div><div>In this work, we demonstrate that cobalt catalysis can be utilized to access novel cyclopropane products through the activation of dihaloalkanes. The content of this thesis will focus on the limitations of Zn carbenoid chemistry and addressing them with cobalt catalyzed, reductive cyclopropanations. In addition to this reactivity, we also demonstrate the dimethylcyclopropanation of activated alkenes to furnish valuable products applicable to natural product synthesis and pharmaceutically relevant compounds. Finally, we will show the unique character of the cobalt catalyzed cyclopropanation reaction through mechanistic experiments and characterization of reaction intermediates. In whole, these studies offer a complementary method to zinc carbenoid chemistry in producing novel and diverse cyclopropane products.</div>